Novel small molecule inhibitors of TEAD transcription factor

Abstract

The present invention relates to novel small molecule inhibitors of TEAD transcription factors. Compounds of the present disclosure, as well as compositions and methods of use thereof. The compounds inhibit the activity of TEAD transcription factor and are useful in the treatment of diseases associated with the activity of TEAD transcription factor, including, for example, cancer and other diseases.

Description

[0001] This application is a divisional application of a Chinese patent application with an application date of March 13, 2020, application number 202080035177.9, and invention name “Novel small molecule inhibitors of TEAD transcription factors”.

[0002] Priority claim

[0003] This application claims priority to U.S. patent application serial number 62 / 819,347 filed on March 15, 2019, the entire contents of which are hereby incorporated by reference.

[0004] Government support

[0005] This invention was made with government support under Grant Nos. 1R01CA181537 and R01DK107651 awarded by the National Institutes of Health. The government has certain rights in this invention. Technical Field

[0006] The present application relates to pharmaceutically acceptable compounds. The present disclosure provides novel compounds and compositions and methods of use thereof. The compounds inhibit the autopalmitoylation of TEAD-transcription factors and are therefore useful for treating diseases associated with the activity of TEAD-transcription factors, including, for example, cancer and other diseases. Background Art

[0007] Hippo signaling plays a key role in organ size control and tumor suppression. Signal transduction involves a core kinase cascade, including MST1 / 2 and Lats1 / 2 kinases, which lead to YAP / TAZ phosphorylation, cytoplasmic retention and inhibition 3 . Physiological or pathological inactivation of these kinases leads to dephosphorylation and nuclear accumulation of YAP / TAZ. Subsequently, nuclear YAP / TAZ bind to TEA domain transcription factors (TEAD1-4 in mammals and Scalloped in Drosophila) to mediate target gene expression. The TEAD-YAP complex regulates the normal development of skin, muscle, lung, and liver, and is also an oncogenic factor amplified in many human cancers. TEAD can also bind to Vgll4, which is considered a tumor suppressor by competing with YAP / TAZ for binding to TEAD. Therefore, TEAD is essential in regulating the transcriptional output of the Hippo pathway. Although targeting TEAD-YAP may be a promising therapeutic approach for diseases with dysregulated Hippo pathway, directly inhibiting transcription factors with small molecules remains challenging. Therefore, understanding the regulation of TEAD may provide new therapeutic opportunities for drug discovery.

[0008] Post-translational S-palmitoylation attaches a 16-carbon palmitate to a cysteine ​​residue via a reversible thioester bond. A large number of palmitoylated proteins have been identified through proteomic studies. Dynamic S-palmitoylation plays a key role in regulating the transport, membrane localization, and function of many proteins, including Src family kinases, GTPases, and synaptic adhesion molecules. Asp-His-His-Cys (DHHC) family proteins are evolutionarily conserved protein palmitoyl acyltransferases (PATs) that mediate enzymatic S-palmitoylation. In addition, some proteins can directly bind to palmitoyl-coenzyme A (CoA) and undergo self-palmitoylation independent of PAT. However, self-palmitoylation has not been fully characterized. Most reported examples of self-palmitoylation have been observed at non-physiological, high concentrations of palmitoyl-CoA (>100 μM). To date, only a few proteins, including the yeast transporter Bet3, have been self-palmitoylated at physiological concentrations of palmitoyl-CoA (1-10 μM). Therefore, it is important to uncover additional autopalmitoylated proteins and understand their regulation and function. Summary of the invention

[0009] The present disclosure provides, inter alia, compounds of formula (I):

[0010]

[0011] or a pharmaceutically acceptable salt thereof; wherein the variables are as defined below.

[0012] The present disclosure also provides a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

[0013] The present disclosure also provides methods for treating cancer and other diseases, comprising administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0014] The details of one or more embodiments are set forth in the description below. Other features, objects, and advantages will be apparent from the description and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 Schematic diagram showing the structures of examples of compounds within the scope of the present invention.

[0016] Figure 2 is a schematic diagram showing the structures of some reference compounds.

[0017] Figure 3is a graph showing the results of streptavidin and histidine blotting, which shows the results of assays of the inhibition of TEAD2 autopalmitoylation in vitro by compounds CP-1, flufenamic acid, CP-41, CP-42, CP-51, CP-52, CP-53, CP-54, CP-55, CP-56, CP-57, and CP-58.

[0018] Figure 4 is a graph showing the results of streptavidin and histidine blotting, which shows the results of assaying the inhibition of TEAD2 autopalmitoylation in vitro by compound CP-55 at different concentrations.

[0019] Figure 5 is a collection of graphs showing the inhibition of cell proliferation of 92.1 uveal melanoma cell line, cellosaurus OCM1 cell line, human liver cancer huh7 cell line, SNU398 human liver hepatocellular carcinoma cell line, and MDA-MB-453 human breast metastatic carcinoma cell line by compound CP-55 at different concentrations.

[0020] Figure 6 is a collection of graphs showing the inhibition of gene expression of CYR61, CTGF, and ANKRD1 genes in huh7 human liver cancer cell line by compound CP-55 at different time points and concentrations.

[0021] Figure 7 is a graph showing the results of streptavidin and histidine blotting, which shows the results of assaying the inhibition of TEAD2 autopalmitoylation in vitro by compound CP-58 at different concentrations.

[0022] Figure 8 is a graph showing the inhibition of cell proliferation in 92.1 uveal melanoma cell line by compounds CP-1, CP-52, CP-55 and CP-58 at different concentrations.

[0023] Fig. 9 is a graph showing the inhibition of cell proliferation in huh7 human hepatoma cell line by compound CP-57 at different concentrations.

[0024] Fig.10 is a graph showing the inhibition of cell proliferation in huh7 human hepatoma cell line by compound CP-58 at different concentrations.

[0025] Fig.11 is a pair of graphs showing the inhibition of gene expression of genes CYR61 and CTGF and ANKRD1 gene in huh7 human hepatoma cell line by compound CP-58 after 24 hours compared to control.

[0026] Fig.12is a graph showing the results of streptavidin and histidine blotting, which shows the results of assaying the inhibition of TEAD2 autopalmitoylation in vitro by compounds CP-1, CP-55, CP-58, CP-59, CP-60, CP-61, and CP-62.

[0027] Fig.13 The graph shows the inhibition of cell proliferation in huh7 human liver cancer cell line by compounds CP-58, CP-59, CP-60, CP-61 and CP-62 at different concentrations. DETAILED DESCRIPTION

[0028] The terms "for example" and "such as" and their grammatical equivalents, unless expressly stated otherwise, should be understood to be followed by the phrase "without limitation."

[0029] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0030] The term "about" means "approximately" (eg, + / - approximately 10% of the indicated value).

[0031] The expressions "ambient temperature" and "room temperature" (abbreviated "rt") typically refer to a temperature about the temperature of the room in which the reaction is carried out (e.g., reaction temperature), such as a temperature of about 20°C to about 30°C, typically about 25°C.

[0032] Through proteomic and biochemical studies, TEAD transcription factors have been identified to be palmitoylated at evolutionarily conserved cysteine ​​residues. It has been found that TEAD undergoes PAT-independent autopalmitoylation at physiological concentrations of palmitoyl-CoA. The crystal structure of lipid-bound TEAD has revealed a novel ligand-binding site in TEAD. Furthermore, autopalmitoylation plays a key role in regulating TEAD-YAP association and its physiological functions in vitro and in vivo. Therefore, palmitoylation of TEAD plays an important role in regulating the Hippo pathway transcriptional complex.

[0033] The discovery of new ligand binding sites in TEAD has led to the discovery of small molecule inhibitors of TEAD self-palmitoylation. Although not bound by any theory, it is understood that the ligand binds to the palmitate binding pocket and inhibits TEAD-YAP interaction, cancer cell proliferation and migration. Therefore, direct inhibition of TEAD self-palmitoylation activity can be used to inhibit these oncogenic transcription factors.

[0034] I. Compounds

[0035] The present disclosure provides, inter alia, compounds of formula (I):

[0036]

[0037] or a pharmaceutically acceptable salt thereof, wherein:

[0038] L 1 does not exist or is of the formula N(R N ) or C(O);

[0039] D is a group of formula (D1), (D2), (D3), (D4), (D5), (D6) or (D7):

[0040]

[0041] m is 1, 2 or 3;

[0042] A 1 C(O)R 1 、S(O)2R 1 、NHC(O)R 1 , (C 1-3 Alkylene)-C(O)R 1 NH(C 1-3 Alkylene)-C(O)R 1 , CN, NO2, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (C 1-3 (C 1-3 alkylene)-4-10 membered heterocycloalkyl, wherein A 1 (C 1-3 Alkylene)-C(O)R 1 The group (C 1-3 The alkylene) group is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halogen, OR a1 NR c1 R d1 NR a1 (CO)(C 1-6 Alkyl) and NR a1 (CO)O(C 1-6 alkyl); and wherein the formation of A 1 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (C 1-3 (C 1-3 alkylene)-4-10 membered heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halogen, OR a1 , SR a1 、C(O)OR a1 NR c1 R d1 and C(O)NR c1 R d1 ;

[0043] L 2 does not exist or is of the formula N(R N ), O or C(O) groups;

[0044] L 3 Does not exist or is of the formula CH2, C≡C, N(R N ) or C(O);

[0045] Each R N Independently H, C 1-6 Alkyl, C(O)C 1-6 Alkyl or C(O)OC 1-6 alkyl;

[0046] R 1 H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Cy 1A , OH, OC 1-6 Alkyl, OCy 1A 、O(C 1-3 Alkylene)Cy 1A 、NH2、NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, NHCy 1A NH(C 1-3 Alkylene)Cy 1A 、N(C 1-6 Alkyl)Cy 1A or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 1A , which forms R 1 Each C 1-6 The alkyl group is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents, each of which is independently selected from halogen, OR a1 , SR a1 and NR c1 R d1 ;

[0047] Cy 1A C 6-10 Aryl, C 3-15 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein Cy 1A C 6-10 Aryl, C 3-15 Each of the cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl groups is unsubstituted or substituted with 0, 1 or 2 Cy 1Band 0, 1, 2, 3, 4 or 5 substituents each independently selected from unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0048] Each Cy 1B C 6-10 Aryl, C 3-15 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein Cy 1B C 6-10 Aryl, C 3-15 Each of the cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents each independently selected from the group consisting of unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 ; and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0049] A 2 CR 2 or N;

[0050] A 3 CR 3 or N;

[0051] A 4 CR 4 or N;

[0052] A 5 CR5 or N;

[0053] A 6 CR 6 or N;

[0054] A 7 CR 7 or N;

[0055] A 8 CR 8 or N;

[0056] A 9 CR 9 or N;

[0057] A 10 CR 10 or N;

[0058] A D41 CH, C(C 1-6 Alkyl) or N;

[0059] A D42 CH2, NH or NC 1-6 alkyl;

[0060] R 2 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0061] R 3 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)ORa1 、C(O)NR c1 R d1 or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0062] R 4 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0063] R 5 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0064] R 6 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C1-6 Haloalkyl, CN, OR a1 , SR a1 、S(O)2R b1 、S(O)2NR c1 R d1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 , Cy 7A , OCy 7A 、O(C 1-3 Alkylene)Cy 7A 、C(O)OCy 7A 、C(O)O(C 1-3 Alkylene)Cy 7A ,NHCy 7A NH(C 1-3 Alkylene)Cy 7A 、N(C 1-6 Alkyl)Cy 7A 、N(C(O)C 1-6 Alkyl)Cy 7A 、N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 7A 、C(O)NHCy 7A 、C(O)NH(C 1-3 Alkylene)Cy 7A 、C(O)N(C 1-6 Alkyl)Cy 7A 、C(O)N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 7A or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0065] R 7 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、S(O)2NRc1 R d1 、C(O)NR c1 R d1 , Cy 7A , OCy 7A 、O(C 1-3 Alkylene)Cy 7A 、C(O)OCy 7A 、C(O)O(C 1-3 Alkylene)Cy 7A ,NHCy 7A NH(C 1-3 Alkylene)Cy 7A 、N(C 1-6 Alkyl)Cy 7A 、N(C(O)C 1-6 Alkyl)Cy 7A 、N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 7A 、C(O)NHCy 7A 、C(O)NH(C 1-3 Alkylene)Cy 7A 、C(O)N(C 1-6 Alkyl)Cy 7A 、C(O)N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 7A or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0066] Cy 7A C 6-10 Aryl, C 3-15 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein Cy 7A C 6-10 Aryl, C 3-15 Each of the cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is unsubstituted or substituted with 0, 1 or 2 groups selected from Cy 7B , OCy 7B ,NHCy 7B and C(O)NHCy 7B and 0, 1, 2, 3, 4 or 5 substituents independently selected from the following: unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0067] Each Cy 7B C 6-10 Aryl, C 3-15 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein Cy 7B C 6-10 Aryl, C 3-15 Each of the cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents each independently selected from the group consisting of unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0068] R 8 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 、S(O)2NR c1 R d1 , SR a1 NRc1 R d1 NR c1 S(O)2R b1 、C(O)OR a1 、C(O)NR c1 R d1 , Cy 8A , OH, OCy 8A 、O(C 1-3 Alkylene)Cy 8A 、C(O)OCy 8A 、C(O)O(C 1-3 Alkylene)Cy 8A ,NHCy 8A 、N(Cy 8A )2、NH(C 1-3 Alkylene)Cy 8A 、N(C 1-6 Alkyl)Cy 8A 、N(C(O)C 1-6 Alkyl)Cy 8A SO2NHCy 8A 、N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8A 、C(O)NHCy 8A , C 1-3 Alkylene-C(O)NHCy 8A 、C(O)NH(C 1-3 Alkylene)Cy 8A 、C(O)N(C 1-6 Alkyl)Cy 8A 、C(O)N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8A or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0069] Cy 8A C 6-10 Aryl, C 3-15 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein Cy 8A C 6-10 Aryl, C 3-15 Each of the cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is unsubstituted or substituted with 0, 1 or 2 groups selected from Cy 8B, OCy 8B ,NHCy 8B and C(O)NHCy 8B and 0, 1, 2, 3, 4 or 5 substituents independently selected from the following: unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0070] Each Cy 8B C 6-10 Aryl, C 3-15 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein Cy 8B C 6-10 Aryl, C 3-15 Each of the cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents each independently selected from the group consisting of unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0071] R 9 H, unsubstituted C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 NR c1 C(O)R b1 、C(O)OR a1 、C(O)NR c1 R d1 or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0072] R 10 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0073] Cy D71 C 6-10 Aryl, C 3-15 Cycloalkyl, 5-14 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein Cy D71 C 6-10 Aryl, C 3-15 Each of the cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is unsubstituted or substituted with 0, 1 or 2 groups selected from Cy D72 、CH2Cy D72 , OCy D72 ,NHCy D72 , OC 1-6 Alkylene-Cy D72 、N(C1-6 Alkyl)Cy D72 、N(C(O)C 1-6 Alkyl)Cy D72 and C(O)NHCy D72 and 0, 1, 2, 3, 4 or 5 substituents independently selected from the following: unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 、S(hal)5、SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 、C(O)OR a1 and NR c1 R d1 Substituents substituted with C 1-6 Alkyl or C 2-6 alkenyl;

[0074] Each Cy D72 C 6-10 Aryl, C 3-15 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein Cy D72 C 6-10 Aryl, C 3-15 Each of the cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents each independently selected from the group consisting of unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-15 Cycloalkyl, 4-10 membered heterocycloalkyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 and 1, 2 or 3 each independently selected from C 6-10 Aryl, C 3-15Cycloalkyl, 4-10 membered heterocycloalkyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 、C(O)OR a1 and NR c1 R d1 Substituents substituted with C 1-6 Alkyl, wherein the C 6-10 Aryl, C 3-15 Cycloalkyl and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2 or 3 independently selected C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 and C(O)NR c1 R d1 substituted with a substituent; and

[0075] R a1 , R b1 , R c1 and R d1 Each independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, HO-C 1-6 Alkylene, amino-C 1-6 Alkylene, C 1-6 Alkylamino-C 1-6 Alkylene, di(C 1-6 alkyl)amino-C 1-6 Alkylene, C 1-6 Alkoxy-C 1-6 Alkylene, C 6-10 Aryl, C 2-6 Alkenyl and C 2-6 Alkynyl; or

[0076] R c1 and R d1 and the nitrogen atom to which they are all attached together form a 4-10 membered unsubstituted heterocycloalkyl ring or a heterocycle substituted by 1, 2 or 3 substituents independently selected from C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 and C(O)NR c1 R d1 ;

[0077] The conditions are:

[0078] When L 2 When C(O), L 1 Formula N(R N )

[0079] When L 2 N(R N ),L 1 is a group of formula C(O);

[0080] When L 1 When C(O), L 2 does not exist or is of the formula N(R N )

[0081] When L 1 N(R N ),L 2 is absent or is a group of formula C(O);

[0082] When A D42 For NH or NC 1-6 When alkyl, A D41 CH, C(C 1-6 alkyl);

[0083] When A D41 For NH or NC 1-6 When alkyl, A D42 is CH2;

[0084] A 2 , A 3 , A 4 and A 5 No more than two of them are N;

[0085] A 6 , A 7 , A 8 , A 9 and A 10 No more than two of them are N; and

[0086] R 1 exists and is Cy 1A , OCy 1A 、O(C 1-3 Alkylene)Cy 1A ,NHCy 1A NH(C 1-3 Alkylene)Cy 1A 、N(C 1-6 Alkyl)Cy 1A or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy1A ;or

[0087] R 7 Cy 7A , OCy 7A 、O(C 1-3 Alkylene)Cy 7A 、C(O)OCy 7A 、C(O)O(C 1-3 Alkylene)Cy 7A ,NHCy 7A NH(C 1-3 Alkylene)Cy 7A 、N(C 1-6 Alkyl)Cy 7A 、N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 7A 、C(O)NHCy 7A 、C(O)NH(C 1-3 Alkylene)Cy 7A 、C(O)N(C 1-6 Alkyl)Cy 7A or C(O)N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 7A ;or

[0088] R 8 Cy 8A , OCy 8A 、O(C 1-3 Alkylene)Cy 8A 、C(O)OCy 8A 、C(O)O(C 1-3 Alkylene)Cy 8A ,NHCy 8A NH(C 1-3 Alkylene)Cy 8A 、N(C 1-6 Alkyl)Cy 8A 、N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8A 、C(O)NHCy 8A 、C(O)NH(C 1-3 Alkylene)Cy 8A 、C(O)N(C 1-6 Alkyl)Cy 8A or C(O)N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8A .

[0089] The present disclosure provides, inter alia, compounds of formula (I):

[0090]

[0091] or a pharmaceutically acceptable salt thereof, wherein:

[0092] L 1 does not exist or is of the formula N(R N ) or C(O);

[0093] D is a group of formula (D1), (D2), (D3), (D4), (D5), (D6) or (D7):

[0094]

[0095] m is 1, 2 or 3;

[0096] A 1 C(O)R 1 、S(O)2R 1 、NHC(O)R 1 , (C 1-3 Alkylene)-C(O)R 1 NH(C 1-3 Alkylene)-C(O)R 1 , CN, NO2, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (C 1-3 (C 1-3 alkylene)-4-10 membered heterocycloalkyl, wherein A 1 (C 1-3 Alkylene)-C(O)R 1 The group (C 1-3 The alkylene) group is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halogen, OR a1 NR c1 R d1 NR a1 (CO)(C 1-6 Alkyl) and NR a1 (CO)O(C 1-6 alkyl); and wherein the formation of A 1 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (C 1-3 (C 1-3 alkylene)-4-10 membered heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halogen, OR a1 , SR a1 、C(O)OR a1NR c1 R d1 and C(O)NR c1 R d1 ;

[0097] L 2 does not exist or is of the formula N(R N ), O or C(O) groups;

[0098] L 3 Does not exist or is of the formula CH2, C≡C, N(R N ) or C(O);

[0099] Each R N Independently H, C 1-6 Alkyl, C(O)C 1-6 Alkyl or C(O)OC 1-6 alkyl;

[0100] R 1 H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Cy 1A , OH, OC 1-6 Alkyl, OCy 1A 、O(C 1-3 Alkylene)Cy 1A 、NH2、NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, NHCy 1A NH(C 1-3 Alkylene)Cy 1A 、N(C 1-6 Alkyl)Cy 1A or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 1A , which forms R 1 Each C 1-6 The alkyl group is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents, each of which is independently selected from halogen, OR a1 , SR a1 and NR c1 R d1 ;

[0101] Cy 1A C 6-10 Aryl, C 3-15 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein Cy 1A C 6-10 Aryl, C 3-15Each of the cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl groups is unsubstituted or substituted with 0, 1 or 2 Cy 1B and 0, 1, 2, 3, 4 or 5 substituents each independently selected from unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0102] Each Cy 1B C 6-10 Aryl, C 3-15 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein Cy 1B C 6-10 Aryl, C 3-15 Each of the cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents each independently selected from the group consisting of unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 ; and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0103] A 2 CR 2 or N;

[0104] A 3 CR 3 or N;

[0105] A 4 CR 4or N;

[0106] A 5 CR 5 or N;

[0107] A 6 CR 6 or N;

[0108] A 7 CR 7 or N;

[0109] A 8 CR 8 or N;

[0110] A 9 CR 9 or N;

[0111] A 10 CR 10 or N;

[0112] A D41 CH, C(C 1-6 Alkyl) or N;

[0113] A D42 CH2, NH or NC 1-6 alkyl;

[0114] R 2 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0115] R 3 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SRa1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0116] R 4 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0117] R 5 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0118] R 6 H, unsubstituted C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0119] R 7 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 , Cy 7A , OCy 7A 、O(C 1-3 Alkylene)Cy 7A 、C(O)OCy 7A 、C(O)O(C 1-3 Alkylene)Cy 7A ,NHCy 7A NH(C 1-3 Alkylene)Cy 7A 、N(C 1-6 Alkyl)Cy 7A 、N(C(O)C 1-6 Alkyl)Cy 7A 、N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 7A 、C(O)NHCy 7A 、C(O)NH(C 1-3 Alkylene)Cy 7A 、C(O)N(C 1-6 Alkyl)Cy 7A 、C(O)N(C 1-6 Alkyl)(C1-3 Alkylene)Cy 7A or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0120] Cy 7A C 6-10 Aryl, C 3-15 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein Cy 7A C 6-10 Aryl, C 3-15 Each of the cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is unsubstituted or substituted with 0, 1 or 2 groups selected from Cy 7B , OCy 7B ,NHCy 7B and C(O)NHCy 7B and 0, 1, 2, 3, 4 or 5 substituents independently selected from the following: unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0121] Each Cy 7B C 6-10 Aryl, C 3-15 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein Cy 7B C 6-10 Aryl, C 3-15 Each of the cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents each independently selected from the group consisting of unsubstituted C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0122] R 8 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 , Cy 8A , OH, OCy 8A 、O(C 1-3 Alkylene)Cy 8A 、C(O)OCy 8A 、C(O)O(C 1-3 Alkylene)Cy 8A ,NHCy 8A 、N(Cy 8A )2、NH(C 1-3 Alkylene)Cy 8A 、N(C 1-6 Alkyl)Cy 8A 、N(C(O)C 1-6 Alkyl)Cy 8A SO2NHCy 8A 、N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8A 、C(O)NHCy 8A , C 1-3 Alkylene-C(O)NHCy 8A 、C(O)NH(C 1-3 Alkylene)Cy 8A、C(O)N(C 1-6 Alkyl)Cy 8A 、C(O)N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8A or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0123] Cy 8A C 6-10 Aryl, C 3-15 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein Cy 8A C 6-10 Aryl, C 3-15 Each of the cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is unsubstituted or substituted with 0, 1 or 2 groups selected from Cy 8B , OCy 8B ,NHCy 8B and C(O)NHCy 8B and 0, 1, 2, 3, 4 or 5 substituents independently selected from the following: unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0124] Each Cy 8B C 6-10 Aryl, C 3-15 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein Cy 8B C 6-10 Aryl, C 3-15Each of the cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents each independently selected from the group consisting of unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0125] R 9 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0126] R 10 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0127] Cy D71 C 6-10 Aryl, C 3-15 Cycloalkyl, 5-14 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein Cy D71 C 6-10 Aryl, C 3-15 Each of the cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is unsubstituted or substituted with 0, 1 or 2 groups selected from Cy D72 、CH2Cy D72 , OCy D72 ,NHCy D72 , OC 1-6 Alkylene-Cy D72 、N(C 1-6 Alkyl)Cy D72 、N(C(O)C 1-6 Alkyl)Cy D72 and C(O)NHCy D72 and 0, 1, 2, 3, 4 or 5 substituents independently selected from the following: unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 、C(O)OR a1 and NR c1 R d1 Substituents substituted with C 1-6 Alkyl or C 2-6 alkenyl;

[0128] Each Cy D72 C 6-10 Aryl, C 3-15Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein Cy D72 C 6-10 Aryl, C 3-15 Each of the cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents each independently selected from the group consisting of unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-15 Cycloalkyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 、C(O)OR a1 and NR c1 R d1 Substituents substituted with C 1-6 Alkyl; and

[0129] R a1 , R b1 , R c1 and R d1 Each independently selected from H, C 1-6 Alkyl, HO-C 1-6 Alkylene, C 1-6 Alkoxy-C 1-6 Alkylene, C 6-10 Aryl, C 2-6 Alkenyl and C 2-6 Alkynyl; or

[0130] R c1 and R d1 and the nitrogen atom to which they are both attached together form a 4-10 membered unsubstituted heterocycloalkyl ring;

[0131] In some embodiments:

[0132] When L 2 When C(O), L 1 Formula N(R N )

[0133] When L 2 N(R N ),L 1is a group of formula C(O);

[0134] When L 1 When C(O), L 2 does not exist or is of the formula N(R N )

[0135] When L 1 N(R N ),L 2 is absent or is a group of formula C(O);

[0136] When A D42 For NH or NC 1-6 When alkyl, A D41 CH, C(C 1-6 alkyl);

[0137] When A D41 For NH or NC 1-6 When alkyl, A D42 is CH2;

[0138] A 2 , A 3 , A 4 and A 5 No more than two of them are N;

[0139] A 6 , A 7 , A 8 , A 9 and A 10 No more than two of them are N; and

[0140] R 1 exists and is Cy 1A , OCy 1A 、O(C 1-3 Alkylene)Cy 1A ,NHCy 1A NH(C 1-3 Alkylene)Cy 1A 、N(C 1-6 Alkyl)Cy 1A or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 1A ;or

[0141] R 7 Cy 7A , OCy 7A 、O(C 1-3 Alkylene)Cy 7A 、C(O)OCy 7A 、C(O)O(C 1-3 Alkylene)Cy7A ,NHCy 7A NH(C 1-3 Alkylene)Cy 7A 、N(C 1-6 Alkyl)Cy 7A 、N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 7A 、C(O)NHCy 7A 、C(O)NH(C 1-3 Alkylene)Cy 7A 、C(O)N(C 1-6 Alkyl)Cy 7A or C(O)N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 7A ;or

[0142] R 8 Cy 8A , OCy 8A 、O(C 1-3 Alkylene)Cy 8A 、C(O)OCy 8A 、C(O)O(C 1-3 Alkylene)Cy 8A ,NHCy 8A NH(C 1-3 Alkylene)Cy 8A 、N(C 1-6 Alkyl)Cy 8A 、N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8A 、C(O)NHCy 8A 、C(O)NH(C 1-3 Alkylene)Cy 8A 、C(O)N(C 1-6 Alkyl)Cy 8A or C(O)N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8A .

[0143] In some embodiments, L 1 Does not exist.

[0144] In some embodiments, L 1 N(R N ), such as NH or NMe.

[0145] In some embodiments, L 1 is C(O).

[0146] In some embodiments, D is a group of formula (D1).

[0147] In some embodiments, D is a group of formula (D2).

[0148] In some embodiments, D is a group of formula (D3).

[0149] In some embodiments, D is a group of formula (D4).

[0150] In some embodiments, D is a group of formula (D5).

[0151] In some embodiments, D is a group of formula (D6).

[0152] In some embodiments, D is a group of formula (D7).

[0153] In some embodiments, A 1 C(O)R 1 , for example, C(O)OH.

[0154] In some embodiments, A 1 is S(O)2R 1 .

[0155] In some embodiments, A 1 NHC(O)R 1 .

[0156] In some embodiments, A 1 NH(C 1-3 Alkylene)-C(O)R 1 .

[0157] In some embodiments, wherein A 1 For (C 1-3 Alkylene)-C(O)R 1 , which forms A 1 (C 1-3 Alkylene)-C(O)R 1 The group (C 1-3 The alkylene) group is unsubstituted or substituted with 0, 1, 2, 3, 4 or 5 substituents each independently selected from halogen, OR a1 NR c1 R d1 NR a1 (CO)(C 1-6 Alkyl) and NR a1 (CO)O(C 1-6 alkyl).

[0158] In some embodiments, A 1 For (C 1-3Alkylene)-C(O)R 1 , which forms A 1 (C 1-3 Alkylene)-C(O)R 1 The group (C 1-3 Alkylene) group is substituted by: NR c1 R d1 NR a1 (CO)(C 1-6 Alkyl) or NR a1 (CO)O(C 1-6 alkyl), for example CH2CH(NH2)C(O)OH.

[0159] In some embodiments, A 1 For CN.

[0160] In some embodiments, A 1 For NO2.

[0161] In some embodiments, A 1 is a 5-10 membered heteroaryl, a 4-10 membered heterocycloalkyl, (C 1-3 (C 1-3 alkylene)-4-10 membered heterocycloalkyl, the substituents are each independently selected from halogen, OR a1 , SR a1 、C(O)OR a1 NR c1 R d1 and C(O)NR c1 R d1 ;

[0162] In some embodiments, A 1 is 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CH2(5-10 membered heteroaryl) or CH2(4-10 membered heterocycloalkyl) which is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halogen, OR a1 , SR a1 、C(O)OR a1 NR c1 R d1 and C(O)NR c1 R d1 ;

[0163] In some embodiments, A 2 CR 2 .

[0164] In some embodiments, R 2 For H.

[0165] In some embodiments, A 2 is N.

[0166] In some embodiments, A 3 CR 3 .

[0167] In some embodiments, R 3 H, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0168] In some embodiments, R 3 is H, methyl or trifluoroethyl.

[0169] In some embodiments, R 3 For H.

[0170] In some embodiments, A 3 is N.

[0171] In some embodiments, A 4 CR 4 .

[0172] In some embodiments, R 4 For H.

[0173] In some embodiments, A 4 is N.

[0174] In some embodiments, A 5 CR 5 .

[0175] In some embodiments, R 5 For H.

[0176] In some embodiments, A 5 is N.

[0177] In some embodiments, A 2 CR 2 , A 3 CR 3 , A 4 CR 4 , and A 5 CR 5 .

[0178] In some embodiments, A 2 CR 2 , A 3 CR 3 , A 4 CR 4 , and A 5 is N.

[0179] In some embodiments, D is a group of formula (D4).

[0180] In some embodiments, A D41 For CH.

[0181] In some embodiments, A D41 C 1-6 alkyl).

[0182] In some embodiments, A D41 is N.

[0183] In some embodiments, A D42 For NH.

[0184] In some embodiments, A D42 For NC 1-6 Alkyl, such as NMe.

[0185] In some embodiments, A D42 For CH2.

[0186] In some embodiments, D is a group of formula (D4), and m is 1.

[0187] In some embodiments, D is a group of formula (D4), and m is 2.

[0188] In some embodiments, D is a group of formula (D4), and m is 3.

[0189] In some embodiments, D is a group of formula (D5).

[0190] In some embodiments, D is a group of formula (D5), and m is 1.

[0191] In some embodiments, D is a group of formula (D5), and m is 2.

[0192] In some embodiments, D is a group of formula (D5), and m is 3.

[0193] In some embodiments, D is a group of formula (D6).

[0194] In some embodiments, D is a group of formula (D6), and m is 1.

[0195] In some embodiments, D is a group of formula (D6), and m is 2.

[0196] In some embodiments, D is a group of formula (D6), and m is 3.

[0197] In some embodiments, D is a group of formula (D7).

[0198] In some embodiments, L 2 Does not exist.

[0199] In some embodiments, L 2 is a group of formula O.

[0200] In some embodiments, L 2 Formula N(R N ) group.

[0201] In some embodiments, L 2 is a group of formula C(O).

[0202] In some embodiments, L 3 Does not exist.

[0203] In some embodiments, L 3 A group of formula CH2.

[0204] In some embodiments, L 3 Formula N(R N ) group.

[0205] In some embodiments, L 3 is a group of formula C(O).

[0206] In some embodiments, L 3 It is a group of formula C≡C.

[0207] In some embodiments, Cy D71 C 6-10 Aryl (eg, phenyl).

[0208] In some embodiments, Cy D71 C 3-15 Cycloalkyl (eg, cyclopropyl).

[0209] In some embodiments, Cy D71 is a 5-10 membered heteroaryl group (e.g., triazole, pyridine, dihydropyrido[2,1-b]pyrimidin-2-one, 3,4-dihydroquinolin-2-one, benzo[d]isothiazole-1,1-dioxide, 2H-indazole, pyrazole, dioxolane, pyrrole, indole, imidazole, benzimidazole).

[0210] In some embodiments, Cy D71 is a 4-10 membered heterocycloalkyl group (eg, piperidine, 1,3-dioxolane, indoline, pyrrolidine).

[0211] In some embodiments, the formation of Cy D71 C 6-10 Aryl, C 3-15The cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is unsubstituted.

[0212] In some embodiments, the formation of Cy D71 C 6-10 Aryl, C 3-15 The cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is substituted.

[0213] In some embodiments, the formation of Cy D71 C 6-10 Aryl, C 3-15 The cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is substituted with 1, 2, 3, 4 or 5 substituents each independently selected from the group consisting of unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 、C(O)OR a1 and NR c1 R d1 Substituents substituted with C 1-6 Alkyl or C 2-6 Alkenyl.

[0214] In some embodiments, the formation of Cy D71 C 6-10 Aryl, C 3-15 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is substituted with 0, 1 or 2 substituents selected from Cy D72 、CH2Cy D72 , OCy D72 ,NHCy D72 , OC 1-6 Alkylene-Cy D72 、N(C 1-6 Alkyl)Cy D72 、N(C(O)C 1-6 Alkyl)Cy D72 and C(O)NHCy D72 .

[0215] In some embodiments, CyD72 C 6-10 Aryl (eg, phenyl).

[0216] In some embodiments, Cy D72 C 3-15 Cycloalkyl (eg, cyclopropyl).

[0217] In some embodiments, Cy D72 is a 5-10 membered heteroaryl group (e.g., triazole, pyridine, dihydropyrido[2,1-b]pyrimidin-2-one, 3,4-dihydroquinolin-2-one, benzo[d]isothiazole-1,1-dioxide, 2H-indazole, pyrazole, dioxolane, pyrrole, indole, imidazole, benzimidazole).

[0218] In some embodiments, Cy D72 is a 4-10 membered heterocycloalkyl group (eg, piperidine, 1,3-dioxolane, indoline, pyrrolidine).

[0219] In some embodiments, the formation of Cy D72 C 6-10 Aryl, C 3-15 The cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is unsubstituted.

[0220] In some embodiments, the formation of Cy D72 C 6-10 Aryl, C 3-15 The cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is substituted.

[0221] In some embodiments, the formation of Cy D72 C 6-10 Aryl, C 3-15 The cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is substituted with 0, 1 or 2 substituents selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-15 Cycloalkyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 、C(O)OR a1 and NRc1 R d1 Substituents substituted with C 1-6 alkyl.

[0222] In some embodiments, R 1 H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Cy 1A , OH, OC 1-6 Alkyl, OCy 1A 、O(C 1-3 Alkylene)Cy 1A 、NH2、NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, NHCy 1A NH(C 1-3 Alkylene)Cy 1A 、N(C 1-6 Alkyl)Cy 1A or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 1A .

[0223] In some embodiments, R 1 Cy 1A , OCy 1A 、O(C 1-3 Alkylene)Cy 1A ,NHCy 1A NH(C 1-3 Alkylene)Cy 1A 、N(C 1-6 Alkyl)Cy 1A or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 1A .

[0224] In some embodiments, R 1 NHCy 1A .

[0225] In some embodiments, R 1 C 1-6 Alkyl (e.g., methyl), C 2-6 Alkenyl, C 2-6 Alkynyl, Cy 1A , OH or OC 1-6 Alkyl (eg, OMe).

[0226] In some embodiments, R 1 For OH.

[0227] In some embodiments, R1 A group of one of the following formulae:

[0228]

[0229] in:

[0230] R 11 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 1B , OH, OCy 1B 、O(C 1-3 Alkylene)Cy 1B ,NHCy 1B NH(C 1-3 Alkylene)Cy 1B 、N(C 1-6 Alkyl)Cy 1B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 1B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0231] R 12 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 1B , OH, OCy 1B 、O(C 1-3 Alkylene)Cy 1B ,NHCy 1B NH(C 1-3 Alkylene)Cy 1B 、N(C 1-6 Alkyl)Cy 1B or N(C 1-6 Alkyl)(C 1-3Alkylene)Cy 1B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0232] R 13 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 1B , OH, OCy 1B 、O(C 1-3 Alkylene)Cy 1B ,NHCy 1B NH(C 1-3 Alkylene)Cy 1B 、N(C 1-6 Alkyl)Cy 1B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 1B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0233] R 14 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 1B , OH, OCy 1B 、O(C 1-3 Alkylene)Cy 1B ,NHCy 1B NH(C 1-3 Alkylene)Cy 1B 、N(C 1-6Alkyl)Cy 1B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 1B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0234] R 15 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 1B , OH, OCy 1B 、O(C 1-3 Alkylene)Cy 1B ,NHCy 1B NH(C 1-3 Alkylene)Cy 1B 、N(C 1-6 Alkyl)Cy 1B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 1B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0235] R 16 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 1B , OH, OCy 1B 、O(C 1-3 Alkylene)Cy 1B ,NHCy 1BNH(C 1-3 Alkylene)Cy 1B 、N(C 1-6 Alkyl)Cy 1B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 1B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0236] R 17 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 1B , OH, OCy 1B 、O(C 1-3 Alkylene)Cy 1B ,NHCy 1B NH(C 1-3 Alkylene)Cy 1B 、N(C 1-6 Alkyl)Cy 1B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 1B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 Alkyl; and

[0237] R 18 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 1B , OH, OCy 1B、O(C 1-3 Alkylene)Cy 1B ,NHCy 1B NH(C 1-3 Alkylene)Cy 1B 、N(C 1-6 Alkyl)Cy 1B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 1B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl.

[0238] In some embodiments, R 1 A group of one of the following formulae:

[0239]

[0240] In some embodiments, Cy 1A is unsubstituted or substituted with 0, 1 or 2 Cy 1B and 0, 1, 2, 3, 4 or 5 substituents substituted with C 6-10 Aryl, such as phenyl, the substituents are each independently selected from unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl.

[0241] In some embodiments, Cy 1A is unsubstituted or replaced by 1 Cy 1B and 0, 1, 2, 3, 4 or 5 substituents substituted with C 6-10 Aryl, such as phenyl, the substituents are each independently selected from unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl.

[0242] In some embodiments, Cy 1A is unsubstituted or replaced by 1 Cy 1B Substituted C 6-10 Aryl, for example phenyl.

[0243] In some embodiments, each Cy 1B is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents. 3-15 Cycloalkyl (e.g., C 3-10 cycloalkyl, such as adamantyl, such as adamantane-1-yl), the substituents being each independently selected from unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl.

[0244] In some embodiments, each Cy 1B For unsubstituted C 3-15 Cycloalkyl (e.g., C 3-10 Cycloalkyl, for example adamantyl, for example adamant-1-yl).

[0245] In some embodiments, Cy 1A A group of one of the following formulae:

[0246]

[0247] in:

[0248] R 11 H, unsubstituted C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 1B , OH, OCy 1B 、O(C 1-3 Alkylene)Cy 1B ,NHCy 1B NH(C 1-3 Alkylene)Cy 1B 、N(C 1-6 Alkyl)Cy 1B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 1B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0249] R 12 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 1B , OH, OCy 1B 、O(C 1-3 Alkylene)Cy 1B ,NHCy 1B NH(C 1-3 Alkylene)Cy 1B 、N(C 1-6 Alkyl)Cy 1B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 1B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0250] R 13 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 1B , OH, OCy 1B 、O(C 1-3 Alkylene)Cy 1B ,NHCy 1B NH(C 1-3 Alkylene)Cy 1B 、N(C 1-6 Alkyl)Cy 1B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 1B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0251] R 14 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 1B , OH, OCy 1B 、O(C 1-3 Alkylene)Cy 1B ,NHCy 1B NH(C 1-3 Alkylene)Cy 1B 、N(C 1-6 Alkyl)Cy 1B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 1B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NRc1 R d1 Substituents substituted with C 1-6 alkyl;

[0252] R 15 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 1B , OH, OCy 1B 、O(C 1-3 Alkylene)Cy 1B ,NHCy 1B NH(C 1-3 Alkylene)Cy 1B 、N(C 1-6 Alkyl)Cy 1B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 1B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0253] R 16 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 1B , OH, OCy 1B 、O(C 1-3 Alkylene)Cy 1B ,NHCy 1B NH(C 1-3 Alkylene)Cy 1B 、N(C 1-6 Alkyl)Cy 1B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 1B or 1, 2 or 3 each independently selected from halogen, C1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0254] R 17 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 1B , OH, OCy 1B 、O(C 1-3 Alkylene)Cy 1B ,NHCy 1B NH(C 1-3 Alkylene)Cy 1B 、N(C 1-6 Alkyl)Cy 1B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 1B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 Alkyl; and

[0255] R 18 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 1B , OH, OCy 1B 、O(C 1-3 Alkylene)Cy 1B ,NHCy 1B NH(C 1-3 Alkylene)Cy 1B 、N(C 1-6 Alkyl)Cy 1B or N(C 1-6 Alkyl)(C1-3 Alkylene)Cy 1B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl.

[0256] In some embodiments, Cy 1A A group of one of the following formulae:

[0257]

[0258] In some embodiments, Cy 1A is unsubstituted or substituted with 0, 1 or 2 Cy 1B and 0, 1, 2, 3, 4 or 5 substituents substituted with C 3-15 Cycloalkyl (e.g., C 3-10 cycloalkyl, such as adamantyl, such as adamantane-1-yl), the substituents being each independently selected from unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 In some embodiments, Cy 1A is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents. 3-15 Cycloalkyl (e.g., C 3-10 cycloalkyl, such as adamantyl, such as adamantane-1-yl), the substituents being each independently selected from unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SRa1 and NR c1 R d1 Substituents substituted with C 1-6 In some embodiments, Cy 1A For unsubstituted C 3-15 Cycloalkyl (e.g., C 3-10 In some embodiments, Cy 1A is unsubstituted or substituted adamantyl, such as adamantane-1-yl. In some embodiments, Cy 1A is an unsubstituted adamantyl group, for example, adamantane-1-yl.

[0259] In some embodiments:

[0260] R 7 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 Alkyl; and

[0261] R 8 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl.

[0262] In some embodiments, R 7 is H, and R 8 It's H.

[0263] In some embodiments, L 2 Does not exist.

[0264] In some embodiments, L 2 N(R N ).

[0265] In some embodiments, L 2 is C(O).

[0266] In some embodiments, R N For H.

[0267] In some embodiments, A 6 CR 6 .

[0268] In some embodiments, R 6 For H.

[0269] In some embodiments, A 6 is N.

[0270] In some embodiments, A 7 CR 7 .

[0271] In some embodiments, R 7 For H.

[0272] In some embodiments, R 7 Cy 7A , OCy 7A 、O(C 1-3 Alkylene)Cy 7A 、C(O)OCy 7A 、C(O)O(C 1-3 Alkylene)Cy 7A ,NHCy 7A NH(C 1-3 Alkylene)Cy 7A 、N(C 1-6 Alkyl)Cy 7A 、N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 7A 、C(O)NHCy 7A 、C(O)NH(C 1-3 Alkylene)Cy 7A 、C(O)N(C 1-6 Alkyl)Cy 7A or C(O)N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 7A .

[0273] In some embodiments, R7 Cy 7A , OCy 7A 、O(C 1-3 Alkylene)Cy 7A ,NHCy 7A NH(C 1-3 Alkylene)Cy 7A 、N(C 1-6 Alkyl)Cy 7A or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 7A .

[0274] In some embodiments, R 7 N(C(O)C 1-6 Alkyl)Cy 7A .

[0275] In some embodiments, R 7 NHCy 7A .

[0276] In some embodiments, R 7 A group of one of the following formulae:

[0277]

[0278] in:

[0279] R 71 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 7B , OH, OCy 7B 、O(C 1-3 Alkylene)Cy 7B ,NHCy 7B NH(C 1-3 Alkylene)Cy 7B 、N(C 1-6 Alkyl)Cy 7B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 7B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 Rd1 Substituents substituted with C 1-6 alkyl;

[0280] R 72 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 7B , OH, OCy 7B 、O(C 1-3 Alkylene)Cy 7B ,NHCy 7B NH(C 1-3 Alkylene)Cy 7B 、N(C 1-6 Alkyl)Cy 7B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 7B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0281] R 73 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 7B , OH, OCy 7B 、O(C 1-3 Alkylene)Cy 7B ,NHCy 7B NH(C 1-3 Alkylene)Cy 7B 、N(C 1-6 Alkyl)Cy 7B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 7B or 1, 2 or 3 each independently selected from halogen, C 1-6Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0282] R 74 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 7B , OH, OCy 7B 、O(C 1-3 Alkylene)Cy 7B ,NHCy 7B NH(C 1-3 Alkylene)Cy 7B 、N(C 1-6 Alkyl)Cy 7B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 7B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0283] R 75 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 7B , OH, OCy 7B 、O(C 1-3 Alkylene)Cy 7B ,NHCy 7B NH(C 1-3 Alkylene)Cy 7B 、N(C 1-6 Alkyl)Cy 7B or N(C 1-6 Alkyl)(C 1-3Alkylene)Cy 7B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0284] R 76 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 7B , OH, OCy 7B 、O(C 1-3 Alkylene)Cy 7B ,NHCy 7B NH(C 1-3 Alkylene)Cy 7B 、N(C 1-6 Alkyl)Cy 7B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 7B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0285] R 77 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 7B , OH, OCy 7B 、O(C 1-3 Alkylene)Cy 7B ,NHCy 7B NH(C 1-3 Alkylene)Cy 7B 、N(C 1-6Alkyl)Cy 7B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 7B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 Alkyl; and

[0286] R 78 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 7B , OH, OCy 7B 、O(C 1-3 Alkylene)Cy 7B ,NHCy 7B NH(C 1-3 Alkylene)Cy 7B 、N(C 1-6 Alkyl)Cy 7B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 7B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl.

[0287] In some embodiments, R 7 A group of one of the following formulae:

[0288]

[0289] In some embodiments, Cy 7A is unsubstituted or substituted with 0, 1 or 2 Cy 7B and 0, 1, 2, 3, 4 or 5 substituents substituted with C 6-10 Aryl, such as phenyl, the substituents are each independently selected from unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl.

[0290] In some embodiments, Cy 7A is unsubstituted or replaced by 1 Cy 7B and 0, 1, 2, 3, 4 or 5 substituents substituted with C 6-10 Aryl, such as phenyl, the substituents are each independently selected from unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl.

[0291] In some embodiments, Cy 7A is unsubstituted or replaced by 1 Cy 7B Substituted C 6-10 Aryl, for example phenyl.

[0292] In some embodiments, each Cy 7B is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents. 3-15 Cycloalkyl (e.g., C 3-10 cycloalkyl, such as adamantyl, such as adamantane-1-yl), the substituents being each independently selected from unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl.

[0293] In some embodiments, each Cy 7B For unsubstituted C 3-15 Cycloalkyl (e.g., C 3-10 Cycloalkyl, for example adamantyl, for example adamant-1-yl).

[0294] In some embodiments, Cy 7A A group of one of the following formulae:

[0295]

[0296] in:

[0297] R 71 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 8B , OH, OCy 8B 、O(C 1-3 Alkylene)Cy 8B ,NHCy 8B NH(C 1-3 Alkylene)Cy 8B 、N(C 1-6 Alkyl)Cy 8B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0298] R 72 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 8B , OH, OCy 8B 、O(C 1-3 Alkylene)Cy 8B ,NHCy 8B NH(C 1-3 Alkylene)Cy 8B 、N(C 1-6 Alkyl)Cy 8B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0299] R 73 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 8B , OH, OCy 8B 、O(C 1-3 Alkylene)Cy 8B ,NHCy 8B NH(C 1-3 Alkylene)Cy 8B 、N(C 1-6 Alkyl)Cy 8B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0300] R 74 H, unsubstituted C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 8B , OH, OCy 8B 、O(C 1-3 Alkylene)Cy 8B ,NHCy 8B NH(C 1-3 Alkylene)Cy 8B 、N(C 1-6 Alkyl)Cy 8B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0301] R 75 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 8B , OH, OCy 8B 、O(C 1-3 Alkylene)Cy 8B ,NHCy 8B NH(C 1-3 Alkylene)Cy 8B 、N(C 1-6 Alkyl)Cy 8B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0302] R 76 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 8B , OH, OCy 8B 、O(C 1-3 Alkylene)Cy 8B ,NHCy 8B NH(C 1-3 Alkylene)Cy 8B 、N(C 1-6 Alkyl)Cy 8B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0303] R 77 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 8B , OH, OCy 8B 、O(C 1-3 Alkylene)Cy 8B ,NHCy 8B NH(C 1-3 Alkylene)Cy 8B 、N(C 1-6 Alkyl)Cy 8B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NRc1 R d1 Substituents substituted with C 1-6 Alkyl; and

[0304] R 78 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 8B , OH, OCy 8B 、O(C 1-3 Alkylene)Cy 8B ,NHCy 8B NH(C 1-3 Alkylene)Cy 8B 、N(C 1-6 Alkyl)Cy 8B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl.

[0305] In some embodiments, Cy 7A A group of one of the following formulae:

[0306]

[0307] In some embodiments, Cy 7A is unsubstituted or substituted with 0, 1 or 2 Cy 7B and 0, 1, 2, 3, 4 or 5 substituents substituted with C 3-15 Cycloalkyl (e.g., C 3-10 cycloalkyl, such as adamantyl, such as adamantane-1-yl), the substituents being each independently selected from unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 and 1, 2 or 3 each independently selected from halogen, C1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 In some embodiments, Cy 7A is unsubstituted or substituted with 01, 2, 3, 4 or 5 substituents. 3-15 Cycloalkyl (e.g., C 3-10 cycloalkyl, such as adamantyl, such as adamantane-1-yl), the substituents being each independently selected from unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 In some embodiments, Cy 7A For unsubstituted C 3-15 Cycloalkyl (e.g., C 3-10 In some embodiments, Cy 7A is unsubstituted or substituted adamantyl, such as adamantane-1-yl. In some embodiments, Cy 7A is an unsubstituted adamantyl group, for example, adamantane-1-yl.

[0308] In some embodiments:

[0309] R 1 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C1-6 Alkyl; and

[0310] R 8 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl.

[0311] In some embodiments, A 1 CR 1 , A 2 CR 2 , A 3 CR 3 , A 4 CR 4 , A 5 CR 5 , A 6 CR 6 , A 8 CR 8 , A 9 CR 9 , and A 10 CR 10 .

[0312] In some embodiments, A 1 CR 1 , A 3 CR 3 , A 4 CR 4 , A 5 N, A 6 CR 6 , A 8 CR 8 , A 9 CR 9 , and A 10 CR 10 .

[0313] In some embodiments, A 7 is N.

[0314] In some embodiments, A8 CR 8 .

[0315] In some embodiments, R 8 For H.

[0316] In some embodiments, R 8 Cy 8A , OCy 8A 、O(C 1-3 Alkylene)Cy 8A 、C(O)OCy 8A 、C(O)O(C 1-3 Alkylene)Cy 8A ,NHCy 8A NH(C 1-3 Alkylene)Cy 8A 、N(C 1-6 Alkyl)Cy 8A 、N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8A 、C(O)NHCy 8A 、C(O)NH(C 1-3 Alkylene)Cy 8A 、C(O)N(C 1-6 Alkyl)Cy 8A or C(O)N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8A .

[0317] In some embodiments, R 8 Cy 8A , OCy 8A 、O(C 1-3 Alkylene)Cy 8A ,NHCy 8A NH(C 1-3 Alkylene)Cy 8A 、N(C 1-6 Alkyl)Cy 8A or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8A .

[0318] In some embodiments, R 8 N(Cy 8A )2.

[0319] In some embodiments, R 8 N(C(O)C 1-6 Alkyl)Cy 8A .

[0320] In some embodiments, R 8 SO2NHCy 8A .

[0321] In some embodiments, R 8 C 1-3 Alkylene-C(O)NHCy 8A .

[0322] In some embodiments, R 8 NHCy 8A .

[0323] In some embodiments, R 8 A group of one of the following formulae:

[0324]

[0325] in:

[0326] R 81 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 8A , OH, OCy 8A 、O(C 1-3 Alkylene)Cy 8A ,NHCy 8A NH(C 1-3 Alkylene)Cy 8A 、N(C 1-6 Alkyl)Cy 8A or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8A or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0327] R 82 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1, SR a1 NR c1 R d1 , Cy 8A , OH, OCy 8A 、O(C 1-3 Alkylene)Cy 8A ,NHCy 8A NH(C 1-3 Alkylene)Cy 8A 、N(C 1-6 Alkyl)Cy 8A or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8A or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0328] R 83 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 8A , OH, OCy 8A 、O(C 1-3 Alkylene)Cy 8A ,NHCy 8A NH(C 1-3 Alkylene)Cy 8A 、N(C 1-6 Alkyl)Cy 8A or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8A or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0329] R 84 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 8A , OH, OCy 8A 、O(C 1-3 Alkylene)Cy 8A ,NHCy 8A NH(C 1-3 Alkylene)Cy 8A 、N(C 1-6 Alkyl)Cy 8A or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8A or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0330] R 85 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 8A , OH, OCy 8A 、O(C 1-3 Alkylene)Cy 8A ,NHCy 8A NH(C 1-3 Alkylene)Cy 8A 、N(C 1-6 Alkyl)Cy 8A or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8A or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0331] R86 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 8A , OH, OCy 8A 、O(C 1-3 Alkylene)Cy 8A ,NHCy 8A NH(C 1-3 Alkylene)Cy 8A 、N(C 1-6 Alkyl)Cy 8A or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8A or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0332] R 87 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 8A , OH, OCy 8A 、O(C 1-3 Alkylene)Cy 8A ,NHCy 8A NH(C 1-3 Alkylene)Cy 8A 、N(C 1-6 Alkyl)Cy 8A or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8A or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1Substituents substituted with C 1-6 Alkyl; and

[0333] R 88 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 8A , OH, OCy 8A 、O(C 1-3 Alkylene)Cy 8A ,NHCy 8A NH(C 1-3 Alkylene)Cy 8A 、N(C 1-6 Alkyl)Cy 8A or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8A or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl.

[0334] In some embodiments, R 8 A group of one of the following formulae:

[0335]

[0336] In some embodiments, Cy 8A is unsubstituted or substituted with 0, 1 or 2 Cy 8B and 0, 1, 2, 3, 4 or 5 substituents substituted with C 6-10 Aryl, such as phenyl, the substituents are each independently selected from unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NRc1 R d1 Substituents substituted with C 1-6 alkyl.

[0337] In some embodiments, Cy 8A is unsubstituted or replaced by 1 Cy 8B and 0, 1, 2, 3, 4 or 5 substituents substituted with C 6-10 Aryl, such as phenyl, the substituents are each independently selected from unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl.

[0338] In some embodiments, Cy 8A is unsubstituted or replaced by 1 Cy 8B Substituted C 6-10 Aryl, for example phenyl.

[0339] In some embodiments, each Cy 8B is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents. 3-15 Cycloalkyl (e.g., C 3-10 cycloalkyl, such as adamantyl, such as adamantane-1-yl), the substituents being each independently selected from unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl.

[0340] In some embodiments, each Cy 8BFor unsubstituted C 3-15 Cycloalkyl (e.g., C 3-10 Cycloalkyl, for example adamantyl, for example adamant-1-yl).

[0341] In some embodiments, Cy 8A A group of one of the following formulae:

[0342]

[0343] in:

[0344] R 81 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 8A , OH, OCy 8A 、O(C 1-3 Alkylene)Cy 8A ,NHCy 8A NH(C 1-3 Alkylene)Cy 8A 、N(C 1-6 Alkyl)Cy 8A or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8A or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0345] R 82 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 8A , OH, OCy 8A 、O(C 1-3 Alkylene)Cy 8A ,NHCy 8A NH(C1-3 Alkylene)Cy 8A 、N(C 1-6 Alkyl)Cy 8A or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8A or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0346] R 83 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 8A , OH, OCy 8A 、O(C 1-3 Alkylene)Cy 8A ,NHCy 8A NH(C 1-3 Alkylene)Cy 8A 、N(C 1-6 Alkyl)Cy 8A or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8A or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0347] R 84 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 8A , OH, OCy 8A 、O(C1-3 Alkylene)Cy 8A ,NHCy 8A NH(C 1-3 Alkylene)Cy 8A 、N(C 1-6 Alkyl)Cy 8A or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8A or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0348] R 85 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 8A , OH, OCy 8A 、O(C 1-3 Alkylene)Cy 8A ,NHCy 8A NH(C 1-3 Alkylene)Cy 8A 、N(C 1-6 Alkyl)Cy 8A or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8A or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0349] R 86 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 Rd1 , Cy 8A , OH, OCy 8A 、O(C 1-3 Alkylene)Cy 8A ,NHCy 8A NH(C 1-3 Alkylene)Cy 8A 、N(C 1-6 Alkyl)Cy 8A or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8A or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0350] R 87 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 8A , OH, OCy 8A 、O(C 1-3 Alkylene)Cy 8A ,NHCy 8A NH(C 1-3 Alkylene)Cy 8A 、N(C 1-6 Alkyl)Cy 8A or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8A or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 Alkyl; and

[0351] R 88 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 8A , OH, OCy 8A 、O(C 1-3 Alkylene)Cy 8A ,NHCy 8A NH(C 1-3 Alkylene)Cy 8A 、N(C 1-6 Alkyl)Cy 8A or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8A or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl.

[0352] In some embodiments, Cy 8A A group of one of the following formulae:

[0353]

[0354]

[0355] In some embodiments, Cy 8A is unsubstituted or substituted with 0, 1 or 2 Cy 8B and 0, 1, 2, 3, 4 or 5 substituents substituted with C 3-15 Cycloalkyl (e.g., C 3-10 cycloalkyl, such as adamantyl, such as adamantane-1-yl), the substituents being each independently selected from unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 In some embodiments, Cy 8Ais unsubstituted or substituted with 01, 2, 3, 4 or 5 substituents. 3-15 Cycloalkyl (e.g., C 3-10 cycloalkyl, such as adamantyl, such as adamantane-1-yl), the substituents being each independently selected from unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 In some embodiments, Cy 8A For unsubstituted C 3-15 Cycloalkyl (e.g., C 3-10 In some embodiments, Cy 8A is unsubstituted or substituted adamantyl, such as adamantane-1-yl. In some embodiments, Cy 8A is an unsubstituted adamantyl group, for example, adamantane-1-yl.

[0356] In some embodiments:

[0357] R 1 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 Alkyl; and

[0358] R 7 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl.

[0359] In some embodiments, A 1 CR 1 , A 2 CR 2 , A 3 CR 3 , A 4 CR 4 , A 5 CR 5 , A 6 CR 6 , A 7 CR 7 , A 8 CR 8 , A 9 CR 9 , and A 10 CR 10 .

[0360] In some embodiments, A 1 CR 1 , A 3 CR 3 , A 4 CR 4 , A 5 N, A 6 CR 6 , A 7 CR 7 , A 8 CR 8 , A 9 CR 9 , and A 10 CR 10 .

[0361] In some embodiments, A 8 is N.

[0362] In some embodiments, A 9 CR 9 .

[0363] In some embodiments, R9 H, C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0364] In some embodiments, R 9 is H, methyl or trifluoroethyl.

[0365] In some embodiments, R 9 For H.

[0366] In some embodiments, A 9 is N.

[0367] In some embodiments, A 10 CR 10 .

[0368] In some embodiments, R 10 For H.

[0369] In some embodiments, A 10 is N.

[0370] In some embodiments, the compound is a compound of one of the following formulae (I-1) to (I-60):

[0371]

[0372]

[0373]

[0374]

[0375]

[0376] in:

[0377] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R N , A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , A 8 , A 9 , A 10, Cy 1A , Cy 1B , Cy 7A , Cy 7B , Cy 8A , Cy 8B , L 1 and L 2 As defined above for a compound of formula (I) or any embodiment thereof;

[0378] L 7 Not present, O, NH or N(C 1-6 alkyl);

[0379] L 8 Not present, O, NH or N(C 1-6 alkyl);

[0380] R 11 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 1B , OH, OCy 1B 、O(C 1-3 Alkylene)Cy 1B ,NHCy 1B NH(C 1-3 Alkylene)Cy 1B 、N(C 1-6 Alkyl)Cy 1B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 1B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0381] R 12 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1, Cy 1B , OH, OCy 1B 、O(C 1-3 Alkylene)Cy 1B ,NHCy 1B NH(C 1-3 Alkylene)Cy 1B 、N(C 1-6 Alkyl)Cy 1B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 1B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0382] R 13 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 1B , OH, OCy 1B 、O(C 1-3 Alkylene)Cy 1B ,NHCy 1B NH(C 1-3 Alkylene)Cy 1B 、N(C 1-6 Alkyl)Cy 1B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 1B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0383] R 14 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, ORa1 , SR a1 NR c1 R d1 , Cy 1B , OH, OCy 1B 、O(C 1-3 Alkylene)Cy 1B ,NHCy 1B NH(C 1-3 Alkylene)Cy 1B 、N(C 1-6 Alkyl)Cy 1B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 1B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0384] R 15 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 1B , OH, OCy 1B 、O(C 1-3 Alkylene)Cy 1B ,NHCy 1B NH(C 1-3 Alkylene)Cy 1B 、N(C 1-6 Alkyl)Cy 1B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 1B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0385] R 16 H, unsubstituted C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 1B , OH, OCy 1B 、O(C 1-3 Alkylene)Cy 1B ,NHCy 1B NH(C 1-3 Alkylene)Cy 1B 、N(C 1-6 Alkyl)Cy 1B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 1B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0386] R 17 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 1B , OH, OCy 1B 、O(C 1-3 Alkylene)Cy 1B ,NHCy 1B NH(C 1-3 Alkylene)Cy 1B 、N(C 1-6 Alkyl)Cy 1B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 1B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0387] R18 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 1B , OH, OCy 1B 、O(C 1-3 Alkylene)Cy 1B ,NHCy 1B NH(C 1-3 Alkylene)Cy 1B 、N(C 1-6 Alkyl)Cy 1B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 1B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0388] R 71 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 7B , OH, OCy 7B 、O(C 1-3 Alkylene)Cy 7B ,NHCy 7B NH(C 1-3 Alkylene)Cy 7B 、N(C 1-6 Alkyl)Cy 7B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 7B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1Substituents substituted with C 1-6 alkyl;

[0389] R 72 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 7B , OH, OCy 7B 、O(C 1-3 Alkylene)Cy 7B ,NHCy 7B NH(C 1-3 Alkylene)Cy 7B 、N(C 1-6 Alkyl)Cy 7B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 7B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0390] R 73 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 7B , OH, OCy 7B 、O(C 1-3 Alkylene)Cy 7B ,NHCy 7B NH(C 1-3 Alkylene)Cy 7B 、N(C 1-6 Alkyl)Cy 7B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 7B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, ORa1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0391] R 74 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 7B , OH, OCy 7B 、O(C 1-3 Alkylene)Cy 7B ,NHCy 7B NH(C 1-3 Alkylene)Cy 7B 、N(C 1-6 Alkyl)Cy 7B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 7B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0392] R 75 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 7B , OH, OCy 7B 、O(C 1-3 Alkylene)Cy 7B ,NHCy 7B NH(C 1-3 Alkylene)Cy 7B 、N(C 1-6 Alkyl)Cy 7B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy7B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0393] R 76 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 7B , OH, OCy 7B 、O(C 1-3 Alkylene)Cy 7B ,NHCy 7B NH(C 1-3 Alkylene)Cy 7B 、N(C 1-6 Alkyl)Cy 7B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 7B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0394] R 77 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 7B , OH, OCy 7B 、O(C 1-3 Alkylene)Cy 7B ,NHCy 7B NH(C 1-3 Alkylene)Cy 7B 、N(C 1-6 Alkyl)Cy7B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 7B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 Alkyl; and

[0395] R 78 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 7B , OH, OCy 7B 、O(C 1-3 Alkylene)Cy 7B ,NHCy 7B NH(C 1-3 Alkylene)Cy 7B 、N(C 1-6 Alkyl)Cy 7B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 7B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0396] R 81 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 8B , OH, OCy 8B 、O(C 1-3 Alkylene)Cy 8B ,NHCy 8B NH(C1-3 Alkylene)Cy 8B 、N(C 1-6 Alkyl)Cy 8B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0397] R 82 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 8B , OH, OCy 8B 、O(C 1-3 Alkylene)Cy 8B ,NHCy 8B NH(C 1-3 Alkylene)Cy 8B 、N(C 1-6 Alkyl)Cy 8B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0398] R 83 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 8B , OH, OCy 8B 、O(C1-3 Alkylene)Cy 8B ,NHCy 8B NH(C 1-3 Alkylene)Cy 8B 、N(C 1-6 Alkyl)Cy 8B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0399] R 84 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 8B , OH, OCy 8B 、O(C 1-3 Alkylene)Cy 8B ,NHCy 8B NH(C 1-3 Alkylene)Cy 8B 、N(C 1-6 Alkyl)Cy 8B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0400] R 85 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 Rd1 , Cy 8B , OH, OCy 8B 、O(C 1-3 Alkylene)Cy 8B ,NHCy 8B NH(C 1-3 Alkylene)Cy 8B 、N(C 1-6 Alkyl)Cy 8B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0401] R 86 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 8B , OH, OCy 8B 、O(C 1-3 Alkylene)Cy 8B ,NHCy 8B NH(C 1-3 Alkylene)Cy 8B 、N(C 1-6 Alkyl)Cy 8B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl;

[0402] R 87 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 8B , OH, OCy 8B 、O(C 1-3 Alkylene)Cy 8B ,NHCy 8B NH(C 1-3 Alkylene)Cy 8B 、N(C 1-6 Alkyl)Cy 8B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 Alkyl; and

[0403] R 88 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 , Cy 8B , OH, OCy 8B 、O(C 1-3 Alkylene)Cy 8B ,NHCy 8B NH(C 1-3 Alkylene)Cy 8B 、N(C 1-6 Alkyl)Cy 8B or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8B or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl.

[0404] In some embodiments, R 1 For OH.

[0405] In some embodiments, R 1 For OC 1-6 Alkyl (eg, OMe).

[0406] In some embodiments, R 1 C 2-6 Alkenyl (eg, vinyl).

[0407] In some embodiments, L 7 For NH.

[0408] In some embodiments, L 8 For NH.

[0409] In some embodiments, R a1 , R b1 , R c1 and R d1 Each independently selected from H, C 1-6 Alkyl, HO-C 1-6 Alkylene, C 1-6 Alkoxy-C 1-6 Alkylene, C 6-10 Aryl, C 2-6 Alkenyl and C 2-6 Alkynyl.

[0410] In some embodiments, the compound is a compound of one of the following formulae or a pharmaceutically acceptable salt thereof:

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430] In some embodiments, the compound is a compound of one of the following formulae or a pharmaceutically acceptable salt thereof:

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441] The compound or any embodiment thereof can be provided in the form of a composition, such as a pharmaceutical composition comprising the compound or a salt thereof, such as a pharmaceutically acceptable salt, and at least one additional agent, such as a pharmaceutically acceptable carrier.

[0442] It should be further understood that certain features of the invention described in the context of separate embodiments for clarity may also be provided in a single embodiment in combination (while intending to combine these embodiments as if written in a multi-subordinate form). Conversely, for brevity, various features of the invention described in the context of a single embodiment may also be provided individually or in any suitable subcombination. Thus, it is contemplated that the features of the embodiments described as compounds of formula (I) may be combined in any suitable combination.

[0443] At various places in this specification, certain features of the compounds are disclosed in groups or ranges. It is specifically intended that this disclosure includes every individual subcombination of the members of such groups and ranges. 1-6 "Alkyl" is specifically intended to individually disclose, but not be limited to, methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0444] The term "n-membered" (where n is an integer) generally describes the number of ring-forming atoms in a moiety, where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridinyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl. When the term is used to refer to a carbocyclic ring (e.g., aryl or cycloalkyl), all of the ring atoms are carbon atoms. When the term is used to refer to a heterocyclic ring (e.g., heteroaryl or heterocycloalkyl), one or more of the ring atoms (e.g., 1, 2, 3, or 4) are heteroatoms (e.g., nitrogen, oxygen, or sulfur) and the remainder (e.g., n-1, n-2, n-3, or n-4) are carbon atoms.

[0445] At various places in this specification, variables defining divalent linking groups are described. It is specifically intended that each linking substituent includes both the forward and reverse forms of the linking substituent. For example, -NR(CR'R") n -Contains NR (CR'R") n - and (CR'R") n NR - both, and it is intended that each form be disclosed separately. Where a structure requires a linking group, the Markush variable listed for that group is understood to be the linking group. For example, if a structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it is understood that "alkyl" or "aryl" means a linking alkylene or arylene group, respectively.

[0446] The term "substituted" refers to an atom or a group of atoms that formally replaces hydrogen as a "substituent" connected to another group. Unless otherwise indicated, the term "substituted" refers to any level of substitution, such as mono, di, tri, tetra or penta substitution, where such substitution is permitted. The substituents are independently selected, and the substitutions can be at any chemically accessible position. It should be understood that substitution at a given atom is limited by valence. The term "optionally substituted" refers to unsubstituted or substituted. The term "substituted" means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent (e.g., oxo) can replace two hydrogen atoms.

[0447] The term "C n-m " indicates a range including endpoints, where n and m are integers and indicate the number of carbons. Examples include C 1-4 , C 1-6 Etc. Whenever the term is used to describe group C n to C m , it is as if each member were explicitly listed. For example, the term C 1-6 It is intended to describe each of members C1, C2, C3, C4, C5 and C6.

[0448] The term "alkyl" used alone or in combination with other terms refers to a saturated hydrocarbon group which may be straight or branched. n-m "Alkyl" refers to an alkyl group having n to m carbon atoms. Alkyl groups formally correspond to alkanes in which one CH bond is replaced by the point of attachment of the alkyl group to the rest of the compound. In some embodiments, the alkyl group contains 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologues such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like.

[0449] The term "alkenyl" used alone or in combination with other terms refers to a straight or branched hydrocarbon radical corresponding to an alkyl radical having one or more carbon-carbon double bonds. Alkenyl formally corresponds to an alkene radical in which one CH bond is replaced by the point of attachment of the alkenyl radical to the rest of the compound. n-m "Alkenyl" refers to an alkenyl group having n to m carbons. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

[0450] The term "alkynyl", used alone or in combination with other terms, refers to a straight or branched hydrocarbon radical corresponding to an alkyl radical having one or more carbon-carbon triple bonds. Alkyl radicals formally correspond to alkynes, in which one CH bond is replaced by the point of attachment of the alkynyl radical to the rest of the compound. n-m "Alkynyl" refers to an alkynyl group having n to m carbons. Example alkynyl groups include, but are not limited to, ethynyl, prop-1-yl, prop-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0451] The term "alkylene", used alone or in combination with other terms, refers to a divalent alkyl linking group. Alkylene formally corresponds to an alkane in which the two CH bonds are replaced by the points of attachment of the alkylene to the rest of the compound. n-m “Alkylene” refers to an alkylene group having n to m carbon atoms. Examples of alkylene groups include, but are not limited to, ethane-1,2-diyl, propylene-1,3-diyl, propylene-1,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, 2-methyl-propylene-1,3-diyl, and the like.

[0452] The term "alkoxy", used alone or in combination with other terms, refers to a radical of the formula -O-alkyl, wherein alkyl is as defined above. n-m "Alkoxy" refers to an alkoxy group whose alkyl group has n to m carbons. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy, and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0453] The terms "halo" or "halogen", used alone or in combination with other terms, refer to fluorine, chlorine, bromine and iodine.

[0454] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms have been replaced by a halogen atom. n-m "Haloalkyl" refers to a C group having n to m carbon atoms and at least one to {2(n to m)+1} halogen atoms. n-m In certain embodiments, the halogen atom is fluorine atom. In certain embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms. Exemplary haloalkyl groups include CF3, C2F5, CHF2, CCl3, CHCl2, C2Cl5, etc. In certain embodiments, the haloalkyl group is a fluoroalkyl group.

[0455] The term "haloalkoxy" used alone or in combination with other terms refers to a radical of the formula -O-haloalkyl, wherein haloalkyl is as defined above. n-m"Haloalkoxy" refers to a haloalkoxy group whose haloalkyl group has n to m carbons. Example haloalkoxy groups include trifluoromethoxy and the like. In some embodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0456] The term "amino" refers to a group of formula -NH2.

[0457] The term "carbamoyl" refers to a group of formula -C(=O)NH2.

[0458] The term "carbonyl," employed alone or in combination with other terms, refers to a C(=O) group, which may also be written as C(O).

[0459] The term "carbonyl," used alone or in combination with other terms, refers to a C(=O) group.

[0460] The term "carboxy" refers to a group of formula -C(=O)OH.

[0461] The term "oxo" refers to oxygen as a divalent substituent to form a carbonyl group, or attached to a heteroatom to form a sulfoxide or sulfone group or an N-oxide group.

[0462] The term "aromatic" refers to a carbocyclic or heterocyclic ring having one or more polyunsaturated rings having aromatic character (ie, having (4n+2) delocalized π (pi) electrons, where n is an integer).

[0463] The term "aryl", used alone or in combination with other terms, refers to an aromatic hydrocarbon group which may be monocyclic or polycyclic (eg, having 2, 3 or 4 fused rings). n-m "Aryl" refers to an aromatic group having n to m ring carbon atoms. Aryl groups include, for example, phenyl, naphthyl, indenyl, and the like. In some embodiments, the aryl group has 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl.

[0464] The term "arylalkylene" used alone or in combination with other terms refers to an aryl group, as defined herein, attached to an alkylene group, as defined herein. n-m Aryl C o-p "Alkylene" refers to an arylalkylene group in which an aryl group having n to m ring carbon atoms is linked to an alkylene group having o to p carbon atoms. Arylalkylene groups include, for example, benzyl, phenethyl, and the like.

[0465] The term "heteroaryl" or "heteroaromatic", used alone or in combination with other terms, refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen and nitrogen. In some embodiments, the heteroaryl is a 5- or 6-membered monocyclic heteroaromatic ring. In some embodiments, the heteroaryl is a 5 to 10-membered C 1-9Heteroaryl, which is monocyclic or bicyclic and has 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, any ring-forming N in the heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl has 5-10 ring atoms, including carbon atoms and 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl has 5-6 ring atoms and 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a five-membered or six-membered heteroaryl ring. Example heteroaryl groups include, but are not limited to, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, oxazolyl, oxazole, thiazole, imidazole, furan, thiophene, quinoline, isoquinoline, indole, benzothiophene, benzofuran, benzisoxazole, imidazo[1,2-b]thiazole, imidazo[1,2-b]pyridazine, purine, furanopyridine (e.g., furano[3,2-b]pyridine), thienopyridine (e.g., thieno[3,2-b]pyridine), and the like.

[0466] A five-membered heteroaryl ring is a heteroaryl group having five ring atoms, wherein one or more (e.g., 1, 2, 3, or 4) of the ring atoms are independently selected from N, O, and S. Exemplary five-membered heteroaryl groups include thienyl, furanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.

[0467] A six-membered heteroaryl ring is a heteroaryl group having six ring atoms, wherein one or more (e.g., 1, 2, or 3) of the ring atoms are independently selected from N, O, and S. Exemplary six-membered ring heteroaryl groups are pyridinyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

[0468] The term "heteroarylalkylene" used alone or in combination with other terms refers to a heteroaryl group, as defined herein, attached to an alkylene group, as defined herein. o-p "Alkylene" refers to a heteroaryl group having n to m ring atoms attached to an alkylene group having o to p carbon atoms. Heteroarylalkylene includes, for example, pyridylmethyl, pyridylethyl, and the like.

[0469] The term "cycloalkyl", used alone or in combination with other terms, refers to a non-aromatic, saturated, monocyclic, bicyclic or polycyclic hydrocarbon ring system, including cyclized alkyl and alkenyl groups. n-m"Cycloalkyl" refers to a cycloalkyl group having n to m ring member carbon atoms. Cycloalkyl groups may include monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocyclic groups. Cycloalkyl groups may have, for example, 3, 4, 5, 6, 7, 8, 9 or 10 ring carbon atoms (C 3-10 ) or 3, 4, 5, 6 or 7 ring carbons (C 3-7 In some embodiments, the cycloalkyl group has 3 to 6 ring members, 3 to 5 ring members, or 3 to 4 ring members. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is C 3-6 The cycloalkyl of monocycle. The ring carbon atom of cycloalkyl can be optionally substituted by oxo or thio. Cycloalkyl also includes cycloalkylidene. The example of cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, norbornyl, norindenyl, bicyclo [2.1.1] hexyl, bicyclo [1.1.1] pentyl, adamantyl etc. In certain embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The definition of cycloalkyl also includes the part of one or more aromatic rings fused (i.e., having a common key with it) with cycloalkyl ring (for example, benzo or thienyl derivatives of cyclopentane, cyclohexane etc., such as indanyl or tetralin). The cycloalkyl containing fused aromatic ring can be connected by any ring-forming atom including the ring-forming atom of fused aromatic ring.

[0470] The term "arylalkylene" used alone or in combination with other terms refers to a cycloalkyl group, as defined herein, attached to an alkylene group, as defined herein. n-m Cycloalkyl C o-p "Alkylene" refers to a cycloalkylalkylene group in which a cycloalkyl group having n to m ring carbon atoms is attached to an alkylene group having o to p carbon atoms. Cycloalkylalkylene groups include, for example, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclohexylmethyl, and the like.

[0471] The term "heterocycloalkyl" used alone or in combination with other terms refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of a ring structure, independently having at least one heteroatom ring member selected from nitrogen, sulfur, oxygen and phosphorus and having 4-10 ring members, 4-7 ring members or 4-6 ring members. Heterocycloalkyl includes monocyclic 4-, 5-, 6- and 7-membered heterocycloalkyls. Heterocycloalkyl may include monocyclic or bicyclic (e.g., having two condensed rings or bridged rings) ring systems. In certain embodiments, heterocycloalkyl is a monocyclic group with 1,2 or 3 heteroatoms independently selected from nitrogen, sulfur and oxygen. Examples of heterocycloalkyl include azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, pyran, azepane, tetrahydropyran, tetrahydrofuran, dihydropyran, dihydrofuran, etc. The ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group may be optionally substituted with oxo or thio (e.g., C(=O), S(=O), C(S) or S(=O)2, etc.), or the nitrogen atom may be quaternized. The heterocycloalkyl group may be connected via a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. The definition of heterocycloalkyl also includes a portion having one or more aromatic rings fused to (i.e., having a common bond with) a heterocycloalkyl ring (e.g., benzo or thienyl derivatives of piperidine, morpholine, azepine, etc.). The heterocycloalkyl group containing a fused aromatic ring may be connected via any ring-forming atom including the ring-forming atom of the fused aromatic ring. Examples of heterocycloalkyl groups include 1,2,3,4-tetrahydroquinoline, dihydrobenzofuran, azetidine, azepane, diazepane (eg, 1,4-diazepane), pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, pyran, tetrahydrofuran, and dihydropyran and tetrahydropyran.

[0472] The term "heterocycloalkylalkylene" used alone or in combination with other terms refers to a heterocycloalkyl group, as defined herein, attached to an alkylene group, as defined herein. o-p "Alkylene" refers to a heterocycloalkyl group having n to m ring atoms attached to an alkylene group having o to p carbon atoms. Heteroarylalkylene includes, for example, tetrahydrofuranylmethyl.

[0473] In some places, definition or embodiment refers to a specific ring (e.g., azetidine ring, pyridine ring, etc.). Unless otherwise indicated, these rings can be connected to any ring member, provided that the valence of the atom is not exceeded. For example, the azetidine ring can be connected at any position of the ring, while the azetidine-3-yl ring is connected at the 3-position.

[0474] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers (such as enantiomers and diastereomers) are intended. Compounds of the present invention containing asymmetrically substituted carbon atoms may be separated in optically active forms or racemic forms. Methods for preparing optically active forms from optically inactive starting materials are known in the art, such as by splitting a racemic mixture or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, etc. may also be present in the compounds described herein, and all such stable isomers are considered in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described, and they may be separated into mixtures of isomers or individual isomeric forms.

[0475] The racemic mixture of compound can be split by any method in numerous methods known in the art.A method comprises the fractional recrystallization using chiral resolution acid, and the acid is a kind of optically active salified organic acid.Suitable resolving agent for fractional recrystallization method is for example optically active acid, such as tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acid (such as β-camphorsulfonic acid) of D-type and L-type.Other resolving agents suitable for fractional crystallization method include methylbenzylamine (for example, S and R form, or diastereoisomerism pure form), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane etc.

[0476] The racemic mixture can also be resolved by eluting on a column filled with an optically active resolving agent (eg, dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by one skilled in the art.

[0477] In some embodiments, the compounds of the invention have an (R)-configuration. In other embodiments, the compounds have an (S)-configuration. In compounds with more than one chiral center, unless otherwise specified, each chiral center in the compound can independently be (R) or (S).

[0478] The compounds of the present invention also include tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond along with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Example proton tautomers include keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions of a heterocyclic system, such as 1H- and 3H-imidazoles, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles. Tautomeric forms can be in equilibrium or, by appropriate substitution, sterically locked into one form.

[0479] The compounds of the present invention may also contain isotopes of all atoms present in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0480] The term "compound" is intended to encompass all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structure.

[0481] All compounds and pharmaceutically acceptable salts thereof may be found together with other substances such as water and solvents (e.g., hydrates and solvates) or may be isolated. When in the solid state, the compounds described herein and their salts may exist in various forms and may, for example, take the form of solvates, including hydrates. The compound may be in any solid state form, such as a polymorph or solvate, and therefore, unless otherwise expressly stated, references to the compound and its salt in the specification should be understood to encompass any solid state form of the compound.

[0482] In some embodiments, the compounds of the present invention or their salts are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially isolated from the environment in which it is formed or detected. Partial separation can include, for example, a composition rich in the compounds of the present invention. Substantially separating can include a composition comprising at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% of the compounds of the present invention or their salts by weight.

[0483] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0484] The expressions "ambient temperature" and "room temperature" are as understood in the art, and generally refer to a temperature about the temperature of the room in which the reaction is carried out (eg, reaction temperature), such as a temperature from about 20°C to about 30°C.

[0485] The present invention also includes salts of the compounds described herein, specifically pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a derivative of a disclosed compound in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral salts or organic acid salts of basic residues such as amines; alkali metal salts or organic salts of acidic residues such as carboxylic acids; etc. The pharmaceutically acceptable salts of the present invention include, for example, non-toxic salts of the parent compound formed from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound containing a basic or acidic moiety by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or in an organic solvent or in a mixture of the two; typically, non-aqueous media like ether, ethyl acetate, alcohol (e.g., methanol, ethanol, isopropanol or butanol) or acetonitrile (MeCN) are preferred. Lists of suitable salts can be found in: Remington's Pharmaceutical Sciences, 17th ed., (Mack Publishing Company, Easton, 1985), p. 1418; Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19 and Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). In some embodiments, the compounds described herein include N-oxide forms.

[0486] The following abbreviations may be used herein: AcOH (acetic acid); Ac2O (acetic anhydride); Al2O3 (aluminum oxide); aq. (aqueous); atm. (atmospheric pressure); Boc (tert-butoxycarbonyl); Boc2O (di-tert-butyl dicarbonate); BOP ((benzotriazol-1-yloxy)tris(dimethylamino)phosphorus hexafluorophosphate); br (broad); c-Pr (cyclopropyl); Cbz (carboxybenzyl); calc. (calculated); CeCl3·7H2O (cerium(III) chloride heptahydrate); Cs2CO3 (cesium carbonate); CuI (copper(I) iodide); d (doublet); dd (double doublet); DCM (dichloromethane); DIPEA (N,N-diisopropylethylamine); DMA P (4-dimethylaminopyridine); DMF (N,N-dimethylformamide); DMSO (dimethyl sulfoxide); Et (ethyl); EtOAc (ethyl acetate); EtOH (ethanol); Fmoc (9-fluorenylmethylmethoxycarbonyl); g (gram); h (hour); H2 (hydrogen); H2O2 (hydrogen peroxide); HATU (N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate); HBr (hydrogen bromide); HCl (hydrochloric acid or hydrogen chloride); HPLC (high performance liquid chromatography); Hz (hertz); i-Pr (isopropyl); i-PrOH (isopropanol); J (coupling constant); KOAc (potassium acetate); K3PO4 (potassium phosphate); K3PO4·H2O (tripotassium phosphate hydrate); LCMS (liquid chromatography-mass spectrometry); LiAlH4 (lithium tetrahydroaluminate); LiBH4 (lithium tetrahydroborate); LiOH (lithium hydroxide); LiOH·H2O (lithium hydroxide monohydrate); m (multiplet); M (molar); mCPBA (meta-chloroperbenzoic acid); Me (methyl); MeCN (acetonitrile); MeOH (methanol); MgSO4 (magnesium sulfate); MS (mass spectrometry); mg (milligram); min. (minute) mL (milliliter); mmol (millimole); N (normal); N2 (nitrogen); NaHCO3 (sodium bicarbonate); NaIO4 (sodium metaperiodate); NaN3 (sodium azide); NaOH (hydrogen); =Na2O4; Na2SO4 (sodium sulfate); n-Bu (n-butyl); n-BuLi (n-butyl lithium); NH4Cl (ammonium chloride); NH4OH (ammonium hydroxide); nM (nanomolar); NMR (nuclear magnetic resonance spectroscopy); Pd (palladium); Pd(dppf)Cl2 ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)); Pd(OAc)2 (palladium acetate); Pd(tBu3P)2 (bis(tri-tert-butylphosphine)palladium); pM (picomolar); Pd(PPh3)4 (tetrakis(triphenylphosphine)palladium(0)); PPh3 (triphenylphosphine); psi (pounds per square inch); PTFE (polytetrafluoroethylene); RP-HPLC (reverse phase high performance liquid chromatography); rt(room temperature); s (singlet); t (triplet or tert); tert (tert); tt (triplet); TBAF (tetra-n-butylammonium fluoride); t-Bu (tert-butyl); TEA (triethylamine); TFA (trifluoroacetic acid); THF (tetrahydrofuran); μg (microgram); μL (microliter); μm (micromole); wt% (weight percent). .

[0487] II. Synthesis

[0488] The compounds of the present invention (including salts thereof) can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes as shown in the following schemes.

[0489] The reaction for preparing the compound of the present invention can be carried out in a suitable solvent that can be easily selected by a technician in the field of organic synthesis. Suitable solvents can be substantially non-reactive with starting materials (reactants), intermediates or products at a temperature (e.g., a temperature ranging from the freezing temperature of the solvent to the boiling temperature of the solvent) for carrying out the reaction. A given reaction can be carried out in a solvent or a mixture of more than one solvent. Depending on the specific reaction steps, the suitable solvent for a specific reaction step can be selected by a technician.

[0490] The preparation of the compounds of the present invention may involve the protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups can be readily determined by those skilled in the art. The chemistry of protecting groups is described, for example, in Kocienski, Protecting Groups, (Thieme, 2007); Robertson, Protecting Group Chemistry, (Oxford University Press, 2000); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th ed. (Wiley, 2007); Peturssion et al., Protecting Groups in Carbohydrate Chemistry, J. Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groups in Organic Synthesis, 4th ed. (Wiley, 2006).

[0491] The reaction can be monitored by any suitable method known in the art. For example, the reaction can be monitored by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (eg, visible UV), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC) to monitor product formation.

[0492] The following schemes provide general guidance for preparing compounds of the present invention. One skilled in the art will appreciate that general knowledge of organic chemistry can be used to modify or optimize the preparations shown in the schemes to prepare various compounds of the present invention.

[0493] The compound of formula (I) can be prepared by coupling aniline of formula (II) with a compound of formula III as shown in Scheme 1, wherein L is a suitable leaving group, which may comprise a halogen, such as bromine or iodine or a sulfonate group (alkyl or aryl sulfonate, such as methanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p-toluenesulfonate or naphthalenesulfonate). The reaction may be carried out in the presence of a base such as potassium carbonate and a copper salt such as copper (I) iodide or copper (I) oxide. The reaction may also be carried out in the presence of a suitable organometallic catalyst, for example using Buchwald-Hartwig cross-coupling conditions. Suitable solvents for the reaction include tetrahydrofuran, 1,4-dioxane, toluene or 1,2-dichlorobenzene. A preferred solvent is 1,2-dichlorobenzene. The reaction may typically be carried out at a temperature of 0-200° C., for example at a temperature of 100-150° C.

[0494] The present disclosure provides, inter alia, methods for preparing certain compounds of formula (I) according to formula (Ia) by the route shown in Scheme 1:

[0495]

[0496] Compounds of formula (II) and (III) are either commercially available, known in the literature or can be prepared by methods known to those skilled in the art.

[0497] Certain compounds of formula (I) can be used as intermediates for synthesizing other compounds of formula (I). 1 For OC 1-6 Alkyl, OCy 1A 、O(C 1-3 Alkylene)Cy 1A ,NHCy 1A NH(C 1-3 Alkylene)Cy 1A 、N(C 1-6 Alkyl)Cy 1A or N(C1-6 Alkyl)(C 1-3 Alkylene)Cy 1A The compounds of formula (I) can be used to synthesize compounds wherein R 1 A compound of formula (I) wherein R is OH.

[0498] It will be appreciated by those skilled in the art that the methods described are not the only means by which the compounds of the invention can be synthesized, and that a wide range of synthetic organic reactions can potentially be used to synthesize the compounds of the invention. Those skilled in the art know how to select and implement appropriate synthetic routes. Suitable synthetic methods for starting materials, intermediates and products can be determined by reference to the literature, including the following reference sources, such as: "Advances in Heterocyclic Chemistry", Volumes 1-107 (Elsevier, 1963-2012); "Journal of Heterocyclic Chemistry", Volumes 1-49 (Journal of Heterocyclic Chemistry, 1964-2012); Carreira et al. (eds.) "Science of Synthesis", Volumes 1-48 (2001-2010) and "Knowledge Updates" KU 2010 / 1-4; 2011 / 1-4; 2012 / 1-2 (Thieme, 2001-2012); Katritzky et al. (eds.) "Comprehensive Organic Functional Transformations", Volumes 1-49 (2001-2010); Group Transformations, (Pergamon Press, 1996); Katritzky et al. (eds.); Comprehensive Organic Functional Group Transformations II (Elsevier, 2nd ed., 2004); Katritzky et al. (eds.), Comprehensive Heterocyclic Chemistry (Pergamon Press, 1984); Katritzky et al., Comprehensive Heterocyclic Chemistry II, (Pergamon Press, 1996); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th ed. (Wiley, 2007); Trost et al. (eds.), Comprehensive Organic Synthesis (Pergamon Press, 1991).

[0499] III. Uses of the Compounds

[0500] The compounds of the invention can inhibit the autopalmitoylation of TEAD-transcription factors and are therefore useful for treating diseases and disorders associated with the activity of TEAD-transcription factors.For the uses described herein, any compound of the invention may be used, including any embodiments thereof.

[0501] Therefore, the present disclosure provides a method for treating a TEAD-transcription factor-related disease or condition in an individual (e.g., a patient) by administering a therapeutically effective amount or therapeutically effective dose of a compound of formula (I) or any of its embodiments or its pharmaceutical composition to the individual in need of such treatment. The present disclosure also provides a compound of formula (I) or any of its embodiments or its pharmaceutical composition for treating a TEAD-transcription factor-related disease or condition. Also provided is the use of a compound of formula (I) or any of its embodiments or its pharmaceutical composition in the manufacture of a drug for treating a TEAD-transcription factor-related disease or condition. The disease or condition may be a disease or condition associated with TEAD1, TEAD2, TEAD3 or TEAD4.

[0502] TEAD-transcription factor related diseases may include any disease, disorder or condition directly or indirectly related to the expression or activity of TEAD-transcription factors, including overexpression and / or abnormal activity levels. Abnormal activity levels can be determined by comparing the activity levels in normal, healthy tissues or cells with the activity levels in diseased cells. TEAD-transcription factor related diseases may also include any disease, disorder or condition that can be prevented, improved, suppressed or cured by regulating the activity of TEAD-transcription factors. In some embodiments, the disease is characterized by abnormal activity or expression (e.g., overexpression) of TEAD-transcription factors. TEAD-transcription factor related diseases may also refer to any disease, disorder or condition in which regulating the expression or activity of TEAD-transcription factors is beneficial.

[0503] TEAD-transcription factor-related diseases that can be treated with the compounds of the present invention include cancer. Cancer includes solid tumors, such as prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc. Other TEAD-transcription factor-related diseases include hepatocellular carcinoma, medulloblastoma, squamous cell carcinoma of the skin, lung cancer, pancreatic cancer, esophageal cancer, liver cancer, colon cancer, melanoma or uveal melanoma. TEAD-transcription factor-associated diseases also include hematological cancers, such as lymphomas, leukemias such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin lymphoma (including relapsed non-Hodgkin lymphoma, refractory non-Hodgkin lymphoma and relapsed follicular non-Hodgkin lymphoma), Hodgkin lymphoma and multiple myeloma.

[0504] The cancer can be a cancer in which abnormally proliferating cancer cells express one or more TEADs, such as a cancer expressing one or more of TEAD1, TEAD2, TEAD3, and / or TEAD4. The method can include testing the expression of one or more TEADs, such as one or more of TEAD1, TEAD2, TEAD3, and / or TEAD4, in cancer cells of an individual, and determining to treat the cancer based on the following according to the methods described herein: the cancer expresses TEAD1, TEAD2, TEAD3, and / or TEAD4.

[0505] The terms "subject" or "patient," which are used interchangeably, refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans.

[0506] The phrase "therapeutically effective amount" refers to that amount of an active compound or agent that elicits the biological or medical response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, physician or other clinician.

[0507] The terms "treating" or "treatment" refer to one or more of the following: (1) inhibiting a disease; e.g., inhibiting the disease, condition, or disorder in an individual who is experiencing or displaying the pathology or symptomology of the disease, condition, or disorder (i.e., preventing further development of the pathology and / or symptomology); and (2) ameliorating a disease; e.g., ameliorating the disease, condition, or disorder in an individual who is experiencing or displaying the pathology or symptomology of the disease, condition, or disorder (i.e., reversing the pathology and / or symptomology), such as reducing the severity of the disease. In one embodiment, treatment comprises preventing or reducing the risk of developing a disease; e.g., preventing or reducing the risk of developing a disease, condition, or disorder in an individual who may be susceptible to the disease, condition, or disorder but does not yet experience or display the pathology or symptomology of the disease.

[0508] Combination therapy

[0509] The growth and survival of cancer cells are affected by a variety of signaling pathways. Therefore, it is useful to combine different chemotherapeutic agents to treat such conditions. The use of combination therapy can reduce the likelihood of drug resistance emerging in the cell population and / or reduce the toxicity of the treatment.

[0510] The compounds can be administered in combination with one or more anticancer drugs, such as chemotherapeutic agents. Exemplary chemotherapeutic agents include any of the following: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, bleomycin, bortezombi, bortezomib, busulfan intravenous, busulfan oral oral), calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolone propionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citratecitrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenylpropionate phenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim, pemetrexeddisodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronate.

[0511] When more than one agent is administered to a patient, the agents may be administered simultaneously, sequentially, or in combination (eg, for more than two agents).

[0512] VI. Formulations, Dosage Forms, and Administration

[0513] When used as a drug, the compound of the present invention can be administered in the form of a pharmaceutical composition. Therefore, the present disclosure provides a composition including a compound of formula (I) or a pharmaceutically acceptable salt thereof or any embodiment thereof and at least one pharmaceutically acceptable carrier. These compositions can be prepared in a manner well known in the pharmaceutical field and can be administered by a variety of routes, depending on whether local treatment or systemic treatment and the area to be treated are required. Administration can be local (including transdermal, epidermal, ocular and to mucosa, including intranasal, vaginal and rectal delivery), pulmonary (for example, by inhalation or blowing into powder or aerosol, including by a nebulizer; intratracheal or intranasal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial (for example, intrathecal or intraventricular) administration. Parenteral administration can be in the form of a single bolus dose, or can be performed, for example, by a continuous infusion pump. Pharmaceutical compositions and preparations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous bases, powders or oily bases, thickeners, etc. may be necessary or desirable.

[0514] The present invention also includes pharmaceutical compositions containing a combination of a compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient and one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the composition is suitable for oral administration. In preparing the composition of the present invention, the active ingredient is typically mixed with an excipient, diluted with an excipient or encapsulated within such a carrier, which is in the form of, for example, a capsule, a sachet, paper or other container. When the excipient acts as a diluent, it can be a solid, semisolid or liquid material that can act as a vehicle, carrier or medium for the active ingredient. The composition can therefore be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0515] In preparing the formulation, the active compound may be ground to provide an appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it may be ground to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size may be adjusted by grinding to provide a substantially uniform distribution in the formulation, e.g., about 40 mesh.

[0516] The compounds of the invention may be ground using known grinding procedures such as wet milling to obtain particle sizes suitable for tablet formation and for other formulation types. Finely divided (nanoparticulate) preparations of the compounds of the invention may be prepared by methods known in the art, see for example WO 2002 / 000196.

[0517] Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulation may additionally include: lubricants such as talc, magnesium stearate, mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; sweeteners; and flavoring agents. The compositions of the present invention may be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient using procedures known in the art.

[0518] In some embodiments, the pharmaceutical composition comprises silicified microcrystalline cellulose (SMCC) and at least one compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the silicified microcrystalline cellulose comprises about 98% microcrystalline cellulose and about 2% silicon dioxide w / w.

[0519] In some embodiments, the composition is a sustained release composition comprising at least one compound described herein or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. In some embodiments, the composition comprises at least one compound described herein or a pharmaceutically acceptable salt thereof and at least one component selected from microcrystalline cellulose, lactose monohydrate, hydroxypropyl methylcellulose and polyethylene oxide. In some embodiments, the composition comprises at least one compound described herein or a pharmaceutically acceptable salt thereof and microcrystalline cellulose, lactose monohydrate and hydroxypropyl methylcellulose. In some embodiments, the composition comprises at least one compound described herein or a pharmaceutically acceptable salt thereof and microcrystalline cellulose, lactose monohydrate and polyethylene oxide. In some embodiments, the composition further comprises magnesium stearate or silicon dioxide. In some embodiments, microcrystalline cellulose is Avicel PH102 TM In some embodiments, the lactose monohydrate is Fast-flo 316 TM In some embodiments, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208 K4M (e.g., Methocel K4 M Premier TM ) and / or hydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel K00LV TMIn some embodiments, the polyethylene oxide is polyethylene oxide WSR 1105 (e.g., Polyox WSR 1105 TM ).

[0520] In some embodiments, a wet granulation process is used to produce the composition. In some embodiments, a dry granulation process is used to produce the composition.

[0521] The composition can be formulated into a unit dosage form, each dose containing about 5 to about 1,000 mg (1 g) of active ingredient, more typically about 100 mg to about 500 mg of active ingredient. In some embodiments, each dose contains about 10 mg of active ingredient. In some embodiments, each dose contains about 50 mg of active ingredient. In some embodiments, each dose contains about 25 mg of active ingredient. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect and a suitable pharmaceutical excipient.

[0522] The components used to formulate the pharmaceutical composition are of high purity and substantially free of potentially harmful contaminants (e.g., at least national food grade, typically at least analytical grade, and more typically at least pharmaceutical grade). In particular for human consumption, the composition is preferably manufactured or formulated according to good manufacturing practice standards defined in applicable regulations of the U.S. Food and Drug Administration. For example, suitable formulations may be sterile and / or substantially isotonic and / or fully comply with all good manufacturing practice regulations of the U.S. Food and Drug Administration.

[0523] The active compound can be effective over a wide dosage range and is generally administered in a therapeutically effective amount. However, it should be understood that the amount of compound actually administered will generally be determined by a physician based on the relevant circumstances (including the condition to be treated, the route of administration selected, the actual compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.).

[0524] The therapeutic dose of the compound of the present invention can vary according to, for example, the specific use for treatment, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The ratio or concentration of the compound of the present invention in the pharmaceutical composition can vary depending on many factors (including dosage, chemical characteristics (e.g., hydrophobicity) and route of administration). For example, the compound of the present invention can be provided in an aqueous physiological buffer solution for parenteral administration, the solution containing about 0.1 to about 10% w / v of the compound. Some typical dosage ranges are from about 1 μg / kg body weight / day to about 1g / kg body weight / day. In some embodiments, the dosage range is from about 0.01mg / kg body weight / day to about 100mg / kg body weight / day. The dosage may depend on variables such as the type and degree of progression of the disease or condition, the overall health of the specific patient, the relative biological efficacy of the selected compound, the formulation of the excipient and its route of administration. The effective dose can be extrapolated from a dose-response curve derived from an in vitro or animal model test system.

[0525] For the preparation of solid compositions (such as tablets), the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformulated composition containing a uniform mixture of the compound of the present invention. When these preformulated compositions are called uniform, the active ingredient is typically evenly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms, such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the above type, which contain, for example, from about 0.1 mg to about 1000 mg of the active ingredient of the present invention.

[0526] Tablet of the present invention or pill can be coated or otherwise mixed, to obtain providing the dosage form of extended effect advantage.For example, tablet or pill can comprise inner dosage component and outer dosage component, the latter adopts the form of coating on the former.Two kinds of components can be separated by enteric layer, and described enteric layer is used to resist the disintegration in stomach and allows inner component to be transmitted into duodenum intact or delayed release.Multiple materials can be used for this enteric layer or coating, and this material comprises multiple polymeric acid and polymeric acid and the mixture of such materials as shellac, hexadecanol and cellulose acetate.

[0527] Liquid forms of the compounds and compositions of the invention which may be incorporated for oral administration or injection include aqueous solutions, appropriately flavored syrups, aqueous or oily suspensions, and flavored emulsions containing edible oils (such as cottonseed oil, sesame oil, coconut oil or peanut oil) as well as elixirs and similar pharmaceutical vehicles.

[0528] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In certain embodiments, these compositions are administered by oral or nasal respiratory routes for obtaining local or systemic effects. Compositions may be atomized by the use of inert gases. Atomized solutions may be inhaled directly from an atomizing device, or the atomizing device may be attached to a mask tampon or intermittent positive pressure breathing machine. Solutions, suspensions or powder compositions may be administered orally or nasally from a device that delivers formulations in an appropriate manner.

[0529] Topical formulations can contain one or more conventional carriers. In certain embodiments, ointments can contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white vaseline, etc. The carrier composition of creams can be based on water and glycerol and one or more other components (for example, glyceryl monostearate, PEG-glyceryl monostearate and hexadecearyl alcohol) combination. Isopropyl alcohol and water can be used, appropriately combined with other components (for example, glyceryl, hydroxyethyl cellulose, etc.) to prepare gels. In certain embodiments, topical formulations contain at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2 or at least about 5wt% of the compound of the present invention. Topical formulations can be suitably packaged in, for example, a 100g tube, which optionally carries instructions for treating selected indications (for example, psoriasis or other skin conditions).

[0530] The amount of the compound or composition administered to a patient will vary depending on the drug being administered, the purpose of the administration (e.g., prevention or treatment), the patient's state, the mode of administration, etc. In therapeutic applications, the composition may be administered to a patient already suffering from the disease in an amount sufficient to cure or at least partially inhibit the symptoms of the disease and its complications. The effective dose will depend on the disease condition being treated and will depend on factors such as the severity of the disease, the patient's age, weight, and general condition, etc., at the discretion of the attending clinician.

[0531] The composition administered to the patient can be in the form of the above-mentioned pharmaceutical composition. These compositions can be sterilized by conventional sterilization techniques, or can be aseptically filtered. The aqueous solution can be packaged for use as is, or lyophilized, and the lyophilized preparation is combined with a sterile aqueous carrier before administration. The pH of the compound preparation is generally between 3 and 11, more preferably 5 to 9, and most preferably 7 to 8. It should be understood that the use of some of the aforementioned excipients, carriers or stabilizers should result in the formation of pharmaceutically acceptable salts.

[0532] The therapeutic dose of the compound of the present invention can vary according to, for example, the specific use for treatment, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The ratio or concentration of the compound of the present invention in the pharmaceutical composition can vary depending on many factors (including dosage, chemical characteristics (e.g., hydrophobicity) and route of administration). For example, the compound of the present invention can be provided in an aqueous physiological buffer solution for parenteral administration, the solution containing about 0.1 to about 10% w / v of the compound. Some typical dosage ranges are from about 1 μg / kg body weight / day to about 1g / kg body weight / day. In some embodiments, the dosage range is from about 0.01mg / kg body weight / day to about 100mg / kg body weight / day. The dosage may depend on variables such as the type and degree of progression of the disease or condition, the overall health of the specific patient, the relative biological efficacy of the selected compound, the formulation of the excipient and its route of administration. The effective dose can be extrapolated from a dose-response curve derived from an in vitro or animal model test system.

[0533] IV. Labeled compounds and assay methods

[0534] The compounds of the present invention can be further used to study biological processes in normal and abnormal tissues. Therefore, another aspect of the present invention relates to the labeled compounds of the present invention (radiolabeled, fluorescently labeled, etc.), which can be used not only for imaging techniques, but also for positioning and quantifying TEAD transcription factors in tissue samples (including humans) in vitro and in vivo assays, and identifying TEAD transcription factor ligands by inhibiting the binding of labeled compounds. Therefore, the present invention includes assays containing such labeled compounds.

[0535] The present invention further encompasses isotopically labeled compounds of the present invention. An "isotopically labeled" or "radiolabeled" compound is a compound of the present invention in which one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated into the compounds of the present invention include, but are not limited to 3 H (tritium is also written as T), 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 18 F. 35 S. 36 Cl, 82 Br, 75 Br, 76 Br,77 Br, 123 I. 124 I. 125 I and 131 I. The radionuclide incorporated into the radiolabeled compounds of the invention will depend on the specific application of the radiolabeled compound. For example, for in vitro labeling and competition assays, incorporation of 3 H. 14 C. 82 Br, 125 I. 131 I. 35 Compounds containing S will generally be the most useful. For radiographic applications, 11 C. 18 F. 125 I. 123 I. 124 I. 131 I. 75 Br, 76 Br or 77 Br will usually be the most useful.

[0536] It is understood that a "radiolabeled" or "labeled compound" is a compound that has incorporated at least one radionuclide. In some embodiments, the radionuclide is selected from the group consisting of: 3 H. 14 C. 125 I. 35 S and 82 Br. In some embodiments, the compounds incorporate 1, 2, or 3 deuterium atoms. Synthetic methods for incorporating radioisotopes into organic compounds are known in the art.

[0537] Specifically, the labeled compounds of the present invention can be used for screening assays to identify and / or evaluate compounds. For example, a newly synthesized or identified labeled compound (i.e., a test compound) can be evaluated for its ability to bind to TEAD transcription factors by monitoring its concentration changes when in contact with TEAD transcription factors by means of a tracking label. For example, the ability of a test compound (labeled) to reduce the binding of another compound known to bind to a TEAD transcription factor (i.e., a standard compound) can be evaluated. Therefore, the ability of a test compound to compete with a standard compound for binding to TEAD transcription factors is directly related to its binding affinity. In contrast, in some other screening assays, the standard compound is labeled and the test compound is not labeled. Therefore, the concentration of the labeled standard compound is monitored to evaluate the competition between the standard compound and the test compound, thereby determining the relative binding affinity of the test compound.

[0538] V. Kit

[0539] The present disclosure also includes a drug kit that can be used, for example, to treat or prevent TEAD transcription factor-related diseases or conditions such as cancer, the drug kit comprising one or more containers containing a pharmaceutical composition, the pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or any embodiment thereof. Such a kit may further include one or more conventional drug kit components, such as a container with one or more pharmaceutically acceptable carriers, another container, etc., which is obvious to those skilled in the art. The kit may also include instructions (as an insert or as a label) indicating the amount of the component to be administered, instructions for administration, and / or instructions for mixing the components.

[0540] The present invention will be described in more detail by specific examples. The following examples are provided for illustrative purposes and are not intended to limit the present invention in any way. Those skilled in the art will readily recognize multiple non-critical parameters that can be changed or modified to produce substantially the same results.

[0541] Examples

[0542] Compound synthesis

[0543] experiment:

[0544] The MS (mass spectrometry) data provided in the examples were obtained using the following equipment: API 2000 LC / MS / MS / triple quadrupole; Agilent (1260 infinity) LCMS-SQD 6120 / single quadrupole and Shimadzu LCMS-2020 / single quadrupole.

[0545] The NMR data provided in the examples were obtained using the equipment 1 HNMR: 1 HNMR: Varian-400 MHz, JEOL-400 MHz.

[0546] Abbreviations used throughout the specification may be summarized below with their specific meanings.

[0547] ℃ (Celsius); δ (delta); % (percent); (BOC)2O (Boc anhydride); bs (broad singlet); CDCl3 (deuterated chloroform); DCM (dichloromethane); DMF (dimethylformamide); DIPEA (N,N-diisopropylethylamine); DMAP (dimethylaminopyridine); (DMSO-d6 (deuterated DMSO); d (doublet); dd (double doublet); Fe (iron powder); g or gm (gram) HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate); H or H2 (hydrogen); H2O (water); HCl (hydrochloric acid); h or hr (hour); Hz (hertz); HPLC (high performance liquid chromatography); J (coupling constant); LiOH (lithium hydroxide); MeOH (methanol); mmol (millimole); M (mole); mL (milliliter); mg (milligram); m (multiplet); mm (millimeter); MHz (megahertz); min (minute); NaH (sodium hydride); NaHCO3 (sodium bicarbonate); Na2SO4 (sodium sulfate); N2 (nitrogen); NMR (nuclear magnetic resonance spectroscopy); Pd / C (palladium on carbon); RT (room temperature); s (singlet); TEA (triethylamine); TFA (trifluoroacetic acid); TLC (thin layer chromatography) chromatography); THF (tetrahydrofuran); t (triplet); rac. BINAP ((±)-2,2'-bis(diphenylphosphine)-1,1'-binaphthyl); Pd2dba3 (tris(dibenzylideneacetone)dipalladium(0)); XPhos (2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl); invacuo (under vacuum); eq. (equivalent); ppt (precipitated); NA (not applicable).

[0548] The general procedure for the synthesis of certain exemplified compounds is shown in Scheme II below:

[0549]

[0550] Potassium carbonate (1.5mmol) was added to a solution of iodide (1mmol) and amine (1mmol) in 1,2-dichlorobenzene under a nitrogen atmosphere, followed by copper iodide (0.05mmol). The resulting mixture was stirred at room temperature for 1 hour, and then heated at 180 ° C for 2 days. After the reaction was completed, the resulting mixture was diluted with dichloromethane (50mL) and filtered through a diatomaceous earth bed. The organic solution was dried with MgSO4, concentrated under vacuum and purified by flash column chromatography using hexane / ethyl acetate (pure hexane to 20 / 1 hexane / ethyl acetate gradient) as eluent, in a yield of 40-69%.

[0551] Compound 2a was confirmed by proton NMR and mass spectrometry (ESI) as well as (Rf 0.3 with pure hexane as eluent, TLC).

[0552] For compound 2a, 1 H NMR (500 MHz, CDCl3): δ9.46 (s, 1H), 7.98-7.94 (m, 1H), 7.40 (s, 1H), 7.35 (m, 1H), 7.28 (d, 1H), 7.19-7.13 (m, 3H), 6.79 (m, 1H), 3.90 (s, 3H) ppm. Quality (M+H, 307.1), yield 56%.

[0553] Compounds 2b (M+H 306.1), 2c (M+H 375.1), 2d (M+H 325.1), 2e (M+H 443.1) were confirmed by mass spectrometry (LC-MS / ESI) and were also consistent with the retention factor (Rf of 0.3 with pure hexane as the eluent) on TLC.

[0554] The general procedure for the synthesis of the starting materials for compounds CP-59 and CP-65 is shown in Scheme 3 below:

[0555]

[0556] Required amine (1mmol) and chloronicotinate (1mmol) are dissolved in ethylene glycol, and then heated at 140 ℃ for 24 hours.After reaction is completed, gained mixture is diluted with ethyl acetate (50mL) and washed three times with 20mL water.With organic solution MgSO4 drying, under vacuum, concentrate and use hexane / ethyl acetate (pure hexane to the gradient of 15 / 1 hexane / ethyl acetate) as eluent through flash column chromatography purification.Yield is 55-59%.

[0557] Compounds 2f (M+H, 376.1) and 2g (M+H, 322.1) were confirmed by spectroscopy (ESI) and (Rf of 0.1 with pure hexane as eluent, TLC).

[0558] The cross-coupling procedure used to prepare several example compounds is shown in Scheme 4 below.

[0559]

[0560] In oven dried Schlenk tube, add amine (1mmol) and bromide (1mmol) and toluene (3mL).In above-mentioned homogeneous solution, add t-BuONa (1.5mmol).After stirring for 5 minutes, under nitrogen atmosphere, add Pd (dba) (0.05mmol) and Bu P (0.075mmol).Mixture was stirred for 24 hours at 110 ℃.After cooling to room temperature, reaction mixture was diluted with ethyl acetate (50mL) and filtered through diatomite bed.By organic solution MgSO Dry, concentrate under vacuum and use hexane / ethyl acetate (pure hexane to 10 / 1 hexane / ethyl acetate gradient) as eluent by flash column chromatography purification, to obtain desired product.Yield is 42-55%.

[0561] For compound 3a, 1 H NMR (500MHz, CDCl3): δ9.45(s,1H),8.01(s,1H),7.5-7.7.30(m,2H),7.2-7.1(m,2H),6. 98(s,1H),6.8(s,1H)6.78-6,26(m,4H),5.99(s,1H)3.90(s,3H),2.23-1.97(m,15H)ppm

[0562] For compound 3c, 1 H NMR (500MHz, CDCl3): δ9.45(s,1H),8.01(s,1H),7.45-7.23.(d,2H),7.23-7.01(m, 6H),6.98-7.01(d,2H),6.94(s,1H),3.93(s,3H),5.99(s,1H)2.21-1.98(m,15H)ppm

[0563] For compound 3d, 1 H NMR (500MHz, CDCl3): δ9.45(s,1H),8.01(s,1H),7.45-7.01(m,4H),6.94(s,1H) ,6.63(s,1H)6.65-6,20(m,4H),5.98(s,1H)3.92(s,3H),2.21-1.98(m,15H)ppm

[0564] The cross-coupling procedure used to prepare several example compounds is shown in Scheme 5 below.

[0565]

[0566] In oven dried Schlenk tube, add amine (1mmol) and bromide (1mmol) and toluene (3mL).In above-mentioned homogeneous solution, add t-BuONa (1.5mmol).After stirring for 5 minutes, under nitrogen atmosphere, add Pd (dba) (0.05mmol) and Bu P (0.075mmol).Mixture was stirred for 24 hours at 110 ℃.After cooling to room temperature, reaction mixture was diluted with ethyl acetate (50mL) and filtered through diatomite bed.By organic solution MgSO Dry, concentrate under vacuum and use hexane / ethyl acetate (pure hexane to 10 / 1 hexane / ethyl acetate gradient) as eluent by flash column chromatography purification, to obtain desired product.Yield is 50-54%.

[0567] For compound 3f, 1 H NMR (500MHz, CDCl3): δ9.45(s,1H),8.01(s,1H),7.49-7.33.(d,2H),7.23-7.01(m, 5H),6.91-7.04(d,2H),6.94(s,1H),3.93(s,3H),5.99(s,1H)2.21-1.98(m,15H)ppm

[0568] Compound 3g was confirmed by LC-MS / ESI (M+H 468.57).

[0569] The cross-coupling procedure used to prepare several example compounds is shown in Scheme 6 below.

[0570]

[0571] In oven dried Schlenk tube, add amine (1mmol) and bromide (1mmol) and toluene (3mL).In above-mentioned homogeneous solution, add t-BuONa (1.5mmol).After stirring for 5 minutes, under nitrogen atmosphere, add Pd (dba) (0.05mmol) and Bu P (0.075mmol).Mixture was stirred for 24 hours at 110 ℃.After cooling to room temperature, reaction mixture was diluted with ethyl acetate (50mL) and filtered through diatomite bed.With organic solution MgSO Dry, concentrate under vacuum and use hexane / ethyl acetate (pure hexane to 10 / 1 hexane / ethyl acetate gradient) as eluent by flash column chromatography purification, to obtain desired product (39-55% yield).

[0572] For compound 3b, 1H NMR (500MHz, CDCl3): δ9.45(s,1H),8.01(s,1H),7.67-7.56(d,2H),7.2-7.1(m,2H),6.9 8(s,1H),6.82(s,1H)6.78-6,26(m,2H),5.99(s,1H)3.92(s,3H),2.23-1.97(m,15H)ppm

[0573] For compound 3e, 1 H NMR (500MHz, CDCl3): δ9.46(s,1H),8.05(s,1H),7.79-7.56(m,4H),7.2-6.99(m,4H),6.98(s,1H,5.99(s,1H)3.94(s,3H),2.23-1.97(m,15H)ppm

[0574] The carboxylic acid compounds were prepared by hydrolysis reactions as shown in Schemes 7, 8, 9 and 10 and the experimental procedures described below.

[0575]

[0576] To the solution of ester (1mmol) in ethanol (10mL), add 2mmol of 2N NaOH solution and heat at 40 ℃ for 24-48 hours.After reaction is completed, reaction is cooled on ice and acidified with 2N hydrochloride solution and extracted three times with 10mL of ethyl acetate.By organic solution MgSO4 drying, concentrate under vacuum and use hexane / ethyl acetate (pure hexane to 5 / 1 hexane / ethyl acetate gradient) as eluent by flash column chromatography purification, to obtain desired product.Yield is 70-79%.

[0577] CP-52 was confirmed by LC-MS (ESI, M+H 439.1).

[0578] CP-57 was confirmed by LC-MS (ESIM+H 521.1).

[0579] CP-62 was confirmed by LC-MS (ESIM+H 457.1).

[0580]

[0581] To the solution of ester (1mmol) in ethanol (10mL), add 2mmol of 2N NaOH solution and heat at 40 ℃ for 24-48 hours.After reaction is completed, reaction is cooled on ice and acidified with 2N hydrochloride solution and extracted three times with 10mL of ethyl acetate.By organic solution MgSO4 drying, concentrate under vacuum and use hexane / ethyl acetate (pure hexane to 5 / 1 hexane / ethyl acetate gradient) as eluent by flash column chromatography purification, to obtain desired product.Yield is 80-83%.

[0582] CP-59 was confirmed by LC-MS (ESI, M+H 509.1).

[0583] CP-65 was confirmed by LC-MS (ESI, M+H 454.1).

[0584]

[0585] CP-55 was confirmed by LC-MS (ESI, M+H 439.12).

[0586] CP-64 was confirmed by LC-MS (ESI, M+H 474.1).

[0587]

[0588] To the solution of ester (1mmol) in ethanol (10mL), add 2mmol of 2N NaOH solution and heat at 40 ℃ for 24-48 hours.After reaction is completed, reaction is cooled on ice and acidified with 2N hydrochloride solution and extracted three times with 10mL of ethyl acetate.By organic solution MgSO4 drying, concentrate under vacuum and use hexane / ethyl acetate (pure hexane to 5 / 1 hexane / ethyl acetate gradient) as eluent by flash column chromatography purification, to obtain desired product.Yield is 73-87%.

[0589] CP-55 was confirmed by LC-MS (ESI, M+H 521.1).

[0590] CP-64 was confirmed by LC-MS (ESI, M+H 575.1).

[0591] As shown in Scheme 11 and the experimental procedure described below, the carboxylic acid compound is converted to the vinyl ketone compound.

[0592]

[0593] The acid was converted to Weinreb amide. To a solution of the acid (0.1 mmol) in dichloromethane (1 mL) was added triethylamine (0.25 mmol), followed by Weinreb amine salt (0.2 mmol), HATU (0.2 mmol) and stirred at room temperature for 16 hours. After the reaction was complete, water was added and extracted three times with 10 mL of ethyl acetate. The organic solution was dried over MgSO4, concentrated under vacuum and purified by flash column chromatography using hexane / ethyl acetate (gradient from pure hexane to 5 / 1 hexane / ethyl acetate) as eluent to obtain the desired product.

[0594] To an ice-cooled solution of Weinreb amide (1 mmol) in anhydrous THF (10 mL) was added 4 mL of a 1 M solution of vinyl magnesium bromide in THF and warmed to room temperature and stirred for 4 hours after the reaction was completed, quenched with a 1 N hydrochloric acid solution at 0°C, and extracted three times with 10 mL of ethyl acetate. The organic solution was dried over MgSO4, concentrated under vacuum and purified by flash column chromatography using hexane / ethyl acetate (gradient from pure hexane to 5 / 1 hexane / ethyl acetate) as the eluent to obtain the desired product. The yield was 42-57%.

[0595] CP-55 was confirmed by LC-MS (ESI, M+H 449.14).

[0596] CP-64 was confirmed by LC-MS (ESI, M+H 449.16).

[0597] Certain exemplary compounds can be synthesized and characterized as discussed below.

[0598] Intermediate-I

[0599]

[0600] Step-a: Synthesis of N-(4-((3r,5r,7r)-adamantan-1-yl)phenyl)acetamide (Ia)

[0601] To a solution of acetanilide (50g, 369mmol, 1.0eq.) in 1,1,2,2-tetrachloroethane (300mL) 1-bromoadamantane (87.5g, 406mmol, 1.1eq.) was added and stirred for 5 minutes. Anhydrous zinc chloride (25.1g, 184mmol, 0.5eq.) was added and stirred at 100°C for 36 hours. The reaction mixture was cooled to room temperature and excess tetrachloroethane was removed by concentration under vacuum. The residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, adsorbed by silica and purified by flash column chromatography to obtain the title product (58g, 58%) as a white solid.

[0602] 1 H NMR (400MHz, DMSO-d6) δ9.81 (s, 1H), 7.47 (d, J = 8.8Hz, 2H), 7.25 (d, J = 8.8Hz, 2H), 2.04 (bs, 2H), 2.00 (s, 3H), 1.82 (s, 6H), 1.72 (s, 6H); LC-MS: m / z 270.1(M+H) +

[0603] The following intermediates were prepared by similar procedures to Intermediate-Ia using appropriate reactants and reagents in the presence of a suitable solvent and appropriate reaction conditions.

[0604]

[0605] Step-b: Synthesis of N-(4-((3r,5r,7r)-adamantan-1-yl)-2-chlorophenyl)acetamide (Ib)

[0606] To a solution of N-(4-((3r,5r,7r)-adamantan-1-yl)phenyl)acetamide (25 g, 92.8 mmol, 1.0 eq.) in DMF (500 mL) was added N-chlorosuccinimide (13.6 g, 101 mmol, 1.1 eq.) at 0 ° C. The reaction mixture was allowed to reach room temperature and stirred for 16 hours. Excess DMF was removed by concentrating under vacuum. The residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude solid (22 g, 78%) obtained was used in the next step without further purification.

[0607] 1 H NMR (400MHz, DMSO-d6) δ9.42(s,1H),7.58(d,J=8.3Hz,1H),7.37(d,J=2.5Hz,1H),7. 29(dd, J1=2.85Hz, J2=8.8Hz, 1H), 2.06(bs, 6H), 1.75(s, 6H), 1.69(s, 6H); LC-MS: m / z 304.10(M+H) +

[0608] The following intermediates were prepared by similar procedures to Intermediate-Ib using appropriate reactants and reagents in the presence of a suitable solvent and appropriate reaction conditions.

[0609]

[0610] Step-c: Synthesis of 4-((3r,5r,7r)-adamantan-1-yl)-2-chloroaniline (Intermediate-I)

[0611] To a solution of N-(4-((3r,5r,7r)-adamantan-1-yl)-2-chlorophenyl)acetamide (17 g, 56 mmol, 1.0 eq.) in methanol (150 mL) was added concentrated HCl (150 mL) and refluxed at 100 ° C for 8 hours. Excess methanol was removed under vacuum. The obtained white precipitate was filtered out. The filtered solid was washed with sodium bicarbonate solution and water in turn and dried under vacuum. The desired product (13 g, 88%) was obtained as a white solid.

[0612] 1 H NMR (400MHz, DMSO-d6) δ7.08 (d, J=2.4Hz, 1H), 7.02 (dd, J1=1.9Hz, J2=8.3Hz, 1H), 6. 73(d,J=8.3Hz,1H),5.09(bs,2H),2.01(s,3H),1.76(s,6H),1.66(s,6H); LC-MS:m / z 262.2(M+H) +

[0613] The following intermediates were prepared by similar procedures to Intermediate-I using appropriate reactants and reagents in the presence of a suitable solvent and appropriate reaction conditions.

[0614]

[0615]

[0616] The following intermediates were prepared by procedures analogous to those described in the literature using appropriate reactants and reagents in the presence of a suitable solvent and appropriate reaction conditions.

[0617]

[0618]

[0619]

[0620]

[0621]

[0622]

[0623] Intermediate-II:

[0624]

[0625] Step-a: Synthesis of methyl 2-((4-bromophenyl)amino)benzoate (Intermediate-II)

[0626] To a solution of methyl 2-iodobenzoate (30 g, 114.5 mmol, 1.0 eq.) and 4-bromoaniline (19.3 g, 114.5 mmol, 1.0 eq.) in toluene (500 mL) was added cesium carbonate (49 g, 150 mmol, 1.3 eq.) and degassed with N2 gas for 15 minutes. Palladium acetate (1.28 g, 5.7 mmol, 0.05 eq.) and rac.BINAP (3.56 g, 5.7 mmol, 0.05 eq.) were added and degassed for 5 minutes. The reaction mass was heated at 110 ° C for 16 hours. The reaction mass was filtered through celite, concentrated under vacuum and purified by combi-flash to obtain the title product (33 g, 94%) as a light brown liquid.

[0627] 1 H NMR (400MHz, DMSO-d6) δ9.25(s,1H),7.89(dd,J1=2.0Hz,J2=8.3Hz,1H),7.51(d,J=2.9Hz,2H),7.48(t,J =1.9Hz, 1H), 7.26 (d, J = 7.8Hz, 1H), 7.21 (d, J = 4.9Hz, 2H), 6.87 (t, J = 1.0Hz, 1H), 3.84 (s, 3H); LC-MS: m / z 307.9(M+H) 2+

[0628] The following intermediates were prepared by similar procedures as Intermediate-II using appropriate reactants and reagents, employing suitable Pd and Fe catalysts and ligands in the presence of suitable solvents and suitable reaction conditions.

[0629]

[0630]

[0631]

[0632]

[0633] Intermediate-II.28:

[0634]

[0635] Step-a: Synthesis of methyl 2-((5-bromopyrimidin-2-yl)(tert-butoxycarbonyl)amino)benzoate (II.28)

[0636] To a solution of Intermediate-II.3 (1.3 g, 4.3 mmol, 1 eq.) in THF (30 mL) was added DMAP (0.1 g, 0.84 mmol, 0.2 eq.), pyridine (0.67 g, 8.7 mmol, 2 eq.), Boc anhydride (1.38 g, 6.3 mmol, 1.5 eq.) and heated at 60 °C overnight. The reaction mass was concentrated under vacuum and purified by combi-flash to give the title product (1.4 g, 82%) as an off-white solid. LC-MS: m / z 408.2 (M+H) +

[0637] The following intermediates were prepared by similar procedures to Intermediate-II.28 using appropriate reactants and reagents and in the presence of a suitable solvent and appropriate reaction conditions.

[0638]

[0639] The following intermediates were prepared by a procedure similar to that of Intermediate-II using appropriate reactants and reagents, employing suitable Pd catalyst and ligand in the presence of a suitable solvent and appropriate reaction conditions.

[0640]

[0641] Intermediates-IIIa and IIIb:

[0642]

[0643] Step-a: ethyl 2-(5-bromo-1H-indazol-1-yl)acetate and ethyl 2-(5-bromo-2H-indazol-2-yl)acetate Synthesis of (IIIa and IIIb)

[0644] To a solution of 5-bromo-1H-indazole (1 g, 5.1 mmol, 1.0 eq.) in acetonitrile (25 mL) was added potassium carbonate (1.8 g, 12.8 mmol, 2.5 eq.) under stirring. Ethyl bromoacetate (0.7 mL, 6.1 mmol, 1.2 eq.) was added dropwise and the reaction mass was heated to reflux overnight. The reaction mass was concentrated under vacuum, adsorbed by silica after water washing and purified by combi-flash to obtain the title products IIIa (400 mg, 28%, white solid) and IIIb (180 mg, 13%, yellow solid).

[0645] Intermediate-IIIa: 1H NMR(400MHz,DMSO-d6)δ8.10(s,1H),8.05(s,1H),7.68-7.65(m,1H),7.53-7.51(m ,1H),5.40(s,2H),4.18-4.12(m,2H),1.19(t,J=6.8Hz,3H); LC-MS:m / z283.0(M+H) +

[0646] Intermediate-IIIb: 1 H NMR(400MHz,DMSO-d6)δ8.41(s,1H),8.02(s,1H),7.60-7.58(m,1H),7.35-7.32(m ,1H),5.42(s,2H),4.20-4.15(m,2H),1.18(t,J=6.4Hz,3H); LC-MS:m / z283.0(M+H) +

[0647] The following intermediates were prepared by similar procedures to Intermediate-IIIa and IIIb using appropriate reactants and reagents and in the presence of a suitable solvent and appropriate reaction conditions.

[0648]

[0649]

[0650]

[0651] Intermediate-IV:

[0652]

[0653] Step-a: Synthesis of methyl 2-(4-bromobenzamido)benzoate (Intermediate-IV)

[0654] To a solution of 2-aminobenzoic acid methyl ester (5g, 33.1mmol, 1.0eq.) in DCM (50mL), triethylamine (11g, 108mmol, 3eq.) was added, followed by addition of 4-bromobenzoyl chloride (7.2g, 33.1mmol, 1.0eq.) and stirred at room temperature overnight. The reaction mixture was extracted from water with ethyl acetate and concentrated under vacuum. The crude product was washed with n-pentane and dried to obtain the title product (9g, 85%).

[0655] 1H NMR (400MHz, DMSO-d6) δ11.52(s,1H),8.47(d,J=8.3Hz,1H),8.04(d,J=8.4Hz,1H),7.89(d,J =8.8Hz,2H),7.83(d,J=8.8Hz,2H),7.67(t,J=7.3Hz,1H),7.24(t,J=7.3Hz,1H),3.87(s,3H).

[0656] The following intermediates were prepared by similar procedures to Intermediate-IV using appropriate reactants and reagents and in the presence of a suitable solvent and appropriate reaction conditions.

[0657]

[0658] Intermediate-V:

[0659]

[0660] Step-a: Synthesis of methyl 2-((4-bromophenyl)(methyl)amino)nicotinate (Intermediate-V):

[0661] To a solution of intermediate-II.10 (0.4 g, 1.3 mmol, 1.0 eq.) in DMF (3 mL) was added sodium hydride (50%, 0.16 g, 3.9 mmol, 3 eq.) and stirred for 10 minutes. Iodomethane (0.25 mL, 3.9 mmol, 3 eq.) was added dropwise and stirred overnight at room temperature in a sealed tube. The reaction mass was poured into water, extracted with ethyl acetate and concentrated under vacuum. The crude was purified by combi-flash to give the title product (0.21 g, 50%) as a colorless liquid.

[0662] 1 H NMR (400MHz, DMSO-d6) δ8.46 (dd, J1=2.0Hz, J2=4.0Hz, 1H), 7.85 (dd, J1=2.0Hz, J2=7.6Hz, 1H), 7.44-7 .40(m,2H),7.05(dd,J1=3.6Hz,J2=7.2Hz,1H),6.94-6.90(m,2H),3.44(s,3H),3.29(s,3H); LC-MS:m / z 321.0(M+H) +

[0663] The following intermediates were prepared by similar procedures to Intermediate-V using appropriate reactants and reagents and in the presence of a suitable solvent and appropriate reaction conditions.

[0664]

[0665]

[0666] Intermediate-VI:

[0667]

[0668] Step-a: Methyl 2-((4-((4-((3R,5R)-adamantan-1-yl)phenyl)amino)phenyl)amino)benzoate Synthesis of (Intermediate-VI):

[0669] A solution of intermediate-II (0.5 g, 1.63 mmol, 1.0 eq.) and intermediate-I.1 (0.37 g, 1.63 mmol, 1.0 eq.) in toluene (10 mL) was degassed with N2 gas for 15 minutes. Pd2dba3 (0.12 g, 0.13 mmol, 0.08 eq.) and XPhos (0.16 g, 0.326 mmol, 0.2 eq.) were added and degassed for 5 minutes. The reaction mass was heated at 110 ° C for 16 hours. The reaction mass was filtered through Celite, concentrated under vacuum and purified by combi-flash to obtain the title product (0.26 g, 35%) as a light yellow solid.

[0670] 1 H NMR (400MHz, DMSO-d6) δ9.14(s,1H),8.02(s,1H),7.86(dd,J1=1.4Hz,J2=7.8Hz,1H),7.35(t,J=1.4Hz,1H),7.21(d,J =8.8Hz,2H),7.12-6.96(m,7H),6.69(t,J=6.8Hz,1H),3.85(s,3H),2.04(s,3H),1.83(s,6H),1.72(s,6H); LC-MS: m / z 452.4(M+H) +

[0671] The following intermediates were prepared by similar procedures to Intermediate-VI using appropriate reactants and reagents, employing suitable Pd catalyst and ligand in the presence of suitable solvent and appropriate reaction conditions.

[0672]

[0673]

[0674]

[0675]

[0676]

[0677]

[0678]

[0679]

[0680]

[0681]

[0682]

[0683]

[0684]

[0685]

[0686]

[0687]

[0688]

[0689] Intermediate-VII:

[0690]

[0691] Step-d: 4-((3R,5R)-adamantan-1-yl)-2-chloro-N-(4-nitrophenyl)aniline (Intermediate-VII) synthesis

[0692] The solution of intermediate-I (8.5g, 32.5mmol, 1eq.) and 4-bromonitrobenzene (6.57g, 32.5mmol, 1eq.) in toluene (100mL) was degassed by bubbling nitrogen for 5 minutes. Cesium carbonate (16g, 48.9mmol, 1.5eq.) was added, followed by palladium acetate (0.72g, 3.25mmol, 0.1eq.) and XPhos (2.32g, 4.88mmol, 0.15eq.) and degassed again for 5 minutes. The reaction mixture was heated at 110 ° C for 16 hours under stirring. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and filtered through Celite diatomaceous earth. The organic layer was adsorbed by silica and purified by flash column chromatography. The desired product was eluted in hexane containing 5% to 10% ethyl acetate. Concentrated under vacuum to obtain a dark yellow oil (7g, 57%).

[0693] 1H NMR(400MHz,DMSO-d6)δ8.98(s,1H),8.09-8.07(m,2H),7.44(s,1H),7.38( s,2H),6.83-6.79(m,2H),2.06(s,3H),1.88(s,6H),1.74(s,6H); LC-MS:m / z 383.2(M+H) +

[0694] The following intermediates were prepared by a procedure similar to Intermediate-VII using appropriate reactants and reagents, employing suitable Pd catalyst and ligand in the presence of a suitable solvent and appropriate reaction conditions.

[0695]

[0696]

[0697]

[0698]

[0699]

[0700]

[0701]

[0702]

[0703]

[0704]

[0705] The following intermediates were prepared by similar procedures to Intermediate-V using appropriate reactants and reagents, employing suitable Pd catalyst and ligand in the presence of suitable solvent and suitable reaction conditions.

[0706]

[0707]

[0708]

[0709]

[0710]

[0711]

[0712]

[0713]

[0714] Intermediate-VIII:

[0715]

[0716] Step-a: N-(4-((3R,5R)-adamantan-1-yl)phenyl)-3-nitrobenzamide (Intermediate-VIII) synthesis

[0717] The title compound (1.6 g, 96%) was synthesized from Intermediate-I.1 (1 g, 4.4 mmol, 1 eq.) and 3-nitrobenzoyl chloride (0.82 g, 4.4 mmol, 1 eq.) using a procedure similar to Intermediate-IV. LC-MS: m / z 377.2 (M+H) +

[0718] The following intermediates were prepared by similar procedures to Intermediate-VIII using appropriate reactants and reagents and in the presence of a suitable solvent and appropriate reaction conditions.

[0719]

[0720]

[0721] Intermediate-IX:

[0722]

[0723] Step-a: Synthesis of (3R,5R)-1-(3-chloro-4-(4-nitrophenoxy)phenyl)adamantane (Intermediate-IX)

[0724] To a solution of 4-fluoronitrobenzene (0.6 mL, 5.7 mmol) and Intermediate-I.25 (1.5 g, 6.84 mmol, 1.2 eq.) in DMSO (10 mL) was added potassium carbonate (1.57 g, 11.4 mmol, 2 eq.) and stirred at room temperature overnight. The reaction mass was poured into cold water and the solid obtained was filtered and dried to afford the title compound (2 g, 91%) as an off-white solid.

[0725] 1 H NMR (400MHz, DMSO-d6) δ8.26(d,J=9.3Hz,2H),7.58(s,1H),7.47(d,J=2.0Hz,1H),7.32( d,J=8.8Hz,1H),7.1(d,J=8.3Hz,2H),2.07(bs,2H),1.89(s,6H),1.7(s,6H).LC-MS:m / z 382.0(MH) -

[0726] The following intermediates were prepared by similar procedures to Intermediate-IX using appropriate reactants and reagents and in the presence of a suitable solvent and appropriate reaction conditions.

[0727]

[0728]

[0729]

[0730] Intermediate-X:

[0731]

[0732] Step-a: Synthesis of (3r,5r,7r)-1-(3-chloro-4-methylphenyl)adamantane (Xa)

[0733] N-Chlorosuccinimide was added in batches to a solution of (3r, 5r, 7r)-1-(p-tolyl)adamantane (2 g, 8.8 mmol) in acetic acid over a period of 30 minutes. The reaction mass was heated at 75 °C overnight. The reaction mass was poured into cold water, and the obtained solid was filtered out and dried under vacuum. The title compound (2.2 g, 96%) was obtained as a white solid. 1 H NMR (400MHz, DMSO-d6) δ7.31(d,J=1.9Hz,1H),7.26-7.22(m,2H),2.27(s,3H),2.04(s,3H),1.83(s,6H),1.72(s,6H).

[0734] Step-b: Synthesis of (3r,5r,7r)-1-(4-(bromomethyl)-3-chlorophenyl)adamantane (Xb)

[0735] To a solution of compound Xa (1 g, 3.8 mmol) in carbon tetrachloride (40 mL) was added bromine (0.61 g, 3.8 mmol) and benzoyl peroxide (catalytic) dropwise. The reaction mass was heated to reflux overnight. Concentrated under vacuum, and the crude was purified by column chromatography to give the title product (0.5 g, 38%) as an off-white solid. 1 H NMR (400MHz, DMSO-d6) δ7.38(d,J=8.0Hz,2H),7.24(m,1H),4.58(s,2H),2.10(s,3H),1.81(s,6H),1.72(s,6H).

[0736] Step-c: 1-(4-((3R,5R)-adamantan-1-yl)-2-chlorobenzyl)-4-nitro-1H-pyrazole (Intermediate-X) Synthesis

[0737] This intermediate was prepared according to the similar procedure described for Intermediate-III by using Intermediate-Xb (0.3 g, 0.88 mmol, 1 eq.) and 4-nitropyrazole (0.12 g, 1.06 mmol, 1.2 eq.) to afford the title product as an off-white solid (0.3 g, 91%). 1 H NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.28(s,1H),7.41(d,J=2.0Hz,1H),7.35(dd,J1=1.9Hz ,J2=8.3Hz,1H),7.21(d,J=8.3Hz,1H),5.47(s,2H),2.04(s,3H),1.83(s,6H),1.72(s,6H).

[0738] The following intermediates were prepared by similar procedures to Intermediate-X using appropriate reactants and reagents and in the presence of a suitable solvent and appropriate reaction conditions.

[0739]

[0740]

[0741] Intermediate-XI:

[0742]

[0743] Step-a: Preparation of N1-(4-((3R,5R)-adamantan-1-yl)-2-chlorophenyl)benzene-1,4-diamine (Intermediate-XI) synthesis

[0744] To the solution of intermediate-VII (7g, 18.3mmol, 1eq.) in THF:water (50mL+50mL), ammonium chloride (19.42g, 36.6mmol, 20eq.) was added, and then zinc powder (11.91g, 183mmol, 10eq.) was added and stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and filtered through Celite diatomite. The filtrate was washed with water and brine successively. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude was washed with n-pentane and dried under vacuum to obtain the desired product (5.9g, 91%) in yellow gum. It was used for the next step without further purification.

[0745] 1H NMR (400MHz, DMSO-d6) δ7.20 (d, J=1.9Hz, 1H) 7.04 (dd, J1=2.0Hz, J2=8.3Hz, 1H), 6.84 (d, J=8.8Hz, 2H), 6.78 (s, 1H), 6.72 (d, J=8.8Hz, 1H), 6.54 (d, J=8.8Hz, 2H), 4.85 (s, 2H), 2.02 (s, 3H), 1.78 (s, 6H), 1.70 (s, 6H); LC-MS: m / z 353.1(M+H) +

[0746] The following intermediates were prepared by similar procedures to Intermediate-XI using appropriate reactants and reagents and in the presence of a suitable solvent and appropriate reaction conditions.

[0747]

[0748]

[0749]

[0750]

[0751]

[0752]

[0753]

[0754]

[0755]

[0756]

[0757]

[0758]

[0759]

[0760] Intermediate-XII:

[0761]

[0762] Step-a: 2-((4-((4-((3r,5r,7r)-adamantan-1-yl)-2-chlorophenyl)amino)phenyl)amino)nicotinic acid Synthesis of methyl ester (Intermediate-XII)

[0763] The solution of intermediate-XI (8g, 22.72mmol, 1eq.) and 2-chloronicotinate methyl ester (4.27g, 25mmol, 1.1eq.) in toluene (100mL) was degassed by bubbling nitrogen for 5 minutes. Cesium carbonate (11.1g, 34.1mmol, 1.5eq.) was added, followed by palladium acetate (0.5g, 2.27mmol, 0.1eq.) and rac.BINAP (2.12g, 3.41mmol, 0.15eq.) and degassed again for 5 minutes. The reaction mixture was heated at 110°C for 16 hours under stirring. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and filtered through Celite diatomaceous earth. The organic layer was adsorbed by silica and purified by flash column chromatography. The desired product was eluted in hexane containing 10% ethyl acetate. Concentrated under vacuum to obtain a yellow solid (5.4g, 49%).

[0764] 1 H NMR (400MHz, DMSO-d6) δ9.93(s,1H),8.37(dd,J1=2.0Hz,J2=4.4Hz,1H),8.22(dd,J1=2.0Hz,J2=7.6Hz,1H),7.55(d,J=8.8Hz,2H),7.41(s,1H),7 .31(d,J=1.6Hz,1H),7.19-7.12(m,2H),7.04(d,J=8.8Hz,2H),6.84-6.8 1(m,1H),3.89(s,3H),2.04(s,3H),1.83(s,6H),1.72(s,6H); LC-MS:m / z 488.1(M+H) +

[0765] The following intermediates were prepared by similar procedures to Intermediate-XII using appropriate reactants and reagents, employing suitable Pd catalyst and ligand in the presence of suitable solvent and suitable reaction conditions.

[0766]

[0767]

[0768]

[0769]

[0770]

[0771]

[0772]

[0773]

[0774]

[0775]

[0776]

[0777]

[0778]

[0779]

[0780]

[0781]

[0782]

[0783]

[0784]

[0785]

[0786]

[0787]

[0788]

[0789]

[0790]

[0791]

[0792]

[0793]

[0794]

[0795]

[0796] Intermediate-XIII:

[0797]

[0798] Step-a: Synthesis of methyl 2-((1,4-dioxaspiro[4.5]decane-8-yl)amino)benzoate (XIIIa)

[0799] To a solution of methyl anthranilate (3 g, 20 mmol, 1 eq.) and 1,4-cyclohexanedione monoacetal (4.6 g, 30 mmol, 1.5 eq.) in dichloroethane (50 mL) was added acetic acid (20 mL) and stirred at room temperature for 2 hours. The reaction mass was cooled to 0 ° C and sodium triacetoxyborohydride (6.3 g, 30 mmol, 1.5 eq.) was added and stirred at room temperature for 36 hours. Saturated bicarbonate solution was added to the reaction mass and extracted with dichloromethane, and purified by combi-flash to obtain the title product (1.01 g, 17%).

[0800] 1 H NMR (400MHz, DMSO-d6) δ7.77(d,J=7.6Hz,1H),7.71(d,J=7.6Hz,1H),7.39-7.35(m,1H),6.83(d,J=8.8Hz,1H),6.57-6.53(m,1H ),3.87(s,4H),3.78(s,3H),3.60-3.58(m,1H),1.95-1.90(m,2H),1.70-1.61(m,4H),1.60-1.48(m,2H); LC-MS: m / z292.0(M+H) +

[0801] Step-b: Synthesis of methyl 2-((4-oxocyclohexyl)amino)benzoate (XIIIb)

[0802] To a solution of compound XIIIa (1.01 g, 3.4 mmol, 1 eq.) in acetone (30 mL) was added 2N HCl (10 mL) and stirred at room temperature overnight. The reaction mass was extracted from water with ethyl acetate and concentrated under vacuum. The crude product was used without further purification.

[0803] 1 H NMR (400MHz, DMSO-d6) δ7.81 (dd, J1=0.8Hz, J2=7.6Hz, 1H), 7.75 (d, J=7.6Hz, 1H), 6.94 (d, J=8.8Hz, 1H), 6.59 (t, J=7.6Hz,1H),3.97-3.95(m,1H),3.79(s,3H),2.57-2.53(m,2H),2.29-2.19(m,4H),1.77-1.72(m,2H); LC-MS: m / z 248.2(M+H) +

[0804] Step-c: 2-((4-((4-((3r,5r,7r)-adamantan-1-yl)-2-chlorophenyl)amino)cyclohexyl)amino) Synthesis of Methyl Benzoate (Intermediate-XIII)

[0805] To a solution of compound XIIIb (0.5 g, 2.02 mmol, 1 eq.) and intermediate-I (0.53 g, 2.02 mmol, 1 eq.) in acetic acid (10 mL) was added sodium triacetoxyborohydride (1.28 g, 6.06 mmol, 3 eq.) and heated at 80 ° C for 16 hours. The reaction mass was extracted with ethyl acetate from saturated bicarbonate and brine and concentrated under vacuum. The crude was purified by combi-flash to give the title compound (0.67 g, 67%) as a light pink liquid. LC-MS: m / z 493.3 (M+H) +

[0806] The following intermediates were prepared by similar procedures to Intermediate-XIII using appropriate reactants and reagents and in the presence of a suitable solvent and appropriate reaction conditions.

[0807]

[0808]

[0809]

[0810] Intermediate-XIV:

[0811]

[0812] Step-a: Synthesis of 4-((2-(methoxycarbonyl)phenyl)amino)benzoic acid (Intermediate-XIV)

[0813] A solution of intermediate-II.20 (3 g, 9.1 mmol, 1 eq.) in DCM (30 mL) was cooled in ice for 10 minutes. TFA (3 mL) was added dropwise and stirred at room temperature for 16 hours. The reaction mass was concentrated under vacuum. The crude was ground with n-pentane and dried under vacuum to give the title product (2.0 g, 80%) as a light green solid.

[0814] 1 H NMR (400MHz, DMSO-d6) δ12.58(s,1H),9.40(s,1H),7.93(dd,J1=1.6Hz,J2=8.0Hz,1H),7.87(dd,J1=2.0 Hz,J2=6.8Hz,2H),7.52-7.46(m,2H),7.26(d,J=8.8Hz,2H),7.01-6.97(m,1H),3.84(s,3H); LC-MS:m / z 272.1(M+H) +

[0815] Alternative or general procedure for the synthesis of corresponding carboxylic acid compounds with methyl and ethyl esters:

[0816] To a solution of the ester (1 mmol) in THF:MeOH:H2O (4+4+2 mL) was added LiOH.H2O (5 mmol) and stirred at room temperature for 16 hours. The reaction mass was concentrated under vacuum, diluted with water and acidified to pH 5 with 2N HCl. The obtained precipitate was filtered and dried under vacuum. The solid was washed with a mixture of hexane containing 10% ether and dried to give the desired acid.

[0817] The following intermediates were prepared by similar procedures to Intermediate-XIV using appropriate reactants and reagents and in the presence of a suitable solvent and appropriate reaction conditions.

[0818]

[0819]

[0820]

[0821]

[0822] Intermediate-XV:

[0823]

[0824] Step-a: 2-((4-((4-((3R,5S)-adamantan-1-yl)phenyl)carbamoyl)phenyl)amino)benzyl Synthesis of methyl ester (Intermediate-XV)

[0825] A solution of compound-XIV (0.2 g, 0.74 mmol, 1 eq.) and intermediate-I.1 (0.185 g, 0.81 mmol, 1.1 eq.) was cooled in ice. HATU (0.34 g, 0.89 mmol, 1.2 eq.) was added followed by DIPEA (0.39 mL, 2.22 mmol, 3 eq.) and stirred at room temperature for 16 hours. The reaction mass was slowly added to ice water under stirring. The obtained precipitate was filtered, washed twice with cold water, then washed twice with n-pentane, and dried under vacuum to give the title compound (0.35 g, 98%) as a cream solid.

[0826] 1H NMR (400MHz, DMSO-d6) δ10.01(s,1H),9.43(s,1H),7.96-7.91(m,3H),7.69(d,J=8.4Hz,2H),7.54-7.49(m,1H),7.45(d ,J=8.0Hz,1H),7.34-7.31(m,4H),6.95(t,J=6.8Hz,1H),3.86(s,3H),2.06(s,3H),1.87(s,6H),1.74(s,6H); LC-MS: m / z 481.1(M+H) +

[0827] The following intermediates were prepared by similar procedures to Intermediate-XV using appropriate reactants and reagents and in the presence of a suitable solvent and appropriate reaction conditions.

[0828]

[0829]

[0830]

[0831]

[0832]

[0833]

[0834]

[0835]

[0836]

[0837]

[0838]

[0839] Intermediate-XVI:

[0840]

[0841] Step-a: N-(4-(N-(4-((3r,5r,7r)-adamantan-1-yl)phenyl)sulfamoyl)phenyl)acetamide Synthesis of (Intermediate-XVI)

[0842] A solution of Intermediate-I.1 (0.5 g, 2.2 mmol) in dichloromethane (10 mL) was cooled to 0 °C and triethylamine (0.66 g, 6.6 mmol, 3 eq.) was added followed by 4-acetamidobenzenesulfonyl chloride (0.51 g, 2.2 mmol) and stirred at room temperature for 3 hours. The reaction mass was concentrated under vacuum and cold water was added. The obtained solid was filtered and dried under vacuum to give the title product (0.88 g, 94%). LC-MS: m / z 425.1 (M+H) +

[0843] The following intermediates were prepared by similar procedures to Intermediate-XVI using appropriate reactants and reagents and in the presence of a suitable solvent and appropriate reaction conditions.

[0844]

[0845]

[0846] Intermediate-XVII:

[0847]

[0848] Step-a: N-(4-((3r,5r,7r)-adamantan-1-yl)phenyl)-4-aminobenzenesulfonamide (Intermediate-XVII) Synthesis

[0849] This compound was prepared from Intermediate-XVI (0.85 g, 2 mmol, 1 eq.) by a procedure similar to that described for Intermediate-I from Ib to afford the title product (0.75 g, 98%) as a white solid.

[0850] 1 H NMR (400MHz, DMSO-d6) δ9.73 (s, 1H), 7.38 (d, J = 8.8Hz, 2H), 7.17 (d, J = 8.8Hz, 2H), 6.98 (d, J = 8. 8Hz, 2H), 6.52 (d, J = 8.8Hz, 2H), 5.93 (s, 2H), 2.01 (s, 3H), 1.77 (s, 6H), 1.69 (s, 6H); LC-MS: m / z 383.0(M+H) +

[0851] The following intermediates were prepared by similar procedures to Intermediate-XVII using appropriate reactants and reagents and in the presence of a suitable solvent and appropriate reaction conditions.

[0852]

[0853] Intermediate-XVIII:

[0854]

[0855] Step-a: 2-((4-(N-(4-((3R,5R)-adamantan-1-yl)phenyl)sulfamoyl)phenyl)amino)benzyl Synthesis of methyl ester of 1-(2-hydroxy-1-oxo-2-yl)-1-nitroprop

[0856] Intermediate-XVIII was prepared from Intermediate-XVII and methyl 2-bromobenzoate by a procedure similar to that described in Intermediate-II.

[0857] 1 H NMR (400MHz, DMSO-d6) δ10.01(s,1H),9.31(s,1H),7.89(d,J=8.4Hz,1H),7.63(d,J=8.4Hz,2H),7.50(t,J=7.6Hz,1H),7. 42(d,J=8.0Hz,1H),7.24-7.19(m,4H),7.03-6.99(m,3H),3.77(s,3H),2.00(s,3H),1.76(s,6H),1.69(s,6H); LC-MS: m / z 517.1(M+H) +

[0858] The following intermediates were prepared by similar procedures to Intermediate-XVIII using appropriate reactants and reagents, employing suitable Pd catalyst and ligand in the presence of suitable solvent and suitable reaction conditions.

[0859]

[0860]

[0861] Intermediate-XIX:

[0862]

[0863] Step-a: Synthesis of phenyl (4-((3r,5r,7r)-adamantan-1-yl)phenyl)carbamate (XIXa)

[0864] To a solution of Intermediate-I.1 (0.5 g, 2.2 mmol, 1 eq.) and phenyl chloroformate (0.42 g, 2.64 mmol, 1.2 eq.) in DCM was added triethylamine (0.44 g, 4.4 mmol, 2 eq.) and stirred at room temperature for 2 hours. The reaction mixture was washed with water, concentrated under vacuum and purified by combi-flash to give the title compound (0.48 g, 63%) as a white solid.

[0865] 1H NMR (400MHz, DMSO-d6) δ10.10(s,1H),7.44-7.39(m,4H),7.31-7.19(m,5H),2.05(s,3H),1.84(s,6H),1.73(s,6H); LC-MS: m / z 348.1(M+H) +

[0866] Step-b: 2-((4-(3-(4-((3R,5R)-adamantan-1-yl)phenyl)ureido)phenyl)amino)nicotinate Synthesis of (Intermediate-XIX)

[0867] Intermediate-XIXa (0.285 g, 0.82 mmol, 1 eq.) and 2-((4-aminophenyl)amino)nicotinic acid methyl ester (0.2 g, 0.82 mmol, 1 eq.) were added to THF (20 mL) and triethylamine (0.8 mL) was added and refluxed overnight. The reaction mass was concentrated under vacuum, and the obtained crude product was washed twice with n-hexane and dried under vacuum. The crude product was further utilized without purification.

[0868] 1 H NMR(400MHz, DMSO-d6)δ9.96(s,1H),8.52(d,J=14.0Hz,2H),8.38-8.37(m,1H),7.76(d,J=8.4Hz,2H),7.41-7.35(m,4H),7.25( d, J=8.4Hz, 2H), 6.84 (dd, J1=4.4Hz, J2=8.0Hz, 1H), 3.87 (s, 3H), 2.05 (s, 3H), 1.84 (s, 6H), 1.73 (s, 6H); LC-MS: m / z497.2 (M+H) +

[0869] The following intermediates were prepared by similar procedures to Intermediate-XIX using appropriate reactants and reagents and in the presence of a suitable solvent and appropriate reaction conditions.

[0870]

[0871]

[0872] Intermediate-XIX.4:

[0873]

[0874] Step-a: ((4-((4-((3R,5S)-adamantan-1-yl)-2-chlorophenyl)amino)phenyl)carbamoyl)proline Synthesis of amino acid methyl ester (XIX.4)

[0875] To a solution of Intermediate-XI (0.1 g, 0.283 mmol, 1 eq.) in DCM (10 mL) was added triphosgene (0.084 g, 0.283 mmol, 1 eq.) dropwise at 0°C and stirred for 1 hour at 0°C. This solution was added to a solution of proline methyl ester (0.056 g, 0.32 mmol, 1.2 eq.) in DCM (10 mL) and stirred for 1 hour at 0°C. It was quenched with saturated bicarbonate solution and extracted with DCM, purified by column chromatography to give the title product (0.13 g, 90%) as a light brown solid.

[0876] 1 H NMR (400MHz, DMSO-d6) δ8.18(s,1H),7.34(d,J=8.8Hz,2H),7.28(d,J=2.0Hz,1H) ,7.26(s,1H),7.14(dd,J1=2.0Hz,J2=8.0Hz,1H),7.04(d,J=8.8Hz,1H),6.96(d, J=9.6Hz,2H),4.37-4.34(m,1H),3.62(s,3H),3.56-3.46(m,2H),2.21-2.14(m,1 H), 2.03 (s, 3H), 1.98-1.84 (m, 3H), 1.81 (d, J = 2.4Hz, 6H), 1.71 (s, 6H); LC-MS: m / z 508.4(M+H) +

[0877] The following intermediates were prepared by a procedure similar to Intermediate-XIX.4 using appropriate reactants and reagents and in the presence of a suitable solvent and appropriate reaction conditions.

[0878]

[0879]

[0880] Intermediate-XX:

[0881]

[0882] Step-a: 2-((4-((4-((3R,5R)-adamantan-1-yl)phenyl)(methyl)amino)phenyl)(methyl)amino Synthesis of methyl benzoate (intermediate-XX)

[0883] A solution of intermediate-VI (4g, 8.85mmol, 1eq.) in DMF (80mL) was cooled to 0°C and sodium hydride (1.06g, 44.2mmol, 5eq.) was added in batches and stirred for 15 minutes. Iodomethane (6.3g, 44.2mmol, 5eq.) was added dropwise and the reaction mass was heated at 80°C for 16 hours in a sealed tube. The reaction mass was cooled to room temperature and poured into cold water. The precipitated solid was filtered and dried. This crude material was absorbed by silica and purified by combi-flash to obtain the title product (3g, 70.7%) as a light yellow solid.

[0884] 1 H NMR (400MHz, DMSO-d6) δ7.65 (dd, J1=2.0Hz, J2=8.0Hz, 1H), 7.60 (t, J=7.6Hz ,1H),7.33(d,J=7.6Hz,1H),7.26(t,J=7.2Hz,1H),7.13(d,J=8.8Hz,2H),6.9 0(d,J=8.8Hz,2H),6.67(d,J=8.8Hz,2H),6.59(d,J=8.8Hz,2H),3.55(s,3H) ,3.20(s,3H),3.13(s,3H),2.02(s,3H),1.80(s,6H),1.71(s,6H); LC-MS:m / z 480.25(M+H) +

[0885] The following intermediates were prepared by similar procedures to Intermediate-XX using appropriate reactants and reagents and in the presence of a suitable solvent and appropriate reaction conditions.

[0886]

[0887]

[0888]

[0889]

[0890]

[0891]

[0892] The following compounds were prepared by a procedure similar to Intermediate-VI using appropriate reactants and reagents, employing appropriate Pd catalyst and ligand in the presence of a suitable solvent and appropriate reaction conditions.

[0893]

[0894]

[0895]

[0896]

[0897]

[0898]

[0899]

[0900] The following compounds were prepared by a procedure similar to Intermediate-XIII using appropriate reactants and reagents and in the presence of a suitable solvent and appropriate reaction conditions.

[0901]

[0902]

[0903] The following compounds were prepared by similar procedures to Intermediate-XI using appropriate reactants and reagents and in the presence of a suitable solvent and appropriate reaction conditions.

[0904]

[0905] The following compounds were prepared by similar procedures to Intermediate-XIX using appropriate reactants and reagents and in the presence of a suitable solvent and appropriate reaction conditions.

[0906]

[0907] 2-((4-((4-((3R,5R)-adamantan-1-yl)phenyl)amino)phenyl)amino)benzoic acid (Compound 24 Synthesis of (CP-55)

[0908]

[0909] To a solution of intermediate-VI (8.5 g, 16.5 mmol, 1 eq.) in THF:MeOH:HO (40+40+20 mL) was added LiOH×HO (3.3 g, 82.4 mmol, 5 eq.) and stirred at room temperature for 16 hours. The reaction mass was concentrated under vacuum, diluted with water and acidified to pH 5 with 2N HCl. The obtained precipitate was filtered and dried under vacuum. This solid was washed with a hexane mixture containing 10% ether and dried to give the title product (5.5 g, 67%) as an off-white solid.

[0910] 1H NMR (400MHz, DMSO-d6) δ12.99(s,1H),9.42(s,1H),8.00(s,1H),7.85(d,J=6.8Hz,1H),7.32(t,1H),7.21(d ,J=8.8Hz,2H),7.11-6.96(m,7H),6.67(t,J=3.4Hz,1H),2.08(s,3H),1.83(s,6H),1.72(s,6H); LC-MS:m / z 438.4(M+H) +

[0911] The following compounds were prepared by a procedure similar to that described in Compound-24 by using appropriate reagents under appropriate reaction conditions in the presence of a suitable solvent. The physicochemical properties of the compounds are also summarized.

[0912]

[0913]

[0914]

[0915]

[0916]

[0917]

[0918]

[0919]

[0920]

[0921]

[0922]

[0923]

[0924]

[0925]

[0926]

[0927]

[0928]

[0929]

[0930]

[0931]

[0932]

[0933]

[0934]

[0935]

[0936]

[0937]

[0938]

[0939]

[0940]

[0941]

[0942]

[0943]

[0944]

[0945]

[0946]

[0947]

[0948]

[0949]

[0950]

[0951]

[0952]

[0953]

[0954]

[0955]

[0956]

[0957]

[0958]

[0959]

[0960]

[0961]

[0962]

[0963]

[0964]

[0965]

[0966]

[0967]

[0968]

[0969]

[0970]

[0971]

[0972]

[0973]

[0974]

[0975]

[0976]

[0977]

[0978]

[0979]

[0980]

[0981]

[0982]

[0983]

[0984]

[0985]

[0986]

[0987]

[0988]

[0989]

[0990]

[0991]

[0992]

[0993]

[0994]

[0995]

[0996]

[0997] The following compounds were prepared by similar procedures to Intermediate-XV using appropriate reactants and reagents and in the presence of a suitable solvent and appropriate reaction conditions.

[0998]

[0999]

[1000]

[1001] The following compounds were prepared by a procedure similar to Intermediate-XIV using appropriate reactants and reagents and in the presence of a suitable solvent and appropriate reaction conditions.

[1002]

[1003]

[1004]

[1005] 2-((4-((4-((3r,5r,7r)-adamantan-1-yl)-2-chlorophenyl)amino)phenyl)carbamoyl)benzyl Synthesis of acid (Compound 293) (CP-119):

[1006]

[1007] Step (i): A solution of Intermediate-XI (0.05 g, 0.16 mmol, 1 eq.) and phthalic anhydride (0.024 g, 0.16 mmol, 1 eq.) in DCM was stirred at room temperature for 2 hours. The obtained precipitate was filtered and dried under vacuum to give the title product as a light yellow solid (0.01 g, 12.5%).

[1008] 1 H NMR (400MHz, DMSO-d6) δ12.98(s,1H),10.17(s,1H),7.86(d,J=7.8Hz,1H),7.63(d,J=7.3Hz,1H),7.57-7.52(m,4H),7.41 (s,1H),7.31(d,J=1.6Hz,1H),7.17-7.12(m,2H),7.04(d,J=8.8Hz,2H),2.05(s,3H),1.83(s,6H),1.72(s,6H).LC-MS:m / z 501.1(M+H) +2

[1009] The following compounds were prepared by a procedure similar to compound 293 using appropriate reactants and reagents and in the presence of a suitable solvent and appropriate reaction conditions.

[1010]

[1011]

[1012]

[1013]

[1014] Experimental procedures and physicochemical properties of compound CP-453

[1015] Intermediates:

[1016]

[1017] The above intermediate was prepared by a similar procedure to Intermediate-XII by using Intermediate-XI.16 (0.145 g, 0.43 mmol, 1 eq.) and methyl 2-bromo-5-isobutoxybenzoate (0.125 g, 0.43 mmol, 1 eq.) to afford the title product (0.05 g, 22%) as a brown solid. 1 H NMR (400MHz, DMSO-d6): δ8.79(s,1H),7.54-7.52(m,1H),7.44-7.42(m,1H),7.28-6.98(m,9H),3.85(s,3H),3.8 0(d,J=2.4Hz,2H),3.37(s,3H),2.04(s,3H),2.00-1.96(m,1H),1.83(s,6H),1.72(s,6H),0.97(d,J=6.4Hz,6H).

[1018] Final compound:

[1019]

[1020] The above compounds were prepared by the similar procedure as described in Compound-24 by using appropriate reagents in the presence of suitable solvents under appropriate reaction conditions. The physicochemical properties of the compounds are also summarized.

[1021] 1 H NMR (400MHz, DMSO-d6): δ13.10(s,1H),9.12(s,1H),7.37(d,J=2.0Hz,1H),7.23(d,J= 8.4Hz,2H),7.10(d,J=9.2Hz,2H),7.05(dd,J1=2.8Hz,J2=9.2Hz,2H),6.97(d,J=8.8Hz ,2H),6.89(d,J=8.8Hz,2H),3.68(d,J=6.4Hz,2H),3.21(s,3H),2.04(s,3H),2.01-1.9 8(m,1H),1.83(d,J=2.6Hz,6H),1.72(s,6H),0.97(d,J=6.8Hz,6H).LC-MS:525.3(M+H) +

[1022] Bioassay

[1023] In vitro palmitoylation

[1024] Recombinant GST-TEAD2 or His6TEAD2 (500 ng) protein was pre-incubated with the indicated concentrations of compounds for 15 minutes and then incubated with 1 μM alkyne palmitoyl-5CoA (Cayman Chemical) for 30 minutes or with 50 mM MES, pH 6.4, followed by click reactions with biotin-azide as described previously (Zheng, B. et al., Journal of the American Chemical Society (J. Am. Chem. Soc.), 2013, 135, 7082-7085). Click reactions were performed at room temperature with 100 μM biotin-azide, 1 mM tris(2-carboxyethyl)phosphine hydrochloride (TCEP), 100 μM tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA) and 1 mM CuSO4 for 1 hour.

[1025] The reaction was terminated by adding 12 μL of 6×SDS sample loading buffer (50 mM Tris-HCl, pH 6.8, 6% SDS, 48% glycerol, 0.03% bromophenol blue, 30 mM EDTA, 9% MeSH). Samples were analyzed by SDS-PAGE and Western blotted by independent detection with streptavidin HRP and histidine HRP antibodies. The band intensity obtained from the streptavidin blot was quantified using the BIORAD, Gel doc system, and the percentage inhibition of Tead2 self-palmitoylation was determined by comparing with samples treated with the DMSO control.

[1026] The activity of these compounds in inhibiting TEAD2 palmitoylation was tested in the above assay. The data for the compounds are provided in the table below as the percent inhibition of TEAD2 palmitoylation at a concentration of 10 μM of the compound.

[1027] Cell proliferation

[1028] HuH7 cells (or other cells) were cultured in DMEM supplemented with 10% FBS. Cells were seeded in 96 wells at a density of 5000 cells / well. After the cells attached to the wells, a DMSO solution (1% DMSO concentration) containing the compound was added to the cells and serially diluted to a specified final concentration. The cells were further incubated for 3 days. Cell viability was then determined using CellTiterGlo, MTT or crystal violet staining. Inhibition curves were drawn using GraphPad.

[1029] qRT-PCR

[1030] YAP target gene expression was analyzed using LightCycler 480 (Roche). Total RNA was isolated from cells using TRIzol (Life Technologies), and then used to generate cDNA using the Transcripton First Strand cDNA Synthesis Kit (Roche). The resulting cDNA was then used to react with LightCycler 480 SYBR Green I Master mix (Roche), where probes detected CTGF or CYR61 and GAPDH.

[1031] CMP determination

[1032] 7-Diethylamino-3-(4'-maleimidophenyl)-4-methylcoumarin (CPM) reacts with the thiol of CoA released in the enzymatic reaction and produces a fluorescent signal (excitation ~350-380, emission ~460-480). The assay detects the product (free CoA) produced by palmitoyl-CoA as a method for detecting enzyme activity. Therefore, test compounds that inhibit TEAD activity can block the CMP fluorescent signal.

[1033] TEAD2 / 4 protein (10 μL of 50 ng / μL solution) and test compound solution (0.5 μL, different concentrations) were pre-incubated at room temperature for 30 minutes. A mixture prepared from MES pH 6.4 buffer (6.5 μL of 50 mM solution), EDTA (1 μL of 20 mM solution), palmitoyl-CoA (1 μL of 20 μM solution) and 7-diethylamino-3-(4'-maleimidophenyl)-4-methylcoumarin (1 μL of 10 μM solution) was added and the resulting mixture was mixed thoroughly using a pipette. The solution was then incubated at room temperature in the dark for 30-120 minutes, and fluorescence was detected at 350 nm every 30 minutes until the fluorescence signal was saturated. The IC of the ability of the compound to inhibit fluorescence was calculated from the results. 50 .

[1034] The results of the bioassay are shown in Figure 3-12 and in Tables 1 and 2.

[1035] Compounds with TEAD palmitoylation inhibitor activity

[1036] Exemplary compounds were tested for their activity in inhibiting TEAD2 palmitoylation in the above assay and in the CMP assay. The data for the compounds in Table 1 are provided as percent inhibition of TEAD2 palmitoylation at a concentration of 10 μM or as IC50 in the CMP assay.

[1037] Table 1. Activity of compounds as TEAD palmitoylation inhibitors

[1038]

[1039]

[1040]

[1041] Table 2. Activity of compounds as TEAD2 palmitoylation inhibitors

[1042]

[1043]

[1044]

[1045]

[1046]

[1047]

[1048]

[1049]

[1050]

[1051]

[1052]

[1053]

[1054]

[1055]

[1056]

[1057]

[1058]

[1059]

[1060]

[1061]

[1062]

[1063]

[1064]

[1065]

[1066]

[1067]

[1068]

[1069]

[1070]

[1071]

[1072] Table 3. Activity of compounds as TEAD2 palmitoylation inhibitors

[1073]

[1074]

[1075]

[1076]

[1077]

[1078]

[1079]

[1080]

[1081]

[1082]

[1083]

[1084]

[1085]

[1086]

[1087]

[1088]

[1089]

[1090]

[1091]

[1092] In addition to those described herein, various modifications of the present invention will become clear to those skilled in the art from the foregoing description. Such modifications are also expected to fall within the scope of the appended claims. Each reference cited in this application, including but not limited to all patents, patent applications and publications, is incorporated herein by reference in its entirety.

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: L 1 does not exist or is of the formula N(R N ) or C(O); D is a group of formula (D1), (D2), (D3), (D4), (D5), (D6) or (D7): m is 1, 2 or 3; A 1 C(O)R 1 、S(O)2R 1 、NHC(O)R 1 , (C 1-3 Alkylene)-C(O)R 1 NH(C 1-3 Alkylene)-C(O)R 1 , CN, NO2, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (C 1-3 (C 1-3 alkylene)-4-10 membered heterocycloalkyl, wherein A 1 (C 1-3 Alkylene)-C(O)R 1 The group (C 1-3 The alkylene) group is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halogen, OR a1 NR c1 R d1 NR a1 (CO)(C 1-6 Alkyl) and NR a1 (CO)O(C 1-6 alkyl); and wherein the formation of A 1 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (C 1-3 (C 1-3 alkylene)-4-10 membered heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents each independently selected from halogen, OR a1 , SR a1 、C(O)OR a1 NR c1 R d1 and C(O)NR c1 R d1 ; L 2 does not exist or is of the formula N(R N ), O or C(O) groups; L 3 Does not exist or is of the formula CH2, C≡C, N(R N ) or C(O); Each R N Independently H, C 1-6 Alkyl, C(O)C 1-6 Alkyl or C(O)OC 1-6 alkyl; R 1 H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, Cy 1A , OH, OC 1-6 Alkyl, OCy 1A 、O(C 1-3 Alkylene)Cy 1A 、NH2、NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, NHCy 1A NH(C 1-3 Alkylene)Cy 1A 、N(C 1-6 Alkyl)Cy 1A or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 1A , which forms R 1 Each C 1-6 The alkyl group is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents, each of which is independently selected from halogen, OR a1 , SR a1 and NR c1 R d1 ; Cy 1A C 6-10 Aryl, C 3-15 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein Cy 1A C 6-10 Aryl, C 3-15 Each of the cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl groups is unsubstituted or substituted with 0, 1 or 2 Cy 1B and 0, 1, 2, 3, 4 or 5 substituents each independently selected from unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl; Each Cy 1B C 6-10 Aryl, C 3-15 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein Cy 1B C 6-10 Aryl, C 3-15 Each of the cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents each independently selected from the group consisting of unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 ; and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl; A 2 CR 2 or N; A 3 CR 3 or N; A 4 CR 4 or N; A 5 CR 5 or N; A 6 CR 6 or N; A 7 CR 7 or N; A 8 CR 8 or N; A 9 CR 9 or N; A 10 CR 10 or N; A D41 CH, C(C 1-6 Alkyl) or N; A D42 CH2, NH or NC 1-6 alkyl; R 2 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl; R 3 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl; R 4 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl; R 5 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl; R 6 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 、S(O)2R b1 、S(O)2NR c1 R d1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 , Cy 7A , OCy 7A 、O(C 1-3 Alkylene)Cy 7A 、C(O)OCy 7A 、C(O)O(C 1-3 Alkylene)Cy 7A ,NHCy 7A NH(C 1-3 Alkylene)Cy 7A 、N(C 1-6 Alkyl)Cy 7A 、N(C(O)C 1-6 Alkyl)Cy 7A 、N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 7A 、C(O)NHCy 7A 、C(O)NH(C 1-3 Alkylene)Cy 7A 、C(O)N(C 1-6 Alkyl)Cy 7A 、C(O)N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 7A or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl; R 7 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、S(O)2NR c1 R d1 、C(O)NR c1 R d1 , Cy 7A , OCy 7A 、O(C 1-3 Alkylene)Cy 7A 、C(O)OCy 7A 、C(O)O(C 1-3 Alkylene)Cy 7A ,NHCy 7A NH(C 1-3 Alkylene)Cy 7A 、N(C 1-6 Alkyl)Cy 7A 、N(C(O)C 1-6 Alkyl)Cy 7A 、N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 7A 、C(O)NHCy 7A 、C(O)NH(C 1-3 Alkylene)Cy 7A 、C(O)N(C 1-6 Alkyl)Cy 7A 、C(O)N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 7A or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl; Cy 7A C 6-10 Aryl, C 3-15 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein Cy 7A C 6-10 Aryl, C 3-15 Each of the cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is unsubstituted or substituted with 0, 1 or 2 groups selected from Cy 7B , OCy 7B ,NHCy 7B and C(O)NHCy 7B and 0, 1, 2, 3, 4 or 5 substituents independently selected from the following: unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl; Each Cy 7B C 6-10 Aryl, C 3-15 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein Cy 7B C 6-10 Aryl, C 3-15 Each of the cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents each independently selected from the group consisting of unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 Substituents substituted with C 1-6 alkyl; R 8 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 、S(O)2NR c1 R d1 , SR a1 NR c1 R d1 NR c1 S(O)2R b1 、C(O)OR a1 、C(O)NR c1 R d1 , Cy 8A , OH, OCy 8A 、O(C 1-3 Alkylene)Cy 8A 、C(O)OCy 8A 、C(O)O(C 1-3 Alkylene)Cy 8A ,NHCy 8A 、N(Cy 8A )2、NH(C 1-3 Alkylene)Cy 8A 、N(C 1-6 Alkyl)Cy 8A 、N(C(O)C 1-6 Alkyl)Cy 8A SO2NHCy 8A 、N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8A 、C(O)NHCy 8A , C 1-3 Alkylene-C(O)NHCy 8A 、C(O)NH(C 1-3 Alkylene)Cy 8A 、C(O)N(C 1-6 Alkyl)Cy 8A 、C(O)N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8A or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl; Cy 8A C 6-10 Aryl, C 3-15 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein Cy 8A C 6-10 Aryl, C 3-15 Each of the cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is unsubstituted or substituted with 0, 1 or 2 groups selected from Cy 8B , OCy 8B ,NHCy 8B and C(O)NHCy 8B and 0, 1, 2, 3, 4 or 5 substituents independently selected from the following: unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl; Each Cy 8B C 6-10 Aryl, C 3-15 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein Cy 8B C 6-10 Aryl, C 3-15 Each of the cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents each independently selected from the group consisting of unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl; R 9 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 NR c1 C(O)R b1 、C(O)OR a1 、C(O)NR c1 R d1 or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl; R 10 H, unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 or 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 and NR c1 R d1 Substituents substituted with C 1-6 alkyl; Cy D71 C 6-10 Aryl, C 3-15 Cycloalkyl, 5-14 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein Cy D71 C 6-10 Aryl, C 3-15 Each of the cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is unsubstituted or substituted with 0, 1 or 2 groups selected from Cy D72 、CH2Cy D72 , OCy D72 ,NHCy D72 , OC 1-6 Alkylene-Cy D72 、N(C 1-6 Alkyl)Cy D72 、N(C(O)C 1-6 Alkyl)Cy D72 and C(O)NHCy D72 and 0, 1, 2, 3, 4 or 5 substituents independently selected from the following: unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, CN, OR a1 、S(hal)5、SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 and 1, 2 or 3 each independently selected from halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 、C(O)OR a1 and NR c1 R d1 Substituents substituted with C 1-6 Alkyl or C 2-6 alkenyl; Each Cy D72 C 6-10 Aryl, C 3-15 Cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl, wherein Cy D72 C 6-10 Aryl, C 3-15 Each of the cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents each independently selected from the group consisting of unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-15 Cycloalkyl, 4-10 membered heterocycloalkyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 、C(O)NR c1 R d1 and 1, 2 or 3 each independently selected from C 6-10 Aryl, C 3-15 Cycloalkyl, 4-10 membered heterocycloalkyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 、C(O)OR a1 and NR c1 R d1 Substituents substituted with C 1-6 Alkyl, wherein the C 6-10 Aryl, C 3-15 Cycloalkyl and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2 or 3 independently selected C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 and C(O)NR c1 R d1 substituted with a substituent; and R a1 , R b1 , R c1 and R d1 Each independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, HO-C 1-6 Alkylene, amino-C 1-6 Alkylene, C 1-6 Alkylamino-C 1-6 Alkylene, di(C 1-6 alkyl)amino-C 1-6 Alkylene, C 1-6 Alkoxy-C 1-6 Alkylene, C 6-10 Aryl, C 2-6 Alkenyl and C 2-6 Alkynyl; or R c1 and R d1 and the nitrogen atom to which they are all attached together form a 4-10 membered unsubstituted heterocycloalkyl ring or a heterocycle substituted by 1, 2 or 3 substituents independently selected from C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, CN, OR a1 , SR a1 NR c1 R d1 、C(O)OR a1 and C(O)NR c1 R d1 ; The conditions are: When L 2 When C(O), L 1 Formula N(R N ) When L 2 N(R N ),L 1 is a group of formula C(O); When L 1 When C(O), L 2 does not exist or is of the formula N(R N ) When L 1 N(R N ),L 2 is absent or is a group of formula C(O); When A D42 For NH or NC 1-6 When alkyl, A D41 CH, C(C 1-6 alkyl); When A D41 For NH or NC 1-6 When alkyl, A D42 is CH2; A 2 , A 3 , A 4 and A 5 No more than two of them are N; A 6 , A 7 , A 8 , A 9 and A 10 No more than two of them are N; and R 1 exists and is Cy 1A , OCy 1A 、O(C 1-3 Alkylene)Cy 1A ,NHCy 1A NH(C 1-3 Alkylene)Cy 1A 、N(C 1-6 Alkyl)Cy 1A or N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 1A ;or R 7 Cy 7A , OCy 7A 、O(C 1-3 Alkylene)Cy 7A 、C(O)OCy 7A 、C(O)O(C 1-3 Alkylene)Cy 7A ,NHCy 7A NH(C 1-3 Alkylene)Cy 7A 、N(C 1-6 Alkyl)Cy 7A 、N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 7A 、C(O)NHCy 7A 、C(O)NH(C 1-3 Alkylene)Cy 7A 、C(O)N(C 1-6 Alkyl)Cy 7A or C(O)N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 7A ;or R 8 Cy 8A , OCy 8A 、O(C 1-3 Alkylene)Cy 8A 、C(O)OCy 8A 、C(O)O(C 1-3 Alkylene)Cy 8A ,NHCy 8A NH(C 1-3 Alkylene)Cy 8A 、N(C 1-6 Alkyl)Cy 8A 、N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8A 、C(O)NHCy 8A 、C(O)NH(C 1-3 Alkylene)Cy 8A 、C(O)N(C 1-6 Alkyl)Cy 8A or C(O)N(C 1-6 Alkyl)(C 1-3 Alkylene)Cy 8A .

2. A compound or claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from any one of the following compounds:

3. A composition comprising the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

4. A method for inhibiting palmitoylation of a TEAD-transcription factor, the method comprising contacting the TEAD-transcription factor with a compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, or with a composition according to claim 3.

5. A method for treating a disease or condition associated with the activity of a TEAD transcription factor, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, or a composition according to claim 3.

6. A method for treating cancer, the method comprising administering a therapeutically effective amount of a compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, or a composition according to claim 3 to a patient in need of such treatment.

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