Benzo[C][2,6]naphthyrizine derivatives, compositions and their therapeutic use

Abstract

This invention provides compounds for use in treating diseases and conditions involving CK2α. [Solution] A compound of formula I is provided. The compound is an inhibitor of casein kinase 2 alpha (CK2α) and is useful for treating proliferative disorders (e.g., cancer), viral infections, inflammation, diabetes, vascular and ischemic disorders, neurodegeneration, and regulating circadian rhythms. JPEG2026122953000357.jpg73170

Description

[Technical Field]

[0001] [Introduction] This invention relates to a novel therapeutic compound. More specifically, this invention relates to a part of the CK2 holoenzyme. Casein kinase 2 alpha subunit (CK2α(CSNK2A1) and This relates to novel therapeutic compounds that inhibit / or CK2α'(CSNK2A2)). Therefore, the novel therapeutic compounds are intended to treat and / or prevent diseases and conditions involving CK2α activity. Prevention, for example, but not limited to, proliferative disorders (e.g., cancer), viral infections, inflammation Treatment and / or prevention of diabetes, vascular and ischemic disorders, neurodegeneration, and circadian rhythm It is useful for regulating the rhythm.

[0002] The present invention also includes pharmaceutical compositions comprising novel therapeutic compounds as defined herein, and these compounds Methods for synthesizing substances, and treatments for diseases and / or conditions involving CK2α activity. Regarding their use for placement. [Background technology]

[0003] CK2α is a serine / threonine kinase that is an important regulator of many cellular processes. It is involved in cell proliferation and anti-apoptotic mechanisms (Battistutta (Lolli, Mol. Cell. Biochem. 2011). It is mainly, It consists of dimers of two catalytic (α and / or α') and regulatory (β) subunits. It exists as a holoenzyme, but can also be found as a separated subunit (N iefind et al., EMBO J 2001). Unlike most other kinases, it It is constitutively active, and more than 300 proteins have been identified as putative CK2α substrates. Therefore, it is one of the most multifaceted proteins in eukaryotes (Me Ggio and Pinna, FASEB 2003).

[0004] CK2α transmits multiple signals to cells, resulting in proliferation and anti-apoptotic phenotypes. It is a survival-promoting kinase that acts across signaling pathways. Therefore, cancer cells are often C Described as K2α activity-dependent, high-profile genome-wide CRISPR-Ca The s9 screen identifies CK2 as a top priority drug target for colorectal cancer (CRC). α was identified (Behan et al., Nature 2019). The target is multi-layered, including CRC. Human data linking low patient survival rates in various tumor types to increased CK2α expression This has been thoroughly verified (Lin et al., PLoS ONE 2011). Furthermore, clinical trials Data from this study indicate that CK2α expression is upregulated in many tumor types. (Ortega et al., PLoS ONE 2014; Di Maira et al., 2019).

[0005] The human genetics of CRCs have been well-characterized, with approximately 80% of tumors being due to wnt pathway mutations. It has been identified as a driving type (e.g., APC, β-catenin) (Zhan et al., Onco (gene 2017). The wnt pathway is sensitive to CK2α activity and is amplified by it. It is known that this can be inhibited by loss of CK2α function (Gao and Wang, (JBC 2006). For example, in animal models, CK2α inhibition affects the wnt pathway. This prevents tumor growth driven by different mutations (Dowling et al., ACS 2 016).

[0006] CK2α is also known to be a wnt-dysregulating tumor type of cholangiocarcinoma (CCA). It contributes to malignant phenotypes in (Zhan et al., Oncogene 2017). CK2α It is overexpressed in human CCA samples and CCA tumor cell lines (Di Maira et al., Oncogenesis 2019), disruption of CK2α activity in CCA cell models It has been reported that it inhibits tumorigenic properties (Zakharia et al., Transla (Journal Oncology 2019).

[0007] As monotherapy, in combination with standard chemotherapy, or in combination with other targeted therapies under development. In combination, for example, but not limited to, C given in combination with a KRAS inhibitor K2α inhibitors help restore the normal balance of apoptosis and proliferation. By reversing the abnormal mutation-driven upregulation of NAL transmission, CRC tumor growth is inhibited. It has been hypothesized that this will happen.

[0008] Existing CK2α inhibitors target highly conserved ATP binding sites. This design strategy In many cases, such inhibitors have a lower selectivity profile than other kinases. It drips down. Therefore, it binds to the catalytic ATP site of CK2α (driving potent enzyme inhibition). ) In addition, it interacts with other regions of CK2α, such as the αD site (more than other kinases). A potent and more selective CK2α inhibitor is needed, which also drives a high level of selectivity. Yes, they are.

[0009] This invention was conceived with the above in mind. [Overview of the Initiative]

[0010] In one embodiment, the present invention relates to a compound of formula I as defined herein, and / or Provides pharmaceutically acceptable salts, hydrates, or solvates.

[0011] In another embodiment, the present invention relates to a compound of formula I as defined herein, or its pharmaceutically acceptable properties. Tolerable salts, hydrates or solvates, and one or more pharmaceutically acceptable The present invention provides a pharmaceutical composition containing an excipient.

[0012] In another embodiment, the present invention provides a therapeutic application of Formula I as defined herein. The compound of, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or as specified herein. The present invention provides a pharmaceutical composition as defined by [the specified formula].

[0013] In another embodiment, the present invention relates to the treatment of diseases or conditions involving CK2α activity. For use, compounds of formula I as defined herein, or pharmaceutically acceptable salts thereof, The present invention provides hydrates or solvates, or pharmaceutical compositions as defined herein.

[0014] In another embodiment, the present invention relates to the treatment of diseases or conditions associated with abnormal activity of CK2α. For use in the foregoing, a compound of formula I as defined herein, or a pharmaceutically acceptable compound thereof. The present invention provides salts, hydrates, or solvates of a compound, or pharmaceutical compositions as defined herein.

[0015] In another embodiment, the present invention relates to proliferative disorders (e.g., cancer or benign neoplasms), viruses Treatment of infections, inflammatory diseases or conditions, diabetes, vascular and ischemic disorders, and neurodegenerative disorders. , and / or for use in the regulation of circadian rhythms, Formula I as defined herein The compound of, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or as specified herein. The present invention provides a pharmaceutical composition as defined by [the specified formula].

[0016] In another embodiment, the present invention is for use in the treatment of cancer, as defined herein. Compounds of formula I, or their pharmaceutically acceptable salts, hydrates, or solvates, or The present invention provides a pharmaceutical composition as defined in the specification.

[0017] In another embodiment, the present invention relates to use in the treatment of viral infections as described herein. Compounds of formula I as defined, or their pharmaceutically acceptable salts, hydrates, or solvates, Alternatively, the invention provides a pharmaceutical composition as defined herein.

[0018] In another embodiment, the present invention relates to the treatment of diseases or conditions involving CK2α activity. Compounds of formula I as defined herein, or their pharmaceuticals, in the manufacture of pharmaceuticals for use. The use of generally acceptable salts, hydrates, or solvates is provided.

[0019] In another embodiment, the present invention relates to the treatment of diseases or conditions associated with abnormal activity of CK2α. In the manufacture of a pharmaceutical product for use in the foregoing, a compound of formula I as defined herein, or The use of pharmaceutically acceptable salts, hydrates, or solvates of is provided.

[0020] In another embodiment, the present invention relates to proliferative disorders (e.g., cancer or benign neoplasms), viruses Treatment of infections, inflammatory diseases or conditions, diabetes, vascular and ischemic disorders, and neurodegenerative disorders. , and / or in the manufacture of pharmaceuticals for use in regulating circadian rhythms, this specification Compounds of formula I as defined in the book, or their pharmaceutically acceptable salts, hydrates, or solvates. To provide the use of an item.

[0021] In another embodiment, the present invention relates to the manufacture of a pharmaceutical product for use in the treatment of cancer, Compounds of formula I as defined herein, or pharmaceutically acceptable salts, hydrates, or The use of solvates is provided.

[0022] In another embodiment, the present invention relates to the manufacture of pharmaceuticals for use in the treatment of viral infections. The compound of formula I as defined herein, or its pharmaceutically acceptable salt or hydrate. Alternatively, the use of a solvate is provided.

[0023] In another embodiment, the present invention relates to a method for treating a disease or condition involving CK2α activity. The subject requiring treatment is given an effective amount of the compound of formula I as defined herein, This refers to the pharmaceutically acceptable salt, hydrate, or solvate thereof, or the medical as defined herein. The present invention provides a method comprising the step of administering a drug composition.

[0024] In another embodiment, the present invention addresses diseases or conditions related to abnormal activity of CK2α. A method for applying an effective amount of a compound of formula I as defined herein to a target requiring treatment. or a pharmaceutically acceptable salt, hydrate or solvate thereof, or as defined herein The present invention provides a method comprising the step of administering a pharmaceutical composition.

[0025] In another embodiment, the present invention relates to proliferative disorders (e.g., cancer or benign neoplasms), viruses Treatment of infections, inflammatory diseases or conditions, diabetes, vascular and ischemic disorders, and neurodegenerative disorders. a method for regulating the circadian rhythm, which is used in subjects requiring treatment. The efficacy of the compound of formula I as defined herein, or its pharmaceutically acceptable salts and hydrates, also A method comprising the step of administering a solvate or a pharmaceutical composition as defined herein. To provide.

[0026] In another embodiment, the present invention relates to a method for treating cancer, wherein the subject requiring treatment is , an effective amount of the compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, hydrate The process includes the step of administering a substance or a solvate, or a pharmaceutical composition as defined herein. Provide a method.

[0027] In another embodiment, the present invention relates to a method for treating a viral infection, which requires treatment To the target, an effective amount of the compound of formula I as defined herein, or its pharmaceutically acceptable form Steps to administer a salt, hydrate, or solvate, or a pharmaceutical composition as defined herein. Provides a method that includes the pu.

[0028] In another embodiment, the present invention, together with one or more additional therapeutic agents, is described herein. A compound of formula I as defined, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. The combination therapy is provided.

[0029] In another embodiment, the present invention, together with one or more therapeutic agents as defined herein, Compounds of formula I, or their pharmaceutically acceptable salts and hydrates as defined herein. The present invention provides a method for preparing solvates.

[0030] Preferred, suitable, and optional features of any one specific embodiment of the present invention are optional. These are also preferred, suitable, and optional features of other embodiments. [Modes for carrying out the invention]

[0031] [Definition] Unless otherwise specified, the following terms used in this specification and in the claims: This has the following meanings:

[0032] The use of "to treat" or "treatment" implies prevention and establishment of a disease condition. Please understand that this includes alleviating the symptoms. Therefore, "treatment" refers to a condition, disorder, or illness. "To do" or "treatment" means (1) to be able to suffer from a condition, disorder or illness, or to be affected Although susceptible, the clinical or potential symptoms of the condition, disease, or illness are not yet present. Clinical symptoms of a condition, disorder, or illness that develops in a person who has not experienced or manifested it (2) Prevention or delay of the onset of the disease, (3) inhibition of a condition, disorder or disease, i.e., the onset of the disease Or a relapse (in the case of maintenance therapy), or at least one clinical or latent (3) Relief or reduction of the symptoms, or (4) alleviation or reduction of the disease, i.e., The regression of a state, disease, or condition, or at least one of its clinical or potential symptoms. Including bringing about.

[0033] "Therapeutic dose" is the amount administered to a mammal to treat a disease, and is effective in treating that disease. This refers to the amount of compound sufficient to achieve the desired treatment. "Therapeutic dose" refers to the amount of compound... It varies depending on the disease and its severity, as well as the age, weight, etc., of the mammal being treated. .

[0034] References to “casein kinase 2 alpha” or “CK2α” in this specification are in accordance with the C2α standard. Includes K2α (CSNK2A1) and / or CK2α' (CSNK2A2). CK2 The compounds of the present invention, as defined herein, that inhibit α or are CK2α inhibitors, are referred to herein. If so, the compound is CK2α(CSNK2A1) and / or CK2α'(CS This means that it functions as an inhibitor of NK2A2 and CK2 holoenzymes. In the application, the compound of the present invention inhibits CK2α (CSNK2A1). Another application Morphologically, the compounds of the present invention inhibit CK2α'(CSNK2A2).

[0035] The compounds and intermediates described herein are those of the IUPAC (International Union of Pure and Applied Chemistry) or It can be named according to the CAS (Chemical Abstract Service) nomenclature. (Opposite meaning) Unless explicitly stated otherwise, the terms “compound of formula I,” “compound of the present invention,” and more generally The term "compound" as used herein is defined by and / or by reference to Formula I. It should be understood that this refers to and includes all compounds that are identified. These terms refer to all stereoisomers of such compounds, namely cis and trans isomers. The enantiomers, as well as the optical isomers, namely R and S enantiomers, in substantially pure forms and It should be understood that this is to be included as any mixture of the above in any proportion. This understanding is that one or more compounds of formula I, either alone or in combination with additional agents, The scope also extends to pharmaceutical compositions and treatment methods that use or contain substances.

[0036] Unless otherwise specified, atoms in this specification are those listed in the IUPAC periodic table. It is represented by the chemical symbol. For example, "C" refers to a carbon atom.

[0037] The use of "(m~nC)" or "(m~nC) base" as a standalone prefix or prefix. The term refers to any group having m to n carbon atoms.

[0038] In this specification, the term "alkyl" includes both linear and branched alkyl groups. Includes. References to individual alkyl groups such as "propyl" are limited to linear forms only, and "isopropyl" is used. References to individual branched alkyl groups such as "ropil" are specific only to branched-chain types. For example, "(1-6C) alkyl" refers to (1-4C) alkyl, (1-3C) alkyl, and propyl This includes isopropyl and t-butyl. Similar conventions apply to other groups, for example, "f "Phenyl(1-6C)alkyl" refers to phenyl(1-4C)alkyl, benzyl, 1-phenyl Contains ylethyl and 2-phenylethyl.

[0039] The alkylene group is located between two other chemical groups and functions to connect them. It is an alkyl group. Therefore, "(1-6C)alkylene" has 1 to 6 carbon atoms. A straight-chain saturated divalent hydrocarbon group, or a branched saturated divalent hydrocarbon group with 3 to 6 carbon atoms, e.g. For example, this refers to methylene, ethylene, propylene, 2-methylpropylene, pentylene, etc. .

[0040] "(3-6C) cycloalkyl" refers to a hydrocarbon ring containing 3 to 6 carbon atoms, for example, cycloalkyl. Clopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or This means bicyclo[2.2.1]heptyl.

[0041] The terms "halo" or "halogeno" refer to fluoro, chloro, bromo, and iodine. To point.

[0042] When used herein, either alone or in conjunction with other terms, "haloalkyl" And "haloalkyl group" means that one or more hydrogen atoms are replaced by halogen atoms. This refers to an alkyl group. Typical examples, though not limited to these, include -CF3 and -CHF. 2, -CH2F, -CF2CF3, -CHFCF3, and -CH2CF3 are preferred. The haloalkyl group is selected from -CHF2 and -CF3, preferably -CF3. be.

[0043] When used herein, either alone or in conjunction with other terms, "haloalkoxy" is used. " and "haloalkoxy group" are defined as groups in which one or more hydrogen atoms are separated by a halogen atom. This refers to a substituted alkoxy group (i.e., an O-alkyl group). Typical examples are limited to these. Not specified, but includes -OCF3, -OCHF2, -OCH2F, and -OCF2CF3. Preferably, the haloalkoxy group is selected from -OCHF2 and -OCF3, It is -OCF3.

[0044] "Heterocyclyl," "heterocyclic," or "heterocyclic" refers to a non-aromatic saturated or partial compound. This refers to saturated monocyclic, condensed, bridged, or spironic heterocyclic ring systems. The cyclic ring contains approximately 3 to 12 (preferably 3 to 7) ring atoms, and within the ring are nitrogen, oxygen and It has 1 to 5 (preferably 1, 2, or 3) heteroatoms selected from sulfur. A bicyclic heterocycle contains 7 to 17 ring-member atoms, preferably 7 to 12 ring-member atoms, within the ring. Hmm. Bicyclic heterocyclic rings may also be condensed, spiro, or bridging ring systems. Heterocyclic Examples of the group include cyclic ethers, for example, oxyranyl, oxetani, etc., but are not limited to these. Includes tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Contains nitrogen. Heterocycles include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and teto This includes lahydrotriazinyl, tetrahydropyrazolyl, etc. Typical sulfur-containing heterocycles are tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H-thiop It contains oran and hexahydrothiepine. Other heterocycles include dihydrooxathiolyl. Tetrahydrooxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazo Lyl, tetrahydrooxathiazolyl, hexahydrotriazinyl, tetrahydrooxa Dinyl, Morpholinyl, Thiomorpholinyl, Tetrahydropyrimidinyl, Dioxolinyl , octahydrobenzofuranil, octahydro benzimidazolyl, and octahydro Contains benzothiazolyl. The sulfur-containing heterocycle contains sulfur oxides containing SO or SO2 groups. Heterocycles are also included. An example is the tetrahydrothienyl and thiomorpholinyl Rufoxide and sulfone forms, for example, but not limited to these, tetrahydrothiene Contains 1,1-dioxide and thiomorpholinyl 1,1-dioxide. One or two The preferred values ​​of the heterocyclyl group having an oxo (=O) or thioxo (=S) substituent are For example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazoli Dinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxop With loridinil, 2,5-dioxoimidazolidinil, or 2,6-dioxopiperidinil Yes. Certain heterocyclyl groups are selected from nitrogen, oxygen, or sulfur (1, 2, or 3). Saturated monocyclic 3- to 7-membered heterocyclines containing heteroatoms, such as azetidinyl, tetra Hydrofuranil, tetrahydropyranil, pyrrolidinil, morpholinil, tetrahydroth Enyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl Lu-1,1-dioxide, piperidinil, homopiperidinil, piperazinil or homopiperidinil It is radinyl. As will be understood by those skilled in the art, it can be formed via any suitable atom, for example, carbon. Alternatively, any heterocycle may be linked to another group via a nitrogen atom. However, this specification In the book, references to piperidino or morpholino refer to piperidino linked via a nitrogen ring. This refers to the 1-yl or morpholine-4-yl ring.

[0045] A "bridged ring system" refers to a ring system in which two rings share three or more atoms. For example, Ad vanced Organic Chemistry, by Jerry March, Volume 4 See edition, Wiley Interscience, pp. 131-133, 1992. Examples of cross-linked heterocyclyl ring systems include aza-bicyclo[2.2.1]heptane and 2-oxy sa-5-azabicyclo[2.2.1]heptane, azabicyclo[2.2.2]octane , containing aza-bicyclo[3.2.1]octane and quinuclidine.

[0046] A "spiro-dicyclic ring system" is a ring system in which two ring systems share one common spirocarbon atom. In other words, the heterocyclic ring is further carbocyclic or heterocyclic via a single common spirocarbon atom. This means that it is linked to a therocyclic ring. An example of a spirocyclic system is 6-azaspiro[3.4 ]Octane, 2-oxa-6-azapiro[3.4]Octane, 2-azapiro[3.3 [3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 7-oxa-2-azas Pyro[3.5]nonane, 6-oxa-2-azapiro[3.4]octane, 2-oxa- 7-Azaspiro[3.5]nonane and 2-Oxa-6-Azaspiro[3.5]nonane include.

[0047] The terms "heteroaryl" or "heteroaromatic" refer to compounds derived from nitrogen, oxygen, or sulfur. Select one or more (e.g., 14, in particular 1, 2, or 3) heteroatoms It refers to an incorporated aromatic monocyclic, bicyclic, or polycyclic ring. The term includes both monovalent and divalent species. Examples of heteroaryl groups include those with 5 to 12 ring members. Heteroaryl groups are more commonly monocyclic and bicyclic groups containing 5 to 10 ring members. For example, a 5 or 6-membered monocyclic ring or a 9 or 10-membered bicyclic ring, for example, a condensed ring The structure may be a bicyclic structure formed from 5- and 6-membered rings or two fused 6-membered rings. It can typically contain up to about four heteroatoms selected from nitrogen, sulfur, and oxygen. Typically, heteroaryl rings have up to three heteroatoms, more commonly up to two, for example. For example, it contains a single heteroatom. In one embodiment, the heteroaryl ring is at least It also contains one ring nitrogen atom. The nitrogen atom in the heteroaryl ring is either imidazole or It may be basic, as in the case of pyridine, or it may be indole or pyrrole. It may be essentially non-basic, as in the case of nitrogen. In general, any amino group substitution of the ring. The number of basic nitrogen atoms present in the heteroaryl group containing the group is less than 5.

[0048] Examples of heteroaryls include furyl, pyrrolyl, thienyl, oxazolyl, and isoxazoli. Lu, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thia Diazolyl, triazolyl, tetrazolyl, pyridyl, pyridadinil, pyrimidinil, pi Radzinyl, 1,3,5-triazeninyl, benzofuranyl, indolyl, isoindolyl, Benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzo Thiazolyl, indazolyl, prinyl, benzoflazanyl, quinolyl, isoquinolyl, ki Nazolinil, quinoxalinil, synnolinil, pteridinil, naphthilidinil, carbazo Lil, phenazinyl, benzoisoquinolinyl, pyridopyrazinyl, thieno[2,3b]- Furanyl-,2H-Flo[3,2b]-pyranyl-,5H-pyrido[2,3-d]-oxy Sadinyl-,1H-pyrazolo[4,3-d]-oxazolyl,4H-imidazo[4,5d ] Thiazolyl, pyrazino[2,3d]pyridazinyl, -imidazo[2,1b]thiazolyl , contains -imidazo[1,2b][1,2,4]-triazinyl. "Heteroaryl" is Furthermore, at least one ring is an aromatic ring, and one or more of the other rings are non-aromatic saturated or It is a partially saturated ring, however at least one ring is selected from nitrogen, oxygen, or sulfur. This also includes partially aromatic bicyclic or polycyclic ring systems containing one or more selected heteroatoms. Examples of partially aromatic heteroaryl groups include, for example, tetrahydroisoquinolinyl, tetrahydroisoquinolinyl. Hydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobe Nzothienyl, dihydrobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxy Nyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-ben Zothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl, 1,2,3 ,4-tetrahydro-1,8-naphthilidinyl, 1,2,3,4-tetrahydropyrido[ [2,3-b]pyrazinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]o Xazadinyl and 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]p Contains Rajnil.

[0049] Examples of five-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, and thienyl. Lu, imidazolyl, flazanil, oxazolyl, oxadiazolyl, oxatriazolyl isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and te Contains a torazolyl group.

[0050] Examples of six-membered heteroaryl groups are not limited to these, but include pyridyl, pyrazinyl, and pyridyl. Includes dadinyl, pyrimidinyl, and triazinyl.

[0051] Bicyclic heteroaryl groups are, for example, A benzene ring condensed into a 5- or 6-membered ring containing one, two, or three ring heteroatoms; A pyridine ring condensed into a 5- or 6-membered ring containing one, two, or three ring heteroatoms; A pyrimidine ring condensed into a 5- or 6-membered ring containing one or two ring heteroatoms; A pyrrole ring condensed into a 5- or 6-membered ring containing one, two, or three ring heteroatoms; A pyrazole ring condensed into a 5- or 6-membered ring containing one or two ring heteroatoms; A pyrazine ring condensed into a 5- or 6-membered ring containing one or two ring heteroatoms; An imidazole ring condensed into a 5- or 6-membered ring containing one or two ring heteroatoms; An oxazole ring fused to a 5- or 6-membered ring containing one or two ring heteroatoms; An isoxazole ring fused to a 5- or 6-membered ring containing one or two ring heteroatoms; A thiazole ring fused to a 5- or 6-membered ring containing one or two ring heteroatoms; An isothiazole ring fused to a 5- or 6-membered ring containing one or two ring heteroatoms; A thiophene ring condensed into a 5- or 6-membered ring containing one, two, or three ring heteroatoms; A furan ring fused to a 5- or 6-membered ring containing one, two, or three ring heteroatoms; Cyclo condensed on a 5 or 6-membered heteroaromatic ring containing one, two, or three ring heteroatoms Hexyl ring; and A cyclamate condensed into a 5-membered or 6-membered heteroaromatic ring containing one, two, or three ring heteroatoms. lopentyl ring The base may be selected from among them.

[0052] Specific examples of bicyclic heteroaryl groups containing a six-membered ring fused to a five-membered ring are not limited to these. However, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazo Lyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzo Furanyl, indolyl, isoindolyl, indolidinyl, indolinyl, isoindolyl Nyl, prinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxol Contains a pyrazolopyridinyl group.

[0053] Specific examples of bicyclic heteroaryl groups containing two fused six-membered rings are limited to these. However, quinolinyl, isoquinolinyl, chromanil, thiochromanil, chromenil, iso Clomenil, Chromanil, Isochromanil, Benzodioxanil, Quinolidinil, Benzo Oxazinyl, benzodiadinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, It contains synnolinyl, phthalazinyl, naphthilidinyl, and pteridinyl groups.

[0054] The term "aryl" refers to a cyclic or polycyclic aromatic ring having 5 to 12 carbon atoms. It means that the term aryl includes both monovalent and divalent species. Examples of aryl groups are , but not limited to, phenyl, biphenyl, naphthyl, etc. Specific Embodiments In this case, aryl is phenyl.

[0055] This specification also uses several compound terms to describe groups containing two or more functional groups. Use such terms. Such terms will be understood by those skilled in the art. For example, heterocyclyl (m~n C) Alkyl includes (m~nC) alkyl substituted with heterocyclyl.

[0056] The term "aryl(1-2C)alkyl" refers to the covalent bond between (1-2C)alkylene groups. This refers to a combined aryl group, both of which are defined herein. aryl-( 1-2C) Examples of alkyl groups include benzyl and phenylethyl.

[0057] "Heteroaryl(1-3C)alkyl" is covalently bonded to a (1-3C)alkylene group. This refers to heteroaryl groups, both of which are defined herein. Examples of yl-alkyl groups include pyridine-3-ylmethyl and 2-(benzofuran-2-yl). Contains ethyl, etc.

[0058] "Heterocyclyl(1-2C)alkyl" is a group covalently bonded to a (1-2C)alkylene group. This refers to heterocyclyl groups, both of which are defined herein.

[0059] "(3-6C)cycloalkyl-(1-2C)alkyl" is equivalent to (1-2C)alkylene This refers to a (3-6C) cycloalkyl group covalently bonded to a base, and both are used herein. It is defined.

[0060] The term "optionally substituted" refers to the substituted group, structure, or molecule, and the substitution. It refers to those that have not been done. 1 One of the groups / any CH, CH2, CH3 group or H The term "the terror atom (i.e., NH) is optionally substituted" is preferably used in the context of R 1 base This means that one of the hydrogen groups is substituted by a specified group related to it.

[0061] If the optional substituent is selected from "one or more" groups, this definition applies to all The substituent is selected from one of the specified groups, or the substituent is selected from two of the specified groups. Please understand that this includes making a selection from the above options.

[0062] Wavy line connection ( [ka] ) is used herein to indicate a bonding point.

[0063] The phrase "compound of the present invention" is not disclosed in general or specifically herein. It means both compounds present.

[0064] When used herein, either alone or in conjunction with other terms, "pharmaceutically acceptable" "to be" generally refers to chemical and / or interactions with other components (for example, when related to the formulation). Physical compatibility, and / or compatibility with its recipient (e.g., object, etc.) This refers to materials that are physiologically compatible.

[0065] When used alone or in combination with another term in this specification, "subject" and " patient" preferably refer to mammals, particularly humans.

[0066] <Compound of the present invention> In a first aspect, the present invention relates to a compound having the structural formula I shown below, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

Chemical formula

Chemical formula

[0067] The specific compounds of the present invention include, for example, the compound of formula I, or a pharmaceutically acceptable salt thereof. Includes hydrates and / or solvates, unless otherwise specified, R1, Q, R a , R b , R c , R d and R e Each of them has one of the meanings defined above. Or, as defined in any one of the following paragraphs (1) to (60).

[0068] (1) R1 is -C(O)OH;

[0069] (2) R1 is -C(O)NH2;

[0070] (3) Q is expression Ia or Ib: [ka] (The combination a in formulas Ia and Ib corresponds to the combination a in formula I, and the combination in formulas Ia and Ib b corresponds to the combination b in equation I; R2 and R3 are independently selected from hydrogen or methyl; X is selected from O;

[0071] (4) Q is expression Ia or Ib: [ka] (The combination a in formulas Ia and Ib corresponds to the combination a in formula I, and the combination in formulas Ia and Ib b corresponds to the combination b in equation I; R2 and R3 are either both hydrogen, or one of R2 and R3 is hydrogen and the other is methylcellulose. It is; X is selected from O;

[0072] (5) Q is expression Ia or Ib: [ka] (The combination a in formulas Ia and Ib corresponds to the combination a in formula I, and the combination in formulas Ia and Ib b corresponds to the combination b in equation I; R2 and R3 are both hydrogen; X is selected from O;

[0073] (6) Q is expression Ia or Ib: [ka] (The combination a in formulas Ia and Ib corresponds to the combination a in formula I, and the combination in formulas Ia and Ib b corresponds to the combination b in equation I; R2 and R3 are independently selected from hydrogen or methyl; X is selected from NH;

[0074] (7) Q is either formula Ia or Ib: [ka] (The combination a in formulas Ia and Ib corresponds to the combination a in formula I, and the combination in formulas Ia and Ib b corresponds to the combination b in equation I; R2 and R3 are either both hydrogen, or one of R2 and R3 is hydrogen and the other is methyl Chill; X is selected from NH; or Q is either Ia or Ib in the above formula. (The combination a in formulas Ia and Ib corresponds to the combination a in formula I, and the combination in formulas Ia and Ib b corresponds to the combination b in equation I; R2 and R3 are both hydrogen; X is selected from NH;

[0075] (8) Q is equation Ia: [ka] (The bond a in formula Ia corresponds to the bond a in formula I, and the bond b in formula Ia corresponds to the bond b in formula I.) Corresponds to; R2 and R3 are independently selected from hydrogen or methyl; X is selected from NH or O;

[0076] (9) Q is the base of equation Ia defined in section (3) above;

[0077] (10) Q is the base of equation Ia defined in section (4) above;

[0078] (11) Q is the base of equation Ia defined in section (5) above;

[0079] (12) Q is the base of equation Ia defined in section (6) above;

[0080] (13) Q is the base of equation Ia defined in section (7) above;

[0081] (14) Q is equation Ib: [ka] (The bond a in formula Ib corresponds to the bond a in formula I, and the bond b in formula Ib corresponds to the bond b in formula I.) It is the basis of (corresponding to);

[0082] (15)R a and R e These are, independently, hydrogen, methyl, fluoro, chloro or Selected from Bromo;

[0083] (16)R a and R e These are, independently, hydrogen, fluoro, chloro, or bromo. Selected from;

[0084] (17)R a and R e These are, independently, hydrogen, methyl, fluoro, or chloro Selected from;

[0085] (18)R a and R e Each is independently selected from hydrogen, fluoro, or chloro. Become;

[0086] (19)R a and R e Each is independently selected from hydrogen or chloro;

[0087] (20)R a and R e They are both hydrogen;

[0088] (21)R a and R e One of them is hydrogen, and the other is hydrogen, methyl, or halo;

[0089] (22)R a and R e One is hydrogen, and the other is hydrogen, methyl, fluoro, chloro or bromo;

[0090] (23)R a and R e One is hydrogen, and the other is hydrogen, methyl, fluoro, or chromium. It is Rolo;

[0091] (24)R a and R e One of them is hydrogen, and the other is either hydrogen or methyl;

[0092] (25)R a and R e One is hydrogen, and the other is hydrogen or fluoro;

[0093] (26)R a and R e One is hydrogen, and the other is hydrogen or chloroform;

[0094] (27)R b and R d These are, independently, hydrogen, halo, cyano, and (1-4C)al. kill, -[CH2] 0-2 -(1~4C)alkoxy, -[CH2] 0-2-C(O)NH2, -[CH2] 0-2 -C(O)NH(1-4C)alkyl, -[CH2] 0-2 -C(O)N[(1-4C)alkyl]2, -[CH2] 0-2 -NH(1-4C)alkyl, -[CH2] 0-2 -N[(1-4C)alkyl]2, -[CH2] 0-2 -S(O) q -(1-4C)alkyl (where q is 0, 1 or 2 ), -[CH2] 0-2 -C(O)(1-4C)alkyl, -[CH2] 0-2 -C(O)O-(1-4C)alkyl, -[CH2] 0-2 -NHC(O)-(1-4C)alkyl, -[CH2] 0-2 -S(O)2NH(1-4C)alkyl, -[CH2] 0-2 -S(O)2N[(1-4C)alkyl]2, -[CH2] 0-2 ​​​​​​​​​​​​​​​​​​​​​​​​​​One or more substituents selected from lucoxy or (3-4C)cycloalkoxy Replaced by optional means; Z1 is halo, hydroxy, cyano, amino, -C(O)OH, -C(O)NH2, (1 (~2C)alkoxy, (1~2C)alkyl, (3~4C)cycloalkyl, (3~4C )Cycloalkoxy, -C(O)NH(1~2C)alkyl, -C(O)N[(1~2C )alkyl]2,-NH(1~2C)alkyl,-N[(1~2C)alkyl]2,-S (O) q -(1~2C)alkyl(wherein q is 0, 1 or 2), -C(O)( 1~2C)alkyl, -C(O)O-(1~2C)alkyl, -N(R f )C(O)-( 1~2C)alkyl,-S(O)2NH(1~2C)alkyl,-S(O)2N[(1~ [2C)alkyl]2, or one selected from -NHSO2-(1~2C)alkyl Alternatively, it may be optionally substituted with multiple substituents, and any (1-2C)alkoxy, (1-2 C) alkyl, (3-4C) cycloalkyl, or (3-4C) cycloalkoxy groups are Halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy or (1 One or more substituents selected from (~2C)alkoxy-(1~2C)alkyl It has been replaced by an optional choice;

[0095] (28)R b and R d These are, independently, hydrogen, halo, cyano, and (1-4C)al. kill, -[CH2] 0-1 -(1~4C)alkoxy, -[CH2] 0-1 -C(O)NH2, -[CH2] 0-1-C(O)NH(1~4C)alkyl, -[CH2] 0-1 -C(O)N[(1~4C)alkyl]2, -[CH2] 0-1 -NH(1~4C)alkyl, -[CH2] 0-1 -N[(1~4C)alkyl]2, -[CH2] 0-1 -S(O) q -(1~4C)alkyl(wherein q is 0, 1 or 2) (is), -[CH2] 0-1 -C(O)(1~4C)alkyl, -[CH2] 0-1 -C(O)O-(1~4C)alkyl, -[CH2] 0-1 -NHC(O)-(1~4C)alkyl, -[CH2] 0-1 -S(O)2NH(1~4C)alkyl, -[CH2] 0-1 -S(O)2N[(1~4C)alkyl]2, -[CH2] 0-1 -NHSO2-(1~4C)alkyl, formula: -Y1-[CH2] 0-1 -Z1 (In the formula, Y1 is either nonexistent, or -O-, -NH-, -NMe-, -S-, -S(O )- or -S(O)2-; Z1 is a (3-6C) cycloalkyl, phenyl, 4-6 membered heterocycline or 5-membered heterocycline. (The base is a 6-membered heteroaryl) Selected from; Any alkyl, alkoxy or R b and R d Any alkyl portion within the substituent is Ro, hydroxy, cyano, amino, -C(O)OH, -C(O)NH2, (1~2C)a One or more substituents selected from lucoxy or (3-4C)cycloalkoxy Replaced by optional means; Z1 is halo, hydroxy, cyano, amino, -C(O)OH, -C(O)NH2, (1 (~2C)alkoxy, (1~2C)alkyl, (3~4C)cycloalkyl, (3~4C )Cycloalkoxy, -C(O)NH(1~2C)alkyl, -C(O)N[(1~2C )alkyl]2,-NH(1~2C)alkyl,-N[(1~2C)alkyl]2,-S (O) q -(1~2C)alkyl(wherein q is 0, 1 or 2), -C(O)( 1~2C)alkyl, -C(O)O-(1~2C)alkyl, -N(R f )C(O)-( 1~2C)alkyl,-S(O)2NH(1~2C)alkyl,-S(O)2N[(1~ [2C)alkyl]2, or one selected from -NHSO2-(1~2C)alkyl Alternatively, it may be optionally substituted with multiple substituents, and any (1-2C)alkoxy, (1-2 C) alkyl, (3-4C) cycloalkyl, or (3-4C) cycloalkoxy groups are Halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy or (1 One or more substituents selected from (~2C)alkoxy-(1~2C)alkyl It has been replaced by an optional choice;

[0096] (29)R b and R d These are, independently, hydrogen, halo, cyano, and (1-4C)al. kill, -[CH2] 0-2 -(1~2C)alkoxy, -[CH2] 0-2 -C(O)NH2, -[CH2] 0-2 -C(O)NH(1~2C)alkyl, -[CH2] 0-2-C(O)N[(1~2C)alkyl]2, -[CH2] 0-2 -NH(1~2C)alkyl, -[CH2] 0-2 -N[(1~2C)alkyl]2, -[CH2] 0-2 -S(O) q -(1~2C)alkyl (wherein q is 0, 1 or 2) (is), -[CH2] 0-2 -C(O)(1~2C)alkyl, -[CH2] 0-2 -C(O)O-(1~2C)alkyl, -[CH2] 0-2 -NHC(O)-(1~2C)alkyl, -[CH2] 0-2 -S(O)2NH(1~2C)alkyl, -[CH2] 0-2 -S(O)2N[(1~2C)alkyl]2, -[CH2] 0-2 -NHSO2-(1~2C)alkyl, formula: -Y1-[CH2] 0-2 -Z1 (In the formula, Y1 is either nonexistent, or -O-, -NH-, -NMe-, -S-, -S(O )- or -S(O)2-; Z1 is a (3-6C) cycloalkyl, phenyl, 4-6 membered heterocycline or 5-membered heterocycline. (The base is a 6-membered heteroaryl) Selected from; Any alkyl, alkoxy or R b and R d Any alkyl portion within the substituent is Ro, hydroxy, cyano, amino, -C(O)OH, -C(O)NH2, (1~2C)a One or more substituents selected from lucoxy or (3-4C)cycloalkoxy Replaced by optional means; Z1 is halo, hydroxy, cyano, amino, -C(O)OH, -C(O)NH2, (1 (~2C)alkoxy, (1~2C)alkyl, (3~4C)cycloalkyl, (3~4C )Cycloalkoxy, -C(O)NH(1~2C)alkyl, -C(O)N[(1~2C )alkyl]2,-NH(1~2C)alkyl,-N[(1~2C)alkyl]2,-S (O) q -(1~2C)alkyl(wherein q is 0, 1 or 2), -C(O)( 1~2C)alkyl, -C(O)O-(1~2C)alkyl, -N(R f )C(O)-( 1~2C)alkyl,-S(O)2NH(1~2C)alkyl,-S(O)2N[(1~ [2C)alkyl]2, or one selected from -NHSO2-(1~2C)alkyl Alternatively, it may be optionally substituted with multiple substituents, and any (1-2C)alkoxy, (1-2 C) alkyl, (3-4C) cycloalkyl, or (3-4C) cycloalkoxy groups are Halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy or (1 One or more substituents selected from (~2C)alkoxy-(1~2C)alkyl It has been replaced by an optional choice;

[0097] (30)R b and R d These are, independently, hydrogen, halo, cyano, and (1-4C)al. kill, -[CH2] 0-1 -(1~2C)alkoxy, -[CH2] 0-1 -C(O)NH2, -[CH2] 0-1 -C(O)NH(1~2C)alkyl, -[CH2] 0-1 -C(O)N[(1~2C)alkyl]2, -[CH2]0-1 -NH(1~2C)alkyl, -[CH2] 0-1 -N[(1~2C)alkyl]2, -[CH2] 0-1 -S(O) q -(1~2C)alkyl (wherein q is 0, 1 or 2) (is), -[CH2] 0-1 -C(O)(1~2C)alkyl, -[CH2] 0-1 -C(O)O-(1~2C)alkyl, -[CH2] 0-1 -NHC(O)-(1~2C)alkyl, -[CH2] 0-1 -S(O)2NH(1~2C)alkyl, -[CH2] 0-1 -S(O)2N[(1~2C)alkyl]2, -[CH2] 0-1 -NHSO2-(1~2C)alkyl, formula: -Y1-[CH2] 0-1 -Z1 (In the formula, Y1 is either nonexistent, or -O-, -NH-, -NMe-, -S-, -S(O )- or -S(O)2-; Z1 is a (3-6C) cycloalkyl, phenyl, 4-6 membered heterocycline or 5-membered heterocycline. (The base is a 6-membered heteroaryl) Selected from; Any alkyl, alkoxy or R b and R d Any alkyl portion within the substituent is Ro, hydroxy, cyano, amino, -C(O)OH, -C(O)NH2, (1~2C)a One or more substituents selected from lucoxy or (3-4C)cycloalkoxy Replaced by optional means; Z1 is halo, hydroxy, cyano, amino, -C(O)OH, -C(O)NH2, (1 (~2C)alkoxy, (1~2C)alkyl, (3~4C)cycloalkyl, (3~4C )Cycloalkoxy, -C(O)NH(1~2C)alkyl, -C(O)N[(1~2C )alkyl]2,-NH(1~2C)alkyl,-N[(1~2C)alkyl]2,-S (O) q -(1~2C)alkyl(wherein q is 0, 1 or 2), -C(O)( 1~2C)alkyl, -C(O)O-(1~2C)alkyl, -N(R f )C(O)-( 1~2C)alkyl,-S(O)2NH(1~2C)alkyl,-S(O)2N[(1~ [2C)alkyl]2, or one selected from -NHSO2-(1~2C)alkyl Alternatively, it may be optionally substituted with multiple substituents, and any (1-2C)alkoxy, (1-2 C) alkyl, (3-4C) cycloalkyl, or (3-4C) cycloalkoxy groups are Halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy or (1 One or more substituents selected from (~2C)alkoxy-(1~2C)alkyl It has been replaced by an optional choice;

[0098] (31)R b and R d These are, independently, hydrogen, halo, cyano, and (1-4C)al. kill, -[CH2] 0-2 -(1~4C)alkoxy, -[CH2] 0-2 -C(O)NH2, -[CH2] 0-2 -C(O)NH(1~4C)alkyl, -[CH2] 0-2 -C(O)N[(1~4C)alkyl]2, -[CH2] 0-2 -NH(1~4C)alkyl, -[CH2]0-2 -N[(1~4C)alkyl]2, -[CH2] 0-2 -S(O) q -(1~4C)alkyl(wherein q is 0, 1 or 2) (is), -[CH2] 0-2 -C(O)(1~4C)alkyl, -[CH2] 0-2 -C(O)O-(1~4C)alkyl, -[CH2] 0-2 -N(R f )C(O)-(1~4C)alkyl, -[CH2] 0-2 -S(O)2NH(1~4C)alkyl, -[CH2] 0-2 -S(O)2N[(1~4C)alkyl]2, -[CH2] 0-2 -NHSO2-(1~4C)alkyl, formula: -Y1-[CH2] 0-2 -Z1 (In the formula, Y1 is either nonexistent, or -O-, -NH-, -NMe-, -S-, -S(O )- or -S(O)2-; Z1 is a (3-6C) cycloalkyl, phenyl, or 5- or 6-membered heteroaryl compound. The basis of) Selected from; Any alkyl, alkoxy or R b and R d Any alkyl portion within the substituent is From √hydroxy, cyano, amino, -C(O)NH2 or (1-2C)alkoxy Optionally substituted by one or more substituents of choice; Z1 is a halo, hydroxy, cyano, amino, (1-2C)alkoxy, (1-2C)a Lukil, -C(O)NH(1~2C)alkyl, -C(O)N[(1~2C)alkyl] 2,-NH(1~2C)alkyl,-N[(1~2C)alkyl]2,-S(O)q -( 1-2C)alkyl (wherein q is 0, 1, or 2), -C(O)(1-2C) One or more alkyl groups selected from -C(O)O-(1~2C)alkyl groups It is optionally substituted by a substitution group, and any (1-2C) alkoxy or (1-2C) alkoxy The kill group is one selected from halo, cyano, hydroxy, or (1-2C)alkoxy. or optionally substituted by multiple substituents;

[0099] (32)R b and R d These are, independently, hydrogen, halo, cyano, and (1-4C)al. kill, -[CH2] 0-1 -(1~4C)alkoxy, -[CH2] 0-1 -C(O)NH2, -[CH2] 0-1 -C(O)NH(1~4C)alkyl, -[CH2] 0-1 -C(O)N[(1~4C)alkyl]2, -[CH2] 0-1 -NH(1~4C)alkyl, -[CH2] 0-1 -N[(1~4C)alkyl]2, -[CH2] 0-1 -S(O) q -(1~4C)alkyl(wherein q is 0, 1 or 2) (is), -[CH2] 0-1 -C(O)(1~4C)alkyl, -[CH2] 0-1 -C(O)O-(1~4C)alkyl, -[CH2] 0-1 -N(R f )C(O)-(1~4C)alkyl, -[CH2] 0-1 -S(O)2NH(1~4C)alkyl, -[CH2] 0-1-S(O)2N[(1~4C)alkyl]2, -[CH2] 0-1 -NHSO2-(1~4C)alkyl, formula: -Y1-[CH2] 0-1 -Z1 (In the formula, Y1 is either nonexistent, or -O-, -NH-, -NMe-, -S-, -S(O )- or -S(O)2-; Z1 is a (3-6C) cycloalkyl, phenyl, or 5- or 6-membered heteroaryl compound. The basis of) Selected from; Any alkyl, alkoxy or R b and R d Any alkyl portion within the substituent is From √hydroxy, cyano, amino, -C(O)NH2 or (1-2C)alkoxy Optionally substituted by one or more substituents of choice; Z1 is a halo, hydroxy, cyano, amino, (1-2C)alkoxy, (1-2C)a Lukil, -C(O)NH(1~2C)alkyl, -C(O)N[(1~2C)alkyl] 2,-NH(1~2C)alkyl,-N[(1~2C)alkyl]2,-S(O) q -( 1-2C)alkyl (wherein q is 0, 1, or 2), -C(O)(1-2C) One or more alkyl groups selected from -C(O)O-(1~2C)alkyl groups It is optionally substituted by a substitution group, and any (1-2C) alkoxy or (1-2C) alkoxy The kill group is one selected from halo, cyano, hydroxy, or (1-2C)alkoxy. or optionally substituted by multiple substituents;

[0100] (33)R b and R d These are, independently, hydrogen, halo, cyano, and (1-4C)al. kill, -[CH2] 0-1 -(1~4C)alkoxy, -[CH2] 0-1 -C(O)NH2, -[CH2] 0-1 -C(O)NH(1~4C)alkyl, -[CH2] 0-1 -C(O)N[(1~4C)alkyl]2, -[CH2] 0-1 -NH(1~4C)alkyl, -[CH2] 0-1 -N[(1~4C)alkyl]2, -[CH2] 0-1 -S(O) q -(1~4C)alkyl(wherein q is 0, 1 or 2) (is), -[CH2] 0-1 -C(O)(1~4C)alkyl, -[CH2] 0-1 -C(O)O-(1~4C)alkyl, formula: -Y1-[CH2] 0-1 -Z1 (In the formula, Y1 is either nonexistent, or -O-, -NH-, -NMe-, -S-, -S(O )- or -S(O)2-; Z1 is a (3-6C) cycloalkyl or 5 or 6-membered heteroaryl group. Selected from; Any alkyl, alkoxy or R b and R d Any alkyl portion within the substituent is From √hydroxy, cyano, amino, -C(O)NH2 or (1-2C)alkoxy Optionally substituted by one or more substituents of choice; Z1 is a halo, hydroxy, cyano, amino, (1-2C)alkoxy, (1-2C)a The substitution is made by one or more substituents selected from alkyl or (1-2C) haloalkyl. It has been replaced by a selective substitution;

[0101] (34)R b and R d These are, independently, hydrogen, halo, cyano, and (1-4C)al. kill, -[CH2] 0-1 -(1~4C)alkoxy, -[CH2] 0-1 -C(O)NH2, formula: [CH2] 0-1 -Z1 (In the formula, Z1 is a (3-6C) cycloalkyl or a 5 or 6-membered heteroaryl) The basis of Selected from; Any alkyl, alkoxy or R b and R d Any alkyl portion within the substituent is From √hydroxy, cyano, amino, -C(O)NH2 or (1-2C)alkoxy Optionally substituted by one or more substituents of choice; Z1 is a halo, hydroxy, cyano, amino, (1-2C)alkoxy, (1-2C)a The substitution is made by one or more substituents selected from alkyl or (1-2C) haloalkyl. It has been replaced by a selective substitution;

[0102] (35)R b and R d These are, independently, hydrogen, halo, cyano, and (1-4C)al. Kill, -(1~4C)alkoxy, -[CH2] 0-1 -C(O)NH2, formula: [CH2] 0-1 -Z1 (wherein Z1 is a (3-6C) cycloalkyl or 5-membered heteroaryl group) Selected from; Any alkyl, alkoxy or R b and R d Any alkyl portion within the substituent is From √hydroxy, cyano, amino, -C(O)NH2 or (1-2C)alkoxy Optionally substituted by one or more substituents of choice; Z1 is determined by one or more substituents selected from halo, hydroxy, or cyano. It has been replaced by a selective substitution;

[0103] (36)R b and R d These are, independently, hydrogen, halo, cyano, and (1-4C)al. Kill, (1-4C)alkoxy, -[CH2] 0-1 -C(O)NH2, formula: [CH2] 0-1 -Z1 (wherein Z1 is a (3-6C) cycloalkyl or 5-membered heteroaryl group) Selected from; Any alkyl, alkoxy or R b and R d Any alkyl portion within the substituent is From √hydroxy, cyano, amino, -C(O)NH2 or (1-2C)alkoxy Optionally substituted by one or more substituents of choice; Z1 is optionally replaced by one or more cyanonucleotides;

[0104] (37)R b and R d These are, independently, hydrogen, halo, cyano, and (1-4C)al. Kill, Halo(1-4C)alkyl, Hydroxy(1-4C)alkyl, Cyano(1-4C) )alkyl, amino(1-4C)alkyl, (1-2C)alkoxy(1-4C)alkyl Lu, (1-4C)alkoxy, Halo(1-4C)alkoxy, Hydroxy(1-4C) Lucoxy, -[CH2] 0-3 -C(O)NH2, formula: [CH2] 0-1 -Z1 (wherein Z1 is a (3-6C) cycloalkyl or 5-membered heteroaryl group) Selected from; Z1 is optionally replaced by one or more cyanonucleotides;

[0105] (38)R b and R d These are, independently, hydrogen, halo, (1-2C)alkyl, ( 1-2C) Alkoxy, formula: [CH2] 0-1 -Z1 (wherein Z1 is a (3-4C) cycloalkyl group) Selected from; Any alkyl, alkoxy or R b and R d Any alkyl portion within the substituent is It is optionally substituted with one or more substituents selected from (b);

[0106] (39)R b and R d These are, independently, hydrogen, fluoro, chloro, bromo, and shea. No, methyl, ethyl, methoxy, ethoxy, -CH2OH, -CH2OCH3, -CH2 NH2, -CH2CN, -CH2CH2OH, -CF3, -OCF3, -O-CH2CH 2OH, -O-CH2CF3, -C(O)NH2, -CH2-C(O)NH2, -CH( CH3)CN,-C(CH3)2CN, cyclopropyl, 1-cyanocyclopropyl, cyanocyclopropyl Clopropylmethyl, furanylmethyl (e.g., fran-3-ylmethyl), imidazolyl Methyl (e.g., imidazo-1-ylmethyl), pyrazolylmethyl (e.g., pyrazole-4) Selected from oxazolylmethyl (e.g., oxazo-4-ylmethyl) ru;

[0107] (40)R b and R d These are, independently, hydrogen, fluoro, chloro, bromo, and methyl. Selected from , -OCF3, or cyclopropyl;

[0108] (41)R b and R d One of them is hydrogen, halogen, (1-2C)alkyl, halo(1 ~2C)alkyl, (1~2C)alkoxy, halo(1~2C)alkoxy, (1~2C ) Alkoxy(1-2C)alkyl, (3-4C)cycloalkyl, (3-4C)cyclo It is an alkyl(1-2C)alkyl, and the other is defined in items (27) to (40) above. One of the following options will be selected;

[0109] (42)R b and R d One of them is hydrogen, halogen, or -OCF3, and the other These are hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, methoxy, ethoxy, -CH2OH, -CH2OCH3, -CH2NH2, -CH2CN, -CH2CH2OH , -CF3, -OCF3, -O-CH2CH2OH, -O-CH2CF3, -C(O)N H2, -CH2-C(O)NH2, -CH(CH3)CN, -C(CH3)2CN, Siku Ropropyl, 1-cyanocyclopropyl, cyclopropylmethyl, furanylmethyl (for example) (e.g., furan-3-ylmethyl), imidazolylmethyl (e.g., imidazo-1-ylmethyl) , pyrazolylmethyl (e.g., pyrazole-4-ylmethyl), oxazolylmethyl (e.g., Selected from (oxazo-4-ylmethyl);

[0110] (43)R b and R dOne of them is hydrogen, halogen, or -OCF3, and the other These are selected from hydrogen, fluoro, chloro, bromo, methyl, -OCF3, or cyclopropyl. To be selected;

[0111] (44)R c These are hydrogen, halo, cyano, -C(O)NH2, (1~4C)alkyl, -[CH2] 0-2 -(1~4C)alkoxy, -[CH2] 0-2 -(3~6C)Cycloalkoxy, -[CH2] 0-2 -C(O)NH2, -[CH2] 0-2 -C(O)NH(1~4C)alkyl, -[CH2] 0-2 -C(O)N[(1~4C)alkyl]2, -[CH2] 0-2 -NH(1~4C)alkyl, -[CH2] 0-2 -N[(1~4C)alkyl]2, -[CH2] 0-2 -S(O) q -(1~4C)alkyl(wherein q is 0, 1 or 2) (is), -[CH2] 0-2 -C(O)(1~4C)alkyl, -[CH2] 0-2 -C(O)O-(1~4C)alkyl, -[CH2] 0-2 -N(H)C(O)-(1~4C)alkyl, -[CH2] 0-2 -S(O)2NH(1~4C)alkyl, -[CH2] 0-2 -S(O)2N[(1~4C)alkyl]2, -[CH2] 0-2 -N(H)SO2-(1~4C)alkyl, formula: -Y2-[CH2] 0-2 -Z2 (In the formula, Y2 is either nonexistent, or -O-, -NH-, -NMe-, -S-, -S(O )- or -S(O)2-; Z2 is a (3-6C) cycloalkyl, phenyl, 4-6 member heterocycline or 5-membered heterocycline. (The base is a 6-membered heteroaryl) Selected from; Any alkyl, alkoxy or R c Any alkyl portion within the substituent is a halo, hydro Xy, cyano, amino, -C(O)OH, -C(O)NH2, (1~2C)alkoxy, Alternatively, optionally, by one or more substituents selected from (3-4C) cycloalkoxys. Replaced by selection; Z2 is halo, hydroxy, cyano, amino, -C(O)OH, -C(O)NH2, (1 (~2C)alkoxy, (1~2C)alkyl, (3~4C)cycloalkyl, (3~4C )Cycloalkoxy, -C(O)NH(1~2C)alkyl, -C(O)N[(1~2C )alkyl]2,-NH(1~2C)alkyl,-N[(1~2C)alkyl]2,-S (O) q -(1~2C)alkyl(wherein q is 0, 1 or 2), -C(O)( 1~2C)alkyl, -C(O)O-(1~2C)alkyl, -N(R f )C(O)-( 1~2C)alkyl,-S(O)2NH(1~2C)alkyl,-S(O)2N[(1~ [2C)alkyl]2, or one selected from -NHSO2-(1~2C)alkyl Alternatively, it may be optionally substituted with multiple substituents, and any (1-2C)alkoxy, (1-2 C) alkyl, (3-4C) cycloalkyl, or (3-4C) cycloalkoxy groups are Select from halo, cyano, hydroxy, (1-2C)alkyl, or (1-2C)alkoxy. It is optionally substituted with one or more substituents of choice;

[0112] (45)R c These are hydrogen, halo, cyano, -C(O)NH2, (1~4C)alkyl, -[CH2] 0-1 -(1~4C)alkoxy, -[CH2] 0-1 -(3~6C)Cycloalkoxy, -[CH2] 0-1 -C(O)NH2, -[CH2] 0-1 -C(O)NH(1~4C)alkyl, -[CH2] 0-1 -C(O)N[(1~4C)alkyl]2, -[CH2] 0-1 -NH(1~4C)alkyl, -[CH2] 0-1 -N[(1~4C)alkyl]2, -[CH2] 0-1 -S(O) q -(1~4C)alkyl(wherein q is 0, 1 or 2) (is), -[CH2] 0-1 -C(O)(1~4C)alkyl, -[CH2] 0-1 -C(O)O-(1~4C)alkyl, -[CH2] 0-1 -N(H)C(O)-(1~4C)alkyl, -[CH2] 0-1 -S(O)2NH(1~4C)alkyl, -[CH2] 0-1 -S(O)2N[(1~4C)alkyl]2, -[CH2] 0-1 -N(H)SO2-(1~4C)alkyl, formula: -Y2-[CH2] 0-1 -Z2 (In the formula, Y2 is either nonexistent, or -O-, -NH-, -NMe-, -S-, -S(O )- or -S(O)2-; Z2 is a (3-6C) cycloalkyl, phenyl, 4-6 member heterocycline or 5-membered heterocycline. (The base is a 6-membered heteroaryl) Selected from; Any alkyl, alkoxy or R c Any alkyl portion within the substituent is a halo, hydro Xy, cyano, amino, -C(O)OH, -C(O)NH2, (1~2C)alkoxy, Alternatively, optionally, by one or more substituents selected from (3-4C) cycloalkoxys. Replaced by selection; Z2 is halo, hydroxy, cyano, amino, -C(O)OH, -C(O)NH2, (1 (~2C)alkoxy, (1~2C)alkyl, (3~4C)cycloalkyl, (3~4C )Cycloalkoxy, -C(O)NH(1~2C)alkyl, -C(O)N[(1~2C )alkyl]2,-NH(1~2C)alkyl,-N[(1~2C)alkyl]2,-S (O) q -(1~2C)alkyl(wherein q is 0, 1 or 2), -C(O)( 1~2C)alkyl, -C(O)O-(1~2C)alkyl, -N(R f )C(O)-( 1~2C)alkyl,-S(O)2NH(1~2C)alkyl,-S(O)2N[(1~ [2C)alkyl]2, or one selected from -NHSO2-(1~2C)alkyl Alternatively, it may be optionally substituted with multiple substituents, and any (1-2C)alkoxy, (1-2 C) alkyl, (3-4C) cycloalkyl, or (3-4C) cycloalkoxy group, Select from halo, cyano, hydroxy, (1-2C)alkyl, or (1-2C)alkoxy. It is optionally substituted with one or more substituents of choice;

[0113] (46)R cThese are hydrogen, halo, cyano, -C(O)NH2, (1~4C)alkyl, -[CH2] 0-2 -(1~2C)alkoxy, -[CH2] 0-2 -(3~6C)Cycloalkoxy, -[CH2] 0-2 -C(O)NH2, -[CH2] 0-2 -C(O)NH(1~2C)alkyl, -[CH2] 0-2 -C(O)N[(1~2C)alkyl]2, -[CH2] 0-2 -NH(1~2C)alkyl, -[CH2] 0-2 -N[(1~2C)alkyl]2, -[CH2] 0-2 -S(O) q -(1~2C)alkyl (wherein q is 0, 1 or 2) (is), -[CH2] 0-2 -C(O)(1~2C)alkyl, -[CH2] 0-2 -C(O)O-(1~2C)alkyl, -[CH2] 0-2 -N(H)C(O)-(1~2C)alkyl, -[CH2] 0-2 -S(O)2NH(1~2C)alkyl, -[CH2] 0-2 -S(O)2N[(1~2C)alkyl]2, -[CH2] 0-2 -N(H)SO2-(1~2C)alkyl, formula: -Y2-[CH2] 0-2 -Z2 (In the formula, Y2 is either nonexistent, or -O-, -NH-, -NMe-, -S-, -S(O )- or -S(O)2-; Z2 is a (3-6C) cycloalkyl, phenyl, 4-6 member heterocycline or 5-membered heterocycline. (The base is a 6-membered heteroaryl) Selected from; Any alkyl, alkoxy or R c Any alkyl portion within the substituent is a halo, hydro Xy, cyano, amino, -C(O)OH, -C(O)NH2, (1~2C)alkoxy, Alternatively, optionally, by one or more substituents selected from (3-4C) cycloalkoxys. Replaced by selection; Z2 is halo, hydroxy, cyano, amino, -C(O)OH, -C(O)NH2, (1 (~2C)alkoxy, (1~2C)alkyl, (3~4C)cycloalkyl, (3~4C )Cycloalkoxy, -C(O)NH(1~2C)alkyl, -C(O)N[(1~2C )alkyl]2,-NH(1~2C)alkyl,-N[(1~2C)alkyl]2,-S (O) q -(1~2C)alkyl(wherein q is 0, 1 or 2), -C(O)( 1~2C)alkyl, -C(O)O-(1~2C)alkyl, -N(R f )C(O)-( 1~2C)alkyl,-S(O)2NH(1~2C)alkyl,-S(O)2N[(1~ [2C)alkyl]2, or one selected from -NHSO2-(1~2C)alkyl Alternatively, it may be optionally substituted with multiple substituents, and any (1-2C)alkoxy, (1-2 C) alkyl, (3-4C) cycloalkyl, or (3-4C) cycloalkoxy group, Select from halo, cyano, hydroxy, (1-2C)alkyl, or (1-2C)alkoxy. It is optionally substituted with one or more substituents of choice;

[0114] (47)R c These are hydrogen, halo, cyano, -C(O)NH2, (1~4C)alkyl, -[CH2] 0-1 -(1~2C)alkoxy, -[CH2]0-1 -(3~6C)Cycloalkoxy, -[CH2] 0-1 -C(O)NH2, -[CH2] 0-1 -C(O)NH(1~2C)alkyl, -[CH2] 0-1 -C(O)N[(1~2C)alkyl]2, -[CH2] 0-1 -NH(1~2C)alkyl, -[CH2] 0-1 -N[(1~2C)alkyl]2, -[CH2] 0-1 -S(O) q -(1~2C)alkyl (wherein q is 0, 1 or 2) (is), -[CH2] 0-1 -C(O)(1~2C)alkyl, -[CH2] 0-1 -C(O)O-(1~2C)alkyl, -[CH2] 0-1 -N(H)C(O)-(1~2C)alkyl, -[CH2] 0-1 -S(O)2NH(1~2C)alkyl, -[CH2] 0-1 -S(O)2N[(1~2C)alkyl]2, -[CH2] 0-1 -N(H)SO2-(1~2C)alkyl, formula: -Y2-[CH2] 0-1 -Z2 (In the formula, Y2 is either nonexistent, or -O-, -NH-, -NMe-, -S-, -S(O )- or -S(O)2-; Z2 is a (3-6C) cycloalkyl, phenyl, 4-6 member heterocycline or 5-membered heterocycline. (The base is a 6-membered heteroaryl) Selected from; Any alkyl, alkoxy or R c Any alkyl portion within the substituent is a halo, hydro Xy, cyano, amino, -C(O)OH, -C(O)NH2, (1~2C)alkoxy, Alternatively, optionally, by one or more substituents selected from (3-4C) cycloalkoxys. Replaced by selection; Z2 is halo, hydroxy, cyano, amino, -C(O)OH, -C(O)NH2, (1 (~2C)alkoxy, (1~2C)alkyl, (3~4C)cycloalkyl, (3~4C )Cycloalkoxy, -C(O)NH(1~2C)alkyl, -C(O)N[(1~2C )alkyl]2,-NH(1~2C)alkyl,-N[(1~2C)alkyl]2,-S (O) q -(1~2C)alkyl(wherein q is 0, 1 or 2), -C(O)( 1~2C)alkyl, -C(O)O-(1~2C)alkyl, -N(R f )C(O)-( 1~2C)alkyl,-S(O)2NH(1~2C)alkyl,-S(O)2N[(1~ [2C)alkyl]2, or one selected from -NHSO2-(1~2C)alkyl Alternatively, it may be optionally substituted with multiple substituents, and any (1-2C)alkoxy, (1-2 C) alkyl, (3-4C) cycloalkyl, or (3-4C) cycloalkoxy groups are Select from halo, cyano, hydroxy, (1-2C)alkyl, or (1-2C)alkoxy. It is optionally substituted with one or more substituents of choice;

[0115] (48)R c These are hydrogen, halo, cyano, -C(O)NH2, (1~4C)alkyl, -[CH2] 0-2 -(1~4C)alkoxy, -[CH2] 0-2 -(3~6C)Cycloalkoxy, -[CH2] 0-2 -C(O)NH2, -[CH2] 0-2 -C(O)NH(1~4C)alkyl, -[CH2] 0-2 -C(O)N[(1~4C)alkyl]2, -[CH2] 0-2 -NH(1~4C)alkyl, -[CH2] 0-2 -N[(1~4C)alkyl]2, -[CH2] 0-2 -S(O) q -(1~4C)alkyl(wherein q is 0, 1 or 2) (is), -[CH2] 0-2 -C(O)(1~4C)alkyl, -[CH2] 0-2 -C(O)O-(1~4C)alkyl, -[CH2] 0-2 -N(H)C(O)-(1~4C)alkyl, -[CH2] 0-2 -S(O)2NH(1~4C)alkyl, -[CH2] 0-2 -S(O)2N[(1~4C)alkyl]2, -[CH2] 0-2 -N(H)SO2-(1~4C)alkyl, formula: -Y2-[CH2] 0-2 -Z2 (In the formula, Y2 is either nonexistent, or -O-, -NH-, -NMe-, -S-, -S(O )- or -S(O)2-; Z2 is a (3-6C) cycloalkyl, phenyl, 4-6 member heterocycline or 5-membered heterocycline. (The base is a 6-membered heteroaryl) Selected from; Any alkyl, alkoxy or R c Any alkyl portion within the substituent is a halo, hydro Xy, cyano, amino, -C(O)OH, -C(O)NH2, or (1-2C)alco Optionally substituted with one or more substituents selected from xy; Z2 is a halo, hydroxy, cyano, amino, (1-2C)alkoxy, (1-2C)a Lukil, -C(O)NH(1~2C)alkyl, -C(O)N[(1~2C)alkyl] 2,-NH(1~2C)alkyl,-N[(1~2C)alkyl]2,-S(O) q -( 1-2C)alkyl (wherein q is 0, 1, or 2), -C(O)(1-2C) One or more alkyl groups selected from -C(O)O-(1~2C)alkyl groups It is optionally substituted by a substitution group, and any (1-2C) alkoxy or (1-2C) alkoxy The kill group is one selected from halo, cyano, hydroxy, or (1-2C)alkoxy. or optionally substituted by multiple substituents;

[0116] (49)R c These are hydrogen, halo, cyano, -C(O)NH2, (1~4C)alkyl, -[CH2] 0-1 -(1~4C)alkoxy, -[CH2] 0-1 -(3~6C)Cycloalkoxy, -[CH2] 0-1 -C(O)NH2, -[CH2] 0-1 -C(O)NH(1~4C)alkyl, -[CH2] 0-1 -C(O)N[(1~4C)alkyl]2, -[CH2] 0-1 -NH(1~4C)alkyl, -[CH2] 0-1 -N[(1~4C)alkyl]2, -[CH2] 0-1 -S(O) q -(1~4C)alkyl(wherein q is 0, 1 or 2) (is), -[CH2] 0-1 -C(O)(1~4C)alkyl, -[CH2] 0-1-C(O)O-(1~4C)alkyl, -[CH2] 0-1 -N(H)C(O)-(1~4C)alkyl, -[CH2] 0-1 -S(O)2NH(1~4C)alkyl, -[CH2] 0-1 -S(O)2N[(1~4C)alkyl]2, -[CH2] 0-1 -N(H)SO2-(1~4C)alkyl, formula: -Y2-[CH2] 0-1 -Z2 (In the formula, Y2 is either nonexistent, or -O-, -NH-, -NMe-, -S-, -S(O )- or -S(O)2-; Z2 is a (3-6C) cycloalkyl, phenyl, 4-6 member heterocycline or 5-membered heterocycline. (The base is a 6-membered heteroaryl) Selected from; Any alkyl, alkoxy or R c Any alkyl portion within the substituent is a halo, hydro Xy, cyano, amino, -C(O)OH, -C(O)NH2, or (1-2C)alco Optionally substituted with one or more substituents selected from xy; Z2 is a halo, hydroxy, cyano, amino, (1-2C)alkoxy, (1-2C)a Lukil, -C(O)NH(1~2C)alkyl, -C(O)N[(1~2C)alkyl] 2,-NH(1~2C)alkyl,-N[(1~2C)alkyl]2,-S(O) q -( 1-2C)alkyl (wherein q is 0, 1, or 2), -C(O)(1-2C) One or more alkyl groups selected from -C(O)O-(1~2C)alkyl groups It is optionally substituted by a substitution group, and any (1-2C) alkoxy or (1-2C) alkoxy The kill group is one selected from halo, cyano, hydroxy, or (1-2C)alkoxy. or optionally substituted by multiple substituents;

[0117] (50)R c These are hydrogen, halo, cyano, (1-4C) alkyl, and (1-4C) alcoholic compounds. C, formula: -Y2-[CH2] 0-1 -Z2 (In the formula, Y2 is either nonexistent or -O-; Z2 is a group (3-6C) cycloalkyl or phenyl Selected from; Any alkyl or alkoxy substituent can be halo, hydroxy, cyano, amino, or -C( One of the following selected from O)OH, -C(O)NH2, or (1-2C)alkoxy Optionally substituted by multiple substituents; Z2 is a halo, hydroxy, cyano, amino, (1-2C)alkoxy, (1-2C)a Lukil, -C(O)NH(1~2C)alkyl, -C(O)N[(1~2C)alkyl] 2,-NH(1~2C)alkyl,-N[(1~2C)alkyl]2,-S(O) q -( 1-2C)alkyl (wherein q is 0, 1, or 2), -C(O)(1-2C) One or more alkyl groups selected from -C(O)O-(1~2C)alkyl groups It is optionally substituted by a substitution group, and any (1-2C) alkoxy or (1-2C) alkoxy The kill group is one selected from halo, cyano, hydroxy, or (1-2C)alkoxy. or optionally substituted by multiple substituents;

[0118] (51)R c These are hydrogen, halo, cyano, (1-4C) alkyl, and (1-4C) alcoholic compounds. C, formula: -Y2-[CH2] 0-1 -Z2 (In the formula, Y2 is either nonexistent or -O-; Z2 is a group (3-6C) cycloalkyl or phenyl Selected from; Any alkyl or alkoxy substituent may be halo, hydroxy, cyano, or (1-2) C) optionally substituted with one or more substituents selected from alkoxy; Z2 is a halo, hydroxy, cyano, amino, (1-2C)alkoxy, or (1-2 C) Optionally substituted with one or more substituents selected from alkyl groups, (1-2C)alkoxy or (1-2C)alkyl groups are halo, cyano, hydroxyl... Alternatively, one or more substituents selected from (1-2C)alkoxys may be optionally placed It has been replaced;

[0119] (52)R c These are hydrogen, halo, cyano, (1-4C) alkyl, and (1-4C) alcoholic compounds. C, formula: -Y2-[CH2] 0-1 -Z2 (In the formula, Y2 is either nonexistent or -O-; Z2 is a group (3-6C) cycloalkyl or phenyl Selected from; Any alkyl or alkoxy substituent may be one or more selected from halo or cyano Optionally substituted by multiple substituents; Z2 is optionally substituted with one or more (1-2C) alkyl substituents, (1 ~2C) The alkyl group is optionally substituted with one or more hydroxy substituents. There is;

[0120] (53)Rc These are hydrogen, halo, cyano, (1-2C) alkyl or (1-2C) Selected from Koxi, Any alkyl or alkoxy substituent can be optionally selected by one or more halo substituents. It is replaced by;

[0121] (54)R c This is selected from hydrogen, halo, or (1-2C)alkoxy, The alkoxy substituent is optionally substituted with one or more halo substituents;

[0122] (55)R c This is selected from hydrogen, halo, or halo(1-2C)alkoxy;

[0123] (56)R c This is selected from hydrogen, halo, or (1-2C)alkoxy, The alkoxy substituent is optionally substituted with one or more fluoro substituents. ;

[0124] (57)R c These are hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, and methyl C, Ethoxy, -O-CH(CH3)2, -CH2CN, -CF3, -OCF3, -O- CH2CF3, cyclopropyl, cyclopropoxy, cyclobutoxy, cyclopentoxy Selected from phenyl or 2-hydroxymethylphenyl;

[0125] (58)R c is hydrogen, fluoro, chloro, bromo, cyano, methoxy, ethoxy, - O-CH(CH3)2, -CH2CN, -CF3, -OCF3, -O-CH2CF3, Clopropyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, phenyl or Selected from 2-hydroxymethylphenyl;

[0126] (59)R c This is selected from hydrogen, fluoro, chloro, or -OCF3;

[0127] (60)R c This is selected from hydrogen, chloroform, or -OCF3.

[0128] Preferably, in any of the definitions of formula I described herein, R a , R b , R c , R d or R e At least one of them is a non-hydrogen substituent. R a , R b , R c , R d or R e Any one of the options defined herein with respect to This refers to substituents selected from R. More preferably, a , R b , R c , R d or R e of 1 to 4 are non-hydrogen substituents. Most preferably, R a , R b , R c , R d or R e 1 ~3 of them are non-hydrogen substituents.

[0129] Preferably, in any of the definitions of formula I described herein, R a , R b , R c , R d or R e Up to four of them are hydrogen atoms, and the rest are non-hydrogen substituents (i.e., non-hydrogen substituents). R a , R b , R c , R d or R eAny one of the options described herein with respect to (Selected from). More preferably, R a , R b , R c , R d or R e 2 to 4 of them are hydrogen The rest are non-hydrogen substituents.

[0130] In a specific group of compounds of formula I, R c The formula is -Y2-[CH2] 0-3 -Based on Z2 In that case, R b and R d The formula is -Y1-[CH2] 0-3 -This is impossible under the Z1's specifications.

[0131] In a further group of compounds of formula I, R b and R d One or both of the above are defined herein. The formula being defined is Y1-[CH2] 0-3 -If Z1 is the basis, R c is formula -Y2-[CH2 ] 0-3 -This is impossible under the Z2 system.

[0132] In a specific group of compounds of formula I, (i)R c The formula is -Y2-[CH2] 0-3 -If Z2 is the basis, R b and R d is formula- Y1-[CH2] 0-3 -Cannot be the basis of Z1; and / or (ii)R b and R d One or both of the formulas defined herein are -Y1-[CH2] 0-3 -If Z1 is the basis, R c The formula is -Y2-[CH2] 0-3 -This could be the basis for Z2 do not have.

[0133] In another specific group of compounds of formula I, (i)R c The formula is -Y2-[CH2] 0-3 -If Z2 is the basis, R b and R d is formula- Y1-[CH2] 0-3 -Cannot be the basis for Z1; (ii)R b and R d One of them is the formula -Y1-[CH2] defined herein. 0-3 -Z If it is the base of 1, the other is formula -Y1-[CH2] 0-3 - It cannot be the basis for Z1, and also R c The formula is -Y2-[CH2] 0-3 -This is impossible under the Z2 system.

[0134] Preferably, in any of the definitions of Formula I described herein, the heteroaryl is N, Five or six-membered heteroatoms containing one, two, or three heteroatoms selected from O or S. It is an aryl ring.

[0135] Preferably, in any of the definitions of Formula I described herein, the heterocyclyl group is N , 4, 5, or 6 member groups containing 1, 2, or 3 heteroatoms selected from O or S. It is a heterocyclyl ring. Most preferably, the heterocyclyl group is selected from N, O, or S. A 4, 5, or 6-membered ring containing one or two heteroatoms [e.g., morpholinyl ( For example, 4-morpholinil, piperidinil, piperazinil, or pyrrolidinil.

[0136] Preferably, in any of the definitions of Formula I described herein, R1 is defined by Formula I above. As described above, or as defined in item (1) and / or (2) above. In a specific group of compounds of the present invention, R1 is as defined in item (1) above. In another specific group of compounds, R1 is as defined in item (2) above.

[0137] Preferably, in any of the definitions of formula I described herein, Q is defined in formula I above. As defined above, or as defined in any one of items (3) to (14).

[0138] Preferably, in any of the definitions of formula I described herein, R a and R e The above As defined by any one of items (15) to (26). More preferably, R a Oh biR e This refers to any one of the above items (16), (21), (22), (23), or (26). As defined by the two, more preferably, R a and R e The above item (21), As defined by any one of (22), (23), or (26). Most preferably R a and R e This is as defined in section (23) or (26) above.

[0139] In a specific group of compounds of formula I, R a and R e This is defined in the above section (16). It is R1, Q, R b , R c , and R d These are defined by equation I above, respectively. be.

[0140] In a specific group of compounds of formula I, R a and R e This is defined in the above section (21). It is R1, Q, R b, R c , and R d These are defined by equation I above, respectively. be.

[0141] In a specific group of compounds of formula I, R a and R e This is defined in the above section (22). It is R1, Q, R b , R c , and R d These are defined by equation I above, respectively. be.

[0142] In a specific group of compounds of formula I, R a and R e This is defined in the above section (23). It is R1, Q, R b , R c , and R d These are defined by equation I above, respectively. be.

[0143] In a specific group of compounds of formula I, R a and R e This is defined in the above section (26). It is R1, Q, R b , R c , and R d These are defined by equation I above, respectively. be.

[0144] Preferably, in any of the definitions of formula I described herein, R b and R d The above As defined by any one of items (27) to (43). More preferably, R b Oh biR d The above items (36), (37), (38), (39), (40), (41), (4 2) or (43) as defined in either one of the above. More preferably, R a and R e This refers to any of the above items (39), (40), (41), (42), or (43). It is defined by one of the following. Most preferably, R a and R e The above item (38) also This is defined in (43).

[0145] In a specific group of compounds of formula I, R b and R d This is defined in the above section (28). It is R1, Q, R a , R c , and R e These are defined by equation I above, respectively. be.

[0146] In a specific group of compounds of formula I, R b and R d This is defined in the above paragraph (30). It is R1, Q, R a , R c , and R e These are defined by equation I above, respectively. be.

[0147] In a specific group of compounds of formula I, R b and R d This is defined in the above paragraph (32). It is R1, Q, R a , R c , and R e These are defined by equation I above, respectively. be.

[0148] In a specific group of compounds of formula I, R b and R d This is defined in the above section (34). It is R1, Q, R a , R c , and R e These are defined by equation I above, respectively. be.

[0149] In a specific group of compounds of formula I, R b and R d This is defined in the above paragraph (36). It is R1, Q, R a , R c , and R e These are defined by equation I above, respectively. be.

[0150] In a specific group of compounds of formula I, R b and R d This is defined in the above paragraph (37). It is R1, Q, R a , R c , and R e These are defined by equation I above, respectively. be.

[0151] In a specific group of compounds of formula I, R b and R d This is defined in the above paragraph (38). It is R1, Q, R a , R c , and R e These are defined by equation I above, respectively. be.

[0152] In a specific group of compounds of formula I, R b and R d This is defined in the above paragraph (39). It is R1, Q, R a , R c , and R e These are defined by equation I above, respectively. be.

[0153] In a specific group of compounds of formula I, R b and R d This is defined in the above paragraph (40). It is R1, Q, R a , R c , and R eThese are defined by equation I above, respectively. be.

[0154] In a specific group of compounds of formula I, R b and R d This is defined in the above paragraph (41). It is R1, Q, R a , R c , and R e These are defined by equation I above, respectively. be.

[0155] In a specific group of compounds of formula I, R b and R d This is defined in the above paragraph (42). It is R1, Q, R a , R c , and R e These are defined by equation I above, respectively. be.

[0156] In a specific group of compounds of formula I, R b and R d This is defined in the above section (43). It is R1, Q, R a , R c , and R e These are defined by equation I above, respectively. be.

[0157] Preferably, in any of the definitions of formula I described herein, R c The above item (44) As defined by any one of (60). More preferably, R c The above item (5 1), (52), (53), (54), (55), (56), (57), (58), (5 As defined by either 9) or (60). More preferably, R c This refers to any of the above items (56), (56), (57), (58), (59), or (60). It is defined by one of the following. Most preferably, R c The above paragraphs (58), (59) and This is as defined in (60).

[0158] In a specific group of compounds of formula I, R c This is as defined in item (45) above, R1, Q, R a , R b , R d and R e These are defined by equation I above.

[0159] In a specific group of compounds of formula I, R c This is as defined in item (47) above, R1, Q, R a , R b , R d and R e These are defined by equation I above.

[0160] In a specific group of compounds of formula I, R c This is as defined in item (49) above, R1, Q, R a , R b , and R e These are defined by equation I above.

[0161] In a specific group of compounds of formula I, R c This is as defined in item (51) above, R1, Q, R a , R b , R d and R e These are defined by equation I above.

[0162] In a specific group of compounds of formula I, R c This is as defined in item (53) above, R1, Q, R a , R b , R d and R eThese are defined by equation I above.

[0163] In a specific group of compounds of formula I, R c This is as defined in item (55) above, R1, Q, R a , R b , R d and R e These are defined by equation I above.

[0164] In a specific group of compounds of formula I, R c This is as defined in item (56) above, R1, Q, R a , R b , R d and R e These are defined by equation I above.

[0165] In a specific group of compounds of formula I, R c This is as defined in item (57) above, R1, Q, R a , R b , R d and R e These are defined by equation I above.

[0166] In a specific group of compounds of formula I, R c This is as defined in item (58) above, R1, Q, R a , R b , R d and R e These are defined by equation I above.

[0167] In a specific group of compounds of formula I, R c This is as defined in item (59) above, R1, Q, R a , R b , R d and R e These are defined by equation I above.

[0168] In a specific group of compounds of formula I, R c This is as defined in item (60) above, R1, Q, R a , R b , R d and R e These are defined by equation I above.

[0169] In a specific group of compounds of formula I as defined herein, R1 and Q are both defined by equation I above; R a and R e These are both as defined in item (23) above; R b and R d These are both as defined in item (27) above; R e This is as defined in item (44) above.

[0170] In a specific group of compounds of formula I as defined herein, R1 and Q are both defined by equation I above; R a and R e These are both as defined in item (23) above; R b and R d These are both as defined in item (28) above; R e This is as defined in item (45) above.

[0171] In a specific group of compounds of formula I as defined herein, R1 and Q are both defined in equation I; R a and R e These are both as defined in item (23) above; R b and R d These are both as defined in paragraph (29) above; R eThis is as defined in item (46) above.

[0172] In a specific group of compounds of formula I as defined herein, R1 and Q are both defined in equation I; R a and R e These are both as defined in item (23) above; R b and R d These are both as defined in item (30) above; R e This is as defined in item (47) above.

[0173] In a specific group of compounds of formula I as defined herein, R1 and Q are both defined in equation I; R a and R e These are both as defined in item (23) above; R b and R d These are both as defined in item (31) above; R e This is as defined in item (48) above.

[0174] In a specific group of compounds of formula I as defined herein, R1 and Q are both defined in equation I; R a and R e These are both as defined in item (23) above; R b and R d These are both as defined in item (32) above; R e This is as defined in item (49) above.

[0175] In a specific group of compounds of formula I as defined herein, R1 and Q are both defined in equation I; R aand R e These are both as defined in item (23) above; R b and R d These are both as defined in item (33) above; R e This is as defined in item (50) above.

[0176] In a specific group of compounds of formula I as defined herein, R1 and Q are both defined in equation I; R a and R e These are both as defined in item (23) above; R b and R d These are both as defined in item (34) above; R e This is as defined in item (51) above.

[0177] In a specific group of compounds of formula I as defined herein, R1 and Q are both defined in equation I; R a and R e These are both as defined in item (23) above; R b and R d These are both as defined in item (35) above; R e This is as defined in item (52) above.

[0178] In a specific group of compounds of formula I as defined herein, R1 and Q are both defined in equation I; R a and R e These are both as defined in item (23) above; R b and R d These are both as defined in paragraph (36) above; R eThis is as defined in item (53) above.

[0179] In a specific group of compounds of formula I as defined herein, R1 and Q are both defined in equation I; R a and R e These are both as defined in paragraph (26) above; R b and R d These are both as defined in item (37) above; R e This is as defined in item (54) above.

[0180] In a specific group of compounds of formula I as defined herein, R1 and Q are both defined in equation I; R a and R e These are both as defined in paragraph (26) above; R b and R d These are both as defined in item (38) above; R e This is as defined in item (54) above.

[0181] In a specific group of compounds of formula I as defined herein, R1 and Q are both defined in equation I; R a and R e These are both as defined in paragraph (26) above; R b and R d These are both as defined in paragraph (39) above; R e This is as defined in item (58) above.

[0182] In a specific group of compounds of formula I as defined herein, R1 and Q are both defined in equation I; R aand R e These are both as defined in paragraph (26) above; R b and R d These are both as defined in item (41) above; R e This is as defined in item (58) above.

[0183] In a specific group of compounds of formula I as defined herein, R1 and Q are both defined in equation I; R a and R e These are both as defined in paragraph (26) above; R b and R d These are both as defined in item (40) above; R e This is as defined in item (59) above.

[0184] In a specific group of compounds of formula I as defined herein, R1 and Q are both defined in equation I; R a and R e These are both as defined in paragraph (26) above; R b and R d These are both as defined in item (43) above; R e This is as defined in item (59) above.

[0185] In a specific group of compounds of formula I as defined herein, R1 and Q are both defined in equation I; R a and R e These are both as defined in paragraph (26) above; R b and R d These are both as defined in item (40) above; R eThis is as defined in item (60) above.

[0186] In a specific group of compounds of formula I as defined herein, R1 and Q are both defined in equation I; R a and R e These are both as defined in paragraph (26) above; R b and R d These are both as defined in item (43) above; R e This is as defined in item (60) above.

[0187] In a specific group of compounds of the present invention, the compound is a compound of formula I as defined herein. Yes, Q is as defined in item (11) above, that is, the compound is as shown below A compound having formula Ic, or a pharmaceutically acceptable salt thereof, [ka] In the formula, R1, R a , R b , R c , R d and R e Each of these terms is defined as described herein. It has one of the following characteristics.

[0188] In a specific group of compounds of formula Ic, R1 is selected from -C(O)OH or -C(O)NH2; R a and R e These are both as defined in item (23) above; R b and R d These are both as defined in paragraph (36) above; R C This is as defined in item (50) above.

[0189] In a specific group of compounds of formula Ic, R1 is selected from -C(O)OH or -C(O)NH2; R a and R e These are both as defined in paragraph (26) above; R b and R d These are both as defined in item (38) above; R C This is as defined in item (54) above.

[0190] In a specific group of compounds of formula Ic, R1 is selected from -C(O)OH or -C(O)NH2; R a and R e These are both as defined in item (20) above; R b and R d These are both as defined in item (40) above; R C This is as defined in item (58) above.

[0191] In a specific group of compounds of formula Ic, R1 is -C(O)OH; R a and R e These are both as defined in item (20) above; R b and R d These are both as defined in item (43) above; R C This is as defined in item (60) above.

[0192] In a specific group of compounds of the present invention, the compound is a compound of formula I as defined herein. Yes, Q is as defined in item (11) above, and R a and R e The above item (20 As defined in ), that is, the compound has the formula Id shown below, and It is a pharmaceutically acceptable salt, [ka] In the formula, R1, R b , R c and R d Each of these has one of the definitions described above. ru.

[0193] In a specific group of compounds of formula Id, R1 is selected from -C(O)OH or -C(O)NH2; R b and R d These are both as defined in paragraph (36) above; R C This is as defined in item (50) above.

[0194] In a specific group of compounds of formula Id, R1 is selected from -C(O)OH or -C(O)NH2; R b and R d These are both as defined in item (38) above; R C This is as defined in item (54) above.

[0195] In a specific group of compounds of formula Id, R1 is selected from -C(O)OH or -C(O)NH2; R b and R d These are both as defined in item (40) above; R C This is as defined in item (58) above.

[0196] In a specific group of compounds of formula Id, R1 is -C(O)OH; R b and R d These are both as defined in item (43) above; RC This is as defined in item (60) above.

[0197] In a specific group of compounds of formula I, Ic, or Id as defined herein, R b and R d This is selected from hydrogen or fluorocarbon.

[0198] In a specific group of compounds of formula I, Ic, or Id as defined herein, R b and R d It is hydrogen.

[0199] In a specific group of compounds of formula I, Ic, or Id as defined herein, R b and R d It is fluoro.

[0200] In a specific group of compounds of formula I, Ic, or Id as defined herein, R c teeth,- It is OCF3.

[0201] In a specific group of compounds of formula I, Ic, or Id as defined herein, R b and R d R is selected from hydrogen or fluoro, c It is -OCF3.

[0202] In a specific group of compounds of formula I, Ic, or Id as defined herein, R b and R d is hydrogen, and R c It is -OCF3.

[0203] In a specific group of compounds of formula I, Ic, or Id as defined herein, R b and R d is fluoro, and R c It is -OCF3.

[0204] The specific compounds of the present invention are the compounds described in the Examples section of this application, or pharmaceutically acceptable compounds thereof. Contains any of the following: salts, hydrates, or solvates, particularly any of the following:

[0205] JPEG2026122953000013.jpg107170JPEG2026122953000014.jpg255162JPEG2026122953000015.jpg255162JPEG2026122953000016.jpg255163 JPEG2026122953000017.jpg255162JPEG2026122953000018.jpg255161JPEG2026122953000019.jpg255162JPEG2026122953000020.jpg106170

[0206] The present invention may be further described by any optional, preferred, or suitable features, or by any particular embodiment. In relation to any compound or a particular group of compounds as defined herein, it may be related to any compound or a particular group of compounds as defined herein. However, the present invention also relates to any of the above-mentioned optional, preferred, or suitable features, or specific This may also relate to any compound or a particular group of compounds that specifically exclude the embodiments.

[0207] Preferably, the present invention relates to any individual compound that does not have biological activity as defined herein. To remove an item.

[0208] <Salts and solvates> The compounds described herein (including the final product and intermediates) are isolated and themselves It may be used, or isolated in the form of a salt, preferably a pharmaceutically acceptable salt. The terms “salt” and “salt form,” used alone or in conjunction with other terms, Unless otherwise specified, industrially acceptable salts as defined herein, and as specified herein It is understood that this includes all inorganic and organic salts, including pharmaceutically acceptable salts as defined by [the relevant definition]. It should be done. When used herein, industrially permissible salts are manufactured A salt generally suitable for processing (including refining), as well as for transport and storage. It does not have to be a salt typically administered for clinical or therapeutic use. Industrially acceptable. Possible salts are available on a laboratory scale, i.e., in amounts of a few grams or less, or on a larger scale, i.e. It can be prepared in quantities of 1 kilogram or less, or more.

[0209] pharmaceutically acceptable salts, when used herein, are other components of the formulation. This generally involves chemical and / or physical compatibility, as well as / or its recipe Salts that are generally physiologically compatible with the nucleotide. Pharmaceutically acceptable salts are those that are produced on a laboratory scale. , that is, less than a few grams, or larger, that is, less than 1 kilogram or so It can be prepared using the above. Pharmaceutically acceptable salts are used clinically or therapeutically in humans. Typically administered for the purpose of, or approved by the FDA or equivalent foreign regulatory body. Not limited to accredited salts. Some salts are industrially and pharmaceutically acceptable. Those skilled in the art will readily understand that it is a salt. All of these, including mixed salt forms It should be understood that salts such as the above are included in the scope of this application.

[0210] In one embodiment, compounds of formula I and its subformulas are pharmaceutically acceptable salts. It is isolated.

[0211] A suitable pharmaceutically acceptable salt of the compound of the present invention is, for example, a sufficiently basic salt of the present invention. Acid addition salts of compounds, for example, inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphorus It is an acid addition salt, such as an acid, trifluoroacetic acid, formic acid, citric acid, or maleic acid. A suitable pharmaceutically acceptable salt of the compound of the present invention, which is sufficiently acidic, is an alkali metal salt. For example, sodium or potassium salts, alkaline earth metal salts, for example, calcium or This produces magnesium salts, ammonium salts, or physiologically acceptable cations in organic compounds. Salts with bases, for example, methylamine, dimethylamine, trimethylamine, piperidine, It is a salt of morpholine or tris-(2-hydroxyethyl)amine.

[0212] Generally, the salts of this application are used in the isolation and / or purification of compounds (including intermediates). In situ, or the compound (or intermediate) is subjected to a suitable organic or inorganic acid or salt. Prepared by reacting the group (as appropriate) separately and isolating the salt thus formed. It is possible. The degree of ionization of salt can vary from completely ionized to almost non-ionized. In reality, it varies. A salt may precipitate (with the addition of one or more cosolvents and / or poor solvents, or The salts of this application can be collected by filtration or recovered by evaporation of the solvent. Also, "salt switch" or ion exchange / double substitution reaction, in other words If one ion is replaced (whole or partially) by another ion with the same charge... It can be formed by the reaction. The salt is prepared using a single method or a combination of methods. Those skilled in the art will understand that it can be mixed and / or isolated.

[0213] Typical salts include, but are not limited to, acetates, aspartates, benzoates, and benzoates. Silates, bicarbonates / carbonates, bisulfates / sulfates, borates, cansilates, citrates , edisylate, esylate, formate, fumarate, gluceptate, gluconate, Lucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide Bromides, hydroiodides / Iodides, isethionates, lactates, malates, malein Salts, malonates, mesylates, methylsulfates, naphthylates, 2-napsylates, nicotine Zinates, nitrates, orotates, oxalates, palmitates, pamoates, phosphates / Hydrogen phosphate / dihydrogen phosphate, sugar salt, stearate, succinate, tartrate, toshi This includes salts such as sulfates and trifluoroacetates. Other typical examples of salts include alkalis or alkalis. Earth metal cations, for example, but not limited to these, include sodium, lithium, and potassium. calcium, magnesium, etc., and not limited to these, ammonium, tetraphosphate Tramethylammonium, tetraethylammonium, lysine, arginine, benzathine , non- Contains toxic ammonium, quaternary ammonium, and amine cations.

[0214] Certain compounds of formula I and its subformulas exist in both solvated and non-solvated forms, for example. If so, it may exist in a hydrated form, etc. The present invention relates to all of the biologically active substances described herein. Please understand that this includes such solvation forms.

[0215] <Polymorph> Certain compounds of formula I and its subformulas can exhibit polymorphism, and the present invention is inherently apparent. It should also be understood that this includes all such forms possessing the biological activity described in the details. .

[0216] <N-オキシド> Compounds of formula I and its subformulas containing an amine functional group can also form N-oxides. References herein to compounds of formula I and its subformulas containing an amine functional group are N- Oxides are also included. If the compound contains several amine functional groups, one or more. The nitrogen atom can be oxidized to form an N-oxide. A specific example of an N-oxide is a tertiary a It is an N-oxide of the nitrogen atom of a mine or nitrogen-containing heterocycle. N-oxides are these While not limited to the use of hydrogen peroxide or peracids (e.g., peroxycarboxylic acids), oxidizing agents such as peroxide or peracids may be used. It can be formed by treatment with the corresponding amine, for example, Advanced Or ganic Chemistry, by Jerry March, 4th edition, Wiley I See the page on Interscience. More specifically, N-oxides are, for example, , but not limited to, m-chlorophosphate of amine compounds in an inert solvent such as dichloromethane. LW Deady (Syn. Comm.) reacts with benzoic acid (mCPBA). It can be manufactured by following the procedure described in 1977, 7, 509-514.

[0217] <Tautomers> Compounds of formula I and its subformulas may exist in several different tautomer forms, and formula I And references to compounds of its subformula include all such forms. To avoid misunderstanding. Therefore, a compound may exist as one of several tautomer forms, and only one can be specifically described. Or, even if shown, all others are encompassed by Equation I and its sub-equations. Examples of tautomer forms include, for example, keto / enol (shown below), pyrimidone / hydr Roxypyrimidine, imine / enamine, amide / iminoalcohol, amidine / amidine , nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro This includes keto, enol, and enolate forms, as in the case of mutant pairs.

[0218] [ka]

[0219] <Isomers> They have the same molecular formula, but their properties, the arrangement of their atomic bonds, or the structure of their atoms in space differ. Compounds with different compositions are called "isomers." Isomers are compounds in which the composition of their atoms in space differs. These are called "stereoisomers." Stereoiomers that are not mirror images of each other are called "diastereomers." Stereoisomers, which are mirror images of each other and cannot be superimposed on one another, are called "enantiomers." It will be discovered. If a compound has a chiral center, for example, if it is bonded to four different groups, enantiomers will be found. Pairs of enantiomers are possible. Enantiomers can be characterized by the absolute configuration of their chiral centers. This is possible, due to the R and S sequence rules of Cahn and Prelog, or the molecule is polarized at the plane of polarization. Rotate it and make it dextrorotatory or levorotatory (i.e., (+) or (-) different, respectively) The chiral compounds are described by the form specified as the enantiomers. They can exist as mixtures of them. A mixture containing equal proportions of enantiomers is called "La It is called a "semi-mixture."

[0220] Certain compounds of formula I and its subformulas may have one or more chiral centers, Therefore, it can exist in multiple stereoisomer configurations. As a result, such compounds can exist in enantiomer configurations. Synthesize and / or synthesize as a mixture of enantiomers and / or as individual (pure) enantiomers. It can be isolated, and in the case of two or more asymmetric centers, a single diastereomer and / or It can be synthesized and / or isolated as a mixture of diastereomers. This application covers all of the Enantiomers and diastereomers such as these, as well as mixtures thereof in all proportions. It should be understood that this includes [something].

[0221] <Isotopes> The compounds of the present invention have structural formulas that do not specifically list the mass numbers or isotopic ratios of the constituent atoms. This is described herein using the following. Therefore, this application is described in which the constituent atoms are any isotopic. It contains compounds that exist in the following ratio. For example, carbon atoms are 12 C, 13 C, and 14 C's role Hydrogen atoms can exist in proportion to one another, 1 H, 2 H, and 3 It can exist in any ratio of H, etc. More precisely, the constituent atoms in the compound of the present invention exist in the natural ratio of their isomer forms.

[0222] <Prodrugs and metabolites> Compounds of formula I and its subformulas are broken down in the body of a human or animal to form the compounds of the present invention. It may be administered in the form of a prodrug that releases the compound of the present invention. It can be used to modify the physical and / or pharmacokinetic properties. The compound of the present invention contains a suitable group or substituent to which a characteristic modifying group can be bonded. This can be achieved. An example of a prodrug is a compound of formula I with a carboxyl or hydroxyl group. In vivo cleavable ester derivatives that can be formed, as well as compounds of formula I and its subformulas It includes in vivo cleavable amide derivatives that can be formed with a carboxyl group or an amino group.

[0223] Therefore, the present invention, when made available by organic synthesis, and its product When the cleavage of the ligament makes it available in the body of a human or animal, the formula I defined above and compounds of the lower formulas thereof. Therefore, the present invention is produced by organic synthesis means. The compound of formula I, as well as the precursor compound, are produced in the body of humans or animals through metabolism. Such compounds are included, that is, compounds of formula I and its subformulas are produced synthetically. The compound may be a compound that has been produced or a compound that has been metabolized.

[0224] Suitable pharmaceutically acceptable prodrugs of compounds of formula I and its subformulas are, preferably Suitable for administration into the human or animal body without pharmacological activity and without excessive toxicity. This is based on a rational medical judgment.

[0225] For example, various forms of prodrugs are described in the following literature. a) Methods in Enzymology, Vol. 42, pp. 309-396, K. Widder et al. (eds.) (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard (Else vier, 1985); c)A Textbook of Drug Design and Development ent, Krogsgaard-Larsen and H. Bundgaard, eds., No. 5 Chapter “Design and Application of Pro-drugs”, H . Bundgaard, pp. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Re Views, 8, 1-38 (1992); e) H. Bundgaard et al., Journal of Pharmaceutica Sciences, 77, 285 (1988); f) N. Kakeya et al., Chem. Pharm. Bull., 32, 692(1 984); g) T. Higuchi and V. Stella, "Pro-Drugs as N ovel Delivery Systems”, ACS Symposium Series, Volume 14; and h) E. Roche (editor), "Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0226] Suitable pharmaceutically acceptable compounds of formula I and its subformulas having a carboxyl group The drug is, for example, its in vivo cleavable ester. The chemical formula I containing a carboxyl group. The in vivo cleavable ester of the compound cleaves, for example, in the body of a human or animal to produce a hydrophilic acid. It is a pharmaceutically acceptable ester. With respect to carboxylation, it is a pharmaceutically acceptable ester. Esters are not limited to these, but include C1, methyl, ethyl, and tert-butyl. 1~ 6-alkyl esters, and not limited to methoxymethyl esters, etc. 1~6 Arco oxymethyl esters, and not limited to these, pivaloyloxymethyl esters, 3-f C such as talidyl esters 1~6 Alkanoyloxymethyl esters, and not limited to these. Iga cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxy C esters such as ethyl esters 3~8 Cycloalkylcarbonyloxy-C 1~6 Alkyl Este This includes, but is not limited to, 5-methyl-2-oxo-1,3-dioxolene-4-ylmethyl 2-oxo-1,3-dioxolenylmethyl esters such as tyl esters, and these Not limited to methoxycarbonyloxymethyl and 1-methoxycarbonyloxymethyl C esters such as ethyl esters 1~6 Alkoxycarbonyloxy-C 1~6 Alkyl esters include.

[0227] Suitable pharmaceutically acceptable compounds of formula I and its subformulas having a hydroxyl group The drug is, for example, its in vivo cleavable ester or ether. In vivo cleavable esters or ethers of compounds of formula I and its subformulas, for example, If so, it is pharmaceutically acceptable to cleave within the body of a human or animal to produce a hydroxyl-facing compound. It is an ester or ether. A pharmaceutically acceptable ester with respect to the hydroxyl group. The phosphate-forming group is not limited to this, but includes phosphate esters (phosphoramide cyclic esters). Includes inorganic esters such as ). More pharmaceutically acceptable esters with respect to the hydroxyl group The tel-forming groups are not limited to these, but include acetyl, benzoyl, phenylacetyl, and others. substituted benzoyl and phenylacetyl groups, etc. 1~10 Alkanoyl groups, and not limited to these. It is not defined, but ethoxycarbonyl, N,N-(C 1~6 ) 2 carbamoyl, 2-dialyx C such as 2-carboxyacetyl and 2-carboxyacetyl groups 1~10 Alkoxycarbonyl It contains the group. Examples of ring substituents on phenylacetyl and benzoyl groups are aminomethyl, N -Alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, pipera Zin-1-ylmethyl and 4-(C 1~4 Contains alkyl)piperazine-1-ylmethyl The pharmaceutically acceptable ether-forming groups suitable for the hydroxyl group are not limited to these. However, α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups Contains a lu group.

[0228] Suitable pharmaceutically acceptable compounds of formula I and its subformulas having a carboxyl group The drug is, for example, its in vivo cleavage amide, for example, but not limited to ammonia. C amines such as nia, and not limited to these, such as methylamine. 1~4 Alkylamine, this Not limited to, but including dimethylamine, N-ethyl-N-methylamine or diethylamine (C) 1~4 Alkyl)2-amines, but not limited to 2-methoxyethylamines C etc. 1~4 Alkoxy-C 2~4 Alkylamines, and not limited to benzylamines. Phenyl-C 1~4 Alkylamines, and other amino acids such as glycine, but not limited to alkylamines. or an amide formed from its ester.

[0229] Suitable pharmaceutically acceptable prodromal compounds of formula I and its subformulas having an amino group The lignes is, for example, its in vivo cleavable amide derivative. Suitable pharmaceutically active ingredients derived from the amino group Acceptable amides include, but are not limited to, acetyl, benzoyl, and phenyl Cylacetyl as well as substituted benzoyl and phenylacetyl groups. 1~10Arcanoy Includes amides formed with benzoyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups. This includes aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, and moles. folinomethyl, piperazine-1-ylmethyl and 4-(C 1~4 Alkyl)piperazine Contains -1-ylmethyl

[0230] The in vivo effect of compounds of formula I and its subformulas is, in part, due to formula I and its subformulas. One or more metabolites formed in the human or animal body after administration of the compound It can be exerted. As mentioned above, the in vivo effect of compounds of formula I and its subformulas is also This can be exerted through the metabolism of a precursor compound (prodrug).

[0231] <Pharmaceutical composition> According to a further aspect of the present invention, in combination with a pharmaceutically acceptable diluent or carrier, the above The compounds of the present invention as defined in [the relevant section], or their pharmaceutically acceptable salts, hydrates, or solvates. A pharmaceutical composition containing a substance is provided.

[0232] The composition of the present invention is in a form suitable for oral use (e.g., tablets, drops, hard or soft). Capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups Or elixirs), in a form suitable for topical use (e.g., cream, ointment, gel, or Aqueous or oily solution or suspension), in a form suitable for administration by inhalation (e.g., micronized) (Powder or liquid aerosol), a form suitable for administration by air (e.g., finely ground powder), or a form suitable for parenteral administration (e.g., intravenous, subcutaneous, intramuscular, intraperitoneal, or intramuscular administration) It may also be used as a sterile aqueous or oily solution for medicinal purposes, or as a suppository for rectal administration. stomach.

[0233] The composition of the present invention uses conventional pharmaceutical excipients that are well known in the art, It can be obtained by procedure. Therefore, compositions intended for oral use are, for example, one type Alternatively, it may contain multiple types of colorants, sweeteners, flavorings, and / or preservatives.

[0234] The effective amount of the compound of the present invention for therapeutic use is the amount referred to herein. To treat or prevent reproductive diseases, inhibit their progression, and / or related conditions. This is a sufficient amount to reduce the symptoms.

[0235] The amount of the active ingredient that, when combined with one or more excipients, produces a single dosage form is necessarily Specifically, it varies depending on the individual being treated and the specific route of administration. For example, when administered to humans. Formulations intended for oral administration generally contain approximately 5% to 98% by weight of the total composition. Formulated with an appropriate and convenient amount of excipients that can vary up to 1 mg, for example, 0.5 mg to 1 mg. 0.5g of active agent (more preferably 0.5mg to 600mg, for example 1mg to 200mg) It contains.

[0236] The size of the therapeutic or prophylactic dose of the compound of formula I is, of course, determined by well-known medical principles. Accordingly, the nature and severity of the disease, the age and sex of the animal or patient, and the administration period are taken into consideration. It varies depending on the route.

[0237] The dosage and regimen of medication will vary depending on the type and severity of the condition to be alleviated. A single or multiple dose over a specific period (number of days or hours), i.e., QD (1 day) Please note that this may include administration such as once a day, BID (twice a day), etc. Furthermore, any special For specific subjects or patients, individual needs, and the person or administration of the pharmaceutical composition. It may be necessary to adjust certain medication regimens over time, in accordance with the professional judgment of the person supervising them. Please understand that this may be the case. For example, the dosage may affect clinical effects such as toxic effects and / or clinical effects. It can be adjusted based on pharmacokinetic or pharmacodynamic parameters, including laboratory values. Therefore, this application encompasses intra-patient dose escalation as determined by those skilled in the art. Appropriate dosage The procedures and processes for determining the drug regimen are well known in the art. Yes, and this will be readily apparent to those skilled in the art. Therefore, the dosage range described herein The box is for illustrative purposes only and does not limit the scope or practice of the pharmaceutical compositions described herein. It will be readily understood and recognized by those skilled in the art that this is not the intended purpose.

[0238] In the use of the compounds of the present invention for therapeutic or preventive purposes, the compounds are generally used as needed. It is then administered in divided doses, for example, within the range of 0.1 mg / kg body weight to 75 mg / kg body weight. It is administered to receive the daily dose of [amount]. Generally, when parenteral routes are used, lower The dose is administered. Therefore, for example, in the case of intravenous or intraperitoneal administration, for example, 0.1 Doses ranging from mg / kg body weight to 30 mg / kg body weight are commonly used. Similarly, inhalation doses are also used. When administered by [method], for example, a dose within the range of 0.05 mg / kg body weight to 25 mg / kg body weight. This is used.

[0239] The compounds of the present invention are particularly suitable for oral administration. It can be formulated as tablets, capsules or liquids for use. Preferably, the compounds of the present invention are It is formulated into oral dosage forms (e.g., tablets or capsules). Typically, Each unit dosage form contains approximately 0.5 mg to 1.5 g of the compound of the present invention.

[0240] <Synthesis> The compounds of the present invention are prepared by any suitable technique known in the art. It is possible. Specific methods for forming compounds of formula I as defined herein are described below. This will be shown in the accompanying examples.

[0241] The synthesis methods described herein, and any reference materials used to prepare the starting materials In the description of the synthesis method, the selection of solvent, reaction atmosphere, reaction temperature, experimental period, and processing are described. It should be understood that all proposed reaction conditions, including the procedure, can be selected by those skilled in the art. .

[0242] Those skilled in organic synthesis will know that the functional groups present on various parts of a molecule affect the reagents used and It is understood that the reaction conditions must be met.

[0243] During the synthesis of the compounds of the present invention in the process defined herein, or in a certain manner, During the synthesis of generating materials, certain substituents are protected to prevent undesirable reactions. It will be understood that this is sometimes desirable. For a skilled chemist, this is always Is protection necessary, and how is such a protective group introduced into place? It will then be understood whether it can be removed later.

[0244] For examples of protecting groups, see one of the many general texts on the subject, for example, T "Protective Groups in Or See "Ganic Synthesis" (Publisher: John Wiley & Sons). Please do so. The protecting group is described in the literature as suitable for removing the protecting group in question. It can be removed by any convenient method known to a skilled chemist, however This method aims to achieve the removal of protecting groups while minimizing interference with other groups on the molecule. Selected.

[0245] Therefore, if the reactants contain groups such as amino, carboxy, or hydroxyl, In addition, it is desirable to protect the group in some of the reactions referred to herein. There is.

[0246] For example, suitable protecting groups for amino or alkylamino groups include, for instance, acyl groups, for example. However, this is not limited to alkanoyl groups such as acetyl, alkoxycarbonyl groups, for example Methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl group, aryl Methoxycarbonyl group, e.g., benzyloxycarbonyl, or alloyl group, e.g., benzyloxycarbonyl It is a nucleotide. The deprotection conditions for the above protecting group inevitably vary depending on the choice of protecting group. Therefore, for example, an alkanoyl or alkoxycarbonyl group or an alloyl group, etc. The acyl group can be, for example, alkali metal hydroxides, for example, lithium hydroxide. It can be removed by hydrolysis with a suitable base such as um or sodium. Alternatively, Acyl groups such as tert-butoxycarbonyl groups are soluble in hydrochloric acid, sulfuric acid, or phosphoric acid or t It can be removed by treatment with a suitable acid such as refluoroacetic acid, and benzyl oxycarbon Arylmethoxycarbonyl groups such as bonyl groups are hydrogenated on catalysts such as palladium carbon. Alternatively, it can be removed by treatment with a Lewis acid, such as tris(trifluoroacetic acid)boron. It is possible. Suitable alternative protecting groups for primary amino groups include, for example, alkylamines, for example, dimethylamines. F can be removed by treatment with thioaminopropylamine or hydrazine. It is a taloyl group.

[0247] Suitable protecting groups for hydroxyl groups include, for example, acyl groups, and alkaloids such as acetyl. The group is an alloyl group, such as benzoyl, or an arylmethyl group, such as benzyl. The deprotection conditions for the above protecting groups inevitably vary depending on the choice of protecting group. Therefore, for example... For example, acyl groups such as alkanoyl or aroyl groups are alkali metal hydroxides, such as water. Hydrolysis with lithium oxide, sodium hydroxide, or a suitable base such as ammonia Therefore, it can be removed. Alternatively, arylmethyl groups such as benzyl groups can be removed from palladium carbon It can be removed by hydrogenation on catalysts such as those listed above.

[0248] Suitable protecting groups for carboxyl groups include, for example, esterifying groups such as sodium hydroxide. Methyl or ethyl groups that can be removed by hydrolysis with a base, or, for example, t-butyl can be removed by treatment with an acid, such as an organic acid like trifluoroacetic acid. The base, or the ben which can be removed by hydrogenation on a catalyst such as palladium carbon. It is a zyl group.

[0249] Resins can also be used as a protective group.

[0250] The method used to synthesize the compound of formula (I) is R1, Q, R a , R b , R c , R dand R e , and also vary depending on the properties of any substituents associated with them. Preferred methods for their preparation are further described in the accompanying examples.

[0251] Once the compound of formula (I) is synthesized by any of the methods defined herein, Furthermore, the said method includes, (i) Remove any residual protecting groups present; or any (e.g., at position R1) A step to optionally convert the COOMe group to CONH2; (ii) The step of converting compound formula (I) to another compound of formula (I); (iii) A compound of formula I that forms a pharmaceutically acceptable salt, hydrate, or solvate. Step; and / or (iv) Step of forming a compound prodrug of formula I It may further include one or more of the following.

[0252] As an example of (ii) above, if the compound of formula (I) is synthesized, R1, Q, R a , R b , R c , R d and R e Further reacting one or more of the groups changes the properties of the group, and formula This can provide an alternative compound to (I).

[0253] The resulting compound of formula (I) is isolated and obtained using techniques well known in the art. It can be purified.

[0254] A further aspect of the present invention is a method for preparing the compound of formula (I) described above. hand, (a) By reacting the compound of formula (III) with the compound of formula (II), the compound of formula (I) is obtained. A step of preparing a compound, followed by a suitable deprotection step as needed, [ka] Scheme 1 During the ceremony, a Q b and R a~e As stated above, R1 is -CONH2, -CO2H Alternatively, the protected form of -CO2H is CO2PG (where PG is methyl). Step; or (b) By reacting the compound of formula (IV) with the compound of formula (V), the compound of formula (I) is obtained. A step of preparing, followed by a suitable deprotection step if necessary, [ka] Scheme 2 During the ceremony, a Q b and R a~e As stated above, R1 is -CONH2, -CO2H Alternatively, the protected form of -CO2H is CO2PG (where PG is methyl). Step; or (c) By reacting the compound of formula (VII) with the compound of formula (VI), the compound of formula (I) is obtained. A step of preparing a compound, followed by a suitable deprotection step as needed, [ka] Scheme 3 During the ceremony, a Q b and R a~e As stated above, R1 is -CONH2, -CO2H Alternatively, the protected form of -CO2H is CO2PG (where PG is methyl). Step A method including this is provided.

[0255] In the above process (a), Step (i) involves a reduction amination step, which typically involves an acid or base. Formation of imines in an alcohol solvent, or without, followed by reduction with a hydride-based reagent. Includes the original. Preferred conditions are 0°C to 50°C with sodium acetate or DIPEA. Sodium triacetoxyborohydride or sodium triacetoxyborohydride in methanol, or without it. Contains umcyanoborohydride.

[0256] If R1 is -CO2PG, step (ii) is a mixture of water and alcohol solvent. This includes hydrolysis reactions with suitable inorganic hydroxides in a given substance. Preferred conditions are water at room temperature. It contains lithium hydroxide in methanol.

[0257] In the above process (b), Steps (i) and (ii) are performed as described in process (a), reducing amino The process includes a deprotection step, which may be suitable if necessary, following the chemical treatment step.

[0258] In the above process (c), Step (iii) typically involves an aromatic substitution reaction involving a base in a suitable organic solvent. The preferred conditions include the presence of NaH in THF at 0°C to 60°C.

[0259] If a protecting group is used, step (ii) includes a deprotection reaction. If PG is a Boc group In this case, preferred conditions include the presence of HCl in 1,4-dioxane.

[0260] Compounds of formula (II), (III), (IV), (V), (VI), or (VII) are: It may be commercially available, prepared according to the method described herein, or according to the literature. It is prepared.

[0261] <Therapeutic use and applications> The compounds of the present invention are potent inhibitors of casein kinase 2-alpha (CK2α). Data demonstrating CK2α inhibition for the exemplified compounds are shown in the accompanying Examples section. Yes, they are.

[0262] The compound of the present invention binds to the catalytic ATP site of CK2α (driving potent enzyme inhibition). ) and bind to the αD site (driving a higher level of selectivity than other kinases) It is designed to [Brear et al., Chem Sci 2016].

[0263] Therefore, the compound of formula I is used for the treatment of diseases and conditions involving CK2α activity and / Or prevention, for example, but not limited to, proliferative disorders (e.g., cancer), viral infections Treatment and / or prevention of infection, inflammation, diabetes, vascular and ischemic disorders, neurodegeneration, and It is useful for regulating circadian rhythms.

[0264] In another embodiment, the present invention provides a therapeutic application of Formula I as defined herein. The compound of, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or as specified herein. The present invention provides a pharmaceutical composition as defined by [the specified formula].

[0265] In another embodiment, the present invention relates to the treatment of diseases or conditions involving CK2α activity. For use, compounds of formula I as defined herein, or pharmaceutically acceptable salts thereof, The present invention provides hydrates or solvates, or pharmaceutical compositions as defined herein.

[0266] In another embodiment, the present invention relates to the treatment of diseases or conditions involving CK2α activity. Compounds of formula I as defined herein, or their pharmaceuticals, in the manufacture of pharmaceuticals for use. The use of generally acceptable salts, hydrates, or solvates is provided.

[0267] In another embodiment, the present invention relates to a method for treating a disease or condition involving CK2α activity. The subject requiring treatment is given an effective amount of the compound of formula I as defined herein, This refers to the pharmaceutically acceptable salt, hydrate, or solvate thereof, or the medical as defined herein. The present invention provides a method comprising the step of administering a drug composition.

[0268] In another embodiment, the present invention relates to the treatment of diseases or conditions associated with abnormal activity of CK2α. For use in the foregoing, a compound of formula I as defined herein, or a pharmaceutically acceptable compound thereof. The present invention provides salts, hydrates, or solvates of a compound, or pharmaceutical compositions as defined herein.

[0269] In another embodiment, the present invention relates to the treatment of diseases or conditions associated with abnormal activity of CK2α. In the manufacture of a pharmaceutical product for use in the foregoing, a compound of formula I as defined herein, or The use of pharmaceutically acceptable salts, hydrates, or solvates of is provided.

[0270] In another embodiment, the present invention addresses diseases or conditions related to abnormal activity of CK2α. A method for applying an effective amount of a compound of formula I as defined herein to a target requiring treatment. or a pharmaceutically acceptable salt, hydrate or solvate thereof, or as defined herein The present invention provides a method comprising the step of administering a pharmaceutical composition.

[0271] In another embodiment, the present invention relates to proliferative disorders (e.g., cancer or benign neoplasms), viruses Treatment of infections, inflammatory diseases or conditions, diabetes, vascular and ischemic disorders, and neurodegenerative disorders. , and / or for use in the regulation of circadian rhythms, Formula I as defined herein The compound of, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or as specified herein. The present invention provides a pharmaceutical composition as defined by [the specified formula].

[0272] In another embodiment, the present invention relates to proliferative disorders (e.g., cancer or benign neoplasms), viruses Treatment of infections, inflammatory diseases or conditions, diabetes, vascular and ischemic disorders, and neurodegenerative disorders. , and / or in the manufacture of pharmaceuticals for use in regulating circadian rhythms, this specification Compounds of formula I as defined in the book, or their pharmaceutically acceptable salts, hydrates, or solvates. To provide the use of an item.

[0273] In another embodiment, the present invention relates to proliferative disorders (e.g., cancer or benign neoplasms), viruses Treatment of infections, inflammatory diseases or conditions, diabetes, vascular and ischemic disorders, and neurodegenerative disorders. a method for regulating the circadian rhythm, which is used in subjects requiring treatment. The efficacy of the compound of formula I as defined herein, or its pharmaceutically acceptable salts and hydrates, also A method comprising the step of administering a solvate or a pharmaceutical composition as defined herein. To provide.

[0274] In another embodiment, the present invention relates to use in the treatment of proliferative disorders as specified herein. Compounds of formula I as defined, or their pharmaceutically acceptable salts, hydrates, or solvates, The invention provides pharmaceutical compositions as defined herein.

[0275] In another embodiment, the present invention relates to the treatment of proliferative disorders (e.g., cancer or benign neoplasms). Compounds of formula I as defined herein, or the compound of formula I, as defined herein, in the manufacture of a pharmaceutical for use in a pharmaceutical. The use of pharmaceutically acceptable salts, hydrates, or solvates is provided.

[0276] In another embodiment, the present invention addresses proliferative disorders (e.g., cancer or benign neoplasms). A method comprising applying an effective amount of a compound of formula I as defined herein to an object requiring treatment. or a pharmaceutically acceptable salt, hydrate or solvate thereof, or as defined herein The present invention provides a method comprising the step of administering a pharmaceutical composition.

[0277] The terms “proliferative disorder” and “proliferative condition” are used synonymously herein. Therefore, whether in vitro or in vivo, undesirable excess such as neoplasms or hypertrophic growth. Or relating to the unwanted or unregulated proliferation of abnormal cells.

[0278] Examples of proliferative conditions include, but are not limited to, cancer, psoriasis, bone diseases, and fibroproliferative disorders. For example, connective tissue, and precancerous and malignant cell proliferation including atherosclerosis. However, it is not limited to these. It is not limited to these, but also includes the lungs, colon, breasts, ovaries, and prostate. Any type of cell can be treated, including those from the liver, pancreas, brain, blood, and skin.

[0279] In certain aspects of the present invention, proliferative disorders are cancer, preferably lung cancer, colon / colon Rectal cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, pancreatic cancer, brain tumor, blood cancer, bile duct cancer It is a type of cancer selected from tubular cell carcinoma and skin cancer.

[0280] In certain aspects of the present invention, proliferative disorders are associated with colorectal cancer, cholangiocarcinoma, and egg cancer. It is either tumor cancer or prostate cancer.

[0281] In a particular embodiment of the present invention, the proliferative disorder is colorectal cancer.

[0282] In a particular embodiment of the present invention, proliferative disorders are myeloid and granulocytic leukemias (bone marrow). Malignant neoplasms of the leukocyte lineage (both lymphoid and granulocytic); lymphoid, lymphocytic and lymphoblastic leukocytes Hematological diseases (malignancies of the lymphoid and lymphocytic blood cell lineages); polycythemia vera and erythroma (red blood cells) Malignant tumors of various blood cell products dominated by blood cells; as well as hematopoietic tumors, including myelofibrosis. It is a ulcer.

[0283] Benign neoplasms include, for example, hemangiomas, hepatocellular adenomas, cavernous hemangiomas, focal nodular hyperplasia, and auditory Neuroma, neurofibroma, cholangioadenoma, cholangiocystadenoma, fibroma, lipoma, leiomyoma, mesothelioma, Teratoma, myxoma, nodular hyperplasia, trachoma, pyogenic granuloma, mole, uterine fibroid It may be a thyroid adenoma, an adrenocortical adenoma, or a pituitary adenoma. Benign neoplasms are endometrial It may be a transplant or a keratocystic odontogenic tumor.

[0284] In another embodiment, the present invention is for use in the treatment of cancer, as defined herein. Compounds of formula I, or their pharmaceutically acceptable salts, hydrates, or solvates, or The present invention provides a pharmaceutical composition as defined in the specification.

[0285] In another embodiment, the present invention relates to the manufacture of a pharmaceutical product for use in the treatment of cancer, Compounds of formula I as defined herein, or pharmaceutically acceptable salts, hydrates, or The use of solvates is provided.

[0286] In another embodiment, the present invention relates to a method for treating cancer, wherein the subject requiring treatment is , an effective amount of the compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, hydrate The process includes the step of administering a substance or a solvate, or a pharmaceutical composition as defined herein. Provide a method.

[0287] Cancer may be non-metastatic or metastatic, and may be a solid tumor or a blood ("humoral") tumor. It may be cancer. Cancer may be selected from, for example, the following:

[0288] (1) For example, tumors originating from stratified squamous epithelium (squamous cell carcinoma) and within organs or glands Carcinomas, including tumors (adenocarcinomas) that develop. Examples include breast cancer, colon cancer, lung cancer, prostate cancer, Ovarian cancer, esophageal cancer (but not limited to these, including esophageal adenocarcinoma and squamous cell carcinoma) basal-like breast carcinoma, Base cell carcinoma (a form of skin cancer), squamous cell carcinoma (in various tissues), head and neck cancer (limited to these). Although not limited to squamous cell carcinoma, gastric cancer (including, but not limited to, gastric adenocarcinoma, digestive cancer) (including tubulostromal tumors), signet ring cell carcinoma, bladder cancer (transitional cell carcinoma (malignant neoplasm of the bladder)) (including), bronchogenic cancer, colorectal cancer (but not limited to these, colorectal cancer and rectal cancer) (including cancer), anal cancer, stomach cancer, lung cancer (but not limited to these, small cell lung cancer ( SCLC) and non-small cell carcinoma (NSCLC), lung adenocarcinoma, squamous cell carcinoma, large cell carcinoma, (including bronchioloalveolar carcinoma and mesothelioma), neuroendocrine tumors (but not limited to these) Carcinoid tumors (including carcinoid tumors of the gastrointestinal tract, breast, and other organs), adrenocortical cancer, thyroid cancer, Pancreatic cancer (not limited to these, but including pancreatic ductal adenocarcinoma, pancreatic adenocarcinoma, acinar cell carcinoma, invasive cancer) Intraductal papillary mucinous neoplasms with invasive carcinoma, mucinous cystic neoplasms with invasive carcinoma, islet cell carcinoma and (including neuroendocrine tumors), breast cancer (but not limited to ductal carcinoma, lobular carcinoma, inflammatory cancer) Breast cancer (including clear cell carcinoma and mucinous carcinoma), ovarian cancer (but not limited to these, serous carcinoma) Ovarian epithelial carcinomas, including endometrioid tumors and mucinous cystadenocarcinomas, sex cord-stromal tumors, or superficial (including cutaneous-stromal tumors), liver and cholangiocarcinoma, (but not limited to these, hepatocellular carcinoma, (including cholangiocarcinoma and hemangioma), prostate cancer, adenocarcinoma, brain tumors (and not limited to these) However, including gliomas, glioblastomas and medulloblastomas, germ cell tumors, sweat gland cancers, and sebaceous gland cancers Hmm, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, kidney cancer (but not limited to these, but kidney cells) (including clear cell carcinoma and Wilms' tumor), medullary carcinoma, in situ ductal carcinoma, This includes bile duct cancer, choriocarcinoma, seminoma, embryonic carcinoma, cervical cancer, and uterine cancer (not limited to these). Although not diagnosed, endometrial adenocarcinoma and uterine papillary serous carcinoma are also known as uterine papillary carcinoma. Uterine clear cell carcinoma, uterine sarcoma and smooth muscle Tumors, including mixed Müllerian tumors, testicles Oral cancer, osteogenic cancer, epithelial cancer, sarcomatoid cancer, nasopharyngeal cancer, pharyngeal cancer; oral cavity and oropharynx Including squamous cell carcinoma;

[0289] (2) Osteosarcoma and osteogenic sarcoma (bone); chondrosarcoma (cartilage); leiomyosarcoma (smooth muscle); transverse Amonosarcoma (skeletal muscle); mesosarcoma and mesothelioma (inner lining of body cavities); fibrosarcoma (fibrous tissue); hematopoiesis Tubosarcoma and hemangioendothelioma (vascular); liposarcoma (adipose tissue); glioma and astrocytoma ( Neurogenic connective tissue found in the brain; myxosarcoma (primitive embryonic connective tissue); chordoma, endosarcoma, Lymphangiosarcoma, Intralymphatic Sarcoma OMA, synovial tumors, Ewing's sarcoma, mesenchymal and mixed mesodermal tumors (mixed connective tissue type) Sarcomas including other soft tissue sarcomas;

[0290] (3) Myeloma and multiple myeloma;

[0291] (4) Myeloid and granulocytic leukemia (malignant neoplasms of myeloid and granulocytic leukocyte lineages); Lymphocytic, lymphocytic, and lymphoblastic leukemia (lymphatic and lymphocytic hematopoietic cell lineages) Malignant tumors of polycythemia vera and erythremia (malignant production of various blood cells dominated by red blood cells) Tumors; hematopoietic malignancies, including myelofibrosis.

[0292] (5) Lymphomas, including Hodgkin and non-Hodgkin lymphomas;

[0293] (6) Medulloblastoma, craniopharyngioma, ependymal cell tumor, pineal gland, hemangioblastoma, acoustic neuroma, oligodendroma Solid tumors of the nervous system, including gliomas, meningiomas, neuroblastomas, and schwann cell tumors;

[0294] (7) Melanoma, uveal melanoma and retinoblastoma; and

[0295] (8) Mixed type including adenosquamous carcinoma, mixed mesodermal tumor, carcinosarcoma or teratocarcinoma cells, etc. .

[0296] Preferably, the compounds of the present invention, or pharmaceutically acceptable salts thereof, are used in lung cancer, colon / colon cancer. Rectal cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, pancreatic cancer, brain tumor, blood cancer, bile duct cancer Use in the treatment of cancers selected from tubular cell carcinoma and skin cancer. It could be for that purpose.

[0297] More preferably, the cancer is colorectal cancer, prostate cancer, ovarian cancer, or cholangiocarcinoma. It will be selected from.

[0298] In a particular aspect of the present invention, the cancer is colorectal cancer.

[0299] In a particular aspect of the present invention, the cancer is cholangiocarcinoma.

[0300] In another embodiment of the present invention, cancer is a hematopoietic malignancy.

[0301] The compounds of the present invention are effective against WNT pathway mutant cancers, such as WNT pathway mutant colorectal cancer. Alternatively, it has been hypothesized that it may be particularly suitable for the treatment of cholangiocarcinoma (Di M aira et al., 2019).

[0302] In addition to having functions that have been well-characterized in wnt pathway activity, CK2α , other important cellular pathways known to be upregulated in cancer, for example, not limited to this. Although not yet established, it also plays a role in the DNA damage response (Ruzzene and Pin na, 2010;Montenarh, Transl. Cancer Res 201 6) Therefore, the compounds of the present invention are effective against PARP-insensitive tumors in prostate / ovarian cancer. It may be further used in the treatment of [the subject].

[0303] CK2a has also recently been identified as a heavy protein necessary for viral replication (for example, in SARS-CoV-2). It has been identified as a key host protein and therefore can be used as an antiviral treatment (Go Rdon et al., Nature 2020).

[0304] Therefore, in another embodiment, the present invention is for use in the treatment of viral infections , a compound of formula I as defined herein, or a pharmaceutically acceptable salt or hydrate thereof This provides a solvate, or pharmaceutical composition as defined herein.

[0305] In another embodiment, the present invention relates to the manufacture of pharmaceuticals for use in the treatment of viral infections. The compound of formula I as defined herein, or its pharmaceutically acceptable salt or hydrate. Alternatively, the use of a solvate is provided.

[0306] In another embodiment, the present invention relates to a method for treating a viral infection, which requires treatment To the target, an effective amount of the compound of formula I as defined herein, or its pharmaceutically acceptable form Steps to administer a salt, hydrate, or solvate, or a pharmaceutical composition as defined herein. Provides a method that includes the pu.

[0307] Preferably, the virus is a coronavirus, such as SARS-CoV-2.

[0308] <Route of administration> The compounds of the present invention or pharmaceutical compositions containing these compounds are used systemically / peripherally or topically. Regardless of the location (i.e., the desired site of action), administer to the target via any convenient route of administration. It is possible.

[0309] The routes of administration are not limited to these, but include: oral (e.g., by food ingestion); oral cavity; sublingual; Transdermal (e.g., patches, plasters); transmucosal (e.g., patches, plasters) - by medications, etc.; in the nasal cavity (for example, by nasal sprays); in the eyes (for example, by eye drops, eye ointments, etc.) to; lungs (for example by aerosol, for example through the nose or mouth, for example inhalation therapy or inhalation) By suppositories or enemas; rectally (e.g., by suppositories or enemas); vaginally (e.g., by pessaries) Parenteral administration, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrameningeal, intrathecal, sacral This includes intracellular, intracapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intraarticular, intraarachnoid, and intrasternal regions. By injection; for example, by subcutaneous or transmuscular injection in the form of a depot or reservoir dose. Including those caused by Land.

[0310] The compounds of the present invention are particularly suitable for oral administration.

[0311] <Combination therapy> The compounds of the present invention as defined above, and their salts and solvates, are applied as monotherapies. Alternatively, in addition to the compound of the present invention, one or more additional therapeutic agents, for example It may also contain antitumor drugs.

[0312] In the context of cancer treatment, in addition to the compounds of the present invention, the treatment involves conventional surgery or radiation therapy. This may include therapy or chemotherapy. Such chemotherapy may include the following antitumor drugs. It may contain one or more Goryes.

[0313] - Other antiproliferative / antineoplastic drugs and their combinations used in medical oncology, e.g. For example, but not limited to these, alkylating agents (e.g., cisplatin, oxaliplatin) Carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chloramb Sil, busulfan, temozolamide and nitrosourea); antimetabolites (e.g., ge Mucitabine and folate antagonists, such as fluoropyrimidines, for example, not limited to these. For example, 5-fluorouracil, and tegafur, larcitrexed, methotrexate, Cytosine arabinoside and hydroxyurea); antitumor antibiotics (e.g., anthracite) Ikurin, for example, Adriamycin, Bleomycin, Doxorubicin, Daunomycin Epirubicin, idarubicin, mitomycin-C, dactinomycin and mitrama Icin); antimitotic agents (e.g., vinca alkaloids, e.g., vincristine, vinbra) Stine, vindesine and vinorelbine, as well as taxoids, such as Taxol and Taxoteles, as well as polokinase inhibitors; and topoisomerase inhibitors (e.g., E Pipodophyllotoxins, such as etoposide and teniposide, amsacrin, and topotecan. and camptothecin);

[0314] - Cell proliferation inhibitors, for example, but not limited to, anti-estrogen drugs (e.g., ta Moxifen, fulvestrant, toremifene, raloxifene, droloxifene (and iodoxifen), antiandrogen drugs (e.g., bicalutamide, flutamide, nitrate) Mido and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g.) For example, goserelin, leuprorelin and buserelin), progestogens (for example, megesterone acetate) Strol), aromatase inhibitors (e.g., anastrozole, letrozole, borazol) Inhibitors of 5α-reductase (and exemestane) and 5α-reductase, for example, not limited thereto Finasteride;

[0315] - Anti-invasive agents [e.g., c-Src kinase family inhibitors, e.g., 4-(6-clo (Ro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazine-1-I Ethoxy-5-tetrahydropyran-4-yloxyquinazoline (AZD0530) International patent application WO01 / 94341), N-(2-chloro-6-methylphenyl)-2 -{6-[4-(2-hydroxyethyl)piperazine-1-yl]-2-methylpyrimid 4-ylaminothiazole-5-carboxamide (dasatinib, BMS-3548) 25; J. Med. Chem., 2004, 47, 6658~6661) and Boss Tinib (SKI-606), and metalloproteinase inhibitors, such as Marimust. Inhibitors of urokinase plasminogen activator receptor function or heparanase Antibodies against them;

[0316] - Inhibitors of growth factor function: For example, such inhibitors include growth factor antibodies and growth factor antibodies. Receptor antibodies (e.g., anti-erbB2 antibody trastuzumab [Herceptin(trademark)]) ], anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab [Erbitux, C 225] and Stern et al. (Critical reviews in oncolo Disclosed in gy / haematology, 2005, Vol. 54, pp. 11-29. This includes any growth factor or growth factor receptor antibody; such inhibitors also include Tyrosine kinase inhibitors, for example, inhibitors of the epidermal growth factor family (e.g., EGFR inhibitors) Myri tyrosine kinase inhibitors, for example, but not limited to these, N-(3-chloro-4- Fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4 -amine(gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bi (2-methoxyethoxy)quinazoline-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-mo Ruforinopropoxy)-Quinazoline-4-amine (CI 1033), erbB2 tyrosine Hepatocyte growth factor family; for example, lapatinib, but not limited to hepatocyte growth factor family Inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family Inhibitors, such as but not limited to imatinib and / or nilotinib (AMN1 07); Serine / threonine kinase inhibitors (e.g., Ras / Raf signaling inhibitors) Agents, such as, but not limited to, farnesyltransferase inhibitors, such as Soraf Enib (BAY 43-9006), Chipifarnib (R115777) and Ronaldo Lunib (SCH66336), MEK and / or AKT kinase-mediated cell signature Inhibitors of NAL signaling, c-kit inhibitors, ABL kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like enzymes) (Proliferation factor) kinase inhibitors; Aurora kinase inhibitors (e.g., AZD1152, PH739) 358, VX-680, MLN8054, R763, MP235, MP529, VX-5 28 and AX39459) and cyclin-dependent kinase inhibitors, for example, not limited to these. Unspecified but includes CDK2 and / or CDK4 inhibitors;

[0317] - Anti-angiogenic drugs, such as, but not limited to, those that inhibit the effects of vascular endothelial growth factor. things like [for example, the anti-vascular endothelial growth factor antibody bevacizumab (Avastin®)] and, for example, VEGF receptor tyrosine kinase inhibitors, for example, but not limited to these, Ndetanib (ZD6474), Batalanib (PTK787), Sunitinib (SU1124) 8) Axitinib (AG-013736), Pazopanib (GW786034) and 4 -(4-fluoro-2-methylindole-5-yloxy)-6-methoxy-7-(3 -Pyrrolidine-1-ilpropoxy)Quinazoline (AZD2171;WO00 / 4721) Examples 240) and, but not limited to, those in international patent application WO97 / 22596, W Disclosed in O97 / 30035, WO97 / 32856 and WO98 / 13354 Compounds such as those that are being used, as well as compounds that act by other mechanisms (for example, linamide, Inhibitors of integrin αvβ3 function and angiostatins);

[0318] - Vascular damage drugs, for example, but not limited to, combretastatin A4 and country International patent applications WO99 / 02166, WO00 / 40529, WO00 / 41669, WO Disclosed in 01 / 92224, WO02 / 04434 and WO02 / 08213 Compounds containing;

[0319] - Endothelin receptor antagonists, such as dibotentan (ZD4054) or Atracentan;

[0320] - Antisense therapy, for example, against the targets listed above, for example, not limited to these. ISIS2503, anti-RAS antisense;

[0321] - Abnormal genes, for example, but not limited to these, abnormal p53 or abnormal BRCA1 This approach involves replacing BRCA2, or GDEPT (gene-directed enzyme prodrug therapy). ) Approaches, for example, but not limited to these, include cytosine deaminase and thymidine kinase. or treatments using bacterial nitroreductase enzymes, and chemotherapy or radiotherapy. Approaches to enhance patient resistance to drugs, including gene therapy for multidrug resistance. Legal approach; and,

[0322] - Ex vivo and in vivo approaches to enhance the immunogenicity of patient tumor cells. For example, but not limited to this, cytokines, such as interleukin-2, interleuk Transfection with 4 or granulocyte-macrophage colony-stimulating factor, T Approaches to reduce cellular anergy, such as transfected immune cells. Approaches using cytokine-transfected dendritic cells, but not limited to these. Chi, an approach using cytokine-transfected tumor cell lines, and anti Immunotherapy approaches, including approaches using idiotype antibodies.

[0323] In certain embodiments, the antiproliferative treatment defined above is performed in addition to the compound of the present invention. This may include conventional surgery, radiation therapy, or chemotherapy.

[0324] In further specific embodiments, the antiproliferative treatment defined above is applied to the compound of the present invention. In addition, it may include standard chemotherapy for the related cancer.

[0325] In certain embodiments, the antiproliferative treatment defined above is performed in addition to the compound of the present invention. K-ras inhibitors and / or DNA damage repair inhibitors (e.g., PARP inhibitors) Treatment may be included.

[0326] Such combined treatments involve simultaneous, sequential, or separate administration of the individual components of the treatment. This can be achieved. The products of such combinations are compounds of the present invention within the above-mentioned dose range, Use other pharmaceutically active drugs within their approved dosage range.

[0327] According to this aspect of the present invention, the compound of the present invention as defined above, or its pharmaceutically acceptable properties. A suitable salt, hydrate or solvate, and another antitumor agent, including cancer (e.g., solid) A combination is provided for use in the treatment of cancer (including tumors).

[0328] According to this aspect of the present invention, the compound of the present invention as defined above, or its pharmaceutically acceptable properties. A salt, hydrate, or solvate of the substance, and any one of the antitumor agents listed above. Proliferative conditions including, for example but not limited to, cancer (e.g., cancer including solid tumors) A combination for use in the treatment is provided.

[0329] In a further embodiment of the present invention, another which is optionally selected from those listed above The compound of the present invention or for use in the treatment of cancer in combination with antitumor agents A pharmaceutically acceptable salt, hydrate, or solvate is provided.

[0330] Where the term “combination” is used herein, it means simultaneous, separate It should be understood that this refers to, or sequential administration. In one embodiment of the present invention, “combination” is This refers to simultaneous administration. In another embodiment of the present invention, "combination" refers to separate administrations. In further embodiments of the invention, “combination” refers to sequential administration. In the case of individual components, a delay in the administration of the second component would result in the loss of the beneficial effect of the combination. It should not be. In one embodiment, the combination refers to the product of the combination.

[0331] According to a further aspect of the present invention, in combination with a pharmaceutically acceptable diluent or carrier, ( The present invention, combined with an antitumor agent (selected at will from those listed below), A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt, hydrate, or solvate thereof is proposed. To be served.

[0332] <Biological activity> The biological assay described in the Examples section (Biological Assay 1) is a drug assay of the compound of the present invention. It can be used to measure the effect.

[0333] The pharmacological properties of the compound of formula I vary with structural changes, as predicted, but in this invention The compound was found to be active in the assay described in Biological Assay 1. Generally, the compounds of the present invention are found to be at a concentration of 500 nM or less in the assay described in Biological Assay 1. The IC below 50 The preferred compounds of the present invention have an IC of 100 nM or less. 50 This shows, The most preferred compound of the invention is IC with a concentration of 30 nM or less. 50 This indicates.

[0334] The compounds of the present invention are also active in assay 3 described in the section on accompanying biological assays. It can indicate sexuality. [Examples]

[0335] The present invention will be described by referring to the specific embodiments described in the following examples, however These are not the only examples. Compounds are named using the conventional IUPAC nomenclature. It is named by the chemical supplier or by the company itself.

[0336] The following synthesis procedure is provided to illustrate the method used and the given preparation or steps In this process, the precursor used is used in individual batches synthesized according to the steps of the given description. It doesn't need to be derived from.

[0337] <Analysis method (AM)> When the examples and preparations refer to analytical data, unless otherwise specified, the following analytical methods are used. I used it.

[0338] All LC-MS spectra were obtained using one of the following methods. Method 1 (AM1): (5-95 A-B_1.5 min_220 and 254 nm): Machine Instrument: Agilent 1100 / G1956A; Column: Kinetex@5um EV O C18 30×2.1mm×5μm; Run time: 1.5 min; Solvent: A) Water 0.03 75% TFA (volume / volume), B) 0.01875% TFA in acetonitrile (volume / volume) (Quantity). Perform a concentration gradient at 5% B; concentration gradient: 5-95% B including A, 0.8 min; 95 Hold at %B for 1.2 minutes; hold at 5%B and 5%B for 1.5 minutes at 1.21 minutes @1.5 mL / min, 50°C. Method 2 (AM2): (5-95 A-B_1.5 min_220 and 254 nm): Machine Instrument: Agilent 1200 / G6110A; Column: Kinetex@5um EV O C18 30×2.1mm×5μm; Run time: 1.5 min; Solvent: A) Water 0.03 75% TFA (volume / volume), B) 0.01875% TFA in acetonitrile (volume / volume) (Quantity). Perform a concentration gradient at 5% B; concentration gradient: 5-95% B including A, 0.8 min; 95 Hold at %B for 1.2 minutes; hold at 5%B and 5%B for 1.5 minutes at 1.21 minutes @1.5 mL / min, 50°C. Method 3 (AM3): (5-95 A-B_1.55 min_220 and 254 nm): Equipment: SHIMADZU LCMS-2020; Column: Kinetex EVO C1 8. 30 × 2.1 mm × 5 μm; Run time: 1.55 min; Solvent: A) 0.0375% in water TFA (volume / volume), B) 0.01875% TFA in acetonitrile (volume / volume). Perform a concentration gradient at 5%B; concentration gradient: 5-95%B including A, 0.8 min; at 95%B Hold for 1.2 minutes; hold for 1.21 minutes with 5% B and for 1.55 minutes with 5% B at 1.5 mL each. / min, 50℃. Method 4 (AM4): (5-95 A-B_1.5 min_220 and 254 nm): Machine Instrument: Agilent 1200 LC / G1956A MSD; Column: Kinetex EVO C18 30×2.1mm×5μm; Run time: 1.5 min; Solvent: A) Water 0 0.0375% TFA (volume / volume), B) 0.01875% TFA in acetonitrile (volume) (Quantity / Volume). Perform a concentration gradient at 5%B; concentration gradient: 5-95%B including A, 0.8 min ;Hold at 95%B for up to 1.2 minutes;Hold at 5%B and 5%B for up to 1.5 minutes @ 1.5mL / min, 50℃. Method 5 (AM5): (0-60 A-B_1.55 min_220 and 254 nm): Equipment: SHIMADZU LCMS-2020; Column: Kinetex EVO C1 8. 30 × 2.1 mm × 5 μm; Run time: 1.55 min; Solvent: A) 0.0375% in water TFA (volume / volume), B) 0.01875% TFA (volume / volume) in ACN. Concentration gradient. Run at 0%B; concentration gradient: 0-60%B including A, 0.8 min; 1.20 min at 60%B Hold for up to 1 minute; hold for 1.21 minutes at 0%B and up to 1.55 minutes at 0%B @ 1.5 mL / min. 50℃. Method 6 (AM6): (0-60 C-D_2.20 min_220 and 254 nm): Equipment: SHIMADZU LCMS-2020; Column: Kinetex EVO C1 8. 30 × 2.1 mm × 5 μm; Run time: 2.20 min; Solvent: A) 0.025% N in water H3·H2O (volt / volt), B) Acetonitrile. Perform a concentration gradient with 0% B; concentration Gradient: 0-60% B including A, 1.2 min; held at 60% B up to 1.6 min; 0 at 1.61 min Hold at %B and 0%B for up to 2.2 minutes at 1.5 mL / min, 40°C. Method 7 (AM7): (5-95 C-D_1.5 min_R_220 and 254_PO S): Equipment: SHIMADZU LCMS-2020; Column: Kinetex EVO C18 30×2.1mm×5μm; Run time: 1.5 min; Solvent A) 0.025% in water NH3·H2O (volume / volume) B) Acetonitrile. Perform a concentration gradient at 5% B. Gradient: A 5-95% B 0.8 min, held up to 1.2 min at 95% B; 5 at 1.21 min Hold at %B and 5%B for up to 1.5 minutes at 1.5 ml / min, 40°C. Method 8 (AM8): (10⁻⁸ C-D_2.00 min_220 and 254 nm) Equipment: Agilent 1200 / G6110A; Column: ACE Excel 5 C18 30×2.1mm×5μm; Run time: 2.00 min; Solvent: A) Water 0.025 %NH3·H2O (volume / volume), B) Acetonitrile (volume / volume). Concentration gradient 10 Run at %B; concentration gradient: 10-80%B including A, 1.2 min; 1.6 min at 80%B Hold at 1.61 min with 10% B and hold at 1.00 mL / min for up to 2.00 min with 10% B. 40℃. Method 9 (AM9): (10⁻⁸ A-B 7 mins 220 and 254 nm): Instrument :SHIMADZU LCMS-2020; Column:AB:Xtimate C18 3 0 × 2.1 mm × 3 μm; Run time: 7.0 min; Solvent: A) 0.0375% TFA in water (Volume / Volume), B) 0.01875% TFA in acetonitrile (Volume / Volume). Concentration gradient Run at 10%B; concentration gradient: 10-80%B including A, 6.5 min; 7 min at 80%B Hold until 6.5 minutes with 10% B and hold until 7 minutes with 10% B at 1.5 mL / min, 50°C .

[0339] 1 The 1H NMR spectrum was obtained using the Bruker NMR spectrum with the residual non-deuterated solvent as a reference. Acquisitions were performed using the Avance III spectrometer at 400 MHz and annotated using ACD Labs. I added it. <Purification method (PM)> chromatography

[0340] JPEG2026122953000025.jpg97170 Reverse-phase HPLC conditions

[0341] JPEG2026122953000026.jpg147170JPEG2026122953000027.jpg255162JPEG2026122953000028.jpg255162JPEG2026122953000029.jpg25516 1JPEG2026122953000030.jpg255161JPEG2026122953000031.jpg255162JPEG2026122953000032.jpg255161JPEG2026122953000033.jpg75170

[0342] <abbreviation> When using the following abbreviations, the following meanings apply: ACN is acetonitrile, AcOH is acetic acid. AlCl3 is aluminum chloride. AM is an analytical method, aq. is an aqueous solution. 9-BBN is 9-borabicyclo(3.3.1)nonane, Boc2O is a di-tert-butyl dicarbonate, Br2 is a bromine solution, CBr4 is carbon tetrabromide. CDI is 1,1'-carbonyldiimidazole, CHCl3-d is deuterated chloroform, CsCO3 is cesium carbonate, CsF is cesium fluoride. CuI is copper iodide, DCE is dichloroethane, DCM is dichloromethane, DIPEA is N,N-diisopropylethylamine, DMAP is dimethylaminopyridine, DME is 1,2-dimethoxyethane, DMF is N,N-dimethylformamide, DMP is Des-Martin-Periodinan, DMS is dimethyl sulfide, DMSO is dimethyl sulfoxide, DMSO-d6 is deuterated dimethyl sulfoxide, dppf is 1,1'-ferrocenediyl-bis(diphenylphosphine), EA is ethyl acetate, EDCI is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride. can be, EtOH is ethanol, FA is formic acid, Fmoc is 9-fluorenylmethoxycarbonyl, h is time, NMR is nuclear magnetic resonance, HATU is 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[ [4,5-b]pyridinium 3-oxide hexafluorophosphate, HCl is hydrochloric acid, HOBt is 1-hydroxybenzotriazole, H2O is water, H2O2 is hydrogen peroxide. HPLC is a high-performance liquid chromatography, KF stands for potassium fluoride. K2CO3 is potassium carbonate, K2SO4 is potassium sulfate, LAH is lithium aluminum hydride, LCMS is liquid chromatography-mass spectrometry. LiOH·H2O is lithium hydroxide monohydrate. mCPBA is meta-chloroperbenzoic acid, MeI is methyl iodide, MeOH is methanol, MeOH-d4 is deuterated methanol. min is minutes, MnO2 is manganese dioxide, MS is a molecular sieve, MTBE is methyl tert-butyl ether, N2 is nitrogen gas, NaH is sodium hydride, NH4Cl is ammonium chloride, NaHCO3 is sodium bicarbonate. NaHMDS is sodium bis(trimethylsilyl)amide, NaOH is sodium hydroxide, NaOMe is sodium methoxide, Na2SO4 is anhydrous sodium sulfate, n-BuLi is n-butyllithium, NCS is N-chlorosuccinimide, Pd(PPh3)4 is tetrakis(triphenylphosphine)palladium(0), Pd(dppf)Cl2 is [1,1'-bis(diphenylphosphino)ferrocene]di It is loropaladium(II), Pd(dppf)Cl2·CH2Cl2 is [1,1'-bis(diphenylphosphinol)f It is a complex of erocene]dichloropalladium(II) and dichloromethane, PE is petroleum ether, PM is a purification method. POCl3 is oxychloride phosphite, rt is the retention time, SEM is silylethoxymethyl, SOCl2 is thionyl chloride, TBAC is tetrabutylammonium chloride, TBAF is tetrabutylammonium fluoride, TBAI is tetramethylammonium iodide, TEA is triethylamine, TFA is trifluoroacetic acid, TFAA is trifluoroacetic anhydride, THF is tetrahydrofuran, TLC is a thin-layer chromatography technique. TMEDA is N'-tetramethylethylenediamine, TMSCN is a trimethylsilyl cyanide, T3P is propylphosphonic anhydride, TsOH·H2O is p-toluenesulfonic acid monohydrate.

[0343] <Preparation of intermediates> The following preparations describe the methods used for common intermediates required for the synthesis of the examples.

[0344] Compound 1.1 is described in J.Med.Chem.2011,54(2),635-654. It can be prepared according to the method described. <Synthesis of intermediate E> tert-butyl(4-(cyanomethoxy)butyl)carbamate 1.19

[0345] [ka] tert-butyl(4-hydroxybutyl)carbamate (7g, 36.99mmol) ) and 2-bromoacetonitrile (8.87 g, 73.98 mmol) DCM (10 Add silver(I) oxide (18.55 g, 80.05 mmol) to the mixture in 0 mL at 25°C. Then TBAI (2.94 g, 7.96 mmol) was added. The mixture was stirred at 25°C for 16 hours. The mixture was filtered, and the filtrate was washed with NaHCO3 aqueous solution (100 mL) and Na2SO4. The mixture was dried in 4, filtered, and concentrated under vacuum. The crude product was purified (PM7) to obtain compound 1.19. (1.0 g, 4.38 mmol, yield 11.8%) was obtained as a yellow oily substance. 1 H NMR (CDCl3, 400 MHz) δ: 4.56 (br s, 1H), 4.24 (s, 2H), 3.62-3.59 (t, 2H), 3. 18-3.13 (m, 2H), 1.71-1.63 (m, 2H), 1.58-1.53 ​​(m, 2H), 1.45 (s, 9H) ppm. tert-butyl(4-(2-aminoethoxy)butyl)carbamate 1.20

[0346] [ka] A solution of compound 1.19 (1.0 g, 4.38 mmol) in MeOH (10 mL) contains nitrogen Ammonium hydroxide (2 mL, 25 wt%) and Raney nickel (1 (00 mg, 1.17 mmol) was added. The suspension was degassed three times under vacuum and purged with hydrogen. The mixture was stirred at 25°C under hydrogen (45 psi) for 16 hours. The mixture was filtered, and the filtrate was... The compound was concentrated under vacuum to obtain 1.20 g of compound as a green oily substance, which was then used in the next step. I used it directly. Methyl 5-((2-(4-((tert-butoxycarbonyl)amino)butoxy)eth (L)amino)benzo[c][2,6]naphthyridine-8-carboxylate, 1.58

[0347] [ka] A solution of compound 1.1 (3.20 g, 11.74 mmol) in DMSO (50 mL) is prepared. At 25℃, DIPEA (3.03g, 23.48mmol) and compound 1.20 (3g, 12.91 mmol) was added sequentially. The reaction mixture was then heated to 75°C and stirred for 12 hours. The mixture was diluted with water (100 mL) and extracted with EA (100 mL x 2). The organic layer was washed with brine (100 mL), dehydrated with anhydrous Na2SO4, filtered, and vacuum-sealed. The compound was concentrated to obtain 1.58 (5g) of compound as a brownish solid. LCMS (AM3): rt = 0.841 min, (469.3 [M+H] + ), purity 63.4%. 5-((2-(4-((tert-butoxycarbonyl)amino)butoxy)ethyl) Mino)benzo[c][2,6]naphthyridine-8-carboxylic acid, 1.59

[0348] [ka] Compound 1.58 (5g, 10.67 mmol) in THF (15mL), MeOH (15 In a solution in (15 mL) and water, NaOH (853.65 mg, 21.3 mL) was added at 20°C. 4 mmol) was added. The reaction mixture was then stirred at 20°C for 4 hours. The organic solvent was removed under vacuum. The solution was concentrated, and the remaining aqueous solution was acidified to pH 5 with HCl aqueous solution (1N). The resulting precipitate was then... The compound was filtered and dried under vacuum to obtain compound 1.59 (4.5 g) as a brownish solid. LCMS (AM3): rt = 0.808 min, (455.3 [M+H] + ), purity 88.98%. tert-butyl(4-(2-((8-carbamoylbenzo[c][2,6]naphthilidi 1.60 methyl

[0349] [ka] Mixing solution of compound 1.59 (4.5 g, 9.90 mmol) in DMF (25 mL): At 20℃, EDCI (2.85g, 14.85 mmol), HOBt (2.01g, 14. (85 mmol), DIPEA (1.92 g, 14.85 mmol) and NH4Cl (2 (0.12g, 39.60 mmol) was added sequentially. The reaction mixture was then stirred at 20°C for 3 hours. The reaction mixture was diluted with water (100 mL) and extracted with EA (100 mL x 2). Wash the combined organic layer with brine (80 mL x 2), dehydrate with anhydrous Na2SO4, and filter. The mixture was concentrated under vacuum. The residue was purified (PM19) to obtain compound 1.60 (3.8g, 6.70). mmol (67.6% yield, TFA salt) was obtained as a yellow oily substance. LCMS (AM3): rt = 0.758 min, (454.4 [M+H] + ), purity 59.9%. 5-((2-(4-aminobutoxy)ethyl)amino)benzo[c][2,6]naphthili Zin-8-carboxamide, intermediate E

[0350] [ka] A solution of compound 1.60 (3.8 g, 8.38 mmol) in MeOH (5 mL) is prepared at 0°C. Then, a solution of HCl in MeOH (4M, 2.09 mL) was added dropwise. Next, the reaction mixture was prepared. The mixture was heated to 20°C and stirred for 2 hours. The reaction mixture was concentrated under vacuum to obtain intermediate E (2.8 g, 7.18 mmol (85.7% yield, HCl salt) was obtained as a yellow solid. LCMS (AM3): rt = 0.229 min, (354.1 [M+H] + ), purity 89.5%. Synthesis of intermediate 1.57 tert-butyl(4-(allyloxy)butyl)carbamate, 1.53

[0351] [ka] NaOH (2.11g, 52.84 mmol) 1,4-dioxane (176.1mL) ) Add tert-butyl N-(4-hydroxybutyl)carbamate (1 (0g, 52.84 mmol) and 3-bromopropa-1-ene (12.78g, 105 (0.68 mmol) was added sequentially. The reaction mixture was heated to 70°C and stirred for 12 hours. The mixture was diluted with water (100 mL) and extracted with EA (100 mL x 3). Combined organic Wash the layers with brine (80 mL x 2), dehydrate with anhydrous Na2SO4, filter, and concentrate under vacuum. It shrunk. The residue was purified (PM6) to obtain compound 1.53 (5.5g, 23.98 mmol, A yield of 45.4% was obtained as a pale yellow oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 5.93-5.82 (m, 1H), 5.27-5.20 (m, 1H), 5.16-5.11 (m , 1H), 4.70 (br, s, 1H), 3.93-3.91 (m, 2H), 3.43-3.39 (t, 2H), 3.12-3.08 (m, 2H) , 1.62-1.49 (m, 4H), 1.40 (s, 9H) ppm. tert-butyl(4-(2-hydroxyethoxy)butyl)carbamate, 1.54

[0352] [ka] The mixture was heated to -78°C until it turned blue. Compound 1.53 (5.5g, 23.9g) Blow 8 mmol) of the solution into 50 mL of DCM, then warm the reaction mixture to 0°C. Then, NaBH4 (1.77 g, 46.79 mmol) was slowly added at 0°C. The reaction was then mixed. The mixture was heated to 20°C and stirred for 12 hours. The reaction mixture was quenched with water (50 mL) and DCM was used. Extraction was performed using (80 mL x 2). The combined organic layer was washed with brine (80 mL x 2) and then removed. The solution was dehydrated with water (Na2SO4), then filtered, and concentrated under vacuum. The residue was purified (PM3). Compound 1.54 (2.65 g, 11.36 mmol, yield 47.4%) was prepared as a colorless oil. I obtained it. 1 H NMR (400 MHz, CHCl3-d) δ: 4.78 (br s, 1H), 3.72-3.71 (m, 2H), 3.53-3.51 (t, 2H), 3.51-3.46 (t, 2H), 3.13-3.12 (m, 2H), 2.41 (br s, 1H), 1.66-1.50 (m, 4H), 1 0.42 (s, 9H) ppm. 5-(2-(4-((tert-butoxycarbonyl)amino)butoxy)ethoxy)be Nzo[c][2,6]naphthyridine-8-carboxylic acid, 1.55

[0353] [ka] Mixing of compound 1.54 (427.79 mg, 1.83 mmol) in DMF (10 mL). Add NaH (110.02 mg, 2.75 mmol) to the substance in one go under nitrogen protection at 0°C. Next, compound 1.1 (500 mg, 1.83 mmol) was added. Then the mixture was heated to 80°C. The mixture was heated and stirred for 12 hours. The mixture was diluted with water (50 mL) and EA (50 mL x 2) Extraction was performed using [method]. The combined organic phase was washed with brine (50 mL) and dehydrated with Na2SO4. The solution was concentrated under vacuum. The residue was purified (PM20) to obtain compound 1.55 (300 mg, 645 mg). 44 μmol was obtained as a pale yellow solid with a yield of 35.2% and a purity of 98.2%. LCMS (AM3): rt = 0.903 min, (456.3 [M+H] + ), purity 98.2%. tert-butyl(4-(2-((8-carbamoylbenzo[c][2,6]naphthilidi 1.56 yl(oxy(ethoxy)butyl)carbamate

[0354] [ka] Compound 1.55 (300 mg, 645.44 μmol), ammonium chloride (51.7 (9 mg, 968.16 μmol) and DIPEA (208.54 mg, 1.61 mmol) l) Mixture in DMF (10 mL) is heated at 25°C to HATU (294.50 mg, 774 mg). 53 μmol was added. The resulting mixture was stirred at 25°C under nitrogen protection for 11 hours. The mixture is filtered and concentrated under vacuum to obtain the residue, which is then purified (PM21) to obtain compound 1.5 6 (250 mg, 473.03 μmol, yield 73.3%, purity 86.2%) solidified into a pale yellow solid. I acquired it physically. LCMS (AM3): rt = 0.757 min, (455.3 [M+H] + ), purity 86.2%. 5-(2-(4-aminobutoxy)ethoxy)benzo[c][2,6]naphthyridine-8 -Carboxamide, 1.57

[0355] [ka] Compound 1.56 (250 mg, 473.03 μmol, 1 equivalent) in a 20 mL DCM solution. Add TFA (6.16 g, 54.03 mmol, 4 mL) to the mixture at 25°C and mix. The mixture was stirred for 0.5 hours. The reaction mixture was concentrated under vacuum and purified (PM21) to obtain compound 1. 0.57 (220 mg, 432.09 μmol, yield 91.3%, purity 92.1%, TFA) The salt was obtained as a pale yellow solid. LCMS (AM3): rt = 0.675 min, (355.2 [M+H] + ), purity 92.1%. Synthesis of intermediate Q 5-(2-(4-aminobutoxy)ethoxy)benzo[c][2,6]naphthyridine-8 -carboxylic acid; intermediate Q

[0356] [ka] In a solution of compound 1.55 (100 mg, 219.54 μmol) in DCM (5 mL), TFA (1 mL, 13.51 mmol) was added. The mixture was stirred at 25°C for 0.5 hours. The mixture was concentrated under vacuum to obtain intermediate Q (100 mg, 213.03 μmol, 97% yield). The TFA salt was obtained as a brownish solid and used without purification. LCMS (AM3): rt = 0.745 min, (356.3 [M+H] +), purity 79.9%. Synthesis of intermediate 1.154 Methyl 5-((2-(4-aminobutoxy)ethyl)amino)benzo[c][2,6]na Futhyridine-8-carboxylate 1.154

[0357] [ka] Compound 1.58 (200 mg, 426.85 μmol) of 1,4-dioxane (5 mL) To the solution, 1,4-dioxane solution in HCl (4M, 5mL) was added at 20°C. The mixture was stirred at 20°C for 1 hour. The mixture was concentrated under vacuum to obtain compound 1.154 (201m). The HCl salt (g) was obtained as a yellow oily substance and used directly without purification. LCMS (AM3): rt = 0.673 min, (369.2 [M+H] + ), 99% purity. Synthesis of intermediate R 5-((2-(4-aminobutoxy)ethyl)amino)benzo[c][2,6]naphthili Zin-8-carboxylic acid; intermediate R

[0358] [ka] Compound 1.59(4) in HCl solution of 1,4-dioxane (40.00 mL, 4 M) (g, 8.80 mmol) was stirred at 25°C for 16 hours. The precipitate was filtered and dried under vacuum. Intermediate R (2.5 g, HCl salt) was obtained as a yellow solid. LCMS (AM3): rt = 0.501 min, (354.9 [M+H] + ), purity 96.1%. Synthesis of intermediate O Benzyl 3-(4-((tert-butoxycarbonyl)amino)butoxy)azetidine -1-carboxylate 1.493

[0359] [ka] 4-((tert-butoxycarbonyl)amino)butyl 4-methylbenzene sulfone (77.3g, 225.08mmol)(Journal of Medicina l Chemistry, 2006, 49(14), 4183-4195), benzyl 3 -Hydroxyazetidine-1-carboxylate (31.09g, 150.05mmol) ), TBAI (13.86g, 37.51 mmol) toluene (500mL) and water NaOH (60.02 g, 1.50 mol) was added to the mixture in (100 mL). The mixture was heated to 60°C and stirred for 12 hours. The mixture was diluted with water (1L) and MTBE(20 Extraction was performed using 0 mL x 3. The combined organic layer was washed with brine (200 mL) and Na2S The residue was dehydrated with O4 and concentrated under vacuum. The residue was purified (PM2) to obtain compound 1.493 (43). 5g was obtained, with a yield of 76.6%. 1 H NMR (400 MHz, CHCl3-d) δ: 7.35-7.26 (m, 5H), 5.07 (s, 2H), 4.74 (br s, 1H), 4.23-4.17 (m, 1H), 4.14-4.07 (m, 2H), 3.88-3.85 (m, 2H), 3.34 (t, J = 5.6 Hz, 2H ), 3.12-3.08 (m, 2H), 1.61-1.48 (m, 4H), 1.41 (s, 9H) ppm. tert-butyl(4-(azetidine-3-yloxy)butyl)carbamate 1.49 4

[0360] [ka] Compound 1.493 (43.5g, 114.94 mmol) in MeOH (500mL) To the solution, 10% carbon-supported palladium (5g) was added under nitrogen protection at 20°C. The reaction mixture was then prepared. The mixture was degassed three times and purged with hydrogen. The mixture was hydrogenated at 20°C under 1 atm of H2 for 12 hours. The mixture was filtered and concentrated under vacuum to obtain compound 1.494 (26.37 g, yield 93.9%). The substance was obtained as a pale yellow oily material and used without further purification. 1 H NMR (400 MHz, CHCl3-d) δ: 4.89 (br s, 1H), 4.26-4.19 (m, 1H), 3.67-3.65 (m, 2H), 3.55 (t, J = 5.6 Hz, 2H), 3.28 (t, J = 6.0 Hz, 2H), 3.10-3.00 (m, 2H), 1.55 -1.45 (m, 4H), 1.37 (s, 9H) ppm. Methyl 5-(3-(4-((tert-butoxycarbonyl)amino)butoxy)azeti Zin-1-yl)benzo[c][2,6]naphthyridine-8-carboxylate 1.49 5

[0361] [ka] Compound 1.1 (9.5g, 34.84 mmol) and Compound 1.494 (11.07 A solution of 45.29 mmol of DIPEA (g) in DMSO (200 mL) is prepared by adding DIPEA (22.51 (g, 174.19 mmol) was added. The mixture was heated to 80°C and stirred for 12 hours. The solution was poured into 600 mL of water and stirred for 10 minutes. The precipitate was filtered and dried under vacuum. Solidified, compound 1.495 (14.1g, 27.29 mmol, yield 78.3%) was yellow It was obtained as a solid. LCMS (AM3): rt = 0.839 min, (481.3 [M+H] + ), purity 93.3%. 5-(3-(4-((tert-butoxycarbonyl)amino)butoxy)azetidine- 1-yl)benzo[c][2,6]naphthyridine-8-carboxylic acid 1.496

[0362] [ka] Compound 1.495 (14.1g, 29.34 mmol) in THF (100mL), water ( A mixture of 100 mL of lithium hydroxide monohydrate (6.1 mL) and MeOH (50 mL) is added. 6g (146.71 mmol) was added, and the reaction mixture was heated to 50°C and stirred for 3 hours. The solvent was removed under reduced pressure, and the solution was acidified to pH 5 with a 1M HCl aqueous solution. The precipitate was collected by filtration. The excess cake was washed with water and vacuum dried to obtain compound 1.496 (15.6g) as a yellow solid. I obtained it. LCMS (AM3): rt = 0.813 min, (467.3 [M+H] + ), purity 98.7%. 5-(3-(4-aminobutoxy)azetidine-1-yl)benzo[c][2,6]naph Tyridine-8-carboxylic acid; intermediate O

[0363] [ka] Compound 1.496 (7.6g) in a HCl solution of dioxane (80.07 mL, 4 M) The mixture (16.29 mmol) was stirred at 20°C for 1 hour. The mixture was concentrated under vacuum to obtain the intermediate. O (6.9 g, HCl salt) was obtained as a yellow solid. LCMS (AM5): rt = 0.737 min, (367.2 [M+H] + ), purity 99.3%. Synthesis of intermediate P tert-butyl(4-((1-(8-carbamoylbenzo[c][2,6]naphthilidi (5-yl)azetidine-3-yl)oxy)butyl)carbamate 1.497

[0364] [ka] Compound 1.496 (8g, 17.15mmol), HATU (15.65g, 20.5 DMF (100ml) of 8 mmol) and DIPEA (6.65g, 51.44 mmol) NH4Cl (917.27 mg, 17.15 mmol) was added to the solution in (L). The mixture was stirred at 20°C for 12 hours. The mixture was poured into water (200 mL) and EA ( Extraction was performed using 100 mL x 2. The combined organic phase was washed with brine (100 mL) and Na Dehydrated with 2SO4 and concentrated under vacuum. The residue was purified (PM22) to obtain compound 1.497( 6.6 g, 14.05 mmol, yielded as a yellow solid (81.9%). LCMS (AM3): rt = 0.793 min, (466.3 [M+H] + ), purity 99.2%. 5-(3-(4-aminobutoxy)azetidine-1-yl)benzo[c][2,6]naph Tyridine-8-carboxamide; intermediate P

[0365] [ka] Compound 1.497 (6.6) in HCl solution of 1,4-dioxane (35 mL, 4 M) The mixture (g, 14.18 mmol) was stirred at 20°C for 1 hour. The mixture was concentrated under vacuum to obtain the intermediate solution. Form P (5.5 g, HCl salt) was obtained as a yellow solid. LCMS (AM5): rt = 0.690 min, (366.2 [M+H] + ), purity 92.4% Synthesis of intermediate 1.32 3-Chloro-4-cyclobutoxybenzaldehyde 1.32

[0366] [ka] Bromocyclobutane (0.25 mL, 2.65 mmol), 3-chloro-4-hydrox Cibenzaldehyde (200 mg, 1.28 mmol) and potassium carbonate (440 mg) The mixture (3.18 mmol) in DMF (10 mL) was stirred at 80°C for 15 hours. Pour the solution into water (60 mL), and extract the resulting mixture with EA (20 mL x 3). The combined organic phase was washed with brine (30 mL), dehydrated with anhydrous Na2SO4, and filtered. The mixture was then concentrated under vacuum to obtain the crude product, which was purified (PM11) to obtain compound 1.32(1 34 mg was obtained as a colorless oily substance with a yield of 49.8%. LCMS (AM1): rt = 0.969 min, (211.0 [M+H] + ), purity 66.6%. Synthesis of intermediate 1.33 3-Chloro-4-(cyclopentyloxy)benzaldehyde 1.33

[0367] [ka] Bromocyclopentane (0.274 mL, 2.56 mmol), 3-chloro-4-hydr Roxybenzaldehyde (200 mg, 1.28 mmol) and potassium carbonate (44 Mixture (1 mg, 3.19 mmol) in DMF (10 mL) and stir at 80°C for 15 hours. The reaction mixture was poured into water (60 mL), and the resulting mixture was divided into three EA (20 mL x 3) units. Extraction was performed using [method]. The combined organic phase was washed with brine (30 mL) and dehydrated with anhydrous Na2SO4. The product was filtered and concentrated under vacuum. The crude product was purified (PM11) to obtain compound 1.33(27 0 mg was obtained as a colorless oil with a yield of 93.9%. LCMS (AM3): rt = 1.017 min, (266.0 [M+H2O+Na] + ), purity 96.9%. Synthesis of intermediate 1.47 3-Bromo-4-cyclobutoxybenzaldehyde 1.46

[0368] [ka] 3-bromo-4-hydroxybenzaldehyde (1.0 g, 4.97 mmol) and A mixture of bromocyclobutane (1.01 g, 7.46 mmol) in DMF (10 mL) Potassium carbonate (2.06 g, 14.92 mmol) was added at room temperature. The resulting mixture The mixture was heated to 80°C and stirred for 12 hours. The reaction mixture was concentrated under vacuum to obtain the residue, which was then diluted with water. Poured into 10 mL and extracted with EA (50 mL x 3). The combined organic phase was brined. Washed with (50 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified. PM4) Compound 1.46 (1.0g, 3.80 mmol, yield 76.4%, purity 9) 7% was obtained as a yellow solid. LCMS (AM3): rt = 0.983 min, (257.0 [M+H] + ), purity 86.62%. 1 H NMR (400 MHz, MeOD-d4) δ: 9.79 (s, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 2.0, 8.5 Hz, 1H), 7.03 (d, J = 8.6 Hz, 1H), 4.93-4.85 (m, 1H), 2.61-2.48 (m, 2H), 2.29-2.14 (m, 2H), 1.99-1.65 (m, 2H) ppm. 2-Cyclobutoxy-5-formylbenzonitrile 1.47

[0369] [ka] Compound 1.46 (200 mg, 783.98 μmol) in a mixture of DMF (1 mL) Under nitrogen protection at 25°C, zinc cyanide (460.32 mg, 3.92 mmol) and tetracycline were used. Lax(triphenylphosphine)palladium (90.59 mg, 78.40 μmol) The following were added sequentially. The reaction mixture was then heated to 100°C and stirred for 12 hours. The mixture was then vacuum-sealed. The compound was concentrated and purified (PM38) to obtain compound 1.47 (80 mg, 397.57 μmol). A white solid was obtained with a yield of 50.7% and a purity of 100%. LCMS (AM3): rt = 0.885 min, (202.0 [M+H] + ), purity 100.0%. 1 H NMR (400 MHz, CHCl3-d) δ: 9.88 (s, 1H), 8.09 (d, J = 2.0 Hz, 1H), 8.03 (dd, J = 2.0, 8.8 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 4.88-4.81 (m, 1H), 2.59-2.49 (m, 2H), 2.38-2.28 (m, 2H), 2.03-1.91 (m, 1H), 1.85-1.73 (m, 1H) ppm. Synthesis of intermediate 1.52 2-Cyclopropyl-5-formylbenzonitrile 1.52

[0370] [ka] Cyclopropylboronic acid (122.69 mg, 1.43 mmol) and 2-bromo 1,4-dioxa 5-formylbenzonitrile (200 mg, 952.26 μmol) A mixture of fermented milk (1 mL) and water (0.1 mL) is subjected to fermentation of Pd (dppf) at 25°C under nitrogen protection. Cl2·CH2Cl2 (77.77 mg, 95.23 μmol) and potassium carbonate (2 63.22 mg (1.90 mmol) was added sequentially. The mixture was heated to 90°C for 12 hours. The mixture was stirred. The mixture was concentrated under vacuum and subjected to preparative TLC (SiO2, PE:EA=3:1). After purification, compound 1.52 (100 mg, 566.61 μmol, yield 59.5%, purity) was obtained. 97% was obtained as a white solid. LCMS (AM3): rt = 0.808 min, (172.2 [M+H] + ), purity 97.81%. 1 H NMR (400 MHz, CHCl3-d) δ: 9.96 (s, 1H), 8.09 (d, J = 1.6 Hz, 1H), 7.97 (dd, J = 1.6, 8.4 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 2.40 (m, 1H), 1.31-1.30 (m, 2H), 0.95–0.93 (m, 2H) ppm. Synthesis of intermediate 1.90 3-Chloro-4-cyclopropoxybenzaldehyde 1.90

[0371] [ka] 3-Chloro-4-fluorobenzaldehyde (1.8g, 11.35mmol) Potassium carbonate (2.35g, 17.03m) is dissolved in cetonitrile (20mL) at 25°C. (mol) and cyclopropanol (725.27 mg, 12.49 mmol) were added. The reaction mixture was heated to 80°C and stirred for 12 hours. The reaction mixture was filtered and concentrated under vacuum. The residue was purified (PM11), and compound 1.90 (120 mg, 610.28 μmol) was obtained. A yellow oily substance was obtained with a yield of 5%. 1 H NMR (400 MHz, CHCl3-d) δ: 9.87 (s, 1H), 7.90 (d, J = 2.1 Hz, 1H), 7.79 (dd, J = 2.0, 8.5 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 3.94-3.87 (m, 1H), 0.92 (d, J = 4.5 Hz (4H) ppm. Synthesis of intermediate 1.102 3-Chloro-5-(hydroxymethyl)benzaldehyde, 1.102

[0372] [ka] (3-Bromo-5-chlorophenyl)methanol (2g, 9.03 mmol) and In THF (20 mL) of TMEDA (2.10 g, 18.05 mmol, 2.72 mL) To the mixture, n-BuLi (2.4 M, 7.53 mL) was added dropwise at -78°C, and then obtained The mixture was heated to -20°C and stirred for 1 hour. The reaction mixture was then cooled again to -78°C. Then, 10 mL of DMF was added. The resulting mixture was heated to 20°C and stirred separately for 1 hour. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride (100 mL), and EA (20 Extraction was performed using 3 mL of solution. The combined organic layers were washed with brine (10 mL) and Na2SO4. The mixture was dehydrated, filtered, and concentrated under vacuum. The residue was purified (PM2) to obtain compound 1.102(4 00 mg, 2.34 mmol, yield 26% was obtained as a yellow oily substance. 1H NMR (400 MHz, CHCl3-d) δ: 9.99 (s, 1H), 7.78 (m, 2H), 7.65 (s, 1H), 4.80 (d, J = 4.6 Hz, 2H) pm. Synthesis of intermediate 1.134 2-(3-(hydroxymethyl)phenyl)acetonitrile 1.133

[0373] [ka] Methyl 3-(cyanomethyl)benzoate (1.5g, 8.56 mmol) THF( In a 15 mL solution, add LiBH4 (2M, 12.84 mL, 25.69 mmol) at ambient temperature. l) was added. The reaction mixture was then heated to 70°C and stirred for 4 hours. The mixture was cooled to room temperature. Instead, the solution was quenched with HCl aqueous solution (1N, 50 mL) and extracted with EA (20 mL x 3). The combined organic phases were washed with brine (50 mL), dehydrated with anhydrous Na2SO4, and concentrated under vacuum. It shrunk. The residue was purified (PM6) to obtain compound 1.133 (1.0g, 6.79 mmol). A yield of 79.3% was obtained as a colorless oil. 1 H NMR (400 MHz, CHCl3-d) δ: 7.35-7.18 (m, 4H), 4.65 (s, 2H), 3.68 (s, 2H) ppm. 2-(3-formylphenyl)acetonitrile 1.134

[0374] [ka] A solution of compound 1.133 (500 mg, 3.40 mmol) in DCM (20 mL) was prepared. At 30°C, manganese(IV) oxide (2.95 g, 33.97 mmol) was added. The reaction was mixed. The mixture was stirred at 30°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. Prepared (PM6), compound 1.134 (50 mg, 344.45 μmol, yield 10.1) %) was obtained as a yellow oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 10.05 (s, 1H), 7.89-7.87 (m, 2H), 7.67-7.57 (m, 2H ), 3.86 (s, 2H) ppm. Synthesis of intermediate 1.136 5-Formyl-2-(trifluoromethoxy)benzonitrile 1.136

[0375] [ka] 3-Bromo-4-(trifluoromethoxy)benzaldehyde (500mg, 1.86 In a solution of mmol) in DMF (15 mL), add zinc cyanide (0.82 g, 6.5 mL) at ambient temperature. 98 mmol) and tetrakis(triphenylphosphine)palladium (214.78 (mg, 185.86 μmol) was added. The reaction mixture was then heated to 100°C and stored under nitrogen. The mixture was stirred under air for 12 hours. The mixture was cooled to room temperature and poured into water (50 mL). The mixture was extracted with EA (20 mL x 3). The combined organic phase was washed with brine (50 mL). The solution was then dehydrated with anhydrous Na2SO4 and concentrated under vacuum. The resulting residue was purified (PM12). Compound 1.136 (170 mg, 790.23 μmol, yield 42.5%) was extracted into a brownish oil. It was obtained as a substance. 1 H NMR (400 MHz, CHCl3-d) δ: 10.03 (s, 1H), 8.25 (d, J = 1.4 Hz, 1H), 8.19 (dd, J = 8.4, 1.4 Hz, 1H), 7.58 (dd, J = 8.4, 1.8 Hz, 1H) ppm. Synthesis of intermediate 1.153 Methyl 5-bromo-2-(trifluoromethoxy)benzoate, 1.150

[0376] [ka] M of 5-bromo-2-(trifluoromethoxy)benzoic acid (2g, 7.02 mmol) Dissolve SOCl2 (1.67g, 14.03 mmol) in ice-cold solution in eOH (20 mL). The mixture was added slowly. The resulting mixture was heated to 70°C and stirred for 1 hour. The mixture was concentrated under vacuum. The resulting residue was diluted with EA (100 mL). The organic phase was then diluted with sodium bicarbonate (50 mL). Wash with L) and brine (50 mL), dehydrate with Na2SO4, concentrate under vacuum, and chemically. A mixture of 1.150 ml (2.9 g) was obtained as a yellow oily substance, which was used directly without further purification. did. 1 H NMR (400 MHz, CHCl3-d) δ: 8.09 (d, J = 2.6 Hz, 1H), 7.68 (dd, J = 2.5, 8.7 H z, 1H), 7.22 (dd, J = 1.0, 8.7 Hz, 1H), 3.95 (s, 3H) ppm. (5-Bromo-2-(trifluoromethoxy)phenyl)methanol, 1.151

[0377] [ka] A solution of compound 1.150 (2.9 g, 9.70 mmol) in THF (20 mL) was added with nitrogen. LiAlH4 (368.07 mg, 9.70 mmol) was added at sub-zero temperature. Mixture 2 The mixture was heated to 0°C and stirred for 1 hour. The mixture was cooled to 0°C and diluted with EA (10 mL). Next, the resulting mixture was diluted with water (0.2 mL), followed by a 10% NaOH aqueous solution (0.2 mL) Quenched by adding ) and water (0.6 mL). Anhydrous Na2SO4 (5 g) was added. The resulting suspension was stirred separately for 0.5 hours and then filtered. The filtrate was concentrated under vacuum and chemically processed. A compound of 1.151 (2.23 g, 8.23 ​​mmol, yield 84.8%) was obtained as a white solid. This was used directly without further purification. LCMS (AM3): rt = 0.801 min, (290.3 [M+NH4] + ), purity 85.1%. (2-(trifluoromethoxy)-5-vinylphenyl)methanol, 1.152

[0378] [ka] Compound 1.151 (2.23 g, 8.23 ​​mmol) and tributyl (vinyl) sta In a solution of nanan (2.61 g, 8.23 ​​mmol) in toluene (50 mL), under nitrogen protection... Pd(PPh3)4 (665.54 mg, 575.95 μmol) was added at ambient temperature. The mixture was heated to 95°C and stirred for 12 hours. The residue was then placed in saturated KF aqueous solution (100 mL). The mixture was poured in, stirred for 15 minutes, and then extracted with EA (50 mL x 3). The combined organic phases were washed with brine (100 mL x 3), dried with anhydrous sodium 2SO4, and filtered. The mixture was then concentrated under vacuum. The residue was purified (PM7) to obtain compound 1.152 (1.43g, 6 0.55 mmol, yielding 79.7%, was obtained as a yellow oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 7.49 (d, J = 2.2 Hz, 1H), 7.26 (dd, J = 2.2, 8.4 H z, 1H), 7.10-7.08 (dd, 1H), 6.61 (dd, J = 10.9, 17.6 Hz, 1H), 5.67 (d, J = 17.6 Hz, 1H), 5.21 (d, J = 10.9 Hz, 1H), 4.67 (s, 2H), 2.12-2.04 (br s, 1H) ppm. 3-(hydroxymethyl)-4-(trifluoromethoxy)benzaldehyde, 1.15 3

[0379] [ka] Ozone was added to the mixture at -70°C until the mixture turned blue. Compound 1.152 (500 mg, 2 It was then bubbling into a solution of 0.29 mmol) in DCM (10 mL). Dimethyl sulfate (1 (0.42g, 22.92 mmol) was added. The mixture was heated to 20°C and stirred for 12 hours. The mixture was concentrated under vacuum and purified (PM7) to obtain compound 1.153 (326 mg, 1 0.48 mmol, yielding 64.6%, was obtained as a pale yellow oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 9.93 (s, 1H), 8.06 (d, 1H), 7.79 (dd, J = 2.1, 8.5 Hz, 1H), 7.31 (dd, J = 1.8, 8.4 Hz, 1H), 4.77 (s, 2H), 2.40 (br s, 1H) ppm. Synthesis of intermediate 1.202 3-Chloro-4-cyclopropylbenzaldehyde 1.202

[0380] [ka] Cyclopropylboronic acid (156 mg, 1.82 mmol) 1,4-dioxane (8 Mixture of (mL) and water (2mL) is heated at ambient temperature with 4-bromo-3-chlorobenzal Dehyde (200 mg, 0.911 mmol) was added, followed by K2CO3 (315 mg, 2 Add 0.28 mmol) and Pd(dppf)Cl2 (66 mg, 0.090 mmol). The mixture was degassed three times, purged with nitrogen, then heated to 80°C and stirred for 14 hours. Mixed. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified (PM11) and chemically processed. A mixture of 1.202 ml (130 mg, yield 79%) was obtained as a colorless oil. 1 H NMR (400 MHz, MeOH-d4) δ: 9.89 (s, 1H), 7.87 (d, J = 1.6 Hz, 1H), 7.73 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 2.35-2.29 (m, 1H), 1.18-1.12 (m, 2H), 0.84-0.80 (m, 2H) ppm. Synthesis of intermediate 1.345 2-Chloro-2'-(hydroxymethyl)-[1,1'-biphenyl]-4-carbard Hid, 1.345

[0381] [ka] (2-(hydroxymethyl)phenyl)boronic acid (250 mg, 1.65 mmol), 4-bromo-3-chlorobenzaldehyde (361 mg, 1.64 mmol) and K2 CO3 (569 mg, 4.12 mmol) with 1,4-dioxane (8 mL) and water (2 In a mL mixture, Pd(dppf)Cl2·CH2Cl2 (67 mg, 0.082 mm) (ol) was added. The reaction mixture was degassed three times and purged with nitrogen, then the reaction mixture was heated to 80°C. The mixture was heated and stirred for 17 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified (P M6) Compound 1.345 (400 mg, yield 98.6%) was obtained as a colorless oil. . 1 H NMR (400 MHz, DMSO-d6) δ: 10.05 (s, 1H), 8.07 (d, J = 1.6 Hz, 1H), 7.92 (dd, J = 1.6 Hz, 8.0 Hz, 1H), 7.61 (dd, J = 0.8 Hz, 7.6 Hz, 1H), 7.55 (d, J = 7.6 Hz , 1H), 7.47-7.44 (t, 1H), 7.38-7.34 (t, 1H), 7.14 (dd, J = 1.2 Hz, 7.6 Hz, 1H), 5.12 (t, J = 5.6 Hz, 1H), 4.30-4.15 (qd, 2H) ppm. Synthesis of intermediate 1.366 2-(3-chloro-5-vinylphenyl)acetonitrile 1.365

[0382] [ka] 2-(3-bromo-5-chlorophenyl)acetonitrile (500 mg, 1.08 mm) ol)(US2008221127A1), Tributyl (vinyl) stannan (343. 94 mg, 1.08 mmol) and Pd(PPh3)4 (125 mg, 1.08 μmol) The mixture was stirred in toluene (10 mL) at 90°C for 15 hours. The mixture was saturated with KF. The solution was poured into an aqueous solution (100 mL), and then extracted with EA (100 mL x 2). The organic phase was washed with brine (50 mL), dehydrated with Na2SO4, and concentrated. The residue was then purified. The compound was prepared (PM14) to obtain 1.365 (200 mg) of compound as a yellow oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 7.37 (s, 1H), 7.23 (d, J = 6.0 Hz, 2H), 6.69-6.62 (dd, 1H), 5.82 (d, J = 12 Hz, 1H), 5.40 (d, J = 16.4 Hz, 1H), 3.74 (s, 2H) ppm. 2-(3-chloro-5-formylphenyl)acetonitrile 1.366

[0383] [ka] Add compound 1.365 (200 mg, 1.13 mmol) until the reaction mixture turns blue. To the solution in DCM (20 mL), ozone was blown in at -78°C for 0.5 hours, followed by DM S (3.66 g, 58.91 mmol) was slowly added to the above mixture at -78°C. Reaction The mixture was heated to 20°C and stirred separately for 12 hours. The reaction mixture was concentrated under vacuum, and the residue was removed. The compound was purified (PM7) to obtain compound 1.366 (150 mg, 835.18 μmol, yield 7 4.2% was obtained as a white solid. 1 H NMR (400 MHz, CHCl3-d) δ: 9.99 (s, 1H), 7.84 (t, J = 1.6 Hz, 1H), 7.75 (d, J = 1.6 Hz, 1H), 7.62 (t, J = 1.2 Hz, 1H), 3.84 (s, 2H) ppm. Synthesis of intermediate 1.402 2-(5-bromo-2-(trifluoromethoxy)phenoxy)ethanol 1.401

[0384] [ka] 5-Bromo-2-(trifluoromethoxy)phenol (900 mg, 3.5 mmol) ), 2-bromoethanol (0.63 mL, 8.87 mmol) and K2CO3 (1. A mixture of 21g (8.73 mmol) acetonitrile (18 mL) is heated to 80°C. The mixture was stirred for 15 hours. The reaction mixture was concentrated under vacuum, and the residue was purified (PM6) to obtain compound 1. 0.401 (850 mg, yield 80.6%) was obtained as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) δ: 7.48 (d, J = 2.4 Hz, 1H), 7.32 (dd, J = 8.8 Hz, 1. 2 Hz, 1H), 7.2 (dd, J = 8.8 Hz, 2.4Hz, 1H), 4.90 (t, J = 5.2 Hz, 1H), 4.12 (t, J = 4.8 Hz, 2H), 3.71 (q, J = 5.2 Hz, 2H) ppm. 3-(2-hydroxyethoxy)-4-(trifluoromethoxy)benzaldehyde 1. 402

[0385] [ka] Compound 1.401 (650 mg, 2.16 mmol), DMF (315 mg, 4.32 ( mmol) and TMEDA (500 mg, 4.31 mmol) in THF (20 mL) To the mixture, n-BuLi (1.76 mL, 2.5 M in hexane) was added at -70°C. The mixture was stirred at -70°C for 1 hour, then heated to 25°C and stirred again for 1 hour. The reaction mixture was quenched by adding water (1 mL), and EA (50 mL x 2) was prepared. Extraction was performed using [method]. The combined organic phase was washed with brine (30 mL) and dehydrated with Na2SO4. The compound was concentrated under vacuum. The residue was purified (PM47) to obtain compound 1.402 (48 mg, yield 6%). ) was obtained as a yellow oily substance. LCMS (AM2): rt = 0.739 min, (251.1 [M+H] + ), purity 66.6%. Synthesis of intermediate 1.406 Methyl 3-(2-hydroxyethoxy)-4-(trifluoromethyl)benzoate 1. 404

[0386] [ka] Methyl 3-hydroxy-4-(trifluoromethyl)benzoate (1.1g, 5.0 0mmol)(Journal of Medicinal Chemistry,20 05,48(9),3290-3312), 2-bromoethanol (0.71 mL, 10 DMF (15 mL) of mmol) and K2CO3 (1.39 g, 10.03 mmol) The mixture was stirred at 80°C for 16 hours. The reaction mixture was filtered, and the filtrate was mixed with water (100 mL). Pour the mixture into the container and extract with EA (50 mL x 2). Combine the organic phases and use brine (30 mL The residue was washed with ( ), dehydrated with Na2SO4, and concentrated under vacuum. The residue was purified (PM47) and chemically processed. A mixture of 1.404 mg (850 mg, yield 64.4%) was obtained as a brownish oily substance. LCMS (AM2): rt = 0.779 min, (286.9 [M+Na] + ), 100% pure. 2-(5-(hydroxymethyl)-2-(trifluoromethyl)phenoxy)ethanol 1.405

[0387] [ka] A mixture of LAH (345 mg, 9.09 mmol) in THF (15 mL) was heated at 0°C. Compound 1.404 (800 mg, 3.03 mmol) was added to HF (5 mL). Next... The reaction mixture was then warmed to room temperature and stirred for 2 hours. Water (0.4 mL) was added to the reaction mixture, followed by Na Quenched by adding 0.4 mL of OH aqueous solution (10%) and water (1.2 mL), then 0. After stirring for 5 hours, add Na2SO4, stir the resulting suspension separately for 30 minutes, and filter. The filtrate was concentrated under vacuum to obtain compound 1.405 (600 mg) as a brownish oily substance. It was used directly without further purification. 1 H NMR (400 MHz, DMSO-d6) δ: 7.54 (d, J = 8.0 Hz. 1H), 7.19 (s, 1H), 7.02 (d, J = 8.0 Hz, 1H), 5.41 (br, s, 1H), 4.86 (br, s, 1H), 4.55 (s, 2H), 4.10 (t, J = 5 .2 Hz, 2H), 3.73 (t, J = 5.2 Hz, 2H) ppm. 3-(2-hydroxyethoxy)-4-(trifluoromethyl)benzaldehyde 1.4 06

[0388] [ka] Compound 1.405 (550 mg, 2.33 mmol) and manganese(IV)(2 Mix the 0.02g (23.28 mmol) solution in 20mL of DCM and stir at room temperature for 20 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The crude product was purified (PM5) and chemically prepared. A mixture of 1.406 (380 mg, yield 59.2%) was obtained as a brownish oily substance. 1 H NMR (400 MHz, DMSO-d6) δ: 10.08 (s, 1H), 7.86 (d, J = 8.0 Hz. 1H), 7.75 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 4.90 (t, J = 5.2 Hz, 1H), 4.24 (t, J = 5.2 Hz, 2H ), 3.76 (q, J = 5.2 Hz, 2H) ppm. Synthesis of intermediate 1.410 3-(2-hydroxyethoxy)-4-methoxybenzaldehyde 1.408

[0389] [ka] 3-Hydroxy-4-methoxybenzaldehyde (8.8g, 57.84mmol) , 2-bromoethanol (8 mL, 113 mmol) and K2CO3 (16 g, 116 A mixture of mmol) in acetonitrile (100 mL) was stirred at 80°C for 14 hours. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified (PM3) to obtain compound 1.40. 8 (7.8g, yield 66.7%) was obtained as a white solid. LCMS (AM3): rt = 0.778 min, (197.2 [M+H] + ), purity 97.2%. 4-Hydroxy-3-(2-hydroxyethoxy)benzaldehyde 1.409

[0390] [ka] A solution of compound 1.408 (7.7 g, 39.25 mmol) in DCM (200 mL) Then, AlCl3 (26.18 g, 196.34 mmol) was added at room temperature. The reaction mixture was then heated in the room. The mixture was stirred at warm temperature for 15 hours. The reaction mixture was poured into water (300 mL) at 0°C, and DCM and M were added. Extraction was performed with a solvent mixture of eOH (volume / volume = 10:1, 50 mL x 10). The organic phase was washed with brine (400 mL), dehydrated with anhydrous Na2SO4, filtered, and then vacuum-filtered. The compound was concentrated. The residue was purified (PM2) to obtain compound 1.409 (5.3g, yield 74.1%). It was obtained as a yellow solid. LCMS (AM3): rt = 0.699 min, (183.2 [M+H] +), purity 97.9%. 4-Cyclobutoxy-3-(2-hydroxyethoxy)benzaldehyde 1.410

[0391] [ka] Compound 1.409 (200 mg, 1.10 mmol), Bromocyclobutane (296 mg) DMF (g, 2.19 mmol) and K2CO3 (378 mg, 2.73 mmol) The mixture in 10 mL was stirred at 100°C for 24 hours. The reaction mixture was then added to water (30 mL). The mixture was poured in and extracted with EA (10 mL x 5). The combined organic phase was then bleached. The residue was washed with 50 mL of water, dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. After purification (PM4), compound 1.410 (250 mg, yield 96.4%) was obtained as a pale yellow oil. It was obtained as such. LCMS (AM3): rt = 0.805 min, (237.6 [M+H] + ), purity 98.5%. Synthesis of intermediate 1.412 4-Chloro-3-(2-hydroxyethoxy)benzaldehyde, 1.412

[0392] [ka] 4-Chloro-3-hydroxybenzaldehyde (200 mg, 1.28 mmol), 2-Bromoethanol (0.2 mL, 2.82 mmol) and K2CO3 (440 mg) The mixture in 3.18 mmol of acetonitrile (4 mL) was stirred at 80°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified (PM6) to obtain compound 1. 0.412 (240 mg, yield 93.6%) was obtained as a colorless oil. LCMS (AM3): rt = 0.723 min, (201.1 [M+H] + ), purity 93.4%. Synthesis of intermediate 1.469 1-Bromo-3-(chloromethyl)-5-(trifluoromethyl)benzene 1.466

[0393] [ka] (3-Bromo-5-(trifluoromethyl)phenyl)methanol (2g, 7.84m) In a solution of 1,4-dioxane (10 mL) at 0°C, add SOCl2 (1.87 g) (15.68 mmol) was added. The mixture was then heated to 90°C and stirred for 1 hour. The substance was concentrated under vacuum to obtain compound 1.466 (2g, crude product) as a black oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 7.75 (d, J = 1.0 Hz, 2H), 7.59 (s, 1H), 4.59 (s, 2 H) ppm. 2-(3-bromo-5-(trifluoromethyl)phenyl)acetonitrile 1.467

[0394] [ka] Trimethylsilanecarbonitride (870.62 mg, 8.78 mmol) and compound To a solution of 1.466 (2g, 7.31 mmol) of substance in acetonitrile (4mL), TBA F (8.78 mL, 8.78 mmol, 1 M in THF) was added. The mixture was incubated at 25°C for 12 minutes. The mixture was stirred for a certain amount of time. The mixture was concentrated under vacuum, and the residue was purified (PM14) to obtain compound 1.467. (1.48 g, 5.61 mmol, yield 76.6%) was obtained as a pale yellow oily substance. 1H NMR (400 MHz, CHCl3-d) δ: 7.77 (s, 1H), 7.72 (s, 1H), 7.55 (s, 1H), 3.83 (s, 2H) ppm. 2-(3-(trifluoromethyl)-5-vinylphenyl)acetonitrile 1.468

[0395] [ka] Compound 1.467 (1.38 g, 5.23 mmol) and 4,4,5,5-tetramethyl Chil-2-vinyl-1,3,2-dioxaborolane (1.21g, 7.84mmol, 1 In a solution of 0.33 mL of DME (20 mL), Pd(dppf)Cl2(382.42 mL) was added. (g, 522.64 μmol) and CsF (1.59 g, 10.45 mmol) were added. The mixture was heated to 80°C and stirred under nitrogen protection for 12 hours. The reaction mixture was then mixed with water (50 mL). Pour into the container and stir for 1 minute. Extract the aqueous phase with EA (30 mL x 3). Combined The phase was washed with brine (80 mL x 2), dried with anhydrous Na2SO4, filtered, and vacuum filtered. The compound was concentrated. The residue was purified (PM13) to obtain compound 1.468 (500 mg, 2.37 mm). ol was obtained as a red oily substance with a yield of 45.3%. 1 H NMR (400 MHz, CHCl3-d) δ: 7.63 (s, 1H), 7.56 (s, 1H), 7.47 (s, 1H), 6.75 (dd , J = 17.6, 11.2 Hz, 1H), 5.88 (d, J = 17.6 Hz, 1H), 5.45 (d, J = 11.2 Hz, 1H), 3.83 (s, 2H) ppm. 2-(3-formyl-5-(trifluoromethyl)phenyl)acetonitrile 1.469

[0396] [ka] Remove ozone from the mixture at -70°C until the mixture turns blue. Compound 1.468 (500 mg, 2 It was blown into a solution of 0.37 mmol) in DCM (10 mL). Excess ozone was purged. Then, DMS (1.47 g, 23.68 mmol) was added at -70°C. The mixture was then prepared. The mixture was heated to 20°C and stirred for 12 hours. The mixture was concentrated under vacuum and (PM7) was used to obtain compound 1. 0.469 (262 mg, 1.23 mmol, yield 51.9%) was obtained as a pale yellow oily substance. . 1 H NMR (400 MHz, CHCl3-d) δ: 10.10 (s, 1H), 8.14 (s, 1H), 8.08 (s, 1H), 7.88 (s , 1H), 3.95 (s, 2H) ppm. Synthesis of intermediate 1.472 2-(3-fluoro-5-vinylphenyl)acetonitrile 1.471

[0397] [ka] 2-(3-bromo-5-fluorophenyl)acetonitrile (1.6g, 7.48mm) Tor In a 30 mL solution of ene, Pd(PPh3)4 (604.68 mg, 523.28 μm) (ol) was added. The resulting mixture was heated to 95°C and stirred under nitrogen protection for 12 hours. The substance was poured into a saturated KF aqueous solution (100 mL) and stirred for 15 minutes. The aqueous phase was converted to EA(5 Extraction was performed using 0 mL x 3. The combined organic phase was washed with brine (100 mL x 3) and anhydrous solution was used. The residue was dried with Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM14) to obtain the compound. 1.471 (900 mg, 5.58 mmol, yield 74.6%) was obtained as a pale yellow oily substance. Ta. 1 H NMR (400 MHz, CHCl3-d) δ: 7.15 (s, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.66 (dd, J = 17.6, 10.8 Hz, 1H), 5.80 (d, J = 17.6 Hz, 1H), 5.3 8 (d, J = 10.8 Hz, 1H), 3.75 (s, 2H) ppm. 2-(3-fluoro-5-formylphenyl)acetonitrile 1.472

[0398] [ka] Add ozone at -70°C until the reaction mixture turns blue, then add compound 1.471 (500 mg) It was blown into a solution of 3.10 mmol) in DCM (10 mL). Excess ozone was removed. After mixing, DMS (1.93g, 31.02 mmol) was added. The mixture was allowed to cool to 20°C. The mixture was heated and stirred for 12 hours. The mixture was concentrated under vacuum, and the residue was purified (PM7) to obtain the compound. 1.472 (390 mg, 2.39 mmol, yield 77.1%) was obtained as a pale yellow oily substance. Ta. 1 H NMR (400 MHz, CHCl3-d) δ: 10.09 (s, 1H), 7.68 (s, 1H), 7.56 (dd, J = 8.4, 1. 2 Hz, 1H), 7.36 (dd, J = 8.4, 1.2 Hz, 1H), 3.87 (s, 2H) ppm. Synthesis of intermediate 1.475 2-(3-methyl-5-vinylphenyl)acetonitrile 1.474

[0399] [ka] 2-(3-bromo-5-methylphenyl)acetonitrile (1.6g, 7.62mO) l) and tributyl(vinyl) stannane (2.42g, 7.62mmol) In a 30 mL solution, Pd(PPh3)4 (616.09 mg, 533.16 μmol) l) was added. The mixture was heated to 95°C and stirred under nitrogen protection for 12 hours. The mixture was saturated with K Pour the aqueous phase into 100 mL of aqueous solution F and stir for 15 minutes. The aqueous phase was then mixed with EA (50 mL x 3 Extraction was performed using ). The combined organic phase was washed with brine (100 mL x 3) and anhydrous sodium 2SO4. The mixture was dried in 4, filtered, and concentrated under vacuum. The residue was purified (PM14) to obtain compound 1.474. (820 mg, 5.22 mmol, yield 68.5%) was obtained as a yellow oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 7.19 (s, 1H), 7.16 (s, 1H), 7.05 (s, 1H), 6.68 (dd , J = 17.6, 10.8 Hz, 1H), 5.77 (d, J = 17.6 Hz, 1H), 5.29 (d, J = 10.8 Hz, 1H), 3.72 (s, 2H), 2.37 (s, 3H) ppm. 2-(3-formyl-5-methylphenyl)acetonitrile 1.475

[0400] [ka] Add compound 1.474 (500 mg) to the reaction mixture at -70°C until the mixture turns blue. It was blown into a solution of 3.18 mmol) in DCM (10 mL). Excess ozone was removed. After mixing, DMS (1.98 g, 31.80 mmol) was added. The reaction mixture was then allowed to cool to 20°C. The mixture was heated and stirred for 12 hours. The mixture was concentrated under vacuum and purified (PM7) to obtain compound 1.4 75 (320 mg, 2.01 mmol, yield 63.2%) was obtained as a pale yellow oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 10.00 (s, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.45 (s, 1H), 3.81 (s, 2H), 2.47 (s, 3H) ppm. Synthesis of intermediate 1.478 2-(2-chloro-5-vinylphenyl)acetonitrile 1.477

[0401] [ka] 2-(5-bromo-2-chlorophenyl)acetonitrile (1.4g, 6.07mmo) l) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane Pd(dppf)C in a solution of (1.40g, 9.11 mmol) in DME (20 mL) l2 (444.44 mg, 607.40 μmol) and CsF (1.85 g, 12.1 (5 mmol) was added. The reaction mixture was heated to 80°C and stirred under nitrogen protection for 12 hours. The mixture was poured into water (50 mL), and the aqueous phase was extracted with EA (30 mL x 3). The organic phase was washed with brine (80 mL x 2), dried with anhydrous Na2SO4, filtered, and then... Concentrated in an empty container. The residue was purified (PM17) to obtain compound 1.477 (600 mg, 3.38 mmol (55.6% yield) was obtained as a pale yellow oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 7.43 (s, 1H), 7.25 (m, 1H), 7.24-7.21 (m, 1H), 6.5 9 (dd, J = 17.6, 10.8, Hz, 1H), 5.70 (d, J = 17.6 Hz, 1H), 5.25 (d, J = 10.8 Hz, 1H), 3.74 (s, 2H) ppm. 2-(2-chloro-5-formylphenyl)acetonitrile 1.478

[0402] [ka] Add ozone at -70°C until the reaction mixture turns blue, then add compound 1.477 (400 mg) It was blown into a solution of 2.25 mmol) of DCM (10 mL). Excess ozone was removed. After mixing, DMS (1.40 g, 22.52 mmol) was added. The reaction mixture was then heated to 20°C. The mixture was heated to a certain temperature and stirred for 12 hours. The mixture was concentrated under vacuum and purified (PM11) to obtain the compound. 1.478 (200 mg, 1.11 mmol, yield 49.5%) was obtained as a pale yellow solid. . 1 H NMR (400 MHz, CHCl3-d) δ: 10.03 (s, 1H), 8.05 (d, J = 1.6 Hz, 1H), 7.86 (dd, J = 8.4, 1.6 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 3.93 (s, 2H) ppm. Synthesis of intermediate 1.483 1-Bromo-2-chloro-3-(chloromethyl)benzene 1.480

[0403] [ka] (3-Bromo-2-chlorophenyl)methanol (1g, 4.52 mmol) 1,4 - In a 10 mL solution of dioxane, add SOCl2 (1.07 g, 9.03 mmol) at 0°C. ) was added. The reaction mixture was heated to 90°C and stirred for 1 hour. The mixture was concentrated under vacuum. Compound 1.480 (1 g) was obtained as a black oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 7.63 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.0, 1H), 7 .16 (t, J = 8.0 Hz, 1H), 4.74 (s, 2H) ppm. 2-(3-bromo-2-chlorophenyl)acetonitrile 1.481

[0404] [ka] Trimethylsilyl cyanide (516.86 mg, 5.21 mmol) and compound 1. In a solution of 480 (1g, 4.17 mmol) acetonitrile (20mL), at 25°C, T BAF (5.22 mL, 5.22 mmol, 1 M in THF) was added. The mixture was heated at 25°C. The mixture was stirred for 12 hours. The mixture was concentrated under vacuum, and the residue was purified (PM14) to obtain compound 1.4. 81 (837 mg, 3.63 mmol, yield 87.1%) was obtained as a white solid. 1 H NMR (400 MHz, CHCl3-d) δ: 7.66 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H) , 7.21 (t, J = 8.0 Hz, 1H), 3.90 (s, 2H) ppm. 2-(2-chloro-3-vinylphenyl)acetonitrile 1.482

[0405] [ka] Compound 1.481 (837 mg, 3.63 mmol) and 4,4,5,5-tetramethyl Chil-2-vinyl-1,3,2-dioxaborolane (838.93 mg, 5.45 mmol) l) In the solution in DME (10 mL), add CsF (1.10 g, 7.26 mmol) and P d(dppf)Cl2 (265.71 mg, 363.14 μmol) was added to the mixture. The mixture was heated to 80°C and stirred under nitrogen protection for 12 hours. The mixture was then poured into water (50 mL). The aqueous phase was extracted with EA (30 mL x 3). The combined organic phase was extracted with brine (80 mL x 2). The residue was washed, dried with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM12 Compound 1.482 (300 mg, 1.69 mmol, yield 46.5%) was then prepared as a pale yellow compound. It was obtained as an oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 7.58 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H) , 7.30 (t, J = 8.0 Hz, 1H), 7.12 (dd, J = 17.6, 12.0 Hz, 1H), 5.77 (d, J = 17.6 Hz, 1H), 5.45 (dd, J = 12.0 Hz, 1H), 3.87 (s, 2H) ppm. 2-(2-chloro-3-formylphenyl)acetonitrile 1.483

[0406] [ka] Add ozone at -70°C until the reaction mixture turns blue, then add compound 1.482 (300 mg) It was blown into a solution of 1.69 mmol) of DCM (10 mL). Excess ozone was removed. After mixing, DMS (1.05g, 16.89 mmol) was added. The mixture was left to stand at 20°C. The mixture was heated and stirred for 12 hours. The mixture was concentrated under vacuum and purified by (PM9) to obtain the compound. 1.483 (297 mg, 1.65 mmol, yield 97.9%) was obtained as a white solid. 1 H NMR (400 MHz, CHCl3-d) δ: 10.53 (s 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 3.94 (s, 2H) ppm. Synthesis of intermediate 1.485 (2-Chloro-3-vinylphenyl)methanol 1.484

[0407] [ka] Tributyl(vinyl) stannan (1.43g, 4.52 mmol) and (3-bro Mo-2-chlorophenyl)methanol (1.00 g, 4.52 mmol) with toluene (2 Add Pd(PPh3)4 (365.62 mg, 316.40 μmol) to a 0 mL solution. Added. The mixture was heated to 95°C and stirred under nitrogen protection for 12 hours. Reaction mixture saturated KF The solution was poured into 100 mL of aqueous solution and stirred for 1 hour. The aqueous phase was then divided into three EA (50 mL x 3) Extraction was performed. The combined organic phase was washed with brine (100 mL x 3) and then treated with anhydrous Na2SO4. The mixture was dried, filtered, and concentrated under vacuum. The residue was purified with (PM9) to obtain compound 1.484. (650 mg, 3.85 mmol, yield 85.3%) was obtained as a yellow oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 7.50 (dd, J = 8.0, 1.6 Hz, 1H), 7.40 (dd, J = 8.0, 1.6 Hz, 1H), 7.25-7.23 (m, 1H), 7.15 (dd, J = 17.6, 10.0 Hz, 1H), 5.72 (d, J = 17.6 Hz, 1H), 5.39 (d, J = 10.0 Hz, 1H), 4.78 (s, 2H), 2.04 (br s, 1H) ppm. 2-Chloro-3-(hydroxymethyl)benzaldehyde 1.485

[0408] [ka] Add ozone at -70°C until the reaction mixture turns blue, then add compound 1.484 (379.7 Excess ozone was blown into a solution of 1 mg (2.25 mmol) in DCM (10 mL). After purging, DMS (1.40 g, 22.52 mmol) was added. The mixture was then heated at 20°C. The mixture was heated to [temperature] and stirred for 12 hours. The mixture was concentrated under vacuum and purified using (PM9). Compound 1.485 (230 mg, 1.35 mmol, yield 59.9%) was prepared as a pale yellow solid. I obtained it. 1 H NMR (400 MHz, CHCl3-d) δ: 10.53 (s, 1H), 7.87 (dd, J = 7.6, 1.6 Hz, 1H), 7.7 9 (d, J = 7.6 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 4.88 (s, 2H), 2.22 (s, 1H) ppm. Synthesis of intermediate 1.488 (3-(trifluoromethoxy)-5-vinylphenyl)methanol

[0409] [ka] [3-Bromo-5-(trifluoromethoxy)phenyl]methanol (800 mg, 2 0.95 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-diole A solution of xaborolane (681.90 mg, 4.43 mmol) in DME (10 mL) Pd(dppf)Cl2 (215.98 mg, 295.17 μmol) and CsF(8 96.72 mg (5.90 mmol) was added. The mixture was heated to 80°C and sterilized under nitrogen protection. The mixture was stirred for 2 hours. The mixture was poured into water (50 mL) to form the aqueous phase EA (30 mL x 3). Extraction was performed using [method]. The combined organic phase was washed with brine (80 mL x 2) and then [method] with anhydrous Na2SO4. The mixture was dried, filtered, and concentrated under vacuum. The residue was purified (PM12) to obtain compound 1.487(6 00 mg was obtained as a colorless oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 7.38 (t, J = 8.0 Hz, 1H), 7.33 (s, 1H), 7.25 (s, 1 H), 6.69 (dd, J = 17.6, 10.8 Hz, 1H), 5.80 (d, J = 17.2 Hz, 1H), 5.35 (d, J = 10 0.8 Hz, 1H), 4.73 (s, 2H) ppm. 3-(hydroxymethyl)-5-(trifluoromethoxy)benzaldehyde 1.488

[0410] [ka] Remove ozone at -70°C until the reaction mixture turns blue, then add compound 1.487 (200 mg) The excess ozone was blown into a solution of 916.71 μmol in DCM (10 mL). After purging, DMS (569.55 mg, 9.17 mmol) was added. The mixture was then divided into 20 portions. The mixture was heated to ℃ and stirred for 12 hours. The mixture was concentrated under vacuum and purified (PM6) to form a compound. Substance 1.488 (110 mg, 499.67 μmol, yield 54.5%) was prepared as a yellow oily substance. I obtained it. 1H NMR (400 MHz, CHCl3-d) δ: 10.02 (s, 1H), 7.83 (s, 1H), 7.65 (s, 1H), 7.52 (s , 1H), 4.84 (s, 2H) ppm. Synthesis of intermediate 1.491 2-(3-methoxy-5-vinylphenyl)acetonitrile 1.490

[0411] [ka] 2-(3-bromo-5-methoxyphenyl)acetonitrile (1.1g, 4.87mg) mol)(US2014 / 73629A1) and 4,4,5,5-tetramethyl-2- DME(2) of vinyl-1,3,2-dioxaborolane (1.12 g, 7.30 mmol) In a 0 mL solution, add Pd(dppf)Cl2 (356.03 mg, 486.58 μmol) ) and CsF (1.48 g, 9.73 mmol) were added. The mixture was heated to 80°C. The mixture was stirred for 12 hours under the protection of a nitrogen atmosphere. The mixture was poured into water (50 mL) and the aqueous phase was added. Extraction was performed using EA (30 mL x 3). The combined organic phase was washed with brine (80 mL x 2). The mixture was dried with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM11). Compound 1.490 (550 mg, 3.18 mmol, yield 65.3%) was prepared as a yellow oily substance. I obtained it. 1 H NMR (400 MHz, CHCl3-d) δ: 6.96 (s, 1H), 6.90 (s, 1H), 6.77 (s, 1H), 6.67 (dd , J = 17.2, 10.8 Hz, 1H), 5.78 (d, J = 17.6 Hz, 1H), 5.32 (d, J = 10.8 Hz, 1H), 3.84 (s, 3H), 3.73 (s, 2H) ppm. 2-(3-formyl-5-methoxyphenyl)acetonitrile 1.491

[0412] [ka] Remove ozone at -70°C until the reaction mixture turns blue, then add compound 1.490 (550 mg) It was blown into a solution of 3.18 mmol) in DCM (10 mL). Excess ozone was removed. After mixing, DMS (1.97g, 31.75 mmol) was added. The mixture was then allowed to cool to 20°C. The mixture was heated and stirred for 12 hours. The mixture was concentrated under vacuum and (PM7) was used to obtain compound 1.491. (240 mg, 1.37 mmol, yield 43.2%) was obtained as a yellow solid. 1 H NMR (400 MHz, CHCl3-d) δ: 9.98 (s, 1H), 7.43 (s, 1H), 7.38 (s, 1H), 7.16 (s, 1H), 3.90 (s, 3H), 3.82 (s, 2H) ppm. Synthesis of intermediate 1.500 (3-Fluoro-5-vinylphenyl)methanol 1.49g

[0413] [ka] (3-Bromo-5-fluorophenyl)methanol (3g, 14.63 mmol), 4,4,5,5-Tetramethyl-2-vinyl-1,3,2-dioxaborolane(3.38 Solution of 1,4-dioxane (60 mL) and water (6 mL) (g, 21.95 mmol) In addition, K2CO3 (4.04g, 29.26 mmol) and Pd(dppf)Cl under nitrogen. 2·CH2Cl2 (1.19 g, 1.46 mmol) was added. The resulting mixture was heated at 90°C. The mixture was stirred for 12 hours. The mixture was concentrated under vacuum, and the residue (PM7) was removed to obtain compound 1.499. (2.0 g, 13.15 mmol, yield 91%) was obtained as a yellow oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 7.22 (s, 1H), 7.08 (dd, J = 10.0, 1.6 Hz, 1H), 6.9 9 (d, J = 9.6 1H), 6.72 (dd, J = 17.6, 10.8 Hz, 1H), 5.82 (d, J = 17.6 Hz, 1H), 5.29 (d, J = 10.8 Hz, 1H), 4.60 (s, 2H) ppm. 3-Fluoro-5-(hydroxymethyl)benzaldehyde 1,500

[0414] [ka] Add ozone at -70°C until the reaction mixture turns blue (compound 1.499 (3.15g)). It was blown into a solution of 20.70 mmol) of DCM (50 mL). Excess ozone was then removed. After rinsing, DMS (12.86 g, 207.01 mmol) was added. The mixture was then heated at 20°C. The mixture was heated to [temperature] and stirred for 12 hours. The mixture was concentrated under vacuum and purified (PM6) to obtain the compound. 1.500 (2.9g, 11.06 mmol, yield 53.4%) was obtained as a pale yellow oily substance. Ta. 1 H NMR (400 MHz, CHCl3-d) δ: 9.98 (s, 1H), 7.67 (s, 1H), 7.48 (dd, J = 4.0, 2.4 Hz, 1H), 7.36 (d, J = 4.0 Hz, 1H), 4.80 (s, 2H) ppm. Synthesis of intermediate 1.501 3-(hydroxymethyl)-5-(trifluoromethyl)benzaldehyde 1.501

[0415] [ka] (3-Bromo-5-(trifluoromethyl)phenyl)methanol (10g, 39.2g) In a 1 mmol solution of THF (100 mL), add n-BuLi (2.5 M, 3) at -78°C. 2.94 mL was added dropwise. After stirring for 0.5 hours, DMF (3.02 mL, 39. (21 mmol) was added. The resulting mixture was stirred separately at -78°C for 0.5 hours. The mixture was heated to 20°C and quenched with water (100 mL). The mixture was then divided into three EA (150 mL x 3) portions. Extraction was performed using [method]. The combined organic phase was washed with brine (100 mL) and dehydrogenated with anhydrous Na2SO4. The solution was diluted with water, filtered, and concentrated under vacuum. The residue was purified (PM7) to obtain compound 1.501 (3.8 g, 18.61 mmol, yield 47.47%) was obtained as a yellow oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 10.08 (s, 1H), 8.06 (s, 1H), 7.92 (s, 1H), 7.65 (s , 1H), 4.89 (s, 2H), 2.49 (d, J = 8.0 Hz, 1H) ppm. Synthesis of intermediate 1.504 1-(chloromethyl)-3-(trifluoromethoxy)-5-vinylbenzene 1.502

[0416] [ka] Compound 1.487 (8.3g, 38.04 mmol) contains 1,4-dioxane (100m SOCl2 (9.05 g, 76.09 mmol) was slowly added to the solution in (L) at 0°C. Next, the mixture was heated to 90°C and stirred for 1 hour. The mixture was concentrated, and EA (20 mL) The mixture was diluted with EA (80 mL). The mixture was poured into an aqueous solution of NaHCO3 (150 mL) and EA (80 mL) was added. Extraction was performed using ×3). The combined organic phase was washed with brine (150 mL × 2) and anhydrous sodium 2 The mixture was dried with SO4, filtered, and concentrated under vacuum. The residue was purified (PM14) to obtain compound 1.5. O2 (3.5g, 14.79 mmol, yield 38.9%) was obtained as a yellow oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 7.35 (s, 1H), 7.21 (s, 1H), 7.16 (s, 1H), 6.69 (dd , J = 17.6, 11.2 Hz, 1H), 5.81 (d, J = 17.6 Hz, 1H), 5.39 (d, J = 11.2 Hz, 1H), 4.58 (s, 2H) ppm. 2-(3-(trifluoromethoxy)-5-vinylphenyl)acetonitrile 1.503

[0417] [ka] Trimethylsilyl cyanide (1.33 g, 13.41 mmol) and compound 1.50 TBAF in a solution of 2 (3.5 g, 14.79 mmol) in acetonitrile (50 mL) (18.54 mL, 18.54 mmol, 1 M in THF) was added. The mixture was heated at 25°C for 1 The mixture was stirred for 2 hours. The mixture was concentrated under vacuum and purified (PM13) to obtain compound 1.503(2 0.6 g, 11.44 mmol, yield 77.4% was obtained as a pale yellow oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 7.31 (s, 1H), 7.23 (s, 1H), 7.08 (s, 1H), 6.69 (dd , J = 17.6, 10.8 Hz, 1H), 5.83 (d, J = 17.6 Hz, 1H), 5.41 (d, J = 10.8 Hz, 1H), 3.78 (s, 2H) ppm. 2-(3-formyl-5-(trifluoromethoxy)phenyl)acetonitrile 1.50 4

[0418] [ka] Add compound 1.503 (2.6g) at -70°C until the reaction mixture turns blue. It was blown into a solution of 11.44 mmol) DCM (30 mL). Excess ozone was removed. After mixing, DMS (7.11g, 114.45 mmol) was added. The mixture was then heated to 20°C. The mixture was heated and stirred for 12 hours. The mixture was concentrated under vacuum and (PM7) was used to obtain compound 1.50. 4 (1.9 g, 8.29 mmol, yield 72.5%) was obtained as a yellow oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 10.03 (s, 1H), 7.83 (s, 1H), 7.73 (s, 1H), 7.48 (s , 1H), 3.90 (s, 2H) ppm. Synthesis of intermediate 1.507 1,3-Difluoro-2-(trifluoromethoxy)-5-vinylbenzene 1.506

[0419] [ka] 4,4,5,5-Tetramethyl-2-vinyl-1,3,2-dioxaborolane(6.2 6g, 40.62 mmol) and 5-bromo-1,3-difluoro-2-(trifluoro Solution of methyl(methoxybenzene) (7.5g, 27.08 mmol) in DME (100mL) Pd(dppf)Cl2 (1.98g, 2.71mmol) and CsF (8.23 (g, 54.15 mmol) was added. The mixture was heated to 80°C and stirred under nitrogen for 12 hours. The mixture was poured into water (300 mL), and the aqueous phase was extracted with EA (150 mL x 3). The combined organic phases were washed with brine (300 mL x 2) and dried with anhydrous Na2SO4. The mixture was filtered and concentrated under vacuum. The residue was purified (PM14) to obtain compound 1.506 (3.2g, 14.28 mmol, yielding 52.7%, was obtained as a yellow oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 7.05 (s, 1H), 7.03 (s, 1H), 6.61 (dd, J = 17.6, 10 .8 Hz, 1H), 5.78 (d, J = 17.2 Hz, 1H), 5.43 (d, J = 10.8 Hz, 1H) ppm. 3,5-Difluoro-4-(trifluoromethoxy)benzaldehyde 1.507

[0420] [ka] Add compound 1.506 (3.2g) at -70°C until the reaction mixture turns blue. It was blown into a 14.28 mmol (14.28 mmol) DCM (40 mL) solution. Excess ozone was removed. After mixing, DMS (8.87g, 142.78mmol) was added. The mixture was then heated to 20°C. The mixture was heated and stirred for 12 hours. The mixture was concentrated under vacuum and purified (PM6) to obtain compound 1. 507 (1.2 g, 5.31 mmol, yield 37.2%) was obtained as a yellow oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 9.95 (s, 1H), 7.59 (s, 1H), 7.57 (s, 1H) ppm. Synthesis of intermediate 1.509 3-Cyclopropyl-5-(trifluoromethoxy)benzaldehyde 1.509

[0421] [ka] 3-Bromo-5-(trifluoromethoxy)benzaldehyde (2g, 7.43mO) l) Cyclopropylboronic acid (702.47 mg, 8.18 mmol) and Pd(d 1,4-dioxane (2 ppf)Cl2 (271.99 mg, 371.73 μmol) Mixture of (0 mL) and water (2 mL) contains K2CO3 (2.05 g, 14.87 mmol) ) was added. The mixture was stirred at 80°C for 12 hours under nitrogen protection. The mixture was concentrated under vacuum, and the remainder The residue was purified (PM14) to obtain compound 1.509 (1.1g, 4.78 mmol, yield 64%). 0.3% was obtained as a yellow oily substance. LCMS (AM3): rt = 0.958 min, (231.1 [M+H] + ), purity 97.7%. Synthesis of intermediate 1.521 2-(4-chloro-3-vinylphenyl)acetonitrile 1.520

[0422] [ka] 2-(3-bromo-4-chlorophenyl)acetonitrile (1.2g, 5.21mmo) l) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane 1,4-dioxane (1.20 g, 7.81 mmol) (10 mL) and water (1 mL) ) Mixture containing Pd(dppf)Cl2·CH2Cl2 (425.17 mg, under nitrogen protection) (520.63 μmol) and K2CO3 (1.44 g, 10.41 mmol) were added. The mixture was heated to 90°C and stirred for 12 hours. The mixture was concentrated under vacuum, and the residue was purified (P M6) Compound 1.520 (840 mg, 4.73 mmol, yield 90.8%) was yellow It was obtained as a colored oily substance. 1 H NMR (400 MHz, MeOH-d4) δ: 7.61 (d, J = 2.0 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H) , 7.23 (dd, J = 8.4, 2.4 Hz, 1H), 7.07 (dd, J = 17.6, 11.2 Hz 1H), 5.82 (d, J = 17.6 Hz, 1H), 5.42 (d, J = 11.2 Hz, 1H), 3.89 (s, 2H) ppm. 2-(4-chloro-3-formylphenyl)acetonitrile 1.521

[0423] [ka] Remove ozone at -78°C until the reaction mixture turns blue, then add compound 1.520 (840 mg) It was blown into a solution of 4.73 mmol) DCM (20 mL). Excess ozone was removed. After mixing, DMS (2.94 g, 47.29 mmol) was added at -78°C. Then it was mixed. The mixture was heated to 25°C and stirred for 12 hours. The mixture was concentrated under vacuum, and the residue was EA (60 mL). Dissolve in (), wash with brine (50 mL x 2), dry with anhydrous Na2SO4, filter, The compound was concentrated under vacuum. The residue was purified (PM11) to obtain compound 1.521 (600 mg, 3.3 4 mmol (70.6% yield) was obtained as a yellow solid. 1 H NMR (400 MHz, MeOH-d4) δ: 10.42 (s, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.64-7.56 (m, 2H), 3.99 (s, 2H) ppm. Synthesis of intermediate 1.524 2-(2-chloro-4-vinylphenyl)acetonitrile 1.523

[0424] [ka] 2-(4-bromo-2-chlorophenyl)acetonitrile (1.6g, 6.94mg) ol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxavorola 1,4-dioxane (10 mL) and water (1.60 g, 10.41 mmol) In a mixture of (mL), under nitrogen protection, Pd(dppf)Cl2·CH2Cl2(566.89mL) Add g (694.18 μmol) and K2CO3 (1.92 g, 13.88 mmol). The mixture was heated to 90°C and stirred for 12 hours. The mixture was concentrated under vacuum, and the residue was purified. (PM6) Compound 1.523 (1.1g, 6.19 mmol, yield 89.2%) It was obtained as a yellowish oily substance. 1 H NMR (400 MHz, MeOH-d4) δ: 7.50 (s, 1H), 7.46-7.43 (d, 1H), 7.40-7.38 (d, 1H) , 6.69 (dd, J = 17.6, 11.8 Hz, 1H), 5.84 (d, J = 17.6 Hz, 1H), 5.33 (d, J = 11.8 Hz, 1H), 3.93 (s, 2H) ppm. 2-(2-chloro-4-formylphenyl)acetonitrile 1.524

[0425] [ka] Add ozone at -78°C until the reaction mixture turns blue, then add compound 1.523 (1.1g). The solution was blown into a 20 mL solution of DCM containing 6.19 mmol. Excess ozone was purged. Then, DMS (3.85 g, 61.93 mmol) was added. The mixture was heated to 25°C. The mixture was stirred for 12 hours. The mixture was concentrated under vacuum to remove the solvent. The residue EA (60 mL) Dissolve in (), wash with brine (50 mL x 2), dry with anhydrous Na2SO4, filter, The compound was concentrated under vacuum. The residue was purified (PM11) to obtain compound 1.524 (0.6g, 3.34). mmol (53.9% yield) was obtained as a pink solid. 1 H NMR (400 MHz, MeOH-d4) δ: 9.97 (s, 1H), 8.00 (s, 1H), 7.91 (dd, J = 7.6, 1.6 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 4.10 (s, 2H) ppm. Synthesis of intermediate 1.526 2-Cyclopropyl-4-formylbenzonitrile 1.526

[0426] [ka] Cyclopropylboronic acid (122.69 mg, 1.43 mmol) and 2-bromo 1,4-Dioxy 4-formyl-benzonitrile (200 mg, 952.26 μmol) In a mixture of Sun (10 mL) and water (1 mL), Pd(dppf)Cl2· under nitrogen protection. CH2Cl2 (77.77 mg, 95.23 μmol) and K2CO3 (263.22 (mg, 1.90 mmol) was added. The mixture was heated to 90°C and stirred for 12 hours. The substance is concentrated under vacuum and purified (PM4) to obtain compound 1.526 (100 mg, 584.13 μmol (61.3% yield) was obtained as a yellow oily substance, which was used without characterization. Synthesis of intermediate 1.530 (5-Bromo-2-(2,2,2-trifluoroethoxy)phenyl)methanol 1.5 28

[0427] [ka] 4-Bromo-2-(hydroxymethyl)phenol (2g, 9.85 mmol) and 2,2,2-Trifluoroethyltrifluoromethanesulfonate (2.29g, 9.8 In a 5 mmol solution in DMF (10 mL), add K2CO3 (2.04 g, 14.78 mm) Add water (100 ol). Heat the mixture to 80°C and stir for 12 hours. Diluted in mL and extracted with EA (100 mL x 3). The combined organic layer was then treated with brine (10 Wash with 0 mL x 2), dehydrate with Na2SO4, filter, and concentrate under vacuum to obtain the residue. The compound was purified (PM10) to obtain compound 1.528 (1.83g, 6.42 mmol, yield 65%). 0.2% was obtained as a yellow solid. 1 H NMR (400 MHz, CHCl3-d) δ: 7.48 (d, J = 2.4 Hz, 1H), 7.32 (dd, J = 8.4, 2.4 H z, 1H), 6.65 (d, J = 8.4 Hz, 1H), 4.64 (s, 2H), 4.31 (q, J = 4.8 Hz, 2H), 1.87 ( br s, 1H) ppm. (2-(2,2,2-trifluoroethoxy)-5-vinylphenyl)methanol 1.5 29

[0428] [ka] A solution of compound 1.528 (400 mg, 1.40 mmol) in toluene (5 mL) Tributyl(vinyl) stannan (489.45 mg, 1.54 mmol) and Pd( PPh3)4 (81.08 mg, 70.16 μmol) was added. The reaction mixture was heated at 100°C. The mixture was heated and stirred under nitrogen protection for 12 hours. The reaction mixture was diluted with saturated KF aqueous solution (80 mL). The mixture was separated and extracted with EA (60 mL x 2). The organic layer was washed with brine (70 mL) and Na The mixture was dehydrated with 2SO4, filtered, and concentrated under vacuum. The residue was purified (PM10) to obtain compound 1. 529 (580 mg) was obtained as a yellow oily substance, which was used directly without characterization. 3-(hydroxymethyl)-4-(2,2,2-trifluoroethoxy)benzaldehyde 1.530

[0429] [ka] Remove ozone at -78°C until the reaction mixture turns blue, then add compound 1.529 (200 mg) The excess ozone was blown into a solution of 861.33 μmol in DCM (20 mL). After purging, DMS (535.14 mg, 8.61 mmol) was added. The mixture was divided into 25 portions. The mixture was heated to °C and stirred for 12 hours. The mixture was concentrated under vacuum and dissolved in EA (60 mL), and b The solution was washed in two 50mL lines, dehydrated with Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM6) to obtain compound 1.530 (60 mg, 256.22 μmol, yield 2 9.7% was obtained as a yellow solid. 1 H NMR (400 MHz, MeOH-d4) δ: 9.90 (s, 1H), 8.05 (s, 1H), 7.86 (dd, J = 8.4, 2.0 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 4.74-4.67 (m, 4H) ppm. Synthesis of intermediate 1.537 Methyl 2-bromo-5-vinylbenzoate 1.534

[0430] [ka] A solution of methyl 2-bromo-5-iodobenzoate (5 g, 14.67 mmol) in toluene (80 mL) was added with tributyl(vinyl)stannane (5.430 g, 17.12 m mol) and Pd(PPh3)4 (1.69 g, 1.47 mmol). The reaction mixture was heated to 90 °C and stirred for 12 hours under nitrogen protection. The reaction mixture was poured into saturated KF aqueous solution (4 0 mL), and extracted with EA (50 mL × 3). The combined organic layers were washed with brine (80 mL × 2), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified (PM1) to obtain compound 1.534 (3.2 g) as a white solid. 1 H NMR (400 MHz, CHCl3-d) δ: 7.79 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H) , 7.35 (dd, J = 8.0, 2.4 Hz, 1H), 6.65 (dd, J = 17.2, 10.8 Hz, 1H), 5.79 (d, J = 17.2 Hz, 1H), 5.34 (d, J = 10.8 Hz, 1H), 3.93 (s, 3H) ppm. ((Z)-2-Bromo-5-vinylphenyl)methanol 1.535

[0431]

Chemical formula

[0432] [ka] Remove ozone from the mixture at -78°C until the mixture turns blue (compound 1.535 (2.5g, 11) It was blown into a solution of 0.73 mmol) in DCM (20 mL). Excess ozone was purged. Then, DMS (15.6 g, 251.23 mmol) was added. The reaction mixture was then heated to 20°C. The mixture was heated and stirred for 12.5 hours. The residue was concentrated under vacuum and then diluted with water (40 mL). The mixture was extracted with DCM (50 mL x 2), and the combined organic phase was treated with brine (50 mL x 2). The sample was washed, dehydrated with Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM12). Compound 1.536 (1.5g, 6.98 mmol, yield 59.45%) was then prepared as a pale yellow oil. I obtained it as a physical object. 1H NMR (400 MHz, CHCl3-d) δ: 9.99 (s, 1H), 8.03 (s, 1H), 7.70 (dd, J = 8.4, 2.0 Hz, 1H), 7.65 (dd, J = 8.4, 2.0 Hz, 1H), 4.81 (s, 2H), 2.47 (br s, 1H) ppm. 4-Cyclopropyl-3-(hydroxymethyl)benzaldehyde 1.537

[0433] [ka] Compound 1.536 (1.3g, 6.05 mmol), cyclopropylboronic acid (571 (0.20 mg, 6.65 mmol), Na2CO3 (1.28 g, 12.09 mmol) and Pd(dppf)Cl2 (442.34 mg, 604.53 μmol) 1,4-di The mixture of oxane (20 mL) and water (2 mL) was stirred at 80°C for 12 hours under nitrogen protection. The reaction mixture was diluted with water (30 mL) and extracted with EA (50 mL x 2). The organic layer was washed with brine (80 mL x 2), dehydrated with Na2SO4, filtered, and vacuum-sealed. The compound was concentrated. The residue was purified (PM47) to obtain compound 1.537 (120 mg, 681.00 mg). μmol, yield 11.3%, was obtained as a yellow oily substance. LCMS (AM3): rt = 0.763 min, (177.7 [M+H] + ), purity 94.3%. MeOH Synthesis of intermediate 1.589 Methyl 2-(trifluoromethyl)-5-vinylbenzoate 1.587

[0434] [ka] Methyl 5-bromo-2-(trifluoromethyl)benzoate (730 mg, 2.58 A solution of mmol) in 1,4-dioxane (15 mL) and water (1.5 mL) contains 4,4 ,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane(595.83m (g, 3.87 mmol), K2CO3 (712.92 mg, 5.16 mmol) and P Add d(dppf)Cl2·CH2Cl2 (210.62 mg, 257.91 μmol). Next, the reaction mixture was heated to 90°C and stirred under nitrogen protection for 12 hours. The reaction mixture was then filtered. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified (PM7) to obtain compound 1.587 (600 ml). g) was obtained as a pink oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 7.79 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 6.75 (dd, J = 17.6, 10.8 Hz, 1H), 5.90 (d, J = 17.6 Hz, 1H), 5.4 6 (d, J = 10.8 Hz, 1H), 3.94 (s, 3H) ppm. (2-(trifluoromethyl)-5-vinylphenyl)methanol 1.588

[0435] [ka] A solution of compound 1.587 (600 mg, 2.61 mmol) in THF (10 mL) LAH (98.92 mg, 2.61 mmol) was slowly added at 0°C. Reaction mixture 0 The mixture was stirred at °C for 2 hours. The reaction mixture was slowly added to the water (0.1 mL) at 0°C, followed by 10% The solution was quenched by adding 0.1 mL of NaOH aqueous solution, followed by 0.3 mL of water. After stirring at 0°C for 10 minutes, Na2SO4 (2g) was added. The resulting suspension was then heated for 0.5 hours. The mixture was stirred and then filtered. The filtrate was concentrated under vacuum to obtain compound 1.588 (450 mg, 2 0.23 mmol (85.4% yield) was obtained as a colorless oil. 1 H NMR (400 MHz, CHCl3-d) δ: 7.75 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 6.78 (dd, J = 17.6, 10.8 Hz, 1H), 5.88 (d, J = 17.6 Hz, 1H), 5.4 0 (d, J = 10.8 Hz, 1H), 4.88 (d, J = 5.4 Hz, 2H), 1.95 (br s, 1H) ppm. 3-(hydroxymethyl)-4-(trifluoromethyl)benzaldehyde 1.589

[0436] [ka] Remove ozone at -78°C until the reaction mixture turns blue, then add compound 1.588 (450 mg). The excess ozone was blown into a solution of 2.23 mmol) in DCM (10 mL). After purging, DMS (1.46 g, 23.50 mmol) was added. Reaction reaction 2 The mixture was heated to 0°C and stirred for 15.5 hours. The reaction mixture was concentrated under vacuum and purified (PM6). Compound 1.589 (380 mg, 1.86 mmol, yield 83.63%) was obtained as a colorless oil. It was obtained as such. 1 H NMR (400 MHz, CHCl3-d) δ: 10.11 (s, 1H), 8.30 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 4.98 (s, 2H) ppm. Synthesis of intermediate 1.630 1-(3-Chloro-5-vinylphenyl)cyclopropanecarbonitrile 1.629

[0437]

Chem.

[0438]

Chem.

[0439] [ka] A solution of compound 1.365 (3.85 g, 21.67 mmol) in DMF (50 mL) NaH (2.17g, 54.19 mmol, 60% dispersion in oil) was added at 0°C. After stirring for 0.5 hours, slowly add MeI (6.75 mL, 108.37 mmol). The mixture was heated to 25°C and stirred for 11.5 hours. The reaction mixture was mixed with water (15 Quenched by adding (0 mL), then extracted with EA (100 mL x 3). Combined The organic layer was washed with brine (100 mL x 2), dehydrated with Na2SO4, filtered, and vacuum-sealed. The compound was concentrated. The residue was purified (PM17) to obtain compound 1.631 (4g, 19.45 mmol). A red oily substance was obtained with a yield of 89.7%. 1H NMR (400 MHz, CHCl3-d) δ: 7.38 (s, 1H), 7.32-7.20 (m, 2H), 6.60 (dd, J = 17. 6, 10.8 Hz, 1H), 5.73 (d, J = 17.6 Hz, 1H), 5.29 (d, J = 11.2 Hz, 1H), 1.19 (s, 6H) ppm. 2-(3-chloro-5-formylphenyl)-2-methylpropanenitrile 1.632

[0440] [ka] Ozone was applied to compound 1.631 (4g, 19.45m) at -78°C until the color changed to blue. The solution was blown into a 40 mL solution of (mol) DCM. After purging excess ozone with nitrogen, Then, DMS (15.71 g, 252.82 mmol) was added. The mixture was heated to 25°C. The mixture was stirred for 12 hours. The mixture was concentrated under vacuum and purified (PM16) to obtain compound 1.63. 2 (750 mg, 3.61 mmol, yield 18.6%) was obtained as a yellow oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 10.00 (s, 1H), 7.87 (s, 1H), 7.83 (s, 1H), 7.75 (s , 1H), 1.78 (s, 6H) ppm. Synthesis of intermediate 1.635 (5-Bromo-2-ethoxyphenyl)methanol 1.633

[0441] [ka] 4-Bromo-2-(hydroxymethyl)phenol (1g, 4.93 mmol) and A solution of iodoethane (845.80 mg, 5.42 mmol) in ACN (5 mL) contains 3 K2CO3 (1.02g, 7.39 mmol) was added at 5°C. The mixture was incubated at 35°C for 12 hours. Stirring was maintained. The reaction mixture was diluted with water (100 mL) and extracted with EA (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dehydrated with Na2SO4, and filtered. The mixture was then concentrated under vacuum. The residue was purified (PM11) to obtain compound 1.633 (860 mg). 3.72 mmol, yielding 75.5%, was obtained as a white solid. 1 H NMR (400 MHz, CHCl3-d) δ: 7.43 (d, J = 2.4 Hz, 1H), 7.36 (dd, J = 8.8, 2.4 H z, 1H), 6.76 (d, J = 8.8 Hz, 1H), 4.67 (s, 2H), 4.08 (q, J = 7.2 Hz, 2H), 1.46 ( t, J = 7.2 Hz, 3H) ppm. (2-Ethoxy-5-vinylphenyl)methanol 1.634

[0442] [ka] A solution of compound 1.633 (400 mg, 1.73 mmol) in toluene (5 mL) Tributyl(vinyl) stannan (600 mg, 1.89 mmol) and Pd (PPh 3)4 (100.01 mg, 86.55 μmol) was added. The reaction mixture was heated to 100°C. The mixture was heated and stirred under nitrogen protection for 12 hours. The reaction mixture was then poured into saturated KF aqueous solution (80 mL). The mixture was added and extracted with EA (60 mL x 2). The organic layer was washed with brine (70 mL) and Na The mixture was dehydrated with 2SO4, filtered, and concentrated under vacuum. The residue was purified (PM10) to obtain compound 1. 634 (280 mg, 1.41 mmol, yield 81.6%) was obtained as a yellow oily substance. 1H NMR (400 MHz, CHCl3-d) δ: 7.43 (d, J = 2.4 Hz, 1H), 7.29 (dd, J = 8.1, 2.4 H z 1H), 6.74 (d, J = 8.8 Hz, 1H), 6.67 (dd, J = 17.6, 10.8 Hz, 1H), 5.63 (d, J = 17.6 Hz, 1H), 5.14 (d, J = 10.8 Hz, 1H), 4.66 (d, J = 6.4 Hz, 2H), 4.08-4.05 (m, 2H), 1.45-1.44 (m, 3H) ppm. 4-Ethoxy-3-(hydroxymethyl)benzaldehyde 1.635

[0443] [ka] Remove ozone from the mixture at -78°C until the mixture turns blue. Compound 1.634 (280 mg, 1 It was blown into a solution of 0.57 mmol) in DCM (30 mL). Excess ozone was removed with nitrogen. After rinsing, DMS (1.27g, 20.42 mmol) was added. The mixture was then heated to 25°C. The mixture was heated and stirred for 12 hours. The mixture was concentrated under vacuum, and the residue was purified (PM8) to form a compound. 1.635 (170 mg, 943.40 μmol, yield 60.1%) of the substance was prepared as a yellow oily substance. I obtained it. 1 H NMR (400 MHz, CHCl3-d) δ: 9.90 (s, 1H), 7.88 (d, J = 2.0 Hz, 1H), 7.82 (dd, J = 8.4, 2.0 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 4.76 (s, 2H), 4.19 (q, J = 7.2 H z, 2H), 1.49 (t, J = 6.8 Hz, 3H) ppm. Synthesis of intermediate 1.661 4-Chloro-3-(hydroxymethyl)benzaldehyde 1.661

[0444] [ka] (5-Bromo-2-chlorophenyl)methanol (1g, 4.52 mmol) To a solution in F (10 mL), add n-BuLi (3.79 mL, 2.5 M) at -78°C. After stirring for 0.5 hours, add DMF (330.03 mg, 4.52 mmol) at -78°C. The mixture was added. The resulting mixture was stirred at -78°C for an additional 0.5 hours. The reaction mixture was then mixed with water (50%). Quenched with (mL), and extracted with EA (100mL x 3). The combined organic layer was brined ( The residue was washed with 100 mL x 2, dehydrated with Na2SO4, filtered, and concentrated under vacuum. Prepared using PM7, compound 1.661 (450 mg, 2.64 mmol, yield 58.4%). ) was obtained as a white solid. LCMS (AM3): rt = 0.474 min, (171.1 [M+H] + ), purity 75.7%. Synthesis of intermediate 1.668 (5-Bromo-2-isopropoxyphenyl)methanol 1.666

[0445] [ka] 4-Bromo-2-(hydroxymethyl)phenol (1g, 4.93 mmol) and 2-iodopropane (921.87 mg, 5.42 mmol) dissolved in ACN (10 mL) K2CO3 (1.02g, 7.39 mmol) was added to the solution at 35°C. The mixture was then cooled at 35°C. The mixture was stirred for 12 hours. The reaction mixture was diluted with water (100 mL) and EA (100 mL x 3) Extraction was performed using [method]. The combined organic layers were washed with brine (100 mL x 2) and decontaminated with Na2SO4. The solution was diluted with water, filtered, and concentrated under vacuum. The residue was purified (PM10) to obtain compound 1.666(90). 0 mg, 3.67 mmol, yield 74.5% was obtained as a yellow oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 7.43 (d, J = 2.4 Hz, 1H), 7.35 (dd, J = 8.8, 2.4 H z, 1H), 6.77 (d, J = 8.8 Hz, 1H), 4.64 (s, 2H), 4.58 (quintet, J = 6.0 Hz, 1H), 1 .95 (br s, 1H), 1.37 (d, J = 6.0 Hz, 6H) ppm. (2-Isopropoxy-5-vinylphenyl)methanol 1.667

[0446] [ka] A solution of compound 1.666 (400 mg, 1.73 mmol) in toluene (5 mL) Tributyl(vinyl) stannan (569.22 mg, 1.80 mmol) and Pd( PPh3)4 (94.29 mg, 81.60 μmol) was added. The reaction mixture was heated at 100°C. The mixture was heated and stirred under a nitrogen atmosphere for 12 hours. The reaction mixture was then mixed in saturated KF aqueous solution (80 mL). The mixture was poured into a container and then extracted with EA (60 mL x 2). The organic layer was then treated with brine (70 mL). The mixture was washed, dehydrated with Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM11). Compound 1.667 (200 mg, 1.04 mmol, yield 63.7%) was converted into a yellow oily substance. I obtained it by doing so. 1 H NMR (400 MHz, CHCl3-d) δ: 7.42 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H) , 6.85 (d, J = 8.8 Hz, 1H), 6.66 (dd, J = 17.6, 10.8 Hz, 1H), 5.63 (d, J = 17.6 Hz, 1H), 5.14 (d, J = 10.8 Hz, 1H), 4.67 (s, 2H), 4.59-4.55 (m, 1H), 1.36 (d, J = 6.0 Hz, 6H) ppm. 3-(hydroxymethyl)-4-isopropoxybenzaldehyde 1.668

[0447] [ka] Ozone was added to the mixture at -78°C until the mixture turned blue. Compound 1.667 (190 mg, 9 The solution was blown into a 30 mL solution of DCM containing 88.28 μmol. Excess ozone was removed with nitrogen. After purging, DMS (614.02 mg, 9.88 mmol) was added. The mixture was then divided into 25 portions. The mixture was heated to ℃ and stirred for 12 hours. The mixture was concentrated under vacuum, and the residue was purified (PM6). Compound 1.668 (20 mg, 102.97 μmol, yield 10.4%) was found as a yellow oily substance. It was obtained as such. 1 H NMR (400 MHz, MeOH-d4) δ: 9.83 (s, 1H), 7.98 (d, J = 2.0 Hz, 1H), 7.81 (dd, J = 8.4, 2.0 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 4.83-4.78 (m, 1H), 4.65 (s, 2H), 1.38 ppm (d, J = 6.0 Hz, 6H). Synthesis of intermediate 1.671 (5-Bromo-2-(cyclopentyloxy)phenyl)methanol 1.669

[0448] [ka] 4-Bromo-2-(hydroxymethyl)phenol (1g, 4.93 mmol) and Bromocyclopentane (808.18 mg, 5.42 mmol) in DMF (10 mL) K2CO3 (1.02 g, 7.39 mmol) was added to the solution. The mixture was heated to 80°C. The mixture was stirred for 12 hours. The reaction mixture was diluted with water (100 mL) and EA (100 mL x 3) Extracted using ). The combined organic layers were washed with brine (100 mL x 2) and then treated with Na2SO4. The mixture was dehydrated, filtered, and concentrated under vacuum. The residue was purified (PM10) to obtain compound 1.669(7 00 mg, 2.58 mmol, yield 52.4% was obtained as a yellow oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 7.40 (d, J = 2.4 Hz, 1H), 7.33 (dd, J = 8.8, 2.8 H z, 1H), 6.75 (d, J = 8.8 Hz, 1H), 4.82-4.78 (m, 1H), 4.61 (s, 2H), 1.97-1.74 (m, 6H), 1.72-1.58 (m, 2H) ppm. (2-(cyclopentyloxy)-5-vinylphenyl)methanol 1.670

[0449] [ka] A solution of compound 1.669 (400 mg, 1.48 mmol) in toluene (5 mL) Tributyl(vinyl) stannan (514.56 mg, 1.62 mmol) and Pd( PPh3)4 (85.23 mg, 73.76 μmol) was added. The reaction mixture was heated at 100°C. The mixture was heated and stirred under a nitrogen atmosphere for 12 hours. The reaction mixture was then mixed in saturated KF aqueous solution (80 mL). The mixture was poured into a container and extracted with EA (60 mL x 2). The organic layer was washed with brine (70 mL). The mixture was dehydrated with Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM10) and combined 1.670 (300 mg, 1.37 mmol, yield 93.2%) was obtained as a yellow oily substance. Ta. 1 H NMR (400 MHz, CHCl3-d) δ: 7.47 (d, J = 2.0 Hz, 1H), 7.32 (dd, J = 8.4, 2.0 H z, 1H), 6.80 (d, J = 8.4 Hz, 1H), 6.68 (dd, J = 17.6, 10.8 Hz, 1H), 5.69 (d, J = 17.6 Hz, 1H), 5.21 (d, J = 10.8 Hz, 1H), 4.75-4.72 (m, 2H), 4.45-4.43 (m, 1H), 1.68-1.52 (m, 4H), 1.42-1.25 (m, 4H) ppm. 4-(cyclopentyloxy)-3-(hydroxymethyl)benzaldehyde 1.671

[0450] [ka] Ozone was added to the mixture at -78°C until the mixture turned blue. Compound 1.670 (300 mg, 1 It was blown into a solution of 0.37 mmol) in DCM (30 mL). Excess ozone was removed with nitrogen. After rinsing, DMS (1.28g, 20.61mmol) was added. The mixture was then heated to 25°C. The mixture was heated and stirred for 12 hours. The mixture was concentrated under vacuum and purified (PM6) to obtain compound 1. 671 (50 mg, 227.00 μmol, yield 16.5%) was obtained as a yellow oily substance. 1H NMR (400 MHz, CHCl3-d) δ: 9.85 (s, 1H), 7.98 (d, J = 1.6 Hz, 1H), 7.82 (dd, J = 8.4, 2.0 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 5.01-4.98 (m, 1H), 4.64 (s, 2H), 1.90-1.81 (m, 4H), 1.75-1.65 (m, 4H) ppm. Synthesis of intermediate 1.675 3-Bromo-5-(trifluoromethoxy)benzamide 1.673

[0451] [ka] 3-Bromo-5-(trifluoromethoxy)benzoic acid (2g, 7.02 mmol) Add DIPEA (1.81g, 14.03 mmol) to the solution in MF (20 mL) at 20°C. Add HATU (4.00g, 10.53 mmol). Stir at 20°C for 0.1 hours. Then, NH4Cl (1.50 g, 28.07 mmol) was added. The reaction mixture was left at 20°C. Stirred for 12 hours. Pour the reaction mixture into water (100 mL) and add EA (50 mL x 2). Extraction was performed using [method]. The combined organic phase was washed with brine (100 mL) and dehydrated with Na2SO4. The solution was concentrated under vacuum. The residue was purified (PM47) to obtain compound 1.673 (980 mg, 3. 27 mmol (46.6% yield) was obtained as a yellow solid. LCMS (AM3): rt = 0.867 min, (284.0 [M+H] + ), purity 91.5%. 3-(trifluoromethoxy)-5-vinylbenzamide 1.674

[0452] [ka] Compound 1.673 (980 mg, 3.45 mmol) of 1,4-dioxane (10 mL) ) and a mixture in water (1 mL) containing K2CO3 (953.72 mg, 6.90 mmol) , 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (797 0.10 mg, 5.18 mmol) and Pd(dppf)Cl2 (252.46 mg, 3 45.03 μmol was added sequentially. The reaction mixture was then heated to 80°C under a nitrogen atmosphere. The mixture was stirred for 12 hours. The reaction mixture was filtered, concentrated under vacuum, and the crude product was purified (PM4). Compound 1.674 (700 mg, 2.62 mmol, yield 75.8%) was obtained as a white solid. I obtained it. LCMS (AM3): rt = 0.870 min, (232.1 [M+H] + ), purity 87.6%. 3-Formyl-5-(trifluoromethoxy)benzamide 1.675

[0453] [ka] Solution of compound 1.674 (0.7g, 2.62 mmol) in DCM (10mL) -7 The mixture was cooled to 8°C and blown with ozone until it turned blue. Excess ozone was removed. The system was purged with nitrogen, and then DMS (2.170 g, 34.92 mmol) was slowly added. The reaction mixture was heated to 20°C and stirred separately for 12.5 hours. The reaction mixture was concentrated under vacuum. The crude product was obtained and purified (PM150) to obtain compound 1.675 (260 mg, 1. 12 mmol (36.8% yield) was obtained as a white solid. LCMS (AM3): rt = 0.731 min, (234.1 [M+H] + ), purity 97.5%. Synthesis of intermediate 1.704 Methyl 3,4-dichloro-5-(trifluoromethoxy)benzoate 1.702

[0454] [ka] 3,4-Dichloro-5-(trifluoromethoxy)benzoic acid (500 mg, 1.82 mg) Mixture in 30 mL of MeOH (mol) at 0°C, SOCl2 (1.08 g, 9.09 The mmol was slowly added. The mixture was then heated to 60°C and stirred for 0.5 hours. The mixture is poured into a saturated NaHCO3 aqueous solution (50 mL) and extracted with EA (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried with anhydrous Na2SO4, and filtered. The mixture was then concentrated under vacuum to obtain compound 1.702 (500 mg, 1.73 mmol, yield 95%). 2% was obtained as a yellow oily substance. 1 H NMR (400 MHz, MeOH-d4) δ: 8.15 (d, J = 2.0 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H) , 3.95 (s, 3H) ppm. (3,4-Dichloro-5-(trifluoromethoxy)phenyl)methanol 1.703

[0455] [ka] A solution of compound 1.702 (500 mg, 1.73 mmol) in THF (20 mL) LiAlH4 (78.78 mg, 2.08 mmol) was slowly added at 0°C. Then mixed... The mixture was heated to 25°C and stirred for 0.5 hours. The mixture was cooled to 0°C, and EA (10 mL) was added. Diluted with water (0.2 mL), stirred for 2 minutes. Quenched by adding (mL) and water (0.6 mL). After stirring for 0.5 hours, anhydrous Na2SO4 (3g) was added and stirred separately for 0.5 hours. The resulting suspension was filtered and the filtrate was obtained. The compound 1.703 (400 mg, 1.4 mg) was concentrated under vacuum. The residue was purified (PM2) to obtain compound 1.703. 8 mmol (83% yield) was obtained as a yellow oily substance. 1 H NMR (400 MHz, MeOH-d4) δ: 7.55 (d, J = 1.6 Hz, 1H), 7.40 (d, J = 1.6 Hz, 1H) , 4.61 (s, 2H) ppm. 3,4-Dichloro-5-(trifluoromethoxy)benzaldehyde 1.704

[0456] [ka] A solution of compound 1.703 (400 mg, 1.53 mmol) in DCM (100 mL) Then, MnO2 (1.33g, 15.32 mmol) was added at 25°C. The mixture was heated at 25°C for 2 The mixture was stirred for a certain amount of time. The mixture was filtered and concentrated under vacuum. The residue was purified (PM7) to obtain compound 1. 0.704 (140 mg, 540.52 μmol, yield 35.3%) was obtained as a yellow oily substance. Ta. 1 H NMR (400 MHz, MeOH-d4) δ: 9.96 (s, 1H), 8.12 (d, J = 1.2 Hz, 1H), 7.92 (d, J = 1.2 Hz, 1H) ppm. Synthesis of intermediate 1.707 2-Methoxy-1-(trifluoromethoxy)-4-vinylbenzene 1.706

[0457] [ka] 4,4,5,5-Tetramethyl-2-vinyl-1,3,2-dioxaborolane(596 0.66 mg, 3.87 mmol) and 4-bromo-2-methoxy-1-(trifluoro 1,4-dioxane (10 mL) of methoxybenzene (0.7 g, 2.58 mmol) And in the mixture in H2O (1 mL), K2CO3 (713.90 mg, 5.17 mmol) ) and Pd(dppf)Cl2·CH2Cl2 (105.46 mg, 129.14 μm (ol) was added. The mixture was heated to 90°C and stirred under a nitrogen atmosphere for 12 hours. The mixture was filtered. The mixture was passed through a vacuum, concentrated, and the residue was purified (PM14) to obtain compound 1.706 (0.28g, 1 0.28 mmol, yield 49.7%, was obtained as a colorless oil. 1 H NMR (400 MHz, MeOH-d4) δ: 7.19-7.14 (m, 2H), 7.03 (dd, J = 2.0, 8.4 Hz, 1H), 6.73 (dd, J = 17.6, 10.8 Hz, 1H), 5.81 (d, J = 17.6 Hz, 1H), 5.29 (d, J = 0.8, 11.2 Hz, 1H), 3.89 (s, 3H) ppm. 3-Methoxy-4-(trifluoromethoxy)benzaldehyde 1.707

[0458] [ka] Compound 1.706(0) was cooled to -78°C with ozone until the mixture turned blue. The excess ozonite was blown into a solution of 0.28 g (1.28 mmol) in DCM (20 mL). After purging with nitrogen, DMS (797.37 mg, 12.83 mmol) was added. The mixture was stirred at 25°C for 12 hours. The mixture was concentrated under vacuum, and the residue was subjected to column chromatography. Purified using Raffy (PM14), compound 1.707 (0.22g, 999.34μ) A quantity of mol, yielding 77.9%, was obtained as a colorless oil. 1 H NMR (400 MHz, MeOH-d4) δ: 9.96 (s, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.57 (dd, J = 8.1, 2.0 Hz, 1H), 7.47 (dd, J = 8.4, 1.2 Hz, 1H), 3.96 (s, 3H) ppm. Synthesis of intermediate 1.709 3-Methyl-4-(trifluoromethoxy)benzaldehyde 1.709

[0459] [ka] 3-Bromo-4-(trifluoromethoxy)benzaldehyde (750 mg, 2.7g) mmol), Pd(PPh3)4(322.16mg, 278.79μmol), 2,4 ,6-trimethyl-1,3,5,2,4,6-trioxatrivolinan (1.40g, 5 1,4-dioxypropyl alcohol (0.58 mmol) and K2CO3 (1.16 g, 8.36 mmol) The mixture in 7 mL of San was stirred at 100°C under a nitrogen atmosphere for 12 hours. The residue was then rinsed with water (20 The mixture was poured into a solution (mL) and extracted with EA (10mL x 3). The combined organic phase was then mixed with brine (3 Washed with 0 mL x 2), dried with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was then saturated. Purified by ricagel chromatography (PM1), compound 1.709 (400 mg) was obtained. 1.96 mmol (70.3% yield) was obtained as a yellow oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 9.99 (s, 1H), 7.81 (d, J = 1.2 Hz, 1H), 7.76 (dd, J = 8.4, 1.2 Hz, 1H), 7.37 (dd, J = 8.4, 1.2 Hz, 1H), 2.40 (s, 3H) ppm. Synthesis of intermediate 1.710 3-Cyclopropyl-4-(trifluoromethoxy)benzaldehyde 1.710

[0460] [ka] 3-Bromo-4-(trifluoromethoxy)benzaldehyde (500mg, 1.86 mmol), cyclopropylboronic acid (239.48 mg, 2.79 mmol), Pd( dppf)Cl2·CH2Cl2 (151.78 mg, 185.86 μmol) and K 1,4-dioxane (10 mL) in 2CO3 (513.76 mg, 3.72 mmol) The mixture was stirred in H2O (1 mL) under a nitrogen atmosphere at 90°C for 12 hours. The solution was concentrated in an empty container, and the residue was separated and purified by TLC (SiO2, PE / EA=3 / 1) to form a compound. 1.710 (350 mg, 1.52 mmol, yield 81.8%) was obtained as a yellow oily substance. Ta. 1 H NMR (400 MHz, DMSO-d6) δ: 9.94 (s, 1H), 7.79 (dd, J = 8.4, 2.0 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.44 (dd, J = 8.4, 1.6 Hz, 1H), 2.22-2.15 (m, 1H), 1.13-1. 07 (m, 2H), 0.83-0.78 (m, 2H) ppm. Synthesis of intermediate 1.712 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5 -(trifluoromethoxy)benzaldehyde 1.711

[0461] [ka] 3-Bromo-5-(trifluoromethoxy)benzaldehyde (5g, 18.59mg) ol), KOAc (3.65g, 37.19mmol), Pin2B2 (5.65g, 2 2.25 mmol) and Pd(dppf)Cl2 (700 mg, 0.96 mmol) The mixture in 1,4-dioxane (100 mL) was degassed three times and purged with nitrogen. The reaction mixture was heated to 80°C and stirred under a nitrogen atmosphere for 16 hours. The reaction mixture was then concentrated under vacuum. The residue was then purified (PM7) to obtain compound 1.711 (6.1g) as a yellow oily substance. . 1 H NMR (400 MHz, CHCl3-d) δ: 10.05 (s, 1H), 8.23 ​​(s, 1H), 7.88 (d, J = 1.2 Hz, 1H), 7.82-7.81 (m, 1H), 1.38 (s, 12H) ppm. 3-(oxazole-4-ylmethyl)-5-(trifluoromethoxy)benzaldehyde 1.712

[0462] [ka] Compound 1.711 (1.83g, 5.79mmol), 4-(chloromethyl)oxazo K2CO3 (680mg, 5.79mmol), K2CO3 (2.04g, 14.76mmol) ) and 1,4-dioxane Pd(dppf)Cl2 (212 mg, 0.29 mol) The mixture in (16 mL) and H2O (4 mL) was degassed three times and purged with nitrogen. Next The reaction mixture was heated to 80°C and stirred under a nitrogen atmosphere for 2 hours. The reaction mixture was then concentrated under vacuum. The residue was then purified (PM7) to obtain compound 1.712 (170 mg, yield 10.8%), which was then yellow. It was obtained as a colored oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 9.98 (s, 1H), 7.88 (s, 1H), 7.73 (s, 1H), 7.61 (s, 1H), 7.49 (s, 1H), 7.41 (s, 1H), 4.01 (s, 2H) ppm. Synthesis of intermediate 1.713 3-(oxazole-5-ylmethyl)-5-(trifluoromethoxy)benzaldehyde 1.713

[0463] [ka] Compound 1.711 (2.03 g, 6.41 mmol), 5-(chloromethyl)oxazo K2CO3 (750mg, 6.38mmol), K2CO3 (2.25g, 16.28mmol) ) and 1,4-dioxa (Pd(dppf)Cl2 (240 mg, 0.33 mmol)) The mixture in 16 mL of ethanol and 4 mL of H2O was degassed three times and purged with nitrogen. The reaction mixture was then heated to 80°C and stirred under a nitrogen atmosphere for 2 hours. The reaction mixture was concentrated under vacuum. The mixture was reduced, and the residue was purified (PM7) to obtain compound 1.713 (650 mg, yield 37.6%). It was obtained as a yellowish oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 9.99 (s, 1H), 7.84 (s, 1H), 7.70 (s, 1H), 7.64 (s, 1H), 7.35 (s, 1H), 6.89 (s, 1H), 4.13 (s, 2H) ppm. Synthesis of intermediate 1.714 3-Formyl-5-(trifluoromethoxy)benzonitrile 1.714

[0464] [ka] 3-Bromo-5-(trifluoromethoxy)benzaldehyde (700mg, 2.60 mmol), Zn(CN)2 (910 mg, 7.75 mmol), and Pd(PPh3) The mixture of 4 (300 mg, 0.26 mmol) in DMF (10 mL) was degassed three times and then nitrified. The mixture was purged with a solvent. The reaction mixture was heated to 90°C and stirred under a nitrogen atmosphere for 1.5 hours. The mixture was filtered, and the filtrate was diluted with water (40 mL). The resulting mixture was then prepared using EA (20 mL × 3) Extract the combined organic phase, wash with brine (60 mL), and dehydrate with Na2SO4. The mixture was filtered and concentrated under vacuum. The residue was purified (PM12) to obtain compound 1.714 (0.23 g, yielding 41.1%, was obtained as a white solid. 1 H NMR (400 MHz, CHCl3-d) δ: 10.05 (s, 1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.76 (s , 1H) ppm. Synthesis of intermediate 1.718 2-(3-bromo-5-(trifluoromethoxy)phenoxy)ethanol 1.716

[0465] [ka] 3-Bromo-5-(trifluoromethoxy)phenol (930 mg, 3.62 mmol) l) 2-bromoethanol (500 mg, 4.00 mmol) and K2CO3 (1. Mix the 00g, 7.24 mmol DMF (10 mL) and stir at 100°C for 16 hours. The reaction mixture was diluted with water (40 mL), and the resulting mixture was divided into three EA (10 mL x 3) Extraction was performed. The combined organic phase was washed with brine (30 mL), dehydrated with Na2SO4, and filtered. The mixture was then concentrated under vacuum. The residue was purified (PM7) to obtain compound 1.716 (1.1g). It was obtained as a colored oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 7.03-7.02 (m, 2H), 6.74 (s, 1H), 4.08 (t, J = 4.8 Hz, 2H), 3.97 (t, J = 4.8 Hz, 2H) ppm. 2-(3-(trifluoromethoxy)-5-vinylphenoxy)ethanol 1.717

[0466] [ka] Compound 1.716 (1.1g, 3.65 mmol), 4,4,5,5-tetramethyl- 2-Vinyl-1,3,2-dioxaborolane (1.1g, 7.14 mmol), K2CO 3 (1.01 g, 7.31 mmol) and Pd(dppf)Cl2 (134 mg, 0. Mix 18 mmol) of 1,4-dioxane (10 mL) and H2O (2 mL) together. The mixture was degassed three times and purged with nitrogen. The reaction mixture was heated to 80°C and stirred under N2 for 16 hours. The reaction mixture was concentrated under vacuum, and the residue was purified (PM4) to obtain compound 1.717 (630m). g, yielding 69.5%, was obtained as a brownish oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 6.89 (d, J = 2.0 Hz, 2H), 6.69-6.61 (m, 2H), 5.77 (d, J = 17.2 Hz, 1H), 5.34 (d, J = 10.8 Hz, 1H), 4.10 (t, J = 4.8 Hz, 2H), 3.98 (t, J = 4.8 Hz, 2H) ppm. 3-(2-hydroxyethoxy)-5-(trifluoromethoxy)benzaldehyde 1. 718

[0467] [ka] Ozone was added to the solution at -70°C until the solution turned blue, then compound 1.717 (630 mg) was added. The solution was blown into a 10 mL solution of 2.54 mmol DCM. Excess ozone was removed with nitrogen. The mixture was then mixed and DMS (1.58 g, 25.38 mmol) was added. The mixture was then allowed to cool to room temperature. The mixture was heated and stirred for 14 hours. The reaction mixture was concentrated under vacuum, and the residue was purified (PM6). 1.718 (400 mg, yield 63.0%) of the substance was obtained as a colorless oil. 1 H NMR (400 MHz, CHCl3-d) δ: 9.95 (s, 1H), 7.36 (d, J = 2.4 Hz, 1H), 7.34 (d, J = 0.8 Hz, 1H), 7.06 (d, J = 1.2 Hz, 1H), 4.17 (t, J = 4.4 Hz, 2H), 4.02 (t, J = 4.4 Hz, 2H) ppm. Synthesis of intermediate 1.723 Methyl 3-allyl-5-(trifluoromethoxy)benzoate 1.720

[0468] [ka] Methyl 3-bromo-5-(trifluoromethoxy)benzoate (5g, 16.72mg) mol), 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.21g, 25.08mmol), K2CO3(4.62g, 33.44mmol) and 1,4-dioxane Pd(dppf)Cl2 (612 mg, 0.84 mmol) The mixture in (40 mL) and H2O (10 mL) was degassed three times and purged with nitrogen. The reaction mixture was heated to 80°C and stirred for 16 hours. The reaction mixture was concentrated under vacuum, and the residue was purified. (PM17) Compound 1.720 (3.95g, yield 90.8%) was converted into a colorless oil. I obtained it. 1 H NMR (400 MHz, CHCl3-d) δ: 7.83 (s, 1H), 7.74 (s, 1H), 7.24 (s, 1H), 6.00-5.9 0 (m, 1H), 5.17-5.10 (m, 2H), 3.94 (s, 3H), 3.46 (d, J = 5.6 Hz, 2H) ppm. Methyl 3-(2-hydroxyethyl)-5-(trifluoromethoxy)benzoate 1. 721

[0469] [ka] Add ozone at -70°C until the reaction solution changes color to blue, then add compound 1.720 (3.95 g of ozone was blown into a 40 mL solution of DCM (15.18 mmol). Excess ozone was removed by nitrification. After purging with plain water, add NaBH4 (2g, 52.87 mmol) and reaction mixture 25 The mixture was heated to °C and stirred for 16 hours. The reaction mixture was then mixed with saturated NH4Cl aqueous solution (40 mL). The mixture was then extracted with DCM (40 mL x 3). The combined organic phase was then treated with brine (120 mL). The solution was washed with (mL), dehydrated with Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM7 Compound 1.721 (1.7g, yield 42.4%) was obtained as a yellow oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 7.86 (s, 1H), 7.75 (s, 1H), 7.30 (s, 1H), 3.95-3.8 9 (m, 5H), 2.93 (t, J = 6.4 Hz, 2H), 1.75 (br s, 1H) ppm. 2-(3-(hydroxymethyl)-5-(trifluoromethoxy)phenyl)ethanol 1.722

[0470] [ka] A solution of compound 1.721 (0.8 g, 3.03 mmol) in THF (10 mL) contains 0 LAH (0.2g, 5.27 mmol) was added at °C. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with an aqueous HCl solution (1N, 30 mL), and the resulting mixture was EA Extraction was performed using (20 mL x 3). The combined organic phase was washed with brine (60 mL) and Na2 Dehydrated with SO4, filtered, and concentrated under vacuum, compound 1.722 (0.67 g, yield 93%) was obtained. 7% was obtained as a yellow oily substance, which was used directly without further purification. 1 H NMR (400 MHz, CHCl3-d) δ: 7.16 (s, 1H), 7.08 (s, 1H), 7.00 (s, 1H), 4.65 (s, 2H), 3.84 (t, J = 6.4 Hz, 2H), 2.86 (t, J = 6.4 Hz, 2H), 2.45-2.05 (br s, 2H) p pm. 3-(2-hydroxyethyl)-5-(trifluoromethoxy)benzaldehyde 1.7 twenty three

[0471] [ka] Compound 1.722 (0.67 g, 2.84 mmol) and MnO2 (2.47 g, 2 The mixture in 20 mL of DCM (8.37 mmol) was stirred at 25°C for 16 hours. The mixture was concentrated under vacuum, and the residue was purified (PM2) to obtain compound 1.723 (520 mg, yield 78.3% was obtained as a yellow oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 9.99 (s, 1H), 7.72 (s, 1H), 7.60 (s, 1H), 7.38 (s, 1H), 3.97-3.92 (m, 2H), 2.98 (t, J = 6.4 Hz, 2H) ppm. Synthesis of intermediate 1.741 Ethyl 3-bromo-5-ethoxybenzoate 1.736

[0472] [ka] 3-Bromo-5-hydroxybenzoic acid (2.8g, 12.90 mmol) ACN( In a 50 mL solution, add K2CO3 (8.92 g, 64.51 mmol) at ambient temperature and Iodoethane (5.03 g, 32.26 mmol) was added. The resulting mixture was heated to 80°C. The mixture was heated and stirred for 12 hours. The mixture was filtered and concentrated under vacuum to obtain compound 1.736(3. 4 g, 12.45 mmol, yield 96.5% was obtained as a pale yellow oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 7.74 (t, J = 1.6 Hz, 1H), 7.48 (t, J = 1.6 Hz, 1H) , 7.22 (t, J = 2.0 Hz, 1H), 4.37 (q, J = 7.2 Hz, 2H), 4.06 (q, J = 7.2 Hz, 2H), 1.44-1.40 (t, 3H), 1.40-1.36 (t, 3H) ppm. Ethyl 3-ethoxy-5-vinylbenzoate 1.737

[0473] [ka] A solution of compound 1.736 (3.6 g, 13.18 mmol) in DME (50 mL) CsF (4.00g, 26.36mmol), 4,4,5,5-tetramethyl-2-vinyl Lu-1,3,2-dioxaborolane (3.05g, 19.77mmol) and Pd(d Add ppf)Cl2 (964.45 mg, 1.32 mmol). Heat the mixture to 80°C. The mixture was heated and stirred under a nitrogen atmosphere for 12 hours. The mixture was concentrated under vacuum, and the residue was purified (PM17). Then, compound 1.737 (2.4g, 10.90 mmol, yield 82.7%) was extracted into a pale yellow oil. It was obtained as a substance. 1 H NMR (400 MHz, CHCl3-d) δ: 7.68 (t, J = 1.2 Hz, 1H), 7.45 (t, J = 1.2 Hz, 1H) , 7.13 (t, J = 2.0 Hz, 1H), 6.71 (dd, J = 17.6, 10.8 Hz, 1H), 5.81 (d, J = 16.8 Hz, 1H), 5.31 (d, J = 11.2 Hz, 1H), 4.38 (q, J = 7.2 Hz, 2H), 4.09 (q, J = 7.2 H z, 2H), 1.45-1.41 (t, 3H), 1.41-1.37 (t, 3H) ppm. (3-Ethoxy-5-vinylphenyl)methanol 1.738

[0474] [ka] A solution of compound 1.737 (2.4 g, 10.90 mmol) in THF (30 mL) LAH (620.33 mg, 16.34 mmol) was added at 0°C. The mixture was then heated to 25°C. The mixture was heated and stirred for 1 hour. By adding HCl aqueous solution (1M) at 0°C to adjust the pH to 3, The reaction mixture was quenched. The mixture was diluted with water (50 mL) and extracted with EA (50 mL x 3). The combined organic phase was washed with brine (50 mL), dried with Na2SO4, and filtered. Then, it was concentrated under vacuum to obtain compound 1.738 (2.2g) as a pale yellow oily substance, and this was directly It was used in contact with the device. 1 H NMR (400 MHz, CHCl3-d) δ: 6.99 (s, 1H), 6.88 (s, 1H), 6.83 (s, 1H), 6.68 (dd , J = 17.6, 10.8 Hz, 1H), 5.75 (d, J = 17.6 Hz, 1H), 5.26 (d, J = 10.8 Hz, 1H), 4.66 (s, 2H), 4.06 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H) ppm. 1-(chloromethyl)-3-ethoxy-5-vinylbenzene 1.739

[0475] [ka] Compound 1.738 (2.2g, 12.34 mmol) of 1,4-dioxane (30mL) Add SOCl2 (3g, 25.22 mmol) to the solution and heat the resulting mixture at 60°C. The mixture was stirred for 12 hours. The mixture was concentrated under vacuum, and the residue was diluted with EA (30 mL) and saturated with N2. Washed with aHCO3 aqueous solution (10 mL). The organic layer was separated and dehydrated with Na2SO4. Concentrated in an empty container, compound 1.739 (2.2 g, 90.5% yield) was obtained as a brownish oily substance. This was used directly without further purification. 2-(3-ethoxy-5-vinylphenyl)acetonitrile 1.740

[0476] [ka] A solution of compound 1.739 (2.2 g, 11.19 mmol) in ACN (20 mL) TMSCN (4.44g, 44.74mmol) and TBAF (16.78mL, TH) 2M of F was added. The resulting mixture was heated to 80°C and stirred for 1 hour. The mixture was then vacuum-sealed. The compound was concentrated and the residue purified (PM11) to obtain compound 1.740 (1.4g, yield 66.8%). ) was obtained as a yellow oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 6.92 (s, 1H), 6.90 (s, 1H), 6.76 (s, 1H), 6.67 (dd , J = 17.6, 10.8 Hz, 1H), 5.77 (d, J= 17.6 Hz, 1H), 5.30 (d, J = 11.2 Hz, 1H), 4 .06 (q, J = 7.2 Hz, 2H), 3.71 (s, 2H), 1.43 (t, J = 7.2 Hz, 3H) ppm. 2-(3-ethoxy-5-formylphenyl)acetonitrile 1.741

[0477] [ka] Remove ozone at -78°C until the reaction mixture changes color to blue, then add compound 1.740 (1.4 The solution (g, 7.48 mmol) in DCM (20 mL) was bubbling into it. Excess ozone was removed by nitrogen. After purging, DMS (8.46 g, 136.16 mmol) was added. The mixture was then mixed for 20 minutes. The mixture was heated to °C and stirred for 3 hours. The reaction mixture was concentrated under vacuum, and the residue was purified (PM11). Compound 1.741 (635 mg, 3.36 mmol, yield 44.9%) was obtained as a white solid. I obtained it. 1H NMR (400 MHz, CHCl3-d) δ: 9.97 (s, 1H), 7.41 (s, 1H), 7.35 (s, 1H), 7.15 (s, 1H), 4.12 (q, J = 6.8 Hz, 2H), 3.81 (s, 2H), 1.46 (t, J = 6.8 Hz, 3H) ppm. Synthesis of intermediate 1.744 Methyl 3-cyclopropyl-5-vinylbenzoate 1.742

[0478] [ka] Compound 1.683 (4.4g, 18.25 mmol) and cyclopropylboronic acid ( 1,4-dioxane (44 mL) (1.72 g, 20.08 mmol) and H2O (4 In a 0.4 mL mixture, add K2CO3 (5.04 g, 36.50 mmol) and Pd (d Add ppf)Cl2 (667.72 mg, 912.56 μmol). Heat the mixture at 80°C. The mixture was heated and stirred under a nitrogen atmosphere for 12 hours. The mixture was concentrated under vacuum, and the residue was purified (PM1 4, R f =0.43) Compound 1.742 (1.45g, 7.17 mmol, yield 3 9.3% was obtained as a yellow oily substance, which was used directly. (3-Cyclopropyl-5-Vinylphenyl)Methanol 1.743

[0479] [ka] A solution of LAH (251.47 mg, 6.63 mmol) in THF (20 mL) is prepared at 0°C. Compound 1.742 (1.34 g, 6.63 mmol) was then added. The mixture was incubated at 0°C for 2 hours. The mixture was stirred. The reaction was quenched by adding HCl (1M) at 0°C to bring the pH to 3. The mixture was diluted with water (50 mL) and extracted with EA (50 mL x 3). The phase was washed with brine (50 mL), dried with Na2SO4, filtered, and concentrated under vacuum. Compound 1.743 (1.2 g) was obtained as a yellow oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 7.22 (s, 1H), 7.07 (s, 1H), 7.01 (s, 1H), 6.71 (dd , J = 17.6, 10.8 Hz, 1H), 5.76 (d, J = 17.6 Hz, 1H), 5.26 (d, J = 10.8 Hz, 1H), 4.68 (d, J = 3.6 Hz, 2H), 1.96-1.89 (m, 1H), 1.01-0.96 (m, 2H), 0.76-0.72 (m, 2H ) ppm. 3-Cyclopropyl-5-(hydroxymethyl)benzaldehyde 1.744

[0480] [ka] Remove ozone at -78°C until the reaction mixture changes color to blue, then add compound 1.743(300) The solution (mg, 1.72 mmol) in DCM (8 mL) was bubbling into it. Excess ozone was removed by nitrogen. After purging, DMS (1.39 g, 22.38 mmol) was added. The mixture was heated at 25°C. The mixture was heated and stirred for 12 hours. The mixture was concentrated under vacuum, and the residue was purified (PM11). The mixture 1.744 (200 mg, 1.14 mmol, yield 65.9%) is treated as a colorless oil. I got it. 1 H NMR (400 MHz, CHCl3-d) δ: 9.97 (s, 1H), 7.65 (s, 1H), 7.49 (s, 1H), 7.37 (s, 1H), 4.75 (s, 2H), 2.02-1.95 (m, 1H), 1.07-1.02 (m, 2H), 0.79-0.75 (m, 2H) ppm. Synthesis of intermediate 1.747 1-(chloromethyl)-3-cyclopropyl-5-vinylbenzene 1.745

[0481] [ka] Compound 1.743 (900 mg, 5.17 mmol) of 1,4-dioxane (10 mL) To the solution in ), SOCl2 (1.84 g, 15.50 mmol) was added at 0°C. The mixture The mixture was heated to 70°C and stirred for 2 hours. The reaction mixture was then mixed with saturated NaHCO3 aqueous solution (10 mL). Quenched by addition, extracted with EA (100 mL x 3). The combined organic layer was brined. Wash with (100 mL x 2), dehydrate with Na2SO4, filter, and concentrate under vacuum to obtain the compound. 1.745 (940 mg) was obtained as a yellow oily substance and used directly in the next step. 2-(3-cyclopropyl-5-vinylphenyl)acetonitrile 1.746

[0482] [ka] Compound 1.745 (940 mg, 4.88 mmol), TMSCN (677.56 mg) ACN (80 ml) of TBAF (6.83 mmol) and TBAF (6.34 mL, 1 M in THF) The solution in (L) was stirred at 25°C for 12 hours. The mixture was concentrated under vacuum, and the residue was purified (PM1 6) Compound 1.746 (760 mg, 4.15 mmol, yield 85%) was then dissolved in a yellow oil. I obtained it as a physical object. 1H NMR (400 MHz, CHCl3-d) δ: 7.06 (s, 1H), 6.99 (s, 1H), 6.84 (s, 1H), 6.57 (dd , J = 17.6, 11.2 Hz, 1H), 5.68 (d, J = 17.6 Hz, 1H), 5.21 (d, J = 11.2 Hz, 1H), 3.63 (s, 2H), 1.86-1.78 (m, 1H), 0.94-0.89 (m, 2H), 0.66-0.62 (m, 2H) ppm. 2-(3-cyclopropyl-5-formylphenyl)acetonitrile 1.747

[0483] [ka] Ozone was added to compound 1.746 (760 mg) at -78°C until the mixture turned blue. The solution was blown into a 4.15 mmol (DCM) solution (8 mL). Excess ozone was removed with nitrogen. After rinsing, add DMS (3.35g, 53.92mmol) and warm the mixture to 25°C. The mixture was stirred for 12 hours. The mixture was concentrated under vacuum to obtain the residue, which was then purified (PM7). Compound 1.747 (380 mg, 2.05 mmol, yield 49.5%) was prepared as a yellow oily substance. I obtained it. 1 H NMR (400 MHz, CHCl3-d) δ: 9.91 (s, 1H), 7.53 (s, 1H), 7.45 (s, 1H), 7.27 (s, 1H), 3.73 (s, 2H), 1.96-1.89 (m, 1H), 1.04-0.98 (m, 2H), 0.73-0.69 (m, 2H) ppm. Synthesis of intermediate 1.754 Methyl 3-bromo-5-(2,2,2-trifluoroethoxy)benzoate 1.749

[0484] [ka] Methyl 3-bromo-5-hydroxybenzoate (4.1g, 17.75mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (4.12g, 1 In a solution of 7.75 mmol) in DMF (40 mL), add K2CO3 (3.68 g, 26.6 Add 2 mmol of water to the reaction mixture. Heat the mixture to 80°C and stir for 12 hours. The mixture was diluted with 100 mL and extracted with EA (100 mL x 3). The combined organic layer was then brined. Wash with (200 mL x 3), dehydrate with Na2SO4, filter, and concentrate under vacuum to obtain the compound. 1.74g (5.75g) was obtained as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ: 7.74 (d, J = 1.6 Hz, 1H), 7.65 (t, J = 1.6 Hz, 1H) , 7.56 (t, J = 1.6 Hz, 1H), 4.92 (q, J = 8.8 Hz, 2H), 3.87 (s, 3H) ppm. Methyl 3-(2,2,2-trifluoroethoxy)-5-vinylbenzoate 1.750

[0485] [ka] Compound 1.749 (5.75 g, 18.37 mmol) and 4,4,5,5-tetra Methyl-2-vinyl-1,3,2-dioxaborolane (4.53g, 29.39mmol) In a solution of 4.98 mL of DME (60 mL), add Pd(dppf)Cl2 (1.34 g) (1.84 mmol) and CsF (5.86 g, 38.57 mmol) were added. Mix The substance was heated at 80°C under a nitrogen atmosphere for 12 hours. The reaction mixture was diluted with water (100 mL). Extraction was performed using EA (100 mL x 3). The combined organic layer was washed with brine (100 mL x 2). The solution was purified, dehydrated with Na2SO4, filtered, and concentrated under vacuum. The residue was then purified (PM18). Compound 1.750 (3g, 11.53 mmol, yield 62.8%) was obtained as a yellow oily substance. Ta. 1 H NMR (400 MHz, CHCl3-d) δ: 7.81 (s, 1H), 7.49 (t, J = 1.6 Hz, 1H), 7.22 (t, J = 2.0 Hz, 1H), 6.72 (dd, J = 17.6, 10.8 Hz, 1H), 5.86 (d, J = 17.6 Hz, 1H), 5.3 8 (d, J = 10.8 Hz, 1H), 4.43 (q, J = 8.0 Hz, 2H), 3.95 (s, 3H) ppm. (3-(2,2,2-trifluoroethoxy)-5-vinylphenyl)methanol 1.7 51

[0486] [ka] A solution of LAH (481.34 mg, 12.68 mmol) in THF (40 mL) contains 0 1.750 ml (3.3 g, 12.68 mmol) of compound was added at 0°C. The mixture was left to stand at 0°C for 2 hours. The mixture was stirred. By adding HCl aqueous solution (1M) at 0°C to bring the pH to 3, the reaction products were broken down. Quenched. The mixture was diluted with water (100 mL) and extracted with EA (100 mL x 3). The combined organic phases were washed with brine (100 mL), dried with Na2SO4, and filtered. The compound was concentrated under vacuum. The residue was purified (PM7) to obtain compound 1.751 (2.4g, 10.34 mmol (81.5% yield) was obtained as a yellow oily substance. 1H NMR (400 MHz, CHCl3-d) δ: 7.09 (s, 1H), 6.92 (s, 1H), 6.88 (s, 1H), 6.68 (dd , J = 17.6, 10.8 Hz, 1H), 5.77 (d, J = 17.6 Hz, 1H), 5.30 (d, J = 10.8 Hz, 1H), 4.69 (s, 2H), 4.42-4.35 (m, 2H) ppm. 1-(chloromethyl)-3-(2,2,2-trifluoroethoxy)-5-vinylbenz 1.752

[0487] [ka] Compound 1.751 (2.4g, 10.34 mmol) of 1,4-dioxane (30mL) Add SOCl2 (3.69g, 31.01 mmol, 2.25mL) to the solution at 0°C. It was added slowly. Then the mixture was heated to 70°C and stirred for 2 hours. The reaction mixture was saturated with N Quench by slowly adding 10 mL of aqueous solution of aHCO3, then add water (10 Diluted with 0 mL and extracted with EA (100 mL x 3). The combined organic layer was then treated with brine (1 Wash with 200 mL x 2), dehydrate with Na2SO4, filter, and concentrate under vacuum to obtain compound 1. 752 (2.62 g) was obtained as a yellow oily substance, which was used directly without further purification. 2-(3-(2,2,2-trifluoroethoxy)-5-vinylphenyl)acetoni Ru 1.753

[0488] [ka] Compound 1.752 (2.62g, 10.45mmol), TMSCN (1.45g, 1 ACN (80 ml) of 4.63 mmol) and TBAF (13.59 mL, 1 M in THF) The mixture was stirred at 25°C for 12 hours. The mixture was concentrated under vacuum and purified (PM16). Then, compound 1.753 (1.5g, 6.22 mmol, yield 59.5%) was obtained as a yellow oily substance. It was obtained as such. 1 H NMR (400 MHz, CHCl3-d) δ: 7.06 (s, 1H), 6.95 (s, 1H), 6.83 (s, 1H), 6.67 (dd , J = 17.6, 10.8 Hz, 1H), 5.78 (d, J = 17.6 Hz, 1H), 5.35 (d, J = 10.8 Hz, 1H), 4.38 (q, J = 8.0 Hz, 2H), 3.74 (s, 2H) ppm. 2-(3-formyl-5-(2,2,2-trifluoroethoxy)phenyl)acetonite Lil 1.754

[0489] [ka] Ozone was added to compound 1.753 (1.5g) at -78°C until the mixture turned blue. The solution was blown into a 15 mL solution of 6.22 mmol DCM. Excess ozone was removed with nitrogen. After rinsing, DMS (5.02g, 80.84mmol) was added. The mixture was then heated to 25°C. The mixture was heated and stirred for 12 hours. The mixture was concentrated under vacuum, and the residue was purified (PM7) to obtain compound 1. 0.754 (1g, 4.11 mmol, yield 66.1%) was obtained as a yellow oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 10.01 (s, 1H), 7.56 (s, 1H), 7.42 (d, J = 1.2 Hz, 1H), 7.27 (t, J = 1.6 Hz, 1H), 4.47 (q, J = 8.0 Hz, 2H), 3.86 (s, 2H) ppm. Synthesis of intermediate 1.803 3-Bromo-5-(methoxymethyl)benzoic acid 1.797

[0490] [ka] Methyl 3-bromo-5-(bromomethyl)benzoate (900 mg, 2.92 mmol) (1) Mixture in MeOH (10 mL) contains NaOMe (1.58 g, 29.22 mmol) ) was added. The mixture was heated to 65°C and stirred for 4 hours. The mixture was cooled to 25°C and vacuum-sealed. It was concentrated. The residue was diluted with water (2 mL) and the pH was adjusted to 5 with HCl aqueous solution (1 M). The mixture was extracted with EA (20 mL x 2), and the combined organic phase was washed with brine (20 mL). Purify, dry with anhydrous Na2SO4, filter, and concentrate under vacuum to obtain compound 1.797(700 (mg) was obtained as a pale yellow solid. 1 H NMR (400 MHz, MeOH-d4) δ: 8.05 (s, 1H), 7.94 (s, 1H), 7.73 (s, 1H), 4.50 (s, 2H), 3.41 (s, 3H) ppm. 3-(methoxymethyl)-5-vinylbenzoic acid 1.798

[0491] [ka] Compound 1.797 (0.7g, 2.86mmol), CsF (867.75mg, 5. 71 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxabond Loran (659.87 mg, 4.28 mmol) and Pd(dppf)Cl2·CH2 A mixture of Cl2 (116.63 mg, 142.82 μmol) in DME (10 mL) The mixture was stirred at 90°C under a nitrogen atmosphere for 12 hours. The mixture was filtered, concentrated, and the residue was purified (PM7). Compound 1.798 (400 mg, 2.08 mmol, yield 72.8%) was then extracted into yellow oil. It was obtained as a substance. 1 H NMR (400 MHz, MeOH-d4) δ: 8.00 (s, 1H), 7.89 (s, 1H), 7.64 (s, 1H), 6.80 (dd , J = 17.6, 10.8 Hz, 1H), 5.87 (d, J = 17.6 Hz, 1H), 5.33 (d, J = 11.2 Hz, 1H), 4.51 (s, 2H), 3.41 (s, 3H) ppm. Methyl 3-(methoxymethyl)-5-vinylbenzoate 1.799

[0492] [ka] Mixture of compound 1.798 (400 mg, 2.08 mmol) in MeOH (30 mL) Add SOCl2 (1.24g, 10.41 mmol) at 0°C, then steep the mixture for 60°C. The mixture was heated to °C and stirred for 0.5 hours. The mixture was cooled to 25°C and a saturated NaHCO3 aqueous solution was used. It was poured into 50 mL. The aqueous phase was extracted with EA (50 mL x 3), and the combined organic phase was The sample was washed with brine (50 mL), dried with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM7) to obtain compound 1.799 (380 mg, 1.84 mmol, yield 8 8.5% was obtained as a yellow oily substance. 1 H NMR (400 MHz, MeOH-d4) δ: 7.98 (s, 1H), 7.87 (s, 1H), 7.64 (s, 1H), 6.79 (dd , J = 17.6, 11.2 Hz, 1H), 5.87 (d, J = 17.6 Hz, 1H), 5.33 (d, J = 11.2 Hz, 1H), 4.50 (s, 2H), 3.91 (s, 3H), 3.40 (s, 3H) ppm. (3-(methoxymethyl)-5-vinylphenyl)methanol 1.800

[0493] [ka] Compound 1.799 (380 mg, 1.84 mmol) in a mixture of THF (20 mL) Under nitrogen protection at 0°C, LAH (83.91 mg, 2.21 mmol) was added in one go. Mixing The mixture was heated to 25°C and stirred for 0.5 hours. The mixture was cooled to 0°C and EA (10 mL) Diluted. The mixture was added to water (0.2 mL), followed by an aqueous NaOH solution (10% by weight, 0.2 mL). Quenched by adding ) and water (0.6 mL). After stirring for 0.5 hours, Na2S O4 (1g) was added and stirring continued for 0.5 hours. The resulting suspension was filtered and concentrated under vacuum. The residue was purified (PM2), and compound 1,800 (260 mg, 1.46 mmol, yield) was obtained. 79.2% was obtained as a yellow oily substance. 1 H NMR (400 MHz, MeOH-d4) δ: 7.36 (s, 1H), 7.31 (s, 1H), 7.23 (s, 1H), 6.75 (dd , J = 17.6, 10.8 Hz, 1H), 5.80 (d, J = 17.6 Hz, 1H), 5.24 (d, J = 10.8 Hz, 1H), 4.60 (s, 2H), 4.46 (s, 2H), 3.38 (s, 3H) ppm. 1-(chloromethyl)-3-(methoxymethyl)-5-vinylbenzene 1.801

[0494] [ka] Compound 1,800 (250 mg, 1.40 mmol) of 1,4-dioxane (20 mL) To the mixture, SOCl2 (333.76 mg, 2.81 mmol) was added at 0°C. The mixture was then heated to 90°C and stirred for 1 hour. The mixture was concentrated under vacuum to obtain compound 1.80. 1 (250 mg) was obtained and used without purification. 1 H NMR (400 MHz, MeOH-d4) δ: 7.41 (s, 1H), 7.36 (s, 1H), 7.29 (s, 1H), 6.74 (dd , J = 17.6, 10.8 Hz, 1H), 5.82 (d, J = 17.6 Hz, 1H), 5.27 (d, J = 10.8 Hz, 1H), 4.64 (s, 2H), 4.46 (s, 2H), 3.39 (s, 3H) ppm. 2-(3-(methoxymethyl)-5-vinylphenyl)acetonitrile 1.802

[0495] [ka] Compound 1.801 (250 mg, 1.27 mmol), TMSCN (189.16 mg ACN (50 ml) of TBAF (1.91 mmol) and TBAF (2.54 mL, 1 M in THF) The mixture in (L) was stirred at 25°C for 12 hours. The mixture was concentrated under vacuum, and the residue was purified (PM). 6) Compound 1.802 (100 mg, 534.08 μmol, yield 42.0%) was then prepared. It was obtained as a yellowish oily substance. 1 H NMR (400 MHz, MeOH-d4) δ: 7.37-7.35 (m, 2H), 7.24 (s, 1H), 6.74 (dd, J = 17. 6, 11.2 Hz, 1H), 5.83 (d, J = 17.6 Hz, 1H), 5.29 (d, J = 11.2 Hz, 1H), 4.46 (s, 2H), 3.89 (s, 2H), 3.39 (s, 3H) ppm. 2-(3-formyl-5-(methoxymethyl)phenyl)acetonitrile 1.803

[0496] [ka] Add ozone at -78°C until the reactant changes color to blue (compound 1.802 (100mg)). The excess ozone was blown into a solution of 534.08 μmol in DCM (20 mL). After purging with nitrogen, DMS (331.83 mg, 5.34 mmol) was added. The mixture was heated to 20°C and stirred for 12 hours. The reaction mixture was concentrated under vacuum, and the residue was purified (PM1 1) Compound 1.803 (80 mg, 422.81 μmol, yield 79.2%) was then used without It was obtained as a colored oily substance. 1 H NMR (400 MHz, MeOH-d4) δ: 9.98 (s, 1H), 7.82-7.81 (m, 2H), 7.64 (s, 1H), 4.5 4 (s, 2H), 4.01 (s, 2H), 3.42 (s, 3H) ppm. Synthesis of intermediate 1.825 3-(chloromethyl)-5-(trifluoromethoxy)benzaldehyde 1.824

[0497] [ka] Add ozone at -78°C until the reactants change color to blue (compound 1.502 (100mg)). The solution (422.62 μmol) in DCM (5 mL) was blown into it. Excess ozone was removed by nitrogen. After purging, DMS (0.44 g, 7.08 mmol) was added. The mixture was then heated to 20°C. The mixture was heated and stirred for 12 hours. The reaction mixture was concentrated under vacuum, and the residue was purified (PM7). The combined mixture 1.824 (60 mg, 251.48 μmol, yield 59.5%) was prepared as a colorless oil. I obtained it. 1 H NMR (400 MHz, CHCl3-d) δ: 10.02 (s, 1H), 7.86 (s, 1H), 7.69 (s, 1H), 7.53 (s , 1H), 4.65 (s, 2H) ppm. 3-((1H-imidazole-1-yl)methyl)-5-(trifluoromethoxy)ben Zualdehyde 1.825

[0498] [ka] A solution of compound 1.824 (500 mg, 2.10 mmol) in ACN (5 mL) is added. Midazole (713.33 mg, 10.48 mmol) was added. Then reaction mixture 6 was added. The mixture was heated to 0°C and stirred for 12 hours. The mixture was concentrated, and the crude product was purified (PM151). Compound 1.825 (450 mg, 1.67 mmol, yield 79.5%) was obtained as a white solid. I obtained it. LCMS (AM3): rt = 0.830 min, (271.0 [M+H] + ), 100% pure. Synthesis of intermediate 1.826 3-(furan-3-ylmethyl)-5-(trifluoromethoxy)benzaldehyde 1. 826

[0499] [ka] Compound 1.824 (500 mg, 2.10 mmol) contains 1,4-dioxane (1.5 mg In a solution of H2O (0.15 mL), add K2CO3 (579.28 mg, 4.19 mm) (ol), furan-3-ylboronic acid (447.29 mg, 2.31 mmol) and Pd (dppf)Cl2 (153.34 mg, 209.56 μmol) was added. Reaction mixture The mixture was heated to 70°C and stirred under a nitrogen atmosphere for 12 hours. The reaction mixture was filtered, and the filtrate was removed under vacuum. The compound was concentrated. The residue was purified (PM150) to obtain compound 1.826 (360 mg, 1.24 ml). A quantity of mol, yielding 59.3%, was obtained as a yellow oily substance. LCMS (AM3): rt = 1.001 min, (271.2 [M+H] + ), purity 94.4%. Synthesis of intermediate 1.834 2-Chloro-5-(hydroxymethyl)benzaldehyde 1.834

[0500] [ka] (3-Bromo-4-chlorophenyl)methanol (1g, 4.52 mmol) TH In a solution in F (10 mL), n-BuLi (3.79 mL, 2.5 mL) was dissolved under a nitrogen atmosphere at -78°C. M) was added. After stirring for 0.5 hours, DMF (330.01 mg, 4.52 mmol) was added. The mixture was stirred at -78°C for 0.5 hours after adding the other ingredients. The reaction mixture was then diluted with water (200 mL). The mixture was then extracted with EA (100 mL x 3). The combined organic layer was then treated with brine (100 mL x 2). Washed, dehydrated with Na2SO4, filtered, and concentrated under vacuum. The crude product was subjected to reverse-phase HPLC. Purified using AM46), compound 1.834 (200 mg, 1.17 mmol, yield 2 5.9% was obtained as a white solid. LCMS (AM3): rt = 0.570 min, (171.0 [M+H] + ), purity 39.0% Synthesis of intermediate 1.64 (5-Bromo-2-cyclobutoxyphenyl)methanol, 1.62

[0501] [ka] 4-Bromo-2-(hydroxymethyl)phenol (2.0g, 9.95mmol) Mix bromocyclobutane (2.66g, 19.70 mmol) with DMF (10mL). Potassium carbonate (3.4g, 24.63 mmol) was added to the mixture under nitrogen protection at ambient temperature. Next, the mixture was heated to 80°C and stirred for 12 hours. The reaction mixture was then mixed with water (100 mL). The mixture was poured into a container, and the aqueous phase was extracted with EA (50 mL x 2). The combined organic phase was then extracted with brine (5 The solution was washed with 0 mL of water, dehydrated with anhydrous Na2SO4, and concentrated under vacuum. The residue was then purified (PM4). Compound 1.62 (1.6g, 6.22 mmol, yield 63.2%) was then obtained as a white solid. I obtained it. 1 H NMR (400 MHz, MeOD) δ: 7.49 (d, J = 2.8 Hz, 1H), 7.28 (dd, J = 2.8, 8.8 Hz, 1H), 6.67 (d, J = 8.8 Hz, 1H), 4.71-4.62 (m, 1H), 4.59 (s, 2H), 2.52-2.39 (m, 2H) ), 2.18-2.05 (m, 2H), 1.83-1.67 (m, 2H) ppm. (2-Cyclobutoxy-5-vinylphenyl)methanol, 1.63

[0502] [ka] Tributyl(vinyl) stannane (1.85 g, 5.83 mmol) and compound 1. Mixture of 62 (1.5g, 5.83 mmol) in toluene (50mL) under nitrogen protection At ambient temperature, tetrakis(triphenylphosphine)palladium (337.06 mg, 291 (0.69 μmol) was added. The mixture was then heated to 100°C and stirred for 12 hours. The substance was cooled to room temperature and then poured into a saturated KF aqueous solution (20 mL). The mixture was left for 30 minutes. The mixture was stirred, and then extracted with EA (50 mL x 4). The combined organic phase was then treated with brine (50 mL). Washed with L), dried with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM 11) Compound 1.63 (600 mg, 2.94 mmol, yield 50.4%) was colorless. It was obtained as an oily substance. 1 H NMR (400 MHz, MeOH-d4) δ: 7.48 (d, J = 2.4 Hz, 1H), 7.23 (dd, J = 2.4, 8.4 H z, 1H), 6.71-6.62 (m, 2H), 5.62 (dd, J = 1.2, 17.6 Hz, 1H), 5.07 (dd, J = 1.2, 1 0.8 Hz, 1H), 4.71-4.64 (m, 1H), 4.62 (s, 2H), 2.50-2.38 (m, 2H), 2.21-2.07 (m, 2 H), 1.86-1.68 (m, 2H) ppm. 4-Cyclobutoxy-3-(hydroxymethyl)benzaldehyde, 1.64

[0503] [ka] Remove ozone at -78°C until the reaction mixture turns blue, compound 1.63 (600 mg, Blow the mixture into a 30 mL solution of DCM (2.94 mmol), then allow the reaction mixture to cool to 0°C. The mixture was heated and DMS (1.82 g, 29.37 mmol) was added. The reaction mixture was then heated to 25°C. The mixture was heated and stirred for 12 hours. The reaction mixture was poured into water (50 mL) and the aqueous solution was prepared using EA ( Extraction was performed using 50 mL x 2. The combined organic phase was washed with brine (50 mL) and anhydrous sodium. It was dehydrated with H2SO4 and concentrated in vacuo. The residue was purified (PM11) to give Compound 1.64 (2 50 mg, 1.21 mmol, 41.3% yield) as a yellow oil. 1 1H NMR (400 MHz, MeOH-d4) δ: 9.83 (s, 1H), 7.98 (d, J = 2.4 Hz, 1H), 7.79 (dd, J = 2.4, 8.4 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 4.74-4.68 (m, 1H), 4.67 (s, 2H), 2.54-2.46 (m, 2H), 2.​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​LCMS (AM3): rt = 0.812 min, (577.1 [M+H] + ), purity 29%. Synthesis of intermediate 1.573 5-((2-(4-((3-chloro-5-cyanobenzyl)amino)butoxy)ethyl) Amino)benzo[c][2,6]naphthyridine-8-carboxamide 1.573

[0505] [ka] Intermediate E (80 mg, 205.19 μmol), sodium acetate (67.33 mg, 8 (20.76 μmol) and 3-chloro-5-formylbenzonitrile (33.97 mg) The mixture (205.19 μmol) in MeOH (3 mL) was stirred at 20°C for 12.5 hours. Next, sodium triacetoxyborhydride (130.47 mg, 615.57 μg) (mol) was added. The reaction mixture was stirred separately at 20°C for 3 hours. The reaction mixture was filtered and filtered. The liquid was concentrated under vacuum. The residue was purified (PM57) to obtain compound 1.573 (60 mg, 11 9.29 μmol, yielding 58.1%, was obtained as a white solid. LCMS (AM7): rt = 0.865 min, (503.1 [M+H] + ), purity 66.1%. Synthesis of intermediate 1.399 tert-butyl3-(4-(((benzyloxy)carbonyl)amino)butoxy)a Zethidine-1-carboxylate 1.395

[0506] [ka] Benzyl N-(4-bromobutyl)carbamate (3.30g, 11.55mmol) tert-butyl 3-hydroxyazetidine-1-carboxylate (1g, 5.77 mmol), NaOH (2.31 g, 57.73 mmol) and TBAI (0.11 g) The mixture (298 mmol) in H2O (5 mL) was stirred at room temperature for 20 hours. The substance was diluted with water (50 mL) and extracted with MTBE (20 mL x 2). The combined organic phase was then... The sample was washed with brine (40 mL), dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM47) to obtain compound 1.395 (1.1g, yield 50.3%) as a pale yellow compound. It was obtained as an oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 7.37-7.28 (m, 5H), 5.10 (s, 2H), 4.86 (br s, 1H), 4.20-4.14 (m, 1H), 4.07-4.03 (m, 2H), 3.82-3.78 (m, 2H), 3.41-3.30 (m, 2H), 3.26 -3.17 (m, 2H), 1.65-1.55 (m, 4H), 1.44 (s, 9H) ppm. Benzyl (4-(azetidine-3-yloxy)butyl)carbamate 1.396

[0507] [ka] Compound 1.395 (1.1 g, 2.91 mmol) and TFA (135.06 mmol) The mixture (10 mL) in DCM (10 mL) was stirred at room temperature for 1 hour. By concentrating under vacuum, compound 1.396 (1.5g, TFA salt) was obtained as a brownish oily substance. It was used directly without further purification. LCMS (AM3): rt = 0.334 min, (279.2 [M+H] + ), purity 71%. Methyl 5-(3-(4-((((benzyloxy)carbonyl)amino)butoxy)azeti Zin-1-yl)benzo[c][2,6]naphthyridine-8-carboxylate 1.39 7

[0508] [ka] Compound 1.396 (0.4g, 1.44mmol), Compound 1.1 (0.3g, 1.1 DMSO (8 mL) of 0 mmol) and DIPEA (0.8 mL, 4.59 mmol) The mixture was stirred at 90°C for 16 hours, and a brownish solid precipitated. The precipitate was filtered and purified. (PM47) was used to obtain compound 1.397 (0.4g, yield 70.7%) as a brownish solid. Ta. LCMS (AM3): rt = 0.875 min, (515.3 [M+H] + ), 100% pure. Methyl 5-(3-(4-aminobutoxy)azetidine-1-yl)benzo[c][2,6 Naphthyridine-8-carboxylate 1.398

[0509] [ka] Compound 1.397 (0.4g, 0.777 mmol), carbon-supported palladium (0.05 g, 10 wt% Pd / C) and ammonium hydroxide (0.5 mL, 3.25 mmol, The mixture was incubated in 20 mL of 25% MeOH under H2 pressure (1 atm) at room temperature for 16 hours. The reaction mixture was heated to 40°C and stirred for 5 hours. The catalyst was filtered off, and the filtrate was concentrated under vacuum. By reducing the compound, compound 1.398 (0.29 g, yield 98.1%) was obtained as a yellow solid. Furthermore, it was used directly without purification. LCMS (AM3): rt = 0.690 min, (381.2 [M+H] + ), purity 94.2%. Methyl 5-(3-(4-((3-chloro-4-(trifluoromethoxy)benzyl)amide (no)butoxy)azetidine-1-yl)benzo[c][2,6]naphthyridine-8-cal Boxylate 1.399

[0510] [ka] 3-Chloro-4-(trifluoromethoxy)benzaldehyde (0.17g, 0.75 7 mmol) and compound 1.398 (0.29 g, 0.762 mmol) of MeOH ( Stir the mixture in 10 mL at room temperature for 16 hours, then add sodium triacetoxyboronhydride. Lilium (0.7g, 3.30 mmol) was added. The reaction mixture was then stirred for 1 hour. The reaction mixture was concentrated under vacuum, and the residue was purified (PM67) to obtain compound 1.399 (0.17 g, yielding 38.1%, was obtained as a yellow solid. LCMS (AM3): rt = 0.815 min, (589.2 [M+H] + ), 100% pure. Synthesis of intermediate 1.625 tert-butyl N-[(1S)-2-[4-(benzyloxycarbonylamino)but [Xyxy]-1-methyl-ethyl]carbamate 1.621

[0511] [ka] tert-butyl N-[(1S)-2-hydroxy-1-methyl-ethyl]carbame (2g, 11.41 mmol), benzyl(4-bromobutyl)carbamate (6.6 (g, 23.06 mmol), NaOH (4.57 g, 114.14 mmol) and TB Mixture of AI (0.21g, 0.569 mmol) in H2O (11mL) at room temperature for 18 minutes. The mixture was stirred for a certain amount of time. Add the reaction mixture to water (80 mL) and add the resulting mixture to EA (20 mL × 3) Extraction was performed. The combined organic phase was washed with brine (40 mL) and then with anhydrous Na2SO4. The mixture was dehydrated, filtered, and concentrated under vacuum. The residue was purified (PM47) to obtain compound 1.621(0 0.93 g, 1.83 mmol, yield 16.1% was obtained as a colorless oil. LCMS (AM3): rt = 0.968 mins, (403.2 [M+Na] + ), purity 75.3%. (S)-Benzyl(4-(2-aminopropoxy)butyl)carbamate 1.622

[0512] [ka] Compound 1.621 (820 mg, 2.16 mmol) of HCl in 1,4-dioxane The mixture in the solution (20 mL, 4 M) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum. The residue was purified (PM123) to obtain compound 1.622 (460 mg, 1.64 mmol, The HCl salt was obtained as a colorless oily substance with a yield of 76.1%. LCMS (AM3): rt = 0.658 min, (281.1 [M+H] + ), 100% pure. (S)-methyl 5-((1-(4-(((benzyloxy)carbonyl)amino)butoxy (C)propan-2-yl)amino)benzo[c][2,6]naphthyridine-8-carboc Silate 1.623

[0513] [ka] Compound 1.622 (440 mg, 1.57 mmol, HCl salt), Compound 1.1 (48 (0.36 mg, 1.73 mmol) and DIPEA (608.50 mg, 4.71 mg) The mixture of ol) in DMSO (10 mL) was stirred at 80°C for 12 hours. The reaction mixture was filtered. The filtrate was purified (PM122) to obtain compound 1.623 (400 mg, 723.26 μg). A quantity of mol, yielding 46.1%, was obtained as a yellow, rubbery substance. LCMS (AM3): rt = 0.849 min, (517.4 [M+H] + ), purity 98.9%. (S)-methyl 5-((1-(4-aminobutoxy)propan-2-yl)amino)ben Zo[c][2,6]naphthyridine-8-carboxylate 1.624

[0514] [ka] Compound 1.623 (400 mg, 723.26 μmol, HCl salt) and ammonium hydroxide A mixture of monium aqueous soluti...

Claims

1. Compounds of formula I, or their salts, hydrates, or solvates 【Chemistry 1】 (In the formula, R １ is -C(O)OH or -C(O)NH ２ Selected from; Q is expression Ia or Ib: 【Chemistry 2】 (The bond a in formulas Ia and Ib corresponds to the bond a in formula I, and the bond in formulas Ia and Ib b corresponds to the combination b in equation I; R ２ and R ３ Each is independently selected from hydrogen or methyl; X is selected from NH or O; R ａ and R ｅ These are independently selected from hydrogen, methyl, or halo; R ｂ and R ｄ These are, independently, hydrogen, halo, cyano, and (1-4C) alkyl, - [CH ２ ０－３ -(1 - 4C) alkoxy,​ -[CH ２ ] ０－３ -C(O)NH ２ 、 - [CH ２ ] ０－３ -C(O)NH(1-4C)alkyl, - [CH ２ ] ０－３ -C(O)N[(1-4C)alkyl] ２ , - [CH ２ ] ０－３ -NH(1-4C) alkyl, - [CH ２ ] ０－３ -N[(1-4C)alkyl] ２ , - [CH ２ ] ０－３ -S(O) ｑ - (1-4C) alkyl (wherein q is 0, 1 or 2) (It is) - [CH ２ ] ０－３ -C(O)(1-4C) alkyl, - [CH ２ ] ０－３ -C(O)O-(1-4C)alkyl, - [CH ２ ] ０－３ -N(R) ｆ )C(O)-(1-4C)alkyl(wherein R ｆ is hydrogen (or methyl) - [CH ２ ] ０－３ -S(O) ２ NH(1-4C) alkyl, - [CH ２ ] ０－３ -S(O) ２ N[(1-4C)alkyl] ２ , - [CH ２ ] ０－３ -N(R) ｇ ) SO ２ - (1-4C) alkyl (wherein R) ｇ is hydrogen (It is methyl) formula: -Y １ -[CH ２ ] ０－３ -Z １ (In the formula, Y １ It does not exist, or -O-, -NH-, -NMe-, -S-, -S(O ) - or -S(O) ２ - and; Z １ (3-6C) cycloalkyl, phenyl, 4-6 membered heterocyclyl or 5-membered (The base is a 6-membered heteroaryl) Selected from; Any alkyl, alkoxy or R ｂ and R ｄ Any alkyl portion within the substituent is Halo, hydroxy, cyano, amino, -C(O)OH, -C(O)NH ２ (1-2C) One or more substitutions selected from alkoxy or (3-4C)cycloalkoxy Replaced by any choice; Z １ Halo, hydroxy, cyano, amino, -C(O)OH, -C(O)NH ２ , ( (1-2C)alkoxy, (1-2C)alkyl, (3-4C)cycloalkyl, (3-4 C) Cycloalkoxy, -C(O)NH(1-2C) alkyl, -C(O)N[(1-2 C) Alkyl] ２ -NH(1-2C)alkyl, -N[(1-2C)alkyl] ２ , - S(O) ｑ -(1-2C)alkyl (wherein q is 0, 1, or 2), -C(O) (1-2C)alkyl, -C(O)O-(1-2C)alkyl, -N(R ｆ ) C(O)- (1-2C) alkyl, -S(O) ２ NH(1-2C) alkyl, -S(O) ２ N[(1 [~2C) alkyl] ２ , or -NHSO ２ - One selected from (1-2C) alkyl groups Alternatively, it may be optionally substituted with multiple substituents, any (1-2C)alkoxy, (1- 2C) alkyl, (3-4C) cycloalkyl, or (3-4C) cycloalkoxy groups , halo, cyano, hydroxy, (1-2C) alkyl, (1-2C) alkoxy or ( One or more substituents selected from 1-2C)alkoxy-(1-2C)alkyl Replaced by more optional selection; R ｃ is hydrogen, halo, cyano, -C(O)NH ２ , (1-4C) alkyl, - [CH ２ ] ０－３ - (1-4C) alkoxy, - [CH ２ ] ０－３ - (3-6C) Cycloalkoxy, -[CH ２ ] ０－３ -C(O)NH ２ 、 - [CH ２ ] ０－３ -C(O)NH(1-4C)alkyl, - [CH ２ ] ０－３ -C(O)N[(1-4C)alkyl] ２ , - [CH ２ ] ０－３ -NH(1-4C) alkyl, - [CH ２ ] ０－３ -N[(1-4C)alkyl] ２ , - [CH ２ ] ０－３ -S(O) ｑ - (1-4C) alkyl (wherein q is 0, 1 or 2) (It is) -[CH ２ ０－３ -C(O)(1-4C)alkyl,​ - [CH ２ ] ０－３ -C(O)O-(1-4C)alkyl, - [CH ２ ] ０－３ -N(R) ｈ )C(O)-(1-4C)alkyl(wherein R ｈ is hydrogen (or methyl) - [CH ２ ０－３ - S(O) ２ NH(1-4C) alkyl,​ - [CH ２ ] ０－３ -S(O) ２ N[(1-4C)alkyl] ２ , - [CH ２ ] ０－３ -N(R) ｉ ) SO ２ - (1-4C) alkyl (wherein R) ｉ is hydrogen (It is methyl) formula: -Y ２ -[CH ２ ] ０－３ -Z ２ (In the formula, Y ２ It does not exist, or -O-, -NH-, -NMe-, -S-, -S(O ) - or -S(O) ２ - and; Z ２ (3-6C) cycloalkyl, phenyl, 4-6 membered heterocyclyl or 5-membered (The base is a 6-membered heteroaryl) Selected from; Any alkyl, alkoxy or R ｃ Any alkyl portion within the substituent is a halo, hydr Roxy, cyano, amino, -C(O)OH, -C(O)NH ２ , (1-2C)alkoxy , or by one or more substituents selected from (3-4C) cycloalkoxys. Replaced by selection; Z ２ Halo, hydroxy, cyano, amino, -C(O)OH, -C(O)NH ２ , ( (1-2C)alkoxy, (1-2C)alkyl, (3-4C)cycloalkyl, (3-4 C) Cycloalkoxy, -C(O)NH(1-2C) alkyl, -C(O)N[(1-2 C) Alkyl] ２ -NH(1-2C)alkyl, -N[(1-2C)alkyl] ２ , - S(O) ｑ -(1-2C)alkyl (wherein q is 0, 1, or 2), -C(O) (1-2C)alkyl, -C(O)O-(1-2C)alkyl, -N(R ｆ ) C(O)- (1-2C) alkyl, -S(O) ２ NH(1-2C) alkyl, -S(O) ２ N[(1 [~2C) alkyl] ２ , or -NHSO ２ - One selected from (1-2C) alkyl groups Alternatively, it may be optionally substituted with multiple substituents, and any (1-2C)alkoxy, (1- 2C) alkyl, (3-4C) cycloalkyl, or (3-4C) cycloalkoxy groups , halo, cyano, hydroxy, (1-2C) alkyl, (1-2C) alkoxy or ( One or more substituents selected from 1-2C)alkoxy-(1-2C)alkyl (More arbitrarily replaced).

2. R １ However, the compound according to claim 1, or its salt or hydrate, is -C(O)OH. Ku is a solvate.

3. R １ However, C(O)NH ２ The compound according to claim 1, or its salt or hydrate, also Ku is a solvate.

4. Q is expression Ia or Ib: 【Transformation 3】 (The bond a in formulas Ia and Ib corresponds to the bond a in formula I, and the bond in formulas Ia and Ib b corresponds to the combination b in equation I; R ２ and R ３ Both are hydrogen, or R ２ and R ３ One side is hydrogen, the other side is me Chill; X is selected from O or NH) as described in any one of claims 1 to 3 A compound, or its salt, hydrate, or solvate.

5. R ａ and R ｅ However, each is independently hydrogen, methyl, fluoro, chloro, or bromo A compound, salt thereof, or hydrate selected from any one of claims 1 to 4. Or, a solvate.

6. R ａ and R ｅ Claim 1, one of which is hydrogen and the other is hydrogen, methyl or halo. A compound described in any one of items 1 through 5, or a salt, hydrate, or solvate thereof.

7. R ａ and R ｅ Claims 1 to 6, one of which is hydrogen and the other is hydrogen or chloro. A compound, or a salt, hydrate, or solvate thereof, as described in any one of the items.

8. R ｂ and R ｄ However, each is independently hydrogen, halo, cyano, (1-4C) alkyl, - [CH ２ ] ０－１ - (1-4C) alkoxy, -[CH ２ ] ０－１ -C(O)NH ２ 、 - [CH ２ ] ０－１ -C(O)NH(1-4C)alkyl, - [CH ２ ] ０－１ -C(O)N[(1-4C)alkyl] ２ , - [CH ２ ] ０－１ -NH(1-4C) alkyl, - [CH ２ ] ０－１ -N[(1-4C)alkyl] ２ , - [CH ２ ] ０－１ -S(O) ｑ - (1-4C) alkyl (wherein q is 0, 1 or 2) (It is) - [CH ２ ] ０－１ -C(O)(1-4C) alkyl, - [CH ２ ] ０－１ -C(O)O-(1-4C)alkyl, - [CH ２ ] ０－１ -NHC(O)-(1-4C)alkyl, - [CH ２ ] ０－１ -S(O) ２ NH(1-4C) alkyl, - [CH ２ ] ０－１ -S(O) ２ N[(1-4C)alkyl] ２ , - [CH ２ ] ０－１ - NHSO ２ - (1-4C) alkyl, formula: -Y １ -[CH ２ ] ０－１ -Z １ (In the formula, Y １ It does not exist, or -O-, -NH-, -NMe-, -S-, -S(O ) - or -S(O) ２ - and; Z １ (3-6C) cycloalkyl, phenyl, 4-6 membered heterocyclyl or 5-membered (The base is a 6-membered heteroaryl) Selected from; Any alkyl, alkoxy or R ｂ and R ｄ Any alkyl portion within the substituent, Halo, hydroxy, cyano, amino, -C(O)OH, -C(O)NH ２ (1-2C) One or more substitutions selected from alkoxy or (3-4C)cycloalkoxy Replaced by any choice; Z １ However, halo, hydroxy, cyano, amino, -C(O)OH, -C(O)NH ２ , ( (1-2C)alkoxy, (1-2C)alkyl, (3-4C)cycloalkyl, (3-4 C) Cycloalkoxy, -C(O)NH(1-2C) alkyl, -C(O)N[(1-2 C) Alkyl] ２ -NH(1-2C)alkyl, -N[(1-2C)alkyl] ２ , - S(O) ｑ -(1-2C)alkyl (wherein q is 0, 1, or 2), -C(O) (1-2C)alkyl, -C(O)O-(1-2C)alkyl, -N(R ｆ ) C(O)- (1-2C) alkyl, -S(O) ２ NH(1-2C) alkyl, -S(O) ２ N[(1 [~2C) alkyl] ２ , or -NHSO ２ - One selected from (1-2C) alkyl groups Alternatively, it may be optionally substituted with multiple substituents, and any (1-2C)alkoxy, (1- 2C) alkyl, (3-4C) cycloalkyl or (3-4C) cycloalkoxy group , halo, cyano, hydroxy, (1-2C) alkyl, (1-2C) alkoxy or ( One or more substituents selected from 1-2C)alkoxy-(1-2C)alkyl A compound according to any one of claims 1 to 7, which is more optionally substituted, The salt, hydrate, or solvate thereof.

9. R ｂ and R ｄ However, each is independently hydrogen, halo, cyano, (1-4C) alkyl, - [CH ２ ] ０－１ - (1-4C) alkoxy, -[CH ２ ] ０－１ -C(O)NH ２ 、 - [CH ２ ] ０－１ -C(O)NH(1-4C)alkyl, - [CH ２ ] ０－１ -C(O)N[(1-4C)alkyl] ２ , - [CH ２ ] ０－１ -NH(1-4C) alkyl, - [CH ２ ] ０－１ -N[(1-4C)alkyl] ２ , - [CH ２ ] ０－１ -S(O) ｑ - (1-4C) alkyl (wherein q is 0, 1 or 2) (It is) - [CH ２ ] ０－１ -C(O)(1-4C) alkyl, - [CH ２ ] ０－１ -C(O)O-(1-4C)alkyl, formula: -Y １ -[CH ２ ] ０－１ -Z １ (In the formula, Y １ It does not exist, or -O-, -NH-, -NMe-, -S-, -S(O ) - or -S(O) ２ - and; Z １ The group is a (3-6C) cycloalkyl or a 5 or 6-membered heteroaryl group. Selected from; Any alkyl, alkoxy or R ｂ and R ｄ Any alkyl portion within the substituent is hydroxycyanoamino-C(O)NH ２ Or from (1-2C)alkoxy Optionally substituted by one or more substituents of choice; Z １ However, halo, hydroxy, cyano, amino, (1-2C)alkoxy, (1-2C)a The substitution is made by one or more substituents selected from lucyl or (1-2C) haloalkyl. A compound according to any one of claims 1 to 8, or a salt thereof, which is selectively substituted. Hydrate or solvate.

10. R ｂ and R ｄ However, each is independently hydrogen, halo, cyano, (1-4C) alkyl, and ha √(1-4C)alkyl, hydroxy(1-4C)alkyl, cyano(1-4C)alkyl L, amino(1-4C)alkyl, (1-2C)alkoxy(1-4C)alkyl, (1 ~4C) alkoxy, halo(1-4C) alkoxy, hydroxy(1-4C) alkoxy ,-[CH ２ ] ０－３ -C(O)NH ２ , or formula: [CH ２ ] ０－１ -Z １ (In the formula, Z １ The group is (3-6C)cycloalkyl or 5-membered heteroaryl. Selected from; Z １ However, the following are optionally replaced by one or more cyanosides: Any compound described in item 1, or a salt, hydrate, or solvate thereof.

11. R ｂ and R ｄ However, each is independently hydrogen, halo, (1-2C)alkyl, (1-2C ) Alkyl, formula: [CH ２ ] ０－１ -Z １ (In the formula, Z １ The group is a (3-4C)cycloalkyl group. Selected from; Any alkyl, alkoxy or R ｂ and R ｄ Any alkyl portion within the substituent, Claim 1, optionally substituted with one or more substituents selected from the halo A compound described in any one of items 10 to 10, or a salt, hydrate, or solvate thereof.

12. R ｂ and R ｄ However, each is independently hydrogen, fluoro, chloro, bromo, cyano, and methyl L, ethyl, methoxy, ethoxy, -CH ２ OH, -CH ２ OCH ３ ien-CH ２ NH ２ , -CH ２ CN、-CH ２ CH ２ OH、-CF ３ 、-OCF ３ 、-O-CH ２ CH ２ OH、 -O-CH ２ CF ３ 、-C(O)NH ２ 、-CH ２ -C(O)NH ２ 、-CH(CH ３ ) CN, -C(CH ３ ) ２ CN, cyclopropyl, 1-cyanocyclopropyl, cyclopro Pyrmethyl, furanylmethyl (e.g., furan-3-ylmethyl), imidazolylmethyl ( For example, imidazo-1-ylmethyl, pyrazolylmethyl (for example, pyrazole-4-ylmethyl) Selected from oxymethyl (e.g., oxazo-4-ylmethyl), claim A compound described in any one of items 1 to 11, or a salt, hydrate, or solvate thereof.

13. R ｂ and R ｄ One of them is hydrogen, halogen, or -OCF ３ And the other is hydrogen Fluoro, chloro, bromo, cyano, methyl, ethyl, methoxy, ethoxy, -CH ２ OH,-CH ２ OCH ３ 、-CH ２ NH ２ 、-CH ２ CN, -CH ２ CH ２ OH, -CF ３ 、-OCF ３ 、-O-CH ２ CH ２ OH、-O-CH ２ CF ３ 、-C(O)NH ２ 、- CH ２ -C(O)NH ２ , -CH(CH ３ )CN, -C(CH ３ ) ２ CN, cyclopropyl 1-Cyanocyclopropyl, Cyclopropylmethyl, Furanylmethyl (e.g., furan) -3-ylmethyl), imidazolylmethyl (e.g., imidazo-1-ylmethyl), pyrazo Lylmethyl (e.g., pyrazole-4-ylmethyl), oxazolylmethyl (e.g., oxazol-4-ylmethyl), A compound selected from zo-4-ylmethyl, according to any one of claims 1 to 12. or its salt, hydrate, or solvate.

14. R ｂ and R ｄ One of them is hydrogen, halogen, or -OCF ３ And the other is hydrogen Fluorochlorobromomethyl-OCF ３ or selected from cyclopropyl , the compound according to any one of claims 1 to 13, or its salt, hydrate, or solvent Japanese items.

15. R ｃ However, hydrogen, halo, cyano, -C(O)NH ２ , (1-4C) alkyl, - [CH ２ ] ０－１ - (1-4C) alkoxy, - [CH ２ ] ０－１ - (3-6C) Cycloalkoxy, -[CH ２ ] ０－１ -C(O)NH ２ 、 - [CH ２ ] ０－１ -C(O)NH(1-4C)alkyl, - [CH ２ ] ０－１ -C(O)N[(1-4C)alkyl] ２ , - [CH ２ ] ０－１ -NH(1-4C) alkyl, - [CH ２ ] ０－１ -N[(1-4C)alkyl] ２ , - [CH ２ ] ０－１ -S(O) ｑ - (1-4C) alkyl (wherein q is 0, 1 or 2) (It is) - [CH ２ ] ０－１ -C(O)(1-4C) alkyl, - [CH ２ ] ０－１ -C(O)O-(1-4C)alkyl, - [CH ２ ] ０－１ -N(H)C(O)-(1-4C)alkyl, - [CH ２ ] ０－１ -S(O) ２ NH(1-4C) alkyl, - [CH ２ ] ０－１ -S(O) ２ N[(1-4C)alkyl] ２ , - [CH ２ ] ０－１ -N(H)SO ２ - (1-4C) alkyl, formula: -Y ２ -[CH ２ ] ０－１ -Z ２ (In the formula, Y ２ It does not exist, or -O-, -NH-, -NMe-, -S-, -S(O ) - or -S(O) ２ - and; Z ２ (3-6C) cycloalkyl, phenyl, 4-6 member heterocyclyl or 5-membered (or a 6-membered heteroaryl) Selected from; Any alkyl, alkoxy or R ｃ Any alkyl portion within the substituent is a halo, hydr Roxy, cyano, amino, -C(O)OH, -C(O)NH ２ , (1-2C)alkoxy , or by one or more substituents selected from (3-4C) cycloalkoxys. Replaced by selection; Z ２ However, halo, hydroxy, cyano, amino, -C(O)OH, -C(O)NH ２ , ( (1-2C)alkoxy, (1-2C)alkyl, (3-4C)cycloalkyl, (3-4 C) Cycloalkoxy, -C(O)NH(1-2C) alkyl, -C(O)N[(1-2 C) Alkyl] ２ -NH(1-2C)alkyl, -N[(1-2C)alkyl] ２ , - S(O) ｑ -(1-2C)alkyl (wherein q is 0, 1, or 2), -C(O) (1-2C)alkyl, -C(O)O-(1-2C)alkyl, -N(R ｆ ) C(O)- (1-2C) alkyl, -S(O) ２ NH(1-2C) alkyl, -S(O) ２ N[(1 [~2C) alkyl] ２ , or -NHSO ２ - One selected from (1-2C) alkyl groups Alternatively, it may be optionally substituted with multiple substituents, and any (1-2C)alkoxy, (1- 2C) alkyl, (3-4C) cycloalkyl or (3-4C) cycloalkoxy group From halo, cyano, hydroxy, (1-2C)alkyl or (1-2C)alkoxy Claims 1 to 14, optionally substituted with one or more substituents selected by choice. A compound, or a salt, hydrate, or solvate thereof, as described in any one of the items.

16. R ｃ However, hydrogen, halo, cyano, (1-4C) alkyl, (1-4C) alkoxy, formula: -Y ２ -[CH ２ ] ０－１ -Z ２ (In the formula, Y ２ It does not exist, or it is -O-; Z ２ The group is (3-6C) cycloalkyl or phenyl. Selected from; Any alkyl or alkoxy substituent can be halo, hydroxy, cyano, amino, or -C. (O)OH, -C(O)NH ２ , or one selected from (1-2C)alkoxy It is optionally replaced by multiple substituents; Z ２ However, halo, hydroxy, cyano, amino, (1-2C)alkoxy, (1-2C) Alkyl, -C(O)NH(1-2C)alkyl, -C(O)N[(1-2C)alkyl ] ２ -NH(1-2C)alkyl, -N[(1-2C)alkyl] ２ , -S(O) ｑ - (1-2C)alkyl (wherein q is 0, 1, or 2), -C(O)(1-2C) One or more alkyl groups selected from -C(O)O-(1-2C)alkyl groups. Optionally substituted by substituents, any (1-2C) alkoxy or (1-2C) a The lukyl group is selected from halo, cyano, hydroxy, or (1-2C)alkoxy groups. Any one of claims 1 to 15, which is optionally substituted with one or more substituents. The compounds listed in the section, or their salts, hydrates, or solvates.

17. R ｃ However, hydrogen, halo, cyano, (1-4C) alkyl, (1-4C) alkoxy, formula: -Y ２ -[CH ２ ] ０－１ -Z ２ (In the formula, Y ２ It does not exist, or it is -O-; Z ２ The group is (3-6C) cycloalkyl or phenyl. Selected from; Any alkyl or alkoxy substituent is selected from halo or cyano. It is optionally replaced by multiple substituents; Z ２ However, it is optionally substituted with one or more (1-2C) alkyl substituents, (1 ~2C) The alkyl group is optionally substituted with one or more hydroxy substituents. The compound described in any one of claims 1 to 16, or a salt or hydrate thereof, or Solvate.

18. R ｃ However, hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, methoxy, eth キシ、-O-CH(CH ３ ) ２ 、-CH ２ CN、-CF ３ 、-OCF ３ 、-O-CH ２ C F ３ , cyclopropyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, phen Selected from 17 of the claims 1 to 17, which is 2-hydroxymethylphenyl. The compounds listed in the section, or their salts, hydrates, or solvates.

19. R ｃ However, selected from hydrogen, halo, or halo(1-2C)alkoxy, from claim 1 A compound described in any one of item 18, or a salt, hydrate, or solvate thereof.

20. R ｃ However, hydrogen, chloro or -OCF ３ Selected from any of claims 1 to 19 The compounds described in item 1, or their salts, hydrates, or solvates.

21. (i) R ａ , R ｂ , R ｃ , R ｄ Or R ｅ At least one of them is a non-hydrogen substituent; (ii) R ａ , R ｂ , R ｃ , R ｄ Or R ｅ 1 to 4 of these are non-hydrogen substituents; (iii) R ａ , R ｂ , R ｃ , R ｄ Or R ｅ One to three of these are non-hydrogen substituents; Taha (iv)R ａ , R ｂ , R ｃ , R ｄ Or R ｅ Two to four of them are hydrogen, and the rest are non-hydrogen. A substituent is the compound according to any one of claims 1 to 20, or a salt or hydrate thereof. Or a solvate.

22. R ｃ is equation -Y ２ - [CH ２ ] ０－３ -Z ２ If it is a base of R ｂ and R ｄ is equation -Y １ - [CH ２ ] ０－３ -Z １ It cannot be the basis of; R ｂ and R ｄ One of them is defined here Formula - Y １ - [CH ２ ] ０－３ -Z １ If it is the basis of, the other is equation -Y １ - [CH ２ ] ０－３ -Z １ It cannot be the basis of R ｃ is equation -Y ２ - [CH ２ ] ０－３ -Z ２ It cannot be the basis for , the compound according to any one of claims 1, 8, 9, 15, 16, or 17, or the Salt, hydrate, or solvate.

23. The compound is selected from any one of the following, as described in any one of claims 1 to 22. The listed compounds, or their salts, hydrates, or solvates:

24. A compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, water A pharmaceutical composition comprising a dihydrate or solvate and a pharmaceutically acceptable excipient.

25. (i) treatment; (ii) Treatment of diseases or conditions involving CK2α activity; (iii) Treatment of diseases or conditions related to abnormal activity of CK2α; (iv) Proliferative disorders (e.g., cancer or benign neoplasms), viral infections, and inflammatory diseases. Treatment of medical conditions, diabetes, vascular and ischemic disorders, neurodegenerative disorders, and / or general Regulation of the circadian rhythm; (v) Treatment of cancer; and / or (vi) Treatment of viral infection For use in, the compound according to any one of claims 1 to 23, or the A pharmaceutically acceptable salt of a solvate, or the pharmaceutical composition according to claim 24.

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