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

Abstract

Compounds of formula I, and salts, hydrates or solvates thereof [Formula 1] JPEG2024508547000358.jpg73170, wherein R1, Q, Ra, Rb, Rc, Rd and Re are each as defined herein. The compounds are inhibitors of casein kinase 2 alpha (CK2α) and are useful for treating and / or preventing diseases and conditions involving CK2α activity, including, but not limited to, proliferative disorders (e.g., cancer), viral infections, inflammation, diabetes, vascular and ischemic disorders, neurodegeneration, and regulating circadian rhythms. The present invention also relates to pharmaceutical compositions comprising the compounds defined herein, methods for synthesizing these compounds, and their use for treating diseases and / or conditions involving CK2α activity.

Description

[Technical Field]

[0001] [Introduction] The present invention relates to novel therapeutic compounds. More specifically, the present invention relates to novel therapeutic compounds that inhibit the casein kinase 2-alpha subunit (CK2α(CSNK2A1) and / or CK2α'(CSNK2A2)) as part of the CK2 holoenzyme. Thus, the novel therapeutic compounds are useful for treating and / or preventing diseases and conditions in which CK2α activity is involved, for example, but not limited to, proliferative disorders (e.g., cancer), viral infections, inflammation, diabetes, vascular and ischemic disorders, neurodegeneration, and regulating circadian rhythms.

[0002] The present invention also relates to pharmaceutical compositions comprising novel therapeutic compounds as defined herein, methods for synthesizing these compounds, and their use for the treatment of diseases and / or conditions involving CK2α activity. [Background technology]

[0003] CK2α is a serine / threonine kinase that is a key regulator of many cellular processes and is involved in cell proliferation and anti-apoptotic mechanisms (Battistutta and Lolli, Mol. Cell. Biochem. 2011). It exists primarily as a holoenzyme composed of dimers of two catalytic (α and / or α') and regulatory (β) subunits, but can also be found as isolated subunits (Niefind et al., EMBO J 2001). Unlike most other kinases, it is constitutively active, with over 300 proteins identified as putative CK2α substrates, making it one of the most pleiotropic proteins in eukaryotes (Meggio and Pinna, FASEB 2003).

[0004] CK2α is a pro-survival kinase that acts across multiple signaling pathways to induce proliferation and anti-apoptotic phenotypes in cells. Therefore, cancer cells are often described as CK2α activity-dependent, and high-profile, genome-wide CRISPR-Cas9 screening has identified CK2α as a critical, high-priority drug target for colorectal cancer (CRC) (Behan et al., Nature 2019). The target has been well validated by human data linking increased CK2α expression to low patient survival rates in many tumor types, including CRC (Lin et al., PLoS ONE 2011). Furthermore, data from clinical samples 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, and approximately 80% of tumors have been identified as wnt pathway mutation-driven (e.g., APC, β-catenin) (Zhan et al., Oncogene 2017). The wnt pathway is known to be sensitive to and amplified by CK2α activity, and can be inhibited by loss of CK2α function (Gao and Wang, JBC 2006). For example, in animal models, CK2α inhibition prevents tumor growth driven by different mutations in the wnt pathway (Dowling et al., ACS 2016).

[0006] CK2α is also known to contribute to the malignant phenotype in cholangiocarcinoma (CCA), which is characterized by a wnt-induced dysregulation (Zhan et al., Oncogene 2017). CK2α is overexpressed in human CCA samples and CCA tumor cell lines (Di Maira et al., Oncogenesis 2019), and disruption of CK2α activity in CCA cell models has been reported to inhibit tumorigenic characteristics (Zakharia et al., Translational Oncology 2019).

[0007] It is hypothesized that CK2α inhibitors given as monotherapy, in combination with standard therapeutic chemotherapy, or in combination with other targeted therapies under development, such as, but not limited to, KRAS inhibitors, inhibit CRC tumor growth by reversing the abnormal mutation-driven upregulation of wnt signaling to restore the normal balance of apoptosis and proliferation.

[0008] Existing CK2α inhibitors target a highly conserved ATP binding site. This design strategy often results in a lower selectivity profile for such inhibitors compared to other kinases. Therefore, there is a need for potent and more selective CK2α inhibitors that not only bind to the catalytic ATP site of CK2α (driving potent enzyme inhibition) but also interact with other regions of CK2α, such as the αD site (driving a higher level of selectivity than other kinases).

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

[0010] In one embodiment, the present invention provides compounds of formula I as defined herein, and / or pharmaceutically acceptable salts, hydrates, or solvates thereof.

[0011] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula I as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and one or more pharmaceutically acceptable excipients.

[0012] In another embodiment, the present invention provides compounds of formula I as defined herein, or pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions as defined herein, for therapeutic use.

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

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

[0015] In another embodiment, the present invention provides compounds of formula I as defined herein, or pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions as defined herein, for use in the treatment of proliferative disorders (e.g., cancer or benign neoplasms), viral infections, inflammatory diseases or conditions, diabetes, vascular and ischemic disorders, neurodegenerative disorders, and / or regulation of circadian rhythms.

[0016] In another embodiment, the present invention provides compounds of formula I as defined herein, or pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions as defined herein, for use in the treatment of cancer.

[0017] In another embodiment, the present invention provides compounds of formula I as defined herein, or pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions as defined herein, for use in the treatment of viral infections.

[0018] In another embodiment, the present invention provides the use of a compound of formula I as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a pharmaceutical for use in the treatment of a disease or condition involving CK2α activity.

[0019] In another embodiment, the present invention provides the use of a compound of formula I as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a pharmaceutical for use in the treatment of a disease or condition associated with abnormal activity of CK2α.

[0020] In another embodiment, the present invention provides the use of compounds of formula I as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, in the manufacture of pharmaceuticals for use in the treatment of proliferative disorders (e.g., cancer or benign neoplasms), viral infections, inflammatory diseases or conditions, diabetes, vascular and ischemic disorders, neurodegenerative disorders, and / or regulation of circadian rhythms.

[0021] In another embodiment, the present invention provides the use of a compound of formula I as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a pharmaceutical for use in the treatment of cancer.

[0022] In another embodiment, the present invention provides the use of a compound of formula I as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a pharmaceutical for use in the treatment of viral infections.

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

[0024] In another embodiment, the present invention provides a method for treating a disease or condition associated with abnormal activity of CK2α, comprising the step of administering to a subject requiring treatment an effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0025] In another embodiment, the present invention provides a method for treating proliferative disorders (e.g., cancer or benign neoplasms), viral infections, inflammatory diseases or conditions, diabetes, vascular and ischemic disorders, neurodegenerative disorders, and / or regulating circadian rhythms, comprising the step of administering to a subject requiring treatment an effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

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

[0027] In another embodiment, the present invention provides a method for treating a viral infection, comprising the step of administering to a subject requiring treatment an effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition as defined herein.

[0028] In another embodiment, the present invention provides a combination treatment comprising a compound of formula I as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more additional therapeutic agents.

[0029] In another embodiment, the present invention provides a method for preparing a compound of formula I as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as defined herein, together with one or more therapeutic agents.

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

[0031] [Definition] Unless otherwise specified, the following terms used in this specification and in the claims have the meanings set forth below:

[0032] It should be understood that any reference to “treatment” or “treatment” includes prevention and the reduction of established symptoms of a condition. Therefore, “treatment” of a condition, disorder or medical condition includes (1) preventing or delaying the onset of clinical symptoms of a condition, disorder or medical condition in a person who is susceptible to or prone to the condition, disorder or medical condition but has not yet experienced or manifested any clinical or potential symptoms of the condition, disorder or medical condition; (2) inhibiting the condition, disorder or medical condition, i.e., stopping, reducing or delaying the onset or recurrence of the disease (in the case of maintenance treatment), or at least one clinical or potential symptom thereof; or (3) alleviating or attenuating the disease, i.e., resulting in the regression of at least one clinical or potential symptom thereof.

[0033] The "therapeutic dose" refers to the amount of a compound that, when administered to a mammal to treat a disease, is sufficient to achieve such treatment of the disease. The "therapeutic dose" varies depending on the compound, 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” herein include CK2α(CSNK2A1) and / or CK2α'(CSNK2A2). Where a compound of the present invention, as defined herein, that inhibits or is a CK2α inhibitor is referred to, it means that the compound functions as an inhibitor of CK2α(CSNK2A1) and / or CK2α'(CSNK2A2) as well as the CK2 holoenzyme. In certain embodiments, the compound of the present invention inhibits CK2α(CSNK2A1). In other embodiments, the compound of the present invention inhibits CK2α'(CSNK2A2).

[0035] The compounds and intermediates described herein may be named according to the nomenclature of IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstract Service). Unless otherwise expressly indicated, the terms “compound of formula I,” “compound of the present invention,” and the more general term “compound” should be understood to refer to and include all compounds described herein by and / or in reference to formula I. Furthermore, these terms should be understood to encompass all stereoisomers of such compounds, i.e., cis and trans isomers, as well as optical isomers, i.e., R and S enantiomers, in substantially pure forms and / or any mixture thereof in any ratio. This understanding also extends to pharmaceutical compositions and treatment methods using or containing one or more compounds of formula I, either alone or in combination with additional agents.

[0036] Unless otherwise specified, atoms are represented herein by their chemical symbols as they appear in the IUPAC periodic table. For example, "C" refers to a carbon atom.

[0037] The term "(m~nC)" or "(m~nC) group," used alone or as a prefix, refers to any group having m to n carbon atoms.

[0038] In this specification, the term “alkyl” includes both linear and branched alkyl groups. References to individual alkyl groups, such as “propyl,” specify only the linear form, and references to individual branched alkyl groups, such as “isopropyl,” specify only the branched form. For example, “(1-6C)alkyl” includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl, and t-butyl. A similar convention applies to other groups; for example, “phenyl(1-6C)alkyl” includes phenyl(1-4C)alkyl, benzyl, 1-phenylethyl, and 2-phenylethyl.

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

[0040] "(3-6C) cycloalkyl" means a hydrocarbon ring containing 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or bicyclo[2.2.1]heptyl.

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

[0042] When used herein, either alone or in conjunction with other terms, “haloalkyl” and “haloalkyl group” refer to an alkyl group in which one or more hydrogen atoms are replaced by halogen atoms. Typical examples, but not limited to, include -CF3, -CHF2, -CH2F, -CF2CF3, -CHFCF3, and -CH2CF3. Preferably, the haloalkyl group is selected from -CHF2 and -CF3, with -CF3 being preferred.

[0043] When used herein, either alone or in conjunction with other terms, “haloalkoxy” and “haloalkoxy group” refer to an alkoxy group (i.e., an O-alkyl group) in which one or more hydrogen atoms are replaced by halogen atoms. Typical examples, but not limited to, include -OCF3, -OCHF2, -OCH2F, and -OCF2CF3. Preferably, the haloalkoxy group is selected from -OCHF2 and -OCF3, with -OCF3 being preferred.

[0044] "Heterocyclyl," "heterocyclic," or "heterocycle" refers to a non-aromatic saturated or partially saturated monocyclic, condensed, bridging, or spiro-dicyclic heterocyclic ring system. A monocyclic heterocyclic ring contains about 3 to 12 (preferably 3 to 7) ring atoms and has 1 to 5 (preferably 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur within the ring. A bicyclic heterocyclic ring contains 7 to 17 ring-member atoms, preferably 7 to 12 ring-member atoms within the ring. A bicyclic heterocyclic ring may be a condensed, spiro, or bridging ring system. Examples of heterocyclic groups include cyclic ethers, for example, but not limited to, oxylanyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Examples of nitrogen-containing heterocycles include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, etc. Typical sulfur-containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiepine. Other heterocycles include dihydrooxathiolyl, tetrahydrooxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxathiazolyl, hexahydrotriazinyl, tetrahydrooxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. Sulfur-containing heterocycles also include sulfur oxide heterocycles containing SO or SO2 groups. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl, for example, but not limited to, tetrahydrothienyl 1,1-dioxide and thiomorpholinyl 1,1-dioxide. Preferred values ​​for the heterocyclyl group having one or two oxo (=O) or thioxo (=S) substituents are, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl, or 2,6-dioxopiperidinyl.Certain heterocyclyl groups are saturated monocyclic 3- to 7-membered heterocyclines containing one, two, or three heteroatoms selected from nitrogen, oxygen, or sulfur, such as azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl, or homopiperazinyl. As will be understood by those skilled in the art, any heterocycle may be linked to another group via any suitable atom, for example, a carbon or nitrogen atom. However, in this specification, references to piperidino or morpholino refer to piperidin-1-yl or morpholin-4-yl rings linked via ring nitrogen.

[0045] A "bridged ring system" refers to a ring system in which two rings share three or more atoms. For example, see Advanced Organic Chemistry, by Jerry March, 4th edition, Wiley Interscience, pp. 131-133, 1992. Examples of bridged heterocyclyl ring systems include azabicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, azabicyclo[2.2.2]octane, azabicyclo[3.2.1]octane, and quinuclidine.

[0046] A "spiro-bicyclic ring system" means that two ring systems share one common spirocarbon atom, i.e., a heterocyclic ring is linked to a further carbocyclic or heterocyclic ring via a single common spirocarbon atom. Examples of spiro-ring systems include 6-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane, 2-azaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 7-oxa-2-azaspiro[3.5]nonane, 6-oxa-2-azaspiro[3.4]octane, 2-oxa-7-azaspiro[3.5]nonane, and 2-oxa-6-azaspiro[3.5]nonane.

[0047] The terms "heteroaryl" or "heteroaromatic" refer to aromatic monocyclic, bicyclic, or polycyclic rings incorporating one or more heteroatoms (e.g., 14, particularly 1, 2, or 3) selected from nitrogen, oxygen, or sulfur. The term heteroaryl includes both monovalent and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing 5 to 12 ring members, more commonly 5 to 10. Heteroaryl groups may be, for example, 5 or 6-membered monocyclic rings or 9 or 10-membered bicyclic rings, e.g., bicyclic structures formed from fused 5 and 6-membered rings or two fused 6-membered rings. Each ring may typically contain up to about 4 heteroatoms selected from nitrogen, sulfur, and oxygen. Typically, a heteroaryl ring contains up to 3 heteroatoms, more commonly up to 2, e.g., a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in a heteroaryl ring may be basic, as in the case of imidazole or pyridine, or they may be inherently non-basic, as in the case of indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in a heteroaryl group containing any amino group substituent of the ring is less than five.

[0048] Examples of heteroaryls include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazeninyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, prinyl, benzoflazanil, quinolyl, isoxyl Includes noryl, quinazolinil, quinoxalinil, synnorinil, pteridinil, naphthilidinil, carbazolyl, phenadinil, benzoisoquinolinil, pyridopyradinil, thieno[2,3b]-furanyl-, 2H-flo[3,2b]-pyranyl-, 5H-pyrido[2,3-d]-oxazinil-, 1H-pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5d]thiazolyl, pyrazino[2,3d]pyridazinil, -imidazo[2,1b]thiazolyl, and -imidazo[1,2b][1,2,4]-triazinil. A "heteroaryl" also includes a partially aromatic bicyclic or polycyclic ring system in which at least one ring is an aromatic ring and one or more of the other rings are non-aromatic saturated or partially saturated rings, provided that at least one ring contains one or more heteroatoms selected from nitrogen, oxygen, or sulfur. Examples of partially aromatic heteroaryl groups include, for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzothienyl, dihydrobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxynyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indlinyl, 1,2,3,4-tetrahydro-1,8-naphthilidinyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazine, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, and 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazine.

[0049] Examples of five-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl groups.

[0050] Examples of six-membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, 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; A cyclohexyl ring condensed to a 5 or 6-membered heteroaromatic ring containing one, two, or three ring heteroatoms; and A cyclopentyl ring condensed onto a 5-membered or 6-membered heteroaromatic ring containing one, two, or three ring heteroatoms. 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 include, but are not limited to, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indollidinyl, indolinyl, isoindolinyl, prinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl, and pyrazolopyridinyl groups.

[0053] Specific examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, clomenyl, isochromanyl, chromanyl, isochromanyl, benzodioxanyl, quinolidinyl, benzooxazinyl, benzodiadinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthilidinyl, and pteridinyl groups.

[0054] The term "aryl" refers to a cyclic or polycyclic aromatic ring having 5 to 12 carbon atoms. The term aryl includes both monovalent and divalent forms. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, and naphthyl. In certain embodiments, the aryl is phenyl.

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

[0056] The term "aryl(1-2C)alkyl" refers to an aryl group covalently bonded to a (1-2C)alkylene group, both of which are defined herein. Examples of aryl-(1-2C)alkyl groups include benzyl and phenylethyl.

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

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

[0059] "(3-6C)cycloalkyl-(1-2C)alkyl" means a (3-6C) cycloalkyl group covalently bonded to a (1-2C) alkylene group, both of which are defined herein.

[0060] The term "optionally substituted" refers to a substituted group, structure, or molecule, and those that are not substituted. 1 The term “one / any CH, CH2, CH3 group or heteroatom (i.e., NH) in the group is optionally substituted” is preferably used in R 1 This means that one of the hydrogen groups of the group is substituted by a specified group related to it.

[0061] When optional substituents are selected from "one or more" groups, it should be understood that this definition includes cases where all substituents are selected from one of the specified groups, or where substituents are selected from two or more of the specified groups.

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

[0063] The phrase "compounds of the present invention" means both the compounds disclosed in general and specifically herein.

[0064] When used herein, either alone or in conjunction with other terms, “pharmaceutically acceptable” means a material that is generally chemically and / or physically compatible with other components (e.g., as relating to a formulation) and / or generally physiologically compatible with its recipient (e.g., a subject).

[0065] When used herein, either alone or in conjunction with other terms, “subject” and “patient” preferably refer to mammals, in particular humans.

[0066] <Inventive compound> In a first embodiment, the present invention relates to a compound having structural formula I shown below, or a pharmaceutically acceptable salt, hydrate, or solvate thereof. [ka] During the ceremony, R1 is selected from -C(O)OH or -C(O)NH2; 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 b in formulas Ia and Ib corresponds to the combination b in formula I; R2 and R3 are 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 dare each independently hydrogen, halo, cyano, (1-4C)alkyl, -[CH2] 0-3 -(1-4C)alkoxy, -[CH2] 0-3 -C(O)NH2, -[CH2] 0-3 -C(O)NH(1-4C)alkyl, -[CH2] 0-3 -C(O)N[(1-4C)alkyl]2, -[CH2] 0-3 -NH(1-4C)alkyl, -[CH2] 0-3 -N[(1-4C)alkyl]2, -[CH2] 0-3 -S(O) q -(1-4C)alkyl (where q is 0, 1 or 2), -[CH2] 0-3 -C(O)(1-4C)alkyl, -[CH2] 0-3 -C(O)O-(1-4C)alkyl, -[CH2] 0-3 -N(R f )C(O)-(1-4C)alkyl (where R f is hydrogen or methyl), -[CH2] 0-3 -S(O)2NH(1-4C)alkyl, -[CH2][[ID=五十三]] 0-3 -S(O)2N[(1-4C)alkyl]2, -[CH2] 0-3 -N(R g )SO2-(1-4C)alkyl (where R g is hydrogen or methyl), Formula: -Y1-[CH2] 0-3 -Z1 (where Y1 is absent or is -O-, -NH-, -NMe-, -S-, -S(O)- or -S(O)2-; Z1 is (3-6C)cycloalkyl, phenyl, 4-6 membered heterocyclyl or 5 or 6 membered heteroaryl) group <00,01392>Selected from; Any alkyl, alkoxy or R b and R d Any alkyl portion within the substituent may be optionally replaced by one or more substituents selected from halo, hydroxy, cyano, amino, -C(O)OH, -C(O)NH2, (1-2C)alkoxy, or (3-4C)cycloalkoxy; Z1 is a 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 (where 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 -NHSO2-(1~2C)alkyl, and any (1~2C)alkoxy, (1~2C)alkyl, (3~4C)cycloalkyl or (3~4C)cycloalkoxy group is optionally substituted with one or more substituents selected from halo, cyano, hydroxy, (1~2C)alkyl, (1~2C)alkoxy or (1~2C)alkoxy-(1~2C)alkyl; R c These are hydrogen, halo, cyano, -C(O)NH2, (1~4C)alkyl, -[CH2] 0-3 -(1~4C)alkoxy, -[CH2] 0-3 -(3~6C)Cycloalkoxy, -[CH2] 0-3 -C(O)NH2, -[CH2] 0-3 -C(O)NH(1~4C)alkyl, -[CH2] 0-3 -C(O)N[(1~4C)alkyl]2, -[CH2] 0-3 -NH(1~4C)alkyl, -[CH2] 0-3 -N[(1~4C)alkyl]2, -[CH2] 0-3 -S(O) q -(1~4C)alkyl (wherein q is 0, 1, or 2), -[CH2] 0-3 -C(O)(1~4C)alkyl, -[CH2] 0-3 -C(O)O-(1~4C)alkyl, -[CH2] 0-3 -N(R h )C(O)-(1~4C)alkyl(wherein R in the formula) h (is hydrogen or methyl), -[CH2] 0-3 -S(O)2NH(1~4C)alkyl, -[CH2] 0-3 -S(O)2N[(1~4C)alkyl]2, -[CH2] 0-3 -N(R i )SO2-(1~4C)alkyl(wherein R is the formula) i (is hydrogen or methyl), formula: -Y2-[CH2] 0-3 -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 heterocyclyl, or 5 or 6 member heteroaryl group. Selected from; Any alkyl, alkoxy or R c Any alkyl portion within the substituent may be optionally replaced by one or more substituents selected from halo, hydroxy, cyano, amino, -C(O)OH, -C(O)NH2, (1-2C)alkoxy, or (3-4C)cycloalkoxy; Z2 is a compound of 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 (where q is 0, 1, or 2), -C(O)(1~2C)alkyl, -C(O)O-(1~2C)alkyl, -N(R f The groups are optionally substituted with one or more substituents selected from C(O)-(1~2C)alkyl, -S(O)2NH(1~2C)alkyl, -S(O)2N[(1~2C)alkyl]2, or -NHSO2-(1~2C)alkyl, and any (1~2C)alkoxy, (1~2C)alkyl, (3~4C)cycloalkyl or (3~4C)cycloalkoxy group is optionally substituted with one or more substituents selected from halo, cyano, hydroxy, (1~2C)alkyl, (1~2C)alkoxy, or (1~2C)alkoxy-(1~2C)alkyl.

[0067] The specific compounds of the present invention include, for example, compounds of formula I, or pharmaceutically acceptable salts, hydrates, and / or solvates thereof, unless otherwise specified, R1, Q, R a , R b , R c , R d and R e Each of these 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 b in formulas Ia and Ib corresponds to the combination b in formula 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 b in formulas Ia and Ib corresponds to the combination b in formula I; R2 and R3 are either both hydrogen, or one of R2 and R3 is hydrogen and the other is methyl; 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 b in formulas Ia and Ib corresponds to the combination b in formula 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 b in formulas Ia and Ib corresponds to the combination b in formula 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 b in formulas Ia and Ib corresponds to the combination b in formula I; R2 and R3 are either both hydrogen, or one of R2 and R3 is hydrogen and the other is methyl; 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 b in formulas Ia and Ib corresponds to the combination b in formula 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; 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) is a base;

[0082] (15)R a and R e Each of these is independently selected from hydrogen, methyl, fluoro, chloro, or bromo;

[0083] (16)R a and R e Each of these elements is independently selected from hydrogen, fluoro, chloro, or bromo;

[0084] (17)R a and R e Each of these is independently selected from hydrogen, methyl, fluoro, or chloro;

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

[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 eOne of them is hydrogen, and the other is hydrogen, methyl, fluoro or chloro;

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

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

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

[0094] (27)R b and R d are each independently hydrogen, halo, cyano, (1-4C)alkyl, -[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 -S(O)2N[(1-4C)alkyl]2, -[CH2] 0-2 -NHSO2-(1-4C)alkyl, Formula: -Y1-[CH2] 0-2 -Z1 (wherein, Y1 is absent or is -O-, -NH-, -NMe-, -S-, -S(O)- or -S(O)2-; Z1 is a group of (3-6C)cycloalkyl, phenyl, 4-6 member heterocyclyl or 5 or 6 member heteroaryl) selected from; Any alkyl, alkoxy or R b and R d Any alkyl moiety within the substituent is optionally substituted by one or more substituents selected from halo, hydroxy, cyano, amino, -C(O)OH, -C(O)NH2, (1-2C)alkoxy, or (3-4C)cycloalkoxy; 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 -NHSO2-(1~2C)alkyl, and any (1~2C)alkoxy, (1~2C)alkyl, (3~4C)cycloalkyl or (3~4C)cycloalkoxy group is optionally substituted with one or more substituents selected from halo, cyano, hydroxy, (1~2C)alkyl, (1~2C)alkoxy or (1~2C)alkoxy-(1~2C)alkyl;

[0095] (28)R b and R d These are, independently, hydrogen, halo, cyano, and (1-4C) alkyl, -[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), -[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 member heterocyclyl, or 5 or 6 member heteroaryl group. Selected from; Any alkyl, alkoxy or R b and R d Any alkyl portion within the substituent may be optionally replaced by one or more substituents selected from halo, hydroxy, cyano, amino, -C(O)OH, -C(O)NH2, (1-2C)alkoxy, or (3-4C)cycloalkoxy; Z1 is a 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 (where 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 -NHSO2-(1~2C)alkyl, and any (1~2C)alkoxy, (1~2C)alkyl, (3~4C)cycloalkyl or (3~4C)cycloalkoxy group is optionally substituted with one or more substituents selected from halo, cyano, hydroxy, (1~2C)alkyl, (1~2C)alkoxy or (1~2C)alkoxy-(1~2C)alkyl;

[0096] (29)R band R d These are, independently, hydrogen, halo, cyano, and (1-4C) alkyl, -[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), -[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 member heterocyclyl, or 5 or 6 member heteroaryl group. Selected from; Any alkyl, alkoxy or R b and R dAny alkyl portion within the substituent may be optionally replaced by one or more substituents selected from halo, hydroxy, cyano, amino, -C(O)OH, -C(O)NH2, (1-2C)alkoxy, or (3-4C)cycloalkoxy; Z1 is a 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 (where 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 -NHSO2-(1~2C)alkyl, and any (1~2C)alkoxy, (1~2C)alkyl, (3~4C)cycloalkyl or (3~4C)cycloalkoxy group is optionally substituted with one or more substituents selected from halo, cyano, hydroxy, (1~2C)alkyl, (1~2C)alkoxy or (1~2C)alkoxy-(1~2C)alkyl;

[0097] (30)R b and R d These are, independently, hydrogen, halo, cyano, and (1-4C) alkyl, -[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), -[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 member heterocyclyl, or 5 or 6 member heteroaryl group. Selected from; Any alkyl, alkoxy or R b and R d Any alkyl portion within the substituent may be optionally replaced by one or more substituents selected from halo, hydroxy, cyano, amino, -C(O)OH, -C(O)NH2, (1-2C)alkoxy, or (3-4C)cycloalkoxy; Z1 is a 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 (where 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 -NHSO2-(1~2C)alkyl, and any (1~2C)alkoxy, (1~2C)alkyl, (3~4C)cycloalkyl or (3~4C)cycloalkoxy group is optionally substituted with one or more substituents selected from halo, cyano, hydroxy, (1~2C)alkyl, (1~2C)alkoxy or (1~2C)alkoxy-(1~2C)alkyl;

[0098] (31)R b and R d These are, independently, hydrogen, halo, cyano, and (1-4C) alkyl, -[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), -[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 group. Selected from; Any alkyl, alkoxy or R b and R d Any alkyl portion within the substituent is optionally substituted with one or more substituents selected from halo, hydroxy, cyano, amino, -C(O)NH2, or (1-2C)alkoxy; Z1 is a 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 The (1-2C) alkyl (wherein q is 0, 1, or 2), the (1-2C) alkyl, or the (1-2C) alkyl is optionally substituted with one or more substituents selected from -(1-2C)alkyl (wherein q is 0, 1, or 2), and any (1-2C) alkoxy or (1-2C) alkyl group is optionally substituted with one or more substituents selected from halo, cyano, hydroxy, or (1-2C) alkoxy;

[0099] (32)R b and R d These are, independently, hydrogen, halo, cyano, and (1-4C) alkyl, -[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), -[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 group. Selected from; Any alkyl, alkoxy or R b and R d Any alkyl portion within the substituent is optionally substituted with one or more substituents selected from halo, hydroxy, cyano, amino, -C(O)NH2, or (1-2C)alkoxy; Z1 is a 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 The (1-2C) alkyl (wherein q is 0, 1, or 2), the (1-2C) alkyl, or the (1-2C) alkyl is optionally substituted with one or more substituents selected from -(1-2C)alkyl (wherein q is 0, 1, or 2), and any (1-2C) alkoxy or (1-2C) alkyl group is optionally substituted with one or more substituents selected from halo, cyano, hydroxy, or (1-2C) alkoxy;

[0100] (33)R b and R d These are, independently, hydrogen, halo, cyano, and (1-4C) alkyl, -[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), -[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 optionally substituted with one or more substituents selected from halo, hydroxy, cyano, amino, -C(O)NH2, or (1-2C)alkoxy; Z1 is optionally substituted with one or more substituents selected from halo, hydroxy, cyano, amino, (1-2C)alkoxy, (1-2C)alkyl, or (1-2C)haloalkyl;

[0101] (34)R b and R d These are, independently, hydrogen, halo, cyano, and (1-4C) alkyl, -[CH2] 0-1 -(1~4C)alkoxy, -[CH2] 0-1 -C(O)NH2, formula: [CH2] 0-1 -Z1 (wherein Z1 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 optionally substituted with one or more substituents selected from halo, hydroxy, cyano, amino, -C(O)NH2, or (1-2C)alkoxy; Z1 is optionally substituted with one or more substituents selected from halo, hydroxy, cyano, amino, (1-2C)alkoxy, (1-2C)alkyl, or (1-2C)haloalkyl;

[0102] (35)Rb and R d These are, independently, hydrogen, halo, cyano, (1-4C)alkyl, -(1-4C)alkoxy, and -[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 optionally substituted with one or more substituents selected from halo, hydroxy, cyano, amino, -C(O)NH2, or (1-2C)alkoxy; Z1 is optionally substituted with one or more substituents selected from halo, hydroxy, or cyano;

[0103] (36)R b and R d These are, independently, hydrogen, halo, cyano, (1-4C)alkyl, (1-4C)alkoxy, and -[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 optionally substituted with one or more substituents selected from halo, hydroxy, cyano, amino, -C(O)NH2, or (1-2C)alkoxy; Z1 is optionally replaced by one or more cyanonucleotides;

[0104] (37)R b and R dThese are, independently, hydrogen, halo, cyano, (1-4C)alkyl, halo(1-4C)alkyl, hydroxy(1-4C)alkyl, cyano(1-4C)alkyl, amino(1-4C)alkyl, (1-2C)alkoxy(1-4C)alkyl, (1-4C)alkoxy, halo(1-4C)alkoxy, hydroxy(1-4C)alkoxy, -[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, and (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 optionally substituted by one or more substituents selected from the halo;

[0106] (39)R b and R dEach is independently selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, methoxy, ethoxy, -CH2OH, -CH2OCH3, -CH2NH2, -CH2CN, -CH2CH2OH, -CF3, -OCF3, -O-CH2CH2OH, -O-CH2CF3, -C(O)NH2, -CH2-C(O)NH2, -CH(CH3)CN, -C(CH3)2CN, cyclopropyl, 1-cyanocyclopropyl, cyclopropylmethyl, furanylmethyl (e.g., fran-3-ylmethyl), imidazolylmethyl (e.g., imidazo-1-ylmethyl), pyrazolylmethyl (e.g., pyrazol-4-ylmethyl), and oxazolylmethyl (e.g., oxazo-4-ylmethyl);

[0107] (40)R b and R d Each is independently selected from hydrogen, fluoro, chloro, bromo, methyl, -OCF3, or cyclopropyl;

[0108] (41)R b and R d One of the elements 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, or (3-4C)cycloalkyl(1-2C)alkyl, and the other is selected from any one of the options defined in paragraphs (27) to (40) above;

[0109] (42)R b and R dOne of the elements is hydrogen, halogen, or -OCF3, and the other is selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, methoxy, ethoxy, -CH2OH, -CH2OCH3, -CH2NH2, -CH2CN, -CH2CH2OH, -CF3, -OCF3, -O-CH2CH2OH, -O-CH2CF3, -C(O)NH2, -CH2-C(O)NH2, -CH(CH3)CN, -C(CH3)2CN, cyclopropyl, 1-cyanocyclopropyl, cyclopropylmethyl, furanylmethyl (e.g., furan-3-ylmethyl), imidazolylmethyl (e.g., imidazo-1-ylmethyl), pyrazolylmethyl (e.g., pyrazole-4-ylmethyl), oxazolylmethyl (e.g., oxazo-4-ylmethyl);

[0110] (43)R b and R d One of the elements is hydrogen, halogen, or -OCF3, and the other is selected from hydrogen, fluoro, chloro, bromo, methyl, -OCF3, or cyclopropyl;

[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), -[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 heterocyclyl, or 5 or 6 member heteroaryl group. Selected from; Any alkyl, alkoxy or R c Any alkyl portion within the substituent may be optionally replaced by one or more substituents selected from halo, hydroxy, cyano, amino, -C(O)OH, -C(O)NH2, (1-2C)alkoxy, or (3-4C)cycloalkoxy; Z2 is a compound of 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 (where 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 -NHSO2-(1~2C)alkyl, and any (1~2C)alkoxy, (1~2C)alkyl, (3~4C)cycloalkyl or (3~4C)cycloalkoxy group is optionally substituted with one or more substituents selected from halo, cyano, hydroxy, (1~2C)alkyl or (1~2C)alkoxy;

[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), -[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 heterocyclyl, or 5 or 6 member heteroaryl group. Selected from; Any alkyl, alkoxy or R c Any alkyl portion within the substituent may be optionally replaced by one or more substituents selected from halo, hydroxy, cyano, amino, -C(O)OH, -C(O)NH2, (1-2C)alkoxy, or (3-4C)cycloalkoxy; Z2 is a compound of 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 (where 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 -NHSO2-(1~2C)alkyl, and any (1~2C)alkoxy, (1~2C)alkyl, (3~4C)cycloalkyl or (3~4C)cycloalkoxy group is optionally substituted with one or more substituents selected from halo, cyano, hydroxy, (1~2C)alkyl or (1~2C)alkoxy;

[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), -[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 heterocyclyl, or 5 or 6 member heteroaryl group. Selected from; Any alkyl, alkoxy or Rc Any alkyl portion within the substituent may be optionally replaced by one or more substituents selected from halo, hydroxy, cyano, amino, -C(O)OH, -C(O)NH2, (1-2C)alkoxy, or (3-4C)cycloalkoxy; Z2 is a compound of 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 (where 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 -NHSO2-(1~2C)alkyl, and any (1~2C)alkoxy, (1~2C)alkyl, (3~4C)cycloalkyl or (3~4C)cycloalkoxy group is optionally substituted with one or more substituents selected from halo, cyano, hydroxy, (1~2C)alkyl or (1~2C)alkoxy;

[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), -[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 heterocyclyl, or 5 or 6 member heteroaryl group. Selected from; Any alkyl, alkoxy or R c Any alkyl portion within the substituent may be optionally replaced by one or more substituents selected from halo, hydroxy, cyano, amino, -C(O)OH, -C(O)NH2, (1-2C)alkoxy, or (3-4C)cycloalkoxy; Z2 is a compound of 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 (where 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 -NHSO2-(1~2C)alkyl, and any (1~2C)alkoxy, (1~2C)alkyl, (3~4C)cycloalkyl or (3~4C)cycloalkoxy group is optionally substituted with one or more substituents selected from halo, cyano, hydroxy, (1~2C)alkyl or (1~2C)alkoxy;

[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), -[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 heterocyclyl, or 5 or 6 member heteroaryl group. Selected from; Any alkyl, alkoxy or R c Any alkyl portion within the substituent is optionally substituted with one or more substituents selected from halo, hydroxy, cyano, amino, -C(O)OH, -C(O)NH2, or (1-2C)alkoxy; Z2 is a 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 The (1-2C) alkyl (wherein q is 0, 1, or 2), the (1-2C) alkyl, or the (1-2C) alkyl is optionally substituted with one or more substituents selected from -(1-2C)alkyl (wherein q is 0, 1, or 2), and any (1-2C) alkoxy or (1-2C) alkyl group is optionally substituted with one or more substituents selected from halo, cyano, hydroxy, or (1-2C) alkoxy;

[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), -[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 heterocyclyl, or 5 or 6 member heteroaryl group. Selected from; Any alkyl, alkoxy or R c Any alkyl portion within the substituent is optionally substituted with one or more substituents selected from halo, hydroxy, cyano, amino, -C(O)OH, -C(O)NH2, or (1-2C)alkoxy; Z2 is a 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 The (1-2C) alkyl (wherein q is 0, 1, or 2), the (1-2C) alkyl, or the (1-2C) alkyl is optionally substituted with one or more substituents selected from -(1-2C)alkyl (wherein q is 0, 1, or 2), and any (1-2C) alkoxy or (1-2C) alkyl group is optionally substituted with one or more substituents selected from halo, cyano, hydroxy, or (1-2C) alkoxy;

[0117] (50)R c These are hydrogen, halo, cyano, (1-4C) alkyl, (1-4C) alkoxy, 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 optionally substituted with one or more substituents selected from halo, hydroxy, cyano, amino, -C(O)OH, -C(O)NH2, or (1-2C)alkoxy; Z2 is a 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) qThe (1-2C) alkyl (wherein q is 0, 1, or 2), the (1-2C) alkyl, or the (1-2C) alkyl is optionally substituted with one or more substituents selected from -(1-2C)alkyl (wherein q is 0, 1, or 2), and any (1-2C) alkoxy or (1-2C) alkyl group is optionally substituted with one or more substituents selected from halo, cyano, hydroxy, or (1-2C) alkoxy;

[0118] (51)R c These are hydrogen, halo, cyano, (1-4C) alkyl, (1-4C) alkoxy, 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 optionally substituted with one or more substituents selected from halo, hydroxy, cyano, or (1-2C)alkoxy; Z2 is optionally substituted with one or more substituents selected from halo, hydroxy, cyano, amino, (1-2C)alkoxy, or (1-2C)alkyl, and any (1-2C)alkoxy or (1-2C)alkyl group is optionally substituted with one or more substituents selected from halo, cyano, hydroxy, or (1-2C)alkoxy;

[0119] (52)R c These are hydrogen, halo, cyano, (1-4C) alkyl, (1-4C) alkoxy, 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 optionally substituted with one or more substituents selected from halo or cyano; Z2 is optionally substituted with one or more (1-2C) alkyl substituents, and the (1-2C) alkyl group is optionally substituted with one or more hydroxy substituents;

[0120] (53)R c This is selected from hydrogen, halo, cyano, (1-2C)alkyl or (1-2C)alkoxy, Any alkyl or alkoxy substituent is optionally substituted with one or more halo substituents;

[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 This is selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, methoxy, ethoxy, -O-CH(CH3)2, -CH2CN, -CF3, -OCF3, -O-CH2CF3, cyclopropyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, phenyl, or 2-hydroxymethylphenyl;

[0125] (58)R cThis is selected from hydrogen, fluoro, chloro, bromo, cyano, methoxy, ethoxy, -O-CH(CH3)2, -CH2CN, -CF3, -OCF3, -O-CH2CF3, cyclopropyl, cyclopropoxy, cyclobutoxy, cyclopentoxy, phenyl, or 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. A "non-hydrogen substituent" is any R other than hydrogen. a , R b , R c , R d or R e This means substituents selected from any one of the options defined herein with respect to R. More preferably, R a , R b , R c , R d or R e 1 to 4 of these are non-hydrogen substituents. Most preferably, R a , R b , R c , R d or R e 1 to 3 of these 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., R atoms other than hydrogen). a , R b, R c , R d or R e (Selected from any one of the options described herein with respect to). More preferably, R a , R b , R c , R d or R e Two to four of these substituents are hydrogen atoms, and 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 -If Z2 is the basis, 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 formulas defined herein are -Y1-[CH2] 0-3 -If Z1 is the basis, R c The formula is -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 The formula is -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 is impossible under the Z2 system.

[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 The formula is -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 -If Z1 is the basis, 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 as described herein, the heteroaryl is a 5 or 6-membered heteroaryl ring containing one, two or three heteroatoms selected from N, O, or S.

[0135] Preferably, in any of the definitions of Formula I as described herein, the heterocyclyl group is a 4, 5, or 6-membered heterocyclyl ring containing one, two, or three heteroatoms selected from N, O, or S. Most preferably, the heterocyclyl group is a 4, 5, or 6-membered ring containing one or two heteroatoms selected from N, O, or S [e.g., morpholinyl (e.g., 4-morpholinyl), piperidinyl, piperazinyl, or pyrrolidinyl].

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

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

[0138] Preferably, in any of the definitions of formula I described herein, R a and R e This is as defined in any one of the above items (15) to (26). More preferably, R a and R e This is as defined in any one of the above items (16), (21), (22), (23), or (26). More preferably, R a and R e This is as defined in any one of the above items (21), (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 These are as defined in section (16) above, and R1, Q, R b , R c , and R d These are defined by equation I above.

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

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

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

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

[0144] Preferably, in any of the definitions of formula I described herein, R b and R d This is as defined in any one of the above items (27) to (43). More preferably, R b and R d This is as defined in any one of the above paragraphs (36), (37), (38), (39), (40), (41), (42), or (43). More preferably, R a and R e This is as defined in any one of the above paragraphs (39), (40), (41), (42), or (43). Most preferably, R a and R e This is as defined in section (38) or (43) above.

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

[0146] In a specific group of compounds of formula I, R b and R d These are as defined in item (30) above, and R1, Q, R a , R c , and R e These are defined by equation I above.

[0147] In a specific group of compounds of formula I, R b and R d These are as defined in section (32) above, and R1, Q, R a , R c , and R e These are defined by equation I above.

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

[0149] In a specific group of compounds of formula I, R b and R d These are as defined in section (36) above, and R1, Q, R a , R c , and R e These are defined by equation I above.

[0150] In a specific group of compounds of formula I, R b and R d These are as defined in section (37) above, and R1, Q, R a , R c , and R e These are defined by equation I above.

[0151] In a specific group of compounds of formula I, R b and R d These are as defined in section (38) above, and R1, Q, R a , R c , and R e These are defined by equation I above.

[0152] In a specific group of compounds of formula I, R b and R dThese are as defined in section (39) above, and R1, Q, R a , R c , and R e These are defined by equation I above.

[0153] In a specific group of compounds of formula I, R b and R d These are as defined in item (40) above, and R1, Q, R a , R c , and R e These are defined by equation I above.

[0154] In a specific group of compounds of formula I, R b and R d These are as defined in item (41) above, and R1, Q, R a , R c , and R e These are defined by equation I above.

[0155] In a specific group of compounds of formula I, R b and R d These are as defined in section (42) above, and R1, Q, R a , R c , and R e These are defined by equation I above.

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

[0157] Preferably, in any of the definitions of formula I described herein, R c This is as defined in any one of the above items (44) to (60). More preferably, R cThis is as defined in any one of the above paragraphs (51), (52), (53), (54), (55), (56), (57), (58), (59), or (60). More preferably, R c This is as defined in any one of the above paragraphs (56), (56), (57), (58), (59), or (60). Most preferably, R c This is as defined in paragraphs (58), (59), or (60) above.

[0158] In a specific group of compounds of formula I, R c These are defined in section (45) above, and 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 These are defined in section (47) above, and 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 These are as defined in section (49) above, and 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 These are as defined in item (51) above, and 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 cThese are as defined in section (53) above, and R1, Q, R a , R b , R d and R e These are defined by equation I above.

[0163] In a specific group of compounds of formula I, R c These are as defined in item (55) above, and 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 These are as defined in section (56) above, and 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 These are defined in section (57) above, and 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 These are as defined in item (58) above, and 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 These are as defined in section (59) above, and 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 These are as defined in item (60) above, and 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; Re This 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; Ra and 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 item (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 item (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 item (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 item (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 item (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 item (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 particular group of compounds of the present invention, the compound is a compound of formula I as defined herein, where Q is as defined in section (11) above, i.e., the compound has formula Ic as shown below, or a pharmaceutically acceptable salt thereof. [ka] In the formula, R1, R a , R b , R c , R d and R e Each has one of the definitions set forth herein.

[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 item (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 particular group of compounds of the present invention, the compound is a compound of formula I as defined herein, where Q is as defined in section (11) above, and R a and R e As defined in item (20) above, the compound is a compound having formula Id shown below, or a pharmaceutically acceptable salt thereof. [ka] In the formula, R1, R b , R c and R d Each of these has one of the definitions described above.

[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; R C 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 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 include any of the compounds described in the Examples section of this application, or any pharmaceutically acceptable salts, hydrates, or solvates thereof, in particular any of the following:

[0205] JPEG0007881600000013.jpg107170JPEG0007881600000014.jpg255162JPEG0007881600000015.jpg255162JPEG0007881600000016.jpg255163 JPEG0007881600000017.jpg255162JPEG0007881600000018.jpg255161JPEG0007881600000019.jpg255162JPEG0007881600000020.jpg106170

[0206] The present invention may relate to any compound or a particular group of compounds as otherwise defined herein by optional, preferred, or suitable features or in relation to a particular embodiment, but the present invention may also relate to any compound or a particular group of compounds that specifically exclude the aforementioned optional, preferred, or suitable features or particular embodiment.

[0207] Preferably, the present invention excludes any individual compounds that do not have the biological activity defined herein.

[0208] <Salts and solvates> The compounds described herein (including final products and intermediates) may be used in isolation or isolated in the form of salts, preferably pharmaceutically acceptable salts. The terms “salt” and “salt form,” used alone or in conjunction with other terms, should be understood to encompass all inorganic and organic salts, including industrially acceptable salts and pharmaceutically acceptable salts as defined herein, unless otherwise specified. As used herein, industrially acceptable salts are generally suitable for manufacture and / or processing (including purification), as well as for transport and storage, but do not necessarily have to be salts typically administered for clinical or therapeutic use. Industrially acceptable salts can be prepared on a laboratory scale, i.e., in quantities of a few grams or less, or on a larger scale, i.e., in quantities of one kilogram or less or more.

[0209] A pharmaceutically acceptable salt is one that, when used herein, is generally chemically and / or physically compatible with the other components of the formulation and / or generally physiologically compatible with its recipient. A pharmaceutically acceptable salt may be prepared on a laboratory scale, i.e., in quantities of a few grams or less, or on a larger scale, i.e., in quantities of one kilogram or less or more. A pharmaceutically acceptable salt is not limited to salts typically administered for clinical or therapeutic use in humans, or approved by the FDA or an equivalent foreign regulatory body. It will be readily apparent to those skilled in the art that some salts are both industrially acceptable and pharmaceutically acceptable. It should be understood that all such salts, including mixed salt forms, are included within the scope of this application.

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

[0211] Suitable pharmaceutically acceptable salts of the compounds of the present invention include, for example, acid addition salts of the compounds of the present invention that are sufficiently basic, such as acid addition salts of inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, or maleic acid. Furthermore, suitable pharmaceutically acceptable salts of the compounds of the present invention that are sufficiently acidic include alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts, or salts with organic bases that produce physiologically acceptable cations, such as salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0212] In general, the salts of this application may be prepared in situ during the isolation and / or purification of the compound (including intermediates), or by reacting the compound (or intermediates) separately with a suitable organic or inorganic acid or base (as appropriate), and then isolating the salt thus formed. The degree of ionization of the salt can vary from complete ionization to nearly non-ionization. In practice, various salts may precipitate (with or without the addition of one or more cosolvents and / or poor solvents) and be collected by filtration or recovered by evaporation of the solvent. The salts of this application may also be formed by "salt switching" or ion exchange / double substitution reactions, i.e., reactions in which one ion is replaced (whole or partially) with another ion having the same charge. It will be understood by those skilled in the art that the salts may be prepared and / or isolated using a single method or a combination of methods.

[0213] Typical salts, though not limited to these, include acetate, aspartate, benzoate, besilate, bicarbonate / carbonate, bisulfate / sulfate, borate, cansilate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesilate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotinate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, sugarate, stearate, succinate, tartrate, tosylate, trifluoroacetate, etc. Other typical salts include alkali or alkaline earth metal cations, such as, but not limited to, sodium, lithium, potassium, calcium, magnesium, and non-toxic ammonium, quaternary ammonium, and amine cations, such as, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, lysine, arginine, benzathine, choline, tromethamine, diolamine, glycine, meglumine, olamine, and others.

[0214] Formula I and certain compounds of its subformulas may exist in solvated and non-solvated forms, such as hydrated forms. It should be understood that the present invention encompasses all such solvated forms having the biological activity described herein.

[0215] <Polymorph> It should be understood that certain compounds of Formula I and its subformulas may exhibit pleomorphism, and that the present invention encompasses all such forms having the biological activity described herein.

[0216] <N-オキシド> Compounds of formula I and its subforms containing amine functional groups can also form N-oxides. References herein to compounds of formula I and its subforms containing amine functional groups also include N-oxides. If a compound contains several amine functional groups, one or more nitrogen atoms may be oxidized to form an N-oxide. Specific examples of N-oxides are those of nitrogen atoms in tertiary amines or nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, Advanced Organic Chemistry, by Jerry March, 4th edition, Wiley Interscience, pp. 509-514. More specifically, N-oxides can be prepared by the procedure of LW Deady (Syn. Comm. 1977, 7, 509-514), for example, by reacting an amine compound with m-chloroperbenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

[0217] <Tautomers> Compounds of formula I and its subformulas may exist in several different tautomer forms, and references to compounds of formula I and its subformulas include all such forms. To avoid misunderstanding, even if a compound may exist as one of several tautomer forms and only one is specifically described or shown, all others are encompassed by formula I and its subformulas. Examples of tautomer forms include keto, enol, and enolate forms, such as the tautomer pairs of keto / enol (shown below), pyrimidone / hydroxypyrimidine, imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro.

[0218] [ka]

[0219] <Isomers> Compounds that have the same molecular formula but differ in their properties, the arrangement of their atomic bonds, or the configuration of their atoms in space are called "isomers." Isomers that differ in the configuration of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are mirror images of each other but cannot be superimposed are called "enantiomers." If a compound has a chiral center, for example, if it is bonded to four different groups, then pairs of enantiomers are possible. Enantiomers can be characterized by the absolute configuration of their chiral center, described by the Cahn and Prelog R and S sequence rules, or by the way the molecule rotates its plane of polarization and is designated as dextrorotatory or levorotatory (i.e., as (+) or (-) isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

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

[0221] <Isotopes> The compounds of the present invention are described herein using structural formulas that do not specifically list the mass numbers or isotopic ratios of the constituent atoms. Therefore, this application includes compounds in which the constituent atoms exist in any ratio of isotopic forms. For example, a carbon atom, 12 C, 13 C, and 14 C can exist in any ratio, and hydrogen atoms, 1 H, 2 H, and 3 H and other elements may exist in any ratio. Preferably, the constituent atoms in the compound of the present invention exist in the natural ratios of their isomer forms.

[0222] <Prodrugs and metabolites> Compounds of formula I and its subformulas may be administered in the form of prodrugs that are broken down in the body of a human or animal to release the compounds of the present invention. Prodrugs may be used to modify the physical and / or pharmacokinetic properties of the compounds of the present invention. Prodrugs may be formed when the compounds of the present invention contain a suitable group or substituent to which a characterizing group can be bound. Examples of prodrugs include in vivo cleavable ester derivatives that can be formed with a carboxyl or hydroxyl group in the compounds of formula I, and in vivo cleavable amide derivatives that can be formed with a carboxyl or amino group in the compounds of formula I and its subformulas.

[0223] Accordingly, the present invention includes compounds of formula I and its subformulas as defined above, when made available by organic synthesis and when made available in the body of a human or animal by cleavage of its prodrug. Accordingly, the present invention includes compounds of formula I produced by organic synthesis means, as well as such compounds produced in the body of a human or animal by metabolism of precursor compounds, i.e., compounds of formula I and its subformulas may be synthetically produced compounds or metabolically produced compounds.

[0224] The suitability of pharmaceutically acceptable prodrugs of compounds of formula I and its subformulas is based on reasonable medical judgment that they are suitable for administration into the body of a human or animal without undesirable pharmacological activity and without excessive toxicity.

[0225] For example, various forms of prodrugs are described in the following literature. a) Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5, "Design and Application of Pro-drugs," H. Bundgaard, pp. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14; and h) E. Roche (editor), "Bioreversible Carriers in Drug Design," Pergamon Press, 1987.

[0226] A suitable pharmaceutically acceptable prodrug for compounds of formula I and its subformations that have a carboxyl group is, for example, their in vivo cleavageable esters. An in vivo cleavageable ester of a compound of formula I containing a carboxyl group is, for example, a pharmaceutically acceptable ester that cleaves in the body of a human or animal to produce a hydrophilic acid. Suitable pharmaceutically acceptable esters with respect to carboxyl groups are, but are not limited to, methyl, ethyl, and tert-butyl C6. 1~6 C, including but not limited to alkyl esters and methoxymethyl esters. 1~6 Alkoxymethyl esters, and not limited to these, C such as pivaloyloxymethyl esters and 3-phthalidyl esters. 1~6 Alkanoyloxymethyl esters, and not limited to these, such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters. 3~8 Cycloalkylcarbonyloxy-C 1~6 Alkyl esters, including but not limited to 2-oxo-1,3-dioxolennyl methyl esters such as 5-methyl-2-oxo-1,3-dioxolennyl methyl ester, and but not limited to C methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl ester. 1~6 Alkoxycarbonyloxy-C 1~6 Contains alkyl esters.

[0227] A suitable pharmaceutically acceptable prodrug for compounds of formula I and its subformations that have a hydroxyl group is, for example, their in vivo cleavable ester or ether. In vivo cleavable esters or ethers for compounds of formula I and its subformations that contain a hydroxyl group are, for example, pharmaceutically acceptable esters or ethers that cleave in the body of a human or animal to produce a parent hydroxyl compound. Suitable pharmaceutically acceptable ester-forming groups with respect to the hydroxyl group include, but are not limited to, inorganic esters such as phosphate esters (including phosphoramido cyclic esters). Even more suitable pharmaceutically acceptable ester-forming groups with respect to the hydroxyl group include, but are not limited to, acetyl, benzoyl, phenylacetyl, and C13, substituted benzoyl and phenylacetyl groups. 1~10 Alkanoyl groups, and not limited to these, ethoxycarbonyl groups, N,N-(C) 1~6 )C such as 2-carbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl groups 1~10 Contains alkoxycarbonyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups are aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl and 4-(C 1~4 It contains alkyl)piperazine-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups with respect to the hydroxyl group include, but are not limited to, α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl.

[0228] Suitable pharmaceutically acceptable prodrugs of compounds of formula I and its subformations having a carboxyl group include, for example, their in vivo cleavable amides, for example, but not limited to amines such as ammonia, and for example, but not limited to methylamine. 1~4 Alkylamines, but not limited to dimethylamine, N-ethyl-N-methylamine or diethylamine, etc. (C 1~4 C(alkyl)2-amines, but not limited to C(2-methoxyethylamines). 1~4 Alkoxy-C 2~4Alkylamines, and not limited to them, such as benzylamines and other phenyl-C 1~4 Alkylamines, and amides formed from amino acids such as glycine or their esters, but not limited to alkylamines.

[0229] A suitable pharmaceutically acceptable prodrug for compounds of formula I and its subformulas having an amino group is, for example, their in vivo cleavable amide derivatives. Suitable pharmaceutically acceptable amides from an amino group include, but are not limited to, acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 1~10 This includes amides formed with an alkanoyl group. Examples of ring substituents on phenylacetyl and benzoyl groups are aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-(C 1~4 Contains alkyl piperazine-1-ylmethyl.

[0230] The in vivo effects of compounds of formula I and its subformulas may be exerted in part by one or more metabolites formed in the human or animal body after administration of compounds of formula I and its subformulas. As described above, the in vivo effects of compounds of formula I and its subformulas may also be exerted through the metabolism of precursor compounds (prodrugs).

[0231] <Pharmaceutical composition> A further aspect of the present invention provides a pharmaceutical composition comprising the compound of the present invention as defined above, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in combination with a pharmaceutically acceptable diluent or carrier.

[0232] The composition of the present invention may be 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., creams, ointments, gels, or aqueous or oily solutions or suspensions), in a form suitable for administration by inhalation (e.g., finely ground powder or liquid aerosol), in a form suitable for administration by air (e.g., finely ground powder), or in a form suitable for parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as a suppository for rectal administration).

[0233] The compositions of the present invention can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Therefore, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavorings, and / or preservatives.

[0234] An effective amount of the compound of the present invention for therapeutic use is sufficient to treat or prevent, inhibit the progression of, and / or reduce symptoms associated with the proliferative disease referred to herein.

[0235] The amount of active ingredient combined with one or more excipients to produce a single dosage form inevitably varies depending on the individual being treated and the specific route of administration. For example, formulations intended for oral administration to humans generally contain, for example, 0.5 mg to 1.5 g of the active agent (more preferably 0.5 mg to 600 mg, e.g., 1 mg to 200 mg) combined with an appropriate and convenient amount of excipients that can vary from about 5% to about 98% by weight of the total composition.

[0236] The size of the therapeutic or prophylactic dose of the compound of Formula I naturally varies according to well-known medical principles, depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[0237] It should be noted that dosages and regimens may vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses over a specific period (days or hours), i.e., QD (once daily), BID (twice daily), etc. Furthermore, it should be understood that for any particular subject or patient, it may be necessary to adjust specific regimens over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the pharmaceutical composition. For example, dosages may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and / or clinical laboratory values. Therefore, this application includes intra-patient dose escalation as determined by those skilled in the art. Procedures and processes for determining appropriate dosages and regimens are well known in the art and will be readily apparent to those skilled in the art. Therefore, it will be readily apparent to those skilled in the art that the dosage ranges described herein are for illustrative purposes only and are not intended to limit the scope or practice of the pharmaceutical compositions described herein.

[0238] In the use of the compounds of the present invention for therapeutic or prophylactic purposes, the compounds are generally administered in divided doses as needed, to a daily dose in the range of, for example, 0.1 mg / kg body weight to 75 mg / kg body weight. Generally, lower doses are administered when parenteral routes are used. For example, in the case of intravenous or intraperitoneal administration, doses in the range of, for example, 0.1 mg / kg body weight to 30 mg / kg body weight are commonly used. Similarly, in the case of administration by inhalation, doses in the range of, for example, 0.05 mg / kg body weight to 25 mg / kg body weight are commonly used.

[0239] Oral administration is particularly preferred for the compounds of the present invention. The compounds of the present invention can be formulated as tablets, capsules, or liquids for oral administration. Preferably, the compounds of the present invention are formulated in oral unit dosage forms (e.g., tablets or capsules). Typically, a unit dosage form contains about 0.5 mg to 1.5 g of the compound of the present invention.

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

[0241] In the description of the synthesis methods described herein, and any referenced synthesis methods used to prepare the starting materials, it should be understood that all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, experimental duration, and processing procedure, can be selected by those skilled in the art.

[0242] Those skilled in organic synthesis will understand that the functional groups present on various parts of a molecule must be compatible with the reagents and reaction conditions used.

[0243] It will be understood that during the synthesis of the compounds of the present invention in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituents to prevent undesirable reactions. A skilled chemist will understand when such protection is necessary and how such protecting groups can be introduced into place and subsequently removed.

[0244] For examples of protecting groups, see one of the many general texts on the subject, for example, "Protective Groups in Organic Synthesis" by Theodora Green (publisher: John Wiley & Sons). Protecting groups can be removed by any convenient method described in the literature as appropriate for the removal of the protecting group in question, or known to a skilled chemist, such a method should be chosen to achieve the removal of the protecting group while minimizing interference with other groups in the molecule.

[0245] Therefore, if the reactants contain groups such as amino, carboxy, or hydroxy, it may be desirable to protect these groups in some of the reactions referred to herein.

[0246] For example, suitable protecting groups for amino or alkylamino groups include, for instance, acyl groups, such as alkanoyl groups (including, but not limited to, acetyl), alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl groups, arylmethoxycarbonyl groups, such as benzyloxycarbonyl, or aroyl groups, such as benzoyl. The deprotection conditions for the above protecting groups inevitably vary depending on the choice of protecting group. Therefore, for example, acyl groups such as alkanoyl or alkoxycarbonyl groups or aroyl groups can be removed by hydrolysis with suitable bases, such as alkali metal hydroxides (but not limited to, lithium or sodium hydroxide). Alternatively, acyl groups such as tert-butoxycarbonyl groups can be removed by treatment with a suitable acid such as hydrochloric acid, sulfuric acid, phosphoric acid, or trifluoroacetic acid, and arylmethoxycarbonyl groups such as benzyloxycarbonyl groups can be removed by hydrogenation on a catalyst such as palladium carbon, or by treatment with a Lewis acid such as tris(trifluoroacetic acid)boron. A suitable alternative protecting group for primary amino groups is the phthaloyl group, which can be removed by treatment with an alkylamine such as dimethylaminopropylamine, or with hydrazine.

[0247] Suitable protecting groups for hydroxyl groups include, for example, acyl groups, such as alkanoyl groups like acetyl, alloyl groups, such as benzoyl, or arylmethyl groups, such as benzyl. The deprotection conditions for these protecting groups inevitably vary depending on the choice of protecting group. Therefore, for example, acyl groups such as alkanoyl or alloyl groups can be removed by hydrolysis with alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, or suitable bases such as ammonia. Alternatively, arylmethyl groups such as benzyl groups can be removed by hydrogenation on a catalyst such as palladium-carbon.

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

[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 d and R e , and their properties vary depending on the properties of any associated substituents. Preferred methods for their preparation are further described in the accompanying examples.

[0251] Once a compound of formula (I) is synthesized by any of the methods defined herein, the method then further: (i) Remove any existing residual protecting groups; or optionally convert any existing COOMe group (e.g., at the R1 position) to CONH2; (ii) The step of converting compound formula (I) to another compound of formula (I); (iii) the step of forming a pharmaceutically acceptable salt, hydrate, or solvate of the compound of formula I; 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 One or more of the groups can be further reacted to change the properties of the groups and provide alternative compounds of formula (I).

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

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

[0255] In the above process (a), Step (i) comprises a reduction-amination step, which typically involves reduction with a hydride-based reagent, followed by imine formation in an alcohol solvent with or without an acid or base. Preferred conditions include sodium triacetoxyborohydride or sodium cyanoborohydride in methanol with or without sodium acetate or DIPEA at 0°C to 50°C.

[0256] If R1 is -CO2PG, step (ii) includes a hydrolysis reaction with a suitable inorganic hydroxide in a mixture of water and an alcohol solvent. Preferred conditions include lithium hydroxide in methanol containing water at room temperature.

[0257] In the above process (b), Steps (i) and (ii) include a reduction amination step followed by a suitable deprotection step as needed, as described in process (a).

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

[0259] If a protecting group is used, step (ii) includes a deprotection reaction. If the PG is a Boc group, the preferred condition is the inclusion of HCl in 1,4-dioxane.

[0260] Compounds of formulas (II), (III), (IV), (V), (VI), or (VII) are commercially available, prepared according to the methods described herein, or prepared according to the literature.

[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.

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

[0263] Therefore, compounds of formula I are useful for the treatment and / or prevention of diseases and conditions involving CK2α activity, such as, but not limited to, proliferative disorders (e.g., cancer), viral infections, inflammation, diabetes, vascular and ischemic disorders, neurodegeneration, and regulation of circadian rhythms.

[0264] In another embodiment, the present invention provides compounds of formula I as defined herein, or pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions as defined herein, for therapeutic use.

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

[0266] In another embodiment, the present invention provides the use of a compound of formula I as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a pharmaceutical for use in the treatment of a disease or condition involving CK2α activity.

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

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

[0269] In another embodiment, the present invention provides the use of a compound of formula I as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a pharmaceutical for use in the treatment of a disease or condition associated with abnormal activity of CK2α.

[0270] In another embodiment, the present invention provides a method for treating a disease or condition associated with abnormal activity of CK2α, comprising the step of administering to a subject requiring treatment an effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition as defined herein.

[0271] In another embodiment, the present invention provides compounds of formula I as defined herein, or pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions as defined herein, for use in the treatment of proliferative disorders (e.g., cancer or benign neoplasms), viral infections, inflammatory diseases or conditions, diabetes, vascular and ischemic disorders, neurodegenerative disorders, and / or regulation of circadian rhythms.

[0272] In another embodiment, the present invention provides the use of compounds of formula I as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, in the manufacture of pharmaceuticals for use in the treatment of proliferative disorders (e.g., cancer or benign neoplasms), viral infections, inflammatory diseases or conditions, diabetes, vascular and ischemic disorders, neurodegenerative disorders, and / or regulation of circadian rhythms.

[0273] In another embodiment, the present invention provides a method for treating proliferative disorders (e.g., cancer or benign neoplasms), viral infections, inflammatory diseases or conditions, diabetes, vascular and ischemic disorders, neurodegenerative disorders, and / or regulating circadian rhythms, comprising the step of administering to a subject requiring treatment an effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0274] In another embodiment, the present invention provides compounds of formula I as defined herein, or pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions as defined herein, for use in the treatment of proliferative disorders.

[0275] In another embodiment, the present invention provides the use of a compound of formula I as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a pharmaceutical for use in the treatment of proliferative disorders (e.g., cancer or benign neoplasms).

[0276] In another embodiment, the present invention provides a method for treating a proliferative disorder (e.g., cancer or a benign neoplasm), comprising the step of administering to a subject requiring treatment an effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition as defined herein.

[0277] The terms “proliferative disorder” and “proliferative condition” are used synonymously herein and relate to unwanted, excessive, or abnormal cell proliferation of neoplasms or hypertrophic growths, whether in vitro or in vivo.

[0278] Examples of proliferative conditions include, but are not limited to, cancer, psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissue), and precancerous and malignant cell proliferations, including atherosclerosis. Any type of cell, including those of the lungs, colon, breast, ovaries, prostate, liver, pancreas, brain, blood, and skin, may be treated.

[0279] In a particular aspect of the present invention, the proliferative disorder is a cancer, preferably selected from lung cancer, colorectal cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, pancreatic cancer, brain tumor, hematological cancer, cholangiocarcinoma, and skin cancer.

[0280] In certain embodiments of the present invention, the proliferative disorder is colorectal cancer, cholangiocarcinoma, ovarian cancer, or prostate cancer.

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

[0282] In certain aspects of the present invention, proliferative disorders include myeloid and granulocytic leukemia (malignancies of myeloid and granulocytic leukocyte lineages); lymphoid, lymphocytic and lymphoblastic leukemia (malignancies of lymphoid and lymphocytic hematological cell lineages); polycythemia vera and erythremia (malignancies of various hematological cell products in which erythrocytes are dominant); and hematopoietic malignancies, including myelofibrosis.

[0283] Benign neoplasms may include, for example, hemangiomas, hepatocellular adenomas, cavernous hemangiomas, focal nodular hyperplasia, auditory neuromas, neurofibromas, cholangioadenomas, cholangiocystadenomas, fibromas, lipomas, leiomyomas, mesotheliomas, teratomas, myxomas, nodular regenerative hyperplasia, trachomas, pyogenic granulomas, moles, uterine fibroids, thyroid adenomas, adrenocortical adenomas, or pituitary adenomas. Benign neoplasms may also include endometrial grafts or keratocystic odontogenic tumors.

[0284] In another embodiment, the present invention provides compounds of formula I as defined herein, or pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions as defined herein, for use in the treatment of cancer.

[0285] In another embodiment, the present invention provides the use of a compound of formula I as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a pharmaceutical for use in the treatment of cancer.

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

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

[0288] (1) Carcinomas including, for example, tumors originating from stratified squamous epithelium (squamous cell carcinoma) and tumors occurring within organs or glands (adenocarcinoma). 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), and basal-like breast cancer. Carcinoma), basal cell carcinoma (a form of skin cancer), squamous cell carcinoma (of various tissues), head and neck cancer (including, but not limited to, squamous cell carcinoma), gastric cancer (including, but not limited to, gastric adenocarcinoma and gastrointestinal stromal tumors), signet ring cell carcinoma, bladder cancer (including, but not limited to, transitional cell carcinoma (malignant neoplasm of the bladder)), bronchogenic cancer, colorectal cancer (including, but not limited to, colon cancer and rectal cancer), anal cancer, stomach cancer, lung cancer (including, but not limited to, small cell carcinoma (SCLC) and non-small cell carcinoma (NSCLC) of the lung, lung adenocarcinoma, squamous cell carcinoma, large cell carcinoma, bronchioloalveolar carcinoma and mesothelioma), neuroendocrine tumors (including, but not limited to, carcinoids of the gastrointestinal tract, breast, and other organs), adrenocortical carcinoma, thyroid cancer, pancreatic cancer (including, but not limited to, pancreatic ductal adenocarcinoma, pancreatic adenocarcinoma) , including acinar cell carcinoma, intraductal papillary mucinous neoplasm with invasive carcinoma, mucinous cystic neoplasm with invasive carcinoma, islet cell carcinoma and neuroendocrine neoplasm), breast cancer (including, but not limited to, ductal carcinoma, lobular carcinoma, inflammatory breast cancer, clear cell carcinoma, mucinous carcinoma), ovarian cancer (including, but not limited to, serous carcinoma, endometrioid carcinoma and mucocystadenocarcinoma, ovarian epithelial carcinoma or surface epithelial-stromal carcinoma including sex cord-stromal carcinoma), liver and cholangiocarcinoma (including, but not limited to, hepatocellular carcinoma, cholangiocarcinoma and hemangioma), prostate cancer, adenocarcinoma, brain tumor (including, but not limited to, glioma, glioblastoma and medulloblastoma), germ cell tumor, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, kidney cancer (including, but not limited to, renal cell carcinoma, clear cell carcinoma and Wilms' tumor), medullary carcinoma, in Situ ductal or bile duct cancer, choriocarcinoma, seminoma, embryonic carcinoma, cervical cancer, uterine cancer (but not limited to these, including endometrial adenocarcinoma and uterine papillary serous carcinoma)Carcinoma, including clear cell carcinoma of the uterus, uterine sarcoma and leiomyosarcoma, mixed Müllerian tumor, testicular cancer, osteogenic carcinoma, epithelial carcinoma, sarcomatoid carcinoma, nasopharyngeal carcinoma, pharyngeal carcinoma; including oral and oropharyngeal squamous cell carcinoma;

[0289] (2) Sarcomas including osteosarcoma and osteogenic sarcoma (bone); chondrosarcoma (cartilage); leiomyosarcoma (smooth muscle); rhabdomyosarcoma (skeletal muscle); mesothelioma and mesothelioma (inner lining of body cavities); fibrosarcoma (fibrous tissue); angiosarcoma and hemangioendothelioma (blood vessels); liposarcoma (adipose tissue); glioma and astrocytoma (neurogenic connective tissue found in the brain); myxosarcoma (primitive embryonic connective tissue); chordoma, endosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovial tumor, Ewing's sarcoma, mesenchymal and mixed mesodermal tumors (mixed connective tissue type), and other soft tissue sarcomas;

[0290] (3) Myeloma and multiple myeloma;

[0291] (4) Myeloid and granulocytic leukemia (malignant neoplasms of myeloid and granulocytic leukocyte lineages); lymphoid, lymphocytic and lymphoblastic leukemia (malignant neoplasms of lymphoid and lymphocytic hematological cell lineages); polycythemia vera and erythremia (malignant neoplasms of various hematological cell products in which red blood cells are dominant); hematopoietic malignancies, including myelofibrosis.

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

[0293] (6) Solid tumors of the nervous system, including medulloblastoma, craniopharyngioma, ependymal cell tumor, pineal glandoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, and schwann cell tumor;

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

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

[0296] Preferably, the compounds of the present invention, or pharmaceutically acceptable salts thereof, may be used for the treatment of cancers selected from among lung cancer, colorectal cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, pancreatic cancer, brain tumors, hematological cancers, cholangiocarcinoma, and skin cancer.

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

[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] It is hypothesized that the compounds of the present invention would be particularly suitable for the treatment of WNT pathway mutation cancers, such as WNT pathway mutation colorectal cancer or cholangiocarcinoma (Di Maira et al., 2019).

[0302] In addition to its well-characterized function in wnt pathway activity, CK2α also plays a role in other important cellular pathways known to be upregulated in cancer, including, but not limited to, the DNA damage response (Ruzzene and Pinna, 2010; Montenarh, Transl. Cancer Res 2016). Therefore, the compounds of the present invention may be further used in the treatment of PARP-insensitive tumors in prostate / ovarian cancer.

[0303] CK2a has also recently been identified as an important host protein necessary for viral replication (e.g., in SARS-CoV-2), and therefore could be an antiviral treatment (Gordon et al., Nature 2020).

[0304] Accordingly, in another embodiment, the present invention provides compounds of formula I as defined herein, or pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions as defined herein, for use in the treatment of viral infections.

[0305] In another embodiment, the present invention provides the use of a compound of formula I as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in the manufacture of a pharmaceutical for use in the treatment of viral infections.

[0306] In another embodiment, the present invention provides a method for treating a viral infection, comprising the step of administering to a subject requiring treatment an effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition as defined herein.

[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 can be administered to a subject by any convenient route of administration, whether systemic, peripheral, or topical (i.e., at the desired site of action).

[0309] Routes of administration are not limited to these, but include: oral (e.g., by food ingestion); oral cavity; sublingual; transdermal (e.g., by patches, plasters, etc.); transmucosal (e.g., by patches, plasters, etc.); intranasal (e.g., by nasal sprays); ocular (e.g., by eye drops, eye ointments, etc.); pulmonary (e.g., by aerosols, e.g., by nose or mouth, e.g., by inhalation therapy or suction therapy); rectal (e.g., by suppositories or enemas); vaginal (e.g., by pessaries); parenteral injection, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrameningeal, intrathecal, intracapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intraarticular, intraarachnoid, and intrasternal; e.g., by implants in the form of subcutaneous or transmuscular depots or reservoir administration.

[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, may be applied as monotherapies, or they may be combined with one or more additional therapeutic agents, such as antitumor agents.

[0312] In the context of cancer treatment, in addition to the compounds of the present invention, the treatment may include conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of antitumor agents.

[0313] - Other antiproliferative / antineoplastic drugs and combinations used in medical oncology, e.g., alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolamide, and nitrosourea); antimetabolites (e.g., gemcitabine and folate antagonists, e.g., fluoropyrimidines (e.g., 5-fluorouracil), tegafur, larcitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumor Antibiotics (e.g., anthracyclines, e.g., adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, and mitramycin); antimitotic agents (e.g., vinca alkaloids, e.g., vincristine, vinblastine, vindesine, and vinorelbine, as well as taxoids, e.g., taxol and taxotere, and polokinase inhibitors); and topoisomerase inhibitors (e.g., epipodophyllotoxins, e.g., etoposide and teniposide, amsacrin, topotecan, and camptothecin);

[0314] - Cell proliferation inhibitors, for example, but not limited to, anti-estrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, doroxifene, and iodoxifene), anti-androgens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin, and buserelin), progestogens (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, borazole, and exemestane), and 5α-reductase inhibitors, for example, but not limited to finasteride;

[0315] - Anti-invasive agents [e.g., c-Src kinase family inhibitors, e.g., 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazine-1-yl)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-methylpyrimidine-4-ylamino}thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661) and bosutinib (SKI-606), as well as metalloproteinase inhibitors, such as marimastat, inhibitors of urokinase plasminogen activator receptor function, or antibodies against heparanase;

[0316] - Inhibitors of growth factor function: For example, such inhibitors include growth factor antibodies and growth factor receptor antibodies (e.g., anti-erbB2 antibody trastuzumab [Herceptin®], anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab [Erbitux, C225], and Stern et al. (Critical reviews in oncology / heematology, 2005, Vol. 1).This includes any growth factor or growth factor receptor antibody disclosed in 54, pp11-29); such inhibitors also include tyrosine kinase inhibitors, e.g., inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors, e.g., 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-bis(2-methoxyethoxy)quinazoline-4-amine (erlotinib, OSI-774), and 6-acrylamide-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazoline-4-amine (CI 1033); erbB2 tyrosine kinase inhibitors, e.g., lapatinib; hepatocyte growth factor family inhibitors; insulin growth factor family inhibitors; platelet-derived growth factor family inhibitors, e.g., imatinib and / or nilotinib (AMN107); serine / threonine kinase inhibitors (e.g., Ras / Raf signaling inhibitors, e.g., farnesyltransferase inhibitors, e.g., sorafenib (BAY) 43-9006), tipifarnib (R115777) and ronafarnib (SCH66336), inhibitors of cell signaling mediated by MEK and / or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; Aurora kinase inhibitors (e.g., AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX39459) and cyclin-dependent kinase inhibitors, including, but not limited to, CDK2 and / or CDK4 inhibitors;

[0317] - Anti-angiogenic agents, such as but not limited to those that inhibit the effects of vascular endothelial growth factor [e.g., the anti-vascular endothelial growth factor antibody bevacizumab (Avastin®)], and VEGF receptor tyrosine kinase inhibitors, such as but not limited to vandetanib (ZD6474), batalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW786034), and 4-(4-fluoro-2-methylin) Compounds such as dole-5-yloxy)-6-methoxy-7-(3-pyrrolidine-1-ylpropoxy)quinazoline (AZD2171; Example 240 in WO00 / 47212), but not limited to those disclosed in international patent applications WO97 / 22596, WO97 / 30035, WO97 / 32856 and WO98 / 13354, as well as compounds acting by other mechanisms (e.g., linamides, inhibitors of integrin αvβ3 function, and angiostatins);

[0318] - Vascular damage agents, such as but not limited to, combretastatin A4 and compounds disclosed in international patent applications WO99 / 02166, WO00 / 40529, WO00 / 41669, WO01 / 92224, WO02 / 04434 and WO02 / 08213;

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

[0320] - Antisense therapies, for example, against the targets listed above, but not limited to, ISIS2503, anti-ras antisense;

[0321] - Approaches to replace abnormal genes, such as but not limited to abnormal p53 or abnormal BRCA1 or BRCA2; GDEPT (gene-directed enzyme prodrug therapy) approaches, such as but not limited to those using cytosine deaminase, thymidine kinase or bacterial nitroreductase enzymes; and gene therapy approaches to enhance patient resistance to chemotherapy or radiotherapy, such as multidrug resistance gene therapy; and

[0322] - Immunotherapy approaches to enhance the immunogenicity of a patient's tumor cells, including, but not limited to, transfection with cytokines such as interleukin-2, interleukin-4, or granulocyte-macrophage colony-stimulating factor; approaches to reduce T cell anergy; approaches using transfected immune cells, such as, but not limited to, cytokine-transfected dendritic cells; approaches using cytokine-transfected tumor cell lines; and approaches using anti-idiotype antibodies.

[0323] In certain embodiments, the antiproliferative treatment defined above may include, in addition to the compounds of the present invention, conventional surgery, radiotherapy, or chemotherapy.

[0324] In further specific embodiments, the antiproliferative treatment defined above may include, in addition to the compounds of the present invention, standard chemotherapy for the relevant cancer.

[0325] In certain embodiments, the antiproliferative treatment defined above may include, in addition to the compounds of the present invention, treatment with a K-ras inhibitor and / or a DNA damage repair inhibitor (e.g., a PARP inhibitor).

[0326] Such combined treatments can be achieved by the simultaneous, sequential, or separate administration of the individual components of the treatment. The products of such combinations use the compounds of the present invention within the aforementioned dose range and other pharmaceutically active agents within their approved dosage ranges.

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

[0328] According to this aspect of the present invention, a combination is provided for use in the treatment of proliferative conditions, such as cancer (including, for example, solid tumors), comprising one of the compounds of the present invention as defined above, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and any of the antitumor agents listed above.

[0329] In a further embodiment of the present invention, compounds of the present invention or pharmaceutically acceptable salts, hydrates, or solvates thereof are provided for use in the treatment of cancer in combination with another antitumor agent optionally selected from those enumerated above.

[0330] Where the term “combination” is used herein, it should be understood that it refers to simultaneous, separate, or sequential administration. In one embodiment of the present invention, “combination” refers to simultaneous administration. In another embodiment of the present invention, “combination” refers to separate administration. In a further embodiment of the present invention, “combination” refers to sequential administration. When the administration is sequential or separate, any delay in the administration of the second component should not be such as to cause loss of the beneficial effect of the combination. In one embodiment, “combination” refers to the product of the combination.

[0331] A further aspect of the present invention provides a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt, hydrate, or solvate thereof, combined with a pharmaceutically acceptable diluent or carrier and an antitumor agent (optionally selected from those listed above).

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

[0333] The pharmacological properties of the compound of formula I vary with structural changes as predicted, but the compound of the present invention was found to be active in the assay described in Biological Assay 1. In general, the compound of the present invention exhibits an IC500 nM or less in the assay described in Biological Assay 1. 50 The preferred compounds of the present invention have an IC of 100 nM or less. 50 The most preferred compound of the present invention is one with an IC of 30 nM or less. 50 This indicates.

[0334] The compounds of the present invention may also exhibit activity in assay 3, as described in the section on accompanying biological assays. [Examples]

[0335] The present invention will be described by reference to, but will not be limited to, the specific embodiments described in the following examples. Compounds are named using conventional IUPAC nomenclature or by the chemical supplier.

[0336] The following synthesis procedure is provided to illustrate the method used, and in a given preparation or step, the precursor used does not need to originate from individual batches synthesized according to the steps of the given description.

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

[0338] All LCMS spectra were obtained using one of the following methods. Method 1 (AM1): (5-95 A-B_1.5 min_220 and 254 nm): Instrument: Agilent 1100 / G1956A; Column: Kinetex@5um EVO C18 30×2.1 mm×5 μm; Run time: 1.5 min; Solvent: A) 0.0375% TFA in water (volume / volume), B) 0.01875% TFA in acetonitrile (volume / volume). Run a concentration gradient with 5% B; Concentration gradient: 5-95% B including A, 0.8 min; Hold up to 1.2 min with 95% B; Hold up to 1.2 min with 5% B and 5% B to 1.5 min @ 1.5 mL / min, 50°C. Method 2 (AM2): (5-95 A-B_1.5 min_220 and 254 nm): Instrument: Agilent 1200 / G6110A; Column: Kinetex@5um EVO C18 30×2.1 mm×5 μm; Run time: 1.5 min; Solvent: A) 0.0375% TFA in water (volume / volume), B) 0.01875% TFA in acetonitrile (volume / volume). Run a concentration gradient with 5% B; Concentration gradient: 5-95% B including A, 0.8 min; Hold up to 1.2 min with 95% B; Hold up to 1.2 min with 5% B and 5% B to 1.5 min @ 1.5 mL / min, 50°C. Method 3 (AM3): (5-95 A-B_1.55 min_220 and 254 nm): Instrument: SHIMADZU LCMS-2020; Column: Kinetex EVO C18 30 × 2.1 mm × 5 μm; Run time: 1.55 min; Solvent: A) 0.0375% TFA in water (volume / volume), B) 0.01875% TFA in acetonitrile (volume / volume). Run a concentration gradient with 5% B; Concentration gradient: 5-95% B including A, 0.8 min; Hold at 95% B up to 1.2 min; Hold at 5% B and 5% B up to 1.55 min @ 1.5 mL / min, 50°C. Method 4 (AM4): (5-95 A-B_1.5 min_220 and 254 nm): Instrument: Agilent 1200 LC / G1956A MSD; Column: Kinetex EVO C18 30 × 2.1 mm × 5 μm; Run time: 1.5 min; Solvent: A) 0.0375% TFA in water (volume / volume), B) 0.01875% TFA in acetonitrile (volume / volume). Run a concentration gradient with 5% B; Concentration gradient: 5-95% B including A, 0.8 min; Hold up to 1.2 min with 95% B; Hold up to 1.2 min with 5% B and 5% B to 1.5 min @ 1.5 mL / min, 50°C. Method 5 (AM5): (0-60 A-B_1.55 min_220 and 254 nm): Instrument: SHIMADZU LCMS-2020; Column: Kinetex EVO C18 30 × 2.1 mm × 5 μm; Run time: 1.55 min; Solvent: A) 0.0375% TFA in water (volume / volume), B) 0.01875% TFA in ACN (volume / volume). Run a concentration gradient with 0% B; Concentration gradient: 0-60% B including A, 0.8 min; Hold at 60% B up to 1.20 min; Hold at 0% B and 0% B up to 1.55 min at 1.21 min @ 1.5 mL / min, 50°C. Method 6 (AM6): (0-60 C-D_2.20 min_220 and 254 nm): Instrument: SHIMADZU LCMS-2020; Column: Kinetex EVO C18 30 × 2.1 mm × 5 μm; Run time: 2.20 min; Solvent: A) 0.025% NH3·H2O (volt / volt) in water, B) Acetonitrile. Run a concentration gradient with 0% B; Concentration gradient: 0-60% B including A, 1.2 min; Hold at 60% B up to 1.6 min; Hold at 0% B and 0% B up to 2.2 min @ 1.5 mL / min, 40°C. Method 7 (AM7): (5-95 C-D_1.5 min_R_220 and 254_POS): Instrument: SHIMADZU LCMS-2020; Column: Kinetex EVO C18 30 × 2.1 mm × 5 μm; Run time: 1.5 min; Solvent A) 0.025% NH3·H2O in water (volt / volt) B) Acetonitrile. Run a concentration gradient with 5% B. Concentration gradient: 0.8 min with A and 0.95% B, hold up to 1.2 min with 95% B; 1.2 min with 5% B and hold up to 1.5 min with 5% B @ 1.5 ml / min, 40°C. Method 8 (AM8): (10-80 C-D_2.00 min_220 and 254 nm): Instrument: Agilent 1200 / G6110A; Column: ACE Excel 5 C18 30 × 2.1 mm × 5 μm; Run time: 2.00 min; Solvent: A) 0.025% NH3·H2O in water (volt / volt), B) Acetonitrile (volt / volt). Run a concentration gradient at 10% B; Concentration gradient: 10-80% B including A, 1.2 min; Hold at 80% B up to 1.6 min; Hold at 10% B and 10% B up to 2.00 min @ 1.0 mL / min, 40°C. Method 9 (AM9): (10-80 A-B_7 min_220 and 254 nm): Instrument: SHIMADZU LCMS-2020; Column: AB: Xtimate C18 30 × 2.1 mm × 3 μm; Run time: 7.0 min; Solvent: A) 0.0375% TFA in water (vol / vol), B) 0.01875% TFA in acetonitrile (vol / vol). Run a concentration gradient at 10% B; Concentration gradient: 10-80% B including A, 6.5 min; Hold at 80% B up to 7 min; Hold at 10% B and 10% B up to 7 min at 6.5 min @ 1.5 mL / min, 50°C.

[0339] 1 ¹H NMR spectra were acquired at a Bruker Avance III spectrometer at 400 MHz using a residual non-deuterated solvent as a reference, and annotated using ACD Labs. <Purification method (PM)> chromatography

[0340] JPEG0007881600000025.jpg97170 Reverse-phase HPLC conditions

[0341] JPEG0007881600000026.jpg147170JPEG0007881600000027.jpg255162JPEG0007881600000028.jpg255162JPEG0007881600000029.jpg25516 1JPEG0007881600000030.jpg255161JPEG0007881600000031.jpg255162JPEG0007881600000032.jpg255161JPEG0007881600000033.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, 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]dichloropalladium(II), Pd(dppf)Cl2·CH2Cl2 is a complex of [1,1'-bis(diphenylphosphin)ferrocene]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 can be prepared according to the method described in J.Med.Chem.2011,54(2),635-654. <Synthesis of intermediate E> tert-butyl(4-(cyanomethoxy)butyl)carbamate 1.19

[0345] [ka] To a mixture of tert-butyl(4-hydroxybutyl)carbamate (7 g, 36.99 mmol) and 2-bromoacetonitrile (8.87 g, 73.98 mmol) in DCM (100 mL), silver(I) oxide (18.55 g, 80.05 mmol) and TBAI (2.94 g, 7.96 mmol) were added at 25°C. The mixture was stirred at 25°C for 16 hours. The mixture was filtered, the filtrate was washed with aqueous NaHCO3 (100 mL), dried over Na2SO4, 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%) as a yellow oil. 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] To a solution of compound 1.19 (1.0 g, 4.38 mmol) in MeOH (10 mL), ammonium hydroxide (2 mL, 25 wt%) and Raney nickel (100 mg, 1.17 mmol) were added under nitrogen protection at 25°C. 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 concentrated under vacuum to obtain compound 1.20 (1 g) as a green oil, which was used directly in the next step. Methyl 5-((2-(4-((tert-butoxycarbonyl)amino)butoxy)ethyl)amino)benzo[c][2,6]naphthyrizine-8-carboxylate, 1.58

[0347] [ka] To a solution of compound 1.1 (3.20 g, 11.74 mmol) in DMSO (50 mL), DIPEA (3.03 g, 23.48 mmol) and compound 1.20 (3 g, 12.91 mmol) were sequentially added at 25 °C. 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 combined organic layer was washed with brine (100 mL), dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain compound 1.58 (5 g) as a brown solid. LCMS (AM3): rt = 0.841 min, (469.3 [M+H] + ), purity 63.4%. 5-((2-(4-((tert-butoxycarbonyl)amino)butoxy)ethyl)amino)benzo[c][2,6]naphthyridine-8-carboxylic acid, 1.59

[0348] [ka] Compound 1.58 (5 g, 10.67 mmol) was dissolved in THF (15 mL), MeOH (15 mL), and water (15 mL), to which NaOH (853.65 mg, 21.34 mmol) was added at 20°C. The reaction mixture was then stirred at 20°C for 4 hours. The organic solvent was concentrated under vacuum, and the remaining aqueous solution was acidified to pH 5 with HCl aqueous solution (1 N). The resulting precipitate was filtered and dried under vacuum to obtain compound 1.59 (4.5 g) as a brown solid. LCMS (AM3): rt = 0.808 min, (455.3 [M+H] + ), purity 88.98%. tert-butyl(4-(2-((8-carbamoylbenzo[c][2,6]naphthyridine-5-yl)amino)ethoxy)butyl)carbamate, 1.60

[0349] [ka] To a stirred solution of compound 1.59 (4.5 g, 9.90 mmol) in DMF (25 mL), EDCI (2.85 g, 14.85 mmol), HOBt (2.01 g, 14.85 mmol), DIPEA (1.92 g, 14.85 mmol), and NH4Cl (2.12 g, 39.60 mmol) were sequentially added at 20°C. 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). The combined organic layers were washed with brine (80 mL x 2), dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM19) to obtain compound 1.60 (3.8 g, 6.70 mmol, yield 67.6%, TFA salt) as a yellow oil. LCMS (AM3): rt = 0.758 min, (454.4 [M+H] + ), purity 59.9%. 5-((2-(4-aminobutoxy)ethyl)amino)benzo[c][2,6]naphthyridine-8-carboxamide, intermediate E

[0350] [ka] A solution of compound 1.60 (3.8 g, 8.38 mmol) in MeOH (5 mL) was added dropwise with a solution of HCl in MeOH (4 M, 2.09 mL) at 0°C. The reaction mixture was then 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, yield 85.7%, HCl salt) 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] To a solution of NaOH (2.11 g, 52.84 mmol) in 1,4-dioxane (176.1 mL), tert-butyl N-(4-hydroxybutyl)carbamate (10 g, 52.84 mmol) and 3-bromopropa-1-ene (12.78 g, 105.68 mmol) were sequentially added at 20 °C. The reaction mixture was heated to 70 °C and stirred for 12 hours. 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 (80 mL x 2), dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM6) to obtain compound 1.53 (5.5 g, 23.98 mmol, yield 45.4%) as a pale yellow oil. 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] O3 was blown at -78°C into a solution of compound 1.53 (5.5 g, 23.98 mmol) in DCM (50 mL) until the mixture turned blue. The reaction mixture was then heated to 0°C, and NaBH4 (1.77 g, 46.79 mmol) was slowly added at 0°C. The reaction mixture was heated to 20°C and stirred for 12 hours. The reaction mixture was quenched with water (50 mL) and extracted with DCM (80 mL x 2). The combined organic layers were washed with brine (80 mL x 2), dehydrated with anhydrous Na2SO4, then filtered, and concentrated under vacuum. The residue was purified (PM3) to obtain compound 1.54 (2.65 g, 11.36 mmol, yield 47.4%) as a colorless oil. 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), 1.42 (s, 9H) ppm. 5-(2-(4-((tert-butoxycarbonyl)amino)butoxy)ethoxy)benzo[c][2,6]naphthyridine-8-carboxylic acid, 1.55

[0353] [ka] To a mixture of compound 1.54 (427.79 mg, 1.83 mmol) in DMF (10 mL), NaH (110.02 mg, 2.75 mmol) was added in one step at 0°C under nitrogen protection, followed by compound 1.1 (500 mg, 1.83 mmol). The mixture was then heated to 80°C and stirred for 12 hours. The mixture was diluted with water (50 mL) and extracted with EA (50 mL x 2). The combined organic phase was washed with brine (50 mL), dehydrated with Na2SO4, and concentrated under vacuum. The residue was purified (PM20) to obtain compound 1.55 (300 mg, 645.44 μmol, yield 35.2%, purity 98.2%) as a pale yellow solid. LCMS (AM3): rt = 0.903 min, (456.3 [M+H] + ), purity 98.2%. tert-butyl(4-(2-((8-carbamoylbenzo[c][2,6]naphthyrizin-5-yl)oxy)ethoxy)butyl)carbamate, 1.56

[0354] [ka] A mixture of compound 1.55 (300 mg, 645.44 μmol), ammonium chloride (51.79 mg, 968.16 μmol), and DIPEA (208.54 mg, 1.61 mmol) in DMF (10 mL) was mixed with HATU (294.50 mg, 774.53 μmol) at 25 °C. The resulting mixture was stirred at 25 °C for 11 hours under nitrogen protection. The reaction mixture was filtered and concentrated under vacuum to obtain a residue, which was purified (PM21) to obtain compound 1.56 (250 mg, 473.03 μmol, yield 73.3%, purity 86.2%) as a pale yellow solid. 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] To a mixture of compound 1.56 (250 mg, 473.03 μmol, 1 equivalent) in DCM (20 mL), TFA (6.16 g, 54.03 mmol, 4 mL) was added at 25 °C, and the mixture was stirred for 0.5 hours. The reaction mixture was concentrated under vacuum and purified (PM21) to obtain compound 1.57 (220 mg, 432.09 μmol, yield 91.3%, purity 92.1%, TFA salt) 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] To 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, yield 97%, TFA salt) as a brown solid, which was 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]naphthyrizine-8-carboxylate 1.154

[0357] [ka] To a solution of compound 1.58 (200 mg, 426.85 μmol) in 1,4-dioxane (5 mL), a solution of 1,4-dioxane in HCl (4 M, 5 mL) 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 (201 mg, HCl salt) as a yellow oily substance, which was 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]naphthyridine-8-carboxylic acid; intermediate R

[0358] [ka] Compound 1.59 (4 g, 8.80 mmol) in a 1,4-dioxane solution in HCl (40.00 mL, 4 M) was stirred at 25°C for 16 hours. The precipitate was filtered and dried under vacuum to obtain intermediate R (2.5 g, HCl salt) 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-methylbenzenesulfonate (77.3 g, 225.08 mmol) (Journal of Medicinal Chemistry, 2006, 49(14), 4183-4195), benzyl 3-hydroxyazetidine-1-carboxylate (31.09 g, 150.05 mmol), and TBAI (13.86 g, 37.51 mmol) were mixed in toluene (500 mL) and water (100 mL) to which NaOH (60.02 g, 1.50 mol) was added. The mixture was heated to 60°C and stirred for 12 hours. The mixture was diluted with water (1 L) and extracted with MTBE (200 mL x 3). The combined organic layer was washed with brine (200 mL), dehydrated with Na2SO4, and concentrated under vacuum. The residue was purified (PM2) to obtain compound 1.493 (43.5 g, yield 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 1.494

[0360] [ka] To a solution of compound 1.493 (43.5 g, 114.94 mmol) in MeOH (500 mL), 10% carbon-supported palladium (5 g) was added under nitrogen protection at 20°C. The reaction 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%) as a pale yellow oil, which was 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)azetidine-1-yl)benzo[c][2,6]naphthyridine-8-carboxylate 1.495

[0361] [ka] To a solution of compound 1.1 (9.5 g, 34.84 mmol) and compound 1.494 (11.07 g, 45.29 mmol) in DMSO (200 mL), DIPEA (22.51 g, 174.19 mmol) was added. The mixture was heated to 80 °C and stirred for 12 hours. The reaction mixture was poured into water (600 mL) and stirred for 10 minutes. The precipitate was filtered and dried under vacuum to obtain compound 1.495 (14.1 g, 27.29 mmol, yield 78.3%) as a yellow 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] To a mixture of compound 1.495 (14.1 g, 29.34 mmol) in THF (100 mL), water (100 mL), and MeOH (50 mL), lithium hydroxide monohydrate (6.16 g, 146.71 mmol) was added. The reaction mixture was heated to 50 °C and stirred for 3 hours. The solvent was removed under reduced pressure, and the mixture was acidified to pH 5 with 1 M aqueous HCl. The precipitate was collected by filtration, the filter cake was washed with water, and the mixture was dried under vacuum to obtain compound 1.496 (15.6 g) as a yellow solid. LCMS (AM3): rt = 0.813 min, (467.3 [M+H] + ), purity 98.7%. 5-(3-(4-aminobutoxy)azetidine-1-yl)benzo[c][2,6]naphthyridine-8-carboxylic acid; intermediate O

[0363] [ka] Compound 1.496 (7.6 g, 16.29 mmol) in a HCl solution of dioxane (80.07 mL, 4 M) was stirred at 20°C for 1 hour. The mixture was concentrated under vacuum to obtain intermediate O (6.9 g, HCl salt) 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]naphthyrizine-5-yl)azetidine-3-yl)oxy)butyl)carbamate 1.497

[0364] [ka] NH4Cl (917.27 mg, 17.15 mmol) was added to a solution of compound 1.496 (8 g, 17.15 mmol), HATU (15.65 g, 20.58 mmol), and DIPEA (6.65 g, 51.44 mmol) in DMF (100 mL). The resulting mixture was stirred at 20°C for 12 hours. The mixture was poured into water (200 mL) and extracted with EA (100 mL x 2). The combined organic phase was washed with brine (100 mL), dehydrated with Na2SO4, and concentrated under vacuum. The residue was purified (PM22) to obtain compound 1.497 (6.6 g, 14.05 mmol, yield 81.9%) as a yellow solid. LCMS (AM3): rt = 0.793 min, (466.3 [M+H] + ), purity 99.2%. 5-(3-(4-aminobutoxy)azetidine-1-yl)benzo[c][2,6]naphthyridine-8-carboxamide; intermediate P

[0365] [ka] Compound 1.497 (6.6 g, 14.18 mmol) in a HCl solution of 1,4-dioxane (35 mL, 4 M) was stirred at 20°C for 1 hour. The mixture was concentrated under vacuum to obtain intermediate P (5.5 g, HCl salt) 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] A mixture of bromocyclobutane (0.25 mL, 2.65 mmol), 3-chloro-4-hydroxybenzaldehyde (200 mg, 1.28 mmol), and potassium carbonate (440 mg, 3.18 mmol) in DMF (10 mL) was stirred at 80°C for 15 hours. The reaction mixture was poured into water (60 mL), and the resulting mixture was extracted with EA (20 mL x 3). The combined organic phase was washed with brine (30 mL), dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the crude product, which was purified (PM11) to obtain compound 1.32 (134 mg, yield 49.8%) as a colorless oil. 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] A mixture of bromocyclopentane (0.274 mL, 2.56 mmol), 3-chloro-4-hydroxybenzaldehyde (200 mg, 1.28 mmol), and potassium carbonate (441 mg, 3.19 mmol) in DMF (10 mL) was stirred at 80°C for 15 hours. The reaction mixture was poured into water (60 mL), and the resulting mixture was extracted with EA (20 mL x 3). The combined organic phase was washed with brine (30 mL), dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was purified (PM11) to obtain compound 1.33 (270 mg, yield 93.9%) as a colorless oil. 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] Potassium carbonate (2.06 g, 14.92 mmol) was added to a mixture of 3-bromo-4-hydroxybenzaldehyde (1.0 g, 4.97 mmol) and bromocyclobutane (1.01 g, 7.46 mmol) in DMF (10 mL) at room temperature. The resulting mixture was heated to 80 °C and stirred for 12 hours. The reaction mixture was concentrated under vacuum to obtain a residue, which was poured into water (10 mL) and extracted with EA (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na₂SO₄, and concentrated under vacuum. The crude product was purified (PM4) to obtain compound 1.46 (1.0 g, 3.80 mmol, yield 76.4%, purity 97%) 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] To a mixture of compound 1.46 (200 mg, 783.98 μmol) in DMF (1 mL), zinc cyanide (460.32 mg, 3.92 mmol) and tetrakis(triphenylphosphine)palladium (90.59 mg, 78.40 μmol) were sequentially added under nitrogen protection at 25°C. The reaction mixture was then heated to 100°C and stirred for 12 hours. The mixture was concentrated under vacuum and purified (PM38) to obtain compound 1.47 (80 mg, 397.57 μmol, yield 50.7%, purity 100%) as a white solid. 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] To a mixture of cyclopropylboronic acid (122.69 mg, 1.43 mmol) and 2-bromo-5-formylbenzonitrile (200 mg, 952.26 μmol) in 1,4-dioxane (1 mL) and water (0.1 mL), Pd(dppf)Cl2·CH2Cl2 (77.77 mg, 95.23 μmol) and potassium carbonate (263.22 mg, 1.90 mmol) were sequentially added at 25°C under nitrogen protection. The mixture was heated to 90°C and stirred for 12 hours. The mixture was concentrated under vacuum and purified by preparative TLC (SiO2, PE:EA=3:1) to obtain compound 1.52 (100 mg, 566.61 μmol, yield 59.5%, purity 97%) as a white solid. LCMS (AM3): rt = 0.808 min, (172.2 [M+H] + ), purity 97.81%. 1H 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] To a solution of 3-chloro-4-fluorobenzaldehyde (1.8 g, 11.35 mmol) in acetonitrile (20 mL), potassium carbonate (2.35 g, 17.03 mmol) and cyclopropanol (725.27 mg, 12.49 mmol) were added at 25 °C. 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) to obtain compound 1.90 (120 mg, 610.28 μmol, yield 5%) as a yellow oil. 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] A mixture of (3-bromo-5-chlorophenyl)methanol (2 g, 9.03 mmol) and TMEDA (2.10 g, 18.05 mmol, 2.72 mL) in THF (20 mL) was added dropwise with n-BuLi (2.4 M, 7.53 mL) at -78 °C. The resulting mixture was then heated to -20 °C and stirred for 1 hour. The reaction mixture was cooled again to -78 °C and DMF (10 mL) 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 extracted with EA (20 mL x 3). The combined organic layers were washed with brine (10 mL), dehydrated with Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM2) to obtain compound 1.102 (400 mg, 2.34 mmol, yield 26%) as a yellow oil. 1 H 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] To a solution of methyl 3-(cyanomethyl)benzoate (1.5 g, 8.56 mmol) in THF (15 mL), LiBH4 (2 M, 12.84 mL, 25.69 mmol) was added at ambient temperature. The reaction mixture was then heated to 70 °C and stirred for 4 hours. The mixture was cooled to room temperature, quenched with aqueous HCl (1 N, 50 mL), and extracted with EA (20 mL x 3). The combined organic phase was washed with brine (50 mL), dehydrated with anhydrous Na2SO4, and concentrated under vacuum. The residue was purified (PM6) to obtain compound 1.133 (1.0 g, 6.79 mmol, yield 79.3%) 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] To a solution of compound 1.133 (500 mg, 3.40 mmol) in DCM (20 mL), manganese(IV) oxide (2.95 g, 33.97 mmol) was added at 30°C. The reaction mixture was stirred at 30°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified (PM6) to obtain compound 1.134 (50 mg, 344.45 μmol, yield 10.1%) as a yellow oil. 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] To a solution of 3-bromo-4-(trifluoromethoxy)benzaldehyde (500 mg, 1.86 mmol) in DMF (15 mL), zinc cyanide (0.82 g, 6.98 mmol) and tetrakis(triphenylphosphine)palladium (214.78 mg, 185.86 μmol) were added at ambient temperature. The reaction mixture was then heated to 100 °C and stirred under nitrogen protection for 12 hours. The mixture was cooled to room temperature and poured into water (50 mL). The aqueous mixture was extracted with EA (20 mL x 3). The combined organic phase was washed with brine (50 mL), dehydrated with anhydrous Na₂SO₄, and concentrated under vacuum. The resulting residue was purified (PM12) to obtain compound 1.136 (170 mg, 790.23 μmol, yield 42.5%) as a brownish oil. 1H 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] To a cold solution of 5-bromo-2-(trifluoromethoxy)benzoic acid (2 g, 7.02 mmol) in MeOH (20 mL), SOCl2 (1.67 g, 14.03 mmol) was slowly added. The resulting mixture was heated to 70°C and stirred for 1 hour. The mixture was concentrated under vacuum, and the resulting residue was diluted with EA (100 mL). The organic phase was washed with sodium bicarbonate (50 mL) and brine (50 mL), dehydrated with Na2SO4, and concentrated under vacuum to obtain compound 1.150 (2.9 g) as a yellow oil, which was used directly without further purification. 1 H NMR (400 MHz, CHCl3-d) δ: 8.09 (d, J = 2.6 Hz, 1H), 7.68 (dd, J = 2.5, 8.7 Hz, 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] To a solution of compound 1.150 (2.9 g, 9.70 mmol) in THF (20 mL), LiAlH4 (368.07 mg, 9.70 mmol) was added under nitrogen at 0°C. The mixture was heated to 20°C and stirred for 1 hour. The mixture was cooled to 0°C and diluted with EA (10 mL). The resulting mixture was then quenched with water (0.2 mL), followed by the addition of 10% NaOH aqueous solution (0.2 mL) and water (0.6 mL). Anhydrous Na2SO4 (5 g) was added, and the resulting suspension was stirred separately for 0.5 hours and then filtered. The filtrate was concentrated under vacuum to obtain compound 1.151 (2.23 g, 8.23 ​​mmol, yield 84.8%) as a white solid, which 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] To a solution of compound 1.151 (2.23 g, 8.23 ​​mmol) and tributyl(vinyl) stannane (2.61 g, 8.23 ​​mmol) in toluene (50 mL), Pd(PPh3)4 (665.54 mg, 575.95 μmol) was added at ambient temperature under nitrogen protection. The mixture was heated to 95 °C and stirred for 12 hours. The residue was poured into saturated KF aqueous solution (100 mL), the resulting mixture was stirred for 15 minutes, and then extracted with EA (50 mL x 3). The combined organic phase was washed with brine (100 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM7) to obtain compound 1.152 (1.43 g, 6.55 mmol, yield 79.7%) as a yellow oil. 1H NMR (400 MHz, CHCl3-d) δ: 7.49 (d, J = 2.2 Hz, 1H), 7.26 (dd, J = 2.2, 8.4 Hz, 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, 1.153

[0379] [ka] Ozone was blown into a solution of compound 1.152 (500 mg, 2.29 mmol) in DCM (10 mL) at -70°C until the mixture turned blue. Dimethyl sulfate (1.42 g, 22.92 mmol) was then 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, 1.48 mmol, yield 64.6%) as a pale yellow oil. 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] To a mixture of cyclopropylboronic acid (156 mg, 1.82 mmol) in 1,4-dioxane (8 mL) and water (2 mL), 4-bromo-3-chlorobenzaldehyde (200 mg, 0.911 mmol) was added at ambient temperature, followed by the addition of K2CO3 (315 mg, 2.28 mmol) and Pd(dppf)Cl2 (66 mg, 0.090 mmol). The mixture was degassed three times, purged with nitrogen, and then heated to 80°C and stirred for 14 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified (PM11) to obtain compound 1.202 (130 mg, yield 79%) 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-carbaldehyde, 1.345

[0381] [ka] (2-(hydroxymethyl)phenyl)boronic acid (250 mg, 1.65 mmol), 4-bromo-3-chlorobenzaldehyde (361 mg, 1.64 mmol), and K2CO3 (569 mg, 4.12 mmol) were mixed in 1,4-dioxane (8 mL) and water (2 mL) to which Pd(dppf)Cl2·CH2Cl2 (67 mg, 0.082 mmol) was added. The reaction mixture was degassed three times and purged with nitrogen, and then the reaction mixture was heated to 80°C and stirred for 17 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified (PM6) to obtain compound 1.345 (400 mg, yield 98.6%) as a colorless oil. 1H 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] A mixture of 2-(3-bromo-5-chlorophenyl)acetonitrile (500 mg, 1.08 mmol) (US2008221127A1), tributyl(vinyl) stannane (343.94 mg, 1.08 mmol), and Pd(PPh3)4 (125 mg, 1.08 μmol) in toluene (10 mL) was stirred at 90°C for 15 hours. The mixture was poured into saturated KF aqueous solution (100 mL) and then extracted with EA (100 mL x 2). The combined organic phase was washed with brine (50 mL), dehydrated with Na2SO4, and concentrated. The residue was purified (PM14) to obtain compound 1.365 (200 mg) 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] Ozone was bubbled into a solution of compound 1.365 (200 mg, 1.13 mmol) in DCM (20 mL) at -78°C for 0.5 hours until the reaction mixture turned blue, and then DMS (3.66 g, 58.91 mmol) was slowly added to the mixture at -78°C. The reaction mixture was heated to 20°C and stirred separately for 12 hours. The reaction mixture was concentrated under vacuum, and the residue was purified (PM7) to obtain compound 1.366 (150 mg, 835.18 μmol, yield 74.2%) 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] A mixture of 5-bromo-2-(trifluoromethoxy)phenol (900 mg, 3.5 mmol), 2-bromoethanol (0.63 mL, 8.87 mmol), and K2CO3 (1.21 g, 8.73 mmol) in acetonitrile (18 mL) was heated to 80°C and stirred for 15 hours. The reaction mixture was concentrated under vacuum, and the residue was purified (PM6) to obtain compound 1.401 (850 mg, yield 80.6%) as a colorless oil. 1H 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] A mixture of 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) was mixed with n-BuLi (1.76 mL, 2.5 M in hexane) at -70°C. The reaction mixture was stirred at -70°C for 1 hour, then heated to 25°C and stirred separately for 1 hour. The reaction mixture was quenched by adding water (1 mL) and extracted with EA (50 mL x 2). The combined organic phase was washed with brine (30 mL), dehydrated with Na2SO4, and concentrated under vacuum. The residue was purified (PM47) to obtain compound 1.402 (48 mg, yield 6%) as a yellow oil. 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] A mixture of methyl 3-hydroxy-4-(trifluoromethyl)benzoate (1.1 g, 5.00 mmol) (Journal of Medicinal Chemistry, 2005, 48(9), 3290-3312), 2-bromoethanol (0.71 mL, 10 mmol), and K2CO3 (1.39 g, 10.03 mmol) in DMF (15 mL) was stirred at 80°C for 16 hours. The reaction mixture was filtered, and the filtrate was poured into water (100 mL) and extracted with EA (50 mL x 2). The combined organic phase was washed with brine (30 mL), dehydrated with Na2SO4, and concentrated under vacuum. The residue was purified (PM47) to obtain compound 1.404 (850 mg, yield 64.4%) as a brownish oil. LCMS (AM2): rt = 0.779 min, (286.9 [M+Na] + ), 100% pure. 2-(5-(hydroxymethyl)-2-(trifluoromethyl)phenoxy)ethanol 1.405

[0387] [ka] Compound 1.404 (800 mg, 3.03 mmol) in THF (5 mL) was added to a mixture of LAH (345 mg, 9.09 mmol) in THF (15 mL) at 0°C. The reaction mixture was then heated to room temperature and stirred for 2 hours. The reaction mixture was quenched by adding water (0.4 mL), followed by 0.4 mL of NaOH aqueous solution (10%) and water (1.2 mL), and stirred for 0.5 hours. After adding Na2SO4, the resulting suspension was stirred separately for 30 minutes, filtered, and the filtrate was concentrated under vacuum to obtain compound 1.405 (600 mg) as a brownish oily substance, which was used directly without further purification. 1H 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 1.406

[0388] [ka] A mixture of compound 1.405 (550 mg, 2.33 mmol) and manganese(IV) oxide (2.02 g, 23.28 mmol) in DCM (20 mL) was stirred at room temperature for 20 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The crude product was purified (PM5) to obtain compound 1.406 (380 mg, yield 59.2%) as a brownish oil. 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] A mixture of 3-hydroxy-4-methoxybenzaldehyde (8.8 g, 57.84 mmol), 2-bromoethanol (8 mL, 113 mmol), and K2CO3 (16 g, 116 mmol) in acetonitrile (100 mL) was stirred at 80°C for 14 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified (PM3) to obtain compound 1.408 (7.8 g, yield 66.7%) 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] To a solution of compound 1.408 (7.7 g, 39.25 mmol) in DCM (200 mL), AlCl3 (26.18 g, 196.34 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into water (300 mL) at 0°C and extracted with a solvent mixture of DCM and MeOH (volt / volt = 10:1, 50 mL × 10). The combined organic phase was washed with brine (400 mL), dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM2) to obtain compound 1.409 (5.3 g, yield 74.1%) 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] A mixture of compound 1.409 (200 mg, 1.10 mmol), bromocyclobutane (296 mg, 2.19 mmol), and K2CO3 (378 mg, 2.73 mmol) in DMF (10 mL) was stirred at 100°C for 24 hours. The reaction mixture was poured into water (30 mL), and the resulting mixture was extracted with EA (10 mL x 5). The combined organic phase was washed with brine (50 mL), dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM4) to obtain compound 1.410 (250 mg, yield 96.4%) as a pale yellow oil. 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] A mixture of 4-chloro-3-hydroxybenzaldehyde (200 mg, 1.28 mmol), 2-bromoethanol (0.2 mL, 2.82 mmol), and K2CO3 (440 mg, 3.18 mmol) in 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 1.412 (240 mg, yield 93.6%) 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] To a solution of (3-bromo-5-(trifluoromethyl)phenyl)methanol (2 g, 7.84 mmol) in 1,4-dioxane (10 mL), SOCl2 (1.87 g, 15.68 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 1.466 (2 g, crude) 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, 2H) ppm. 2-(3-bromo-5-(trifluoromethyl)phenyl)acetonitrile 1.467

[0394] [ka] Trimethylsilanecarbonile (870.62 mg, 8.78 mmol) and compound 1.466 (2 g, 7.31 mmol) were dissolved in acetonitrile (4 mL), to which TBAF (8.78 mL, 8.78 mmol, 1 M in THF) was added. The mixture was stirred at 25°C for 12 hours. 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%) as a pale yellow oil. 1 H 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] To a solution of compound 1.467 (1.38 g, 5.23 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.21 g, 7.84 mmol, 1.33 mL) in DME (20 mL), Pd(dppf)Cl2 (382.42 mg, 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 poured into water (50 mL) and stirred for 1 minute. The aqueous phase was extracted with EA (30 mL x 3). The combined organic phase was washed with brine (80 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM13) to obtain compound 1.468 (500 mg, 2.37 mmol, yield 45.3%) as a red oily substance. 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] Ozone was blown into a solution of compound 1.468 (500 mg, 2.37 mmol) in DCM (10 mL) at -70°C until the mixture turned blue. After purging the excess ozone, DMS (1.47 g, 23.68 mmol) was added at -70°C. The mixture was then heated to 20°C and stirred for 12 hours. The mixture was concentrated under vacuum and (PM7) to obtain compound 1.469 (262 mg, 1.23 mmol, yield 51.9%) as a pale yellow oil. 1H 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] Pd(PPh3)4 (604.68 mg, 523.28 μmol) was added to a solution of 2-(3-bromo-5-fluorophenyl)acetonitrile (1.6 g, 7.48 mmol) and tributyl(vinyl) stannane (2.37 g, 7.48 mmol) in toluene (30 mL). The resulting mixture was heated to 95 °C and stirred under nitrogen protection for 12 hours. The mixture was poured into saturated KF aqueous solution (100 mL) and stirred for 15 minutes. The aqueous phase was extracted with EA (50 mL x 3). The combined organic phase was washed with brine (100 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM14) to obtain compound 1.471 (900 mg, 5.58 mmol, yield 74.6%) as a pale yellow oil. 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), 5.38 (d, J = 10.8 Hz, 1H), 3.75 (s, 2H) ppm. 2-(3-fluoro-5-formylphenyl)acetonitrile 1.472

[0398] [ka] Ozone was blown into a solution of compound 1.471 (500 mg, 3.10 mmol) in DCM (10 mL) at -70°C until the reaction mixture turned blue. After purging the excess ozone, DMS (1.93 g, 31.02 mmol) was added. The mixture was heated to 20°C and stirred for 12 hours. The mixture was concentrated under vacuum, and the residue was purified (PM7) to obtain compound 1.472 (390 mg, 2.39 mmol, yield 77.1%) as a pale yellow oil. 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] Pd(PPh3)4 (616.09 mg, 533.16 μmol) was added to a solution of 2-(3-bromo-5-methylphenyl)acetonitrile (1.6 g, 7.62 mmol) and tributyl(vinyl) stannane (2.42 g, 7.62 mmol) in toluene (30 mL). The mixture was heated to 95 °C and stirred under nitrogen protection for 12 hours. The mixture was poured into saturated KF aqueous solution (100 mL) and stirred for 15 minutes. The aqueous phase was extracted with EA (50 mL x 3). The combined organic phase was washed with brine (100 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM14) to obtain compound 1.474 (820 mg, 5.22 mmol, yield 68.5%) as a yellow oil. 1H 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] Ozone was blown into a solution of compound 1.474 (500 mg, 3.18 mmol) in DCM (10 mL) at -70°C until the reaction mixture turned blue. After purging the excess ozone, DMS (1.98 g, 31.80 mmol) was added. The reaction mixture was heated to 20°C and stirred for 12 hours. The mixture was concentrated under vacuum and purified (PM7) to obtain compound 1.475 (320 mg, 2.01 mmol, yield 63.2%) as a pale yellow oil. 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] To a solution of 2-(5-bromo-2-chlorophenyl)acetonitrile (1.4 g, 6.07 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.40 g, 9.11 mmol) in DME (20 mL), Pd(dppf)Cl2 (444.44 mg, 607.40 μmol) and CsF (1.85 g, 12.15 mmol) were 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 combined organic phase was washed with brine (80 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM17) to obtain compound 1.477 (600 mg, 3.38 mmol, yield 55.6%) 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), 6.59 (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] Ozone was blown into a solution of compound 1.477 (400 mg, 2.25 mmol) in DCM (10 mL) at -70°C until the reaction mixture turned blue. After purging the excess ozone, DMS (1.40 g, 22.52 mmol) was added. The reaction mixture was heated to 20°C and stirred for 12 hours. The mixture was concentrated under vacuum and purified (PM11) to obtain compound 1.478 (200 mg, 1.11 mmol, yield 49.5%) as a pale yellow solid. 1H 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] To a solution of (3-bromo-2-chlorophenyl)methanol (1 g, 4.52 mmol) in 1,4-dioxane (10 mL), SOCl2 (1.07 g, 9.03 mmol) was added at 0°C. The reaction mixture was heated to 90°C and stirred for 1 hour. The mixture was concentrated under vacuum to obtain compound 1.480 (1 g) 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 1.480 (1 g, 4.17 mmol) were dissolved in acetonitrile (20 mL), to which TBAF (5.22 mL, 5.22 mmol, 1 M in THF) was added at 25 °C. The mixture was stirred at 25 °C for 12 hours. The mixture was concentrated under vacuum, and the residue was purified (PM14) to obtain compound 1.481 (837 mg, 3.63 mmol, yield 87.1%) as a white solid. 1H 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] To a solution of compound 1.481 (837 mg, 3.63 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (838.93 mg, 5.45 mmol) in DME (10 mL), CsF (1.10 g, 7.26 mmol) and Pd(dppf)Cl2 (265.71 mg, 363.14 μmol) were added. The 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 combined organic phase was washed with brine (80 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM12) to obtain compound 1.482 (300 mg, 1.69 mmol, yield 46.5%) as a pale yellow oil. 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] Ozone was blown into a solution of compound 1.482 (300 mg, 1.69 mmol) in DCM (10 mL) at -70°C until the reaction mixture turned blue. After purging the excess ozone, DMS (1.05 g, 16.89 mmol) was added. The mixture was heated to 20°C and stirred for 12 hours. The mixture was concentrated under vacuum and purified by (PM9) to obtain compound 1.483 (297 mg, 1.65 mmol, yield 97.9%) 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] To a solution of tributyl(vinyl) stannane (1.43 g, 4.52 mmol) and (3-bromo-2-chlorophenyl)methanol (1.00 g, 4.52 mmol) in toluene (20 mL), Pd(PPh3)4 (365.62 mg, 316.40 μmol) was added. The mixture was heated to 95°C and stirred under nitrogen protection for 12 hours. The reaction mixture was poured into saturated KF aqueous solution (100 mL) and stirred for 1 hour. The aqueous phase was extracted with EA (50 mL x 3). The combined organic phase was washed with brine (100 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified with (PM9) to obtain compound 1.484 (650 mg, 3.85 mmol, yield 85.3%) as a yellow oil. 1H 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] Ozone was blown into a solution of compound 1.484 (379.71 mg, 2.25 mmol) in DCM (10 mL) at -70°C until the reaction mixture turned blue. After purging the excess ozone, DMS (1.40 g, 22.52 mmol) was added. The mixture was heated to 20°C and stirred for 12 hours. The mixture was concentrated under vacuum and purified by (PM9) to obtain compound 1.485 (230 mg, 1.35 mmol, yield 59.9%) as a pale yellow solid. 1 H NMR (400 MHz, CHCl3-d) δ: 10.53 (s, 1H), 7.87 (dd, J = 7.6, 1.6 Hz, 1H), 7.79 (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] To a solution of [3-bromo-5-(trifluoromethoxy)phenyl]methanol (800 mg, 2.95 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (681.90 mg, 4.43 mmol) in DME (10 mL), Pd(dppf)Cl2 (215.98 mg, 295.17 μmol) and CsF (896.72 mg, 5.90 mmol) were added. The 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 combined organic phase was washed with brine (80 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM12) to obtain compound 1.487 (600 mg) as a colorless oil. 1 H NMR (400 MHz, CHCl3-d) δ: 7.38 (t, J = 8.0 Hz, 1H), 7.33 (s, 1H), 7.25 (s, 1H), 6.69 (dd, J = 17.6, 10.8 Hz, 1H), 5.80 (d, J = 17.2 Hz, 1H), 5.35 (d, J = 10.8 Hz, 1H), 4.73 (s, 2H) ppm. 3-(hydroxymethyl)-5-(trifluoromethoxy)benzaldehyde 1.488

[0410] [ka] Ozone was blown into a solution of compound 1.487 (200 mg, 916.71 μmol) in DCM (10 mL) at -70°C until the reaction mixture turned blue. After purging the excess ozone, DMS (569.55 mg, 9.17 mmol) was added. The mixture was heated to 20°C and stirred for 12 hours. The mixture was concentrated under vacuum and purified (PM6) to obtain compound 1.488 (110 mg, 499.67 μmol, yield 54.5%) as a yellow oil. 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] To a solution of 2-(3-bromo-5-methoxyphenyl)acetonitrile (1.1 g, 4.87 mmol) (US2014 / 73629A1) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.12 g, 7.30 mmol) in DME (20 mL), 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 and stirred under a nitrogen atmosphere for 12 hours. The mixture was poured into water (50 mL), and the aqueous phase was extracted with EA (30 mL x 3). The combined organic phase was washed with brine (80 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM11) to obtain compound 1.490 (550 mg, 3.18 mmol, yield 65.3%) as a yellow oily substance. 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] Ozone was blown into a solution of compound 1.490 (550 mg, 3.18 mmol) in DCM (10 mL) at -70°C until the reaction mixture turned blue. After purging the excess ozone, DMS (1.97 g, 31.75 mmol) was added. 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 1.491 (240 mg, 1.37 mmol, yield 43.2%) 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 (3 g, 14.63 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (3.38 g, 21.95 mmol) were dissolved in 1,4-dioxane (60 mL) and water (6 mL). K2CO3 (4.04 g, 29.26 mmol) and Pd(dppf)Cl2·CH2Cl2 (1.19 g, 1.46 mmol) were added under nitrogen. The resulting mixture was stirred at 90°C for 12 hours. The mixture was concentrated under vacuum, and the residue was removed (PM7) to obtain compound 1.499 (2.0 g, 13.15 mmol, yield 91%) as a yellow oil. 1 H NMR (400 MHz, CHCl3-d) δ: 7.22 (s, 1H), 7.08 (dd, J = 10.0, 1.6 Hz, 1H), 6.99 (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] Ozone was blown into a solution of compound 1.499 (3.15 g, 20.70 mmol) in DCM (50 mL) at -70°C until the reaction mixture turned blue. After purging the excess ozone, DMS (12.86 g, 207.01 mmol) was added. The mixture was heated to 20°C and stirred for 12 hours. The mixture was concentrated under vacuum and purified (PM6) to obtain compound 1.500 (2.9 g, 11.06 mmol, yield 53.4%) as a pale yellow oil. 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 (10 g, 39.21 mmol) was dissolved in THF (100 mL) and n-BuLi (2.5 M, 32.94 mL) was added dropwise at -78 °C. 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 warmed to 20 °C and quenched with water (100 mL). The mixture was extracted with EA (150 mL x 3). The combined organic phases were washed with brine (100 mL), dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM7) to obtain compound 1.501 (3.8 g, 18.61 mmol, yield 47.47%) as a yellow oil. 1H 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] To a solution of compound 1.487 (8.3 g, 38.04 mmol) in 1,4-dioxane (100 mL), SOCl2 (9.05 g, 76.09 mmol) was slowly added at 0°C. The mixture was then heated to 90°C and stirred for 1 hour. The mixture was concentrated and diluted with EA (20 mL). The mixture was poured into an aqueous solution of NaHCO3 (150 mL) and extracted with EA (80 mL x 3). The combined organic phase was washed with brine (150 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM14) to obtain compound 1.502 (3.5 g, 14.79 mmol, yield 38.9%) as a yellow oil. 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 1.502 (3.5 g, 14.79 mmol) were dissolved in acetonitrile (50 mL), to which TBAF (18.54 mL, 18.54 mmol, 1 M in THF) was added. The mixture was stirred at 25°C for 12 hours. The mixture was concentrated under vacuum and purified (PM13) to obtain compound 1.503 (2.6 g, 11.44 mmol, yield 77.4%) as a pale yellow oil. 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 1.504

[0418] [ka] Ozone was blown into a solution of compound 1.503 (2.6 g, 11.44 mmol) in DCM (30 mL) at -70°C until the reaction mixture turned blue. After purging the excess ozone, DMS (7.11 g, 114.45 mmol) was added. 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 1.504 (1.9 g, 8.29 mmol, yield 72.5%) as a yellow oil. 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] To a solution of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (6.26 g, 40.62 mmol) and 5-bromo-1,3-difluoro-2-(trifluoromethoxy)benzene (7.5 g, 27.08 mmol) in DME (100 mL), Pd(dppf)Cl2 (1.98 g, 2.71 mmol) and CsF (8.23 g, 54.15 mmol) were 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 phase was washed with brine (300 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM14) to obtain compound 1.506 (3.2 g, 14.28 mmol, yield 52.7%) 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] Ozone was blown into a solution of compound 1.506 (3.2 g, 14.28 mmol) in DCM (40 mL) at -70°C until the reaction mixture turned blue. After purging the excess ozone, DMS (8.87 g, 142.78 mmol) was added. The mixture was heated to 20°C 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%) as a yellow oil. 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 (2 g, 7.43 mmol), cyclopropylboronic acid (702.47 mg, 8.18 mmol), and Pd(dppf)Cl2 (271.99 mg, 371.73 μmol) were mixed in 1,4-dioxane (20 mL) and water (2 mL) to which 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 residue was purified (PM14) to obtain compound 1.509 (1.1 g, 4.78 mmol, yield 64.3%) as a yellow oil. 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] A mixture of 2-(3-bromo-4-chlorophenyl)acetonitrile (1.2 g, 5.21 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.20 g, 7.81 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was mixed with Pd(dppf)Cl2·CH2Cl2 (425.17 mg, 520.63 μmol) and K2CO3 (1.44 g, 10.41 mmol) under nitrogen protection. The mixture was heated to 90°C and stirred for 12 hours. The mixture was concentrated under vacuum, and the residue was purified (PM6) to obtain compound 1.520 (840 mg, 4.73 mmol, yield 90.8%) as a yellow oil. 1H 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] Ozone was blown into a solution of compound 1.520 (840 mg, 4.73 mmol) in DCM (20 mL) at -78°C until the reaction mixture turned blue. After purging the excess ozone, DMS (2.94 g, 47.29 mmol) was added at -78°C. The mixture was then heated to 25°C and stirred for 12 hours. The mixture was concentrated under vacuum, the residue was dissolved in EA (60 mL), washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM11) to obtain compound 1.521 (600 mg, 3.34 mmol, yield 70.6%) 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] To a mixture of 2-(4-bromo-2-chlorophenyl)acetonitrile (1.6 g, 6.94 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.60 g, 10.41 mmol) in 1,4-dioxane (10 mL) and water (1 mL), Pd(dppf)Cl2·CH2Cl2 (566.89 mg, 694.18 μmol) and K2CO3 (1.92 g, 13.88 mmol) were added under nitrogen protection. The mixture was heated to 90°C and stirred for 12 hours. The mixture was concentrated under vacuum, and the residue was purified (PM6) to obtain compound 1.523 (1.1 g, 6.19 mmol, yield 89.2%) as a yellow oil. 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] Ozone was blown into a solution of compound 1.523 (1.1 g, 6.19 mmol) in DCM (20 mL) at -78°C until the reaction mixture turned blue. After purging the excess ozone, DMS (3.85 g, 61.93 mmol) was added. The mixture was heated to 25°C and stirred for 12 hours. The mixture was concentrated under vacuum to remove the solvent. The residue was dissolved in EA (60 mL), washed with brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM11) to obtain compound 1.524 (0.6 g, 3.34 mmol, yield 53.9%) as a pink solid. 1H 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] To a mixture of cyclopropylboronic acid (122.69 mg, 1.43 mmol) and 2-bromo-4-formyl-benzonitrile (200 mg, 952.26 μmol) in 1,4-dioxane (10 mL) and water (1 mL), Pd(dppf)Cl2·CH2Cl2 (77.77 mg, 95.23 μmol) and K2CO3 (263.22 mg, 1.90 mmol) were added under nitrogen protection. The mixture was heated to 90°C and stirred for 12 hours. The mixture was concentrated under vacuum and purified (PM4) to obtain compound 1.526 (100 mg, 584.13 μmol, yield 61.3%) as a yellow oil, which was used without characterization. Synthesis of intermediate 1.530 (5-Bromo-2-(2,2,2-trifluoroethoxy)phenyl)methanol 1.528

[0427] [ka] 4-bromo-2-(hydroxymethyl)phenol (2 g, 9.85 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (2.29 g, 9.85 mmol) were dissolved in DMF (10 mL) and K2CO3 (2.04 g, 14.78 mmol) was added. The mixture was heated to 80 °C and stirred for 12 hours. The reaction mixture was diluted with water (100 mL) and extracted with EA (100 mL x 3). The combined organic layer was washed with brine (100 mL x 2), dehydrated with Na2SO4, filtered, and concentrated under vacuum to obtain a residue, which was purified (PM10) to obtain compound 1.528 (1.83 g, 6.42 mmol, yield 65.2%) 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 Hz, 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 1.529

[0428] [ka] To a solution of compound 1.528 (400 mg, 1.40 mmol) in toluene (5 mL), tributyl(vinyl) stannane (489.45 mg, 1.54 mmol) and Pd(PPh3)4 (81.08 mg, 70.16 μmol) were added. The reaction mixture was heated to 100 °C and stirred under nitrogen protection for 12 hours. The reaction mixture was diluted with saturated KF aqueous solution (80 mL) and extracted with EA (60 mL x 2). The organic layer was washed with brine (70 mL), dehydrated with Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM10) to obtain compound 1.529 (580 mg) as a yellow oily substance, which was used directly without characterization. 3-(hydroxymethyl)-4-(2,2,2-trifluoroethoxy)benzaldehyde 1.530

[0429]

Chem.

[0430]

Chem.

[0431] [ka] To a solution of compound 1.534 (3.2 g, 13.27 mmol) in THF (50 mL), LiAlH4 (503.79 mg, 13.27 mmol) was slowly added at 0°C. The reaction mixture was heated to 20°C and stirred for 0.5 hours. The reaction mixture was quenched at 0°C by adding EA (50 mL), followed by water (0.5 mL), 10% NaOH aqueous solution (0.5 mL), and water (1.0 mL). After stirring for 0.5 hours, anhydrous Na2SO4 was added. The resulting suspension was stirred for 0.5 hours and filtered. The filtrate was concentrated under vacuum to obtain compound 1.535 (2.5 g, 11.73 mmol, yield 88.4%) as a colorless oil. 1 H NMR (400 MHz, CHCl3-d) δ: 7.52 (d, J = 1.6 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.20 (dd, J = 8.0, 2.0 Hz, 1H), 6.68 (dd, J = 17.2, 10.8 Hz, 1H), 5.80 (d, J = 17.2 Hz, 1H), 5.30 (d, J = 10.8 Hz, 1H), 4.74 (d, J = 6.4 Hz, 2H), 2.06 (t, J = 6.0 Hz, 1H) ppm. 4-Bromo-3-(hydroxymethyl)benzaldehyde 1.536

[0432] [ka] Ozone was blown into a solution of compound 1.535 (2.5 g, 11.73 mmol) in DCM (20 mL) at -78°C until the mixture turned blue. After purging the excess ozone, DMS (15.6 g, 251.23 mmol) was added. The reaction mixture was heated to 20°C 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), the combined organic phase was washed with brine (50 mL x 2), dehydrated with Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM12) to obtain compound 1.536 (1.5 g, 6.98 mmol, yield 59.45%) as a pale yellow oil. 1 H 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] A mixture of compound 1.536 (1.3 g, 6.05 mmol), cyclopropylboronic acid (571.20 mg, 6.65 mmol), Na2CO3 (1.28 g, 12.09 mmol), and Pd(dppf)Cl2 (442.34 mg, 604.53 μmol) in 1,4-dioxane (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 combined organic layer was washed with brine (80 mL x 2), dehydrated with Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM47) to obtain compound 1.537 (120 mg, 681.00 μmol, yield 11.3%) as a yellow oil. 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] To a solution of methyl 5-bromo-2-(trifluoromethyl)benzoate (730 mg, 2.58 mmol) in 1,4-dioxane (15 mL) and water (1.5 mL), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (595.83 mg, 3.87 mmol), K2CO3 (712.92 mg, 5.16 mmol), and Pd(dppf)Cl2·CH2Cl2 (210.62 mg, 257.91 μmol) were added. The reaction mixture was then heated to 90°C and stirred under nitrogen protection for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified (PM7) to obtain compound 1.587 (600 mg) as a pink oil. 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), 5.46 (d, J = 10.8 Hz, 1H), 3.94 (s, 3H) ppm. (2-(trifluoromethyl)-5-vinylphenyl)methanol 1.588

[0435] [ka] To 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. The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched at 0°C by slowly adding water (0.1 mL), followed by 10% NaOH aqueous solution (0.1 mL), and then water (0.3 mL). After stirring at 0°C for 10 minutes, Na2SO4 (2 g) was added. The resulting suspension was stirred for 0.5 hours and then filtered. The filtrate was concentrated under vacuum to obtain compound 1.588 (450 mg, 2.23 mmol, yield 85.4%) 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), 5.40 (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] Ozone was blown into a solution of compound 1.588 (450 mg, 2.23 mmol) in DCM (10 mL) at -78°C until the reaction mixture turned blue. After purging the excess ozone with nitrogen, DMS (1.46 g, 23.50 mmol) was added. The reaction mixture was heated to 20°C and stirred for 15.5 hours. The reaction mixture was concentrated under vacuum and purified (PM6) to obtain compound 1.589 (380 mg, 1.86 mmol, yield 83.63%) as a colorless oil. 11H 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]

Chemical Structure

[0438]

Chemical Structure

[0439] [ka] To a solution of compound 1.365 (3.85 g, 21.67 mmol) in DMF (50 mL), NaH (2.17 g, 54.19 mmol, 60% dispersion in oil) was added at 0°C. After stirring at 0°C for 0.5 hours, MeI (6.75 mL, 108.37 mmol) was slowly added. The resulting mixture was heated to 25°C and stirred for 11.5 hours. The reaction mixture was quenched by adding water (150 mL) and then extracted with EA (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dehydrated with Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM17) to obtain compound 1.631 (4 g, 19.45 mmol, yield 89.7%) as a red oil. 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 blown into a solution of compound 1.631 (4 g, 19.45 mmol) in DCM (40 mL) at -78°C until the color changed to blue. After purging the excess ozone with nitrogen, DMS (15.71 g, 252.82 mmol) was added. The mixture was heated to 25°C and stirred for 12 hours. The mixture was concentrated under vacuum and purified (PM16) to obtain compound 1.632 (750 mg, 3.61 mmol, yield 18.6%) as a yellow oil. 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] To a solution of 4-bromo-2-(hydroxymethyl)phenol (1 g, 4.93 mmol) and iodoethane (845.80 mg, 5.42 mmol) in ACN (5 mL), K2CO3 (1.02 g, 7.39 mmol) was added at 35 °C. The mixture was stirred at 35 °C for 12 hours. 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, filtered, and concentrated under vacuum. The residue was purified (PM11) to obtain compound 1.633 (860 mg, 3.72 mmol, yield 75.5%) 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 Hz, 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] To a solution of compound 1.633 (400 mg, 1.73 mmol) in toluene (5 mL), tributyl(vinyl) stannane (600 mg, 1.89 mmol) and Pd(PPh3)4 (100.01 mg, 86.55 μmol) were added. The reaction mixture was heated to 100 °C and stirred under nitrogen protection for 12 hours. The reaction mixture was poured into saturated KF aqueous solution (80 mL) and extracted with EA (60 mL x 2). The organic layer was washed with brine (70 mL), dehydrated with Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM10) to obtain compound 1.634 (280 mg, 1.41 mmol, yield 81.6%) as a yellow oil. 1H NMR (400 MHz, CHCl3-d) δ: 7.43 (d, J = 2.4 Hz, 1H), 7.29 (dd, J = 8.1, 2.4 Hz 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] Ozone was blown into a solution of compound 1.634 (280 mg, 1.57 mmol) in DCM (30 mL) at -78°C until the mixture turned blue. After purging the excess ozone with nitrogen, DMS (1.27 g, 20.42 mmol) was added. The mixture was heated to 25°C and stirred for 12 hours. The mixture was concentrated under vacuum, and the residue was purified (PM8) to obtain compound 1.635 (170 mg, 943.40 μmol, yield 60.1%) as a yellow oil. 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 Hz, 2H), 1.49 (t, J = 6.8 Hz, 3H) ppm. Synthesis of intermediate 1.661 4-Chloro-3-(hydroxymethyl)benzaldehyde 1.661

[0444] [ka] To a solution of (5-bromo-2-chlorophenyl)methanol (1 g, 4.52 mmol) in THF (10 mL), n-BuLi (3.79 mL, 2.5 M) was added at -78 °C. After stirring for 0.5 hours, DMF (330.03 mg, 4.52 mmol) was added at -78 °C. The resulting mixture was stirred for an additional 0.5 hours at -78 °C. The reaction mixture was quenched with water (50 mL) and extracted with EA (100 mL × 3). The combined organic layers were washed with brine (100 mL × 2), dehydrated with Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified (PM7) to obtain compound 1.661 (450 mg, 2.64 mmol, yield 58.4%) 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] To a solution of 4-bromo-2-(hydroxymethyl)phenol (1 g, 4.93 mmol) and 2-iodopropane (921.87 mg, 5.42 mmol) in ACN (10 mL), K2CO3 (1.02 g, 7.39 mmol) was added at 35 °C. The mixture was stirred at 35 °C for 12 hours. 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, filtered, and concentrated under vacuum. The residue was purified (PM10) to obtain compound 1.666 (900 mg, 3.67 mmol, yield 74.5%) as a yellow oil. 1H NMR (400 MHz, CHCl3-d) δ: 7.43 (d, J = 2.4 Hz, 1H), 7.35 (dd, J = 8.8, 2.4 Hz, 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] To a solution of compound 1.666 (400 mg, 1.73 mmol) in toluene (5 mL), tributyl(vinyl) stannane (569.22 mg, 1.80 mmol) and Pd(PPh3)4 (94.29 mg, 81.60 μmol) were added. The reaction mixture was heated to 100 °C and stirred under a nitrogen atmosphere for 12 hours. The reaction mixture was poured into saturated KF aqueous solution (80 mL) and then extracted with EA (60 mL x 2). The organic layer was washed with brine (70 mL), dehydrated with Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM11) to obtain compound 1.667 (200 mg, 1.04 mmol, yield 63.7%) as a yellow oil. 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 blown into a solution of compound 1.667 (190 mg, 988.28 μmol) in DCM (30 mL) at -78°C until the mixture turned blue. After purging the excess ozone with nitrogen, DMS (614.02 mg, 9.88 mmol) was added. The mixture was heated to 25°C and stirred for 12 hours. The mixture was concentrated under vacuum, and the residue was purified (PM6) to obtain compound 1.668 (20 mg, 102.97 μmol, yield 10.4%) as a yellow oil. 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 (d, J = 6.0 Hz, 6H) ppm. Synthesis of intermediate 1.671 (5-Bromo-2-(cyclopentyloxy)phenyl)methanol 1.669

[0448] [ka] 4-bromo-2-(hydroxymethyl)phenol (1 g, 4.93 mmol) and bromocyclopentane (808.18 mg, 5.42 mmol) were dissolved in DMF (10 mL) and K2CO3 (1.02 g, 7.39 mmol) was added. The mixture was heated to 80°C and stirred for 12 hours. 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, filtered, and concentrated under vacuum. The residue was purified (PM10) to obtain compound 1.669 (700 mg, 2.58 mmol, yield 52.4%) as a yellow oil. 1H NMR (400 MHz, CHCl3-d) δ: 7.40 (d, J = 2.4 Hz, 1H), 7.33 (dd, J = 8.8, 2.8 Hz, 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] To a solution of compound 1.669 (400 mg, 1.48 mmol) in toluene (5 mL), tributyl(vinyl) stannane (514.56 mg, 1.62 mmol) and Pd(PPh3)4 (85.23 mg, 73.76 μmol) were added. The reaction mixture was heated to 100 °C and stirred under a nitrogen atmosphere for 12 hours. The reaction mixture was poured into saturated KF aqueous solution (80 mL) and extracted with EA (60 mL x 2). The organic layer was washed with brine (70 mL), dehydrated with Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM10) to obtain compound 1.670 (300 mg, 1.37 mmol, yield 93.2%) as a yellow oil. 1 H NMR (400 MHz, CHCl3-d) δ: 7.47 (d, J = 2.0 Hz, 1H), 7.32 (dd, J = 8.4, 2.0 Hz, 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 blown into a solution of compound 1.670 (300 mg, 1.37 mmol) in DCM (30 mL) at -78°C until the mixture turned blue. After purging the excess ozone with nitrogen, DMS (1.28 g, 20.61 mmol) was added. The mixture was heated to 25°C 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%) as a yellow oil. 1 H 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] To a solution of 3-bromo-5-(trifluoromethoxy)benzoic acid (2 g, 7.02 mmol) in DMF (20 mL), DIPEA (1.81 g, 14.03 mmol) and HATU (4.00 g, 10.53 mmol) were added at 20°C. After stirring at 20°C for 0.1 hours, NH4Cl (1.50 g, 28.07 mmol) was added. The reaction mixture was stirred at 20°C for 12 hours. The reaction mixture was poured into water (100 mL) and extracted with EA (50 mL x 2). The combined organic phase was washed with brine (100 mL), dehydrated with Na2SO4, and concentrated under vacuum. The residue was purified (PM47) to obtain compound 1.673 (980 mg, 3.27 mmol, yield 46.6%) 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] To a mixture of compound 1.673 (980 mg, 3.45 mmol) in 1,4-dioxane (10 mL) and water (1 mL), K2CO3 (953.72 mg, 6.90 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (797.10 mg, 5.18 mmol), and Pd(dppf)Cl2 (252.46 mg, 345.03 μmol) were sequentially added. The reaction mixture was then heated to 80°C and stirred under a nitrogen atmosphere for 12 hours. The reaction mixture was filtered, concentrated under vacuum, and the crude product was purified (PM4) to obtain compound 1.674 (700 mg, 2.62 mmol, yield 75.8%) as a white solid. LCMS (AM3): rt = 0.870 min, (232.1 [M+H] + ), purity 87.6%. 3-Formyl-5-(trifluoromethoxy)benzamide 1.675

[0453] [ka] A solution of compound 1.674 (0.7 g, 2.62 mmol) in DCM (10 mL) was cooled to -78°C and ozone was blown in until the mixture turned blue. Excess ozone 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 to obtain the crude product, which was purified (PM150) to obtain compound 1.675 (260 mg, 1.12 mmol, yield 36.8%) 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] To a mixture of 3,4-dichloro-5-(trifluoromethoxy)benzoic acid (500 mg, 1.82 mmol) in MeOH (30 mL), SOCl2 (1.08 g, 9.09 mmol) was slowly added at 0°C. The mixture was then heated to 60°C and stirred for 0.5 hours. The mixture was poured into a saturated aqueous solution of NaHCO3 (50 mL) and extracted with EA (50 mL x 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain compound 1.702 (500 mg, 1.73 mmol, yield 95.2%) as a yellow oil. 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] To 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. The mixture was then heated to 25°C and stirred for 0.5 hours. The mixture was cooled to 0°C, diluted with EA (10 mL), and stirred for 2 minutes. The mixture was quenched by adding water (0.2 mL), 10% NaOH aqueous solution (0.2 mL), and water (0.6 mL). After stirring for 0.5 hours, anhydrous Na2SO4 (3 g) was added, and the mixture was stirred separately for 0.5 hours. The resulting suspension was filtered, and the filtrate was concentrated under vacuum. The residue was purified (PM2) to obtain compound 1.703 (400 mg, 1.48 mmol, yield 83%) as a yellow oil. 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] To a solution of compound 1.703 (400 mg, 1.53 mmol) in DCM (100 mL), MnO2 (1.33 g, 15.32 mmol) was added at 25°C. The mixture was stirred at 25°C for 2 hours. The mixture was filtered and concentrated under vacuum. The residue was purified (PM7) to obtain compound 1.704 (140 mg, 540.52 μmol, yield 35.3%) as a yellow oil. 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] A mixture of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (596.66 mg, 3.87 mmol) and 4-bromo-2-methoxy-1-(trifluoromethoxy)benzene (0.7 g, 2.58 mmol) in 1,4-dioxane (10 mL) and H2O (1 mL) was mixed with K2CO3 (713.90 mg, 5.17 mmol) and Pd(dppf)Cl2·CH2Cl2 (105.46 mg, 129.14 μmol). The mixture was heated to 90°C and stirred under a nitrogen atmosphere for 12 hours. The mixture was filtered, concentrated under vacuum, and the residue was purified (PM14) to obtain compound 1.706 (0.28 g, 1.28 mmol, yield 49.7%) 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] Ozone was blown into a solution of compound 1.706 (0.28 g, 1.28 mmol) in DCM (20 mL) cooled to -78°C until the mixture turned blue. After purging the excess ozone with nitrogen, DMS (797.37 mg, 12.83 mmol) was added, and the mixture was stirred at 25°C for 12 hours. The mixture was concentrated under vacuum, and the residue was purified by column chromatography (PM14) to obtain compound 1.707 (0.22 g, 999.34 μmol, yield 77.9%) as a colorless oil. 1H 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] A mixture of 3-bromo-4-(trifluoromethoxy)benzaldehyde (750 mg, 2.79 mmol), Pd(PPh3)4 (322.16 mg, 278.79 μmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (1.40 g, 5.58 mmol), and K2CO3 (1.16 g, 8.36 mmol) in 1,4-dioxane (7 mL) was stirred at 100°C for 12 hours under a nitrogen atmosphere. The residue was poured into water (20 mL) and extracted with EA (10 mL x 3). The combined organic phase was washed with brine (30 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PM1) to obtain compound 1.709 (400 mg, 1.96 mmol, yield 70.3%) 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] A mixture of 3-bromo-4-(trifluoromethoxy)benzaldehyde (500 mg, 1.86 mmol), cyclopropylboronic acid (239.48 mg, 2.79 mmol), Pd(dppf)Cl2·CH2Cl2 (151.78 mg, 185.86 μmol), and K2CO3 (513.76 mg, 3.72 mmol) in 1,4-dioxane (10 mL) and H2O (1 mL) was stirred at 90°C for 12 hours under a nitrogen atmosphere. The mixture was concentrated under vacuum, and the residue was purified by preparative TLC (SiO2, PE / EA=3 / 1) to obtain compound 1.710 (350 mg, 1.52 mmol, yield 81.8%) as a yellow oil. 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] A mixture of 3-bromo-5-(trifluoromethoxy)benzaldehyde (5 g, 18.59 mmol), KOAc (3.65 g, 37.19 mmol), Pin2B2 (5.65 g, 22.25 mmol), and Pd(dppf)Cl2 (700 mg, 0.96 mmol) in 1,4-dioxane (100 mL) was degassed three times and purged with nitrogen. The reaction mixture was then heated to 80 °C and stirred under a nitrogen atmosphere for 16 hours. The reaction mixture was concentrated under vacuum, and the residue was purified (PM7) to obtain compound 1.711 (6.1 g) as a yellow oily substance. 1H 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] A mixture of compound 1.711 (1.83 g, 5.79 mmol), 4-(chloromethyl)oxazole (680 mg, 5.79 mmol), K2CO3 (2.04 g, 14.76 mmol), and Pd(dppf)Cl2 (212 mg, 0.29 mol) in 1,4-dioxane (16 mL) and H2O (4 mL) 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, and the residue was purified (PM7) to obtain compound 1.712 (170 mg, yield 10.8%) as a yellow oil. 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] A mixture of compound 1.711 (2.03 g, 6.41 mmol), 5-(chloromethyl)oxazole (750 mg, 6.38 mmol), K2CO3 (2.25 g, 16.28 mmol), and Pd(dppf)Cl2 (240 mg, 0.33 mmol) in 1,4-dioxane (16 mL) and H2O (4 mL) 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, and the residue was purified (PM7) to obtain compound 1.713 (650 mg, yield 37.6%) as a yellow oil. 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] A mixture of 3-bromo-5-(trifluoromethoxy)benzaldehyde (700 mg, 2.60 mmol), Zn(CN)2 (910 mg, 7.75 mmol), and Pd(PPh3)4 (300 mg, 0.26 mmol) in DMF (10 mL) was degassed three times and purged with nitrogen. The reaction mixture was heated to 90°C and stirred under a nitrogen atmosphere for 1.5 hours. The reaction mixture was filtered, and the filtrate was diluted with water (40 mL). The resulting mixture was extracted with EA (20 mL x 3), the combined organic phase was washed with brine (60 mL), dehydrated with Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM12) to obtain compound 1.714 (0.23 g, yield 41.1%) 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] A mixture of 3-bromo-5-(trifluoromethoxy)phenol (930 mg, 3.62 mmol), 2-bromoethanol (500 mg, 4.00 mmol), and K2CO3 (1.00 g, 7.24 mmol) in DMF (10 mL) was stirred at 100°C for 16 hours. The reaction mixture was diluted with water (40 mL), and the resulting mixture was extracted with EA (10 mL x 3). The combined organic phase was washed with brine (30 mL), dehydrated with Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM7) to obtain compound 1.716 (1.1 g) as a colorless oil. 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] A mixture of compound 1.716 (1.1 g, 3.65 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.1 g, 7.14 mmol), K2CO3 (1.01 g, 7.31 mmol), and Pd(dppf)Cl2 (134 mg, 0.18 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) 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 (630 mg, yield 69.5%) as a brownish oil. 1H 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 blown into a solution of compound 1.717 (630 mg, 2.54 mmol) in DCM (10 mL) at -70°C until the solution turned blue. Excess ozone was purged with nitrogen, and then DMS (1.58 g, 25.38 mmol) was added. The mixture was heated to room temperature and stirred for 14 hours. The reaction mixture was concentrated under vacuum, and the residue was purified (PM6) to obtain compound 1.718 (400 mg, yield 63.0%) 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] A mixture of methyl 3-bromo-5-(trifluoromethoxy)benzoate (5 g, 16.72 mmol), 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.21 g, 25.08 mmol), K2CO3 (4.62 g, 33.44 mmol), and Pd(dppf)Cl2 (612 mg, 0.84 mmol) in 1,4-dioxane (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) to obtain compound 1.720 (3.95 g, yield 90.8%) as a colorless oil. 1 H NMR (400 MHz, CHCl3-d) δ: 7.83 (s, 1H), 7.74 (s, 1H), 7.24 (s, 1H), 6.00-5.90 (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] Ozone was blown into a solution of compound 1.720 (3.95 g, 15.18 mmol) in DCM (40 mL) at -70°C until the reaction solution turned blue. After purging the excess ozone with nitrogen, NaBH4 (2 g, 52.87 mmol) was added, and the reaction mixture was heated to 25°C and stirred for 16 hours. The reaction mixture was quenched with saturated NH4Cl aqueous solution (40 mL) and then extracted with DCM (40 mL x 3). The combined organic phase was washed with brine (120 mL), dehydrated with Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM7) to obtain compound 1.721 (1.7 g, yield 42.4%) as a yellow oil. 1H NMR (400 MHz, CHCl3-d) δ: 7.86 (s, 1H), 7.75 (s, 1H), 7.30 (s, 1H), 3.95-3.89 (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] To a solution of compound 1.721 (0.8 g, 3.03 mmol) in THF (10 mL), LAH (0.2 g, 5.27 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was quenched with aqueous HCl (1 N, 30 mL), and the resulting mixture was extracted with EA (20 mL x 3). The combined organic phase was washed with brine (60 mL), dehydrated with Na2SO4, filtered, and concentrated under vacuum to obtain compound 1.722 (0.67 g, yield 93.7%) as a yellow oil, 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) ppm. 3-(2-hydroxyethyl)-5-(trifluoromethoxy)benzaldehyde 1.723

[0471] [ka] A mixture of compound 1.722 (0.67 g, 2.84 mmol) and MnO2 (2.47 g, 28.37 mmol) in DCM (20 mL) was stirred at 25°C for 16 hours. The reaction mixture was concentrated under vacuum, and the residue was purified (PM2) to obtain compound 1.723 (520 mg, yield 78.3%) as a yellow oil. 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] To a solution of 3-bromo-5-hydroxybenzoic acid (2.8 g, 12.90 mmol) in ACN (50 mL), K2CO3 (8.92 g, 64.51 mmol) and iodoethane (5.03 g, 32.26 mmol) were added at ambient temperature. The resulting mixture was heated to 80°C 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%) as a pale yellow oil. 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] To a solution of compound 1.736 (3.6 g, 13.18 mmol) in DME (50 mL), CsF (4.00 g, 26.36 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (3.05 g, 19.77 mmol), and Pd(dppf)Cl2 (964.45 mg, 1.32 mmol) were added. The mixture was heated to 80°C and stirred under a nitrogen atmosphere for 12 hours. The mixture was concentrated under vacuum, and the residue was purified (PM17) to obtain compound 1.737 (2.4 g, 10.90 mmol, yield 82.7%) as a pale yellow oil. 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 Hz, 2H), 1.45-1.41 (t, 3H), 1.41-1.37 (t, 3H) ppm. (3-Ethoxy-5-vinylphenyl)methanol 1.738

[0474] [ka] To 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 heated to 25°C and stirred for 1 hour. The reaction was quenched by adding aqueous HCl (1 M) 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 combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain compound 1.738 (2.2 g) as a pale yellow oil, which was used directly. 1H 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] To a solution of compound 1.738 (2.2 g, 12.34 mmol) in 1,4-dioxane (30 mL), SOCl2 (3 g, 25.22 mmol) was added, and the resulting mixture was stirred at 60°C for 12 hours. The mixture was concentrated under vacuum, the residue was diluted with EA (30 mL), and washed with saturated NaHCO3 aqueous solution (10 mL). The organic layer was separated, dehydrated with Na2SO4, and concentrated under vacuum to obtain compound 1.739 (2.2 g, yield 90.5%) as a brownish oily substance, which was used directly without further purification. 2-(3-ethoxy-5-vinylphenyl)acetonitrile 1.740

[0476] [ka] To a solution of compound 1.739 (2.2 g, 11.19 mmol) in ACN (20 mL), TMSCN (4.44 g, 44.74 mmol) and TBAF (16.78 mL, 2 M in THF) were added. The resulting mixture was heated to 80°C and stirred for 1 hour. The mixture was concentrated under vacuum, and the residue was purified (PM11) to obtain compound 1.740 (1.4 g, yield 66.8%) as a yellow oil. 1H 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] Ozone was blown into a solution of compound 1.740 (1.4 g, 7.48 mmol) in DCM (20 mL) at -78°C until the reaction mixture turned blue. After purging the excess ozone with nitrogen, DMS (8.46 g, 136.16 mmol) was added. The mixture was heated to 20°C and stirred for 3 hours. The reaction mixture was concentrated under vacuum, and the residue was purified (PM11) to obtain compound 1.741 (635 mg, 3.36 mmol, yield 44.9%) as a white solid. 1 H 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 (4.4 g, 18.25 mmol) and cyclopropylboronic acid (1.72 g, 20.08 mmol) were mixed in 1,4-dioxane (44 mL) and H2O (4.4 mL). K2CO3 (5.04 g, 36.50 mmol) and Pd(dppf)Cl2 (667.72 mg, 912.56 μmol) were added. The mixture was heated to 80°C and stirred under a nitrogen atmosphere for 12 hours. The mixture was concentrated under vacuum, and the residue was purified (PM14, R f (=0.43) Compound 1.742 (1.45 g, 7.17 mmol, yield 39.3%) was obtained as a yellow oily substance, which was used directly. (3-Cyclopropyl-5-Vinylphenyl)Methanol 1.743

[0479] [ka] Compound 1.742 (1.34 g, 6.63 mmol) was added to a solution of LAH (251.47 mg, 6.63 mmol) in THF (20 mL) at 0°C. The mixture was stirred at 0°C for 2 hours. The reaction was quenched by adding HCl (1 M) 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 combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain compound 1.743 (1.2 g) as a yellow oil. 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] Ozone was blown into a solution of compound 1.743 (300 mg, 1.72 mmol) in DCM (8 mL) at -78°C until the reaction mixture turned blue. After purging the excess ozone with nitrogen, DMS (1.39 g, 22.38 mmol) was added. The mixture was heated to 25°C and stirred for 12 hours. The mixture was concentrated under vacuum, and the residue was purified (PM11) to obtain compound 1.744 (200 mg, 1.14 mmol, yield 65.9%) as a colorless oil. 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] To a solution of compound 1.743 (900 mg, 5.17 mmol) in 1,4-dioxane (10 mL), SOCl2 (1.84 g, 15.50 mmol) was added at 0°C. The mixture was heated to 70°C and stirred for 2 hours. The reaction mixture was quenched by adding saturated NaHCO3 aqueous solution (10 mL) and extracted with EA (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dehydrated with Na2SO4, filtered, and concentrated under vacuum to obtain compound 1.745 (940 mg) as a yellow oil, which was used directly in the next step. 2-(3-cyclopropyl-5-vinylphenyl)acetonitrile 1.746

[0482] [ka] A solution of compound 1.745 (940 mg, 4.88 mmol), TMSCN (677.56 mg, 6.83 mmol), and TBAF (6.34 mL, 1 M in THF) in ACN (80 mL) was stirred at 25°C for 12 hours. The mixture was concentrated under vacuum, and the residue was purified (PM16) to obtain compound 1.746 (760 mg, 4.15 mmol, yield 85%) as a yellow oil. 1 H 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 blown into a solution of compound 1.746 (760 mg, 4.15 mmol) in DCM (8 mL) at -78°C until the mixture turned blue. After purging the excess ozone with nitrogen, DMS (3.35 g, 53.92 mmol) was added, and the mixture was heated to 25°C and stirred for 12 hours. The mixture was concentrated under vacuum to obtain a residue, which was purified (PM7) to obtain compound 1.747 (380 mg, 2.05 mmol, yield 49.5%) as a yellow oil. 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] To a solution of methyl 3-bromo-5-hydroxybenzoate (4.1 g, 17.75 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (4.12 g, 17.75 mmol) in DMF (40 mL), K2CO3 (3.68 g, 26.62 mmol) was added. The mixture was heated to 80°C and stirred for 12 hours. The reaction mixture was diluted with water (100 mL) and extracted with EA (100 mL x 3). The combined organic layer was washed with brine (200 mL x 3), dehydrated with Na2SO4, filtered, and concentrated under vacuum to obtain compound 1.749 (5.75 g) 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-tetramethyl-2-vinyl-1,3,2-dioxaborolane (4.53 g, 29.39 mmol, 4.98 mL) were dissolved in DME (60 mL), to which Pd(dppf)Cl2 (1.34 g, 1.84 mmol) and CsF (5.86 g, 38.57 mmol) were added. The mixture was heated at 80°C for 12 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (100 mL) and extracted with EA (100 mL x 3). The combined organic layer was washed with brine (100 mL x 2), dehydrated with Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM18) to obtain compound 1.750 (3 g, 11.53 mmol, yield 62.8%) as a yellow oil. 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), 5.38 (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 1.751

[0486] [ka] Compound 1.750 (3.3 g, 12.68 mmol) was added to a solution of LAH (481.34 mg, 12.68 mmol) in THF (40 mL) at 0°C. The mixture was stirred at 0°C for 2 hours. The reaction was quenched by adding aqueous HCl (1 M) at 0°C to bring the pH to 3. The mixture was diluted with water (100 mL) and extracted with EA (100 mL x 3). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM7) to obtain compound 1.751 (2.4 g, 10.34 mmol, yield 81.5%) as a yellow oil. 1 H 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-vinylbenzene 1.752

[0487] [ka] To a solution of compound 1.751 (2.4 g, 10.34 mmol) in 1,4-dioxane (30 mL), SOCl2 (3.69 g, 31.01 mmol, 2.25 mL) was slowly added at 0°C. The mixture was then heated to 70°C and stirred for 2 hours. The reaction mixture was quenched by slowly adding saturated NaHCO3 aqueous solution (10 mL), then 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, filtered, and concentrated under vacuum to obtain compound 1.752 (2.62 g) as a yellow oil, which was used directly without further purification. 2-(3-(2,2,2-trifluoroethoxy)-5-vinylphenyl)acetonitrile 1.753

[0488] [ka] A mixture of compound 1.752 (2.62 g, 10.45 mmol), TMSCN (1.45 g, 14.63 mmol), and TBAF (13.59 mL, 1 M in THF) in ACN (80 mL) was stirred at 25°C for 12 hours. The mixture was concentrated under vacuum and purified (PM16) to obtain compound 1.753 (1.5 g, 6.22 mmol, yield 59.5%) as a yellow oil. 1H 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)acetonitrile 1.754

[0489] [ka] Ozone was blown into a solution of compound 1.753 (1.5 g, 6.22 mmol) in DCM (15 mL) at -78°C until the mixture turned blue. After purging the excess ozone with nitrogen, DMS (5.02 g, 80.84 mmol) was added. The mixture was heated to 25°C and stirred for 12 hours. The mixture was concentrated under vacuum, and the residue was purified (PM7) to obtain compound 1.754 (1 g, 4.11 mmol, yield 66.1%) as a yellow oil. 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] To a mixture of methyl 3-bromo-5-(bromomethyl)benzoate (900 mg, 2.92 mmol) in MeOH (10 mL), 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 concentrated under vacuum. The residue was diluted with water (2 mL) and the pH was adjusted to 5 with aqueous HCl (1 M). The mixture was extracted with EA (20 mL x 2), the combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain compound 1.797 (700 mg) 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] A mixture of compound 1.797 (0.7 g, 2.86 mmol), CsF (867.75 mg, 5.71 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (659.87 mg, 4.28 mmol), and Pd(dppf)Cl2·CH2Cl2 (116.63 mg, 142.82 μmol) in DME (10 mL) was stirred at 90°C for 12 hours under a nitrogen atmosphere. The mixture was filtered, concentrated, and the residue was purified (PM7) to obtain compound 1.798 (400 mg, 2.08 mmol, yield 72.8%) as a yellow oil. 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] To a mixture of compound 1.798 (400 mg, 2.08 mmol) in MeOH (30 mL), SOCl2 (1.24 g, 10.41 mmol) was added at 0°C, and the mixture was then heated to 60°C and stirred for 0.5 hours. The mixture was cooled to 25°C and poured into saturated NaHCO3 aqueous solution (50 mL). The aqueous phase was extracted with EA (50 mL x 3), the combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM7) to obtain compound 1.799 (380 mg, 1.84 mmol, yield 88.5%) as a yellow oil. 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] To a mixture of compound 1.799 (380 mg, 1.84 mmol) in THF (20 mL), LAH (83.91 mg, 2.21 mmol) was added in one step at 0°C under nitrogen protection. The mixture was heated to 25°C and stirred for 0.5 hours. The mixture was cooled to 0°C and diluted with EA (10 mL). The mixture was quenched by adding water (0.2 mL), followed by aqueous NaOH solution (10% by weight, 0.2 mL) and water (0.6 mL). After stirring for 0.5 hours, Na2SO4 (1 g) was added and stirring was continued for another 0.5 hours. The resulting suspension was filtered and concentrated under vacuum. The residue was purified (PM2) to obtain compound 1.800 (260 mg, 1.46 mmol, yield 79.2%) as a yellow oil. 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] To a mixture of compound 1.800 (250 mg, 1.40 mmol) in 1,4-dioxane (20 mL), 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 1.801 (250 mg), which was used without purification. 1H 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, 1.91 mmol), and TBAF (2.54 mL, 1 M in THF) were mixed in ACN (50 mL) and stirred at 25°C for 12 hours. The mixture was concentrated under vacuum, and the residue was purified (PM6) to obtain compound 1.802 (100 mg, 534.08 μmol, yield 42.0%) as a yellow oil. 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] Ozone was blown into a solution of compound 1.802 (100 mg, 534.08 μmol) in DCM (20 mL) at -78°C until the reactants changed color to blue. After purging the excess ozone 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 (PM11) to obtain compound 1.803 (80 mg, 422.81 μmol, yield 79.2%) as a colorless oil. 1 H NMR (400 MHz, MeOH-d4) δ: 9.98 (s, 1H), 7.82-7.81 (m, 2H), 7.64 (s, 1H), 4.54 (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] Ozone was blown at -78°C into a solution of compound 1.502 (100 mg, 422.62 μmol) in DCM (5 mL) until the reactants changed color to blue. After purging the excess ozone with nitrogen, DMS (0.44 g, 7.08 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 (PM7) to obtain compound 1.824 (60 mg, 251.48 μmol, yield 59.5%) as a colorless oil. 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)benzaldehyde 1.825

[0498] [ka] Imidazole (713.33 mg, 10.48 mmol) was added to a solution of compound 1.824 (500 mg, 2.10 mmol) in ACN (5 mL). The reaction mixture was then heated to 60 °C and stirred for 12 hours. The mixture was concentrated, and the crude product was purified (PM151) to obtain compound 1.825 (450 mg, 1.67 mmol, yield 79.5%) as a white solid. 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] To a solution of compound 1.824 (500 mg, 2.10 mmol) in 1,4-dioxane (1.5 mL) and H2O (0.15 mL), K2CO3 (579.28 mg, 4.19 mmol), furan-3-ylboronic acid (447.29 mg, 2.31 mmol), and Pd(dppf)Cl2 (153.34 mg, 209.56 μmol) were added. The reaction mixture was heated to 70°C and stirred under a nitrogen atmosphere for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified (PM150) to obtain compound 1.826 (360 mg, 1.24 mmol, yield 59.3%) as a yellow oil. 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] To a solution of (3-bromo-4-chlorophenyl)methanol (1 g, 4.52 mmol) in THF (10 mL), n-BuLi (3.79 mL, 2.5 M) was added under a nitrogen atmosphere at -78°C. After stirring for 0.5 hours, DMF (330.01 mg, 4.52 mmol) was added, and the mixture was stirred at -78°C for 0.5 hours. The reaction mixture was diluted with water (200 mL) and extracted with EA (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dehydrated with Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by reverse-phase HPLC (AM46) to obtain compound 1.834 (200 mg, 1.17 mmol, yield 25.9%) 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] Potassium carbonate (3.4 g, 24.63 mmol) was added to a mixture of 4-bromo-2-(hydroxymethyl)phenol (2.0 g, 9.95 mmol) and bromocyclobutane (2.66 g, 19.70 mmol) in DMF (10 mL) at ambient temperature under nitrogen protection. The mixture was then heated to 80 °C and stirred for 12 hours. The reaction mixture was poured into water (100 mL), and the aqueous phase was extracted with EA (50 mL x 2). The combined organic phase was washed with brine (50 mL), dehydrated with anhydrous Na₂SO₄, and concentrated under vacuum. The residue was purified (PM4) to obtain compound 1.62 (1.6 g, 6.22 mmol, yield 63.2%) as a white solid. 1H 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] A mixture of tributyl(vinyl) stannane (1.85 g, 5.83 mmol) and compound 1.62 (1.5 g, 5.83 mmol) in toluene (50 mL) was mixed with tetrakis(triphenylphosphine)palladium (337.06 mg, 291.69 μmol) under nitrogen protection at ambient temperature. The mixture was then heated to 100 °C and stirred for 12 hours. The mixture was cooled to room temperature and then poured into saturated KF aqueous solution (20 mL). The mixture was stirred for 30 minutes and then extracted with EA (50 mL x 4). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified (PM11) to obtain compound 1.63 (600 mg, 2.94 mmol, yield 50.4%) as a colorless oil. 1 H NMR (400 MHz, MeOH-d4) δ: 7.48 (d, J = 2.4 Hz, 1H), 7.23 (dd, J = 2.4, 8.4 Hz, 1H), 6.71-6.62 (m, 2H), 5.62 (dd, J = 1.2, 17.6 Hz, 1H), 5.07 (dd, J = 1.2, 10.8 Hz, 1H), 4.71-4.64 (m, 1H), 4.62 (s, 2H), 2.50-2.38 (m, 2H), 2.21-2.07 (m, 2H), 1.86-1.68 (m, 2H) ppm. 4-Cyclobutoxy-3-(hydroxymethyl)benzaldehyde, 1.64

[0503] [Chemical formula] Ozone was bubbled into a solution of compound 1.63 (600 mg, 2.94 mmol) in DCM (30 mL) at -78 °C until the reaction mixture turned blue, then the reaction mixture was warmed to 0 °C and DMS (1.82 g, 29.37 mmol) was added. The reaction mixture was warmed to 25 °C and stirred for 12 hours. The reaction mixture was poured into water (50 mL), and the aqueous solution was extracted with EA (50 mL × 2). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified (PM11) to give compound 1.64 (250 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), 2.22 - 2.10 (m, 2H), 1.92 - 1.70 (m, 2H) ppm. Synthesis of Intermediate 1.155 Methyl 5-((2-(4-((3-chloro-4-(trifluoromethoxy)benzyl)amino)butoxy)ethyl)amino)benzo[c][2,6]naphthyridine-8-carboxylate, 1.155

[0504] [Chemical formula] To a mixture of compound 1.154 (180 mg, 444.57 μmol) and sodium acetate (109.41 mg, 1.33 mmol) in MeOH (15 mL), 3-chloro-4-(trifluoromethoxy)benzaldehyde (90 mg, 400.78 μmol) was added at 20°C. The mixture was stirred at 20°C for 2 hours, and then sodium triacetoxyborohydride (450.00 mg, 2.12 mmol) was added. The mixture was stirred at 20°C for 12 hours. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified (PM33) to obtain compound 1.155 (103 mg, 178.51 μmol, yield 36.5%) as a yellow oil. 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] A mixture of intermediate E (80 mg, 205.19 μmol), sodium acetate (67.33 mg, 820.76 μmol), and 3-chloro-5-formylbenzonitrile (33.97 mg, 205.19 μmol) in MeOH (3 mL) was stirred at 20°C for 12.5 hours, and then sodium triacetoxyborohydride (130.47 mg, 615.57 μmol) was added. The reaction mixture was stirred separately at 20°C for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified (PM57) to obtain compound 1.573 (60 mg, 119.29 μmol, yield 58.1%) as a white solid. LCMS (AM7): rt = 0.865 min, (503.1 [M+H] + ), purity 66.1%. Synthesis of intermediate 1.399 tert-butyl 3-(4-(((benzyloxy)carbonyl)amino)butoxy)azetidine-1-carboxylate 1.395

[0506] [ka] A mixture of benzyl N-(4-bromobutyl)carbamate (3.30 g, 11.55 mmol), tert-butyl 3-hydroxyazetidine-1-carboxylate (1 g, 5.77 mmol), NaOH (2.31 g, 57.73 mmol), and TBAI (0.11 g, 298 mmol) in H2O (5 mL) was stirred at room temperature for 20 hours. The reaction mixture was diluted with water (50 mL) and extracted with MTBE (20 mL x 2). The combined organic phase 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 (1.1 g, yield 50.3%) as a pale yellow oil. 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] A mixture of compound 1.395 (1.1 g, 2.91 mmol) and TFA (135.06 mmol, 10 mL) in DCM (10 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum to obtain compound 1.396 (1.5 g, TFA salt) as a brownish oily substance, which 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)azetidine-1-yl)benzo[c][2,6]naphthyridine-8-carboxylate 1.397

[0508] [ka] A mixture of compound 1.396 (0.4 g, 1.44 mmol), compound 1.1 (0.3 g, 1.10 mmol), and DIPEA (0.8 mL, 4.59 mmol) in DMSO (8 mL) was stirred at 90°C for 16 hours, and a brown solid precipitated. The precipitate was filtered and purified (PM47) to obtain compound 1.397 (0.4 g, yield 70.7%) as a brown solid. 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] A mixture of compound 1.397 (0.4 g, 0.777 mmol), carbon-supported palladium (0.05 g, 10 wt% Pd / C), and ammonium hydroxide (0.5 mL, 3.25 mmol, 25%) in MeOH (20 mL) was hydrogenated at room temperature under H2 pressure (1 atm) 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 to obtain compound 1.398 (0.29 g, yield 98.1%) as a yellow solid, which was used directly without further purification. LCMS (AM3): rt = 0.690 min, (381.2 [M+H] + ), purity 94.2%. Methyl 5-(3-(4-((3-chloro-4-(trifluoromethoxybenzyl)amino)butoxy)azetidine-1-yl)benzo[c][2,6]naphthyridine-8-carboxylate 1.399

[0510] [ka] A mixture of 3-chloro-4-(trifluoromethoxy)benzaldehyde (0.17 g, 0.757 mmol) and compound 1.398 (0.29 g, 0.762 mmol) in MeOH (10 mL) was stirred at room temperature for 16 hours, and then sodium triacetoxyborohydride (0.7 g, 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, yield 38.1%) 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)butoxy]-1-methyl-ethyl]carbamate 1.621

[0511] [ka] A mixture of tert-butyl N-[(1S)-2-hydroxy-1-methyl-ethyl]carbamate (2 g, 11.41 mmol), benzyl (4-bromobutyl)carbamate (6.6 g, 23.06 mmol), NaOH (4.57 g, 114.14 mmol), and TBAI (0.21 g, 0.569 mmol) in H2O (11 mL) was stirred at room temperature for 18 hours. The reaction mixture was added to water (80 mL), and the resulting mixture was extracted with EA (20 mL x 3). The combined organic phase was washed with brine (40 mL), dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM47) to obtain compound 1.621 (0.93 g, 1.83 mmol, yield 16.1%) 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] A mixture of compound 1.621 (820 mg, 2.16 mmol) in HCl in 1,4-dioxane (20 mL, 4 M) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum, and the residue was purified (PM123) to obtain compound 1.622 (460 mg, 1.64 mmol, yield 76.1%, HCl salt) as a colorless oil. LCMS (AM3): rt = 0.658 min, (281.1 [M+H] + ), 100% pure. (S)-Methyl 5-((1-(4-(((benzyloxy)carbonyl)amino)butoxy)propan-2-yl)amino)benzo[c][2,6]naphthyridine-8-carboxylate 1.623

[0513] [ka] A mixture of compound 1.622 (440 mg, 1.57 mmol, HCl salt), compound 1.1 (480.36 mg, 1.73 mmol), and DIPEA (608.50 mg, 4.71 mmol) in DMSO (10 mL) was stirred at 80°C for 12 hours. The reaction mixture was filtered, and the filtrate was purified (PM122) to obtain compound 1.623 (400 mg, 723.26 μmol, yield 46.1%) 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)benzo[c][2,6]naphthyridine-8-carboxylate 1.624

[0514] [ka] Compound 1.623 (400 mg, 723.26 μmol, HCl salt) and an aqueous solution of ammonium hydroxide (1.00 mL, 25%) were mixed in MeOH (10 mL) and 10% palladium catalyst (0.2 g) supported on activated carbon under nitrogen protection was added. The resulting suspension was hydrogenated at room temperature under 1 atm of H2 for 1 hour. The catalyst was filtered off, and the filtrate was concentrated under vacuum to obtain compound 1.624 (170 mg, yield 61.5%) as a yellow solid, which was used directly without further purification. LCMS (AM3): rt = 0.599 min, (383.3 [M+H] + ), purity 88.7%. (S)-methyl 5-((1-(4-((3-chloro-4-(trifluoromethoxy)benzyl)amino)butoxy)propan-2-yl)amino)benzo[c][2,6]naphthyridine-8-carboxylate 1.625

[0515] [ka] A mixture of 3-chloro-4-(trifluoromethoxy)benzaldehyde (60 mg, 267.18 μmol), compound 1.624 (120 mg, 241.70 μmol, TFA salt), and DIPEA (93.72 mg, 725.11 μmol) in MeOH (4 mL) was stirred at room temperature for 12 hours, and then sodium cyanoborohydride (45 mg, 716.08 μmol) was added. The reaction mixture was then stirred separately at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified (PM91) to obtain compound 1.625 (50 mg, yield 29.3%, TFA salt) as a yellow solid. LCMS (AM3): rt = 0.852 min, (591.2 [M+H] + ), purity 98.5%. Synthesis of intermediate 1.609 tert-butyl N-[(1R)-2-[4-(benzyloxycarbonylamino)butoxy]-1-methyl-ethyl]carbamate 1.605

[0516] [ka] A mixture of tert-butyl N-[(1R)-2-hydroxy-1-methyl-ethyl]carbamate (2 g, 11.41 mmol), benzyl(4-bromobutyl)carbamate (6.6 g, 23.06 mmol) (Journal of the American Chemical Society, 2004, 126(14), 4543-4549), NaOH (4.57 g, 114.14 mmol), and TBAI (0.21 g, 0.569 mmol) in H2O (11 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (80 mL), and the resulting mixture was extracted with EA (20 mL x 3). The combined organic phase was washed with brine (40 mL), dehydrated with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM47) to obtain compound 1.605 (0.86 g) as a colorless oil. LCMS (AM3): rt = 0.977 min, (281.2 [M-tBuCO2+2H] + ), purity 49.7%. (R)-Benzyl(4-(2-aminopropoxy)butyl)carbamate 1.606

[0517] [ka] A mixture of compound 1.605 (0.86 g, 2.26 mmol) in HCl in 1,4-dioxane (10 mL, 4 M) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum, and the residue was purified (PM120) to obtain compound 1.606 (0.41 g, yield 57.3%, HCl salt) as a colorless oil. LCMS (AM3): rt = 0.719 min, (281.2 [M+H] + ), 100% pure. (R)-Methyl 5-((1-(4-(((benzyloxy)carbonyl)amino)butoxy)propan-2-yl)amino)benzo[c][2,6]naphthyridine-8-carboxylate 1.607

[0518] [ka] A mixture of compound 1.606 (0.41 g, 1.29 mmol, HCl salt), compound 1.1 (0.36 g, 1.32 mmol), and DIPEA (4.02 mmol, 0.7 mL) in DMSO (4 mL) was stirred at 90°C for 18 hours. The reaction mixture was filtered, the filtrate was concentrated under vacuum, and purified (PM22) to obtain compound 1.607 (0.5 g, yield 67.8%, HCl salt) as a yellow solid. LCMS (AM3): rt = 0.878 min, (517.3 [M+H] + ), purity 97.2%. (R)-Methyl 5-((1-(4-aminobutoxy)propan-2-yl)amino)benzo[c][2,6]naphthyridine-8-carboxylate 1.608

[0519] [ka] Compound 1.607 (0.5 g, 0.904 mmol, HCl salt), a carbon-supported 10% palladium catalyst (0.1 g), and an aqueous ammonium hydroxide solution (1.39 mL, 25%) were mixed in MeOH (20 mL) and hydrogenated at room temperature for 2 hours under a H2 pressure of 1 atm. The catalyst was filtered off, and the filtrate was concentrated under vacuum to obtain compound 1.608 (0.34 g, yield 98.3%) as a yellow solid, which was used directly without purification. LCMS (AM3): rt = 0.703 min, (383.3 [M+H] + ), purity 90.9%. (R)-Methyl 5-((1-(4-((3-chloro-4-(trifluoromethoxy)benzyl)amino)butoxy)propan-2-yl)amino)benzo[c][2,6]naphthyridine-8-carboxylate 1.609

[0520] [ka] A mixture of 3-chloro-4-(trifluoromethoxy)benzaldehyde (0.2 g, 0.891 mmol) and compound 1.608 (0.34 g, 0.889 mmol) in MeOH (4 mL) was stirred at room temperature for 1 hour, and then sodium cyanoborohydride (0.22 g, 3.50 mmol) was added. The reaction mixture was then stirred at room temperature for an additional 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was (PM119) to obtain compound 1.609 (0.15 g, yield 17.89%, TFA salt) as a yellow solid. LCMS (AM3): rt = 0.838 min, (591.2 [M+H] + ), purity 98.9%.

[0521] Synthesis of intermediates 1.837 and 1.838 Intermediates 1.837 and 1.838 have been assigned the following stereochemical nomenclature, but their final stereochemistry has not been fully elucidated by analytical techniques, so they are defined as either enantiomers. (R)-2-(3-chloro-5-vinylphenyl)propanenitrile 1.835 and (S)-2-(3-chloro-5-vinylphenyl)propanenitrile 1.836

[0522] [ka] To a solution of compound 1.365 (1.15 g, 6.47 mmol) in THF (15 mL), NaHMDS (6.47 mL, 1 M) was added at -78 °C. After stirring for 1 hour, MeI (918.93 mg, 6.47 mmol) was slowly added, and the mixture was stirred at -78 °C for 2 hours. The mixture was concentrated under vacuum to obtain a residue, which was purified (PM47) to obtain 430 mg of racemic product. This product was separated by SFC (column: DAISELCHIRALCEL OD 250 mm × 30 mm × 10 μm; mobile phase: [0.1% ammonium hydroxide-IPA]; B%: 15%~15%, 2.4 min; 35 min) to obtain compound 1.835 (160 mg, 826.48 μmol, peak 1) and compound 1.836 (130 mg, 671.51 μmol, peak 2) as a yellow oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 7.37 (t, J = 1.6 Hz, 1H), 7.26 (d, J = 1.2 Hz, 1H), 7.23 (t, J = 1.2 Hz, 1H), 6.66 (dd, J = 17.2, 10.8 Hz 1H), 5.81 (d, J = 17.2 Hz, 1H), 5.38 (d, J = 10.8 Hz, 1H), 3.91-3.86 (q, 1H), 1.66 (d, J = 7.2 Hz, 3H) ppm. (R)-2-(3-chloro-5-formylphenyl)propannitrile 1.837

[0523] [ka] Ozone was blown into a solution of compound 1.835 (160 mg, 834.83 μmol) in DCM (10 mL) at -78°C until the reaction mixture turned blue. After purging the excess ozone with nitrogen, DMS (674.28 mg, 10.85 mmol) was added. The mixture was heated to 25°C and stirred for 12 hours. The mixture was concentrated under vacuum, and the residue was purified (PM7) to obtain compound 1.837 (70 mg, 361.52 μmol, yield 43.3%) as a yellow oil. 1 H NMR (400 MHz, CHCl3-d) δ: 10.00 (s, 1H), 7.84 (t, J = 1.6 Hz, 1H), 7.78 (d, J = 1.2 Hz, 1H), 7.65 (t, J = 1.6 Hz, 1H), 4.00 (q, J = 7.2 Hz, 1H), 1.71 (d, J = 7.2 Hz, 3H) ppm. (S)-2-(3-chloro-5-formylphenyl)propannitrile 1.838

[0524] [ka] Ozone was blown into a solution of compound 1.836 (130 mg, 678.30 μmol) in DCM (15 mL) at -78°C until the reaction mixture turned blue. After purging the excess ozone with nitrogen, DMS (547.85 mg, 8.82 mmol) was added. The mixture was heated to 25°C and stirred for 12 hours. The mixture was concentrated under vacuum, and the residue was purified (PM7) to obtain compound 1.838 (80 mg, 361.52 μmol, yield 43.3%) as a yellow oil. 1 H NMR (400 MHz, CHCl3-d) δ: 10.00 (s, 1H), 7.84 (t, J = 1.6 Hz, 1H), 7.78 (s, 1H), 7.64 (t, J = 1.6 Hz, 1H), 4.00 (q, J = 7.2 Hz, 1H), 1.71 (d, J = 7.6 Hz, 3H) ppm. Synthesis of intermediate 1.734 tert-butyl N-[2-[4-(benzyloxycarbonylamino)butoxy]-1,1-dimethyl-ethyl]carbamate 1.730

[0525] [ka] A mixture of benzyl(4-bromobutyl)carbamate (12 g, 41.93 mmol), tert-butyl(1-hydroxy-2-methylpropan-2-yl)carbamate (4 g, 21.14 mmol), NaOH (8.45 g, 211.36 mmol), and TBAI (0.4 g, 1.08 mmol) in H2O (20 mL) was stirred at room temperature for 14 hours. Water (100 mL) was added, and the resulting mixture was extracted with MTBE (30 mL x 3). The combined organic phase was washed with brine (90 mL), dehydrated with Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM22) to obtain compound 1.730 (0.73 g, yield 8.2%) as a colorless oil. LCMS (AM3): rt = 1.027 mins, (417.4 [M+Na] + ), purity 94.3%. Benzyl (4-(2-amino-2-methylpropoxy)butyl)carbamate 1.731

[0526] [ka] A mixture of compound 1.730 (730 mg, 1.85 mmol) and TFA (5 mL, 67.53 mmol) in DCM (5 mL) was stirred at room temperature for 0.5 hours. The reaction mixture was concentrated under vacuum, and the residue was purified (PM47) to obtain compound 1.731 (0.69 g, yield 91.3%, TFA salt) as a colorless oil. LCMS (AM3): rt = 0.660 min, (295.3 [M+H] + ), purity 98.9%. Methyl 5-((1-(4-(((benzyloxy)carbonyl)amino)butoxy)-2-methylpropan-2-yl)amino)benzo[c][2,6]naphthyridine-8-carboxylate 1.732

[0527] [ka] A mixture of compound 1.731 (690 mg, 1.69 mmol, TFA salt), compound 1.1 (550 mg, 2.02 mmol), and DIPEA (1 mL, 5.74 mmol) in DMSO (9 mL) was stirred at 120 °C for 20 hours. The reaction mixture was filtered, and the filtrate was purified (PM22) to obtain compound 1.732 (250 mg, yield 20.9%) as a yellow solid. LCMS (AM3): rt = 0.915 min, (531.5 [M+H] + ), purity 75.8%. Methyl 5-((1-(4-aminobutoxy)-2-methylpropan-2-yl)amino)benzo[c][2,6]naphthyridine-8-carboxylate 1.733

[0528] [ka] A mixture of compound 1.732 (250 mg, 0.47 mmol), carbon-supported 10% palladium (0.1 g), and aqueous ammonium hydroxide solution (0.3 mL, 1.95 mmol, 25 wt%) in MeOH (10 mL) was hydrogenated at room temperature under 1 atm H2 for 16 hours. The catalyst was filtered off, and the filtrate was concentrated under vacuum. The residue was purified (PM47) to obtain compound 1.733 (90 mg, yield 34.1%, TFA salt) as a yellow oily substance. LCMS (AM3): rt = 0.726 min, (397.0 [M+H] + ), purity 91.2%. Methyl 5-((1-(4-((3-chloro-4-(trifluoromethoxybenzyl)amino)butoxy)-2-methylpropan-2-yl)amino)benzo[c][2,6]naphthyrizine-8-carboxylate 1.734

[0529] [ka] A mixture of 3-chloro-4-(trifluoromethoxy)benzaldehyde (44 mg, 0.20 mmol), compound 1.733 (90 mg, 0.18 mmol, TFA salt), and DIPEA (0.1 mL, 0.54 mmol) in MeOH (2 mL) was stirred at room temperature for 15 hours, and then sodium triacetoxyborohydride (112 mg, 0.53 mmol) was added. The reaction mixture was then stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum, and the residue was purified (PM144) to obtain compound 1.734 (25 mg, yield 21.9%, FA salt) as a white solid. LCMS (AM3): rt = 0.871 min, (605.4 [M+H] + ), purity 94.6%. Synthesis of intermediate 1.689 Methyl 3-bromo-5-vinylbenzoate 1.683

[0530] [ka] To a solution of methyl 3-bromo-5-iodobenzoate (25.7 g, 75.38 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (11.73 g, 76.13 mmol) in DME (300 mL), Pd(dppf)Cl2 (5.52 g, 7.54 mmol) and CsF (22.90 g, 150.76 mmol) were added. The mixture was heated to 80°C and stirred under a nitrogen atmosphere for 12 hours. The mixture was poured into water (300 mL) and extracted with EA (200 mL x 2). The combined organic phase was washed with brine (300 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM1) to obtain compound 1.683 (13.5 g, 56.00 mmol, yield 74.3%) as a pale yellow oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 8.05 (s, 1H), 8.00 (s, 1H), 7.72 (s, 1H), 6.66 (dd, J = 17.6, 10.8 Hz, 1H), 5.84 (d, J = 17.6 Hz, 1H), 5.39 (d, J = 10.8 Hz, 1H), 3.94 (s, 3H) ppm. Methyl 3-bromo-5-ethylbenzoate 1.684

[0531] [ka] To a solution of compound 1.683 (2.5 g, 10.37 mmol) in MeOH (50 mL), PtO2 (588.70 mg, 2.59 mmol) was added under a nitrogen atmosphere. The suspension was degassed three times under vacuum and purged with hydrogen. The mixture was stirred at 25°C for 0.5 hours under H2 pressure of 15 psi. The catalyst was filtered off, and the filtrate was concentrated to obtain compound 1.684 (2.3 g) as a yellow oily substance, which was used directly without purification. LCMS (AM3): rt = 0.982 min, (243.0 [M+H] + ), purity 86.4%. Methyl 3-ethyl-5-vinylbenzoate 1.685

[0532] [ka] To a solution of compound 1.684 (2.3 g, 9.46 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (2.19 g, 14.19 mmol) in DME (50 mL), Pd(dppf)Cl2 (692.29 mg, 946.12 μmol) and CsF (2.87 g, 18.92 mmol) were added. The mixture was heated to 80°C and stirred under a nitrogen atmosphere for 12 hours. The mixture was poured into water (100 mL) and extracted with EA (80 mL x 3). The combined organic phase was washed with brine (100 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM1) to obtain compound 1.685 (1.4 g, 7.36 mmol, yield 77.8%) as a yellow oil. 1 H NMR (400 MHz, CHCl3-d) δ: 7.92 (s, 1H), 7.78 (s, 1H), 7.43 (s, 1H), 6.75 (dd, J = 17.6, 10.8 Hz, 1H), 5.83 (d, J = 17.6 Hz, 1H), 5.31 (d, J = 10.8 Hz, 1H), 3.93 (s, 3H), 2.70 (q, J = 5.2 Hz, 2H), 1.27 (t, J = 5.2 Hz, 3H) ppm. (3-ethyl-5-vinylphenyl)methanol 1.686

[0533] [ka] To a solution of compound 1.685 (1.4 g, 7.36 mmol) in THF (20 mL), LAH (430 mg, 11.33 mmol) was slowly added at 0°C. The reaction mixture was stirred at 0°C for 0.5 hours. The reaction mixture was cooled to 0°C and then diluted with H₂O (0.45 mL), 10% NaOH aqueous solution (0.45 mL), and H₂O (1.35 mL). After stirring for 0.5 hours, Na₂SO₄ (3 g) was added. The mixture was stirred separately at 20°C for 0.5 hours, then filtered, and the filter cake was washed with EA (50 mL x 3). The filtrate was concentrated under vacuum to obtain compound 1.686 (1.1 g, 6.78 mmol, yield 92.1%) as a yellow oil. 1 H NMR (400 MHz, CHCl3-d) δ: 7.29 (s, 1H), 7.22 (s, 1H), 7.15 (s, 1H), 6.76 (dd, J = 17.6, 10.8 Hz, 1H), 5.81 (d, J = 17.6 Hz, 1H), 5.29 (d, J = 10.8 Hz, 1H), 4.72 (s, 2H), 2.74-2.67 (q, 2H), 1.32-1.27 (t, 3H) ppm. 1-(chloromethyl)-3-ethyl-5-vinylbenzene 1.687

[0534] [ka] To a solution of compound 1.686 (1 g, 6.16 mmol) in 1,4-dioxane (15 mL), SOCl2 (1.64 g, 13.78 mmol) was slowly added at 0°C. The reaction mixture was then heated to 90°C and stirred for 2 hours. The reaction mixture was slowly diluted with ice water (80 mL) at 0°C and then extracted with EA (50 mL x 2). The organic layer was washed with brine (80 mL), dehydrated with Na2SO4, filtered, and concentrated under vacuum to obtain compound 1.687 (1.1 g, 6.09 mmol, yield 98.8%) as a yellow oil, which was used directly in the next step. 2-(3-ethyl-5-vinylphenyl)acetonitrile 1.688

[0535] [ka] To a solution of compound 1.687 (1 g, 5.53 mmol) in ACN (20 mL), TMSCN (1.10 g, 11.07 mmol) and TBAF (11.07 mL, 1 M) were added at 20 °C. The reaction mixture was stirred at 20 °C for 12 hours. The reaction mixture was concentrated under vacuum, and the crude product was purified (PM7) to obtain compound 1.688 (900 mg, 5.26 mmol, yield 94.9%) as a yellow oil. 1 H NMR (400 MHz, CHCl3-d) δ: 7.20-7.18 (m, 2H), 7.05 (s, 1H), 6.69 (dd, J = 17.6, 10.8 Hz, 1H), 5.77 (d, J = 17.6 Hz, 1H), 5.28 (d, J = 10.8 Hz, 1H), 3.72 (s, 2H), 2.68-2.62 (q, 2H), 1.26-1.23 (t, 3H) ppm. 2-(3-ethyl-5-formylphenyl)acetonitrile 1.689

[0536] [ka] Ozone was blown into a solution of compound 1.688 (0.9 g, 5.26 mmol) in DCM (15 mL), cooled to -78°C, until the mixture turned blue. DMS (4.90 g, 78.84 mmol) was slowly added. The reaction mixture was heated to 20°C and stirred for 12 hours. The reaction mixture was concentrated under vacuum, and the crude product was purified (PM7) to obtain compound 1.689 (750 mg, 4.33 mmol, yield 82.38%) as a yellow oil. 1 H NMR (400 MHz, CHCl3-d) δ: 10.01 (s, 1H), 7.69 (s, 1H), 7.66 (s, 1H), 7.45 (s, 1H), 3.82 (s, 2H), 2.76 (q, J = 7.6 Hz, 2H), 1.29 (t, J = 7.6 Hz, 3H) ppm. Synthesis of intermediate 1.697 Methyl 3-bromo-5-(cyclopropyl(hydroxy)methyl)benzoate 1.691

[0537] [ka] To a solution of methyl 3-bromo-5-formyl-benzoate (1.5 g, 6.17 mmol) in THF (70 mL), cyclopropyl magnesium bromide (18.51 mL, 0.5 M) was slowly added at 0°C. The mixture was stirred at 0°C for 0.5 hours. The mixture was poured into saturated NH4Cl aqueous solution (100 mL) and extracted with EA (50 mL x 2). The combined organic phase was washed with brine (50 mL), dehydrated with Na2SO4, and concentrated under vacuum. The residue was purified (PM12) to obtain compound 1.691 (570 mg, 2.00 mmol, yield 32.4%) as a red oil. 1 H NMR (400 MHz, CHCl3-d) δ: 8.09 (s, 1H), 8.02 (s, 1H), 7.81 (s, 1H), 4.04 (d, J = 8.1 Hz, 1H), 3.95 (s, 3H), 2.12 (br s, 1H), 1.23-1.13 (m, 1H), 0.71-0.55 (m, 2H), 0.55-0.33 (m, 2H) ppm. Methyl 3-bromo-5-(cyclopropylmethyl)benzoate 1.692

[0538] [ka] Compound 1.691 (1 g, 3.51 mmol) was added to a mixture of TFA (1.73 g, 15.13 mmol) and Et3SiH (815.60 mg, 7.01 mmol) at 20°C. The reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was concentrated under vacuum, and the crude product was purified (PM1) to obtain compound 1.692 (700 mg, 2.60 mmol, yield 74.2%) as a colorless oil. 1H NMR (400 MHz, CHCl3-d) δ: 8.00 (s, 1H), 7.85 (s, 1H), 7.60 (s, 1H), 3.92 (s, 3H), 2.56 (d, J = 6.8 Hz, 2H), 1.02-0.92 (m, 1H), 0.58-0.54 (m, 2H), 0.24-0.19 (m, 2H) ppm. Methyl 3-(cyclopropylmethyl)-5-vinylbenzoate 1.693

[0539] [ka] To a solution of compound 1.692 (600 mg, 2.23 mmol) in 1,4-dioxane (6 mL) and water (0.6 mL), K2CO3 (616.23 mg, 4.46 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (686.71 mg, 4.46 mmol), and Pd(dppf)Cl2 (163.12 mg, 222.94 μmol) were added. The reaction mixture was then heated to 80°C and stirred for 12 hours. The reaction mixture was concentrated under vacuum, and the crude product was purified (PM13) to obtain compound 1.693 (330 mg, 1.53 mmol, yield 68.4%) as a colorless oil. 1 H NMR (400 MHz, CHCl3-d) δ: 7.93 (s, 1H), 7.82 (s, 1H), 7.47 (s, 1H), 6.74 (dd, J = 17.6, 10.8 Hz, 1H), 5.82 (d, J = 17.6 Hz, 1H), 5.31 (d, J = 10.8 Hz, 1H), 3.92 (s, 3H), 2.58 (d, J = 6.8 Hz, 2H), 1.05-0.96 (m, 1H), 0.57-0.53 (m, 2H), 0.24-0.20 (m, 2H) ppm. (3-(cyclopropylmethyl)-5-vinylphenyl)methanol 1.694

[0540] [ka] To a solution of compound 1.693 (330 mg, 1.53 mmol) in THF (5 mL), LAH (57.91 mg, 1.53 mmol) was slowly added at 0°C. The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched with water (0.1 mL), followed by 10% NaOH aqueous solution (0.1 mL) and water (0.3 mL). After stirring for 0.5 hours, Na2SO4 (3 g) was added, and the mixture was stirred at 20°C for 0.5 hours. The mixture was filtered and concentrated under vacuum to obtain compound 1.694 (300 mg) as a colorless oil. 1 H NMR (400 MHz, CHCl3-d) δ: 7.27 (s, 1H), 7.23 (s, 1H), 7.17 (s, 1H), 6.72 (dd, J = 17.6, 11.2 Hz 1H), 5.76 (d, J = 17.6 Hz, 1H), 5.25 (d, J = 11.2, 1H), 4.69 (s, 2H), 2.55 (d, J = 6.8 Hz, 2H), 1.64 (br s, 1H), 1.04-0.96 (m, 1H), 0.56-0.51 (m, 2H), 0.23-0.19 (m, 2H) ppm. 1-(chloromethyl)-3-(cyclopropylmethyl)-5-vinylbenzene 1.695

[0541] [ka] To a solution of compound 1.694 (300 mg, 1.59 mmol) in 1,4-dioxane (5 mL), SOCl2 (492.00 mg, 4.14 mmol) was slowly added at 0°C. The reaction mixture was then heated to 80°C and stirred for 2 hours. The mixture was diluted with H2O (10 mL) and then extracted with EA (50 mL x 2). The organic layer was washed with brine (20 mL), dehydrated with Na2SO4, filtered, and concentrated under vacuum to obtain compound 1.695 (300 mg, 1.45 mmol, yield 91.1%) as a yellow oil, which was used directly. 2-(3-(cyclopropylmethyl)-5-vinylphenyl)acetonitrile 1.696

[0542] [ka] To a solution of compound 1.695 (300 mg, 1.45 mmol) in ACN (20 mL), TMSCN (287.96 mg, 2.90 mmol) and TBAF (2.90 mL, 1 M in THF) were added at 20°C. The reaction mixture was stirred at 20°C for 12 hours. The reaction mixture was concentrated under vacuum, and the crude product was purified (PM7) to obtain compound 1.696 (300 mg) as a yellow oily substance. 1 H NMR (400 MHz, CHCl3-d) δ: 7.27 (s, 1H), 7.20 (s, 1H), 7.12 (s, 1H), 6.70 (dd, J = 17.2, 10.8 Hz, 1H), 5.77 (d, J = 17.2 Hz, 1H), 5.29 (d, J = 10.8 Hz, 1H), 3.72 (s, 2H), 2.55 (d, J = 6.8 Hz, 2H), 1.04-0.95 (m, 1H), 0.55-0.50 (m, 2H), 0.23-0.19 (m, 2H) ppm. 2-(3-(cyclopropylmethyl)-5-formylphenyl)acetonitrile 1.697

[0543] [ka] Ozone was blown into a solution of compound 1.696 (300 mg, 1.52 mmol) in DCM (8 mL), cooled to -78°C, until the mixture turned blue. After purging the excess ozone with nitrogen, DMS (2.31 g, 37.18 mmol) was added. The mixture was heated to 20°C and stirred for 12 hours. The reaction mixture was concentrated under vacuum, and the crude product was purified (PM11) to obtain compound 1.697 (230 mg, 1.15 mmol, yield 75.9%) as a yellow oil. 1H NMR (400 MHz, CHCl3-d) δ: 10.02 (s, 1H), 7.76 (s, 1H), 7.70 (s, 1H), 7.52 (s, 1H), 3.83 (s, 2H), 2.64 (d, J = 6.8 Hz, 2H), 1.06-0.96 (m, 1H), 0.62-0.57 (q, 2H), 0.26-0.23 (q, 2H) ppm. Synthesis of intermediate 1.782 4-((3-chloro-4-(trifluoromethoxy)benzyl)amino)butan-1-ol 1.157

[0544] [ka] A solution of 3-chloro-4-(trifluoromethoxy)benzaldehyde (1 g, 4.45 mmol) and 4-aminobutan-1-ol (1.19 g, 13.36 mmol) in MeOH (10 mL) was stirred at 20°C for 12 hours, and then sodium cyanoborohydride (1.12 g, 17.81 mmol) was added. The resulting mixture was stirred at 20°C for 1 hour. The mixture was concentrated under vacuum and purified (PM150) to obtain compound 1.157 (1.2 g, FA salt) as a white solid. LCMS (AM3): rt = 0.911 min, (298.1 [M+H] + ), purity 96.6%. tert-butyl 3-chloro-4-(trifluoromethoxy)benzyl(4-hydroxybutyl)carbamate 1.158

[0545] [ka] To a solution of compound 1.157 (1.2 g, 3.49 mmol) in THF (10 mL) and water (10 mL), NaHCO3 (439.92 mg, 5.24 mmol) and Boc2O (914.32 mg, 4.19 mmol) were added at 20°C. The mixture was stirred at 20°C for 12 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (90 mL x 3), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM6) to obtain compound 1.158 (890 mg, 2.21 mmol, yield 63.2%) as a pale yellow oil. LCMS (AM3): rt = 1.049 mins, (420.1 [M+Na] + ), purity 73.2%. tert-butyl(4-bromobutyl)(3-chloro-4-(trifluoromethoxy)benzyl)carbamate 1.778

[0546] [ka] To a solution of compound 1.158 (3.1 g, 7.79 mmol) and CBr4 (3.10 g, 9.35 mmol) in DCM (40 mL), PPh3 (2.45 g, 9.35 mmol) was added at 0°C. The reaction mixture was heated to room temperature and stirred for 1 hour. The reaction mixture was concentrated under vacuum, and the residue was purified (PM7) to obtain compound 1.778 (2 g, yield 55.7%) as a colorless oil, which was used directly. tert-butyl 3-chloro-4-(trifluoromethoxy)benzyl(4-((2R)-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)butyl)carbamate 1.779

[0547] [ka] Compound 1.778 (2 g, 4.34 mmol), (2R)-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol (Tetrahedron Letters, 2003, 44(32), 6149-6151), (0.7 g, 4.37 mmol), NaOH (1.74 g, 43.41 mmol), and TBAI (160 mg, 0.43 mmol) were mixed in H2O (4 mL) and stirred at 25°C for 14 hours. The reaction mixture was diluted with water (40 mL), and the resulting mixture was extracted with MTBE (20 mL x 2). The combined organic phase was washed with brine (20 mL), dehydrated with Na2SO4, filtered, and concentrated under vacuum. The residue was purified (PM47) to obtain compound 1.779 (700 mg, yield 20.9%) as a brownish oil. LCMS (AM3): rt = 1.071 min, (456.2 [M-THP+2H] + ), purity 69.8%. (R)-tert-butyl 3-chloro-4-(trifluoromethoxy)benzyl(4-(2-hydroxypropoxy)butyl)carbamate 1.780

[0548] [ka] A mixture of compound 1.779 (0.7 g, 1.30 mmol) and TsOH·H2O (50 mg, 0.26 mmol) in MeOH (15 mL) was stirred at room temperature for 1 hour. K2CO3 (1 g) was added, and the mixture was stirred for 10 minutes. The mixture was then filtered, and the filtrate was concentrated under vacuum to obtain a residue, which was purified (PM6) to obtain compound 1.780 (0.5 g, yield 84.6%) as a pale yellow oil. LCMS (AM3): rt = 1.065 min, (478.1 [M+Na] + ), purity 43.3%. (R)-Methyl 5-((1-(4-((tert-butoxycarbonyl)(3-chloro-4-(trifluoromethoxy)benzyl)amino)butoxy)propan-2-yl)oxy)benzo[c][2,6]naphthyridine-8-carboxylate 1.781

[0549] [ka] To a solution of compound 1.780 (500 mg, 1.10 mmol) in THF (10 mL), NaH (60 mg, 1.50 mmol, 60% dispersion in oil) was added at 0°C. The reaction mixture was stirred at 0°C for 0.5 hours, and then compound 1.1 (450 mg, 1.65 mmol) was added. The reaction mixture was then heated to 60°C and stirred for 20 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to obtain a residue, which was purified (PM47) to obtain compound 1.781 (100 mg, yield 12.5%) as a colorless oil. LCMS (AM3): rt = 1.247 min, (692.3 [M+H] + ), purity 96.8%. (R)-5-((1-(4-((tert-butoxycarbonyl)(3-...

Claims

1. formula: 【Chemistry 1】 Compounds of (5-(2-(4-((3,5-difluoro-4-(trifluoromethoxy)benzyl)amino)butoxy)ethoxy)benzo[c][2,6]naphthyridine-8-carboxylic acid), or pharmaceutically acceptable salts, hydrates, or solvates thereof.

2. A pharmaceutical composition comprising the compound described in claim 1 or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and a pharmaceutically acceptable excipient.

3. (i) treatment; (ii) Treatment of diseases or conditions involving CK2α activity; (iii) Treatment of diseases or conditions related to abnormal activity of CK2α; (iv) Treatment of proliferative disorders, viral infections, inflammatory diseases or conditions, diabetes, vascular and ischemic disorders, neurodegenerative disorders, and / or regulation of circadian rhythms; (v) Treatment of cancer or benign neoplasms; (vi) Treatment of cancer; and / or (vii) Treatment of viral infection The pharmaceutical composition according to claim 2 for use in [the specified area].

4. (i) Treatment; (ii) Treatment of diseases or conditions involving CK2α activity; (iii) Treatment of diseases or conditions related to abnormal activity of CK2α; (iv) Treatment of proliferative disorders, viral infections, inflammatory diseases or conditions, diabetes, vascular and ischemic disorders, neurodegenerative disorders, and / or regulation of circadian rhythms; (v) Treatment of cancer or benign neoplasms; (vi) Treatment of cancer; and / or (vii) Treatment of viral infection Use of the compound according to claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical for the purpose of

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