(hetero) aryl aniline compound with TEAD protease inhibitory activity and medical application

Abstract

The invention provides a (hetero) aryl aniline compound used as a Hippo pathway or a pharmaceutically acceptable form thereof, and a preparation method and application thereof, which are mainly used for treating or preventing proliferative diseases (such as cancers), especially for regulating and treating related diseases caused by abnormal activity of YAP / TEAD.

Description

Technical Field

[0001] This invention belongs to the field of medicine. Specifically, this invention relates to (hetero)aryl aniline compounds used in the Hippo pathway, their preparation methods and uses, mainly for the treatment or prevention of proliferative diseases (such as cancer), especially for regulating and treating diseases related to abnormal activity of YAP / TEAD. Background Technology

[0002] The Hippo pathway is essentially composed of a core kinase cascade that includes the Ste-20 family of protein kinases MST1-2, the scaffold protein Salvador, and the large tumor suppressor kinases LATS1-2, as well as the transcriptional coactivators YAP (Yes1-associated protein) and TAZ (a transcriptional coactivator with a PDZ-binding motif). YAP and TAZ are the main effector factors of the Hippo signaling pathway, acting together with the nuclear TEAD (transcription-enhancing association domain) as transcription factors to increase the expression of target genes such as CTGF (connective tissue growth factor) and CYR61. The Hippo pathway is a crucial regulator of cell growth, proliferation, and migration. TEAD transcription factors are located at the core of the Hippo pathway and are essential for regulating organ growth and wound repair. Dysregulation of TEAD and its regulatory cofactor Yes-associated protein (YAP) has been involved in many human cancers and hyperproliferative pathologies, and dysregulation of this pathway is frequently detected in human cancers. Similar to TEAD proteins, YAP and TAZ activation has been identified in numerous human tumors and is crucial for tumor initiation, progression, and metastasis. Elevated YAP expression is observed in patients with breast, ovarian, colon, liver, and pancreatic cancers and is associated with decreased survival. Consistent with this, activation or overexpression of YAP or TAZ enhances the expression of TEAD-dependent genes (e.g., CCN1, CTGF, ITGB2, and Birc5 / survival protein) and promotes cell proliferation and migration in many cell types. Conversely, blocking the signaling pathway for YAP / TAZ-TEAD complex formation or intervention prevents the expression of many mitotic TEAD target genes, significantly reducing cell proliferation and oncogenic transformation activity. Furthermore, the Hippo pathway crosstalks with other signaling pathways such as Wnt, Notch, Hedgehog, and MAPK, affecting a variety of biological functions. Its dysfunction may be involved not only in cancer but also in many other human diseases. Therefore, the YAP-TEAD complex is a promising therapeutic target. Summary of the Invention

[0003] The purpose of this invention is to provide a novel class of (hetero)aryl aniline compounds or their pharmaceutically acceptable stereoisomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates that have TEAD enzyme inhibitory activity and better pharmacodynamic properties.

[0004] The present invention also provides methods for preparing the (hetero)aryl amide compounds and their intermediates, drug combinations and their pharmaceutical uses.

[0005] Technical Solution: To achieve the above objectives, the present invention provides (hetero)aryl amide compounds and stereoisomers, or their crystal forms, pharmaceutically acceptable salts or solvates as shown in formula (I), wherein the solvates include hydrates:

[0006]

[0007] in:

[0008] Y is selected from CH or N;

[0009] Z is selected from chemical bonds, NR b , O or S;

[0010] R1 is independently selected from hydrogen, halogen, nitrile or hydroxyl, and can be mono, di or polysubstituted;

[0011] R2 is

[0012] X1-X6 are independently selected from CR a Or N, and one of X1, X2, X3 and X4 is a C atom connected to the parent nucleus, and X7 is selected from O, S, Se or NR. b X8 is selected from O, S, Se, NR b or C(R) a )2;

[0013] m can be 0, 1, 2, 3, or 4;

[0014] n is 0, 1, 2, 3, 4, 5, 6 or 7;

[0015] R a Independently selected from hydrogen, halogen, nitrile, nitro, hydroxyl, aldehyde, carboxyl, acetamide, ethoxycarbonyl, aminoacyl, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-7 Heterocyclic alkyl, C 6-10 Aryl or C 5-10 Mixed aromatics;

[0016] R b Independently selected from hydrogen, acetyl, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0017] Or two R atoms on the same atom or adjacent atoms a Group or two R b Group or R a and R b They can form C together 3-7 cycloalkyl, C 3-7 Heterocyclic alkyl, C 6-10 Aryl or C 5-10 Mixed aromatics;

[0018] The halogen mentioned is F, Cl, or Br.

[0019] In some preferred embodiments, the heteroaryl aniline compounds of the present invention are of formula (II), or pharmaceutically acceptable salts, stereoisomers, or solvates thereof:

[0020]

[0021] in:

[0022] Z is selected from chemical bonds or NR. b ;

[0023] R1 is independently selected from hydrogen or halogen;

[0024] R2 is

[0025] X1-X6 are independently selected from CR a Or N, and one of X1, X2, X3 and X4 is a C atom connected to the parent nucleus, and X7 is selected from O, S, Se or NR. b X8 is selected from O, S, Se, NR b or C(R) a )2;

[0026] m can be 0, 1, 2, 3, or 4;

[0027] n is 0, 1, 2, 3, 4, 5, 6 or 7;

[0028] R a Independently selected from hydrogen, halogen, nitrile, nitro, hydroxyl, aldehyde, carboxyl, acetamide, ethoxycarbonyl, aminoacyl, -NH2, -NHC 1-3 Alkyl, -N(C) 1-3 Alkyl)2, C 1-3 Alkyl, C 1-3 Haloalkyl, C1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-7 Heterocyclic alkyl, C 6-10 Aryl or C 5-10 Mixed aromatics;

[0029] R b Independently selected from hydrogen, acetyl, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0030] Or two R atoms on the same atom or adjacent atoms a Group or two R b Group or R a and R b They can form C together 3-7 cycloalkyl, C 3-7 Heterocyclic alkyl, C 6-10 Aryl or C 5-10 Mixed aromatics;

[0031] The halogen mentioned is F, Cl, or Br.

[0032] In some preferred embodiments, the heteroarylamide compounds of the present invention are of formula (III), or pharmaceutically acceptable salts, stereoisomers, solvates, or hydrates thereof:

[0033]

[0034] in:

[0035] R1 is independently selected from hydrogen or halogen;

[0036] R2 is selected from one, two, or three R2 values. a The following groups are substituted:

[0037]

[0038]

[0039] R a Independently selected from hydrogen, halogen, nitrile, nitro, hydroxyl, aldehyde, carboxyl, acetamide, ethoxycarbonyl, aminoacyl, -NH2, -NHC 1-3 Alkyl, -N(C) 1-3 Alkyl)2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-7 Heterocyclic alkyl, C 6-10 Aryl or C 5-10 Mixed aromatics;

[0040] R b Independently selected from hydrogen, acetyl, or C 1-3 alkyl.

[0041] In some preferred embodiments, the heteroarylamide compounds of the present invention are any of the compounds in Table 1 below, their stereoisomers, or their crystal forms, pharmaceutically acceptable salts, or solvates:

[0042] Table 1 Some compounds of the present invention

[0043]

[0044]

[0045] This invention provides pharmaceutical compositions comprising the compounds of the invention and pharmaceutically acceptable carriers or excipients. In specific embodiments, the compounds of the invention are provided in the pharmaceutical composition in an effective amount. In specific embodiments, the compounds of the invention are provided in a therapeutically effective amount. In specific embodiments, the compounds of the invention are provided in a preventatively effective amount.

[0046] The present invention also provides kits containing the compounds of the present invention or their pharmaceutically acceptable forms, and other therapeutic agents, as well as pharmaceutically acceptable carriers, adjuvants, or mediators.

[0047] The present invention also provides the use of compounds of the present invention or in pharmaceutically acceptable forms thereof in the preparation of medicaments for the treatment and / or prevention of diseases caused by TEAD.

[0048] This invention provides compounds or compositions of this invention for the treatment and / or prevention of diseases caused by TEAD.

[0049] In a specific implementation plan, the diseases caused by TEAD can be selected from: solid tumors, sarcomas, lung cancer, gastric cancer, colorectal cancer, liver cancer, pancreatic cancer, ovarian cancer, leukemia, neuroblastoma, kidney cancer, esophageal cancer, uterine cancer, pleural mesothelioma, breast cancer and prostate cancer, tumor formation and other proliferative or proliferative diseases; or the diseases caused by TEAD are metastatic invasive cancers, viral infections or CNS disorders.

[0050] In a specific implementation plan, the disease caused by the TEAD is lung cancer, stomach cancer, colorectal cancer, liver cancer, metastatic invasive cancer, or a combination thereof.

[0051] In specific embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In specific embodiments, the compound is administered for an extended period.

[0052] Other objects and advantages of the invention will become apparent to those skilled in the art from the following detailed embodiments, examples and claims.

[0053] definition

[0054] Chemical definition

[0055] The definitions of specific functional groups and chemical terms are described in more detail below.

[0056] When listing a range of values, it is assumed that each value and the subranges within that range are included. For example, "C 1-6 Alkyl groups include C1, C2, C3, C4, C5, C6, and C6. 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 alkyl.

[0057] It should be understood that, as described herein, any part defined below may be substituted by a number of substituents, and the corresponding definitions are listed below within their scope, including such substituted parts. Unless otherwise stated, the term "substitution" is defined below.

[0058] “C 1-6 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms, also referred to herein as "lower alkyl". In some embodiments, C 1-4 Alkyl groups are particularly preferred. Examples of said alkyl groups include, but are not limited to: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). Unless otherwise stated, each alkyl group is optionally independently substituted, i.e., unsubstituted (“unsubstituted alkyl”) or substituted with one or more substituents (“substituted alkyl”); for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In some embodiments, the alkyl group is an unsubstituted C1. 1-6 Alkyl group (e.g., -CH3). In some embodiments, the alkyl group is a substituted C-molecule. 1-6 alkyl.

[0059] “C 1-6 "Alkoxy" refers to the group -OR, where R is a substituted or unsubstituted carbon group. 1-6 Alkyl group. In some embodiments, C 1-4 Alkoxy groups are particularly preferred. Specific alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy, and 1,2-dimethylbutoxy.

[0060] "Halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In some embodiments, the halogen group is F, Cl, or Br. In some embodiments, the halogen group is Cl. In some embodiments, the halogen group is F. In some embodiments, the halogen group is Br.

[0061] Therefore, "C" 1-6 "Halogenated alkyl" refers to the above "C 1-6 "alkyl" is substituted with one or more halogen groups. In some embodiments, C 1-4 Halogenated alkyl groups are particularly preferred, and C4 groups are more preferred. 1-2 Alkyl halogens. Examples of alkyl halogens include, but are not limited to: -CF3, -CH2F, -CHF2, -CClF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CF2CClF2, -CF2CH3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc.

[0062] “C 3-7 "Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 7 ring carbon atoms and zero heteroatoms. In some embodiments, C 3-6 Cycloalkyl groups are particularly preferred, and C10 is more preferred. 5-6 Cycloalkyl groups. Cycloalkyl groups also include ring systems in which the aforementioned cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the connecting point is on the cycloalkyl ring, and in such cases, the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary cycloalkyl groups include, but are not limited to: cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), etc. Unless otherwise stated, each cycloalkyl group is independently optionally substituted, i.e., unsubstituted (“unsubstituted cycloalkyl”) or substituted with one or more substituents (“substituted cycloalkyl”). In some embodiments, the cycloalkyl group is an unsubstituted C14 group.3-7 Cycloalkyl. In some embodiments, the carbocyclic group is a substituted C. 3-7 Cycloalkyl.

[0063] “C 3-7 "Heterocyclic alkyl" refers to a group having a 3- to 7-membered non-aromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, sulfur, boron, phosphorus, and silicon. In heterocyclic alkyl groups containing one or more nitrogen atoms, the linking point may be a carbon or nitrogen atom, provided the valence allows. In some embodiments, C 3-6 Heterocyclic alkyl groups are particularly preferred, being 3- to 6-membered non-aromatic ring systems having a ring carbon atom and 1 to 3 ring heteroatoms; more preferably, C 5-6 Heterocyclic alkyl groups are 5- to 6-membered non-aromatic ring systems having a ring carbon atom and 1 to 3 ring heteroatoms. Unless otherwise stated, each heterocyclic alkyl group is independently optionally substituted, i.e., unsubstituted (“unsubstituted heterocyclic alkyl”) or substituted with one or more substituents (“substituted heterocyclic alkyl”). In some embodiments, the heterocyclic alkyl group is an unsubstituted C14-carbon ring. 3-7 Heterocyclic alkyl groups. In some embodiments, the heterocyclic alkyl group is a substituted C-shaped alkyl group. 3-7Heterocyclic alkyl groups. Heterocyclic alkyl groups also include ring systems in which the aforementioned heterocyclic alkyl ring is fused with one or more cycloalkyl groups, wherein the linking point is on the cycloalkyl ring; or ring systems in which the aforementioned heterocyclic alkyl ring is fused with one or more aryl or heteroaryl groups, wherein the linking point is on the heterocyclic alkyl ring; and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclic alkyl ring system. Exemplary 3-membered heterocyclic alkyl groups containing one heteroatom include, but are not limited to: azirropropyl, oxetane, and thiorenyl. Exemplary 4-membered heterocyclic alkyl groups containing one heteroatom include, but are not limited to: azirrobutyl, oxetane, and thiorenyl. Exemplary 5-membered heterocyclic alkyl groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolidinyl, and pyrrolidin-2,5-dione. Exemplary 5-membered heterocyclic alkyl groups containing two heteroatoms include, but are not limited to: dioxasulfuranyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic alkyl groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic alkyl groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic alkyl groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, disulfuranyl, and dioxalyl. Exemplary 6-membered heterocyclic alkyl groups containing three heteroatoms include, but are not limited to: triazinanyl. Exemplary 7-membered heterocyclic alkyl groups containing one heteroatom include, but are not limited to: azirheptanyl, oxasulfuranyl, and thioheptanyl. Exemplary 5-membered heterocyclic alkyl groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic alkyl groups) include, but are not limited to: dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinoneyl, etc. Exemplary 6-membered heterocyclic alkyl groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclic alkyl groups) include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0064] “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 shared π electrons arranged in a ring) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). Aryl also includes a ring system in which the aforementioned aryl ring is fused with one or more cycloalkyl or heterocycloalkyl groups, and the connection point is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. Unless otherwise stated, each aryl group is optionally substituted independently, i.e., unsubstituted (“unsubstituted aryl”) or substituted with one or more substituents (“substituted aryl”). In some embodiments, the aryl group is an unsubstituted C 6-10 Aryl. In some embodiments, the aryl group is a substituted C. 6-10 Aryl.

[0065] “C 5-10 "Heteroaryl" refers to a 4n+2 aromatic ring system of a 5-10 membered monocyclic or bicyclic ring (e.g., having 6 or 10 shared π electrons arranged in a ring) having a ring carbon atom and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl containing one or more nitrogen atoms, the bonding point can be a carbon or nitrogen atom, provided the valence allows. A heteroaryl bicyclic system may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the aforementioned heteroaryl ring is fused with one or more cycloalkyl or heterocycloalkyl groups, and the bonding point is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, C 5-6Heteroaryl groups are particularly preferred, being 4n+2 aromatic ring systems of 5-6 membered monocyclic or bicyclic rings having a ring carbon atom and 1-4 ring heteroatoms. Unless otherwise stated, each heteroaryl group is optionally substituted independently, i.e., unsubstituted (“unsubstituted heteroaryl”) or substituted by one or more substituents (“substituted heteroaryl”). In some embodiments, the heteroaryl group is an unsubstituted 5-10 membered heteroaryl group. In some embodiments, the heteroaryl group is a substituted 5-10 membered heteroaryl group. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrole, furanyl, and thiophene. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl, and thiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetraazinyl. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azirmonoheptatrienyl, azirmonoheptatrienyl, and thioheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoyindolyl, indazole, benzotriazolyl, benzothiophene, isobenzothiophene, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to: naphridinyl, pteridinyl, quinolinyl, isoquinolinyl, zolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0066] “Cyano” indicates the group -CN.

[0067] "Nitro" indicates the group -NO2.

[0068] Other definitions

[0069] The term "pharmaceutically acceptable salt" refers to those salts that, to the extent of reliable medical judgment, are suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases.

[0070] The term "subject" in the administration includes, but is not limited to: humans (i.e., men or women of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals, like primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0071] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this article.

[0072] Unless otherwise stated, the term “treatment” as used herein includes effects that occur when a subject has a specific disease, disorder, or condition, which reduce the severity of the disease, disorder, or condition, or delay or slow the development of the disease, disorder, or condition (“therapeutic treatment”), and also includes effects that occur before a subject begins to have a specific disease, disorder, or condition (“preventive treatment”).

[0073] Generally, the "effective amount" of a compound refers to the amount sufficient to elicit a response in the target organism. As will be understood by those skilled in the art, the effective amount of the compounds of the present invention can vary depending on factors such as the biological target, the pharmacokinetics of the compound, the disease being treated, the administration method, and the age, health status, and symptoms of the subject. Effective amounts include both therapeutic and prophylactic effective amounts.

[0074] Unless otherwise stated, the term "therapeuticly effective amount" of a compound as used herein is the amount sufficient to provide therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound refers to the amount of a therapeutic agent, used alone or in combination with other therapies, that provides therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeuticly effective amount" may include amounts that improve overall treatment, reduce or prevent symptoms or causes of a disease or condition, or enhance the therapeutic efficacy of other therapeutic agents.

[0075] Unless otherwise stated, the term "preventively effective amount" of a compound as used herein is a quantity sufficient to prevent a disease, disorder, or condition, or a quantity sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or a quantity sufficient to prevent recurrence of a disease, disorder, or condition. The preventively effective amount of a compound refers to the quantity of a therapeutic agent, used alone or in combination with other agents, that provides preventive benefit in the prevention of a disease, disorder, or condition. The term "preventively effective amount" may include quantities that improve overall prevention or enhance the preventive efficacy of other preventive agents.

[0076] The compounds of this invention may include one or more asymmetric centers and therefore may exist in a variety of stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds of this invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. Isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0077] Those skilled in the art will understand that many organic compounds can form complexes with solvents, react in the solvent, or precipitate or crystallize out of the solvent. These complexes are called "solvates." When the solvent is water, the complex is called a "hydrate." This invention covers all solvates of the compounds of this invention.

[0078] Pharmaceutical compositions, formulations and kits

[0079] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention (also referred to as the "active component") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of the compound of the present invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound of the present invention. In some embodiments, the pharmaceutical composition comprises a preventatively effective amount of the compound of the present invention.

[0080] Pharmaceutically acceptable excipients used in this invention refer to non-toxic carriers, adjuvants, or mediators that do not impair the pharmacological activity of the co-formulated compounds. Pharmaceutically acceptable carriers, adjuvants, or mediators that can be used in the compositions of this invention include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acid metaglycerides, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0081] The present invention also includes a kit (e.g., a pharmaceutical package). The provided kit may include the compounds of the present invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other suitable containers) containing the compounds of the present invention and other therapeutic agents. In some embodiments, the provided kit may optionally include a third container containing pharmaceutical excipients for diluting or suspending the compounds of the present invention and / or other therapeutic agents. In some embodiments, the compounds of the present invention and other therapeutic agents provided in the first and second containers are combined to form a unit dosage form.

[0082] The following formulation examples illustrate representative pharmaceutical compositions that can be prepared according to the present invention. However, the present invention is not limited to the following pharmaceutical compositions.

[0083] Exemplary Formulation 1 - Tablets: The compound of the invention in dry powder form may be mixed with a dry gel binder at a weight ratio of about 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is then formed into 0.3-30 mg tablets (each tablet containing 0.1-10 mg of the active compound) in a tableting machine.

[0084] Exemplary Formulation 2 - Tablets: The compound of the invention in dry powder form can be mixed with a dry gel binder at a weight ratio of about 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is then formed into 30-90 mg tablets (each tablet containing 10-30 mg of the active compound) in a tableting machine.

[0085] Exemplary Formulation 3 - Tablets: The compound of the invention in dry powder form can be mixed with a dry gel binder at a weight ratio of about 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is then formed into 90-150 mg tablets (each tablet containing 30-50 mg of the active compound) in a tableting machine.

[0086] Exemplary Formulation 4 - Tablets: The compound of the invention in dry powder form can be mixed with a dry gel binder at a weight ratio of about 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is then formed into 150-240 mg tablets (each tablet containing 50-80 mg of the active compound) in a tableting machine.

[0087] Exemplary Formulation 5 - Tablets: The compound of the invention in dry powder form can be mixed with a dry gel binder at a weight ratio of about 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is then formed into 240-270 mg tablets (each tablet containing 80-90 mg of the active compound) in a tableting machine.

[0088] Exemplary Formulation 6 - Tablets: The compound of the invention in dry powder form can be mixed with a dry gel binder at a weight ratio of about 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is then formed into 270-450 mg tablets (each tablet containing 90-150 mg of the active compound) in a tableting machine.

[0089] Exemplary Formulation 7 - Tablets: The compound of the invention in dry powder form can be mixed with a dry gel binder at a weight ratio of about 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is then formed into 450-900 mg tablets (each tablet containing 150-300 mg of the active compound) in a tableting machine.

[0090] Exemplary Formulation 8 - Capsules: The compound of the present invention in dry powder form may be mixed with a starch diluent at a weight ratio of approximately 1:1. This mixture is then filled into 250 mg capsules (each capsule containing 125 mg of the active compound).

[0091] Exemplary Formulation 9 - Liquid: The compound of the present invention (125 mg) can be mixed with sucrose (1.75 g) and xanthan gum (4 mg), and the resulting mixture can be blended and passed through a No. 10 US sieve, and then mixed with a pre-prepared aqueous solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg). Sodium benzoate (10 mg), flavoring agent and coloring agent are diluted with water and added with stirring. Then, sufficient water can be added to obtain a total volume of 5 mL.

[0092] Exemplary Formulation 10 - Injection: The compounds of the present invention can be dissolved or suspended in a buffered sterile saline injectable aqueous medium to achieve a concentration of about 5 mg / mL.

[0093] Dosage

[0094] The pharmaceutical compositions provided by this invention can be administered via a variety of routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration via implantation, or other routes of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intra-synovial administration, intrasternal administration, intramenstrual administration, intralesional administration, and intracranial injection or infusion techniques.

[0095] Typically, an effective amount of the compound described herein is administered. The actual amount of compound administered may be determined by the physician based on relevant circumstances, including the condition being treated, the chosen route of administration, the compound actually administered, the individual patient's age, weight and response, the severity of the patient's symptoms, etc.

[0096] When used to prevent the conditions described in this invention, the compounds provided herein are administered to subjects at risk of developing the conditions, typically based on a physician's advice and under physician supervision, at the dosage levels described above. Subjects at risk of developing a specific condition generally include subjects with a family history of the condition, or those identified through genetic testing or screening as particularly susceptible to developing the condition.

[0097] The pharmaceutical compositions provided herein can also be administered long-term (“long-term administration”). Long-term administration means administering the compound or a pharmaceutical composition thereof over a prolonged period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may be administered indefinitely, such as for the remainder of the subject's life. In some embodiments, long-term administration is intended to provide a constant level of said compound in the blood over a prolonged period of time, such as within a therapeutic window.

[0098] Various methods of administration can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered by bolus injection, for instance, to elevate the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active component through the body; for example, an intramuscular or subcutaneous bolus dose results in a slow release of the active component, while a bolus dose delivered directly to a vein (e.g., via IV intravenous infusion) can deliver the component more rapidly, causing the concentration of the active component in the blood to rise quickly to an effective level. In other embodiments, the pharmaceutical composition can be administered in the form of a continuous infusion, for example, via IV intravenous infusion, thereby providing a steady-state concentration of the active component in the subject's body. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition can be administered first, followed by a continuous infusion.

[0099] Oral compositions may be in the form of bulk liquid solutions, suspensions, or bulk powders. However, more commonly, the compositions are provided in unit dose form for the purpose of precise dosing. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined quantity of active substance and suitable pharmaceutical excipients suitable for producing the desired therapeutic effect. Typical unit dose forms include pre-filled, pre-measured ampoules or syringes for liquid compositions, or, in the case of solid compositions, pills, tablets, capsules, etc. In such compositions, the compound is typically a smaller component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various carriers or excipients useful for forming the desired dosage form, as well as processing aids.

[0100] For oral dosage, a typical regimen is one to five oral doses daily, particularly two to four oral doses, typically three oral doses. Using these dosage regimens, each dose provides approximately 0.01 to approximately 20 mg / kg of the compound of the invention, with preferred doses each providing approximately 0.1 to approximately 10 mg / kg, particularly approximately 1 to approximately 5 mg / kg.

[0101] To provide blood levels similar to or lower than those achieved with an injection dose, a transdermal dose is typically selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, more preferably about 0.1 to about 10% by weight, and even more preferably about 0.5 to about 15% by weight.

[0102] From approximately 1 to approximately 120 hours, especially 24 to 96 hours, the injection dose level ranges from approximately 0.1 mg / kg / hour to at least 10 mg / kg / hour. To obtain adequate steady-state levels, a preload bolus of approximately 0.1 mg / kg to approximately 10 mg / kg or more may also be administered. For human patients weighing 40 to 80 kg, the maximum total dose should not exceed approximately 2 g / day.

[0103] Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous carriers, as well as buffers, suspending and dispersing agents, colorants, flavoring agents, etc. Solid forms may include, for example, any of the following components, or compounds with similar properties: binders, such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients, such as starch or lactose; disintegrants, such as alginic acid, Primogel, or corn starch; lubricants, such as magnesium stearate; gliding agents, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavorings.

[0104] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline, or other injectable excipients known in the art. As previously described, in such compositions, the active compound is typically a smaller component, often about 0.05 to 10% by weight, with the remainder being injectable excipients, etc.

[0105] Transdermal compositions are typically formulated as topical ointments or creams containing an active ingredient. When formulated as an ointment, the active ingredient is typically combined with a paraffin-based or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with, for example, an oil-in-water emulsion base. Such transdermal formulations are well known in the art and generally include other components to enhance stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope of this invention.

[0106] The compounds of this invention can also be administered via transdermal devices. Therefore, transdermal drug delivery can be achieved using reservoirs or porous membrane types, or patches with various solid matrices.

[0107] This invention also relates to pharmaceutically acceptable formulations of the compounds of this invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are those consisting of 6, 7, and 8 molecules, respectively. α Composed of -1,4-linked glucose units α -, β-, and γ-cyclodextrins, optionally comprising one or more substituents at the linked sugar moiety, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfonyl ether substituted groups. In some embodiments, the cyclodextrin is a sulfonyl ether β-cyclodextrin, for example, sulfonyl butyl ether β-cyclodextrin, also known as Captisol. Detailed Implementation

[0108] The following examples are provided to provide those skilled in the art with a complete disclosure and illustration of how to implement, prepare, and evaluate the methods and compounds claimed herein, and are intended merely to illustrate the invention and not to limit its scope.

[0109] Synthesis method

[0110] The compounds of the present invention can be prepared according to conventional methods in the art, using suitable reagents, raw materials and purification methods known to those skilled in the art.

[0111] The preparation methods of the compounds of the present invention are described in more detail below, but these specific methods do not constitute any limitation on the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art.

[0112] Typically, in the preparation process, the reactions are carried out in an inert solvent at room temperature to reflux temperature (e.g., 0°C to 100°C, preferably 0°C to 80°C). The reaction time is typically 0.1 h to 60 h, preferably 0.5 h to 24 h.

[0113] Example 1: Preparation of N-(3-(benzo[c][1,2,5]selenodiazole-5-yl)-4-((4-(trifluoromethyl)phenyl)amino) (By)phenyl)acrylamide (compound 1)

[0114]

[0115] Step 1: Synthesis of tert-butyl 3-bromo-4-nitrophenyl)carbamate (compound 1b).

[0116] 3-Bromo-4-nitroaniline (1a, 25.0 g, 116.3 mmol) and (Boc)₂O (16.4 g, 127.9 mmol) were added to a reaction flask and dissolved in 300 mL of anhydrous DCM. TEA (23.5 g, 232.6 mmol) and DMAP (2.8 g, 23.3 mmol) were added, and the mixture was stirred at room temperature for 12 hours. The mixture was diluted with excess water, extracted 3-4 times with ethyl acetate, and the organic phases were combined, washed with saturated brine, concentrated, purified by column chromatography, and dried under vacuum to give 30.1 g of the product, yield: 81.9%.

[0117] Step 2: Synthesis of tert-butyl (4-amino-3-bromophenyl)carbamate (compound 1c).

[0118] Compound 1b (30.1 g, 95.3 mmol), zinc powder (18.3 g, 285.9 mmol), and ammonium chloride (40.4 g, 762.4 mmol) were added to a reaction flask. 200 mL of water and 200 mL of ethanol were added, and the mixture was heated to 50 °C and stirred for 12 hours. The ethanol was removed by vortexing, and the mixture was diluted with excess water. The mixture was extracted with ethyl acetate 3-4 times. The organic phases were combined, washed with saturated brine, concentrated, purified by column chromatography, and dried under vacuum to give 19.1 g of the product. Yield: 70.1%.

[0119] Step 3: Synthesis of tert-butyl (3-bromo-4-((4-(trifluoromethyl)phenyl)amino)phenyl)carbamate (compound 1d).

[0120] Compound 1c (19.1 g, 66.8 mmol), 4-trifluoromethyliodobenzene (21.8 g, 80.2 mmol), Pd2(dba)3 (402.5 mg, 0.7 mmol), XantPhos (578.6 mg, 1.0 mmol), and Cs2CO3 (43.6 g, 133.6 mmol) were added to a reaction flask and dissolved in 210 mL of anhydrous dioxane. The mixture was heated to 100 °C under N2 protection and stirred for 12 hours. The reaction proceeded as determined by TLC. The reactants were dried under vacuum, diluted with excess water, and extracted 3-4 times with ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated, purified by silica gel column chromatography, and dried under vacuum to give 13.4 g of the product (yield: 46.7%).

[0121] Step 4: Synthesis of tert-butyl(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)carbamate (compound 1e).

[0122] Compound 1d (13.4 g, 31.2 mmol), pinacol borate (15.9 g, 62.4 mmol), Pd(dppf)Cl2 (219.6 mg, 0.3 mmol), and potassium acetate (578.6 mg, 124.8 mmol) were added to a reaction flask. 100 mL of anhydrous dioxane was added to dissolve the compound. The mixture was heated to 100 °C under N2 protection and stirred for 12 hours. TLC was used to detect the complete reaction of the starting material. The mixture was dried under vacuum, diluted with excess water, and extracted 3-4 times with ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated, purified by silica gel column chromatography, and dried under vacuum to give 7.8 g of the product, yield: 52.3%.

[0123] Step 5: Synthesis of tert-butyl(3-(benzo[c][1,2,5]selenodiazole-5-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)carbamate (compound 1f).

[0124] Compound 1e (956.4 mg, 2.0 mmol), 5-bromobenzo[c][1,2,5]selenodiazole (628.8 mg, 2.4 mmol), Pd(dppf)Cl2 (14.6 mg, 0.02 mmol), and potassium carbonate (552.0 mg, 4.0 mmol) were added to a reaction flask. 6 mL of dioxane and 6 mL of water were added to dissolve the compound. The mixture was heated to 100 °C under N2 protection and stirred for 12 hours. TLC was used to confirm the reaction was complete. The mixture was dried under vacuum, diluted with excess water, and extracted 3-4 times with ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated, purified by silica gel column chromatography, and dried under vacuum to obtain 560.3 mg of the product (yield: 52.5%).

[0125] Step 6: Synthesis of 2-(benzo[c][1,2,5]selenodiazole-5-yl)-N1-(4-(trifluoromethyl)phenyl)benzene-1,4-diamine (compound 1g).

[0126] Compound 1f (560.3 mg, 1.1 mmol) was added to the reaction flask and dissolved in 4 mL of HCl-dioxane. The mixture was stirred at room temperature for 12 hours, filtered, rinsed three times with water, and dried to obtain 320.1 mg of crude product.

[0127] Step 7: Synthesis of N-(3-(benzo[c][1,2,5]selenodiazole-5-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)acrylamide (compound 1).

[0128] 320.1 mg of crude compound (1 g) was added to a reaction flask and dissolved in 3 mL of anhydrous THF. Then, TEA (202.2 mg, 2.0 mmol) and acryloyl chloride (99.0 mg, 1.1 mmol) were added. The mixture was stirred at 0°C to room temperature for 12 hours. TLC analysis confirmed the reaction was complete. The reactants were dried under vacuum, diluted with excess water, and extracted 3-4 times with ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated, purified by silica gel column chromatography, dried under vacuum, and then purified again by reversed-phase column chromatography. The product was dried under vacuum to give 85.3 mg, yield: 26.5%. LC-MS (ESI): m / z = 511.03 [M + Na] + ; 1 H NMR(300MHz,DMSO-d6)δ10.36(s,1H),8.21(s,1H),7.92(s,1H),7.82-7.63(m,3H),7.52(d,J=2.2Hz,1H),7 .43(d,J=2.3Hz,3H),6.81(d,J=2.3Hz,2H),6.52-6.42(m,1H),6.29(d,J=2.2Hz,1H),5.77(d,J=2.3Hz,1H).

[0129] Example 2 Preparation of N-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-4-((4-(trifluoromethyl)phenyl)amino) base)

[0130] (Phenylacetyl)acrylamide (compound 2)

[0131]

[0132]

[0133] Step 1: Synthesis of tert-butyl(3-(benzo[c][1,2,5]thiadiazol-5-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)carbamate (compound 2f).

[0134] Compound 1e (956.4 mg, 2.0 mmol), 5-bromobenzo[c][1,2,5]thiadiazole (513.4 mg, 2.4 mmol), Pd(dppf)Cl2 (14.6 mg, 0.02 mmol), and potassium carbonate (552.0 mg, 4.0 mmol) were added to a reaction flask. 6 mL of dioxane and 6 mL of water were added to dissolve the compound. The mixture was heated to 100 °C under N2 protection and stirred for 12 hours. TLC was used to confirm the reaction was complete. The reactants were dried under vacuum, diluted with excess water, and extracted 3-4 times with ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated, purified by silica gel column chromatography, and dried under vacuum to obtain 452.8 mg of the product (yield: 52.5%).

[0135] Step 2: Synthesis of 2-(benzo[c][1,2,5]thiadiazol-5-yl)-N1-(4-(trifluoromethyl)phenyl)benzene-1,4-diamine (compound 2g).

[0136] Compound 2f (452.8 mg, 1.0 mmol) was added to the reaction flask and dissolved in 4 mL of HCl-dioxane. The mixture was stirred at room temperature for 12 hours, filtered, rinsed three times with water, and dried to obtain 334.3 mg of crude product.

[0137] Step 3: Synthesis of N-(3-(benzo[c][1,2,5]thiadiazol-5-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)acrylamide (compound 2).

[0138] 2 g of the compound (334.3 mg crude product) was added to a reaction flask and dissolved in 3 mL of anhydrous THF. Then, TEA (202.2 mg, 2.0 mmol) and acryloyl chloride (99.0 mg, 1.1 mmol) were added. The mixture was stirred at 0°C to room temperature for 12 hours. TLC analysis confirmed the reaction was complete. The reactants were dried under vacuum, diluted with excess water, and extracted 3-4 times with ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated, purified by silica gel column chromatography, dried under vacuum, and then purified again by reversed-phase column chromatography. The product was dried under vacuum to give 76.4 mg, yield: 26.3%. LC-MS (ESI): m / z = 463.08 [M + Na] + ; 1 H NMR (300MHz, DMSO-d6) δ10.36(s,1H),8.21(s,1H),8.11(d,J=2.2Hz,2H),7.92(s,1H),7.78(s,1H),7.72(s,1H),7.44 (s,1H),7.40(d,J=2.3Hz,2H),6.81(d,J=2.3Hz,2H),6.52-6.42(m,1H),6.29(d,J=2.2Hz,1H),5.77(d,J=2.3Hz,1H).

[0139] Example 3 Preparation of N-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-4-((4-(trifluoromethyl)phenyl)amino) (By)phenyl)acrylamide (compound 3)

[0140]

[0141] Step 1: Synthesis of tert-butyl(3-(benzo[c][1,2,5]oxadiazol-5-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)carbamate (compound 3f).

[0142] Compound 1e (956.4 mg, 2.0 mmol), 5-bromobenzo[c][1,2,5]oxadiazole (475.1 mg, 2.4 mmol), Pd(dppf)Cl2 (14.6 mg, 0.02 mmol), and potassium carbonate (552.0 mg, 4.0 mmol) were added to a reaction flask. 6 mL of dioxane and 6 mL of water were added to dissolve the compound. The mixture was heated to 100 °C under N2 protection and stirred for 12 hours. TLC was used to confirm the reaction was complete. The reactants were dried under vacuum, diluted with excess water, and extracted 3-4 times with ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated, purified by silica gel column chromatography, and dried under vacuum to obtain 428.4 mg of the product (yield: 45.6%).

[0143] Step 2: Synthesis of 2-(benzo[c][1,2,5]oxadiazol-5-yl)-N1-(4-(trifluoromethyl)phenyl)benzene-1,4-diamine (compound 3g).

[0144] Compound 3f (428.4 mg, 0.9 mmol) was added to the reaction flask and dissolved in 4 mL of HCl-dioxane. The mixture was stirred at room temperature for 12 hours, filtered, rinsed three times with water, and dried to obtain 386.1 mg of crude product.

[0145] Step 3: Synthesis of N-(3-(benzo[c][1,2,5]oxadiazol-5-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)acrylamide (compound 3).

[0146] 386.1 mg of crude compound (3 g) was added to a reaction flask and dissolved in 3 mL of anhydrous THF. Then, TEA (202.2 mg, 2.0 mmol) and acryloyl chloride (99.0 mg, 1.1 mmol) were added. The mixture was stirred at 0°C to room temperature for 12 hours. TLC analysis confirmed the reaction was complete. The reactants were dried under vacuum, diluted with excess water, and extracted 3-4 times with ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated, purified by silica gel column chromatography, dried under vacuum, and then purified again by reversed-phase column chromatography. The product was dried under vacuum to give 56.3 mg, yield: 20.1%. LC-MS (ESI): m / z = 447.10 [M + Na] + ; 1H NMR (300MHz, DMSO-d6) δ10.36(s,1H),8.21(s,1H),8.11(d,J=2.2Hz,2H),7.92(s,1H),7.75(d,J=2.2Hz,1H),7.52(d,J =2.2Hz,1H),7.48-7.41(m,3H),6.88(d,J=2.3Hz,2H),6.52-6.42(m,1H),6.29(d,J=2.2Hz,1H),5.77(d,J=2.3Hz,1H).

[0147] Example 4 Preparation of N-(3-(selenomorpholine-4-carbonyl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)acryloyl Amine (compound 4)

[0148]

[0149]

[0150] Step 1: Synthesis of 5-nitro-2-((4-trifluoromethylphenyl)amino)benzoic acid (compound 4b).

[0151] 2-Fluoro-5-nitrobenzoic acid (4a, 25.0 g, 135.1 mmol) and 4-trifluoromethylaniline (26.1 g, 162.2 mmol) were added to a reaction flask and dissolved in 300 mL of anhydrous DMSO. DIEA (34.9 g, 270.2 mmol) was added, and the mixture was stirred at 120 °C for 12 hours. The mixture was diluted with excess water, extracted 3-4 times with ethyl acetate, and the organic phases were combined, washed with saturated brine, concentrated, purified by column chromatography, and dried under vacuum to give 27.8 g of the product, yield: 63.1%.

[0152] Step 2: Synthesis of (5-nitro-2-((4-(trifluoromethyl)phenyl)amino)phenyl)(selenomorpholine) methyl ketone (compound 4c).

[0153] Compound 4b (5.0 g, 15.3 mmol) was added to the reaction flask, followed by 50 mL of thionyl chloride. The mixture was heated to 80 °C and stirred for 4 hours. The thionyl chloride was then removed by vortexing, and 50 mL of DCM was added. Selenomorpholine (2.3 g, 15.3 mmol) was then added. The mixture was extracted with ethyl acetate 3-4 times. The organic phases were combined, washed with saturated brine, concentrated, purified by column chromatography, and dried under vacuum to give 3.4 g of the product. Yield: 48.4%.

[0154] Step 3: Synthesis of (5-amino-2-((4-(trifluoromethyl)phenyl)amino)phenyl)(selenomorpholine) methyl ketone (compound 4d).

[0155] Compound 4c (3.4 g, 7.4 mmol) and Pd / C (10%) (74.2 mg, 0.7 mmol) were added to a reaction flask and dissolved in 25 mL of anhydrous methanol. The mixture was heated to 40 °C under H2 and stirred for 12 hours. The mixture was filtered, concentrated, and dried under vacuum to give 2.9 g of the product, yield: 91.2%.

[0156] Step 4: Synthesis of N-(3-(selenomorpholine-4-carbonyl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)acrylamide (compound 4).

[0157] Compound 4d (429.0 mg, 1 mmol) was added to a reaction flask and dissolved in 3 mL of anhydrous THF. Then, TEA (202.2 mg, 2.0 mmol) and acryloyl chloride (99.0 mg, 1.1 mmol) were added. The mixture was stirred at 0°C to room temperature for 12 hours. TLC analysis confirmed the reaction was complete. The reactants were dried under vacuum, diluted with excess water, and extracted 3-4 times with ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated, purified by silica gel column chromatography, dried under vacuum, and then purified again by reversed-phase column chromatography. The product was dried under vacuum to give 52.1 mg, yield: 10.8%. LC-MS (ESI): m / z = 506.06 [M + Na] + ; 1 H NMR (300MHz, DMSO-d6) δ10.30(s,1H),8.17(s,1H),7.71(s,1H),7.63(d,J=2.2Hz,1H),7.44(d,J=2.2Hz,2H),7.28(d,J=2.2Hz,1H),7.00(d,J=2.2H z,2H),6.49-6.35(m,1H),6.27(d,J=2.3Hz,1H),5.79(d,J=2.2Hz,1H),3. 88-3.79(m,2H),3.60-3.49(m,2H),2.68-2.61(m,2H),2.59-3.47(m,2H).

[0158] Example 5 Preparation of N-(3-(thiomorpholine-4-carbonyl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)propene Amide (Compound 5)

[0159]

[0160] Step 1: Synthesis of (5-nitro-2-((4-(trifluoromethyl)phenyl)amino)phenyl)(thiomorpholine) methyl ketone (compound 5c).

[0161] Compound 4b (5.0 g, 15.3 mmol) was added to the reaction flask, followed by 50 mL of thionyl chloride. The mixture was heated to 80 °C and stirred for 4 hours. The thionyl chloride was then removed by vortexing, and 50 mL of DCM was added. Thiomorpholine (1.6 g, 15.3 mmol) was then added. The mixture was extracted with ethyl acetate 3-4 times. The organic phases were combined, washed with saturated brine, concentrated, purified by column chromatography, and dried under vacuum to give 2.9 g of the product. Yield: 46.1%.

[0162] Step 2: Synthesis of (5-amino-2-((4-(trifluoromethyl)phenyl)amino)phenyl)(thiomorpholine) methyl ketone (compound 5d).

[0163] Compound 5c (2.9 g, 7.1 mmol) and Pd / C (10%) (74.2 mg, 0.7 mmol) were added to a reaction flask and dissolved in 25 mL of anhydrous methanol. The mixture was heated to 40 °C under H2 and stirred for 12 hours. The mixture was filtered, concentrated, and dried under vacuum to give 2.1 g of the product, yield: 77.6%.

[0164] Step 3: Synthesis of N-(3-(thiomorpholine-4-carbonyl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)acrylamide (compound 5).

[0165] Compound 5d (381.1 mg, 1 mmol) was added to a reaction flask and dissolved in 3 mL of anhydrous THF. Then, TEA (202.2 mg, 2.0 mmol) and acryloyl chloride (99.0 mg, 1.1 mmol) were added. The mixture was stirred at 0°C to room temperature for 12 hours. TLC analysis confirmed the reaction was complete. The reactants were dried under vacuum, diluted with excess water, and extracted 3-4 times with ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated, purified by silica gel column chromatography, dried under vacuum, and then purified again by reversed-phase column chromatography. The product was dried under vacuum to give 48.3 mg, yield: 11.1%. LC-MS (ESI): m / z = 458.11 [M + Na] + ; 1 H NMR (300MHz, DMSO-d6) δ10.26(s,1H),8.20(s,1H),7.71(s,1H),7.63(d,J=2.2Hz,1H),7.48(d,J=2.2Hz,2H),7.29(d,J=2.2Hz,1H),7.00(d,J=2.2H z,2H),6.49-6.35(m,1H),6.27(d,J=2.3Hz,1H),5.79(d,J=2.2Hz,1H),3. 78-3.73(m,2H),3.51-3.43(m,2H),2.61-2.53(m,2H),2.48-2.31(m,2H).

[0166] Example 6 Preparation of N-(3-(morpholino-4-carbonyl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)acrylamide (Compound 6)

[0167]

[0168] Step 1: Synthesis of (5-nitro-2-((4-(trifluoromethyl)phenyl)amino)phenyl)(morpholine) methyl ketone (compound 6c).

[0169] Compound 4b (5.0 g, 15.3 mmol) was added to the reaction flask, followed by 50 mL of thionyl chloride. The mixture was heated to 80 °C and stirred for 4 hours. The thionyl chloride was then removed by vortexing, and 50 mL of DCM was added. Morpholine (1.3 g, 15.3 mmol) was then added. The mixture was extracted with ethyl acetate 3-4 times. The organic phases were combined, washed with saturated brine, concentrated, purified by column chromatography, and dried under vacuum to give 2.7 g of the product. Yield: 44.7%.

[0170] Step 2: Synthesis of (5-amino-2-((4-(trifluoromethyl)phenyl)amino)phenyl)(morpholine) methyl ketone (compound 6d).

[0171] Compound 6c (2.7 g, 6.8 mmol) and Pd / C (10%) (74.2 mg, 0.7 mmol) were added to a reaction flask and dissolved in 25 mL of anhydrous methanol. The mixture was heated to 40 °C under H2 and stirred for 12 hours. The mixture was filtered, concentrated, and dried under vacuum to give 1.9 g of the product, yield: 76.6%.

[0172] Step 3: Synthesis of N-(3-(morpholino-4-carbonyl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)acrylamide (compound 6).

[0173] Compound 6d (365.1 mg, 1 mmol) was added to a reaction flask and dissolved in 3 mL of anhydrous THF. Then, TEA (202.2 mg, 2.0 mmol) and acryloyl chloride (99.0 mg, 1.1 mmol) were added. The mixture was stirred at 0°C to room temperature for 12 hours. TLC analysis confirmed the reaction was complete. The reactants were dried under vacuum, diluted with excess water, and extracted 3-4 times with ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated, purified by silica gel column chromatography, dried under vacuum, and then purified again by reversed-phase column chromatography. The product was dried under vacuum to give 57.8 mg, yield: 13.8%. LC-MS (ESI): m / z = 442.13 [M + Na] + ; 1H NMR (300MHz, DMSO-d6) δ10.29(s,1H),8.28(s,1H),7.71(s,1H),7.63(d,J=2.2Hz,1H),7.48(d,J=2.2Hz,2H),7.29(d,J=2.2Hz,1H),7.00( d,J=2.2Hz,2H),6.49-6.35(m,1H),6.27(d,J=2.3Hz,1H),5.79(d,J=2.2Hz,1H),3.59-3.41(m,4H),3.31-3.25(m,2H),3.23-3.18(m,2H).

[0174] Example 7 Preparation of N-(3-(piperidin-1-carbonyl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)acrylamide (Compound 7)

[0175]

[0176] Step 1: Synthesis of (5-nitro-2-((4-(trifluoromethyl)phenyl)amino)phenyl)(piperidin-1-yl)methyl ketone (compound 7c).

[0177] Compound 4b (5.0 g, 15.3 mmol) was added to a reaction flask, followed by 50 mL of thionyl chloride. The mixture was heated to 80 °C and stirred for 4 hours. The thionyl chloride was then removed by vortexing, and 50 mL of DCM was added. Piperidine (1.3 g, 15.3 mmol) was then added. The mixture was extracted with ethyl acetate 3-4 times. The organic phases were combined, washed with saturated brine, concentrated, purified by column chromatography, and dried under vacuum to give 2.9 g of the product. Yield: 48.2%.

[0178] Step 2: Synthesis of (5-amino-2-((4-(trifluoromethyl)phenyl)amino)phenyl)(piperidin-1-yl)methyl ketone (compound 7d).

[0179] Compound 7c (2.9 g, 7.4 mmol) and Pd / C (10%) (74.2 mg, 0.7 mmol) were added to a reaction flask and dissolved in 25 mL of anhydrous methanol. The mixture was heated to 40 °C under H2 and stirred for 12 hours. The mixture was filtered, concentrated, and dried under vacuum to give 1.8 g of the product. Yield: 67.0%.

[0180] Step 3: Synthesis of N-(3-(piperidin-1-carbonyl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)acrylamide (compound 7).

[0181] Compound 7d (363.2 mg, 1 mmol) was added to a reaction flask and dissolved in 3 mL of anhydrous THF. Then, TEA (202.2 mg, 2.0 mmol) and acryloyl chloride (99.0 mg, 1.1 mmol) were added. The mixture was stirred at 0°C to room temperature for 12 hours. TLC analysis confirmed the reaction was complete. The reactants were dried under vacuum, diluted with excess water, and extracted 3-4 times with ethyl acetate. The organic phases were combined, washed with saturated brine, concentrated, purified by silica gel column chromatography, dried under vacuum, and then purified again by reversed-phase column chromatography. The product was dried under vacuum to give 43.9 mg, yield: 10.5%. LC-MS (ESI): m / z = 440.16 [M + Na] + ; 1 H NMR (300MHz, DMSO-d6) δ10.29(s,1H),8.20(s,1H),7.71(s,1H),7.63(d,J=2.2Hz,1H),7.48(d,J=2.2Hz,2H),7.31(d,J=2.2Hz,1H),7.00(d,J=2.2H z,2H),6.49-6.35(m,1H),6.27(d,J=2.3Hz,1H),5.79(d,J=2.2Hz,1H),3. 59-3.41(m,2H),3.21-3.15(m,2H),1.58-1.43(m,4H),1.30-1.25(m,2H).

[0182] Bioactivity test

[0183] Example 8: In vitro tumor cell proliferation (NCI-H226) inhibitory activity experiment

[0184] 1: Experiments were conducted using the NCI-H226 human chronic myeloid leukemia cell line. The cells were cultured in suspension at 37°C, 5% CO2, and 95% humidity in 1640+10% FBS (Gibco) complete medium.

[0185] 2: The following are general experimental methods:

[0186] Logarithmically growing NCI-H226 cells were digested with trypsin, centrifuged, and the resulting cell pellet was resuspended in fresh culture medium. The cells were then stained with Pan Blue for counting. The cells were diluted to an appropriate concentration, and 50 μL of each cell was seeded into 96-well plates at a density of 3000 cells per well. The cell plates were then incubated overnight in a CO2 incubator.

[0187] Stock solutions of the test compounds were prepared using the compounds described in Examples 1-7 of this invention. All compounds were prepared with 10 mM DMSO stock solutions, stored at -80°C, and aliquoted for use. The stock solutions were diluted with culture medium to a suitable concentration (e.g., 100 nm to 100 μm) according to the required working concentration. 50 μL of the test compound solution was added to each cell well, with three replicates for each test compound.

[0188] The cell plate was placed in a carbon dioxide incubator and cultured for another 3 days.

[0189] 3: Endpoint Reading Board

[0190] 20 μL of MTT reagent per well, incubate at room temperature for 3-4 hours, read the absorbance at 570 nm using a microplate reader, and calculate the cell growth inhibition efficiency.

[0191] 4: Data Processing

[0192] The data were analyzed using GraphPad Prism 9.0 software. A nonlinear S-curve regression was used to fit the data to obtain the dose-response curve, and the IC50 value was calculated from it.

[0193] Cell viability (%) = (OD test drug - OD culture medium control) / (OD cell control - OD culture medium control) × 100%.

[0194] The preliminary screening results of the inhibitory effect on cell proliferation in the examples are summarized in Table 2 below.

[0195] Table 2

[0196]

[0197] The experimental results (Table 2) show that all the compounds provided by this invention have significant inhibitory activity against NCI-H226 cells. Among them, compound 1 showed the most significant inhibitory effect on NCI-H226 activity, indicating that the compounds of this invention are clearly defined NCI-H226 inhibitors.

Claims

1. A compound having the following structural formula (I), Or in a pharmaceutically acceptable form; in: Y is selected from CH or N; Z is selected from chemical bonds, NR b , O or S; R1 is independently selected from hydrogen, halogen, nitrile or hydroxyl, and can be mono, di or polysubstituted; R2 is X1-X6 are independently selected from CR a Or N, and one of X1, X2, X3 and X4 is a C atom connected to the parent nucleus, and X7 is selected from O, S, Se or NR. b X8 is selected from O, S, Se, NR b or C(R) a )2; m can be 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, 4, 5, 6 or 7; R a Independently selected from hydrogen, halogen, nitrile, nitro, hydroxyl, aldehyde, carboxyl, acetamide, ethoxycarbonyl, aminoacyl, -NH2, -NHC 1-6 Alkyl, -N(C) 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-7 Heterocyclic alkyl, C 6-10 Aryl or C 5-10 Mixed aromatics; R b Independently selected from hydrogen, acetyl, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or two R atoms on the same atom or adjacent atoms a Group or two R b Group or R a and R b They can form C together 3-7 cycloalkyl, C 3-7 Heterocyclic alkyl, C 6-10 Aryl or C 5-10 Mixed aromatics; The halogen mentioned is F, Cl or Br.

2. The compound according to claim 1, having the following structural formula (II), in: Z is selected from chemical bonds or NR. b ; R1 is independently selected from hydrogen or halogen; R2 is X1-X6 are independently selected from CR a Or N, and one of X1, X2, X3 and X4 is a C atom connected to the parent nucleus, and X7 is selected from O, S, Se or NR. b X8 is selected from O, S, Se, NR b or C(R) a )2; m can be 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, 4, 5, 6 or 7; R a Independently selected from hydrogen, halogen, nitrile, nitro, hydroxyl, aldehyde, carboxyl, acetamide, ethoxycarbonyl, aminoacyl, -NH2, -NHC 1-3 Alkyl, -N(C) 1-3 Alkyl)2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-7 Heterocyclic alkyl, C 6-10 Aryl or C 5-10 Mixed aromatics; R b Independently selected from hydrogen, acetyl, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Or two R atoms on the same atom or adjacent atoms a Group or two R b Group or R a and R b They can form C together 3-7 cycloalkyl, C 3-7 Heterocyclic alkyl, C 6-10 Aryl or C 5-10 Mixed aromatics; The halogen mentioned is F, Cl, or Br.

3. The compound according to claim 1, having the following structural formula (III), in: R1 is independently selected from hydrogen or halogen; R2 is selected from one, two, or three R2 values. a The following groups are substituted: R a Independently selected from hydrogen, halogen, nitrile, nitro, hydroxyl, aldehyde, carboxyl, acetamide, ethoxycarbonyl, aminoacyl, -NH2, -NHC 1-3 Alkyl, -N(C) 1-3 Alkyl)2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-7 Heterocyclic alkyl, C 6-10 Aryl or C 5-10 Mixed aromatics; R b Independently selected from hydrogen, acetyl, or C 1-3 alkyl.

4. The compound according to claim 1, selected from one of the following compounds: N-(3-(benzo[c][1,2,5]selenodiazole-5-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)acrylamide, N-(3-(benzo[c][1,2,5]thiadiazole-5-yl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)acrylamide, N-(3-(benzo[c][1,2,5]oxadiazole-5-yl)-4-((4-(trifluoromethyl)phenyl)amino)amino)amino N-(3-(selenomorpholine-4-carbonyl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)acrylamide, N-(3-(thiomorpholine-4-carbonyl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)acrylamide, N-(3-(morpholine-4-carbonyl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)acrylamide, N-(3-(piperidin-1-carbonyl)-4-((4-(trifluoromethyl)phenyl)amino)phenyl)acrylamide.

5. The compound according to claim 1, wherein the pharmaceutically acceptable form includes a pharmaceutically acceptable salt, stereoisomer, crystal form, or solvate, and the solvate includes a hydrate.

6. A method for preparing a compound as described in formula (VIII), comprising the following steps: (1) Preparation of intermediate (II) 3-Bromo-4-nitroaniline (I) was dissolved in anhydrous DCM, and (Boc)2O, TEA and DMAP were added. The mixture was stirred at room temperature for 12 hours to obtain intermediate (II). (2) Preparation of intermediate (III) Intermediate (II) was dissolved in ethanol and water in a 1:1 ratio, zinc powder and NH4Cl were added, and the mixture was heated to obtain intermediate (III); (3) Preparation of the target product (IV) The Buchwald coupling reaction involves dissolving intermediate (III) in anhydrous dioxane, adding XantPhos and Cs2CO3 and palladium catalyst, then adding p-trifluoromethyliodobenzene, and heating under inert gas protection to obtain the target product (IV). (4) Preparation of intermediate (V) Intermediate (IV) was dissolved in anhydrous dioxane, potassium acetate, pinacol boronic acid ester, and palladium catalyst were added, and the mixture was heated under inert gas protection to obtain the target product (V). (5) Preparation of the target product (VI) The Suzuki coupling reaction involves dissolving intermediate (V) in dioxane and water in a 1:1 ratio, adding potassium carbonate and palladium catalyst, adding the corresponding halogen, and heating under inert gas protection to obtain the target product (VI). (6) Preparation of the target product (VII) Intermediate (VI) was dissolved in HCl dioxane and stirred at room temperature to obtain the target product (VII); (7) Preparation of the target product (VIII) Intermediate (VII) was dissolved in THF, and TEA and acryloyl chloride were added. The mixture was stirred from 0°C to room temperature to obtain the target product (VIII).

7. A method for preparing a compound as described in formula (XIII), comprising the following steps: (1) Preparation of intermediate (X) 2-Fluoro-5-nitrobenzoic acid (IX) was dissolved in anhydrous DMSO, and DIEA and p-trifluoromethylaniline were added. The mixture was stirred at 120 degrees Celsius for 12 hours to obtain intermediate (X). (2) Preparation of intermediate (XI) Intermediate (X) was dissolved in thionyl chloride, heated for 4 hours, dried by rotary evaporation, and then DCM was added. The corresponding amine was then added and stirred at room temperature to obtain intermediate (XI). (3) Preparation of the target product (XII) The intermediate (XI) was dissolved in anhydrous methanol, a palladium catalyst on carbon was added, and the mixture was heated under hydrogen conditions to obtain the target product (XII). (8) Preparation of the target product (XIII) The intermediate (XII) was dissolved in THF, and TEA and acryloyl chloride were added. The mixture was stirred from 0°C to room temperature to obtain the target product (XIII).

8. A pharmaceutical composition comprising a compound of any one of claims 1-4 or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier or excipient.

9. The use of any compound of claims 1-4 or in a pharmaceutically acceptable form thereof in the preparation of a medicament for the treatment and / or prevention of diseases caused by TEAD.

10. In the application of claim 8, the disease caused by the TEAD is a proliferative disease selected from: solid tumors, sarcomas, lung cancer, gastric cancer, colorectal cancer, liver cancer, pancreatic cancer, ovarian cancer, leukemia, neuroblastoma, kidney cancer, esophageal cancer, uterine cancer, pleural mesothelioma, breast cancer, prostate cancer, tumor formation, and other proliferative or proliferative diseases; or the disease caused by the TEAD is metastatic invasive cancer, viral infection, or CNS disorder.

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