Novel heterocyclic compounds as tead inhibitors

Abstract

The present application provides a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein ring A, Y, Z 1 , Z 2 , Z 3 , R 1 and R 2 as described herein, which are useful as TEAD inhibitors, also provide pharmaceutical compositions comprising the same and their use in the treatment of TEAD-related diseases or conditions, such as cancer.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to international application No. PCT / CN2022 / 106073, filed on July 15, 2022, entitled “NOVEL HETEROCYCLIC COMPOUNDS AS TEAD INHIBITORS”, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention relates to novel heterocyclic compounds that can be used as inhibitors of TEAD, or pharmaceutically acceptable salts, solvates, stereoisomers, or isotopic variants thereof. The invention also relates to pharmaceutical compositions comprising one or more such compounds or pharmaceutically acceptable salts, solvates, stereoisomers, or isotopic variants thereof as active ingredients, and the use of such compounds or pharmaceutically acceptable salts, solvates, stereoisomers, or isotopic variants thereof in the treatment of TEAD-related diseases or conditions (e.g., cancer). Background Technology

[0004] In recent years, the Hippo pathway has become a target for the treatment of hyperproliferative disorders and diseases, particularly cancer (SASmith et al., J. Med. Chem. 2019, 62, 1291-1305; KCLin et al., Annu. Rev. Cancer Biol. 2018, 2: 59-79; C.-L. Kim et al., Cells (2019), 8, 468; KF Harvey et al., Nature Reviews Cancer, Vol. 13, 246-257 (2013)). The Hippo pathway regulates cell growth, proliferation, and migration. It is speculated that the Hippo pathway acts as a tumor suppressor in mammals, and dysfunction of Hippo signaling is frequently observed in human cancers.

[0005] Since the Hippo pathway plays a role in a variety of biological processes—such as in the self-renewal and differentiation of stem cells and progenitor cells, wound healing and tissue regeneration, and interactions with other signaling pathways (e.g., Wnt)—its dysfunction may also play a role in diseases other than cancer in humans (C.-L. Kim et al., Cells (2019), 8, 468; Y. Xiao et al., Genes & Development (2019) 33: 1491-1505; KF Harvey et al., Nature Reviews Cancer, Vol. 13, 246-257 (2013)).

[0006] While several aspects of pathway activity and regulation remain to be further investigated, it has been established that, in its "on" state, the Hippo pathway involves a series of kinases in the cytoplasm (including Mst 1 / 2 and Lats 1 / 2), leading to phosphorylation of two transcriptional coactivators, YAP (Yes-associated protein) and TAZ (a transcriptional coactivator with a PDZ-binding motif). Phosphorylation of YAP / TAZ results in their sequestration in the cytoplasm and ultimately their degradation. Conversely, when the Hippo pathway is "off" or dysfunctional, the unphosphorylated, activated YAP / TAZ coactivators are translocated to the nucleus. Their primary target transcription factors are four proteins of the transcription enhancement-associated domain (TEAD) family of transcription factors (TEAD1–4). The binding and activation of YAP or TAZ with TEAD (or other transcription factors) has been shown to induce the expression of several genes, many of which mediate cell survival and proliferation. Therefore, activated, non-phosphorylated YAP and TAZ may act as oncogenes, while activated, turned-on Hippo pathways may act as tumor suppressors by inactivating, i.e., phosphorylating YAP and TAZ.

[0007] Furthermore, the Hippo pathway may also play a role in the mechanisms of cancer cell resistance to oncology and immuno-oncology therapies (R. Reggiani et al., Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 1873 (2020) 188341, 1-11).

[0008] Therefore, dysfunction or abnormal regulation of the Hippo pathway as a tumor suppressor is considered to play an important role in the development of various cancer types and diseases.

[0009] Therefore, inhibiting YAP, TAZ, TEAD and YAP-TEAD or TAZ-TEAD protein-protein interactions through pharmacological intervention may be a potential, rational and valuable strategy for the prevention and / or treatment of cancer and other hyperproliferative diseases and diseases associated with Hippo pathway dysfunction. Summary of the Invention

[0010] This article discloses novel heterocyclic compounds as inhibitors of TEAD. Therefore, the compounds of this invention are particularly suitable for modulating YAP-TEAD or TAZ-TEAD protein-protein interactions and thus can be used to treat TEAD-related diseases and conditions, such as cancer.

[0011] In one aspect, the present invention relates to a compound of formula (I).

[0012]

[0013] Or pharmaceutically acceptable salts, solvates, stereoisomers or isotopic variants thereof, wherein rings A, Y, Z 1 Z 2 Z 3 R 1 and R 2 As described in this article.

[0014] In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) as provided herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, and a pharmaceutically acceptable carrier or excipient.

[0015] In another aspect, the present invention relates to a method for treating a subject with TEAD-related disease or condition such as cancer, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) as provided herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof.

[0016] In another aspect, the present invention relates to compounds of formula (I) as provided herein, or pharmaceutically acceptable salts, solvates, stereoisomers or isotopic variants thereof, for the treatment of TEAD-related diseases or conditions, such as cancer.

[0017] In another aspect, the present invention relates to the use of compounds of formula (I) as provided herein, or pharmaceutically acceptable salts, solvates, stereoisomers or isotopic variants thereof, in the preparation of medicaments for treating TEAD-related diseases or conditions such as cancer.

[0018] In another aspect, the present invention relates to a kit for treating TEAD-related diseases or conditions such as cancer, the kit comprising: a compound of formula (I) as provided herein, or a pharmaceutically acceptable salt, solvate, stereoisomer or isotopic variant thereof, or a pharmaceutical composition comprising a compound of formula (I) as provided herein, or a pharmaceutically acceptable salt, solvate, stereoisomer or isotopic variant thereof, and a pharmaceutically acceptable carrier or excipient, a container, and optionally a packaging insert or label indicating treatment. Detailed Implementation

[0019] Certain embodiments will now be described in detail, examples of which are illustrated in the accompanying detailed descriptions. While the enumerated embodiments will be described, it should be understood that they are not intended to limit the invention to these embodiments. Rather, the invention is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of the invention as defined by the claims. Those skilled in the art will recognize that many methods and materials similar to or equivalent to those described and materials herein can be used in the practice of the invention. The invention is by no means limited to the methods and materials described. If one or more incorporated documents and similar materials differ from or contradict this disclosure, including but not limited to defined terminology, usage of terms, described techniques, etc., this disclosure shall prevail.

[0020] It will be understood that some features of the invention, described in the context of individual embodiments for clarity, may also be provided in combination in a single embodiment. Conversely, for brevity, the various features of the invention described in the context of individual embodiments may also be provided individually or in any suitable sub-combination.

[0021] This article provides the following content.

[0022] Item 1 A compound of formula (I)

[0023]

[0024] Or its pharmaceutically acceptable salts, solvates, stereoisomers or isotopic variants, wherein

[0025] Ring A is a 6-membered aromatic ring, a 6-membered heteroaromatic ring, or a pyridin-2-one ring, which may optionally be free from halogens, CN, C. 1-10 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkyl or -(CH2) n -R A One or more substituents of the group comprising the alkyl group are substituted; wherein the alkyl group, the alkoxy group, and the cycloalkyl group are optionally further substituted with one or more halogens, R A It is arbitrarily selected free halogen, C 1-10 Alkyl and C 1-10 A phenyl group consisting of one or more substituents of an alkoxy group, where n is 0, 1, or 2;

[0026] Y is CR Y Or N;

[0027] Z 1 Z 2 and Z 3 Each is independently C(R) Z )2;

[0028] R Y Is it H or C? 1-6 Alkyl groups, which are optionally substituted with one or more halogens;

[0029] R Z Each time it appears, it is independently H, halogen, or C. 1-10 Alkyl, or two R Z Together with the same carbon atoms they are attached to, they combine to form C 3-10 A cycloalkane ring, optionally selected from halogens, C 1-10 Alkyl and C 1-10 One or more substituents of the group consisting of alkoxy groups are substituted;

[0030] R 1 It is a 6- to 10-membered aryl, a 5- to 10-membered heteroaryl, or a 3- to 10-membered monocyclic or bicyclic cycloalkyl or heterocyclic group, wherein the aryl, the heteroaryl, the cycloalkyl, and the heterocyclic group are optionally selected from halogens, CN, C. 1-10 Alkyl, C 1-10 Alkoxy and C 3-10 One or more substituents of the group consisting of cycloalkyl groups are substituted, wherein the C 1-10 Alkyl, C 1-10 Alkoxy and C 3-10 The cycloalkyl group is optionally substituted with one or more halogens, and wherein the heteroaryl group and the heterocyclic group contain at least one heteroatom ring member selected from the group consisting of N, O and S;

[0031] R 2 It is -C(=O)R 2A -C(=O)OR 2A -C(=O)N(R) 2A )2、-NR 2A C(=O)R 2A -NR 2A S(=O)R 2A -NR 2A S(=O)2R 2A -S(=O)R 2A -S(=O)2R 2A -S(=O)2OR 2A or -S(=O)2N(R) 2A )2;

[0032] R 2A Each time it appears, it is independently H or C. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or -LR 2AAThe alkyl group, the alkenyl group, and the alkynyl group are optionally substituted with one or more substituents selected from the group consisting of halogens, OH, and NH2; or two R groups. 2A Together with the nitrogen atoms to which they are attached, they combine to form 3- to 10-membered heterocyclic groups, which optionally contain an additional heteroatom ring member selected from the group consisting of N, O and S, wherein the heterocyclic group is optionally substituted by one or more substituents selected from the group consisting of halogens, OH and NH2.

[0033] L is absent or optionally substituted by one or more substituents selected from the group consisting of halogen, OH, and NH2. 1-10 Alkyl groups; and

[0034] R 2AA It is C 3-10 Cycloalkyl, 3- to 10-membered heterocyclic, 6- to 10-membered aryl or 5- to 10-membered heteroaryl, wherein the cycloalkyl, the heterocyclic, the aryl and the heteroaryl are optionally substituted by one or more substituents selected from the group consisting of halogen, OH and NH2;

[0035] The condition is to exclude the following compounds:

[0036] 2-(methylsulfonyl)-5-phenyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole,

[0037] 2-(ethylsulfonyl)-6-fluoro-5-(2-fluorophenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole,

[0038] 8-Fluoro-5-(4-fluorophenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylic acid methyl ester

[0039] ethyl 8-chloro-5-(4-chlorophenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate, and

[0040] 8-Methoxy-5-(4-Methoxyphenyl)-1,3,4,5-Tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester.

[0041] Item 2 According to formula (I) of item 1, a compound or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein

[0042] Ring A is a benzene, pyridine, or pyridin-2-one ring, which may optionally be free from halogens, CN, C. 1-10 Alkyl, C 1-10 Alkoxy, C 3-10Cycloalkyl or -(CH2) n -R A One or more substituents of the group comprising the alkyl group are substituted; wherein the alkyl group, the alkoxy group, and the cycloalkyl group are optionally further substituted with one or more halogens, R A It is arbitrarily selected free halogen, C 1-10 Alkyl and C 1-10 A phenyl group consisting of one or more substituents of an alkoxy group, where n is 0, 1, or 2.

[0043] Item 3 According to formula (I) of item 2, a compound or its pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein

[0044] Ring A is

[0045]

[0046] R X Each time it appears, it is independently of halogen, CN, C. 1-10 Alkyl or C 1-10 Alkoxy;

[0047] m can be 0, 1, 2, 3, or 4.

[0048] Item 4 According to formula (I) of item 3, a compound or its pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein

[0049] Ring A is

[0050]

[0051] Item 5 A compound of formula (I) according to any of the preceding items, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein...

[0052] Y is CH, CCH3, or N;

[0053] Z 1 Z 2 and Z 3 Each is independently C(R) Z )2; and

[0054] R Z It is either H or C each time it appears. 1-10 Alkyl, or two R Z Together with the same carbon atoms attached to them, they combine to form a cyclopropane ring.

[0055] Item 6A compound of formula (I) according to any of the preceding items, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein...

[0056] R 1 It is a phenyl, pyridyl, or 5- to 10-membered monocyclic or bicyclic cycloalkyl or heterocyclic group, wherein the phenyl, the pyridyl, the cycloalkyl, and the heterocyclic group are optionally selected from halogens, CN, C. 1-10 Alkyl, C 1-10 Alkoxy and C 3-10 One, two, or three substituents of the group consisting of cycloalkyl groups are substituted, wherein the C 1-10 Alkyl, C 1-10 Alkoxy and C 3-10 The cycloalkyl group is optionally substituted with one, two or three halogens, and the heterocyclic group contains one or two heteroatom ring members selected from the group consisting of N, O and S.

[0057] Item 7 According to formula (I) of item 6, a compound or its pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein

[0058] R 1 yes

[0059]

[0060] Item 8. A compound of formula (I) according to Item 7, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein

[0061] R 1 yes

[0062]

[0063] Item 9 A compound of formula (I) according to any of the preceding items, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein...

[0064] R 2 It is -C(=O)R 2A -C(=O)OH, -C(=O)OR 2A -C(=O)NHR 2A -C(=O)N(R) 2A )2、-

[0065] NHC(=O)R 2A -S(=O)2R 2A -S(=O)2NHR 2A or -S(=O)2N(R) 2A )2;

[0066] R 2A It is C independently each time it appears. 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl or -LR 2AA The alkyl group, the alkenyl group, and the alkynyl group are optionally substituted with one or more substituents selected from the group consisting of halogens, OH, and NH2;

[0067] L does not exist or C 1-10 Alkyl groups; and

[0068] R 2AA It is C 3-10 The cycloalkyl group, the 3- to 10-membered heterocyclic group, the 6- to 10-membered aryl group, or the 5- to 10-membered heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group are optionally substituted by one or more substituents selected from the group consisting of halogen, OH, and NH2.

[0069] Item 10 A compound of formula (I) according to any of the preceding items, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein...

[0070] R 2 yes

[0071]

[0072] Item 11 The compound of formula (I) according to item 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein the compound of formula (I) has a structure represented by the following formula:

[0073]

[0074]

[0075]

[0076] Item 12 A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, and a pharmaceutically acceptable carrier or excipient.

[0077] Item 13 A method for treating cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof.

[0078] Item 14 According to the method of item 13, the cancer is selected from the group consisting of: breast cancer, lung cancer, mesothelioma, epithelioid hemangioendothelioma, uveal melanoma, liver cancer, ovarian cancer, squamous cell carcinoma, kidney cancer, gastric cancer, medulloblastoma, colon cancer, pancreatic cancer, schwannoma, meningioma, glioma, and basal cell carcinoma.

[0079] Item 15 The compound of formula (I) according to any one of items 1 to 11, or a pharmaceutically acceptable salt, solvate, stereoisomer or isotopic variant thereof, is used to treat cancer.

[0080] Item 16 According to item 15, a compound of formula (I) for the treatment of cancer, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein said cancer is selected from the group consisting of: breast cancer, lung cancer, mesothelioma, epithelioid hemangioendothelioma, uveal melanoma, liver cancer, ovarian cancer, squamous cell carcinoma, kidney cancer, gastric cancer, medulloblastoma, colon cancer, pancreatic cancer, schwannoma, meningioma, glioma, and basal cell carcinoma.

[0081] Item 17 Use of a compound of formula (I) according to any one of items 1 to 11, or a pharmaceutically acceptable salt, solvate, stereoisomer or isotopic variant thereof, in the preparation of a medicament for the treatment of cancer.

[0082] Item 18 According to the purpose of item 17, the cancer mentioned therein is selected from the group consisting of: breast cancer, lung cancer, mesothelioma, epithelioid hemangioendothelioma, uveal melanoma, liver cancer, ovarian cancer, squamous cell carcinoma, kidney cancer, gastric cancer, medulloblastoma, colon cancer, pancreatic cancer, schwannoma, meningioma, glioma, and basal cell carcinoma.

[0083] Item 19 A kit for treating cancer, the kit comprising:

[0084] A compound of formula (I) according to any one of items 1 to 11, or a pharmaceutically acceptable salt, solvate, stereoisomer or isotopic variant thereof, or a pharmaceutical composition according to item 12.

[0085] Containers; and

[0086] Optional instruction leaflets or labels for treatment.

[0087] Item 20According to the kit of item 19, the cancers described are selected from the group consisting of: breast cancer, lung cancer, mesothelioma, epithelioid hemangioendothelioma, uveal melanoma, liver cancer, ovarian cancer, squamous cell carcinoma, kidney cancer, gastric cancer, medulloblastoma, colon cancer, pancreatic cancer, schwannoma, meningioma, glioma, and basal cell carcinoma.

[0088] definition

[0089] Terms used herein but not defined have their usual meanings, and the meaning of such terms is independent each time they appear. However, unless otherwise stated, the following definitions apply throughout the specification and claims.

[0090] As used herein, unless otherwise expressly stated, the singular forms “a,” “an,” and “the” include plural referents.

[0091] As used herein, the terms “comprising” and “including” are intended to specify the presence of the said feature, whole, component or step, but they do not exclude the presence or addition of one or more other features, wholes, components, steps or groups thereof.

[0092] The definitions of specific functional groups and chemical terms are described in more detail below. For the purposes of this invention, chemical elements are identified according to the periodic table, CAS edition, Handbook of Chemistry and Physics, 75th edition, inner cover, and specific functional groups are generally defined as described therein. Furthermore, general principles of organic chemistry, as well as specific functional groups and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0093] Unless otherwise expressly stated, this includes all scopes referenced in this article.

[0094] When listing a series of values, the aim is to cover every value within that range and every subrange. For example, "C1-6 "Aims to cover C1, C2, C3, C4, C5, C6, C 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 .

[0095] When any variable appears more than once in any ingredient, in formula (I), or in any other formula describing and illustrating the compounds of the present invention, its definition for each occurrence is independent of its definition for every other occurrence. Furthermore, combinations of substituents and / or variables are permitted only when such combinations produce stable compounds.

[0096] As used herein, the term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group. The term "C"... i-j "Alkyl" refers to an alkyl group having i to j carbon atoms. Unless otherwise stated, an alkyl group may contain 1 to 10 carbon atoms. In some embodiments, the alkyl group contains 1 to 6 carbon atoms, such as 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl and isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl, neopentyl, etc. As used herein, the term "alkylene" refers to a divalent substituent, which is a monovalent alkyl group having one hydrogen atom substituted in valence.

[0097] As used herein, the term "alkenyl" refers to a straight-chain or branched hydrocarbon group having at least one carbon-carbon double bond, and includes groups having "cis" and "trans" orientations, or optionally, "E" and "Z" orientations. Unless otherwise stated, an alkenyl group may contain 2 to 10 carbon atoms. In some embodiments, an alkenyl group may contain 2 to 6 carbon atoms, such as 2 to 5 carbon atoms, 2 to 4 carbon atoms, or 2 to 3 carbon atoms. In some embodiments, the alkenyl group contains 2 carbon atoms. Non-limiting examples of alkenyl groups include ethylene (vinyl), propenyl, butenyl, pentenyl, 1-methyl-2-buten-1-yl, 5-hexenyl, etc.

[0098] As used herein, the term "alkynyl" refers to a straight-chain or branched hydrocarbon group having at least one carbon-carbon triple bond. Unless otherwise stated, an alkynyl group may contain 2 to 10 carbon atoms. In some embodiments, the alkynyl group contains 2 to 8 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 to 3 carbon atoms. In some embodiments, the alkynyl group contains 2 carbon atoms. Non-limiting examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, etc.

[0099] As used herein, the term "alkoxy" refers to the group -O-alkyl, where alkyl has the meaning as defined herein.

[0100] As used herein, the term "cycloalkyl" refers to non-aromatic, saturated monocyclic and polycyclic cyclic systems in which all cyclic atoms are carbon. Unless otherwise stated, cycloalkyl groups may contain 3 to 10 cyclic carbon atoms (i.e., C14 and C24). 3-10 (Cycloalkyl). In some embodiments, the cycloalkyl group may comprise 3 to 9, 3 to 8, 3 to 7, 3 to 6, 4 to 10, 4 to 9, 4 to 8, 4 to 7, 4 to 6, 4 to 5, 5 to 10, 5 to 9, 5 to 8, 5 to 7, 5 to 6 cyclic carbon atoms, etc. In particular, the cycloalkyl group may be monocyclic or bicyclic. Optionally, the bicyclic cycloalkyl group may include fused, spirocyclic, and bridged cycloalkyl structures.

[0101] On the other hand, it also includes cycloalkyl rings in which one, two, or three heteroatoms are replaced by cyclic carbon atoms. Such groups are referred to as "heterocyclic groups" or "heterocycles," which are cycloalkyl groups as defined above but with at least one heteroatom selected from N, O, and S as a cyclic atom. Unless otherwise stated, heterocyclic groups may contain 3 to 10 cyclic atoms (i.e., 3 to 10-membered heterocyclic groups). In some embodiments, heterocyclic groups may contain 3 to 9, 3 to 8, 3 to 7, 3 to 6, 4 to 10, 4 to 9, 4 to 8, 4 to 7, 4 to 6, 4 to 5, 5 to 10, 5 to 9, 5 to 8, 5 to 7, 5 to 6, etc. In particular, heterocyclic groups may be monocyclic or bicyclic. Optionally, bicyclic heterocyclic groups may include fused, spirocyclic, and bridged heterocyclic structures. Non-limiting examples of heterocyclic groups include ethylene oxide, pyrrolyl, piperidinyl, tetrahydropyranyl, piperazineyl, pyrrolylyl, and morpholinyl. Heterocyclic groups can also be described by the number of carbon atoms. For example, C 3-6A heterocyclic group refers to a heterocyclic group containing three to six cyclic carbon atoms, and may also contain at least one heteroatom, for example, one, two, or three heteroatoms as cyclic atoms. In some embodiments, the heterocyclic group or heterocycle contains one or two heteroatoms as cyclic atoms. In some embodiments, the heterocyclic group may be monocyclic or bicyclic, such as fused bicyclic and spirobicyclic. In the context of this invention, the terms "heterocyclic group" and "heterocycle" are used interchangeably.

[0102] As used herein, the term "aryl" or "aromatic ring" refers to a monocyclic, bicyclic, or polycyclic carbocyclic system having at least one aromatic ring. Unless otherwise stated, an aryl group can be 6 to 10-membered. In some embodiments, the aryl group may contain six cyclic carbon atoms. All atoms within a carbocyclic aryl group are carbon atoms. Non-limiting examples of aryl groups include phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indenyl, indenyl, etc. In the context of this invention, the terms "aryl" and "aromatic ring" are used interchangeably.

[0103] As used herein, the term "heteroaryl" or "heteroary ring" refers to a monocyclic system, or a fused or bridged bicyclic system, wherein the ring system contains one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and at least one ring is an aromatic ring. Unless otherwise stated, the heteroaryl group may be 5 to 10-membered. In some embodiments, the heteroaryl group may be 5- or 6-membered. In some embodiments, the heteroaryl group may contain one, two, or three heteroatoms. In some embodiments, the heteroaryl group may contain one or two heteroatoms. Non-limiting examples of heteroaryl groups include benzimidazolyl, benzofuranyl, benzothiazolyl, benzothiophene, benzooxazolyl, furanyl, imidazolyl, indolyl, isoindazolyl, isoquinolinyl, isothiazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purine, pyrrole, pyridyl, pyrazinyl, pyrimidinyl, quinolinyl, thiadiazolyl, thiazolyl, thiophene, triazolyl, tetrazolyl, dihydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc. A heteroaryl group comprises at least one ring having at least one heteroatom as described above and at least one aromatic ring. For example, the ring having at least one heteroatom may be fused to one, two, or three carbon rings, such as an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, or another monocyclic heterocycle. Non-limiting examples of fused heteroaryl groups include 1,2,3,5,8,8a-hexahydroindene, 2,3-dihydrobenzofuran, 2,3-dihydroindole, 2,3-dihydrobenzothiophene, etc. In the context of this invention, the terms "heteroaryl" and "heteroaryl ring" are used interchangeably.

[0104] As used in this article, the term "oxo" refers to a divalent oxygen atom and the structure of an oxo atom can be shown as =O.

[0105] As used herein, the term "halogenated" or "halogen" refers to fluorides, chlorides, bromides, and iodides. In some embodiments, non-limiting examples of halogenation include fluorides, chlorides, and bromides, and more particularly fluorides and chlorides.

[0106] As used herein, the term “heteroatom” refers to nitrogen (N), oxygen (O), and sulfur (S), and may include any oxidized form of nitrogen and sulfur, as well as any quaternized form of basic nitrogen, unless otherwise stated.

[0107] As used herein, the term "substituted" when referring to a chemical group means that the chemical group has one or more hydrogen atoms that are removed and replaced by substituents. As used herein, the term "substituent" has its common meaning known in the art and refers to a chemical part covalently attached to or, if appropriate, fused to a parent group. It is understood that the substitution of a given atom is limited by its valence. It should be understood that substituents can be further substituted.

[0108] When a portion of formula (I) or any embodiment thereof is indicated to be "optionally" substituted, this means that formula (I) or embodiments thereof cover compounds in which the indicated substituent is substituted on the portion and compounds in which the indicated substituent is not present on the portion (i.e., where the portion is not substituted).

[0109] The compounds provided herein are described with reference to general formulas and specific compounds. Furthermore, the compounds of this invention can exist in a variety of different forms or derivatives, all of which are within the scope of this invention. These include, for example, pharmaceutically acceptable salts, tautomers, stereoisomers, racemic mixtures, positional isomers, prodrugs, solvated forms, different crystal forms or polymorphs, and active metabolites, etc.

[0110] As used herein, unless otherwise stated, the term "pharmaceutically acceptable salt" includes salts that retain the biological effectiveness of a particular compound in its free acid / base form and are not undesirable in biological or other respects. Pharmaceutically acceptable salts can include salts formed with inorganic bases or acids and organic bases or acids. Where the compounds of the present invention contain one or more acidic or basic groups, the present invention also includes their corresponding pharmaceutically acceptable salts. Thus, compounds of the present invention containing acidic groups (e.g., carboxyl groups) can exist in salt form and can be used according to the present invention, for example, alkali metal salts, alkaline earth metal salts, aluminum salts, or ammonium salts. Further non-limiting examples of such salts include lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, barium salts, or salts with ammonia or organic amines (e.g., ethylamine, ethanolamine, diethanolamine, triethanolamine, piperidine, N-methylglutamine, or amino acids). These salts are readily available, for example, by reacting compounds having acidic groups with suitable bases (e.g., lithium hydroxide, sodium hydroxide, sodium propoxide, potassium hydroxide, potassium ethoxide, magnesium hydroxide, calcium hydroxide, or barium hydroxide). Other basic salts of the compounds of the present invention include, but are not limited to, copper (I), copper (II), iron (II), iron (III), manganese (II), and zinc salts. The compounds of the present invention contain one or more basic groups, such as protonable groups, which may exist in the form of salts and may be used according to the present invention as addition salts of these groups with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, hydrogen iodide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, sulfoacetic acid, trifluoroacetic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, carbonic acid, formic acid, propionic acid, neopentanoic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, malonic acid, maleic acid, malic acid, pamoic acid, mandelic acid, aminosulfonic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, taurocholic acid, glutaric acid, stearic acid, glutamic acid, or aspartic acid, and other acids known to those skilled in the art. The salts formed are, in particular, hydrochlorides, chlorides, hydrobromates, bromides, iodides, sulfates, phosphates, methanesulfonates, toluenesulfonates, carbonates, bicarbonates, formates, acetates, sulfoacetates, trifluoromethanesulfonates, oxalates, malonates, maleates, succinates, tartrates, malates, pamoates, mandelates, fumarates, lactates, citrates, glutarate, stearates, aspartate salts, and glutamates. Furthermore, the stoichiometry of the salts formed from the compounds of this invention can be an integer multiple or a non-integer multiple of 1.

[0111] The compounds of the present invention containing basic nitrogen-containing groups can be used with reagents such as C. 1-4 Halogenated alkanes undergo quaternization, for example, methyl, ethyl, isopropyl, and tert-butyl chlorides, bromines, and iodines; di-C 1-4Alkyl sulfates, such as dimethyl sulfate, diethyl sulfate, and dipentyl sulfate; C 10-18 Alkyl halides, such as decyl, dodecyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; and aryl C... 1-4 Alkyl halides, such as benzyl chloride and phenylethyl bromide.

[0112] If the compounds of the present invention contain both acidic and basic groups in the molecule, the present invention also includes, in addition to the salt forms described above, internal salts or betaines (zwitterions). The corresponding salts can be obtained by conventional methods known to those skilled in the art, for example by contacting them with organic or inorganic acids or bases in a solvent or dispersant, or by anion or cation exchange with other salts. The present invention also includes all salts of the compounds of the present invention that, due to their low physiological compatibility, are not directly applicable to pharmaceuticals, but can be used, for example, as intermediates in chemical reactions or for the preparation of pharmaceutically acceptable salts. For a review of more suitable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley-VCH, 2002).

[0113] Compounds of formula (I) and their pharmaceutically acceptable salts may exist in both unsolvated and solvated forms. As used herein, the term "solvate" refers to a molecular complex comprising a compound of formula (I) or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable solvent molecules. For example, the term "hydrate" is used when the solvent is water.

[0114] Compounds of formula (I) may have one or more chiral (asymmetric) centers. This invention covers all stereoisomers of compounds of formula (I). Asymmetric centers present in compounds of formula (I) may independently have (R) or (S) configurations. When the bond to the chiral carbon is described as a straight line in the structural formula of this invention, or when the compound name is described without a (R) or (S) chiral name for the chiral carbon, it should be understood that each such (R) and (S) configuration of the chiral carbon, and therefore each enantiomer or diastereomer and mixture thereof, is included in that formula or name. The generation of a particular stereoisomer or mixture thereof may be identified in instances of obtaining such stereoisomers or mixtures, but this in no way limits the inclusion of all stereoisomers and mixtures thereof within the scope of this invention.

[0115] This invention includes all possible enantiomers and diastereomers, as well as mixtures of two or more stereoisomers, such as mixtures of enantiomers and / or diastereomers in all proportions. Thus, enantiomers are the pure forms (as levorotatory and dextrorotatory enantiomers), racemic forms, and mixtures of two enantiomers in all proportions of the subject matter of this invention. In the case of cis / trans isomers, this invention includes the cis and trans forms, as well as mixtures of these forms in all proportions. If desired, individual stereoisomers can be prepared by separating the mixture by conventional methods, such as by chromatography or crystallization, by using stereochemically homogeneous synthetic starting materials, or by stereoselective synthesis. Optionally, derivatization can be performed prior to stereoisomer separation. The separation of stereoisomer mixtures can be carried out as an intermediate step during the synthesis of compounds of formula (I), or on the final racemic product. Absolute stereochemistry can be determined by X-ray crystallography of the crystalline products or intermediates, if necessary, by derivatizing these products or intermediates with reagents containing stereocenters of known configurations. Alternatively, absolute stereochemistry can be determined by vibrational circular dichroism (VCD) spectroscopy.

[0116] Unless otherwise stated, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms; in other words, compounds in which one or more atoms are replaced by atoms having the same atomic number, but with a different atomic mass or mass number than the dominant atomic mass or mass number found in nature. Such compounds are referred to as “isotope variants.” This invention aims to include all pharmaceutically acceptable isotope variants of compounds of formula (I). Examples of isotopes suitable for inclusion in compounds of this invention include, but are not limited to, isotopes of hydrogen, such as… 2 H (i.e., D) and 3 H; carbon, for example 11 C 13 C and 14 C; chlorine, for example 36 Cl; fluorine, for example 18 F; Iodine, for example 123 I and 125 I; nitrogen, for example 13 N and 15 N; oxygen, for example 15 O、 17 O and 18 O; phosphorus, for example 32 P; and sulfur, for example 35 Certain isotopic variants of compounds of formula (I), such as those doped with radioactive isotopes, can be used for drug and / or substrate tissue distribution studies. In particular, those with isotopic variations are only available when replaced with a heavier isotope (e.g., with deuterium). 2Compounds with different depicted structures in (H or D) replacing hydrogen can provide certain therapeutic advantages, for example, due to greater metabolic stability, increased in vivo half-life, or reduced dose requirements, and may therefore be used in certain specific situations. Isotopic variants of compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the appended examples, and by using appropriate isotopic labeling reagents instead of previously used unlabeled reagents.

[0117] Pharmaceutically acceptable solvates according to the invention may include those in which the crystallization solvent can be replaced by an isotope, such as D2O, d6-acetone, d6-DMSO.

[0118] One way to carry out the invention is by administering the compound of formula (I) as a prodrug. Thus, certain derivatives of the compound of formula (I) may themselves have little or no pharmacological activity, but when administered in vivo or on the body, they are converted into the compound of formula (I) having the desired activity, for example, by hydrolytic cleavage, particularly hydrolytic cleavage promoted by esterases or peptidases. Such derivatives are referred to as “prodrugs”. More information on the use of prodrugs can be found, for example, T. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems”, Vol. 14, ACS Symposium Series, and E.B. Roche (Ed.), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987, American Pharmaceutical Association. See also Nature Reviews / Drug Discovery, 2008, 7, 355, and Current Opinion in Drug Discovery and Development, 2007, 10, 550.

[0119] The prodrug according to the invention can be prepared, for example, by replacing suitable functional groups present in the compound of formula (I) with certain portions known to those skilled in the art, for example, the “pre-part” described in H. Bundgaard, “Design of Prodrugs”, Elsevier, 1985, and Y.M. Hoi-Sledeski and C.G. Wiermuth, “Designing Prodrugs and Bioprecursors”, Practice of Medicinal Chemistry, 4th Edition, Chapter 28, 657-696, Elsevier, 2015. Therefore, the prodrug according to the invention can include, but is not limited to, (a) ester or amide derivatives of carboxylic acids in compounds of formula (I), if present; (b) amide, imine, carbamate, or amine derivatives of amino groups in compounds of formula (I); (c) oxime or imine derivatives of carbonyl groups in compounds of formula (I), if present; or (d) methyl, primary alcohol, or aldehyde groups of carboxylic acids that can be metabolized and oxidized in compounds of formula (I), if present.

[0120] Compounds of formula (I) include the compound itself and its prodrug. This invention includes compounds of such formula (I), pharmaceutically acceptable salts of such compounds, and pharmaceutically acceptable solvates of said compounds and salts.

[0121] Use and application

[0122] The compounds of the present invention—or pharmaceutically acceptable salts, solvates, stereoisomers, or isotopic variants thereof, including mixtures thereof in all proportions—are available as pharmaceuticals. They have been found to exhibit pharmacological activity inhibiting TEAD. It is hypothesized that through this activity, the compounds of the present invention can prevent or reverse dysfunction of the Hippo pathway. By preventing its dysfunction, the Hippo pathway may be able to exert its role as a tumor suppressor. In addition to preventing or reversing Hippo pathway dysfunction and independent of upstream Hippo regulation, the pharmacological activity of the compounds of the present invention may also be beneficial for inhibiting other pathophysiological conditions in which TEAD would be advantageous.

[0123] Therefore, the compounds of the present invention, as TEAD inhibitors, are particularly suitable for treating hyperproliferative diseases and cancers, especially tumors, including solid tumors such as breast cancer, lung cancer, mesothelioma, epithelioid hemangioendothelioma, uveal melanoma, liver cancer, ovarian cancer, squamous cell carcinoma, kidney cancer, gastric cancer, medulloblastoma, colon cancer, pancreatic cancer, schwannoma, meningioma, glioma, and basal cell carcinoma. No specific theory or explanation is intended, but it can be hypothesized that these compounds may achieve this goal by acting directly on cancer cells and / or indirectly by modulating the immune system's response to tumors. Furthermore, the compounds of the present invention can also be used to treat non-cancerous conditions and diseases, such as cardiovascular diseases and fibrosis (e.g., liver fibrosis).

[0124] The compounds of the present invention can be administered in amounts effective in treating the diseases or symptoms described herein. The compounds of the present invention can be administered as the compound itself, or optionally, as a pharmaceutically acceptable salt. For administration and dosing purposes, the compounds of the present invention, or their pharmaceutically acceptable salts, solvates, stereoisomers, or isotopic variants, will be simply referred to as the compounds of the present invention.

[0125] The compounds of the present invention are administered via any suitable route in the form of a pharmaceutical composition suitable for such route, and at a dose effective for the intended treatment. The compounds of the present invention can be administered orally, rectally, vaginally, parenterally, or topically.

[0126] As used herein, the terms “administration” and “administer” mean the absorption, ingestion, injection, inhalation, implantation, or other introduction of the compound or pharmaceutical composition thereof of the present invention. The terms “treatment” and “treat” mean reversing, alleviating, delaying the onset of or inhibiting the progression of a “pathological condition” (e.g., a disease, symptom, or illness, or one or more signs or symptoms thereof) described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of a disease or symptom have developed or been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of a disease or symptom. For example, treatment may be given to susceptible individuals before the onset of symptoms (e.g., based on a history of symptoms and / or based on genetic or other susceptibility factors). Treatment may also continue after symptoms have subsided, for example, to delay or prevent recurrence. As used herein, the terms “disease,” “symptom,” “illness,” and “pathological condition” are used interchangeably.

[0127] Those skilled in the art can determine the appropriate dosage level through routine experiments. Dosing regimens for the compounds of the present invention and / or compositions containing said compounds are based on a variety of factors, including patient type, age, weight, sex, and medical condition; severity of symptoms; route of administration; and the activity of the specific compound used. Therefore, dosage regimens can vary considerably. For example, the dosage level of the compounds of the present invention can be from about 0.001 to about 100 mg / kg per day (i.e., mg / kg body weight). In some embodiments, the total daily dose of the compounds of the present invention, administered in a single or multiple doses, can be from about 0.001 to about 10 mg / kg. It is not uncommon for the administration of the compounds of the present invention to be repeated multiple times within a single day.

[0128] In some embodiments, the compounds of the present invention may be administered in combination with one or more other therapeutic agents. In some embodiments, non-limiting examples of the other therapeutic agents may include anticancer agents. The other therapeutic agents may be administered before, after, or simultaneously with the administration of the compounds of the present invention.

[0129] As used herein, the term "anticancer agent" refers to any pharmaceutical agent administered to a subject suffering from cancer for the purpose of treating cancer. Conventional surgery or radiation therapy or drug therapy can be used in combination with the compounds of the present invention for cancer treatment. Such drug therapies, such as chemotherapy or targeted therapy, may include one or more, but preferably one of the following anticancer agents:

[0130] Alkylating agents: such as hexamethylmelamine, bendamustine hydrochloride, busulfan, carmustine, chlorambucil, nitrogen mustard hydrochloride, cyclophosphamide, dacarbazine, ifosfamide, improsulfan, sultacin, lomustine, melphalan hydrochloride, dibromomannitol, mitolactalol, nimustine hydrochloride, ranimustine, temozolomide, thiotepa, treosulfan, mechloretamine, carboquone, apaziquone, formustine, glufosfamide, palifosfamide, pipebroman, trofosfamide, uramustine, evofosfamide, VAL-083.

[0131] Platinum compounds: such as carboplatin, cisplatin, eptaplatin, miriplatin hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, and satraplatin.

[0132] DNA altering agents include, for example, amrubicin, bisantrene, decitabine, mitoxantrone hydrochloride, procarbazine hydrochloride, trabectedin, clofarabine, acridine, brostallicin, pixantrone, and larumustine.

[0133] Topoisomerase inhibitors: such as etoposide, irinotecan hydrochloride, dexrazoxane, sobuzoxane, teniposide, topotecan hydrochloride, amonafide, belotecone, elliptinium acetate, and voreloxin.

[0134] Microtubule modulators: such as cabazitaxel, docetaxel, iribulin, ixabepilone, paclitaxel, vincristine, vinorelbine, vindesine, vinflunine, fosbretabulin, and tesetaxel.

[0135] Antimetabolites: such as asparaginase, azacitidine, leucovorin calcium, capecitabine, cladribine, cytarabine, enocitabine, fluorouracil, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, azathiopurine, thioguanine, carmoflurane, deoxyfluorouridine, elacytarabine, raltitrexed, sapacitabine, tegafur, and trimetrexate.

[0136] Anticancer antibiotics: such as bleomycin, actinomycin D, doxorubicin, epirubicin, idarubicin, levamisole, miltefosine, mitomycin C, romidepsin, streptozocin, valrubicin, zinostatin, zorubicin, daunurobicin, plicamycin, arubicin, peplomycin, and pirarubicin.

[0137] Hormones / antagonists: such as abarrelix, abiraterone, bicalutamide, buserelin, calusterone, chlorestradiol, degarelix, dexamethasone, estradiol, fluocortolone, fluoxymesterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, medroxyprogesterone acetate, mitotane. Nafarelin, nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen, thyrotropinalfa, toremifene, trilostane, triptorelin, diethylstilbestrol, acolbifene, danazol, deslorelin, epitiostanol, orteronel, enzalutamide.

[0138] Aromatase inhibitors: such as aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone, and formestane.

[0139] Small molecule kinase inhibitors: such as crizotinib, dasatinib, erlotinib hydrochloride, imatinib mesylate, lapatinib tosylate, nilotinib, pazopanib, regorafenib, ruxolitinib phosphate, sorafenib tosylate, sunitinib malate, vandetanib, vemurafenib, bosutinib, gefitinib, axitinib, afatinib maleate, alisertib, dabrafenib mesylate, dacomitinib, dinaciclib, dovitinib, enzastaurin, nintedanib ethoxylate, lenvatinib mesylate, linifanib, lincitinib. sitinib, masitetinib, midostaurin, motesanib, neratinib maleate, orantinib, perifosine, ponatinib, ratotinib, rigosertib, tepotinib, tipifarnib, tivantinib, tivozanib, trametinib, pimasertib, brivanib alanine alaninate, cediranib, apatinib mesylate, cabozantinib S-malate, ibrutinib, icotinib hydrochloride, buparlisib, cipatinib, cobimetinib, idelalisib, fedratinib, tesevatinib.

[0140] Photosensitizers: such as methoxsalen, porfimer sodium, talaporfin, and temoporfin.

[0141] Antibodies: such as alemtuzumab, besilesomab, brentuximab, cetuximab, denosumab, ipilimumab, ofratuximab, panitumumab, rituximab, tositumomab, trastuzumab, bevacizumab, pertuzumab, catumaxomab, elotuzumab, epratuzumab, farletuzumab, mogamulizumab, necitumumab, and nitocinumab. Ocaratuzumab, oxaratuzumab, oregovomab, ramoximumab, rilotumumab, stucciuzumab, tocilizumab, zalutumumab, zanolimumab, matuzumab, dalotuzumab, onartuzumab, racotumomab, tabalumab, EMD-525797, atezolizumab, durvalumab, pembrolizumab, nivolumab.

[0142] Cytokines: such as aldesleukin, interferon α2, interferon α2a, interferon α2b, celmoleukin, tasonermin, teceleukin, oprelvekin, and recombinant interferon β-1a.

[0143] Drug conjugates: such as denileukin diftitox, ibritumomabtiuxetan, iobenguane I 123, prednimustine, trastuzumab emtansine, estrustine, gemtuzumab, Ozogamicin, aflibercept, cintredekin besudotox, edotreotide, oxatuzumab, naptumomab estafenatox, oportuzumab monatox, technetium (99mTc)arcitumomab, and vintafolide.

[0144] Vaccines: such as sipuleucel, vitespen, emepepimut-S, oncoVAX, rindopepimut, troVax, MGN-1601, MGN-1703.

[0145] Others include alitretinoin, bexarotene, bortezomib, everolimus, ibandronic acid, imiquimod, lenalidomide, lentinan, metirosine, mifamurtide, and pamidronic acid. acid), pegaspargase, pentostatin, sipuleucel, sizofiran, tamibarotene, temsirolimus, thalidomide, retinoic acid, vismodegib, zoledronic acid, vorinostat, celecoxib, cilengitide, entinostat, etanidazole, ganetspib, idronoxil, iniparib, ixazomib citrate, lonidamine, nimodipine Nimorazole, panobinostat, peretinoin, plitidepsin, pomalidomide, procodazol, ridaforolimus, tasquinimod, telotristat, thymosin, tirapazamine, tosedostat, trabedersen, ubenimex, valspodar, gendicine, picibanil, reolysin, retaspimycin hydrochloride, trebananib, virulizin, carfilzomib, endostatin, immucothel, belinostat.

[0146] PARP inhibitors: Olaparib, Veliparib.

[0147] MCT1 inhibitors: AZD3965, BAY-8002.

[0148] Pharmaceutical Composition

[0149] In some aspects, the present invention relates to pharmaceutical compositions comprising a compound of formula (I) as provided herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0150] As used herein, the term "pharmaceuticalally acceptable carrier or excipient" refers to a carrier or excipient that can be used to prepare a pharmaceutical composition, is generally safe, non-toxic, and not biologically or otherwise undesirable, and includes carriers or excipients acceptable for veterinary use as well as for human pharmaceutical use. As used herein, a pharmaceutically acceptable carrier or excipient includes one or more such carriers or excipients. The specific carrier or excipient used will depend on the manner and purpose of applying the compounds of the present invention. Suitable carriers and excipients are well known to those skilled in the art and are detailed in, for example, Ansel, Howard C et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R. et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. It may also include one or more of buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow aids, processing aids, colorants, sweeteners, flavorings, diluents, and other known additives to provide a refined performance of the drug (i.e., the compounds or drug compositions provided herein) or to contribute to the production of a drug product (i.e., the drug).

[0151] The compositions of the present invention can be formulated into a variety of forms. These include, for example, liquid, semi-solid, and solid dosage forms, such as liquid solutions (e.g., injectable and infusionable solutions), dispersions or suspensions, tablets, pills, powders, liposomes, suppositories, etc. The form depends on the intended manner of administration and therapeutic application.

[0152] The pharmaceutical compositions of the present invention can be prepared by any well-known pharmaceutical techniques (e.g., effective formulations and administration procedures). The considerations above regarding effective formulations and administration procedures are well known in the art and are described in standard textbooks. For example, formulations of pharmaceutical products are discussed in Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman et al., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Kibbe et al., eds., Handbook of Pharmaceutical Excipients, 3rd edition, American Pharmaceutical Association, Washington, 1999.

[0153] In some embodiments, the pharmaceutical composition comprises a compound of formula (I) as provided herein, or a pharmaceutically acceptable salt, solvate, stereoisomer or isotopic variant thereof, in combination with one or more other therapeutic agents (e.g., anticancer agents), and at least one pharmaceutically acceptable carrier or excipient.

[0154] In another aspect, the present invention relates to a kit for treating TEAD-related diseases or symptoms, comprising a compound of formula (I) as provided herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, or a pharmaceutical composition comprising a compound of formula (I) as provided herein, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, a container, and optionally a packaging insert or label indicating treatment. In some embodiments, the kit may further comprise one or more additional therapeutic agents, such as anticancer agents.

[0155] Treatment

[0156] In another aspect, the present invention relates to a method for treating a subject with TEAD-related disease or condition such as cancer, due to the TEAD-inhibiting activity of the compounds of the present invention, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) as provided herein, or a pharmaceutically acceptable salt, solvate, stereoisomer or isotopic variant thereof.

[0157] As used herein, the term "subject in need" refers to a subject who has TEAD-related disease or symptoms, or a subject who has an increased risk of developing TEAD-related disease or symptoms relative to the general population. In some embodiments, the subject is a warm-blooded animal. In some embodiments, the warm-blooded animal is a mammal. In some embodiments, the warm-blooded animal is a human.

[0158] As used herein, the term "TEAD-related disease or symptom" refers to any pathophysiological condition in which inhibition of TEAD would be beneficial. In some embodiments, a TEAD-related disease or symptom is cancer. In some embodiments, a TEAD-related disease or symptom is cancer selected from the group consisting of: breast cancer, lung cancer, mesothelioma, epithelioid hemangioendothelioma, uveal melanoma, liver cancer, ovarian cancer, squamous cell carcinoma, kidney cancer, gastric cancer, medulloblastoma, colon cancer, pancreatic cancer, schwannoma, meningioma, glioma, and basal cell carcinoma.

[0159] The methods for treating TEAD-related diseases or symptoms described herein can be used as monotherapy. As used herein, the term "monotherapy" refers to the administration of a single active or therapeutic compound to a subject in need. In some embodiments, monotherapy will involve administering to a subject in need of such treatment a therapeutically effective amount of one of the compounds of the present invention or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof.

[0160] Depending on the specific disease or symptom to be treated, the methods described herein for treating TEAD-related diseases or symptoms may include, in addition to administering the compound of formula (I), combination therapy with one or more additional therapeutic agents, such as anticancer agents. As used herein, the term "combination therapy" refers to the combined administration of multiple active therapeutic agents. In some embodiments, the compound of the present invention, or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, may be administered concurrently, alone, or sequentially with treatment with one or more additional therapeutic agents. For example, the additional therapeutic agent may be administered alone with the compound of the present invention as part of a multi-dose regimen. Alternatively, the additional therapeutic agent may be part of a single dosage form, mixed with the compound of the present invention in a single composition.

[0161] In another aspect, the present invention relates to compounds of formula (I) as provided herein, or pharmaceutically acceptable salts, solvates, stereoisomers or isotopic variants thereof, for the treatment of TEAD-related diseases or conditions, such as cancer.

[0162] In another aspect, the present invention relates to the use of compounds of formula (I) as provided herein, or pharmaceutically acceptable salts, solvates, stereoisomers or isotopic variants thereof, in the preparation of medicaments for treating TEAD-related diseases or conditions such as cancer.

[0163] synthesis

[0164] The compounds of the present invention can be prepared using general knowledge known to those skilled in the art of synthetic organic chemistry, by means of the general and specific methods described below. Such general knowledge can be found in standard reference books, for example, Barton and Ollis (eds.), Comprehensive Organic Chemistry, Elsevier; Richard Larock, Comprehensive Organic Transformations: A Guide to the Preparation of Functional Groups, John Wiley and Sons; and Outline of Organic Synthetic Methods, Volumes I-XII, Wiley-Interscience.

[0165] The schemes described below are intended to provide a general description of methods for preparing the compounds of the present invention. Some compounds of the present invention may contain a single or multiple chiral centers having stereochemical names (R) or (S). It will be apparent to those skilled in the art that all synthetic transformations can be carried out in a similar manner, regardless of whether the material is enantiomerically enriched or racemic. Furthermore, the determination of desired optically active materials can be performed using known methods, such as those described herein and in the chemical literature, at any desired point in the procedure.

[0166] Example

[0167] To describe the invention in more detail, the following embodiments are presented. The embodiments described herein are for illustrative purposes only and should not be construed as limiting their scope in any way.

[0168] During synthesis, it may be necessary and / or desirable to protect any sensitive or reactive groups on the relevant molecules. This can be achieved using conventional protecting groups, such as those described in TW Greene and PGM Utts, Protecting Groups in Organic Synthesis, 4th Edition, John Wiley and Sons. Protecting groups can optionally be removed at a convenient subsequent stage using methods well known in the art.

[0169] The compounds of the present invention can be readily prepared using readily available starting materials, reagents, and conventional synthetic procedures according to the following reaction schemes and examples or modifications thereof. Variations known to those skilled in the art but not mentioned in more detail may also be used in these reactions. Furthermore, other methods for preparing the compounds of the present invention based on the reaction schemes and examples described herein will be apparent to those skilled in the art. Unless otherwise stated, all variables are as defined above. Generally, in chemical procedures, all reagents and starting materials are available from commercial suppliers or can be readily prepared by those skilled in the art.

[0170] Exemplary compounds are shown in Table 1.

[0171] Table 1

[0172]

[0173]

[0174]

[0175]

[0176]

[0177] Preparation of intermediate A:

[0178]

[0179] Step 1:

[0180] To a solution of tert-butyl 4-oxoperidin-1-carboxylate (1.00 g, 5.02 mmol) in AcOH (10 mL), p-toluidine (796 mg, 5.02 mmol) was added. The mixture was stirred at 65 °C for 5 hours. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with NaHCO3 (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give A-1. LCMS [M+H] + :287.3.

[0181] Step 2:

[0182] A mixture of A-1 (50 mg, 174 μmol), 1-iodo-4-(trifluoromethyl)benzene (142 mg, 523 μmol, 77.0 μL), CuI (16.6 mg, 87.3 μmol), K3PO4 (111 mg, 523 μmol), and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (12.4 mg, 87.3 μmol) in DMF (1.50 mL) was degassed and purged three times with nitrogen. The resulting mixture was stirred at 90 °C for 3 hours under nitrogen protection. After the reaction was complete, the reaction mixture was diluted with EtOAc (30 mL) and filtered. The filtrate was diluted with water (100 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by preparative TLC to obtain A-2. LCMS [M+H] + :431.3.

[0183] Step 3:

[0184] TFA (1.0 mL) was added to a DCM (3.0 mL) solution of A-2 (100 mg, 0.232 mmol). The resulting reaction mixture was stirred at room temperature for 1.5 hours. After completion, the reaction mixture was concentrated under reduced pressure to give intermediate A. LCMS[M+H] + :331.2.

[0185] Example 1

[0186] Preparation of 6-methyl-9-(4-(trifluoromethyl)phenyl)-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid

[0187]

[0188] The title compound was prepared according to the following procedure.

[0189]

[0190] Step 1:

[0191] A mixture of p-toluenehydrazine hydrochloride (1.50 g, 12.8 mmol) and ethyl 4-oxocyclohexane-1-carboxylate (2.15 mL, 13.5 mmol) in AcOH (702 μL, 12.2 mmol) was heated and stirred at 80 °C for 3 h under nitrogen protection. Afterward, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (80 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give 1-1 LCMS [M+H]. + :258.2.

[0192] Step 2:

[0193] To a mixture of 1-1 (200 mg, 777 μmol) and 1-iodo-4-(trifluoromethyl)benzene (211 mg, 777 μmol, 114 μL) in DMF (10 mL), N,N'-dimethylethane-1,2-diamine (68.5 mg, 777.22 μmol, 83.65 μL), Cs₂CO₃ (506 mg, 1.55 mmol), and CuI (7.4 mg, 38.86 μmol) were added, and the mixture was purged three times with nitrogen. The resulting mixture was stirred at 120 °C for 10 h under nitrogen protection. After completion, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (80 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel chromatography to give 1-2. LCMS [M + H] + :402.2.

[0194] Step 3:

[0195] A solution of LiOH (15.8 mg, 377 μmol) in water (1 mL) was added to a THF solution (4 mL) containing 50.0 mg, 125 μmol. The resulting mixture was stirred at 25 °C for 4 hours. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (80 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by preparative HPLC to give the compound of Example 1. 1 HNMR: (400MHz, CDCl3) δ7.77(d,J=8.3Hz,2H),7.49(d,J=8.2Hz,2H),7.33(s,1H),7.15(d,J=8.4Hz,1H),6.99(dd,J=8.5,1.7Hz,1H ),3.17(dd,J=15.4,5.3Hz,1H),3.07–2.90(m,2H),2.79–2.69(m,2H),2.46(s,3H),2.41–2.29(m,1H),2.12–1.97(m,1H).LCMS[M+H] + 373.9.

[0196] Example 2

[0197] Preparation of 1-(8-methyl-5-(4-(trifluoromethyl)phenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)prop-2-en-1-one

[0198]

[0199] The title compound was prepared according to the following procedure.

[0200] .

[0201] At 0°C, 2-enoyl chloride (9.04 mg, 0.100 mmol) was added to a solution of intermediate A (30.0 mg, 0.0910 mmol) and NaHCO3 (38.1 mg, 0.454 mmol) in THF (2.00 mL) and water (1.00 mL). After the addition was complete, the reaction mixture was stirred at 25°C for 30 minutes. Upon completion, the reaction mixture was diluted with water (50 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed with water (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by preparative HPLC to obtain the compound of Example 2. 1HNMR: (400MHz, CDCl3) δ7.81(d,J=8.2Hz,2H),7.51(d,J=8.1Hz,2H),7.34(d,J=22.6Hz,1H),7.23(d,J=8.8Hz,1H),7.05(d,J=8.5Hz,1H),6.82–6.64 (m,1H),6.38(dd,J=16.8,1.9Hz,1H),5.78(d,J=10.6Hz,1H),4.90(d,J=3 4.6Hz,2H),4.05(s,1H),3.90(s,1H),2.82(s,2H),2.50(s,3H).LCMS[M+H] + :385.3.

[0202] Example 3

[0203] Preparation of 2-chloro-2-fluoro-1-(8-methyl-5-(4-(trifluoromethyl)phenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)acetoone

[0204]

[0205] The title compound was prepared according to the following procedure.

[0206]

[0207] Step 1:

[0208] An aqueous solution of NaOH (5M, 2.85 mL, 14.23 mmol) was added dropwise to ethyl 2-chloro-2-fluoroacetate (2.00 g, 14.2 mmol). After completion, the resulting reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with water (30 mL) and extracted with MTBE (20 mL × 3). The combined organic layers were washed with water (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 3-1.

[0209] Step 2:

[0210] To a solution of 3-1 (100 mg, 0.303 mmol) and intermediate A (68 mg, 0.605 mmol) in DCM (5 mL), DIEA (0.25 mL, 1.51 mmol) and T3P (50 wt% in EtOAc, 0.070 mL, 2.11 mmol) were added. The resulting reaction mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was diluted with water (50 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed with water (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by preparative HPLC to give the compound of Example 3.1 HNMR: (400MHz, CDCl3) δ7.82 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 7.5 Hz, 2H), 7.34 (s, 1H), 7. 23(dd,J=8.4,3.7Hz,1H),7.07(dd,J=8.8,4.0Hz,1H),6.62(dd,J=50.8,14.3Hz,1H), 5.07–4.94(m,1H),4.85(dd,J=24.2,15.8Hz,1H),4.17(ddt,J=33.5,14.1,5.2Hz,1H) ,3.89(dddd,J=25.3,12.7,7.6,4.8Hz,1H),2.98–2.73(m,2H),2.50(d,J=4.8Hz,3H).

[0211] Example 4

[0212] Preparation of 8-methyl-2-(methylsulfonyl)-5-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole

[0213]

[0214] The title compound was prepared according to the following procedure.

[0215]

[0216] At 0°C, methanesulfonic anhydride (32 mg, 0.18 mmol) was added to a solution of intermediate A (30 mg, 0.09 mmol) and TEA (25 μL, 0.18 mmol) in 2.00 mL of DCM. The resulting reaction mixture was stirred at 25°C for 1 hour. After completion, the reaction mixture was diluted with water (50 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed with water (50 mL), dried over anhydrous sodium sulfate, and filtered. The resulting filtrate was concentrated and purified by preparative HPLC to obtain the compound of Example 4. 1 HNMR: (400MHz, CDCl3) δ7.80 (d, J = 8.3Hz, 2H), 7.49 (d, J = 8.2Hz, 2H), 7.28 (s, 1H), 7.20 (d, J = 8.4Hz, 1H), 7.04 (dd, J=8.5,1.7Hz,1H),4.62(s,2H),3.68(t,J=5.7Hz,2H),2.92(s,3H),2.85(t,J=5.6Hz,2H),2.47(s,3H).LCMS[M+H] + :409.2.

[0217] Example 5

[0218] Preparation of 8-methyl-5-(4-(trifluoromethyl)phenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-sulfonamide

[0219]

[0220] The title compound was prepared according to the following procedure.

[0221]

[0222] At 0°C, azirmonyl chloride (104 mg, 0.908 mmol) was added to a solution of intermediate A (100 mg, 0.303 mmol) and NaHCO3 (38.1 mg, 0.454 mmol) in THF (2 mL) and water (1 mL). The resulting reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with DCM (30 mL × 3). The combined organic layers were washed with water (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by preparative HPLC to give the compound of Example 5. 1 HNMR: (400MHz, CDCl3) δ7.82(d,J=8.3Hz,2H),7.51(d,J=8.2Hz,2H),7.30(s,1H),7.22(d,J=8.4Hz,1H),7.06(d d,J=8.4,1.3Hz,1H),4.60(s,2H),4.50(s,2H),3.66(t,J=5.7Hz,2H),2.94–2.87(m,2H),2.49(s,3H).LCMS[M+H] + :410.2.

[0223] Example 6

[0224] Preparation of N,8-dimethyl-5-(4-(trifluoromethyl)phenyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-sulfonamide

[0225]

[0226] The title compound was prepared according to the following procedure.

[0227]

[0228] To a solution of intermediate A (50 mg, 0.151 mmol) in DCM (0.5 mL), methylazasulfonyl chloride (19.61 mg, 0.151 mmol) and TEA (0.063 mL, 0.454 mmol) were added. The reaction was stirred overnight at room temperature, and then eluted with EtOAc and water. The resulting organic layer was washed with brine, concentrated, and purified by preparative HPLC to give the compound of Example 6. 1 H NMR (400MHz, CD3OD) δ7.77(d,J=8.4Hz,2H),7.51(d,J=8.3Hz,2H),7.18(s,1H),7.08(d,J=8.4Hz,1H),6.90(d ,J=8.4Hz,1H),4.39(s,2H),3.51(t,J=5.6Hz,2H),2.74(t,J=5.6Hz,2H),2.57(s,3H),2.33(s,3H).LCMS[M+H] + :424.1.

[0229] Bioactivity evaluation

[0230] The following examples demonstrate the bioactivity of the compounds of the present invention.

[0231] 1. Cell growth assay

[0232] 1.1 Cell Culture

[0233] RPMI 1640 medium (Gibco, 31800) + 10% FBS (Biosera, FB-1058 / 500) was used for NCI-H226 cells (from ATCC).

[0234] 1.2 Reagents

[0235] CellTiter-Glo reagent (CTG reagent, Promega, G7573).

[0236] 1.3 Operating Procedures

[0237] (1) Cells were seeded into 384-well microplates (150 cells / well, 50 mL of culture medium / well). Additional plates were also seeded as a day 0 control. The microplates were incubated overnight at 37°C and 5% CO2.

[0238] (2) The compound was serially diluted 3-fold in DMSO to a maximum final concentration of 30 mM, for a total of 10 concentrations. 0.3% DMSO was used as a solvent control. In addition, 25 mL / well of CTG reagent was added to an additional plate and incubated at room temperature for 30 minutes, and the luminescence signal was detected using an EnVision (PerkinElmer, 2104 Multilabel Reader) as a day 0 control.

[0239] (3) The plates treated with other compounds were incubated at 37°C for another 7 days. 25 mL of CTG reagent was added to the plates and incubated at room temperature for 30 minutes. The luminescence signal was then detected.

[0240] 1.4 Data Analysis

[0241] (1) The luminescence signal on day 0 was used as a negative control or baseline.

[0242] Signal 第0天 = Average luminescence signal of control cells on day 0.

[0243] Signal DMSO溶媒对照 = Average luminescence signal of control cells in DMSO solvent on day 7.

[0244] Signal cpds处理 = Day 7: Compound treatment of cell luminescence signals.

[0245] Suppression % = 1 - (signal) cpds处理 -Signal 第0天 ) / (Signal DMSO溶媒对照 -Signal 第0天 )*100.

[0246] (2) Calculate the 50% growth inhibition (GI) using dose-response curves. 50 ) and maximum inhibition%.

[0247] Table 2

[0248]

[0249] 2. TEAD luciferase reporter gene assay

[0250] 2.1 Cell Culture

[0251] HEK-293T cells were cultured in DMEM medium (Gibco, 10566-016) + 10% FBS (Gibco, 10099-141). Eight tandem repeat sequences of the TEAD binding element upstream of the firefly luciferase reporter plasmid were transfected into HEK-293T cells to establish a stable TEAD reporter gene monoclonal cell line.

[0252] 2.2 Reagents

[0253] Luciferase detection system (Promega, E2940).

[0254] 2.3 Operating Procedures

[0255] (1) 20,000 cells / well were seeded into a 96-well plate (Corning, 3603). The plate was incubated overnight at 37°C and 5% CO2.

[0256] (2) The compound was serially diluted 4-fold in DMSO, with a maximum final concentration of 30 mM, for a total of 10 concentrations. 0.3% DMSO was used as a solvent control. The plates were then incubated at 37°C and 5% CO2 for 24 hours.

[0257] (3) Add 75 ml / well of Glo- reagent to a 9-well plate. Incubate the plate and shake for 10 minutes. Detect firefly bioluminescence using an Envision (PerkinElmer, 2104 Multilabel Reader).

[0258] 2.4 Data Analysis

[0259] (1) The luminescent signal of blank culture medium was used as a negative control.

[0260] Signal 阴性对照 = The average value of the luminescence signal of the negative control.

[0261] Signal DMSO溶媒对照 = The average value of the emission signal of the DMSO control.

[0262] Signal cpds处理 = The luminescent signal processed by the compound.

[0263] Suppression % = (1 - (signal) cpds处理 -Signal 阴性对照 ) / (Signal DMSO溶媒对照 -Signal 阴性对照 ))*100.

[0264] (2) Fitting IC from the nonlinear regression equation 50 :

[0265] Y = bottom + (top - bottom) / (1 + 10^(logIC)) 50 -X)*Hill slope).

[0266] X: Compound concentration.

[0267] Y: Inhibition%.

[0268] Top and bottom: Plateau period in the same unit as Y.

[0269] logIC 50 : The same logarithmic unit as X.

[0270] Hill slope: Slope coefficient or Hill slope.

[0271] Table 3

[0272]

[0273]

[0274] The foregoing description is intended to be merely illustrative of the principles of the invention. Furthermore, since many modifications and variations will be apparent to those skilled in the art, it is not intended to limit the invention to the exact construction and process described above. Therefore, all suitable modifications and equivalents are to be considered to fall within the scope of the invention as defined by the appended claims.

[0275] All publications, patents and patent applications cited herein are incorporated herein by reference in their entirety.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein said compound has a structure represented by the following formula: 、 、 、 、 、 、 , or .

2. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

3. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer.

4. The use as claimed in claim 3, wherein the cancer is selected from the group consisting of: breast cancer, lung cancer, mesothelioma, epithelioid angioendothelioma, uveal melanoma, liver cancer, ovarian cancer, squamous cell carcinoma, kidney cancer, gastric cancer, medulloblastoma, colon cancer, pancreatic cancer, schwannoma, meningioma, glioma, and basal cell carcinoma.

5. A kit comprising: The compound of claim 1 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 2; Containers; and Optional instruction leaflets or labels for treatment.

Images