Macrocyclic compounds as CDK9 inhibitors and their applications

Abstract

The present disclosure provides compounds of formula (I), pharmaceutical compositions thereof, and uses thereof in the treatment and / or prevention of diseases or conditions associated with CDK9 kinase activity. JPEG2025538275000286.jpg3450

Description

[Technical Field]

[0001] (cross reference) This application claims priority based on a Chinese patent application (application number: 202211315138.1, invention title: "Macrocyclic compounds as CDK9 inhibitors and their applications") filed with the State Intellectual Property Office of the People's Republic of China on October 24, 2022, the entire contents of which are incorporated herein by reference.

[0002] The present application relates to compounds as inhibitors of CDK9 kinase activity and methods of using such compounds to treat and / or prevent diseases or conditions associated with abnormal CDK9 kinase activity. [Background technology]

[0003] Protein kinases are enzyme proteins widely distributed within cells and on the surface of cells. Approximately 600 protein kinases have been discovered and characterized to date. These belong to a structurally related protein family, and known members are involved in nearly all cell signaling activities. Protein kinases catalytically transfer the γ-phosphate group in ATP molecules to specific threonine, serine, or tyrosine residues in target proteins, thereby changing the conformation of the target protein and, as a result, changing its function from a dormant state to an activated state. Protein kinases are classified into two types based on their target amino acid specificity: serine / threonine protein kinases (EC 2.7.11.-) and tyrosine protein kinases (EC 2.7.10.-).

[0004] Protein kinase-mediated signal transduction and its regulatory mechanisms are essential for maintaining cellular and organ homeostasis, including cell growth, differentiation, proliferation, angiogenesis, apoptosis, cytoskeletal organization, metabolic regulation, membrane trafficking, and cell motility. Furthermore, protein kinases also play essential roles in non-enzymatic functions, such as allosteric effects, intracellular targeting, protein complex scaffolding, protein-protein competitive interactions, and DNA binding. However, when gene mutations or protein kinase overexpression occur, dysfunctional protein kinases can cause a variety of pathologies, including cancer, inflammation, autoimmune diseases, cardiovascular diseases, and neurological disorders. Therefore, protein kinases are currently a prime target for drug development. The recent success of protein kinase inhibitors in clinical treatment further demonstrates the feasibility of this strategy and suggests a promising future for targeting protein kinases as therapeutic targets.

[0005] Cyclin-dependent kinases (CDKs) are a type of protein kinase that belong to the serine / threonine kinase family and regulate cell cycle and gene transcription. During various stages of cell cycle progression, CDKs phosphorylate specific cyclins to regulate cellular activity. CDK dysregulation significantly affects normal cellular function and is often identified as a cause of carcinogenesis. CDK9 is one of the most important CDKs and can cooperate with four cyclins, including cyclin T1, cyclin K, and cyclin T2a or T2b. CDK9 binds to cyclins to form a heterodimer with positive transcription elongation factor b (P-TEFb). P-TEFb phosphorylates the C-terminal domain (CTD) of RNA polymerase II, promoting transcription from the origin site and serving as a core molecule for transcription elongation. CDK9 kinase dysregulation can lead to a variety of diseases, including hyperproliferative disorders (e.g., cancer), viral infections, and cardiovascular diseases. CDK9 inhibitors can inhibit the transcription process. Because transcriptional processes are deregulated in many cancers, CDK9 inhibitors can be used to treat cancers, including solid tumors and hematopoietic malignancies, such as acute myeloid leukemia (AML), breast cancer, prostate cancer, hepatocellular carcinoma, and pancreatic cancer.

[0006] Given the important role of CDK9 in disease, downregulation of CDK9 offers a great opportunity for the development of targeted therapies for cancer and other diseases. Although many small molecule CDK inhibitors have been reported to date, most lack selectivity for specific CDKs, resulting in low efficacy and a high incidence of adverse events in clinical settings. Therefore, the development of inhibitors that specifically target CDK9 is of great importance for the treatment of human diseases. Summary of the Invention

[0007] The present inventors have created a group of novel macrocyclic compounds that have a significant inhibitory effect on CDK9 activity, exhibit highly effective and highly selective CDK9 kinase inhibitory effects, and can be used to treat or prevent diseases associated with CDK9 activity.

[0008] In particular, the present invention provides a compound represented by formula (I), or a meso form, racemate, enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, for use as a CDK9 kinase activity inhibitor. [ka] [In the formula, X is selected from the group consisting of H, a C1-C3 alkyl group, a halogen, CF3, a carbamoyl group, a cyano group, and a C1-C3 alkoxycarbonyl group; L is a single bond (i.e., directly covalently linked), C6-C 10 aryl group, a 5- to 12-membered heteroaryl group, a C3-C8 cycloalkyl group, and a 3- to 8-membered heterocyclyl group (wherein the C6-C 10 The aryl group, the 5- to 12-membered heteroaryl group, the C3-C8 cycloalkyl group, and the 3- to 8-membered heterocyclyl group may optionally be one or more R 1 further substituted with Ring A is C6-C 10aryl group, a 5- to 12-membered heteroaryl group, a C3-C8 cycloalkyl group, and a 3- to 8-membered heterocyclyl group (wherein the C6-C 10 The aryl group, the 5- to 12-membered heteroaryl group, the C3-C8 cycloalkyl group, and the 3- to 8-membered heterocyclyl group may optionally be one or more R 2 (which is further replaced by Y is a single bond and -CHNR 3 - (wherein R 3 is selected from the group consisting of H, a C1-C3 alkyl group, a C1-C3 alkyl acyl group, and Boc; provided that at least one of L and Y is a single bond; Q is selected from the group consisting of a C4-C5 alkylene group and a C4-C5 alkenylene group, wherein one -CH2- unit in said group is optionally an O atom, an S atom, or an -NR 3 -, preferably Q is [ka] selected from the group consisting of R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, amino, C1-C3 alkylamino, cyano, oxo, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, 3- to 8-membered heterocyclyl, and 3- to 8-membered heterocyclyl substituted with C1-C3 alkyl.

[0009] In a preferred embodiment, the compound represented by formula (I) in the present invention, or a meso form, racemic form, enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, is a compound represented by formula (II), or a meso form, racemic form, enantiomer, diastereomer, or pharmaceutically acceptable salt thereof. [ka] [In formula (II), X, Q, R 2 and R 3 is defined above].

[0010] In another preferred embodiment, the compound represented by formula (I) in the present invention, or a meso isomer, racemic form, enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, is a compound represented by formula (III), or a meso isomer, racemic form, enantiomer, diastereomer, or pharmaceutically acceptable salt thereof. [ka] [In formula (III), X, Q, A and R 1 is defined above].

[0011] In another preferred embodiment, ring A in formula (III) of the present invention is selected from the group consisting of a benzene ring and a pyrazole ring.

[0012] Exemplary compounds of the present invention include, but are not limited to, the following compounds, or their meso forms, racemates, enantiomers, diastereomers, or pharmaceutically acceptable salts: [ka] [ka] [ka] [ka] [ka]

[0013] The present invention further provides a method for producing the compounds of formula (I), formula (II), and formula (III) of the present invention, or meso-isomers, racemates, enantiomers, diastereomers, or pharmaceutically acceptable salts thereof, comprising the following steps:

[0014] General synthetic route 1 [ka] where X and R 3 and A is defined as above, and n and m are 1 or 2. Compound A and compound B1 undergo a nucleophilic substitution reaction to give compound C1. Compound C1 and compound D1 undergo a Buchwald-Hartwig amination reaction in the presence of a palladium catalyst to give compound E1. Compound E1 undergoes an intramolecular RCM olefin metathesis reaction in the presence of a Grubbs catalyst to cyclize and give the target compound F1. The double bond of compound F1 is reduced by hydrogenation to give the target compound G1.

[0015] General synthetic route 2 [ka] where X, Q, R 2 and R 3 is defined as above. Compound A and compound B2 undergo a nucleophilic substitution reaction to give compound C2. In the presence of a reducing agent, the nitro group of compound C2 is reduced to an amino group to give compound D2. Compound D2 undergoes an intramolecular C-N coupling reaction under a palladium catalyst to undergo cyclization, giving the target compound E2.

[0016] General synthetic route 3 [ka] where X and R 1 , R 3and A is defined as above, and n and m are 1 or 2. Compound A and compound B3 undergo a Suzuki coupling reaction to give compound C3. Compound C3 and compound D3 undergo a Buchwald-Hartwig amination reaction under a palladium catalyst to give compound E3. Compound E3 undergoes an intramolecular RCM olefin metathesis reaction in the presence of a Grubbs catalyst to cyclize and give the target compound F3. Compound F3 is reduced by a hydrogenation reaction to form a single bond, giving the target compound G3.

[0017] General synthetic route 4 [ka] where X and R 1 , Q and A are defined as above. Compound A and compound B4 undergo a Suzuki coupling reaction to give compound C4. In the presence of a reducing agent, the nitro group of compound C4 is reduced to an amino group to give compound D4. Compound D4 undergoes an intramolecular C-N coupling reaction to be cyclized to give the target compound E4. Explanation of terms in the invention

[0018] Unless otherwise stated, terms used in this specification and claims have the following meanings:

[0019] In this invention, reference to a "compound" having a particular structural formula generally also includes pharmaceutically acceptable salts, stereoisomers, diastereomers, enantiomers, racemic mixtures, and isotopic derivatives thereof.

[0020] In addition to salts of compounds, those skilled in the art will be aware that solvates and hydrates are alternative forms of compounds that can be converted to compounds under certain conditions, and therefore, when referring to a compound in the present invention, the solvates and hydrates are generally also included.

[0021] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that, when applied to contact the tissues of humans or mammals within the scope of reasonable medical judgment, does not produce undue toxicity, irritation, or allergic reactions, possesses the desired biological activity, and exhibits a reasonable benefit / risk ratio. The salt can be prepared in situ during the final isolation and purification of the compound of the present invention, or can be prepared separately by reacting the free base or free acid with a suitable reagent. For example, the free base can be reacted with a suitable acid. Examples of pharmaceutically acceptable acid addition salts include salts formed from an amino group (amine group) with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid), or salts formed using other conventional methods, such as ion exchange. The pharmaceutically acceptable salts of the present invention can be prepared by conventional methods, for example, by dissolving the compound of the present invention in a water-miscible organic solvent (e.g., methanol, ethanol, acetone, acetonitrile), adding an excess amount of an aqueous solution of an organic or inorganic acid thereto to precipitate a salt from the resulting mixture, removing the solvent and residual free acid, and then isolating the precipitated salt. Other pharmaceutically acceptable salts include sodium alginate, ascorbate, benzenesulfonate, adipate, camphorsulfonate, aspartate, benzoate, hydrogensulfate, borate, butyrate, camphorate, citrate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, heptanoate, hexanoate, hydroiodide, lactobionate, lactate, and laurate. , lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0022] In the specification and claims, a given chemical formula or name is intended to encompass all stereoisomers and optical isomers, as well as racemates in which such isomers exist. Unless otherwise specified, all chiral (enantiomers and diastereomers) and racemic forms are within the scope of the present invention. Many geometric isomers, such as C=C double bonds, C=N double bonds, and ring systems, may also exist in the compounds, and all such stable isomers are encompassed by the present invention. Cis- and trans- (or E- and Z-) geometric isomers of the compounds of the present invention are described herein and can be separated as a mixture of isomers or as isolated isomeric forms.

[0023] The compounds of the present invention can be isolated in optically active or racemic forms. Methods for preparing the compounds of the present invention and the preparation of intermediates therein are all considered to be part of the present invention. When enantiomeric or diastereomeric products are prepared, they can be isolated by conventional methods, such as chromatography or stepwise crystallization. It should be understood that all possible tautomeric forms are included in the present invention. The compounds used in the present invention may be commercially available if they are known compounds in the prior art.

[0024] The term "alkyl group" refers to both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. The alkyl group in the present invention is preferably C1-C 12 Alkyl groups, C1-C 10The alkyl group is a C1-C8 alkyl group, more preferably a C1-C6 alkyl group, particularly preferably a C1-C4 alkyl group, and especially preferably a C1-C3 alkyl group. For example, a "C1-C6 alkyl group" refers to an alkyl group having 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, a methyl group, an ethyl group, a propyl group (e.g., n-propyl group, isopropyl group), a butyl group (e.g., n-butyl group, isobutyl group, tert-butyl group), and a pentyl group (e.g., n-pentyl group, isopentyl group, neopentyl group). The alkyl group may be substituted or unsubstituted. When substituted, the substituent is substituted at any available attachment point. The substituents are preferably independently one or more groups selected from the group consisting of alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogen atoms, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, and carboxyl ester groups. 12 In the alkyl group, 1, 2, 3 or 4 -CH2- units are optionally replaced by an O atom, a S atom or -NH-.

[0025] The term "alkoxy group" refers to -O- (alkyl group) or -O- (unsubstituted cycloalkyl group). For example, "C1-C6 alkoxy group" refers to C1, C2, C3, C4, C5 and C6 alkoxy groups. The alkoxy group is preferably C1-C 10Alkoxy groups include C1-C8 alkoxy groups, more preferably C1-C6 alkoxy groups, particularly preferably C1-C4 alkoxy groups, and especially C1-C3 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy groups. The alkoxy group may be substituted or unsubstituted. When substituted, the substituents are preferably independently one or more groups selected from the group consisting of alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogen atoms, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, and carbonyl ester groups. Similarly, an "alkylthio group" represents an alkyl group as defined above with the indicated number of carbon atoms connected via a sulfur bridge, such as methyl-S- and ethyl-S-. Similarly, alkylthio groups are preferably C1-C 10 Alkylthio groups include C1-C8 alkylthio groups, more preferably C1-C6 alkylthio groups, particularly preferably C1-C4 alkylthio groups, and especially preferably C1-C3 alkylthio groups.

[0026] The term "halo" or "halogen" includes fluorine, chlorine, bromine, and iodine. In the present invention, one or more halogens are each independently selected from the group consisting of fluorine, chlorine, bromine, and iodine.

[0027] The term "haloalkyl group" refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms substituted with one or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, heptachloropropyl, and the like. Preferred haloalkyl groups include halo(C1-C6 alkyl groups) and halo(C1-C4 alkyl groups).

[0028] The term "oxo group" or "carbonyl group" refers to an organic functional group in which a carbon atom and an oxygen atom are connected by a double bond (C=O or C(O)).

[0029] The term "benzyl" refers to the group -CH2-phenyl or "Bn".

[0030] The term "hydroxy" refers to an --OH group.

[0031] The term "amino group" refers to -NH2.

[0032] The term "cyano" refers to -CN.

[0033] The term "nitro group" refers to -NO2.

[0034] The term "carboxy" refers to -C(O)OH.

[0035] The term "thiol group" refers to -SH.

[0036] The term "ester group" or "carboxylic ester group" refers to a -C(O)O- (alkyl group) or a -C(O)O- (cycloalkyl group), where alkyl and cycloalkyl are defined above.

[0037] The term "acyl group" refers to a compound containing a -C(O)R group, where R is an alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group.

[0038] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent. The cycloalkyl ring contains 3 to 20 carbon atoms. The cycloalkyl of the present invention is preferably a C3-C8 cycloalkyl group or a C3-C6 cycloalkyl group. Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl groups. Polycyclic cycloalkyl groups include, but are not limited to, spirocyclic, fused-ring, and bridged-ring cycloalkyl groups such as norbornyl.

[0039] The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocyclyl ring, where the ring connecting to the parent structure is a cycloalkyl group, non-limiting examples of which include, but are not limited to: [ka]

[0040] The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from the group consisting of alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, hydroxyalkyl groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, aryloxy groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, and carboxyl ester groups.

[0041] The term "heterocyclyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 heteroatoms, one or more of which are selected from the group consisting of N, O, and S (provided that the N and S heteroatoms may be optionally oxidized), excluding the -OO-, -OS-, or -SS- ring moieties, with the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms. More preferably, it contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms. Most preferably, it contains 5 to 7 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms. Examples of monocyclic heterocyclyl groups include tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and tetrahydropyranyl. Examples of polycyclic heterocyclyl groups include, but are not limited to, spirocyclic, fused-ring, and bridged-ring heterocyclyl groups.

[0042] The heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclyl group, non-limiting examples of which include, but are not limited to: [ka]

[0043] The heterocyclyl group may be optionally substituted or unsubstituted, and if substituted, the substituents are preferably one or more groups independently selected from the group consisting of alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, hydroxyalkyl groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, aryloxy groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, oxo groups, carboxyl groups, and carboxyl ester groups.

[0044] The term "aryl group" refers to a monocyclic, bicyclic, or tricyclic ring system containing a total of 6 to 14 ring atoms, preferably 6 to 10 carbon atoms, having a conjugated pi-electron system, provided that at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring atoms. In some embodiments of the present invention, "aryl group" refers to aromatic ring systems including, but not limited to, phenyl, naphthyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthyl groups. Aryl groups of the present invention are preferably C6-C8 10 The aryl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from the group consisting of alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, hydroxyalkyl groups, alkylthio groups, alkylamino groups, halogen atoms, mercapto groups, hydroxy groups, nitro groups, cyano groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, aryloxy groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, carboxyl groups, and carboxyl ester groups.

[0045] The term "heteroaryl group" refers to a stable 3-, 4-, 5-, 6-, or 7-membered aromatic monocyclic ring or a 7-, 8-, 9-, 10-, 11-, or 12-membered aromatic bicyclic or polycyclic heterocyclic ring that is fully or partially unsaturated and contains carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, provided that the N and S heteroatoms are optionally oxidized. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or another substituent, as defined). The heterocycle can be attached to a side group at any heteroatom or carbon atom in a stable structure. The heterocyclyl groups herein may be substituted on a carbon or nitrogen atom if the resulting compound is stable. The nitrogen in the heterocycle may be optionally quaternized. Preferably, if the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to one another. Preferably, the total number of S and O atoms in the heterocycle is 1 or less. When the term "heterocycle" is used, it is intended to include heteroaryl groups. Examples of heteroaryl groups include, but are not limited to, acridinyl, imidazolyl, furanyl, thienyl, oxazolyl, thiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzoisothiazolyl, indolyl, indolizinyl, indazolyl, pyrimidinyl, phenazinyl, piperazinyl, piperidinyl, purinyl, pyranyl, pyrazinyl, pyrrolyl, and quinolinyl groups. The term "heteroaryl group" also includes biaryl group structures consisting of the above-defined "aryl group," "heterocyclyl group," or "cycloalkyl group" and a monocyclic "heteroaryl group," such as, but not limited to, "-phenylbipyridyl-," "-phenylbipyrimidyl-," "-pyridylbinaphthyl-," "-pyrimidylbinaphthyl-," and "-pyridylbipyrimidyl-." The present invention also includes, for example, spiro rings, fused rings, and bridged ring compounds containing the above heterocyclyl groups.

[0046] In the present invention, "any" or "optionally" means that the subsequently described event or circumstance may occur, but does not necessarily have to occur, and the description includes cases where the event or circumstance occurs or does not occur. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that the alkyl group may be present, but does not necessarily have to be present, and the description includes both cases where the heterocyclyl group is substituted with an alkyl group and cases where the heterocyclyl group is not substituted with an alkyl group.

[0047] As used herein, "substituted" or "substituted" refers to one or more hydrogen atoms, preferably up to five, more preferably one to three hydrogen atoms in a group, being independently replaced with the corresponding number of substituents, provided that normal valences are maintained and the substitution results in a stable compound. Obviously, substituents exist only at feasible chemical positions, and those skilled in the art would be able to determine (experimentally or theoretically) which substitutions are possible or impossible without undue effort. For example, an amino group or hydroxy group having free hydrogen may be unstable when bonded to a carbon atom having an unsaturated (e.g., olefinic) bond.

[0048] A "pharmaceutical composition" refers to a mixture containing one or more compounds according to the present invention, or their meso-, racemic-, enantiomers, diastereomers, or pharmaceutically acceptable salts, and optionally other components such as physiologically / pharmaceutically acceptable carriers and / or excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism and promote absorption of the active ingredient(s), thereby exerting biological activity. DETAILED DESCRIPTION OF THE INVENTION

[0049] In order to more effectively explain the technical means employed in the present invention and their effects, the present invention will be further described below with reference to non-limiting examples. The examples of the present invention and the descriptions therein are intended to illustrate the embodiments of the present invention and are not intended to limit the scope of the claims. It should be understood by those skilled in the art that many modifications can be made to the disclosed specific embodiments without departing from the spirit and scope of the present invention, while still achieving the same or similar results.

[0050] Unless otherwise stated, all materials / reagents are commercially available from industry suppliers and can be used without further purification. The structures of the compounds in the following examples have been characterized and confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS).

[0051] 1 H NMR spectra were recorded at room temperature on a Bruker Avance 400 MHz spectrometer using solvents such as deuterated dimethyl sulfoxide (DMSO-d), deuterated chloroform (CDCl), deuterated methanol (CDOD), or deuterated water (DO). Chemical shifts (δ) are given in ppm, tetramethylsilane (TMS) or the residual solvent peak is used as the internal standard, and coupling constants (J) are given in hertz (Hz). 1 Abbreviations for peak type multiplicities in H NMR spectra were s (singlet), d (doublet), t (triplet), q (quartet), qn (quintet), m (multiplet), and br (broad peak).

[0052] The liquid chromatography-mass spectrometry (LC-MS) system used was a Shimadzu LCMS-2020. The preparative high-performance liquid chromatography (Prep-HPLC) system used was a Bonna-Agela FLEXA FL-H100G. The silica gel plates used for thin-layer chromatography (TLC) were Yantai Huanghai HSGF254 thin-layer chromatography silica gel plates. The plates used for reaction monitoring were 2.5 x 8 cm with a coating thickness of 0.2 ± 0.03 mm, and the plates used for separation and purification were 20 x 20 cm with a coating thickness of 0.4–0.5 mm. The silica gel column chromatography support used was Qingdao Haiyang 100–200 mesh or 200–300 mesh silica gel.

[0053] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, and any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. Example 1: Synthetic Routes for Compounds 1 and 2

[0054] [ka]

[0055] Step 1: Compound 1-B 2-(3-nitrophenyl)ethyl-1-amine [ka] To a tetrahydrofuran (20 mL) solution containing 2-(3-nitrophenyl)acetonitrile (2.0 g, 12.33 mmol), compound 1-A, was added a borane-tetrahydrofuran solution (24.6 mL, 1 M). The reaction mixture was stirred at 70° C. for 3 hours. TLC monitoring confirmed the completion of the reaction. Methanol (30 mL) was added to the reaction mixture, and the mixture was stirred at 70° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give the crude product, compound 1-B, 2-(3-nitrophenyl)ethyl-1-amine (2.05 g), as a yellow oil. The crude product was used directly in the next step without further purification.

[0056] Step 2: Compound 1-C tert-butyl(3-nitrophenylethyl)carbamate [ka] To a dichloromethane (30 mL) solution containing compound 1-B, 2-(3-nitrophenyl)ethyl-1-amine (2.05 g, 12.34 mmol), triethylamine (2.50 g, 24.67 mmol) and di-tert-butyl dicarbonate (2.96 g, 13.57 mmol) were added. The reaction mixture was stirred at 20 °C for 12 hours. TLC monitoring confirmed the completion of the reaction. The reaction mixture was diluted with water and extracted with dichloromethane (50 mL × 2). The combined organic layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluting with 20% ethyl acetate in petroleum ether) to give compound 1-C, tert-butyl (3-nitrophenylethyl)carbamate (2.54 g), as a yellow oil. LC_MS: (ES+): m / z 279.1 [M+H] + .

[0057] Step 3: Compound 1-E tert-butyl allyl(3-nitrophenylethyl)carbamate [ka] Sodium hydride (180.2 mg, 4.51 mmol, mass fraction 60%) was added to a solution of compound 1-C, tert-butyl (3-nitrophenylethyl)carbamate (1.0 g, 3.76 mmol), in DMF (30 mL) at 0 °C. The mixture was stirred for 30 minutes, and then compound 1-D, 3-bromoprop-1-ene (499.7 mg, 4.13 mmol), was added. The reaction mixture was stirred at 20 °C for 12 hours. LCMS monitoring confirmed the completion of the reaction. The reaction mixture was poured into saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (30 mL × 2). The organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (eluted with a petroleum ether solution containing 10% to 20% ethyl acetate) to obtain compound 1-E, tert-butyl allyl (3-nitrophenylethyl)carbamate (828 mg), as a yellow oil. LC_MS: (ES+): m / z 307.1 [M+H] + .

[0058] Step 4: Compound 1-F tert-butyl allyl(3-aminophenethyl)carbamate [ka] To a solution of compound 1-E, tert-butyl allyl (3-nitrophenylethyl)carbamate (828 mg, 2.70 mmol), in ethanol (10 mL) / water (2 mL) was added iron powder (755 mg, 13.51 mmol) and ammonium chloride (723 mg, 13.51 mmol). The reaction mixture was stirred at 80 °C for 12 hours. TLC monitoring confirmed the completion of the reaction. The reaction mixture was filtered, concentrated, diluted with water (20 mL), and extracted with ethyl acetate (20 mL x 2). The organic layers were then combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluting with 20% ethyl acetate in petroleum ether) to give compound 1-F, tert-butyl allyl (3-aminophenethyl)carbamate (710 mg), as a yellow oil.

[0059] Step 5: Compound 1-I N-allyl-2,5-dichloropyrimidin-4-amine [ka] Potassium carbonate (2.26 g, 16.36 mmol) was added to a solution of 2,4,5-trichloropyrimidine (1.0 g, 5.45 mmol) (compound 1-G) and prop-2-en-1-amine hydrochloride (535.6 mg, 5.72 mmol) (compound 1-H) in acetonitrile (20 mL). The reaction mixture was stirred at 80 °C for 3 hours. TLC monitoring confirmed the completion of the reaction. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 2). The organic layers were then combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 10% ethyl acetate in petroleum ether) to give compound 1-I (N-allyl-2,5-dichloropyrimidin-4-amine) as a white solid (1.129 g). LC_MS: (ES+): m / z 204.0 [M+H] + .

[0060] Step 6: Compound 1-J tert-butyl allyl (3-((4-(allylamino)-5-chloropyrimidin-2-yl)amino)phenethyl)carbamate [ka] Cesium carbonate (2.40 g, 7.35 mmol) and BrettPhos-Pd-G3 (111 mg, 122.5 mmol) were added to a 1,4-dioxane (15 mL) solution containing compound 1-I (N-allyl-2,5-dichloropyrimidin-4-amine) (500 mg, 2.45 mmol) and compound 1-F (tert-butyl allyl(3-aminophenethyl)carbamate) (677.2 mg, 2.45 mmol). The reaction mixture was stirred at 100°C under a nitrogen atmosphere for 12 hours. TLC monitoring confirmed the completion of the reaction. The reaction mixture was filtered, diluted with water (30 mL), and extracted with ethyl acetate (30 mL x 2). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluted with a 25% ethyl acetate-petroleum ether solution) to obtain compound 1-J, tert-butyl allyl (3-((4-(allylamino)-5-chloropyrimidin-2-yl)amino)phenethyl)carbamate (830 mg), as a yellow oil. LC_MS: (ES+): m / z 444.2 [M+H] + .

[0061] Step 7: Compound 1 tert-butyl(Z)-1 5 -Chloro-2,6,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-8-ene-6-carboxylate [ka] To a dichloromethane (30 mL) solution containing tert-butyl allyl (3-((4-(allylamino)-5-chloropyrimidin-2-yl)amino)phenethyl)carbamate (500 mg, 1.13 mmol), compound 1-J, was added Grubbs (143.9 mg, 169.5 mmol) and TsOH·HO (224.9 mg, 1.18 mmol). The reaction mixture was stirred at 45 °C for 12 hours. TLC monitoring confirmed the completion of the reaction. Saturated sodium bicarbonate (20 mL) was added to the reaction mixture, and the organic layer was collected, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluted with a 30%-50% ethyl acetate solution in petroleum ether) to give compound 1, a brown solid, tert-butyl (Z)-1 5 -Chloro-2,6,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-8-ene-6-carboxylate (490 mg) was obtained. LC_MS: (ES+): m / z 416.2 [M+H] + .

[0062] Step 8: Compound 2(Z)-1 5 -chloro-2,6,11-triaza-1(2,4)-pyrimidin-3(1,3)-benzenecycloundecane-8-ene [ka] Compound 1, tert-butyl(Z)-1 5 A solution of 10 mg (24.0 μmol) of 2,6,11-triaz-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-8-ene-6-carboxylate in hydrogen chloride / 1,4-dioxane (1 mL) was added and stirred at 25° C. for 2 hours. LCMS monitoring confirmed the completion of the reaction. The reaction solution was concentrated under reduced pressure to give compound 2 (Z)-1 as a brown solid. 55.7 mg of 1,3-chloro-2,6,11-triaza-1(2,4)-pyrimidin-3(1,3)-benzenecycloundecane-8-ene was obtained. LC_MS: (ES+): m / z 316.1 [M+H] + . Example 2: Synthetic Routes for Compounds 3 and 4

[0063] [ka]

[0064] Step 1: Compound 3 tert-butyl-1 5 -Chloro-2,6,11-triaza-1(2,4)-pyrimidine-3(1.3)-benzenecycloundecane-6-carboxylate [ka] Compound 1, tert-butyl(Z)-1 5 Palladium on carbon (50 mg) was added to a methanol solution containing 100 mg (24.04 umol) of 1,2-chloro-2,6,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-8-ene-6-carboxylate. The reaction solution was stirred under a hydrogen balloon at 20°C for 2 hours. LCMS monitoring confirmed the completion of the reaction. The reaction solution was filtered through Celite, and the residue was separated and purified by pre-TLC (eluted with 50% ethyl acetate in petroleum ether) to give compound 3, a brown solid, as tert-butyl-1 5 1,3-Dichloro-2,6,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-6-carboxylate (26.1 mg) was obtained. LC_MS: (ES+): m / z 418.2 [M+H] + .

[0065] Step 2: Compound 4 1 5-chloro-2,6,11-triaza-1(2,4)-pyrimidine-3(1.3)-benzenecycloundecane [ka] Compound 3, tert-butyl-1 5 A hydrogen chloride / 1,4-dioxane solution (1 mL) containing 2,6,11-triaz-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-6-carboxylate (20 mg, 47.9 μmol) was added and the mixture was stirred at 25° C. for 2 hours. LCMS monitoring confirmed the completion of the reaction. The reaction solution was concentrated under reduced pressure to give compound 4, a brown solid. 5 10.5 mg of 1,3-chloro-2,6,11-triaza-1(2,4)-pyrimidine-3(1.3)-benzenecycloundecane was obtained. LC_MS: (ES+): m / z 318.1 [M+H] + . Example 3: Synthetic Route to Compound 5

[0066] [ka]

[0067] Step 1: Compound 5-C 1-(3-nitrophenyl)guanidine [ka] To a solution of compound 5-A, 3-nitroaniline (10 g, 72.4 mmol), in ethanol (50 mL) was added compound 5-B, cyanamide (3.50 g, 83.26 mmol) and 70% nitric acid (6.52 g, 72.40 mmol). The reaction mixture was stirred at 80 °C for 12 hours under a nitrogen atmosphere. LCMS monitoring confirmed the completion of the reaction. The reaction mixture was concentrated. The residue was slurried with ethanol / methyl tert-butyl ether (1:1) (50 mL), filtered, and the filter cake was collected to give compound 5-C, 1-(3-nitrophenyl)guanidine (6.33 g), as a yellow solid. The crude product was used directly in the next step without further purification. LC_MS: (ES+): m / z 181.0 [M+H] + .

[0068] Step 2: Compound 5-E (E)-N'-(5-((E)-3-(dimethylamino)acryloyl)-4-methylthiazol-2-yl)-N,N-dimethylformimide [ka] A solution of 1,1-dimethoxy-N,N-dimethylmethanamine (30 mL) containing compound 5-D, 1-(2-amino-4-methylthiazol-5-yl)ethan-1-one (5.0 g, 32.01 mmol), was stirred at 120 °C for 12 hours. LCMS monitoring confirmed the completion of the reaction. The residue was slurried with ethyl acetate / petroleum ether = 2:1 (50 mL), filtered, and the filter cake was collected to give compound 5-E, (E)-N'-(5-((E)-3-(dimethylamino)acryloyl)-4-methylthiazol-2-yl)-N,N-dimethylformimide (4.47 g), as a brown solid. The crude product obtained was used directly in the next step without further purification. LC_MS: (ES+): m / z 267.1 [M+H] + .

[0069] Step 3: Compound 5-F (E)-N'-(5-((Z)-3-(dimethylamino)-2-fluoroacryloyl)-4-methylthiazol-2-yl)-N,N-dimethylformimide [ka] At 0°C, 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (8.92 g, 25.173 mmol) was added to a methanol solution (50 mL) containing compound 5-E, (E)-N'-(5-((E)-3-(dimethylamino)acryloyl)-4-methylthiazol-2-yl)-N,N-dimethylformimide (4.47 g, 16.782 mmol), and the reaction solution was stirred at 0°C for 2 hours. Completion of the reaction was confirmed by LCMS monitoring. The reaction solution was filtered and concentrated, and the residue was separated and purified by silica gel column chromatography (eluted with a dichloromethane solution containing 6.6% methanol) to obtain compound 5-F, (E)-N'-(5-((Z)-3-(dimethylamino)-2-fluoroacryloyl)-4-methylthiazol-2-yl)-N,N-dimethylformimide (3.9 g), as a yellow oil. LC_MS: (ES+): m / z 285.1 [M+H] + .

[0070] Step 4: Compound 5-G 5-(5-fluoro-2-((3-nitrophenyl)amino)pyrimidin-4-yl)-4-methylthiazol-2-amine [ka] Sodium hydroxide (549 mg, 13.72 mmol) was added to a solution of (E)-N'-(5-((Z)-3-(dimethylamino)-2-fluoroacryloyl)-4-methylthiazol-2-yl)-N,N-dimethylformimide (3.9 g, 13.72 mmol) (compound 5-F) and 1-(3-nitrophenyl)guanidine (4.94 g, 27.43 mmol) (compound 5-C) in ethylene glycol monomethyl ether (50 mL). The reaction mixture was stirred at 125°C for 12 hours. LCMS monitoring confirmed the completion of the reaction. The reaction mixture was concentrated, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 2). The organic layers were then combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (eluted with a 50% to 66% ethyl acetate solution in petroleum ether) to obtain compound 5-G, 5-(5-fluoro-2-((3-nitrophenyl)amino)pyrimidin-4-yl)-4-methylthiazol-2-amine (1.12 g), as a yellow solid. LC_MS: (ES+): m / z 347.0 [M+H] + .

[0071] Step 5: Compound 5-H (5-(5-fluoro-2-((3-nitrophenyl)amino)pyrimidin-4-yl)-4-methylthiazol-2-yl)carbamate tert-butyl ester [ka] To a tetrahydrofuran (20 mL) solution containing compound 5-G, 5-(5-fluoro-2-((3-nitrophenyl)amino)pyrimidin-4-yl)-4-methylthiazol-2-amine (1.12 g, 3.23 mmol) and di-tert-butyl dicarbonate (776.4 mg, 3.56 mmol), triethylamine (981.7 mg, 9.7 mmol) and 4-dimethylaminopyridine (39.5 mg, 323.38 umol) were added, and the reaction solution was stirred at 20 ° C. for 12 hours. Completion of the reaction was confirmed by LCMS monitoring. The reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography (eluted with a 50% ethyl acetate-petroleum ether solution) to obtain compound 5-H, tert-butyl (5-(5-fluoro-2-((3-nitrophenyl)amino)pyrimidin-4-yl)-4-methylthiazol-2-yl)carbamate (1.275 g), as a yellow solid. LC_MS: (ES+): m / z 447.1 [M+H] + .

[0072] Step 6: Compound 5-I (tert-butyl 5-(2-((3-((tert-butoxycarbonyl)amino)phenyl)amino)-5-fluoropyrimidin-4-yl)-4-methylthiazol-2-yl)carbamate [ka] Di-tert-butyl dicarbonate (623.3 mg, 2.86 mmol) and palladium / carbon (150 mg) were added to a methanol (15 mL) / tetrahydrofuran (15 mL) solution containing compound 5-H, tert-butyl (5-(5-fluoro-2-((3-nitrophenyl)amino)pyrimidin-4-yl)-4-methylthiazol-2-yl)carbamate (1.275 g, 2.86 mmol). The reaction solution was stirred under a hydrogen balloon atmosphere at 20° C. for 120 hours. Completion of the reaction was confirmed by LCMS monitoring. The reaction solution was filtered through Celite, the filtrate was concentrated, and the residue was separated and purified by silica gel column chromatography (eluted with a petroleum ether solution containing 30% to 50% ethyl acetate) to obtain compound 5-I, tert-butyl (5-(2-((3-((tert-butoxycarbonyl)amino)phenyl)amino)-5-fluoropyrimidin-4-yl)-4-methylthiazol-2-yl)carbamate (500 mg), as a yellow solid. LC_MS: (ES+): m / z 517.2 [M+H] +.

[0073] Step 7: Compound 5-K Di-tert-butyl 2 5 -Fluoro-14-methyl-8-oxa-3,5,11-triaza-1(5,2)-thiazole-2(4,2)-pyrimidine-4(1,3)-benzenecycloundecane-5,11-dicarboxylic acid salt [ka] To a solution of compound 5-I, tert-butyl (5-(2-((3-((tert-butoxycarbonyl)amino)phenyl)amino)-5-fluoropyrimidin-4-yl)-4-methylthiazol-2-yl)carbamate (20 mg, 38.72 μmol), in acetonitrile (5 mL) was added sodium tert-butoxide (7.4 mg, 77.43 μmol) and compound 5-J, 1-bromo-2-(2-bromoethoxy)ethane (9.0 mg, 38.72 μmol). The reaction mixture was stirred at 60° C. for 12 hours. LCMS monitoring confirmed the completion of the reaction. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL×2). The organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by pre-TLC (eluted with 33% ethyl acetate in petroleum ether) to give compound 5-K, a yellow solid, as di-tert-butyl 2 5 3 mg of 1,4-fluoro-14-methyl-8-oxa-3,5,11-triaza-1(5,2)-thiazole-2(4,2)-pyrimidine-4(1,3)-benzenecycloundecane-5,11-dicarboxylic acid salt was obtained. LC_MS: (ES+): m / z 587.2 [M+H] + .

[0074] Step 8: Compound 5 2 5 -Fluoro-14-methyl-8-oxa-3,5,11-triaza-1(5,2)-thiazole-2(4,2)-pyrimidine-4(1,3)-benzenecycloundecane [ka] Compound 5-K is di-tert-butyl 2 5A solution of 1,4-dioxane (2 mL) containing 1,4-fluoro-14-methyl-8-oxa-3,5,11-triaza-1(5,2)-thiazole-2(4,2)-pyrimidine-4(1,3)-benzenecycloundecane-5,11-dicarboxylate (3 mg, 5.11 μmol) was stirred at 25°C for 1 hour. LCMS monitoring confirmed the completion of the reaction. The reaction solution was concentrated under reduced pressure and the pH was adjusted to 7 with aqueous ammonia. The residue was separated and purified by pre-TLC (eluting with 10% methanol in dichloromethane) to give compound 5, a yellow solid. 5 1,3-Difluoro-14-methyl-8-oxa-3,5,11-triaza-1(5,2)-thiazole-2(4,2)-pyrimidine-4(1,3)-benzenecycloundecane (0.3 mg). LC_MS: (ES+): m / z 387.1 [M+H] + . Example 4: Synthetic Route to Compound 6

[0075] [ka]

[0076] Step 1: Compound 6-A Nitrogen 1 -(4-(2-amino-4-methylthiazol-5-yl)-5-fluoropyrimidin-2-yl)benzene-1,3-diamine dihydrochloride [ka] To a solution of compound 5-I (20 mg, 0.0387 mmol) in methanol (1 mL) was added a solution of hydrochloric acid / dioxane (1 mL), and the reaction solution was stirred at 45° C. for 12 hours. TLC monitoring confirmed the completion of the reaction. The reaction solution was concentrated to obtain a yellow solid, compound 6-A, with nitrogen. 1 -(4-(2-amino-4-methylthiazol-5-yl)-5-fluoropyrimidin-2-yl)benzene-1,3-diamine dihydrochloride (19 mg) was obtained. LC_MS: (ES+): m / z 317.1 [M+Na] +

[0077] Step 2: Compound 6-C Nitrogen 1 -allyl-nitrogen 3 -(4-(2-(allylamino)-4-methylthiazol-5-yl)-5-fluoropyrimidin-2-yl)benzene-1,3-diamine [ka] At 0°C, compound 6-A is nitrogen 1 To a solution of -(4-(2-amino-4-methylthiazol-5-yl)-5-fluoropyrimidin-2-yl)benzene-1,3-diamine dihydrochloride (19 mg, 0.0488 mmol) in N,N-dimethylformamide (5 ml), sodium hydride (3.9 mg, 0.0976 mmol) was added, and 3-bromoprop-1-ene (71.8 mg, 0.0976 mmol), compound 6-B, was slowly added dropwise. The reaction solution was stirred at 0°C for 5 hours. Completion of the reaction was confirmed by TLC monitoring. The reaction solution was poured into saturated ammonium chloride solution and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by pre-TLC (eluted with 4.76% methanol in dichloromethane) to give compound 6-C, a yellow solid, with nitrogen. 1 -allyl-nitrogen 3-(4-(2-(allylamino)-4-methylthiazol-5-yl)-5-fluoropyrimidin-2-yl)benzene-1,3-diamine (8 mg). LC_MS: (ES+): m / z 397.1 [M+Na] +

[0078] Step 3: Compound 6(Z)-2 5 -Fluoro-1 4 -Methyl-3,5,10-triaza-1(5,2)-thiazoline-2(4,2)-pyrimidin-4(1,3)-benzenecyclodecan-7-ene [ka] Compound 6-C is nitrogen 1 To a dichloromethane (5 ml) solution containing 3-(4-(2-(allylamino)-4-methylthiazol-5-yl)-5-fluoropyrimidin-2-yl)benzene-1,3-diamine (8 mg, 0.0201 mmol), p-toluenesulfonic acid monohydrate (4.01 mg, 0.0211 mmol) and Grubbs' diamine (5.13 mg, 0.006 mmol) were added. The reaction solution was stirred under a nitrogen atmosphere at 42°C for 12 hours. After completion of the reaction was confirmed by TLC monitoring, the reaction solution was diluted with water and extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by pre-TLC (eluted with 4.76% methanol in dichloromethane) to give compound 6, (Z)-2, as a brown solid. 5 -Fluoro-1 4 1.3 mg of 1,3-methyl-3,5,10-triaza-1(5,2)-thiazoline-2(4,2)-pyrimidin-4(1,3)-benzenecyclodecan-7-ene was obtained. LC_MS: (ES+): m / z 369.1 [M+Na] + Example 5: Synthetic Routes for Compounds 7, 8, and 9

[0079] [ka]

[0080] Step 1: Compound 9-C tert-butyl but-3-en-1-yl(3-nitrobenzyl)carbamate [ka] Sodium hydride (60% in kerosene, 233.6 mg, 5.8 mmol) was added to a solution of compound 9-B (tert-butyl but-3-en-1-ylcarbamate, 666 mg, 3.9 mmol) in N,N-dimethylformamide (10 mL) at 0°C. The reaction solution was heated to room temperature and stirred for 30 minutes. After cooling to 0°C, compound 9-A (1-bromomethyl)-3-nitrobenzene (925 mg, 4.3 mmol) was added dropwise. The reaction solution was stirred at room temperature for 12 hours under a nitrogen atmosphere. TLC monitoring confirmed the completion of the reaction. The reaction solution was partitioned between ethyl acetate (30 mL) and water (50 mL). The organic layer was collected, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluted with 20% ethyl acetate in n-hexane) to obtain compound 9-C, but-3-en-1-yl(3-nitrobenzyl) tert-butylcarbamate (900 mg), as a brown oil. 1 H NMR (400 MHz, CDCl3): δ 1.44-1.51 (m, 9H), 2.23-2.28 (m, 2H), 3.26-3.34 (m, 2H), 5.29 (m, 2H), 5.02-5.07 (m, 2H), 5.71-5.79 (m, 1H), 7.48-7.59 (m, 2H), 8.10-8.13 (m, 2H).

[0081] Step 2: Compound 9-D tert-butyl 3-aminobenzyl(but-3-en-1-yl)carbamate [ka] A solution of compound 9-C, tert-butyl but-3-en-1-yl(3-nitrobenzyl)carbamate (900 mg, 2.94 mmol), iron powder (1.6 g, 29.4 mmol), and ammonium chloride (786.5 mg, 14.7 mmol) in ethanol (40 mL) / water (4 mL) was refluxed for 3 hours. TLC monitoring confirmed the completion of the reaction. The iron powder was removed by filtration, and the filter cake was washed with ethanol (2 mL × 2). The combined filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 20% ethyl acetate in n-hexane) to give compound 9-D, tert-butyl 3-aminobenzyl(but-3-en-1-yl)carbamate (460 mg), as a yellow oil. LC_MS: (ES+): m / z 221.2 [M+H] + 1 H NMR (400 MHz, CDCl3): δ 1.45-1.49 (m, 9H), 2.22-2.28 (m, 2H), 3.27-3.18 (m, 2H), 3.66 (s, 2H), 4.35 (s, 2H), 4.98-5.05 (m, 2H), 5.73-5.77 (m, 1H), 6.51-6.62 (m, 3H), 7.09 (t, J = 7.8 Hz, 1H).

[0082] Step 3: Compound 9-E tert-butyl 3-((4-(allylamino)-5-chloropyrimidin-2-yl)amino)benzyl(but-3-en-1-yl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 2 in Example 1. LC_MS: (ES+): m / z 444.6 [M+H] + . 1H NMR (400 MHz, CDCl3): δ 1.45-1.50 (m, 9H), 2.20-2.26 (m, 2H), 3.20-3.29 (m, 2H), 4.13-4.17 (m, 2H), 4.43 (s, 2H), 4.98-5.05 (m, 2H), 5.19-5.36 (m, 3H), 5.74 (s, 1H), 5.94-6.04 (m, 1H), 6.88-6.94 (m, 2H), 7.23-7.27 (m, 1H), 7.40 (s, 1H), 7.53 (s, 1H), 7.91 (s, 1H).

[0083] Step 4: Compound 9-F tert-butyl(Z)-1 5 -Chloro-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-8-ene-5-carboxylate [ka] For the synthesis of this step, see the synthesis process of Step 7 of Compound 2 in Example 1. 1 H NMR (400 MHz, DMSO-d6): δ 1.23-1.41 (m, 9H), 2.16-2.32 (m, 2H), 3.02-3.22 (m, 2H), 3.88-4.00 (m, 1H), 4.18-4.24 (m, 1H), 4.34-4.40 (m, 2H), 5.38-5.43 (m, 1H), 5.58-5.76 (m, 1H), 6.74-6.88 (m, 1H), 6.99-7.04 (m, 1H), 7.14-7.22 (m, 1H), 7.46-7.58 (m, 1H), 7.93 (s, 1H), 8.19-8.33 (m, 1H), 9.18-9.29 (m, 1H).

[0084] Step 5: Compound 7 tert-Butyl 1 5 -Chloro-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-5-carboxylate [ka] For the synthesis of this step, see the synthesis process of Step 1 of Compound 4 in Example 2. LC_MS: (ES+): m / z 418.2 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 0.77-1.10 (m, 9H), 1.61-1.72 (m, 6H), 3.12-3.26 (m, 2H), 3.52-3.60 (m, 2H), 4.39-4.45 (m, 2H), 5.03-5.54 (m, 1H), 6.78-6.81 (m, 1H), 7.05-7.13 (m, 2H), 7.24-7.28 (m, 1H), 7.87-7.89 (m, 1H), 7.28 (s, 1H).

[0085] Step 6: Compound 8 1 5 -chloro-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane [ka] Compound 7 is tert-butyl 1 5 A solution of 1-chloro-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-5-carboxylate (50 mg, 0.12 mmol) and trifluoroacetic acid (1 mL) in dichloromethane (1 mL) was stirred under a nitrogen atmosphere at 0°C for 3 hours. TLC monitoring confirmed the completion of the reaction. The reaction solution was adjusted to pH 7-8 with saturated sodium carbonate and extracted with dichloromethane (10 mL × 2). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by pre-TLC (eluted with 10% methanol in dichloromethane) to give compound 8, a white solid. 5-Chloro-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane (35 mg) was obtained. LC_MS: (ES+): m / z 318.1 [M+H] + 1 H NMR (400 MHz, DMSO-d6): δ 1.50-1.57 (m, 4H), 1.78 (s, 2H), 2.70-2.74 (m, 2H), 3.39-3.48 (m, 3H), 4.01 (s, 2H), 6.99 (d, J = 7.6 Hz, 1H), 7.12-7.14 (m, 1H), 7.27 (t, J = 7.8 Hz, 1H), 7.38 (t, J = 5.8 Hz, 1H), 7.92 (s, 1H), 8.37 (s, 1H), 9.33 (s, 1H).

[0086] Step 7: Compound 9-H tert-butyl (2-(1 5 -chloro-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecan-5-yl)-2-oxoethyl)carbamate [ka] At 0 °C, compound 8 is 5N,N,N,N-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (91.3 mg, 0.24 mmol) was added to a solution of 2-chloro-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane (50 mg, 0.1 mmol), compound 9-G (2-((tert-butoxycarbonyl)amino)acetic acid) (21 mg, 0.12 mmol), and N,N-diisopropylethylamine (61.9 mg, 0.48 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was stirred at room temperature for 2 hours. TLC monitoring confirmed the completion of the reaction. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by pre-TLC (eluted with 3% methanol in dichloromethane) to give an off-white solid compound 9-H, tert-butyl (2-(1 5 -Chloro-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecan-5-yl)-2-oxoethyl)carbamate (30 mg) was obtained.

[0087] Step 8: Compound 9 2-amino-1-(1 5 -chloro-2,5,11-triaza-1(2,4)-pyrimidin-3(1,3)-benzenecycloundecan-5-yl)ethan-1-one [ka] A solution of compound 9-H, tert-butyl (2-(15-chloro-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecan-5-yl)-2-oxoethyl)carbamate (30 mg, 0.06 mmol) and trifluoroacetic acid (1 mL) in dichloromethane (1 mL) was stirred at 0°C for 2 hours. Completion of the reaction was confirmed by TLC monitoring. The reaction solution was adjusted to pH 7-8 with saturated sodium carbonate and extracted with dichloromethane (10 mL × 2). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by pre-TLC (eluted with 10% methanol in dichloromethane) and HPLC to give compound 9, 2-amino-1-(1 5 -chloro-2,5,11-triaza-1(2,4)-pyrimidin-3(1,3)-benzenecycloundecan-5-yl)ethan-1-one (22.1 mg). LC_MS: (ES+): m / z 375.1 [M+H] + 1 H NMR (400 MHz, DMSO-d6): δ 0.74-0.85 (m, 4H), 1.54-1.73 (m, 4H), 3.09-3.17 (m, 2H), 3.34-3.48 (m, 4H), 4.36-4.52 (m, 2H), 6.83-6.94 (m, 1H), 7.03-7.08 (m, 1H), 7.16-7.24 (m, 1H), 7.34-7.40 (m, 1H), 7.91 (s, 1H), 8.35-8.48 (m, 1H), 9.32-9.40 (m, 1H). Example 6: Synthetic Route to Compound 10

[0088] [ka]

[0089] compound 10 1 5-Chloro-5-methyl-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane [ka] Compound 8 is 1 5 A drop of acetic acid solution was added to a methanol (1 ml) solution containing 1-chloro-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane (8 mg, 0.0252 mmol) and formaldehyde (3.78 mg, 0.126 mmol). The reaction mixture was stirred at room temperature for 30 minutes, and sodium cyanoborohydride (2.51 mg, 0.04 mmol) was added. The reaction mixture was then stirred at room temperature for 14 hours. TLC monitoring confirmed the completion of the reaction. The reaction mixture was concentrated. The residue was separated and purified by preparative TLC (eluted with 9.09% methanol in dichloromethane) to give compound 10 as a brown solid. 5 1,3-Dichloro-5-methyl-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane (5.1 mg). Example 7: Synthetic Route to Compound 11

[0090] [ka]

[0091] Step 1: Compound 11-B tert-butyl (R)-2-(1 5 -Chloro-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-5-carbonyl)pyrrolidine-1-carboxylate [ka] For the synthesis of this step, see the synthesis process of Step 7 of Compound 9 in Example 5. LC_MS: (ES+): m / z 515.3 [M+H]+ .

[0092] Step 2: Compound 11(R)-1 5 -Chloro-5-prolyl-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane [ka] For the synthesis of this step, see the synthesis process of Step 8 of Compound 9 in Example 5. LC_MS: (ES+): m / z 415.4 [M+H] + 1 H NMR (400 MHz, DMSO-d6): δ 1.41-1.54 (m, 4H), 1.66-1.82 (m, 4H), 1.95-2.15 (m, 2H), 2.83-3.02 (m, 2H), 3.10-3.19 (m, 2H), 3.38-3.56 (m, 4H), 4.34-4.43 (m, 1H), 4.61-4.72 (m, 1H), 6.83-6.96 (m, 1H), 7.04-7.11 (m, 1H), 7.18-7.23 (m, 1H), 7.36-7.39 (m, 1H), 7.90-7.96 (m, 1H), 8.39-8.44 (m, 1H), 9.34 (s, 1H). Example 8: Synthetic Route to Compound 12

[0093] [ka]

[0094] Step 1: Compound 12-C N-allyl-3-nitroaniline [ka] A solution of 3-nitroaniline (1 g, 7.2 mmol), compound 12-A, 3-bromopropylene (1.3 g, 10.8 mmol), and sodium carbonate (768 mg, 7.2 mmol) in ethanol (4 mL) and water (1 mL) was refluxed for 4 hours. TLC monitoring confirmed the completion of the reaction. The reaction solution was cooled to room temperature and partitioned between water (20 mL) and ethyl acetate (20 mL). The organic layer was collected, and the aqueous layer was extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluting with 1% ethyl acetate in n-hexane) to give compound 12-C, N-allyl-3-nitroaniline (660 mg), as a yellow solid. LC_MS: (ES+): m / z 179.00 [M+H] + 1 H NMR (400 MHz, CDCl3): δ 3.82-3.86 (m, 2H), 4.16 (s, 1H), 5.20-5.33 (m, 2H), 5.89-5.97 (m, 1H), 6.86-6.89 (m, 1H), 7.27 (t, J = 8.0 Hz, 1H), 7.40 (t, J = 2.0 Hz, 1H), 7.51-7.54 (m, 1H).

[0095] Step 2: Compound 12-D tert-butyl allyl(3-nitrophenyl)carbamate [ka] A solution of N-allyl-3-nitroaniline (12-C), triethylamine (477 mg, 4.7 mmol), 4-dimethylaminopyridine (40 mg, 0.3 mmol), and di-tert-butyl dicarbonate (1.1 g, 5.1 mmol) in anhydrous tetrahydrofuran (10 mL) was stirred at 60 °C for 8 h. TLC monitoring confirmed the completion of the reaction. The reaction was quenched by adding water (20 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluting with 3.3% ethyl acetate in n-hexane) to give compound 12-D, tert-butyl allyl(3-nitrophenyl)carbamate (800 mg), as a yellow solid. 1 H NMR (400 MHz, CDCl3): δ 1.48 (s, 9H), 4.29-4.30 (m, 2H), 5.16-5.22 (m, 2H), 5.87-5.97 (m, 2H), 7.47 (t, J = 8.0 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 8.01-8.03 (m, 1H), 8.16 (t, J = 2.0 Hz, 1H).

[0096] Step 3: Compound 12-E tert-butyl allyl(3-aminophenyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 4 of Compound 2 in Example 1. LC_MS: (ES+): m / z 193.30 [M+H-56] + 1H NMR (400 MHz, CDCl3): δ 1.45 (s, 9H), 4.16-4.18 (m, 2H), 5.11-5.18 (m, 2H), 5.87-5.94 (m, 1H), 6.49-6.52 (m, 1H), 6.58-6.62 (m, 2H), 7.08 (t, J = 8.0 Hz, 1H).

[0097] Step 4: Compound 12-G tert-butyl (3-bromo-4-methylphenyl)carbamate [ka] A solution of compound 12-F (3-bromo-4-methylaniline, 5 g, 27 mmol), triethylamine (3.03 g, 30 mmol), 4-dimethylaminopyridine (329 mg, 2.7 mmol), and di-tert-butyl dicarbonate (5.9 g, 27 mmol) in dichloromethane (20 mL) was stirred overnight at room temperature. TLC monitoring confirmed the completion of the reaction. The reaction solution was partitioned between dichloromethane (40 mL) and water (40 mL). The organic layer was collected, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluting with 1.4% ethyl acetate in n-hexane) to afford compound 12-G (tert-butyl (3-bromo-4-methylphenyl)carbamate, 5.3 g) as a white solid. LC_MS: (ES+): m / z 229.85 [M+H-56] +

[0098] Step 5: Compound 12-H tert-butylallyl(3-bromo-4-methylphenyl)carbamate [ka] Sodium hydride (60% mass fraction in kerosene, 280 mg, 7.0 mmol) was added to a tetrahydrofuran (5 mL) solution containing tert-butyl (3-bromo-4-methylphenyl)carbamate (1 g, 3.5 mmol), compound 12-G, at 0°C. The reaction solution was heated to room temperature and stirred for 30 minutes. After cooling to 0°C, 3-bromopropene (635 mg, 5.3 mmol), compound 12-B, was added dropwise. The reaction solution was stirred at room temperature under a nitrogen atmosphere for 14 hours. TLC monitoring confirmed the completion of the reaction. The reaction solution was partitioned between ethyl acetate (30 mL) and ice water (20 mL). The organic layer was collected, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluted with 1% ethyl acetate in n-hexane) to obtain tert-butyl allyl (3-bromo-4-methylphenyl)carbamate (874 mg), which was compound 12-H, as a pale yellow oil. LC_MS: (ES+): m / z 269.85 [M+H-56] + 1 H NMR (400 MHz, CDCl3): δ 1.44 (s, 9H), 2.36 (s, 3H), 4.17-1.49 (m, 2H), 5.12-5.16 (m, 2H), 5.83-5.92 (m, 1H), 7.06-7.08 (m, 1H), 7.14-7.16 (m, 1H), 7.41-7.42 (m, 1H).

[0099] Step 6: Compound 12-I tert-butyl allyl (4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate [ka] PdCl(dppf) (174 mg, 0.24 mmol) was added to a 1,4-dioxane (5 mL) solution containing compound 12-H, tert-butyl allyl(3-bromo-4-methylphenyl)carbamate (774 mg, 2.38 mmol), bis(pinacolato)diboron (907 mg, 3.57 mmol), and potassium acetate (467 mg, 4.76 mmol) at room temperature under a nitrogen atmosphere. The reaction solution was purged with nitrogen gas three times and stirred at 90 °C for 5 hours. TLC monitoring confirmed the completion of the reaction. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (eluted with 2.5% ethyl acetate in n-hexane) to obtain compound 12-I, tert-butyl allyl (4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (745 mg), as a pale yellow oil. LC_MS: (ES+): m / z 318.00 [M+H-56] + 1 H NMR (400 MHz, CDCl3): δ 1.33 (s, 12H), 1.43 (s, 9H), 2.50 (s, 3H), 4.20 (d, J = 3.2 Hz, 2H), 5.09-5.16 (m, 2H), 5.85-5.94 (m, 1H), 7.08-7.16 (m, 2H), 7.57 (d, J = 2.4 Hz, 1H).

[0100] Step 7: Compound 12-K tert-butyl allyl (3-(2,5-dichloropyrimidin-4-yl)-4-methylphenyl)carbamate [ka] Tetrakis(triphenylphosphine)palladium (231 mg, 0.2 mmol) was added to an acetonitrile suspension containing tert-butyl allyl (4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (745 mg, 2.0 mmol), 2,4,5-trichloropyrimidine (727 mg, 4.0 mmol), and sodium carbonate (2 N, 2 mL, 4.0 mmol) in a sealed tube at room temperature under a nitrogen atmosphere. The reaction mixture was purged with nitrogen gas three times and stirred at 70 °C for 2 days. TLC monitoring confirmed the completion of the reaction. The reaction mixture was partitioned between ethyl acetate (20 mL) and water (20 mL). The organic layer was collected, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (eluted with 2% ethyl acetate in n-hexane) to obtain a pale yellow solid, compound 12-K, tert-butyl allyl (3-(2,5-dichloropyrimidin-4-yl)-4-methylphenyl)carbamate (347 mg). LC_MS: (ES+): m / z 337.9 [M+H-56] + 1 H NMR (400 MHz, CDCl3): δ 1.44 (s, 9H), 2.19 (s, 3H), 4.22 (d, J = 6.8 Hz, 2H), 5.12-5.17 (m, 2H), 5.87-5.94 (m, 1H), 7.15 (s, 1H), 7.25 (s, 2H), 8.68 (s, 1H).

[0101] Step 8: Compound 12-M tert-butyl allyl (3-(2-((3-(allyl(tert-butoxycarbonyl)amino)phenyl)amino)-5-chloropyrimidin-4-yl)-4-methylphenyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 2 in Example 1. LC_MS: (ES+): m / z 606.3 [M+H] + 1 H NMR (400 MHz, CDCl3): δ 1.43 (m, 18H), 2.22 (s, 3H), 4.20-4.24 (m, 4H), 5.06-5.18 (m, 4H), 5.83-5.96 (m, 2H), 6.93 (d, J = 8.0 Hz, 1H), 7.14 (s, 1H), 7.22-7.24 (m, 3H), 7.37-7.40 (m, 1H), 7.59 (t, J = 2.0 Hz, 1H), 8.44 (s, 1H).

[0102] Step 9: Compound 12-N Di-tert-butyl(Z)-2 5 -chloro-1 6 -Methyl-3,5,10-triaza-2(4,2)-pyrimidine-1,4(1,3)-dibenzenecyclodecane-7-ene-5,10-dicarboxylate [ka] For the synthesis of this step, see the synthesis process of Step 7 of Compound 2 in Example 1. LC_MS: (ES+): m / z 578.3 [M+H] + 1H NMR (400 MHz, DMSO-d6): δ 1.30 (s, 9H), 1.39 (s, 9H), 2.22 (s, 3H), 3.79-3.84 (m, 1H), 4.04-4.25 (m, 2H), 4.41-4.45 (m, 1H), 5.59-5.60 (m, 2H), 6.81 (d, J = 7.6 Hz, 1H), 7.03-7.06 (m, 1H), 7.21 (t, J = 8.4 Hz, 2H), 7.28 (d, J = 8.4 Hz, 1H), 7.44-7.46 (m, 1H), 8.21-8.22 (m, 1H), 8.63 (s, 1H), 10.08 (s, 1H).

[0103] Step 10: Compound 12 (Z)-2 5 -chloro-1 6 -methyl-3,5,10-triaza-2(4,2)-pyrimidine-1,4(1,3)-dibenzenecyclodecan-7-ene [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 8 in Example 5. LC_MS: (ES+): m / z 378.3 [M+H] + 1 H NMR (400 MHz, CDCl3): δ 2.25 (s, 3H), 3.68-3.91 (m, 4H), 4.10 (s, 2H), 5.58 (d, J = 2.4 Hz, 2H), 6.23-6.32 (m, 2H), 6.65-6.72 (m, 2), 7.00-7.05 (m, 2H), 7.17 (s, 1H), 7.86 (t, J = 2.0 Hz, 1H), 8.34 (s, 1H). Example 9: Synthetic Routes for Compounds 13, 14, 15, and 16

[0104] [ka]

[0105] Step 1: Compound 16-C Ethyl 4-(allylamino)-2-chloropyrimidine-5-carboxylate [ka] Allylamine hydrochloride (790 mg, 4.3 mmol), compound 16-B, was added to a solution of ethyl 2,4-dichloropyrimidine-5-carboxylate (1 g, 4.53 mmol), compound 16-A, and potassium carbonate (1.3 g, 9.42 mmol) in acetonitrile (8 mL) at -10 °C. The reaction mixture was stirred at room temperature for 5 hours. TLC monitoring confirmed the completion of the reaction. The reaction mixture was partitioned between ethyl acetate (20 mL) and water (20 mL). The organic layer was collected, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluting with 5% ethyl acetate in n-hexane) to give compound 16-C, ethyl 4-(allylamino)-2-chloropyrimidine-5-carboxylate (860 mg), as a white solid. LC_MS: (ES+): m / z 241.9 [M+H] + 1 H NMR (400 MHz, CDCl3): δ 1.38-1.41 (t, J = 7.2 Hz, 3H), 4.18-4.20 (t, J = 5.6 Hz, 2H), 4.34-4.39 (q, J = 6.8 Hz, 2H), 5.20-5.29 (m, 2H), 5.90-5.99 (m, 1H), 8.48 (brs, 1H), 8.68 (s, 1H).

[0106] Step 2: Compound 16-D 4-(allylamino)-2-((3-((but-3-en-1-yl(tert-butoxycarbonyl)amino)methyl)phenyl)amino)pyrimidine-5-carboxylate [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 2 in Example 1. LC_MS: (ES+): m / z 482.7 [M+H] +

[0107] Step 3: Compound 16-E 5-(tert-butyl) 1 5 -Ethyl (Z)-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-8-ene-15,5-dicarboxylate [ka] For the synthesis of this step, see the synthesis process of Step 7 of Compound 2 in Example 1. LC_MS: (ES+): m / z 454.4 [M+H] +

[0108] Step 4: Compound 13 5-(tert-butyl) 1 5 -Ethyl-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-15,5-dicarboxylate [ka] For the synthesis of this step, see the synthesis process of Step 1 of Compound 4 in Example 2. LC_MS: (ES+): m / z 456.4 [M+H] + 1H NMR (400 MHz, CDCl3): δ 1.35-1.39 (t, J = 7.2 Hz, 3H), 1.47-1.54 (m, 9H), 1.64-1.70 (m, 4H), 1.80-2.09 (m, 2H), 3.12-3.26 (m, 2H), 3.55-3.58 (m, 2H), 4.28-4.33 (q, J = 6.8 Hz, 2H), 4.40-4.46 (d, J = 25.2 Hz, 2H), 6.84-6.86 (d, J = 8.4 Hz, 1H), 7.10-7.31 (m, 1H), 7.29-7.31 (m, 1H), 7.52-7.55 (m, 1H),8.37-8.39 (d, J = 7.6 Hz, 1H), 8.55-8.56 (m, 1H), 8.62 (brs, 1H).

[0109] Step 5: Compound 16-F 5-(tert-butyloxycarbonyl)-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-1 5 -carboxylic acid [ka] Compound 13, 5-(tert-butyl) 1 5 A solution of 5-tert-butyloxycarbonyl-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-15,5-dicarboxylate (220 mg, 0.48 mmol) and lithium hydroxide monohydrate (41 mg, 0.98 mmol) in tetrahydrofuran (6 mL), water (1.5 mL), and methanol (1.5 mL) was stirred at 70 °C for 13 hours. TLC monitoring confirmed the completion of the reaction. The reaction solution was cooled to room temperature, and the pH was adjusted to 6 by adding citric acid. The mixture was then extracted with ethyl acetate (20 mL × 3). The combined organic layer was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, compound 16-F, 5-(tert-butyloxycarbonyl)-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-15,5-dicarboxylate.5 The crude product obtained was used directly in the next step without further purification. LC_MS: (ES+): m / z 428.4 [M+H] + .

[0110] Step 6: Compound 14 tert-Butyl 1 5 -Carbamoyl-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-5-carboxylate [ka] To a solution of compound 16-F (5-(tert-butoxycarbonyl)-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-15-carboxylic acid) (200 mg, 0.47 mmol) in N,N-dimethylformamide (10 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (102 mg, 0.53 mmol) and N-hydroxybenzotriazole (72 mg, 0.53 mmol) were added and stirred for 45 minutes at 0 °C. Next, aqueous ammonia (1 mL) was added to the reaction solution at 0 °C. The reaction solution was stirred at 40 °C for 2 days. TLC monitoring confirmed the completion of the reaction. The reaction solution was cooled to room temperature and partitioned between saturated aqueous sodium carbonate (20 mL) and ethyl acetate (10 mL). The organic layer was collected, and the aqueous layer was extracted with ethyl acetate (10 mL x 2). The organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by pre-TLC (eluted with 5% methanol in dichloromethane) to give compound 14, a white solid, as tert-butyl 1 5 -carbamoyl-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-5-carboxylate (65 mg) was obtained. LC_MS: (ES+): m / z 427.4 [M+H] + 1H NMR (400 MHz, CDCl3): δ 1.47-1.54 (d, J = 28.8 Hz, 9H), 1.63-1.72 (m, 4H), 1.76 (brs, 2H), 3.11-3.25 (m, 2H), 3.49-3.57 (m, 2H), 4.40-4.46 (d, J = 24.8 Hz, 2H), 5.62 (brs, 2H), 6.82-6.84 (d, J = 8.0 Hz, 1H),7.10-7.18 (m, 1H), 7.28-7.30 (m, 1H), 7.45 (brs, 1H), 8.26 (s, 1H),8.36-8.39 (d, J = 11.6 Hz, 1H), 9.11-9.13 (m, 1H).

[0111] Step 7: Compound 16-G tert-Butyl 1 5 -Cyano-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-5-carboxylate [ka] At −50°C under nitrogen, compound 14, tert-butyl 1 5 Trifluoroacetic anhydride (201 mg, 0.96 mmol) was added to a solution of 15 mL of anhydrous tetrahydrofuran containing 1-carbamoyl-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-5-carboxylate (37 mg, 0.087 mmol) and triethylamine (111 mg, 1.09 mmol). The reaction mixture was stirred at -50 °C for 20 minutes, then heated to 0 °C and stirred for 2 hours. TLC monitoring confirmed the completion of the reaction. The reaction mixture was partitioned between ethyl acetate (20 mL) and saturated aqueous sodium carbonate (20 mL). The organic layer was collected, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by pre-TLC (eluting with 7.5% methanol in dichloromethane) to give compound 16-G, a white solid, as tert-butyl 1-methylpropional. 5-cyano-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-5-carboxylic acid salt (30 mg) was obtained.

[0112] Step 8: Compound 15 2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-1 5 -Nitrile [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 8 in Example 5. LC_MS: (ES+): m / z 309.0 [M+H] + 1 H NMR (400 MHz, DMSO-d6): δ 1.46 (brs, 2H), 1.61 (brs, 4H), 2.55-2.59 (t, J = 7.6 Hz, 2H), 3.40-3.43 (m, 2H), 3.83 (s, 2H), 6.69 (brs, 1H), 6.96-6.98 (d, J = 7.6 Hz, 1H), 7.10-7.12 (d, J = 8.0 Hz, 1H), 7.23-7.27 (d, J = 7.6 Hz, 1H), 7.86-7.89 (m, 1H), 8.32-8.34 (m, 2H), 9.86 (s, 1H).

[0113] Step 9: Compound 16 2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-1 5 -Formamide [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 8 in Example 5. LC_MS: (ES+): m / z 327.2 [M+H] + Example 10: Synthetic Routes for Compounds 17 and 18

[0114] [ka]

[0115] Step 1: Compound 18-C 4-(but-3-en-1-yloxy)-2,5-dichloropyrimidine [ka] Sodium hydride (60% mass fraction in kerosene, 481 mg, 12.0 mmol) was added to a solution of but-3-en-1-ol (787 mg, 10.9 mmol), compound 18-B, in N,N-dimethylformamide (10 mL) at 0 °C. The reaction solution was heated to room temperature and stirred for 1 hour. After cooling to 0 °C, a solution of 2,4,5-trichloropyrimidine (2 g, 10.9 mmol), compound 18-A, in N,N-dimethylformamide (5 mL) was added. The reaction solution was stirred at room temperature under a nitrogen atmosphere for 15 hours. TLC monitoring confirmed the completion of the reaction. The reaction solution was partitioned between ethyl acetate (50 mL) and ice water (50 mL). The organic layer was collected, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluted with 0.3% ethyl acetate in n-hexane) to give compound 18-C, 4-(but-3-en-1-yloxy)-2,5-dichloropyrimidine (1.35 g) as a colorless oil. LC_MS: (ES+): m / z 218.8 [M+H] +

[0116] Step 2: Compound 18-D tert-butyl allyl (3-((4-(but-3-en-1-yloxy)-5-chloropyrimidin-2-yl)amino)phenyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 2 in Example 1. LC_MS: (ES+): m / z 445.0 [M+H] +

[0117] Step 3: Compound 17 tert-butyl(Z)-1 5 -Chloro-11-oxa-2,5-diaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-7-ene-5-carboxylate [ka] For the synthesis of this step, see the synthesis process of Step 7 of Compound 2 in Example 1. LC_MS: (ES+): m / z 417.2 [M+H] + 1 H NMR (400 MHz, DMSO-d6): δ 1.41-1.48 (m, 9H), 2.66-2.67 (m, 2H), 3.70-3.81 (m, 2H), 4.17-4.30 (m, 2H), 4.50-4.67 (m, 2H), 5.38-5.85 (m, 2H), 6.96-7.32 (m, 3H), 8.15-8.39 (m, 2H), 9.81-10.00 (m, 1H)).

[0118] Step 4: Compound 18-E 1 5 -chloro-11-oxa-2,5-diaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-5-carboxylic acid tert-butyl ester [ka] For the synthesis of this step, see the synthesis process of Step 1 of Compound 4 in Example 2.

[0119] Step 5: Compound 18 1 5-chloro-11-oxa-2,5-diaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 8 in Example 5. LC_MS: (ES+): m / z 319.1 [M+H] + 1 H NMR (400 MHz, DMSO-d6): δ 1.49-1.60 (m, 4H), 1.80-1.85 (m, 2H), 2.56 (t, J = 7.2 Hz, 2H), 3.82 (s, 2H), 4.54 (t, J = 8.4 Hz, 2H), 6.91 (d, J = 7.6 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H),8.24 (s, 1H), 8.30 (s, 1H), 9.78 (s, 1H). Example 11: Synthetic Route to Compound 19

[0120] [ka]

[0121] Step 1: Compound 19-C N-(but-3-en-1-yl)-2,5-dichloropyrimidin-4-amine [ka] For the synthesis of this step, see the synthesis process of Step 5 of Compound 2 in Example 1. LC_MS: (ES+): m / z 217.8 [M+H] + 1H NMR (400 MHz, CDCl3): δ 2.39-2.44 (q, J = 6.8 Hz, 2H), 3.58-3.62 (q, J = 6.2 Hz, 2H), 5.15 (s, 1H), 5.18-5.19 (d, J = 6.8 Hz, 1H),5.56 (brs, 1H), 5.77-5.87 (m, 1H), 8.01 (s, 1H).

[0122] Step 2: Compound 19-F 1-((allyloxy)methyl)-3-nitrobenzene [ka] A solution of (3-nitrophenyl)methanol (1 g, 6.5 mmol), potassium hydroxide (733 mg, 13.1 mmol), and tetrabutylammonium hydrogen sulfate (111 mg, 0.32 mmol) in allyl bromide (4 mL), compound 19-E, was stirred at room temperature for 12 hours. TLC monitoring confirmed the completion of the reaction. The reaction was quenched by adding water (20 mL) and extracted with dichloromethane (20 mL × 3). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 15% ethyl acetate in n-hexane) to give compound 19-F, 1-((allyloxy)methyl)-3-nitrobenzene (1.1 g), as a pale yellow oil. 1 H NMR (400 MHz, CDCl3): δ 4.09 (d, J = 5.6 Hz, 2H), 4.61 (s, 2H), 5.24-5.36 (m, 2H), 5.92-6.02 (m, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.23 ​​(s, 1H).

[0123] Step 3: Compound 19-G 3-((allyloxy)methyl)aniline [ka] At 0 °C, tin chloride dihydrate (2.34 g, 10.35 mmol) was added to a solution of compound 19-F, 1-((allyloxy)methyl)-3-nitrobenzene (500 mg, 2.59 mmol), in methanol (5 mL) and dichloromethane (5 mL). The reaction mixture was slowly heated to room temperature and stirred for 12 hours. TLC monitoring confirmed the completion of the reaction. The reaction mixture was concentrated, and the residue was partitioned between dichloromethane (10 mL) and aqueous sodium carbonate (2N, 20 mL). The mixture was filtered through a filter paper, and the organic layer was separated from the mother liquor. The aqueous layer was extracted with dichloromethane (10 mL × 3). The organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (eluted with 33 to 50% ethyl acetate in n-hexane) to obtain 3-((allyloxy)methyl)aniline (355 mg), which was compound 19-G, as a colorless oil. LC_MS: (ES+): m / z 164.0 [M+H] +

[0124] Step 4: Compound 19-HN 2 -(3-((allyloxy)methyl)phenyl)-N 4 -(but-3-en-1-yl)-5-chloropyrimidine-2,4-diamine [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 2 in Example 1. LC_MS: (ES+): m / z 345.2 [M+H] + 1H NMR (400 MHz, CDCl3): δ 2.40-2.45 (m, 2H), 3.57-3.61 (m, 2H), 4.04 (d, J = 5.6 Hz, 2H), 4.52 (s, 2H), 5.13-5.22 (m, 3H), 5.29-5.34 (m, 2H), 5.79-6.01 (m, 2H), 6.97 (t, J = 7.6 Hz, 2H), 7.28 (t, J = 7.2 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.89 (s, 1H).

[0125] Step 5: Compound 19-I (E)-1 5 -chloro-5-oxa-2,11-diaza-1(2,4)-pyrimidin-3(1,3)-benzenecycloundecane-7-ene [ka] For the synthesis of this step, see the synthesis process of Step 7 of Compound 2 in Example 1.

[0126] Step 6: Compound 19 1 5 -chloro-5-oxa-2,11-diaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane [ka] For the synthesis of this step, see the synthesis process of Step 1 of Compound 4 in Example 2. LC_MS: (ES+): m / z 319.3 [M+H] + 1H NMR (400 MHz, DMSO-d6): δ 1.45-1.51 (m, 2H), 1.58-1.65 (m, 2H), 1.74-1.82 (m, 2H), 3.30-3.33 (m, 2H), 3.54 (t, J = 5.8 Hz, 2H), 4.47 (s, 2H), 6.72 (d, J = 7.2 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 7.36 (t, J = 6.0 Hz, 1H), 7.90 (s, 1H), 8.49 (s, 1H), 9.23 (s, 1H). Example 12: Synthetic Routes for Compounds 20 and 21

[0127] [ka]

[0128] Step 1: Compound 21-C 2-(4-methylpiperazin-1-yl)-5-nitrobenzaldehyde [ka] A solution of 2-fluoro-5-nitrobenzaldehyde (5 g, 29.6 mmol), potassium carbonate (6.12 g, 44.3 mmol), and N-methylpiperazine (2.96 g, 29.6 mmol), compound 21-A, in N,N-dimethylformamide (100 mL) was stirred at 50 °C for 15 hours. TLC monitoring confirmed the completion of the reaction. The reaction was quenched by adding water (600 mL), filtered through a filter paper, and the filter cake was washed with water (300 mL × 2). The filter cake was collected and dried to give compound 21-C, 2-(4-methylpiperazin-1-yl)-5-nitrobenzaldehyde (7 g), as a yellow solid. LC_MS: (ES+): m / z 250.2 [M+H] + 1H NMR (400 MHz, CDCl3): δ 2.40 (s, 3H), 2.64-2.66 (t, J = 4.8 Hz, 4H), 3.33-3.36 (t, J = 4.8 Hz, 4H), 7.09-7.11 (d, J = 9.2 Hz, 1H), 8.29-8.32 (m, 1H), 8.62-8.63 (d, J = 2.8 Hz, 1H), 10.10 (s, 1H).

[0129] Step 2: Compound 21-D (2-(4-methylpiperazin-1-yl)-5-nitrophenyl)methanol [ka] Sodium borohydride (763 mg, 20.0 mmol) was added to a solution of 2-(4-methylpiperazin-1-yl)-5-nitrobenzaldehyde (5 g, 20.0 mmol), compound 21-C, in anhydrous tetrahydrofuran (30 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours. TLC monitoring confirmed the completion of the reaction. The reaction mixture was diluted with water (30 mL) and extracted with dichloromethane (3 × 20 mL). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluting with 5% methanol in dichloromethane) to give compound 21-D, (2-(4-methylpiperazin-1-yl)-5-nitrophenyl)methanol (1.3 g), as a yellow solid. LC_MS: (ES+): m / z 252.2 [M+H] + 1H NMR (400 MHz, CD3OD): δ 2.40 (s, 3H), 2.67 (brs, 4H),3.10-3.12 (t, J = 4.8 Hz, 4H), 4.70 (s, 2H), 7.20-7.22 (d, J = 8.8 Hz, 1H), 8.12-8.15 (dd, J = 2.8 Hz, 1H), 8.41-8.42 (d, J = 3.2 Hz, 1H).

[0130] Step 3: Compound 21-F 1-(2-((allyloxy)methyl)-4-nitrophenyl)-4-methylpiperazine [ka] Sodium hydride (60% mass fraction in kerosene, 40 mg, 1.0 mmol) was added to a solution of (2-(4-methylpiperazin-1-yl)-5-nitrophenyl)methanol (228 mg, 0.91 mmol), compound 21-D, in N,N-dimethylformamide (10 mL) at 0°C. The reaction solution was heated to room temperature and stirred for 30 minutes. After cooling to 0°C, 3-bromopropene (130 mg, 1.07 mmol), compound 21-E, was added dropwise. The reaction solution was stirred at room temperature under a nitrogen atmosphere for 15 hours. TLC monitoring confirmed the completion of the reaction. The reaction solution was partitioned between ethyl acetate (30 mL) and ice water (50 mL). The organic layer was collected, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluted with a dichloromethane solution containing 5% methanol) to obtain a yellow solid, 1-(2-((allyloxy)methyl)-4-nitrophenyl)-4-methylpiperazine (242 mg), which was compound 21-F. LC_MS: (ES+): m / z 292.2 [M+H] +

[0131] Step 4: Compound 21-G 3-((allyloxy)methyl)-4-(4-methylpiperazin-1-yl)aniline [ka] For the synthesis of this step, see the synthesis process of Step 3 of Compound 19 in Example 11. 1 H NMR (400 MHz, CDCl3): δ 2.38 (s, 3H), 2.59 (brs, 4H), 2.88-2.90 (t, J = 4.4 Hz, 4H), 3.49 (brs, 2H), 4.05-4.06 (d, J = 5.6 Hz, 2H), 5.55 (s, 2H), 5.19-5.22 (d, J = 10.4 Hz, 1H), 5.30-5.34 (m, 1H), 5.92-6.02 (m, 1H), 6.59-6.61 (dd, J = 2.4 Hz, 1H), 6.81-6.82 (d, J = 2.4 Hz, 1H), 6.96-6.98 (d, J = 8.4 Hz, 1H).

[0132] Step 5: Compound 21-HN 2 -(3-((allyloxy)methyl)-4-(4-methylpiperazin-1-yl)phenyl)-N 4 -(but-3-en-1-yl)-5-chloropyrimidine-2,4-diamine [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 2 in Example 1. LC_MS: (ES+): m / z 443.1 [M+H] + .

[0133] Step 6: Compound 20(E)-1 5 -chloro-3 4 -(4-Methylpiperazin-1-yl)-5-oxa-2,11-diaza-1(2,4)-pyrimidin-3(1,3)-benzenecycloundecane-7-ene [ka] For the synthesis of this step, see the synthesis process of Step 7 of Compound 2 in Example 1. LC_MS: (ES+): m / z 415.3 [M+H] +

[0134] Step 7: Compound 21 1 5 -chloro-3 4 -(4-Methylpiperazin-1-yl)-5-oxa-2,11-diaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane [ka] For the synthesis of this step, see the synthesis process of Step 1 of Compound 21 in Example 2. LC_MS: (ES+): m / z 417.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 1.47-1.53 ​​(m, 2H), 1.62-1.63 (m, 2H), 1.77-1.83 (m, 2H), 2.22 (s, 3H), 2.44-2.47 (m, 4H), 2.75-2.77 (t, J = 8.4 Hz, 4H), 3.31 (s, 2H), 3.58-3.60 (t, J = 5.6 Hz, 2H),4.51 (s, 2H),6.95-7.00 (m, 2H), 7.28-7.31 (t, J = 6.0 Hz, 1H), 7.86 (s, 1H), 8.53 (s, 1H), 9.10 (s, 1H). Example 13: Synthetic Route to Compound 22

[0135] [ka]

[0136] Step 1: Compound 22-A Di-tert-butyl 2 5 -chloro-1 6-Methyl-3,5,10-triaza-2(4,2)-pyrimidine-1,4(1,3)-dibenzenecyclodecane-5,10-dicarboxylate [ka] For the synthesis of this step, see the synthesis process of Step 1 of Compound 4 in Example 2. LC_MS: (ES+): m / z 580.3 [M+H] + 1 H NMR (400 MHz, DMSO-d6): δ1.16 (s, 9H), 1.38 (s, 12H), 1.53-1.58 (m, 1H), 2.23 (s, 3H), 3.51-3.81 (m, 4H), 6.75-6.78 (m, 1H), 7.05-7.08 (m, 1H), 7.19-7.26 (m, 3H), 7.33-7.35 (m, 1H), 8.34 (s, 1H), 8.64 (s, 1H), 10.09 (s, 1H).

[0137] Step 2: Compound 22 5 -chloro-1 6 -Methyl-3,5,10-triaza-2(4,2)-pyrimidine-1,4(1,3)-dibenzenecyclodecane [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 8 in Example 5. LC_MS: (ES+): m / z 380.3 [M+H] + 1H NMR (400 MHz, CDCl3): δ 1.48-1.78 (m, 6H), 2.23 (s, 3H), 3.17 (t, J = 7.2 Hz, 2H), 3.28-3.34 (m, 2H), 6.27-6.35 (m, 2H), 6.69-6.72 (m, 1H), 6.85 (d, J = 2.8 Hz, 1H), 7.02-7.06 (m, 2H), 7.15 (s, 1H), 8.05 (t, J = 2.0 Hz, 1H), 8.36 (s, 1H). Example 14: Synthetic Routes for Compounds 23 and 24

[0138] [ka]

[0139] Step 1: Compound 23 tert-butyl 2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-5-carboxylate [ka] Compound 9-F is tert-butyl(Z)-1 5 Palladium on carbon (50 mg) was added to a methanol solution containing 1,3-chloro-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-8-ene-5-carboxylate (50 mg, 130.38 μmol). The reaction mixture was stirred under a hydrogen balloon at 20°C for 12 hours. LCMS monitoring confirmed the completion of the reaction. The reaction mixture was filtered through Celite, and the residue was separated and purified by pre-TLC (eluting with 50% ethyl acetate in petroleum ether) to obtain compound 23, tert-butyl 2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-5-carboxylate (25.0 mg), as a brown solid. LC_MS: (ES+): m / z 384.2 [M+H] + .

[0140] Step 2: Compound 24 2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane [ka] Compound 23, tert-butyl 2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-5-carboxylate (15 mg, 52.9 μmol), was added to a hydrogen chloride / 1,4-dioxane solution (1 mL) and stirred at 25°C for 2 hours. LCMS monitoring confirmed the completion of the reaction. The reaction solution was concentrated under reduced pressure to give compound 24, 2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane (11.0 mg), as a brown solid. LC_MS: (ES+): m / z 284.2 [M+H] + . Example 15: Synthetic Route to Compound 25

[0141] [ka]

[0142] Step 1: Compound 25-B N-allyl-2,5-dichloro-N-methylpyrimidin-4-amine [ka] Compound 25-A (150 mg, 0.74 mmol) was dissolved in tetrahydrofuran (25 mL) and sodium hydride (31 mg, 0.77 mmol, 60% mass fraction in kerosene) was added in several portions under ice bath conditions. Stirring was continued for 20 minutes under ice bath conditions, and then iodomethane (228 mg, 0.1 mL, 1.60 mmol) was added dropwise. Stirring was then continued for 3 hours under ice bath conditions. After the disappearance of the raw materials was detected by TLC spot plate, the reaction solution was slowly quenched with saturated ammonium chloride solution. Extraction was performed with ethyl acetate (25 mL × 2), and the organic layers were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column chromatography (eluted with petroleum ether containing 0% to 15% ethyl acetate) to obtain compound 25-B, N-allyl-2,5-dichloro-N-methylpyrimidin-4-amine (130 mg), as a yellow oil.

[0143] Step 2: Compound 25-C tert-butyl (3-((4-(allyl(methyl)amino)-5-chloropyrimidin-2-yl)amino)benzyl)(but-3-en-1-yl)carbamate [ka] To a dioxane (2.5 mL) solution containing N-allyl-2,5-dichloro-N-methylpyrimidin-4-amine (130 mg, 0.60 mmol) (compound 25-C) and compound 9-D (166 mg, 0.6 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (44 mg, 0.06 mmol) and cesium carbonate (587 mg, 1.8 mmol) were added. The reaction mixture was stirred at 110 °C under a nitrogen atmosphere for 4.5 hours. LCMS monitoring confirmed the completion of the reaction. The reaction solvent was removed by rotary evaporation under reduced pressure, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column chromatography (eluting with petroleum ether containing 10% to 20% ethyl acetate) to obtain compound 25-C, tert-butyl (3-((4-(allyl(methyl)amino)-5-chloropyrimidin-2-yl)amino)benzyl)(but-3-en-1-yl)carbamate (65 mg), as a colorless oil. LC_MS: (ES+): m / z 458.1 [M+H] +

[0144] Step 3: Compound 25-D tert-butyl (3-((4-(allyl(methyl)amino)-5-chloropyrimidin-2-yl)(tert-butoxycarbonyl)amino)benzyl)(but-3-en-1-yl)carbamate [ka] Di-tert-butyl dicarbonate (91 mg, 0.42 mmol) was added to a solution of compound 25-C, tert-butyl (3-((4-(allyl(methyl)amino)-5-chloropyrimidin-2-yl)amino)benzyl)(but-3-en-1-yl)carbamate (152 mg, 0.33 mmol), triethylamine (42 mg, 0.42 mmol), and 4-dimethylaminopyridine (8 mg, 0.07 mmol) in dichloromethane (3.0 mL). The reaction solution was stirred at 25° C. for 4 hours. TLC monitoring confirmed the completion of the reaction. The reaction solvent was concentrated by rotary evaporation. The residue was purified by silica gel column chromatography (eluted with 0%-15% ethyl acetate in petroleum ether) to give compound 25-D, tert-butyl (3-((4-(allyl(methyl)amino)-5-chloropyrimidin-2-yl)(tert-butoxycarbonyl)amino)benzyl)(but-3-en-1-yl)carbamate (146 mg), as a pale yellow oil. LC_MS: (ES+): m / z 558.2 [M+H] +

[0145] Step 4: Compound 25-E Di-tert-butyl(Z)-1 5 -Chloro-11-methyl-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-8-ene-2,5-dicarboxylate [ka] To a dichloromethane (75 mL) solution containing tert-butyl (3-((4-(allyl(methyl)amino)-5-chloropyrimidin-2-yl)(tert-butoxycarbonyl)amino)benzyl)(but-3-en-1-yl)carbamate (146 mg, 0.26 mmol), compound 25-D, was added Grubbs second-generation catalyst (33 mg, 0.04 mmol). The reaction mixture was stirred at 45°C under a nitrogen atmosphere for 1.0 hour. TLC monitoring confirmed the completion of the reaction. The reaction mixture was concentrated. The residue was separated and purified by silica gel column chromatography (eluted with petroleum ether containing 0% to 25% ethyl acetate) to obtain compound 25-E, a brown solid, di-tert-butyl (Z)-1 5 -Chloro-11-methyl-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-8-ene-2,5-dicarboxylate (124 mg) was obtained. LC_MS: (ES+): m / z 530.2 [M+H] +

[0146] Step 5: Compound 25-F Di-tert-butyl 1 5 -Chloro-11-methyl-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-2,5-dicarboxylate [ka] Compound 25-E, di-tert-butyl (Z)-1 5To a solution of 124 mg (0.23 mmol) of 1,2-chloro-11-methyl-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-8-ene-2,5-dicarboxylate in 25 mL of methanol, platinum dioxide (20 mg, 0.09 mmol) and acetic acid (50 mg) were added. The reaction mixture was purged with hydrogen gas three times and stirred at 25 °C under a hydrogen balloon for 1.0 h. TLC monitoring confirmed the completion of the reaction. Most of the reaction solvent was removed by rotary evaporation. The concentrated reaction solution was adjusted to pH 7-8 with saturated sodium bicarbonate, diluted with water (30 mL), and extracted with ethyl acetate (25 mL × 2). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluted with 0% to 25% ethyl acetate in petroleum ether) to give compound 25-F, a white solid, as di-tert-butyl 1-(2-methyl-2-propanol)- 5 -Chloro-11-methyl-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-2,5-dicarboxylic acid salt (43 mg) was obtained. LC_MS: (ES+): 532.3 [M+H] +

[0147] Step 6: Compound 25 1 5 -chloro-11-methyl-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane [ka] Compound 25-F is di-tert-butyl 1 5Trifluoroacetic acid (1.0 mL) was added to a dichloromethane (1 mL) solution containing 1-chloro-11-methyl-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-2,5-dicarboxylate (43 mg, 0.08 mmol). The reaction solution was stirred at 25°C for 1.5 hours. LCMS monitoring confirmed the completion of the reaction. The reaction solution was concentrated under reduced pressure and dried under high vacuum. Methanol (1 mL) was added to the residue, and the pH was adjusted to 7-8 with saturated sodium bicarbonate under stirring. The suspension was then filtered, and the filter cake was washed with water (5 mL). The filter cake was dried under high vacuum under oil pump conditions. Compound 25, a white solid, was obtained. 5 -Chloro-11-methyl-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane (25.2 mg) was obtained. LC_MS: (ES+): 332.1 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ: 9.31 (s, 1H), 8.11 (s, 1H), 7.97 (s, 1H), 7.24 (t, J = 0.8 Hz, 1H), 7.06 (d, J = 0.8 Hz, 1H), 6.94 (d, J = 0.8 Hz, 1H), 3.88 (s, 2H), 3.57 - 3.52 (m, 2H), 3.27 (s, 3H), 2.58 (t, J = 0.8 Hz, 2H), 1.70 - 1.59 (m, 4H), 1.53 - 1.42 (m, 2H). Example 16: Synthetic Route to Compound 26

[0148] [ka]

[0149] Step 1: Compound 26-C 2,5-dichloro-4-(2-methyl-5-nitrophenyl)pyrimidine [ka] For the synthesis of this step, see the synthesis process of Step 7 of Compound 12 in Example 8. LC_MS: (ES+): m / z 285.0 [M+H] + .

[0150] Step 2: Compound 26-E (tert-butyl 3-((5-chloro-4-(2-methyl-5-nitrophenyl)pyrimidin-2-yl)amino)phenyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 2 in Example 1. LC_MS: (ES+): m / z 456.1 [M+H] + .

[0151] Step 3: Compound 26-F (tert-butyl 3-((4-(5-amino-2-methylphenyl)-5-chloropyrimidin-2-yl)amino)phenyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 4 of Compound 2 in Example 1. LC_MS: (ES+): m / z 426.2 [M+H] + .

[0152] Step 4: Compound 26-G (tert-butyl (3-(2-((3-((tert-butyloxycarbonyl)amino)phenyl)amino)-5-chloropyrimidin-4-yl)-4-methylphenyl)carbamate [ka] Di-tert-butyl dicarbonate (430.43 mg, 1.972 mmol) was added to a solution of tert-butyl (3-((4-(5-amino-2-methylphenyl)-5-chloropyrimidin-2-yl)amino)phenyl)carbamate (700 mg, 1.643 mmol) in ethanol (5 mL), and the reaction mixture was stirred at room temperature for 14 hours. TLC monitoring confirmed the completion of the reaction. The reaction solution was concentrated. The resulting residue was separated and purified by silica gel column chromatography (eluted with petroleum ether containing 0% to 25% ethyl acetate) to give tert-butyl (3-(2-((3-((tert-butoxycarbonyl)amino)phenyl)amino)-5-chloropyrimidin-4-yl)-4-methylphenyl)carbamate (710 mg), a yellow solid, as compound 26-G. LC_MS: (ES+): m / z 527.3 [M+H] + .

[0153] Step 5: Compound 26-I Di-tert-butyl-2 5 -chloro-1 6 -Methyl-8-oxa-3,5,11-triaza-2(4,2)-pyrimidine-1,4(1,3)-dibenzenecycloundecane-5,11-dicarboxylate [ka] To a solution of tert-butyl (3-(2-((3-(tert-butoxycarbonyl)amino)phenyl)amino)-5-chloropyrimidin-4-yl)-4-methylphenyl)carbamate (100 mg) and sodium tert-butoxide (36.52 mg, 0.38 mmol) in acetonitrile (10 mL), 1-bromo-2-(2-bromoethoxy)ethane (44.06 mg, 0.19 mmol), compound 26-H, was added, and the reaction solution was stirred at 60° C. for 8 hours. TLC monitoring confirmed the completion of the reaction. The reaction was quenched by adding water (10 mL) to the reaction solution, and the mixture was extracted with dichloromethane (10 mL × 2). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was separated and purified by pre-TLC (eluted with 25% ethyl acetate in petroleum ether) to obtain a white solid compound 26-I, di-tert-butyl-2 5 -chloro-1 6 1,4(1,3)-dibenzenecycloundecane-5,11-dicarboxylic acid salt (5 mg) was obtained. LC_MS: (ES+): m / z 618.3 [M+Na] + .

[0154] Step 6: Compound 26 2 5 -chloro-1 6 -Methyl-8-oxa-3,5,11-triaza-2(4,2)-pyrimidine-1,4(1,3)-dibenzenecycloundecane [ka] Compound 26-I is di-tert-butyl-2 5 -chloro-1 6To a solution of 1,4-methyl-8-oxa-3,5,11-triaza-2(4,2)-pyrimidine-1,4(1,3)-dibenzenecycloundecane-5,11-dicarboxylate (5 mg, 0.0084 mmol) in methanol (0.5 mL) was added a solution of hydrochloric acid in dioxane (0.5 mL). The reaction solution was stirred at room temperature for 5 hours. TLC monitoring confirmed the completion of the reaction. The reaction solution was concentrated to give compound 26, a yellow solid. 5 -chloro-1 6 -methyl-8-oxa-3,5,11-triaza-2(4,2)-pyrimidine-1,4(1,3)-dibenzenecycloundecane (5 mg, hydrochloride salt) was obtained. LC_MS: (ES+): m / z 396.1 [M+H] + . Example 17: Synthetic Route to Compound 27

[0155] [ka]

[0156] Step 1: Compound 27-B 1-(but-3-en-1-yl)-4-nitro- 1 H-Pyrazole [ka] 4-Bromobut-1-ene (1.31 g, 9.73 mmol) was slowly added dropwise to a mixed solution of compound 27-A (1.0 g, 8.84 mmol) and potassium carbonate (3.05 g, 22.1 mmol) in N,N-dimethylformamide (10 mL) at room temperature, followed by stirring for 12 hours. After the disappearance of the raw materials was detected by TLC spot plate, water (50 mL) was added to the reaction solution while stirring, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic layers were combined, washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was dried under high vacuum to give compound 27-B, 1-(but-3-en-1-yl)-4-nitro-, as a white solid. 1H-pyrazole (1.45 g) was obtained.

[0157] Step 2: Compound 27-C 1-(but-3-en-1-yl)- 1 H-Pyrazol-4-amine [ka] Iron powder (2.42 g, 43.37 mmol) was added to a stirred solution of water (5 mL), ammonium chloride (3.71 g, 69.36 mmol), and compound 27-B (1.45 g, 8.67 mmol) in ethanol (20 mL). The reaction mixture was stirred at 110 °C under a nitrogen atmosphere for 4.5 hours. LCMS monitoring confirmed the completion of the reaction. The reaction solvent was evaporated under reduced pressure by rotary evaporation, followed by the addition of water (30 mL) and ethyl acetate (30 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluted with 2.5%-3.3% methanol in dichloromethane) to give compound 27-C, 1-(but-3-en-1-yl)-, as a brown oil. 1 H-Pyrazol-4-amine (370 mg) was obtained. 1 H NMR (400 MHz, CDCl3) δ: 7.17 (s, 1H), 7.02 (s, 1H), 5.82 - 5.72 (m, 1H), 5.13 - 5.04 (m, 2H), 4.07 (t, J = 8.0 Hz, 2H), 2.89 (brs, 2H), 2.63 - 2.55 (m, 2H).

[0158] Step 3: Compound 27-D tert-butylallyl (3-(2-((1-(but-3-en-1-yl)- 1 H-pyrazol-4-yl)amino)-5-chloropyrimidin-4-yl)-4-methylphenyl)carbamate [ka] To a solution of compound 12-K (170 mg, 0.43 mmol), SPhos (37 mg, 0.09 mmol), and compound 27-C (1.45 g, 0.09 mmol) in 1,4-dioxane (3.5 mL) was added Pd(dba) (37 mg, 0.04 mmol) and cesium carbonate (280 mg, 0.81 mmol). The reaction solution was purged with nitrogen gas three times while stirring, and then the reaction was stirred at 110 °C under a nitrogen atmosphere for 5 h. LCMS monitoring confirmed the completion of the reaction. The reaction solvent was rotary evaporated under reduced pressure, and water (30 mL) and ethyl acetate (30 mL) were added. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified on a silica gel plate (using 30% ethyl acetate in petroleum ether) to give compound 27-D, tert-butylallyl (3-(2-((1-(but-3-en-1-yl)- 1 H-pyrazol-4-yl)amino)-5-chloropyrimidin-4-yl)-4-methylphenyl)carbamate (150 mg) was obtained. LC-MS: (ES+): m / z 495.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ: 8.43 (s, 1H), 7.83 (s, 1H), 7.50 (s, 1H), 7.26 - 7.12 (m, 4H), 6.00 - 5.88 (m, 1H), 5.83 - 5.73 (m, 1H), 5.20 - 5.04 (m, 4H), 4.25 (dt, J = 3.0, 4.0 Hz, 2H), 4.17 - 4.13 (m, 2H), 2.62 (q, J = 8.0 Hz, 2H), 2.23 (s, 3H), 1.45 (s, 9H).

[0159] Step 4: Compound 27-E tert-butyl allyl (3-(2-((1-(but-3-en-1-yl)-1H-pyrazol-4-yl)(tert-butoxycarbonyl)amino)-5-chloropyrimidin-4-yl)-4-methylphenyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 3 of Compound 25 in Example 15. LC-MS: (ES+): m / z 595.3 [M+H] + .

[0160] Step 5: Compound 27-F Di-tert-butyl (4 4 E,7Z)-2 5 -chloro-1 6 -methyl-4 1 H-3,10-diaza-2(4,2)-pyrimidine-4(4,1)-pyrazole-1(1,3)-benzenecyclodecane-7-ene-3,10-dicarboxylic acid salt [ka] For the synthesis of this step, see the synthesis process of Step 4 of Compound 25 in Example 15. LC-MS: (ES+): m / z 567.2 [M+H] + .

[0161] Step 6: Compound 27 (4 4 E,7Z)-2 5 -chloro-1 6 -methyl-4 1 H-3,10-diaza-2(4,2)-pyrimidine-4(4,1)-pyrazol-1(1,3)-benzenecyclodecane-7-ene [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 25 in Example 15. LC-MS: (ES+): 367.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ: 9.80 (s, 1H), 8.47 (s, 1H), 8.18 (s, 1H), 7.26 (s, 1H), 6.99 (d, J = 8.0 Hz, 1H), 6.74 (dd, J = 4.0, 8.0 Hz, 1H), 6.52 (s, 1H), 6.08 (brs, 1H), 4.23 - 4.18 (m, 1H), 4.11 - 4.00 (m, 1H), 3.70 - 3.50 (m, 2H), 2.50 - 2.25 (m, 2H), 2.18 (s, 3H). Example 18: Synthetic Route to Compound 28

[0162] [ka]

[0163] Step 1: Compound 28-A Di-tert-butyl(E)-2 5 -chloro-1 6 -methyl-4 1 H-3,10-diaza-2(4,2)-pyrimidine-4(4,1)-pyrazole-1(1,3)-benzenecyclodecane-3,10-dicarboxylic acid salt [ka] For the synthesis of this step, see the synthesis process of Step 5 of Compound 25 in Example 15. LC-MS: (ES+): m / z 569.3 [M+H] + .

[0164] Step 2: Compound 28 (E)-2 5 -chloro-1 6 -methyl-4 1 H-3,10-diaza-2(4,2)-diaza-2(4,2)-pyrimidine-4(4,1)-pyrazole-1(1,3)-benzenecyclodecane [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 25 in Example 15. LC-MS: (ES+): m / z 369.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ: 9.81 (s, 1H), 8.48 (s, 1H), 8.20 (s, 1H), 7.32 (s, 1H), 6.98 (d, J = 8.0 Hz, 1H), 6.67 (dd, J = 4.0, 8.0 Hz, 1H), 6.56 (d, J = 4.0 Hz, 1H), 5.95 - 5.85 (m, 1H), 4.11 - 4.06 (m, 2H), 3.11 - 2.93 (m, 2H), 2.17 (s, 3H), 2.00 - 1.75 (m, 2H), 1.55 - 1.49 (m, 1H), 1.25 - 1.10 (m, 2H), 1.05 - 0.95 (m, 1H). Example 19: Synthetic Route to Compound 29

[0165] [ka]

[0166] Step 1: Compound 29-B tert-butyl allyl (3-(2-chloro-5-fluoropyrimidin-4-yl)-4-methylphenyl)carbamate [ka] Compound 12-I (0.50 g, 1.34 mmol) was added to a solution of A (0.56 g, 3.35 mmol) and Pd(PPh3)Cl2 (91 mg, 0.13 mmol) in 1,2-dimethoxyethane (10 mL) at room temperature. Sodium carbonate solution (2.0 M, 5 mL) was then added, and the mixture was purged with nitrogen gas three times at room temperature. The reaction solution was stirred at 85 °C under a nitrogen atmosphere for 2.5 hours. After the disappearance of the starting material was detected by TLC spot plate, water (30 mL) was added to the reaction solution, which was then extracted with ethyl acetate (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluting with petroleum ether containing 0%-7% ethyl acetate) to give compound 29-B, tert-butyl allyl (3-(2-chloro-5-fluoropyrimidin-4-yl)-4-methylphenyl)carbamate (475 mg), as a colorless oil. LC-MS: (ES+): m / z 423.2 [M+EtOH] + . 1 H NMR (400 MHz, CDCl3) δ: 8.56 (s, 1H), 7.33 - 7.27 (m, 3H), 5.98 - 5.88 (m, 1H), 5.21 - 5.12 (m, 2H), 4.25 (dt, J = 2.0, 4.0 Hz, 2H), 2.33 (d, J = 4.0 Hz, 3H), 1.49 (s, 9H).

[0167] Step 2: Compound 29-C tert-butyl allyl(3-(2-((3-(allyl(tert-butoxycarbonyl)amino)phenyl)amino)-5-fluoropyrimidin-4-yl)-4-methylphenyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 2 of Compound 25 in Example 15. LC-MS: (ES+): m / z 612.3 [M+Na] + .

[0168] Step 3: Compound 29-D tert-butyl allyl (3-((4-(5-(allyl(tert-butoxycarbonyl)amino)-2-methylphenyl)-5-fluoropyrimidin-2-yl)(tert-butoxycarbonyl)amino)phenyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 3 of Compound 25 in Example 15. LC-MS: (ES+): m / z 690.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ: 8.60 (s, 1H), 7.30 - 7.26 (m, 2H), 7.25 - 7.19 (m, 2H), 7.18 - 7.13 (m, 2H), 7.09 (dt, J = 4.0, 8.0 Hz, 1H), 5.94 - 5.84 (m, 2H), 5.18 - 5.08 (m, 4H), 4.21 (t, J = 4.0 Hz, 4H), 2.16 (s, 3H), 1.46 (s, 9H), 1.45 (s, 9H), 1.41 (s, 9H).

[0169] Step 4: Compound 29-E tri-tert-butyl(Z)-2 5 -Fluoro-1 6 -Methyl-3,5,10-triaza-2(4,2)-pyrimidine-1,4(1,3)-dibenzenecyclodecane-7-ene-3,5,10-tricarboxylate [ka] For the synthesis of this step, see the synthesis process of Step 4 of Compound 25 in Example 15. LC-MS: (ES+): m / z 662.3 [M+H] + . 1H NMR (400 MHz, CDCl3) δ: 8.65 (d, J = 2.0 Hz, 1H), 7.37 - 7.30 (m, 2H), 7.21 - 7.12 (m, 3H), 7.04 (s, 1H), 6.83 (d, J = 4.0 Hz, 1H), 5.75 - 5.50 (m, 2H), 4.42 (d, J = 4.0 Hz, 2H), 4.08 (d, J = 4.0 Hz, 2H), 2.29 (d, J = 4.0 Hz, 3H), 2.16 (s, 3H), 1.48 (s, 9H), 1.46 (s, 9H), 1.43 (s, 9H).

[0170] Step 5: Compound 29 (Z)-2 5 -Fluoro-1 6 -methyl-3,5,10-triaza-2(4,2)-pyrimidine-1,4(1,3)-dibenzenecyclodecan-7-ene [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 25 in Example 15. LC-MS: (ES+): m / z 362.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ: 9.41 (s, 1H), 8.53 (d, J = 2.0 Hz, 1H), 7.67 (s, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.88 (t, J = 8.0 Hz, 1H), 6.75 (dd, J = 4.0, 8.0 Hz, 1H), 6.61 (d, J = 4.0 Hz, 1H), 6.43 (d, J = 8.0 Hz, 1H), 6.25 (d, J = 8.0 Hz, 1H), 6.09 (t, J = 4.0 Hz, 1H), 5.86 (t, J = 4.0 Hz, 1H), 5.40 (s, 2H), 3.70 (s, 2H), 3.54 (s, 2H), 2.14 (d, J = 4.0 Hz, 3H). Example 20: Synthetic Route to Compound 30

[0171] [ka]

[0172] Step 1: Compound 30-A Tri-tert-butyl 2 5 -Fluoro-1 6 -Methyl-3,5,10-triaza-2(4,2)-pyrimidine-1,4(1,3)-dibenzenecyclodecane-3,5,10-tricarboxylate [ka] For the synthesis of this step, see the synthesis process of Step 5 of Compound 25 in Example 15. LC-MS: (ES+): m / z 664.4 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ: 8.64 (d, J = 4.0 Hz, 1H), 7.32 - 7.29 (m, 1H), 7.28 - 7.26 (m, 2H), 7.20 - 7.15 (m, 2H), 7.10 - 7.07 (m, 1H), 6.80 (brs, 1H), 3.69 (t, J = 8.0 Hz, 2H), 3.62 (t, J = 8.0 Hz, 2H), 2.32 (d, J = 4.0 Hz, 3H), 1.58 - 1.35 (m, 31H).

[0173] Step 2: Compound 30 2 5 -Fluoro-1 6 -Methyl-3,5,10-triaza-2(4,2)-pyrimidine-1,4(1,3)-dibenzenecyclodecane [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 25 in Example 15. LC-MS: (ES+): m / z 364.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ: 9.45 (s, 1H), 8.53 (d, J = 4.0 Hz, 1H), 7.83 (s, 1H), 6.99 (d, J = 8.0 Hz, 1H), 6.92 - 6.85 (m, 2H), 6.69 (dd, J = 4.0, 8.0 Hz, 1H), 6.35 (d, J = 8.0 Hz, 1H), 6.22 (dd, J = 2.0, 8.0 Hz, 1H), 5.54 (t, J = 6.0 Hz, 1H), 5.29 (t, J = 6.0 Hz, 1H), 3.19 - 3.17 (m, 3H), 3.10 - 2.95 (m, 2H), 2.10 (d, J = 4.0 Hz, 3H), 1.60 - 1.45 (m, 4H). Example 21: Synthetic Route to Compound 31

[0174] [ka]

[0175] Step 1: Compound 31-C 1-(but-3-enyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka] In a 250 mL single-neck flask, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5 g, 25.77 mmol), 4-bromo-1-butene (5.22 g, 38.66 mmol), and cesium carbonate (16 g, 51.33 mmol) were added to a 250 mL single-neck flask and refluxed in DMF (50 mL) for 2 hours. TLC monitoring confirmed the completion of the reaction. The reaction solution was poured into water (500 mL) and extracted eight times with ethyl acetate (100 mL). The organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 31-C, 1-(but-3-enyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.3 g) as a crude brown oily liquid, which was used directly in the next step without further purification.

[0176] Step 2: Compound 31-E 4-(1-(but-3-enyl)-1H-pyrazol-4-yl)-2,5-dichloropyrimidine [ka] For the synthesis of this step, see the synthesis process of Step 7 of Compound 12 in Example 8. LC_MS: (ES+): m / z 269.15 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.50 (s, 1H), 8.41 (s, 1H), 8.35 (s, 1H), 5.80-5.72 (m, 1H), 5.12-5.08 (m, 2H), 4.26 (t, J = 7.2 Hz, 2H), 2.69-2.67 (m, 2H).

[0177] Step 3: Compound 31-G tert-butyl allyl (3-((4-(1-(but-3-en-1-yl)-1H-pyrazol-4-yl)-5-chloropyrimidin-2-yl)amino)phenyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 2 in Example 1. LC_MS: (ES+): m / z 481.55 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.35-8.30 (m, 3H), 7.56 (t, J = 2.0 Hz, 1H), 7.48-7.45 (m, 1H), 7.30-7.26 (m, 1H), 7.12 (s, 1H), 6.94-6.92 (m, 1H), 5.99-5.90 (m, 1H), 5.84-5.73 (m, 1H), 5.21-5.08 (m, 4H), 4.27-4.24 (m, 4H), 2.71-2.65 (m, 2H), 1.46 (s. 9H).

[0178] Step 4: Compound 31-H tert-butyl(3-(allyl(tert-butoxycarbonyl)amino)phenyl)(4-(1-(but-3-en-1-yl)-1H-pyrazol-4-yl)-5-chloropyrimidin-2-yl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 3 of Compound 25 in Example 15. LC_MS: (ES+): m / z 581.45 [M+H] + . 1H NMR (400 MHz, CDCl3): δ 8.53 (s, 1H), 8.20 (d, J = 1.6 Hz, 2H), 7.33-7.29 (m, 1H), 7.17-7.14 (m, 2H), 7.08-7.06 (m, 1H), 5.93-5.84 (m, 1H), 5.80-5.70 (m, 1H), 5.14-5.06 (m, 4H), 4.23-4.20 (m, 4H), 2.67-2.62 (m, 2H), 1.46 (s. 9H), 1.40 (s. 9H).

[0179] Step 5: Compound 31-I Di-tert-butyl (1 4 Z,7Z)-2 5 -chloro-1 1 H-3,5-diaza-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzenecyclodecane-7-ene-3,5-dicarboxylic acid salt [ka] For the synthesis of this step, see the synthesis process of Step 4 of Compound 25 in Example 15. LC_MS: (ES+): m / z 553.35 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.74 (s, 1H), 8.21 (s, 1H), 7.62 (s, 1H), 7.41-7.38 (m, 1H), 7.32-7.30 (m, 1H), 7.16-7.15 (m, 1H), 7.02-7.00 (m, 1H), 5.57-5.53 (m, 2H), 4.33-4.32 (m, 2H), 4.23-4.21 (m, 2H), 2.45-2.44 (m, 2H), 1.42 (s, 9H), 1.37 (s, 9H).

[0180] Step 6: Compound 31 (1 4 Z,7Z)-2 5 -chloro-1 1H-3,5-diaza-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzenecyclodecane-7-ene [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 25 in Example 15. LC_MS: (ES+): m / z 353.15 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 9.47 (s, 1H), 8.43 (s, 1H), 8.33 (s, 1H), 8.12 (s, 1H), 7.26 (s, 1H), 6.92 (t, J = 8.0 Hz, 1H), 6.34-6.32 (m, 2H), 5.86 (t, J = 6.0 Hz, 1H), 5.76-5.70 (m, 1H), 5.55-5.51 (m, 1H), 4.31-4.29 (m, 2H), 3.60 (s, 2H), 2.52-2.50 (m, 2H). Example 22: Synthetic Route to Compound 32

[0181] [ka]

[0182] Step 1: Compound 32-A Di-tert-butyl(Z)-2 5 -chloro-1 1 H-3,5-diaza-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzenecyclodecane-3,5-dicarboxylate [ka] For the synthesis of this step, see the synthesis process of Step 1 of Compound 23 in Example 14. LC_MS: (ES+): m / z 555.35 [M+H]+ .

[0183] Step 2: Compound 32 (Z)-2 5 -chloro-1 1 H-3,5-diaza-2(4,2)-pyrimidine-1(4,1)-pyrazole-4(1,3)-benzenecyclodecane [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 25 in Example 15. LC_MS: (ES+): m / z 355.10 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 9.49 (s, 1H), 8.49 (s, 1H), 8.46 (s, 1H), 8.17 (s, 1H), 7.52 (s, 1H), 6.89 (t, J = 8.0 Hz, 1H), 6.30-6.28 (m, 1H), 6.21-6.18 (m, 1H), 5.76 (t, J = 6.4 Hz, 1H), 2.89-2.83 (m, 2H), 1.82-1.79 (m, 2H), 1.62-1.60 (m, 2H), 0.86-0.84 (m, 2H). Example 23: Synthetic Route to Compound 33

[0184] [ka]

[0185] Step 1: Compound 33-A 1-(but-3-enyl)-3-chloro-4-nitro-1H-pyrazole [ka] A 50 mL three-neck flask and a thermometer were prepared. Compound 27-B, 1-(1-butenyl)-4-nitropyrazole (580 mg, 3.47 mmol), was added to dry tetrahydrofuran (20 mL) and purged with nitrogen gas three times. The temperature was controlled at -78 °C, and Li-HMDS (8.7 mL, 8.68 mmol, 1 M) was slowly added dropwise. After reacting at -78 °C for 30 minutes, a solution of hexachloroethane (1.2 g, 5.2 mmol) in tetrahydrofuran (5 mL) was slowly added dropwise to the reaction solution. The reaction was continued for 2.5 hours at -78 °C. Completion of the reaction was confirmed by TLC and LCMS monitoring. The reaction was quenched by adding water (20 mL) and extracted three times with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to dryness to give compound 33-A, 1-(but-3-enyl)-3-chloro-4-nitro-1H-pyrazole (853 mg), as a crude yellow oil, which was used directly in the next step without further purification.

[0186] Step 1: Compound 33-B 1-(but-3-enyl)-3-chloro-1H-pyrazol-4-amine [ka] For the synthesis of this step, see the synthesis process of Step 4 of Compound 2 in Example 1. LC_MS: (ES+): m / z 171.75 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 7.21 (s, 1H), 5.82-5.71 (m, 1H), 5.10-5.04 (m, 2H), 4.10 (t, J = 7.6 Hz, 2H), 2.92 (brs, 2H), 2.57-2.52 (m, 2H).

[0187] Step 3: Compound 33-C 4-(1-(but-3-enyl)-1H-pyrazol-4-yl)-nitrogen-(1-(but-3-enyl)-3-chloro-1H-pyrazol-4-yl)-5-chloropyrimidin-2-amine [ka] For the synthesis of this step, see the synthesis process of Step 3 of Compound 25 in Example 15. 1 H NMR (400 MHz, CDCl3): δ 8.34 (s, 1H), 8.30 (s, 1H), 8.26 (s, 1H), 8.06 (s, 1H), 6.54 (s, 1H), 5.83-5.75 (m, 2H), 5.14-5.07 (m, 4H), 4.27-4.18 (m, 4H), 2.68-2.61 (m, 4H).

[0188] Step 4: Compound 33-D tert-butyl 4-(1-(but-3-enyl)-1H-pyrazol-4-yl)-5-chloropyrimidin-2-yl)(1-(but-3-enyl)-3-chloro-1H-pyrazol-4-yl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 3 of Compound 25 in Example 15. LC_MS: (ES+): m / z 504.00 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.54 (s, 1H), 8.23 ​​(s, 1H), 8.21 (s, 1H), 7.56 (s, 1H), 5.82-5.71 (m, 2H), 5.12-5.05 (m, 4H), 4.24-4.20 (m, 4H), 2.66-2.61 (m, 4H), 1.48 (s, 9H).

[0189] Step 5: Compound 33-E tert-butyl (1 4 Z,4 4 E,7Z)-2 5 ,4 3 -chloro-1 1 H,4 1 H-3-Aza-2(4,2)-pyrimidine-1,4(4,1)-bipyrazole cyclodecane-7-ene-3-carbamate [ka] For the synthesis of this step, see the synthesis process of Step 4 of Compound 25 in Example 15. LC_MS: (ES+): m / z 477.65 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.59 (s, 1H), 8.28 (s, 1H), 7.83 (s, 1H), 7.46 (s, 1H), 5.67-5.61 (m, 2H), 4.44-4.35 (m, 2H), 4.27-4.14 (m, 2H), 2.74-2.57 (m, 4H), 1.49 (s, 9H).

[0190] Step 6: Compound 33-F tert-butyl (1 4 Z,4 4 E,7Z)-2 5 ,4 3 -chloro-1 1 H,4 1 H-3-Aza-2(4,2)-pyrimidine-1,4(4,1)-bipyrazole cyclodecane-3-carbamate [ka] For the synthesis of this step, see the synthesis process of Step 1 of Compound 23 in Example 14. LC_MS: (ES+): m / z 478.8 [M+H] + . 1H NMR (400 MHz, CDCl3): δ 8.60 (s, 1H), 8.22 (s, 1H), 7.68 (s, 1H), 7.53 (s, 1H), 4.36-4.25 (m, 2H), 4.14-4.07 (m, 2H), 2.08-1.99 (m, 2H), 1.76-1.65 (m, 2H), 1.51 (s, 9H), 1.47-1.33 (m, 4H).

[0191] Step 7: Compound 33 (1 4 Z,4 4 E,7Z)-2 5 ,4 3 -chloro-1 1 H,4 1 H-3-Aza-2(4,2)-pyrimidine-1,4(4,1)-bipyrazole cyclodecane [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 25 in Example 15. LC_MS: (ES+): m / z 377.95 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.88 (s, 1H), 8.40 (s, 1H), 8.08 (s, 1H), 7.82 (s, 1H), 7.53 (s, 1H), 4.30-4.05 (m, 4H), 2.04-1.87 (m, 2H), 1.77-1.64 (m, 2H), 1.46-1.34 (m, 2H), 1.21-1.12 (m,2H). Example 24: Synthetic Route to Compound 34

[0192] [ka]

[0193] Step 1: Compound 34-C 1-Bromo-3-(4-bromobutoxy)benzene [ka] In a 100 mL single-neck flask, compound 34-A (m-bromophenol, 1 g, 1.0 eq) and compound 34-B (1,4-dibromobutane, 6.24 g, 5.0 eq) were dissolved in DMF (12 mL). Potassium carbonate (4 g, 5.0 eq) was added with stirring at room temperature, and the mixture was heated to 70 °C and reacted for 20 minutes. TLC monitoring confirmed the completion of the reaction. The reaction solution was cooled to room temperature, poured into 100 mL of water, and extracted three times with ethyl acetate (50 mL). The combined organic phases were backwashed twice with 100 mL of water and once with saturated sodium chloride, then dried and concentrated. The crude product was separated and purified by silica gel chromatography (petroleum ether:ethyl acetate = 40:1) to obtain compound 34-C (1-bromo-3-(4-bromobutoxy)benzene, 2.36 g, 60% purity) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ 7.15-7.11 (m, 1H), 7.08-7.04 (m, 2H), 6.83-6.80 (m, 1H), 3.98 (t, J = 6.0 Hz, 2H), 3.50-3.46 (m, 2H), 2.10-2.07 (m, 2H), 1.97-1.92 (m, 2H).

[0194] Step 2: Compound 34-E 4-(3-bromophenoxy)-N-(3-nitrobenzyl)butan-1-amine [ka] In a 100 mL single-neck flask, 1-bromo-3-(4-bromobutyloxy)benzene (2.36 g, 1.0 eq) (compound 34-C) and 3-nitrobenzylamine hydrochloride (4.36 g, 3.0 eq) (compound 34-D) were dissolved in 20 mL of DMF. Potassium carbonate (8.5 g, 8.0 eq) and potassium iodide (1.92 g, 1.5 eq) were added with stirring at room temperature, and the mixture was stirred at 40 °C for 3 hours. TLC monitoring confirmed the completion of the reaction. The reaction solution was cooled to room temperature, poured into 160 mL of water, and extracted twice with ethyl acetate (40 mL). The combined organic phases were backwashed once with 150 mL of water and once with saturated sodium chloride, then dried and concentrated. The crude product was separated and purified by silica gel chromatography (petroleum ether: ethyl acetate: 7M ammonia in methanol = 10:1:0.1) to obtain compound 34-E, 4-(3-bromophenoxy)-N-(3-nitrobenzyl)butan-1-amine (1.18 g), as a pale yellow oil. LC_MS: (ES+): m / z 380.00 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.22 (m, 1H), 8.12-8.10 (m, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.12 (t, J = 8.2 Hz, 1H), 7.07-7.05 (m, 1H), 7.04-7.03 (m, 1H), 6.82-6.79 (m, 1H), 3.96 (t, J = 6.4 Hz, 2H), 3.91 (s, 2H), 2.71 (t, J = 7.0 Hz, 2H), 1.88-1.83 (m, 2H), 1.73-1.66 (m, 2H).

[0195] Step 3: Compound 34-F tert-butyl (4-(3-bromophenoxy)butyl)(3-nitrobenzyl)carbamate [ka] In a 100 mL single-neck flask, compound 34-E, 4-(3-bromophenoxy)-N-(3-nitrobenzyl)butan-1-amine (1.18 g, 1.0 eq) and triethylamine (380 mg, 1.2 eq) were dissolved in 20 mL of dichloromethane. BocO (815 mg, 1.2 eq) was added with stirring at room temperature and the mixture was stirred for 4 hours. TLC monitoring confirmed the completion of the reaction. The reaction solution was poured into 30 mL of water and extracted twice with 20 mL of dichloromethane. The combined organic phases were backwashed with 30 mL of water and once with saturated aqueous sodium chloride (30 mL), then dried and concentrated. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate=6:1) to give compound 34-F, tert-butyl (4-(3-bromophenoxy)butyl)(3-nitrobenzyl)carbamate (1.3 g) as a colorless oil. LC_MS: (ES+): m / z 380.55 [M-100] + . 1 H NMR (400 MHz, CDCl3): δ 8.14-8.12 (m, 2H), 7.57 (brs, 1H), 7.52-7.48 (m, 2H), 7.14-7.10 (m, 1H), 7.08-7.06 (m, 1H), 7.02-7.01 (m, 1H), 6.80-6.78 (m, 1H), 4.53 (brs, 2H), 3.93 (t, J = 4.8 Hz, 2H), 3.28-3.27 (m, 2H), 1.75-1.74 (m, 4H), 1.48-1.45 (m, 9H).

[0196] Step 4: Compound 34-G (3-nitrobenzyl)(4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)butyl)carbamate tert-butyl [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 12 in Example 8. LC_MS: (ES+): m / z 526.90 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.12 (d, J = 7.6 Hz, 2H), 7.57 (brs, 1H), 7.51-7.47 (m, 1H), 7.39 (d, J = 7.2 Hz, 1H), 7.30-7.28 (m, 2H), 6.97-6.95 (m, 1H), 4.57-4.47 (m, 2H), 3.98 (t, J = 5.6 Hz, 2H), 3.34-3.27 (m, 2H), 1.74 (brs, 4H), 1.49-1.45 (m, 9H), 1.34 (s, 12H).

[0197] Step 5: Compound 34-I (tert-butyl 4-(3-(2,5-dichloropyrimidin-4-yl)phenoxy)butyl)(3-nitrobenzyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 7 of Compound 12 in Example 8. LC_MS: (ES+): m / z 547.10 [M+H] + .

[0198] Step 6: Compound 34-J: tert-butyl (3-aminobenzyl)(4-(3-(2,5-dichloropyrimidin-4-yl)phenoxy)butyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 4 of Compound 2 in Example 1. LC_MS: (ES+): m / z 516.90 [M+H] + .

[0199] Step 7: Compound 34-K tert-butyl 2 5-chloro-11-oxa-3,6-diaza-2(4,2)-pyrimidine-1,4(1,3)-dibenzenecycloundecane-6-carboxylate [ka] For the synthesis of this step, see the synthesis process of Step 8 of Compound 35 in Example 24. LC_MS: (ES+): m / z 481.15 [M+H] + . 1 H NMR (400 MHz, d6-DMSO): δ 9.89 (s, 1H), 8.62 (s, 1H), 8.20 (brs, 1H), 7.64-7.62 (m, 2H), 7.43 (t, J = 8.0 Hz, 1H), 7.27 (t, J = 7.8 Hz, 1H), 7.18-7.16 (m, 1H), 7.10-7.08 (m, 1H), 6.94 (d, J = 7.6 Hz, 1H), 4.28 (s, 2H), 4.19 (brs, 2H), 3.17 (brs, 2H), 1.68 (brs, 4H), 1.38 (s, 9H).

[0200] Step 8: Compound 34 2 5 -chloro-11-oxa-3,6-diaza-2(4,2)-pyrimidine-1,4(1,3)-dibenzenecycloundecane [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 25 in Example 15. LC_MS: (ES+): m / z 381.90 [M+H] + . 1H NMR (400 MHz, d6-DMSO): δ 9.97 (s, 1H), 8.66 (s, 1H), 8.30 (s, 1H), 7.61 (m, 1H), 7.50-7.48 (m, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.20-7.16 (m, 3H), 4.28 (t, J = 5.8 Hz, 2H), 4.06 (s, 2H), 3.04-3.00 (m, 2H), 1.83-1.76 (m, 4H). Example 25: Synthetic Route to Compound 35

[0201] [ka]

[0202] Step 1: Compound 35-C 3-((3-nitrobenzyl)amino)propan-1-ol [ka] A mixture of 3-nitrobenzaldehyde (3 g, 19.8 mmol), 3-aminopropan-1-ol (1.5 g, 19.8 mmol), and acetic acid (2.4 g, 39.6 mmol) in methanol (30 mL) was stirred at room temperature for 30 minutes, and then sodium cyanoborohydride (2.5 g, 39.6 mmol) was added. The resulting mixture was stirred at room temperature for 15 hours. TLC monitoring confirmed the completion of the reaction. The reaction mixture was concentrated, and the residue was quenched with saturated aqueous sodium bicarbonate (30 mL). The aqueous phase was extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting product was separated and purified by silica gel column chromatography (eluted with 5% methanol in dichloromethane) to give compound 35-C, 3-((3-nitrobenzyl)amino)propan-1-ol (3.58 g, 86%), as a pale yellow oil. LC_MS: (ES+): m / z 211.00 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 1.74-1.79 (m, 2H), 2.90 (t, J = 6.0 Hz, 2H), 3.81 (t, J = 5.2 Hz, 2H), 3.92 (s, 2H), 7.52 (t, J = 7.6 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 8.12-8.17 (m, 2H).

[0203] Step 2: Compound 35-D tert-butyl (3-hydroxypropyl)(3-nitrobenzyl)carbamate [ka] Di-tert-butyl dicarbonate (985 mg, 4.52 mmol) was added to a solution of 3-((3-nitrobenzyl)amino)propan-1-ol (950 mg, 4.52 mmol), compound 35-C, and sodium carbonate (958 mg, 9.04 mmol) in tetrahydrofuran (10 mL) and water (10 mL) at 0° C. The reaction mixture was heated to room temperature and stirred for 2 hours. TLC monitoring confirmed the completion of the reaction. The reaction mixture was partitioned between ethyl acetate (20 mL) and water (20 mL). The organic layer was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 35-D, tert-butyl (3-hydroxypropyl)(3-nitrobenzyl)carbamate (1.25 g, crude), as a yellow oil. The product was used directly in the next step without further purification. LC_MS: (ES+): m / z 254.80 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 1.46 (s, 9H), 1.70 (s, 2H), 3.39-3.61 (m, 5H), 4.47 (s, 2H), 7.50-7.59 (m, 2H), 8.13-8.15 (m, 2H).

[0204] Step 3: Compound 35-E 3-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)propyl 4-methylbenzenesulfonate [ka] To a solution of tert-butyl (3-hydroxypropyl)(3-nitrobenzyl)carbamate (1.46 g, 4.71 mmol) and triethylamine (953 mg, 9.42 mmol) in dichloromethane (10 mL) at 0°C, 4-toluenesulfonyl chloride (898 mg, 4.71 mmol) was added. The reaction mixture was heated to room temperature and stirred for 14 hours. TLC monitoring confirmed the completion of the reaction. The reaction mixture was partitioned between dichloromethane (20 mL) and water (20 mL). The organic layer was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to give 3-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)propyl 4-methylbenzenesulfonate (1.48 g) as a colorless oil, compound 35-E. LC_MS: (ES+): m / z 364.9 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 1.44 (s, 9H), 1.90 (s, 2H), 2.45 (s, 3H), 3.27 (s, 2H), 4.04 (t, J = 6.0 Hz, 2H), 4.46 (s, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.49-7.54 (m, 2H), 7.77 (d, J = 8.4 Hz, 2H), 8.06-8.14 (m, 2H).

[0205] Step 4: Compound 35-F (tert-butyl 3-((3-bromo-4-methylphenyl)(tert-butoxycarbonyl)amino)propyl)(3-nitrobenzyl)carbamate [ka] Sodium hydride (60% in kerosene) (203 mg, 5.08 mmol) was added to a solution of tert-butyl (3-bromo-4-methylphenyl)carbamate (compound 12-G) in anhydrous N,N-dimethylformamide (10 mL) at 0°C, and the reaction mixture was stirred at room temperature for 30 minutes. Next, 3-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)propyl 4-methylbenzenesulfonate (1.08 g, 2.54 mmol) (compound 35-E) was added to the system at 0°C, and the reaction mixture was stirred at room temperature for 15 hours. TLC monitoring confirmed the completion of the reaction. The reaction mixture was quenched by adding water (100 mL) and extracted with ethyl acetate (30 mL × 2). The organic layers were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (eluted with a 20% ethyl acetate-petroleum ether solution) to obtain compound 35-F, tert-butyl (3-((3-bromo-4-methylphenyl)(tert-butoxycarbonyl)amino)propyl)(3-nitrobenzyl)carbamate (930 mg, 63%), as a yellow oil. 1 H NMR (400 MHz, CDCl3): δ 1.40 (s, 9H), 1.46 (s, 9H), 1.72-1.75 (m, 2H), 2.38 (s, 3H), 3.19-3.23 (m, 2H), 3.60 (t, J = 6.8 Hz, 2H), 4.47 (s, 2H), 6.96-7.00 (m, 1H), 7.16 (d, J = 8.0 Hz, 2H), 7.31 (s, 1H), 7.46-7.52 (m, 2H), 8.06-8.12 (m, 2H).

[0206] Step 5: Compound 35-G tert-butyl (3-((tert-butyloxycarbonyl)(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)propyl)(3-nitrobenzyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 12 in Example 8. LC_MS: (ES+): m / z 725.15 [M+H] + 1 H NMR (400 MHz, CDCl3): δ 1.33 (s, 12H), 1.38 (s, 9H), 1.46 (s, 9H), 1.75 (s, 2H), 2.52 (s, 3H), 3.19-3.24 (m, 2H), 3.62 (t, J = 6.4 Hz, 2H), 4.46 (s, 2H), 7.05-7.11 (m, 2H), 7.44-7.52 (m, 3H), 8.07-8.11 (m, 2H).

[0207] Step 6: Compound 35-I tert-butyl (3-((tert-butoxycarbonyl)(3-(2,5-dichloropyrimidin-4-yl)-4-methylphenyl)amino)propyl)(3-nitrobenzyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 7 of Compound 12 in Example 8. LC_MS: (ES+): m / z 645.95 [M+H] + . 1H NMR (400 MHz, CDCl3): δ 1.39 (s, 9H), 1.44 (s, 9H), 1.75-1.79 (m, 2H), 2.21 (s, 3H), 3.19-3.25 (m, 2H), 3.63 (t, J = 4.8 Hz, 2H), 4.47 (s, 2H), 7.07-7.17 (m, 2H), 7.29-7.34 (m, 1H), 7.46-7.52 (m, 2H), 8.05-8.09 (m, 2H), 8.69 (s, 1H).

[0208] Step 7: Compound 35-J tert-butyl 3-aminobenzyl (3-((tert-butoxycarbonyl)(3-(2,5-dichloropyrimidin-4-yl)-4-methylphenyl)amino)propyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 4 of Compound 2 in Example 1. LC_MS: (ES+): m / z 517.60 [M+H] + 1 H NMR (400 MHz, CDCl3): δ 1.40 (s, 9H), 1.43 (s, 9H), 1.76 (s, 2H), 2.21 (s, 3H), 3.13-3.21 (m, 2H), 3.61-3.66 (m, 4H), 4.30 (s, 2H), 6.50-6.55 (m, 3H), 7.03-7.10 (m, 2H), 7.17 (s, 1H), 7.25 (s, 1H), 8.68 (s, 1H).

[0209] Step 8: Compound 35-K2 5 -chloro-1 6 -methyl-3,6,10-triaza-2(4,2)-pyrimidine-1,4(1,3)-dibenzenecyclodecane-6,10-dicarboxylate di-tert-butyl [ka] Tetrakis(triphenylphosphine)palladium (51 mg, 0.044 mmol) was added to a solution of compound 35-J (tert-butyl 3-aminobenzyl(3-(tert-butoxycarbonyl)(3-(2,5-dichloropyrimidin-4-yl)-4-methylphenyl)amino)propyl)carbamate (90 mg, 0.146 mmol), 1,1'-bis(diphenylphosphino)ferrocene (49 mg, 0.088 mmol), and cesium carbonate (143 mg, 0.44 mmol) in 1,4-dioxane (30 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was purged with nitrogen gas three times. The reaction mixture was stirred at 110°C for 16 hours. TLC monitoring confirmed the completion of the reaction. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (eluted with 25% ethyl acetate in petroleum ether) to give compound 35-K, a white solid. 5 -chloro-1 6 To the obtained product, di-tert-butyl 3,6,10-triaza-2(4,2)-pyrimidine-1,4(1,3)-dibenzenecyclodecane-6,10-dicarboxylate (35 mg, 41%) was obtained. LC_MS: (ES+): m / z 580.25 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 1.44 (s, 9H), 1.45 (s, 9H), 1.85 (s, 2H), 2.31 (s, 3H), 2.99-3.04 (m, 1H), 3.40-3.48 (m, 2H), 4.06-4.15 (m, 2H), 4.25-4.34 (m, 1H), 6.83-6.85 (s, 2H), 7.23 (s, 4H), 7.30 (s, 1H), 8.20-8.27 (m, 1H), 8.39 (s, 1H).

[0210] Step 9: Compound 35 2 5 -chloro-1 6-Methyl-3,6,10-triaza-2(4,2)-pyrimidine-1,4(1,3)-dibenzenecyclodecane [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 25 in Example 15. LC_MS: (ES+): m / z 380.10 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 1.46-1.56 (m, 1H), 1.70-1.80 (m, 1H), 2.12 (s, 3H), 2.69-2.75 (m, 1H), 3.00-3.04 (m, 1H), 3.40-3.52 (m, 3H), 3.73 (d, J = 12.8 Hz, 1H), 5.61-5.65 (m, 1H), 6.66-6.68 (m, 1H), 6.72-6.73 (m, 1H), 6.86 (d, J = 7.6 Hz, 1H), 6.96 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 8.58 (s, 1H), 8.65 (s, 1H), 9.91 (s, 1H). Example 26: Synthetic Route to Compound 36

[0211] [ka]

[0212] Step 1: Compound 36-C 2-Bromo-4-(4-bromobutoxy)-1-methylbenzene [ka] For the synthesis of this step, see the synthesis process of Step 1 of Compound 34 in Example 24. 1H NMR (400 MHz, CDCl3): δ 7.11 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 2.8 Hz, 1H), 6.76-6.73 (m, 1H), 3.95 (t, J = 6.0 Hz, 2H), 3.50-3.48 (m, 2H), 2.32 (s, 3H), 2.07-2.05 (m, 2H), 1.96-1.91 (m, 2H).

[0213] Step 2: Compound 36-E 4-(3-bromo-4-methylphenoxy)-N-(3-nitrobenzyl)butan-1-amine [ka] For the synthesis of this step, see the synthesis process of Step 2 of Compound 34 in Example 24. LC_MS: (ES+): m / z 392.7 [M+H] + .

[0214] Step 3: Compound 36-F tert-butyl (4-(3-bromo-4-methylphenoxy)butyl)(3-nitrobenzyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 3 of Compound 34 in Example 24. 1 H NMR (400 MHz, CDCl3): δ 8.13-8.07 (m, 2H), 7.57 (brs, 1H), 7.52-7.48 (m, 1H), 7.10 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 6.73-6.70 (m, 1H), 4.54-4.50 (m, 2H), 3.91 (t, J = 5.4 Hz, 2H), 3.35-.3.25 (m, 2H), 2.32 (s, 3H), 1.72 (brs, 4H),1.49-1.44 (m, 9H).

[0215] Step 4: Compound 36-G tert-butyl (4-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxybutyl) 3-nitrobenzyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 12 in Example 8. 1 H NMR (400 MHz, CDCl3): δ 8.13-8.11 (m, 2H), 7.56 (brs, 1H), 7.52-7.47 (m, 1H), 7.25 (s, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.84-6.81 (m, 1H), 4.54-4.50 (m, 2H), 3.94 (t, J = 5.4 Hz, 2H),3.34-.3.26 (m, 2H),2.46 (s, 3H), 1.72 (brs, 4H),1.49-1.43 (m, 9H), 1.26 (s, 12H).

[0216] Step 5: Compound 36-I tert-butyl (4-(3-(2,5-dichloropyrimidin-4-yl)-4-methylphenoxy)butyl)(3-nitrobenzyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 7 of Compound 12 in Example 8. LC_MS: (ES+): m / z 561.10 [M+H] + .

[0217] Step 6: Compound 36-J: tert-butyl (3-aminobenzyl)(4-(3-(2,5-dichloropyrimidin-4-yl)-4-methylphenoxy)butyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 4 of Compound 2 in Example 1. LC_MS: (ES+): m / z 530.95 [M+H] + .

[0218] Step 7: Compound 36-K tert-butyl 2 5 -chloro-1 6 -Methyl-11-oxy-3,6-diaza-2(4,2)-pyrimidine-1,4(1,3)-dibenzenecycloundecane-6-carboxylate [ka] For the synthesis of this step, see the synthesis process of Step 8 of Compound 35 in Example 24. LC_MS: (ES+): m / z 495.20 [M+H] + . 1 H NMR (400 MHz, d6-DMSO): δ 9.87 (s, 1H), 8.60 (s, 1H), 8.08 (brs, 1H), 7.24-7.20 (m, 2H), 7.14 (d, J = 2.8 Hz, 1H), 7.05-7.02 (m, 2H), 6.88 (d, J = 7.6 Hz, 1H), 4.31-4.17 (m, 4H), 3.21 (brs, 1H), 2.99 (brs, 1H), 2.14 (s, 3H), 1.70-1.59 (m, 4H), 1.35 (s, 9H).

[0219] Step 8: Compound 36 2 5 -chloro-1 6 -Methyl-11-oxy-3,6-diaza-2(4,2)-pyrimidine-1,4(1,3)-dibenzenecycloundecane [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 25 in Example 15. LC_MS: (ES+): m / z 395.25 [M+H] + . 1 H NMR (400 MHz, d6-DMSO): δ 9.92 (s, 1H), 8.63 (s, 1H), 8.23 ​​(brs, 1H), 7.28 (t, J = 7.6 Hz, 1H), 7.23 (d, J = 2.4 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.08-6.99 (m, 3H), 4.36-4.30 (m, 1H), 4.18-4.08 (m, 1H), 3.93-3.84 (m, 2H), 2.91-2.79 (m, 2H), 2.08 (s, 3H), 1.85-1.57 (m, 4H). Example 27: Synthetic Route to Compound 37

[0220] [ka]

[0221] Step 1: Compound 37-B tert-butyl (3-bromophenyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 4 of Compound 12 in Example 8. LC-MS: (ES+): m / z 217.0 [M+1-56] + .

[0222] Step 2: Compound 37-C tert-Butyl Allyl(3-bromophenyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 5 of Compound 12 in Example 8.

[0223] Step 3: Compound 37-D tert-butyl allyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 12 in Example 8.

[0224] Step 4: Compound 37-F tert-butyl allyl(3-(2-chloro-5-fluoropyrimidin-4-yl)phenyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 7 of Compound 12 in Example 8. 1 H NMR (400 MHz, CDCl3) δ: 8.55 (d, J = 4.0 Hz, 1H), 8.07 (s, 1H), 7.97 (dd, J = 4.0, 8.0 Hz, 1H), 7.53 - 7.45 (m, 2H), 6.01 - 5.02 (m, 1H), 5.23 - 5.17 (m, 2H), 4.31 (d, J = 8.0 Hz, 2H), 1.50 (s, 9H).

[0225] Step 5: Compound 37-G tert-butyl allyl(3-(2-((3-(allyl(tert-butoxycarbonyl)amino)phenyl)amino)-5-fluoropyrimidin-4-yl)phenyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 8 of Compound 12 in Example 8. LC-MS: (ES+): m / z 574.0 [M−H] + .

[0226] Step 6: Compound 37-H Di-tert-butyl(Z)-2 5 -Fluoro-3,5,10-triaza-2(4,2)-pyrimidine-1,4(1,3)-dibenzenecyclooctan-7-ene-5,10-tricarboxylic acid salt [ka] For the synthesis of this step, see the synthesis process of Step 9 of Compound 12 in Example 8.

[0227] Step 7: Compound 37 (Z)-2 5 -Fluoro-3,5,10-triaza-2(4,2)-pyrimidin-1,4(1,3)-dibenzenecyclooctan-7-ene [ka] For the synthesis of this step, see the synthesis process of Step 10 of Compound 12 in Example 8. LC-MS: (ES+): m / z 348.12 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ: 9.42 (s, 1H), 8.54 (d, J = 4.0 Hz, 1H), 7.52 (brs, 1H), 7.29 (s, 1H), 7.23 - 7.17 (m, 2H), 6.92 (brs, 1H), 6.85 (dd, J = 4.0, 8.0 Hz, 1H), 6.40 - 6.31 (m, 3H), 5.99 (brs, 1H), 5.52 (d, J = 16.0 Hz, 1H), 5.42 (d, J = 16.0 Hz, 1H), 3.71 (s, 2H), 3.57 (s, 2H). Example 28: Synthetic Route to Compound 38

[0228] [ka]

[0229] Step 1: Compound 38-A tri-tert-butyl (Z)2 5 -Fluoro-3,5,10-triaza-2(4,2)-pyrimidine-1,4(1,3)-dibenzenecyclodecane-3,5,10-tricarboxylate [ka] For the synthesis of this step, see the synthesis process of Step 3 of Compound 25 in Example 15. LC-MS: (ES+): m / z 648.3 [M+H] + .

[0230] Step 2: Compound 38-B Tri-tert-butyl 2 5 -Fluoro-3,5,10-triaza-2(4,2)-pyrimidine-1,4(1,3)-dibenzenecyclodecane-3,5,10-tricarboxylate [ka] For the synthesis of this step, see the synthesis process of Step 1 of Compound 4 in Example 2. LC-MS: (ES+): m / z 650.4 [M+H] + .

[0231] Step 2: Compound 38 2 5 -Fluoro-3,5,10-triaza-2(4,2)-pyrimidine-1,4(1,3)-dibenzenecyclodecane [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 25 in Example 15. LC-MS: (ES+): m / z 350.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ: 9.79 (s, 1H), 8.59 (d, J = 4.0 Hz, 1H), 8.04 (s, 1H), 7.35 (s, 1H), 7.31 - 7.15 (m, 3H), 6.82 - 6.75 (m, 2H), 6.62 (s, 1H),3.25 (s, 2H), 3.13 (t, J = 4.0 Hz, 2H), 1.73 - 1.62 (m, 2H), 1.58 - 1.51 (m, 2H). Example 29: Synthetic Route to Compound 39

[0232] [ka]

[0233] Step 1: Compound 39-B tert-butyl (3-bromo-4-methoxyphenyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 4 of Compound 12 in Example 8.

[0234] Step 2: Compound 39-C tert-butyl allyl(3-bromo-4-methoxyphenyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 5 of Compound 12 in Example 8. 1H NMR (400 MHz, CDCl3) δ: 7.44 (d, J = 4.0 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 6.85 (dd, J = 4.0, 8.0 Hz, 1H), 5.95 - 5.85 (m, 1H), 5.18 - 5.12 (m, 2H), 4.18 (d, J = 8.0 Hz, 2H), 3.90 (s, 3H), 1.46 (s, 9H).

[0235] Step 3: Compound 39-D tert-butyl allyl (4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 12 in Example 8. 1 H NMR (400 MHz, CDCl3) δ: 7.44 (s, 1H), 7.15 (d, J = 8.0 Hz, 1H), 6.85 (dd, J = 4.0, 8.0 Hz, 1H), 5.93 - 5.87 (m, 1H), 5.18 - 5.10 (m, 2H), 4.18 (d, J = 8.0 Hz, 2H), 3.90 (s, 3H), 1.46 (s, 12H), 1.31 (s, 9H).

[0236] Step 4: Compound 39-F tert-butyl allyl (3-(2-chloro-5-fluoropyrimidin-4-yl)-4-methoxyphenyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 7 of Compound 12 in Example 8. 1H NMR (400 MHz, CDCl3) δ: 8.49 (d, J = 4.0 Hz, 1H), 7.42 - 7.37 (m, 2H), 6.97 (d, J = 8.0 Hz, 1H), 5.98 - 5.89 (m, 1H), 5.21 - 5.16 (m, 2H), 4.24 (d, J = 8.0 Hz, 2H), 3.86 (s, 3H), 1.47 (s, 9H).

[0237] Step 5: Compound 39-G tert-butyl allyl (3-(2-((3-(allyl(tert-butoxycarbonyl)amino)phenyl)amino)-5-fluoropyrimidin-4-yl)-4-methoxyphenyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 8 of Compound 12 in Example 8. LC-MS: (ES+): m / z 606.0 [M+H] + .

[0238] Step 6: Compound 39-H Di-tert-butyl (Z)-2 5 -Fluoro-1 6 -Methoxy-3,5,10-triaza-2(4,2)-pyrimidine-1,4(1,3)-dibenzenecyclooctan-7-ene-5,10-dicarboxylic acid salt [ka] For the synthesis of this step, see the synthesis process of Step 9 of Compound 12 in Example 8.

[0239] Step 7: Compound 39 (Z)-2 5 -Fluoro-1 6 -Methoxy-3,5,10-triaza-2(4,2)-pyrimidin-1,4(1,3)-dibenzenecyclooctan-7-ene [ka] For the synthesis of this step, see the synthesis process of Step 10 of Compound 12 in Example 8. LC-MS: (ES+): m / z 378.17 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ: 9.41 (s, 1H), 8.46 (d, J = 4.0 Hz, 1H), 7.76 (brs, 1H), 7.00 - 6.84 (m, 4H), 6.71 (s, 1H), 6.46 (s, 1H), 6.22 (s, 1H), 5.48 (s, 2H), 3.74 (s, 3H), 3.69 (s, 2H), 3.57 (s, 2H). Example 30: Synthetic Route to Compound 40

[0240] [ka]

[0241] Step 1: Compound 40-A tri-tert-butyl (Z)2 5 -Fluoro-1 6 -Methoxy-3,5,10-triaza-2(4,2)-pyrimidine-1,4(1,3)-dibenzenecyclodecane-7-ene-3,5,10-tricarboxylate [ka] For the synthesis of this step, see the synthesis process of Step 3 of Compound 25 in Example 15. LC-MS: (ES+): m / z 678.3 [M+H] + .

[0242] Step 2: Compound 40-B Tri-tert-butyl 2 5 -Fluoro-1 6-Methoxy-3,5,10-triaza-2(4,2)-pyrimidine-1,4(1,3)-dibenzenecyclodecane-3,5,10-tricarboxylate [ka] For the synthesis of this step, see the synthesis process of Step 1 of Compound 4 in Example 2. LC-MS: (ES+): m / z 680.3 [M+H] + .

[0243] Step 3: Compound 40 2 5 -Fluoro-1 6 -Methoxy-3,5,10-triaza-2(4,2)-pyrimidine-1,4(1,3)-dibenzenecyclodecane [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 25 in Example 15. LC-MS: (ES+): m / z 380.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ: 9.51 (s, 1H), 8.51 (s, 1H), 8.02 (s, 1H), 7.04 - 6.87 (m, 4H), 6.56 (s, 1H), 6.35 (s, 1H), 3.75 (s, 3H), 3.19 (d, J = 8.0 Hz, 2H), 3.06 (t, J = 8.0 Hz, 2H), 1.64 - 1.55 (m, 2H), 1.51 - 1.43 (m, 2H). Example 31: Synthetic Route to Compound 41

[0244] [ka]

[0245] Step 1: Compound 41-C 2-(2-(4-nitro-1H-pyrazol-1-yl)ethoxy)ethan-1-ol [ka] A 100 ml three-neck flask and a thermometer were prepared, and diethylene glycol (7 g, 66.3 mmol) (compound 41-A), 4-nitropyrazole (5 g, 44.2 mmol) (compound 41-B), and triphenylphosphine (23.2 g, 88.4 mmol) were added to dry tetrahydrofuran (50 ml). The mixture was purged with nitrogen gas three times, and the temperature was controlled between 0 ° C and 5 ° C. Diisopropyl azodicarboxylate (15.4 g, 88.4 mmol) was slowly added dropwise to the reaction solution, which was then stirred at room temperature overnight. TLC and LCMS monitoring confirmed the completion of the reaction. The reaction solution was evaporated to dryness using a rotary evaporator, and the crude product was slurried in methyl tert-butyl ether for 30 minutes to precipitate a solid (triphenoxyphos). The filtrate was collected and evaporated to dryness using a rotary evaporator. The crude filtrate was separated and purified by silica gel column chromatography (PE:EA = 5:1 to DCM:MeOH = 15:1) to obtain compound 41-C, 2-(2-(4-nitro-1-hydropyrazol-1-yl)ethoxy)ethan-1-ol (6.5 g), as a pale yellow liquid. LC_MS: (ES+): m / z 201.75 [M+H] + .

[0246] Step 3: Compound 41-D 2-(2-(4-nitro-1H-pyrazol-1-yl)ethoxy)ethyl 4-methylbenzenesulfonate [ka] For the synthesis of this step, see the synthesis process of Step 3 of Compound 35 in Example 25. LC_MS: (ES+): m / z 356.40 [M+H] + .

[0247] Step 4: Compound 41-E (3-bromo-4-methylphenyl)(2-(2-(4-nitro-1H-pyrazol-1-yl)ethoxy)ethyl)carbamate tert-butyl [ka] For the synthesis of this step, see the synthesis process of Step 4 of Compound 35 in Example 25. LC_MS: (ES+): m / z 412.20 [M-56] + . 1 H NMR (400 MHz, CDCl3): δ 8.06 (d, J = 5.2 Hz, 2H), 7.39 (brs, 1H), 7.17 (d, J = 8.0 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 4.26 (t, J = 4.8 Hz, 2H), 3.79-3.73 (m, 4H), 3.58 (t, J = 5.6 Hz, 1H), 2.38 (s, 3H), 1.42 (s, 9H).

[0248] Step 5: Compound 41-F tert-butyl(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(2-(2-(4-nitro-1H-pyrazol-)1-yl)ethoxy)ethyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 12 in Example 8. LC_MS: (ES+): m / z 417.05 [M-100] + .

[0249] Step 6: Compound 41-H (3-(2,5-dichloropyrimidin-4-yl)-4-methylphenyl)(2-(2-(4-nitro-1H-pyrazol-1-yl)ethoxy)ethyl)carbamate tert-butyl ester [ka] For the synthesis of this step, see the synthesis process of Step 7 of Compound 12 in Example 8. LC_MS: (ES+): m / z 480.75 [M-56] + . 1 H NMR (400 MHz, CDCl3): δ 8.69 (s, 1H), 8.02 (s, 2H), 7.29-7.26 (m, 2H), 7.21-7.08 (m, 2H), 4.28 (t, J = 5.0 Hz, 2H), 3.80-3.74 (m, 4H), 3.59 (t, J = 5.4 Hz, 2H), 2.21 (s, 3H), 1.40 (s, 9H).

[0250] Step 7: Compound 41-I tert-butyl(E)-2 5 -chloro-1 6 -methyl-4 1 H-7-oxa-3,10-diaza-2(4,2)-pyrimidine-4(4,1)-pyrazole-1(1,3)-benzenecyclodecane-10-carboxylate [ka] For the synthesis of this step, see the synthesis process of Step 8 of Compound 35 in Example 24. LC_MS: (ES+): m / z 471.25 [M+H] + . 1H NMR (400 MHz, CDCl3): δ 8.41 (s, 1H), 8.36 (s, 1H), 7.49 (brs, 1H), 7.31 (s, 1H), 7.24 (s, 2H), 6.98 (s, 1H), 4.32-4.27 (m, 1H), 4.23-4.17 (m, 1H), 3.90-3.85 (m, 1H), 3.79-3.75 (m, 1H), 3.68-3.62 (m, 2H), 3.57-3.49 (m, 2H), 2.36 (s, 3H), 1.42 (s, 9H).

[0251] Step 8: Compound 41(E)-2 5 -chloro-1 6 -methyl-4 1 H-7-oxa-3,10-diaza-2(4,2)-pyrimidine-4(4,1)-pyrazole-1(1,3)-benzenecyclodecane [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 25 in Example 15. LC_MS: (ES+): m / z 371.30 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.51 (s, 1H), 8.34 (s, 1H), 7.34 (s, 1H), 7.07-7.02 (m, 3H), 6.72-6.69 (m, 1H), 4.38-4.23 (m, 2H), 3.94-3.89 (m, 1H), 3.75-3.70 (m, 1H), 3.67-3.56 (m, 2H), 3.46-3.40 (m, 2H), 2.28 (s, 3H). Example 32: Synthetic Routes for Compounds 42 and 43

[0252] [ka]

[0253] Step 1: Compound 43-C 2-(trimethylsilyl)ethyl 3-((tert-butoxycarbonyl)amino)pyrrolidine-1-carboxylate [ka] In a 100 mL single-neck flask, compound 43-A (tert-butyl pyrrolidin-3-ylcarbamate) (1 g, 5.37 mmol) and compound 43-B (2,5-dioxopyrrolidin-1-yl(2-(trimethylsilyl)ethyl)carbonate) (1.67 g, 6.44 mmol) were dissolved in a mixture of tetrahydrofuran (10 mL) and water (10 mL). Potassium carbonate (1.14 g, 10.74 mmol) was added and the mixture was stirred at room temperature for 2 hours. TLC monitoring confirmed the completion of the reaction. The reaction solution was poured into water (50 mL) and extracted twice with ethyl acetate (30 mL). The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 43-C, 2-(trimethylsilyl)ethyl 3-((tert-butoxycarbonyl)amino)pyrrolidine-1-carboxylate (1.85 g, crude), as a pale yellow oily liquid. The product was used directly in the next step without further purification. 1 H NMR (400 MHz, CDCl3): δ 4.61 (s, 1H), 4.19-4.14 (m, 3H), 3.62-3.59 (m, 1H), 3.46-3.41 (m, 2H), 3.25-3.17 (m, 1H), 2.12-2.10 (m, 1H), 1.84-1.80 (m, 1H), 1.44 (s, 9H), 1.01-0.97 (m, 1H), 0.03 (s, 9H).

[0254] Step 2: Compound 43-D 2-(trimethylsilyl)ethyl 3-((tert-butoxycarbonyl)(3-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)propyl)amino)pyrrolidine-1-carboxylate [ka] For the synthesis of this step, see the synthesis process of Step 4 of Compound 35 in Example 25. 1 H NMR (400 MHz, CDCl3): δ 8.12 (t, J = 8.4 Hz, 2H), 7.56-7.49 (m, 2H), 4.51-4.45 (m, 3H), 4.18 (t, J = 8.0 Hz, 2H), 3.63-3.49 (m, 2H), 3.33-3.10 (m, 6H), 2.00-1.93 (m, 2H), 1.74 (s, 2H), 1.48-1.44 (m, 18H), 0.04 (s, 9H).

[0255] Step 3: Compound 43-E (tert-butyl 3-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)propyl)(pyrrolidin-3-yl)carbamate [ka] In a 10 ml one-neck flask, compound 43-D, 2-(trimethylsilyl)ethyl 3-((tert-butoxycarbonyl)(3-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)propyl)amino)pyrrolidine-1-carboxylate (50 mg, 0.08 mmol) was dissolved in 1 ml of tetrahydrofuran, and a solution of TBAF in THF (0.1 ml, 0.08 mmol, 1 M) was added at room temperature. The mixture was stirred at 30 °C overnight. TLC monitoring confirmed the completion of the reaction. The reaction solution was poured into water (10 ml) and extracted twice with ethyl acetate (10 ml). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by thin layer chromatography (DCM:MeOH=10:1) to give compound 43-E, tert-butyl (3-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)propyl)(pyrrolidin-3-yl)carbamate (21 mg), as a colorless oil. LC_MS: (ES+): m / z 479.60 [M+H] + .

[0256] Step 4: Compound 43-F (tert-butyl 3-((tert-butyloxycarbonyl)(3-nitrobenzyl)amino)propyl)(1-(2,5-dichloropyrimidin-4-yl)pyrrolidin-3-yl)carbamate [ka] Compound 43-E (3-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)propyl)(pyrrolidin-3-yl)carbamate (66 mg, 0.138 mmol), acetonitrile (2 mL), and N,N-diisopropylethylamine (54 mg, 0.414 mmol) were sequentially added to a 10 mL single-neck flask at room temperature. The atmosphere was purged with nitrogen gas three times, and the reaction system was sealed. 2,4,5-trichloropyrimidine (38 mg, 0.207 mmol) was added to the system via a syringe. The resulting reaction system was sealed and reacted at 60°C for 2 hours. Completion of the reaction was confirmed by TLC monitoring. The reaction solution was poured into water (10 mL) and extracted three times with ethyl acetate (10 mL). The organic phases were combined, washed once with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by thin layer chromatography (DCM:MeOH=40:1) to give compound 43-F, tert-butyl (3-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)propyl)(1-(2,5-dichloropyrimidin-4-yl)pyrrolidin-3-yl)carbamate (70 mg), as a colorless viscous oil.

[0257] Step 5: Compound 43-G (tert-butyl 3-((3-aminobenzyl)(tert-butoxycarbonyl)amino)propyl)(1-(2,5-dichloropyrimidin-4-yl)pyrrolidin-3-yl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 4 of Compound 2 in Example 1. LC_MS: (ES+): m / z 595.20 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.00 (s, 1H), 7.08 (t, J = 3.6 Hz, 2H), 6.62-6.53 (m, 3H), 4.42-4.34 (m, 3H), 4.00 (s, 2H), 3.70-3.49 (m, 4H), 3.18-3.02 (m, 4H), 2.03-2.01 (m, 2H), 1.71 (s, 2H), 1.48-1.45 (m, 18H).

[0258] Step 6: Compound 42 Di-tert-butyl 2 5 -Chloro-3,6,10-triaza-2(4,2)-pyrimidine-1(1,3)-pyrrolidine-4(1,3)-benzenecyclodecane-6,10-dicarboxylate [ka] For the synthesis of this step, see the synthesis process of Step 8 of Compound 12 in Example 8. LC_MS: (ES+): m / z 560.55 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 9.32 (s, 1H), 8.04-7.99 (m, 2H), 7.22 (t, J = 8.0 Hz, 1H), 7.03-6.94 (m, 2H), 4.74-4.71 (m, 1H), 4.44 (s, 1H), 3.93-3.69 (m, 5H), 3.42 (m, 2H), 2.96 (s, 1H), 2.67 (s, 1H), 2.06-1.96 (m, 2H), 1.75 (s, 2H), 1.45-1.23 (m, 18H).

[0259] Step 7: Compound 43 25 -chloro-3,6,10-triaza-2(4,2)-pyrimidine-1(1,3)-pyrrolidine-4(1,3)-benzenecyclodecane [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 25 in Example 15. LC_MS: (ES+): m / z 360.15 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 9.25 (s, 1H), 8.45 (s, 1H), 7.95 (s, 1H), 7.13 (t, J = 7.6 Hz, 1H), 6.96-6.94 (m, 1H), 6.79 (d, J = 7.2 Hz, 1H), 3.99-3.88 (m, 1H), 3.87-3.80 (m, 2H), 3.76-3.59 (m, 3H), 3.35-3.28 (m, 3H), 2.89-2.80 (m, 2H), 2.73-2.64 (m, 2H), 2.11-2.06 (m, 1H), 1.85-1.75 (m, 1H), 1.70-1.64 (m, 1H), 1.57-1.48 (m, 1H). Example 33: Synthetic Route to Compound 44

[0260] [ka]

[0261] Step 1: Compound 44-C 4-((3-nitrobenzyl)amino)butan-1-ol [ka] For the synthesis of this step, see the synthesis process of Step 1 of Compound 35 in Example 25. LC_MS: (ES+): m / z 225.05 [M+H] +.

[0262] Step 2: Compound 44-D tert-butyl (4-hydroxybutyl)(3-nitrobenzyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 2 of Compound 35 in Example 25. LC_MS: (ES+): m / z 324.75 [M+H] + .

[0263] Step 3: Compound 44-E 4-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)butyl 4-methylbenzenesulfonate [ka] For the synthesis of this step, see the synthesis process of Step 3 of Compound 35 in Example 25. LC_MS: (ES+): m / z 378.90 [M+H-100] + .

[0264] Step 4: Compound 44-F 2-(trimethylsilyl)ethyl 3-((tert-butoxycarbonyl)(4-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)butyl)amino)pyrrolidine-1-carboxylate [ka] For the synthesis of this step, see the synthesis process of Step 4 of Compound 35 in Example 25. LC_MS: (ES+): m / z 324.75 [M+H] + . 1H NMR (400 MHz, CDCl3): δ 8.13-8.09 (m, 2H), 7.57-7.48 (m, 2H), 4.55-4.44 (m, 2H), 4.24-4.09 (m, 4H), 3.64-3.54 (m, 2H), 3.48-3.41 (m, 1H), 3.27-3.08 (m, 4H), 2.06-1.90 (m, 2H), 1.49, 1.44 (two singles, 18H), 1.30-1.22 (m, 4H), 0.99 (t, J = 8.4 Hz, 2H), 0.03 (s, 9H).

[0265] Step 5: Compound 44-G (tert-butyl 4-((tert-butyloxycarbonyl)(3-nitrobenzyl)amino)butyl)(pyrrolidin-3-yl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 3 of Compound 43 in Example 32. LC_MS: (ES+): m / z 493.30 [M+H] + .

[0266] Step 6: Compound 44-H tert-butyl (4-((tert-butyloxycarbonyl)(3-nitrobenzyl)amino)butyl)(1-(2,5-dichloropyrimidin-4-yl)pyrrolidin-3-yl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 4 of Compound 43 in Example 32. LC_MS: (ES+): m / z 639.20 [M+H] + .

[0267] Step 7: Compound 44-I (tert-butyl 4-((3-aminobenzyl)(tert-butoxycarbonyl)amino)butyl)(1-(2,5-dichloropyrimidin-4-yl)pyrrolidin-3-yl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 4 of Compound 2 in Example 1. LC_MS: (ES+): m / z 609.45 [M+H] + .

[0268] Step 8: Compound 44-J Di-tert-butyl 2 5 -Chloro-3,6,11-triaza-2(4,2)-pyrimidine-1(1,3)-pyrrolidine-4(1,3)-benzenecycloundecane-6,11-dicarboxylate [ka] For the synthesis of this step, see the synthesis process of Step 8 of Compound 12 in Example 8. LC_MS: (ES+): m / z 573.55 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 9.39 (s, 1H), 8.17 (s, 1H), 7.96 (s, 1H), 7.24-7.21 (m, 1H), 7.06-7.04 (m, 1H), 6.91-6.85 (m, 1H), 4.39 (d, J = 14.8 Hz, 1H), 4.17-4.05 (m, 3H), 3.90-3.80 (m, 2H), 3.64 (t, J = 11.2 Hz, 1H), 3.47-3.39 (m, 1H), 3.27-3.19 (m, 1H), 3.15-3.03 (m, 1H), 2.88-2.77 (m, 1H), 2.11-1.90 (m, 2H), 1.45-1.37 (m, 22H).

[0269] Step 9: Compound 44 2 5 -chloro-3,6,11-triaza-2(4,2)-pyrimidine-1(1,3)-pyrrolidine-4(1,3)-benzenecycloundecane [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 25 in Example 15. LC_MS: (ES+): m / z 373.30 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 9.25 (s, 1H), 8.34 (s, 1H), 7.93 (s, 1H), 7.15 (t, J = 7.8 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 4.02-3.98 (m, 3H),3.69-3.62 (m, 2H),3.51-3.40 (m, 2H), 3.27-3.19 (m, 2H), 2.78-2.60 (m, 4H), 2.13-2.08 (m, 1H), 1.57-1.51 (m, 1H), 1.45-1.34 (m, 2H). Example 34: Synthetic Route to Compound 45

[0270] [ka]

[0271] Step 1: Compound 45-C 3-Hydroxypyrrolidine-1-carboxylic acid 2-(trimethylsilyl)ethyl ester [ka] A 100 mL three-neck flask and a thermometer were prepared. Compound 45-A (3-hydroxypyrrolidine, 500 mg, 5.74 mmol) and triethylamine (581 mg, 5.74 mmol) were dissolved in a mixture of acetonitrile (5 mL) and water (5 mL). The temperature was controlled at 0 °C, and substrate compound 45-B (N-[2-(trimethylsilyl)ethoxycarbonyloxy]succinimide (1.5 g, 5.74 mmol) was added dropwise. After the addition was complete, the mixture was heated to room temperature and reacted for 2 hours. TLC monitoring confirmed the completion of the reaction. The reaction mixture was poured into 10 mL of water and extracted twice with ethyl acetate (10 mL). The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 45-C (3-hydroxypyrrolidine-1-carboxylic acid 2-(trimethylsilyl)ethyl ester, 1.2 g) as a colorless oil. The product was used directly in the next step without further purification. 1 H NMR (400 MHz, CDCl3): δ 4.46 (brs, 1H), 4.19-4.15 (m, 2H), 3.55-3.34 (m, 4H), 2.03-1.88 (m, 3H), 0.99 (t, J = 8.4 Hz, 2H), 0.03 (s, 9H).

[0272] Step 2: Compound 45-D 2-(trimethylsilyl)ethyl 3-(3-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)propoxy)pyrrolidine-1-carboxylate [ka] A 50 mL three-neck flask and a thermometer were prepared. Compound 45-C, 3-hydroxypyrrolidine-1-carboxylic acid 2-(trimethylsilyl)ethyl ester (172 mg, 0.74 mmol), was dissolved in DMF (2 mL). The temperature was controlled at 0 °C, and sodium hydrogen sulfide (30 mg, 0.74 mmol) was added in several portions. After purging with nitrogen gas, the mixture was heated to room temperature and reacted for 1 hour. The reaction mixture was then cooled to 0 °C, and a DMF (1 mL) solution of compound 35-E, 3-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)propyl 4-methylbenzenesulfonate (230 mg, 0.5 mmol), was slowly added dropwise. The mixture was heated to room temperature and reacted overnight. Completion of the reaction was confirmed by TLC monitoring. The reaction solution was poured into 30 mL of water and extracted three times with ethyl acetate (10 mL). The organic phases were combined, backwashed twice with water (10 ml), washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the crude product, which was separated and purified by silica gel column chromatography (PE:EA = 10:1 to 3:1) to give compound 45-D, 2-(trimethylsilyl)ethyl 3-(3-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)propoxy)pyrrolidine-1-carboxylate (113 mg), as a pale yellow oil. LC_MS: (ES+): m / z 524.20 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.13-8.04 (m, 2H), 7.55-7.48 (m, 2H), 4.58-4.39 (m, 2H), 4.18-4.14 (m, 2H), 3.98 (brs, 1H), 3.49-3.26 (m, 8H), 2.01-1.88 (m, 2H), 1.84-1.73 (m, 2H), 1.49-1.44 (m, 9H), 0.99 (t, J = 8.2 Hz, 2H), 0.03 (s, 9H).

[0273] Step 3: Compound 45-E tert-butyl (3-nitrobenzyl)(3-(pyrrolidin-3-yloxy)propyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 3 of Compound 43 in Example 32. LC_MS: (ES+): m / z 380.75 [M+H] + .

[0274] Step 4: Compound 45-F (tert-butyl (3-((1-(2,5-dichloropyrimidin-4-yl)pyrrolidin-3-yl)oxy)propyl)(3-nitrobenzyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 4 of Compound 43 in Example 32. LC_MS: (ES+): m / z 526.30 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.13-8.08 (m,2H), 7.98 (s, 1H), 7.54-7.48 (m, 2H), 4.57-4.39 (m, 2H), 4.10-4.05 (m, 1H), 4.03-3.74 (m, 4H), 3.49-3.24 (m, 4H), 2.14-2.07 (m, 1H), 1.98-1.94 (m, 1H), 1.87-1.75 (m, 2H), 1.48-1.43 (m, 9H).

[0275] Step 5: Compound 45-G tert-butyl (3-aminobenzyl)(3-((1-(2,5-dichloropyrimidin-4-yl)pyrrolidin-3-yl)oxy)propyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 4 of Compound 2 in Example 1. LC_MS: (ES+): m / z 496.40 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.16 (s, 1H), 6.93 (t, J = 7.6 Hz, 1H), 6.44-6.39 (m, 2H), 6.31 (d, J = 7.6 Hz, 1H), 5.10 (brs, 2H), 4.20 (s, 2H), 4.08 (brs, 1H), 3.96-3.56 (m, 4H), 3.41-3.36 (m, 2H), 3.21-3.06 (m, 2H), 2.06-1.85 (m, 2H), 1.69-1.63 (m, 2H), 1.39 (brs, 9H).

[0276] Step 6: Compound 45-H tert-butyl 2 5 -chloro-10-oxa-3,6-diaza-2(4,2)-pyrimidine-1(1,3)-pyrrolidine-4(1,3)-benzenecyclodecane-6-carboxylate [ka] For the synthesis of this step, see the synthesis process of Step 8 of Compound 12 in Example 8. LC_MS: (ES+): m / z 460.40 [M+H] + .

[0277] Step 7: Compound 45 2 5 -chloro-10-oxa-3,6-diaza-2(4,2)-pyrimidine-1(1,3)-pyrrolidine-4(1,3)-benzenecyclodecane [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 25 in Example 15. LC_MS: (ES+): m / z 360.30&360.50 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 9.26 (s, 1H), 8.42 (s, 1H), 7.95 (s, 1H), 7.13 (t, J = 7.8 Hz, 1H), 6.95-6.92 (m, 1H), 6.79 (d, J = 7.2 Hz, 1H), 4.14-4.09 (m, 1H), 4.02-3.96 (m, 1H), 3.89-3.66 (m, 5H), 3.60-3.53 (m, 2H), 3.40-3.38 (m, 1H), 2.85-2.79 (m, 1H), 2.71-2.66 (m, 1H), 2.17-2.11 (m, 1H), 1.99-1.92 (m, 1H), 1.73-1.66 (m, 2H). Example 35: Synthetic Route to Compound 46

[0278] [ka]

[0279] Step 1: Compound 46-C (2-hydroxyethyl)(2-(4-nitro-1H-pyrazol-1-yl)ethyl)carbamate tert-butyl [ka] In a 500 ml three-neck flask and a thermometer, N-tert-butoxycarbonyldiethanolamine (25 g, 0.12 mol) (compound 46-A), 4-nitropyrazole (6.9 g, 0.06 mol) (compound 46-B), and triphenylphosphine (32 g, 0.12 mol) were added to dry tetrahydrofuran (200 ml). The mixture was purged with nitrogen gas three times, and the temperature was controlled between 0 and 5 °C. Diisopropyl azodicarboxylate (25 g, 0.12 mol) was slowly added dropwise to the reaction solution, which was then stirred overnight at room temperature. TLC and LCMS monitoring confirmed the completion of the reaction. The reaction solution was evaporated to dryness using a rotary evaporator, and the crude product was slurried with methyl tert-butyl ether for 1 hour to precipitate a solid (triphenoxyphos), which was filtered. The filtrate was collected and evaporated to dryness using a rotary evaporator. The crude filtrate was separated and purified by silica gel column chromatography (DCM:MeOH = 100:1 to 50:1) to obtain compound 46-C, tert-butyl (2-hydroxyethyl)(2-(4-nitro-1H-pyrazol-1-yl)ethyl)carbamate (15.6 g), as a yellow oil. LC_MS: (ES+): m / z 301.15 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.17 (s, 1H), 8.08-8.06 (m, 1H), 4.38 (s, 2H), 3.71 (t, J = 5.6 Hz, 4H), 3.31-3.23 (m, 2H), 1.37 (d, J = 13.6 Hz, 9H).

[0280] Step 2: Compound 46-D tert-butyl (2-(4-nitro-1H-pyrazol-1-yl)ethyl)(2-oxoethyl)carbamate [ka] A 250 mL three-neck flask and a low-temperature thermometer were prepared. Oxalyl chloride (3.7 g, 0.03 mol) was added to dichloromethane (50 mL), protected with nitrogen gas, and the temperature was controlled between -78 °C and -60 °C. DMSO (4.6 g, 0.06 mol) was dissolved in dichloromethane (10 mL) and slowly added dropwise to the reaction solution at a temperature controlled between -78 °C and -60 °C. The reaction was continued for 30 minutes. Next, compound 46-C (2-hydroxyethyl)(2-(4-nitro-1H-pyrazol-1-yl)ethyl) tert-butyl carbamate (5.87 g, 0.02 mol) was dissolved in DCM (10 mL) and slowly added dropwise to the reaction solution at a temperature controlled between -78 °C and -60 °C. The reaction was continued for 30 minutes. Next, triethylamine (11.8 g, 0.12 mol) was dissolved in DCM (10 ml) and slowly added dropwise to the reaction solution, controlling the temperature between -78 °C and -60 °C, for 30 minutes. The cold environment was removed, and the reaction temperature was slowly heated to room temperature. TLC monitoring confirmed the completion of the reaction. The reaction solution was filtered, and the filter cake was washed with ethyl acetate (50 ml). The filtrate was collected and evaporated to dryness using a rotary evaporator. Water (50 ml) and ethyl acetate (100 ml) were added, and the layers were separated by extraction. The organic phase was washed three times with saturated aqueous ammonium chloride solution (50 ml), dried over anhydrous sodium sulfate, filtered, and centrifuged to obtain crude compound 46-D, tert-butyl (2-(4-nitro-1H-pyrazol-1-yl)ethyl)(2-oxoethyl)carbamate (5.8 g), as a yellow oil. The product was used directly in the next step without purification. LC_MS: (ES+): m / z 298.95 [M+H] + .

[0281] Step 3: Compound 46-F (2-((3-bromo-4-methylphenyl)amino)ethyl)(2-(4-nitro-1H-pyrazol-1-yl)ethyl)carbamate tert-butyl ester [ka] In a 250 ml single-neck flask, compound 46-D (2-(4-nitro-1H-pyrazol-1-yl)ethyl)(2-oxoethyl) tert-butyl carbamate (5.8 g, 0.02 mol) and compound 46-E (3.6 g, 0.02 mol) were added to anhydrous methanol (100 ml). The pH was adjusted to 4-5 with acetic acid, and the mixture was allowed to react at room temperature for 30 minutes. Sodium cyanoborohydride (2.5 g, 0.04 mol) was added in several portions, and the mixture was allowed to react overnight at room temperature. Completion of the reaction was confirmed by TLC monitoring. The reaction solution was evaporated to dryness using a rotary evaporator, and then separated and purified by silica gel column chromatography (PE:EA = 4:1) to obtain compound 46-F, tert-butyl (2-((3-bromo-4-methylphenyl)amino)ethyl)(2-(4-nitro-1H-pyrazol-1-yl)ethyl)carbamate (3.46 g), as a yellow oil. LC_MS: (ES+): m / z 468.10 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.07-8.06 (m, 2H), 6.99 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 2.0 Hz, 1H), 6.43-6.41 (m, 1H), 4.35-4.25 (m, 2H), 3.66 (t, J = 6.0 Hz, 2H), 3.31-3.12 (m, 4H), 2.27 (s, 3H), 1.45 (s, 9H).

[0282] Step 4: Compound 46-G tert-butyl (3-bromo-4-methylphenyl)(2-((tert-butoxycarbonyl)(2-(4-nitro-1H-pyrazol-1-yl)ethyl)amino)ethyl)carbamate [ka] In a 250 mL single-neck flask and reflux condenser, compound 46-F (2-((3-bromo-4-methylphenyl)amino)ethyl)(2-(4-nitro-1H-pyrazol-1-yl)ethyl) tert-butyl carbamate (1.3 g, 2.78 mmol), triethylamine (2.8 g, 27.8 mmol), and DMAP (3.4 g, 27.8 mmol) were added to tetrahydrofuran (80 mL), followed by the addition of BocO (6.07 g, 27.8 mmol) in an ice bath. After the addition, the reaction mixture was refluxed (73 °C) overnight and monitored for completion by TLC. The reaction mixture was cooled to room temperature and rotary evaporated. Saturated citric acid solution (50 mL) and ethyl acetate (50 mL) were then added, followed by extraction and separation. The organic phase was washed twice with aqueous citric acid (40 mL) and then with saturated aqueous sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and rotary evaporated to dryness to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 5:1 to 3:1) to obtain compound 46-G (1.2 g), a yellow oily compound, tert-butyl (3-bromo-4-methylphenyl)(2-((tert-butoxycarbonyl)(2-(4-nitro-1H-pyrazol-1-yl)ethyl)amino)ethyl)carbamate. LC_MS: (ES+): m / z 570.10 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.08 (s, 2H), 7.34 (s, 1H), 7.16 (d, J = 8.0 Hz, 1H), 6.99-6.98 (m, 1H), 4.33-4.27 (m,2H), 3.66-3.59 (m, 4H), 3.26-3.14 (m, 2H), 2.36(s, 3H), 1.43 (s, 9H), 1.36 (s, 9H).

[0283] Step 5: Compound 46-H tert-butyl(2-((tert-butoxycarbonyl)(2-(4-nitro-1H-pyrazol-1-yl)ethyl)amino)ethyl)(4-methyl-3-(4,4,5,5-1,3,2-dioxaborolan-2-yl)phenyl)tetramethylcarbamate [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 12 in Example 8. LC_MS: (ES+): m / z 616.15 [M+H] + .

[0284] Step 6: Compound 46-J tert-butyl (2-((tert-butoxycarbonyl)(2-(4-nitro-1H-pyrazol-1-yl)ethyl)amino)ethyl)(3-(2,5-dichloropyrimidin-4-yl)-4-methylphenyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 7 of Compound 12 in Example 8. LC_MS: (ES+): m / z 636.20 [M+H] + .

[0285] Step 7: Compound 46-K tert-butyl (2-((2-(4-amino-1H-pyrazol-1-yl)ethyl)(tert-butoxycarbonyl)amino)ethyl)(3-(2,5-dichloropyrimidin-4-yl)-4-methylphenyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 4 of Compound 2 in Example 1. LC_MS: (ES+): m / z 606.20 [M+H] + .

[0286] Step 8: Compound 46-L Di-tert-butyl(E)-2 5 -chloro-1 6 -methyl-4 1 H-3,7,10-triaza-2(4,2)-pyrimidine-4(4,1)-pyrazole-1(1,3)-benzenecyclodecane-7,10-dicarboxylate [ka] For the synthesis of this step, see the synthesis process of Step 8 of Compound 12 in Example 8. LC_MS: (ES+): m / z 570.60 [M+H] + .

[0287] Step 9: Compound 46(E)-2 5 -chloro-1 6 -methyl-4 1 H-3,7,10-triaza-2(4,2)-pyrimidine-4(4,1)-pyrazole-1(1,3)-benzenecyclodecane [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 25 in Example 15. LC_MS: (ES+): m / z 370.15 [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 9.81 (s, 1H), 8.47 (s, 1H), 8.37 (s, 1H), 7.29 (s, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 2.4 Hz, 1H), 6.68-6.65 (m, 1H), 5.85-5.81 (m, 1H), 4.29-4.22 (m, 1H), 4.10-4.09 (m, 1H), 3.98-3.94 (m, 1H), 3.22-3.19 (m, 2H), 3.04-2.98 (m, 1H), 2.94-2.87 (m, 1H), 2.76-2.73 (m, 1H), 2.37-2.31 (m, 1H), 2.16 (s, 3H). Example 36: Synthetic Route to Compound 47

[0288] [ka]

[0289] Step 1: Compound 47-B Nitrogen 4 -allyl-nitrogen 2 tert-Butyl -(1-(but-3-en-1-yl)-1H-pyrazol-4-yl)-5-chloropyrimidine-2,4-diamine(3-bromo-4-methoxyphenyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 3 of Compound 27 in Example 17. LC-MS: (ES+): m / z 305.1 [M+H] + .

[0290] Step 2: Compound 47-C tert-butyl allyl (2-((1-(but-3-en-1-yl)-1H-pyrazol-4-yl)(tert-butoxycarbonyl)amino)-5-chloropyrimidin-4-yl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 3 of Compound 25 in Example 15. LC-MS: (ES+): m / z 505.1 [M+H] + .

[0291] Step 3: Compound 47-D Di-tert-butyl (3 4 E,6Z)-1 5 -chloro-3 1 H-2,9-diaza-1(2,4)-pyrimidine-3(4,1)-pyrazolecyclononan-6-ene-2,9-dicarboxylate [ka] For the synthesis of this step, see the synthesis process of Step 4 of Compound 25 in Example 15. LC-MS: (ES+): m / z 477.1 [M+H] + .

[0292] Step 4: Compound 47-E Di-tert-butyl (3 4 E,6Z)-1 5 -chloro-3 1 H-2,9-diaza-1(2,4)-pyrimidine-3(4,1)-pyrazolecyclononane-2,9-dicarboxylate [ka] For the synthesis of this step, see the synthesis process of Step 5 of Compound 25 in Example 15. LC-MS: (ES+): m / z 479.1 [M+H] + .

[0293] Step 5: Compound 47(E)-1 5 -chloro-3 1 H-2,9-diaza-1(2,4)-pyrimidine-3(4,1)-pyrazolecyclononane [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 25 in Example 15. LC-MS: (ES+): m / z 279.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ: 7.83 (s, 1H), 7.72 (s, 1H), 7.29 (s, 1H), 6.34 (s, 1H), 5.37 (s, 1H), 4.24 (t, J = 4.0 Hz, 2H), 3.19 - 3.12 (m, 2H), 1.84 - 1.80 (m, 2H), 1.53 - 1.39 (m, 4H). Example 37: Synthetic Route to Compound 48

[0294] [ka]

[0295] Step 1: Compound 48-C Ethyl tert-butyl 2-(2-(2,5-dichloropyrimidin-4-yl)aminoethoxy)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 5 of Compound 2 in Example 1. LC-MS: (ES+): m / z 351.1 [M+H] + .

[0296] Step 2: Compound 48-D 2-(2-aminoethoxy)ethyl-2,5-dichloropyrimidin-4-amine [ka] Trifluoroacetic acid (4 mL) was added to a solution of ethyl tert-butyl 2-(2-(2,5-dichloropyrimidin-4-yl)aminoethoxy)carbamate (340 mg, 0.97 mmol) in dichloromethane (4 mL) with stirring. The reaction solution was stirred at 25° C. for 1.0 hour. After the target mass spectrum was detected by LCMS and the disappearance of the reactants was observed, the reaction solution was concentrated by rotary evaporation under reduced pressure and dried in vacuo to give 2-(2-aminoethoxy)ethyl-2,5-dichloropyrimidin-4-amine (350 mg, trifluoroacetate salt), compound 48-D, as a yellow solid product. LC_MS: (ES+): m / z 251.1 [M+H] +

[0297] Step 3: Compound 48-F 2,5-dichloro-N-(2-(3-nitrobenzylamino)ethoxy)ethyl-4-aminopyrimidine [ka] A reaction mixture of 2-(2-aminoethoxy)ethyl-2,5-dichloropyrimidin-4-amine trifluoroacetate (350 mg, 0.96 mmol), potassium acetate (470 mg, 4.79 mmol), and 3-nitrobenzaldehyde (145 mg, 0.96 mmol), compound 48-D, in 1,2-dichloroethane (3.0 mL) was stirred at 25 °C for 12 hours. TLC monitoring confirmed the completion of the reaction. Sodium cyanoborohydride (90 mg, 1.44 mmol) was added to the reaction mixture in several portions. Stirring was continued at 25 °C for 3.5 hours. After the completion of the reaction was observed by LCMS monitoring and the target mass spectrum was detected, the solvent was rotary evaporated and the crude product, compound 48-F, 2,5-dichloro-N-(2-(3-nitrobenzylamino)ethoxy)ethyl-4-aminopyrimidine (369 mg, theoretical yield of crude product), was used directly in the next step. LC_MS: (ES+): 385.9 [M+H] + .

[0298] Step 4: Compound 48-G tert-butyl 2-(2-(2,5-dichloropyrimidin-4-yl)aminoethoxy)ethyl(3-nitrobenzyl)carbamate [ka] To a suspension of 2,5-dichloro-N-(2-(3-nitrobenzylamino)ethoxy)ethyl-4-aminopyrimidine (369 mg, 0.96 mmol), the crude product Compound 48-F, in tetrahydrofuran (6 mL) was added saturated sodium bicarbonate solution (6 mL). Di-tert-butyl dicarbonate (251 mg, 1.15 mmol) was added with stirring. The reaction mixture was stirred at room temperature overnight. TLC monitoring confirmed the completion of the reaction. The reaction solution was concentrated, water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the crude product. The solid compound obtained by elution and concentration with silica gel column chromatography (using 15%-35% ethyl acetate in petroleum ether) was further purified and separated (using 10%-80% acetonitrile in water) to give compound 48-G, tert-butyl 2-(2-(2,5-dichloropyrimidin-4-yl)aminoethoxy)ethyl(3-nitrobenzyl)carbamate (200 mg), as a pale yellow solid. LC_MS: (ES+): 486.1 [M+H] + .

[0299] Step 5: Compound 48-H tert-butyl (3-aminobenzyl)(2-(2,5-dichloropyrimidin-4-yl(amino)ethoxy)ethylcarbamate [ka] For the synthesis of this step, see the synthesis process of Step 4 of Compound 2 in Example 1. LC_MS: (ES+): 458.4 [M+2+H] + .

[0300] Step 6: Compound 48-I 1 5 tert-Butyl 2-chloro-8-oxa-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-5-carboxylate [ka] For the synthesis of this step, see the synthesis process of Step 8 of Compound 35 in Example 25. LC_MS: (ES+): 420.1 [M+H] + .

[0301] Step 7: Compound 48 1 5 -chloro-8-oxa-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 25 in Example 15. LC_MS: (ES+): 320.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ: 8.42 (s, 1H), 7.91 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.24 (t, J = 8.0 Hz, 1H), 7.13 (s, 1H), 6.90 (d, J = 8.0 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 5.54 (s, 1H), 3.97 (s, 2H), 3.73 (s, 6H), 2.84 (t, J = 4.0 Hz, 2H). Example 38: Synthetic Route to Compound 49

[0302] [ka]

[0303] Step 1: Compound 49-C tert-butyl(5-(1-(3-nitrophenyl)ethyl)amino)pentyl)carbamate [ka] A solution of tert-butyl(5-aminopentyl)carbamate (500 mg, 2.47 mmol), 1-(3-nitrophenyl)ethanone (408 mg, 2.47 mmol), and acetic acid (300 mg, 4.94 mmol) in methanol (5 mL) was stirred at room temperature for 1 hour. Sodium cyanoborohydride (311 mg, 4.94 mmol) was then added to the reaction solution, and the mixture was stirred at 50°C for 16 hours. TLC monitoring confirmed the completion of the reaction. The reaction solution was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (20 mL) and saturated sodium bicarbonate solution (20 mL). The organic layer was collected, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (eluted with a dichloromethane solution containing 5% methanol) to obtain compound 49-C, tert-butyl (5-(1-(3-nitrophenyl)ethyl)amino)pentyl)carbamate (264 mg, 30%) as a yellow oil. LC_MS: (ES+): m / z 352.50 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.20 (t, J = 1.6 Hz, 1H), 8.11-8.08 (m, 1H), 4.52 (s, 1H), 3.90-3.85 (m, 1H), 3.12-3.07 (m, 2H), 2.55-2.34 (m, 2H), 1.48-1.43 (m, 13H), 1.37 (d, J = 6.4 Hz, 3H), 1.34-1.30(m, 2H).

[0304] Step 2: Compound 49-DN 1 -(1-(3-nitrophenyl)ethyl)pentyl-1,5-diamine [ka] A solution of compound 49-C, tert-butyl (5-(1-(3-nitrophenyl)ethyl)amino)pentyl)carbamate (260 mg) and hydrochloric acid-dioxane (4N, 2 ml) in methanol (2 ml) was stirred at room temperature for 2 hours. Completion of the reaction was confirmed by TLC monitoring. The reaction solution was concentrated. The pH of the residue was adjusted to 7-8 with saturated sodium bicarbonate solution, and then extracted with 10% methanol in dichloromethane (10 ml × 3). The combined organic layer was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 49-D, a pale yellow oil. 1 -(1-(3-nitrophenyl)ethyl)pentyl-1,5-diamine (180 mg, 96%) was obtained. LC_MS: (ES+): m / z 252.10 [M+H] +.

[0305] Step 3: Compound 49-F (tert-butyl(5)-(2,5-dichloropyrimidin-4-ylamino)pentyl)(1-(3-nitrophenyl)ethyl)carbamate [ka] At -40°C, triethylamine (84 mg, 0.83 mmol) was added to anhydrous tetrahydrofuran (5 ml) containing 2,4,5-trichloropyrimidine (138 mg, 0.75 mmol), which is compound 49-E, and then N 1-(1-(3-nitrophenyl)ethyl)pentyl-1,5-diamine (180 mg, 0.72 mmol) was added dropwise. The reaction solution was stirred at -40°C under a nitrogen atmosphere for 3 hours. After the reaction was completed, the mixture was heated to room temperature, and triethylamine (84 mg, 0.83 mmol) and di-tert-butyl dicarbonate (197 mg, 0.905 mmol) were added. The reaction mixture was stirred at 50°C overnight. TLC monitoring confirmed the completion of the reaction. The reaction mixture was partitioned between ethyl acetate (20 ml × 2) and water (20 ml). The organic layer was collected, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluting with 10–20% ethyl acetate in petroleum ether) to give compound 49-F, (tert-butyl (5)-(2,5-dichloropyrimidin-4-ylamino)pentyl)(1-(3-nitrophenyl)ethyl)carbamate (350 mg, 98%) as a yellow oil. LC_MS: (ES+): m / z 498.35 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.15-8.12 (m, 2H), 8.00 (s, 1H), 7.63 (d, J = 4.0 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 5.46 (s, 1H), 3.50-3.45 (m, 2H), 3.13-2.96 (m, 2H), 1.62 (d, J = 3.6 Hz, 2H), 1.54-1.52 (m, 2H), 1.44 (s, 9H), 1.30-1.25 (m, 4H).

[0306] Step 4: Compound 49-G (tert-butyl(1)-3-aminophenylethyl)(5-((2,5-dichloropyrimidin-4-yl)amino)pentyl)carbamate [ka] For the synthesis of this step, see the synthesis process of Step 4 of Compound 2 in Example 1. LC_MS: (ES+): m / z 468.20[M+H] + . 1 H NMR (400 MHz, CDCl3): δ 8.00 (s, 1H), 7.10 (t, J = 8.0 Hz, 1H), 6.73-6.57 (m, 3H), 5.53-5.46 (m, 1H), 3.66 (brs, 2H), 3.47-3.38 (m, 2H), 3.10-2.81 (m, 2H), 1.53-1.41 (m, 16H), 1.23-1.14 (m, 2H).

[0307] Step 5: Compound 49-H tert-butyl 1 5 -Chloro-4-methyl-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane-5-carboxylate [ka] For the synthesis of this step, see the synthesis process of Step 8 of Compound 35 in Example 25. LC_MS: (ES+): m / z 432.25 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 9.26 (s, 1H), 8.24 (s, 1H), 7.91 (s, 1H), 7.34 (t, J = 6.0 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 7.2 Hz, 1H), 5.44-5.33 (m, 1H), 3.81-3.73 (m, 1H), 3.14-3.00 (m, 2H), 2.94-2.62 (m, 1H), 1.73-1.62 (m, 2H), 1.48-1.35 (m, 14H), 1.33-1.28 (m, 2H).

[0308] Step 6: Compound 49 1 5-Chloro-4-methyl-2,5,11-triaza-1(2,4)-pyrimidine-3(1,3)-benzenecycloundecane [ka] For the synthesis of this step, see the synthesis process of Step 6 of Compound 25 in Example 15. LC_MS: (ES+): m / z 332.20 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 9.29 (s, 1H), 8.20 (s, 1H), 7.91 (s, 1H), 7.38-7.29 (m, 2H), 7.11-7.05 (m, 2H), 4.31-4.30 (m, 1H), 3.77-3.71 (m, 1H), 3.10-3.03 (m, 1H), 2.76-2.54 (m, 2H), 1.89-1.49 (m, 7H), 1.38-1.31 (m, 2H). Bioactivity test example Biological Test Example 1: Evaluation of CDK9 Kinase Inhibitory Activity (In Vitro Assay)

[0309] The test concentration of the compound was set at 10 nM and detected using replicate wells, or 10 concentrations were prepared starting from 10 μM and diluted 3-fold to give 10 levels and detected using replicate wells.

[0310] The inhibitory effects of compounds on CDK9 protein kinase activity were evaluated using a caliper mobility shift assay. Using an Echo 550 dispenser, 250 nL of compound at a 100x final concentration was transferred to the desired 384-well plate. A 2.5x final kinase solution was prepared using 1x kinase buffer, and 10 μL was added to each compound well and positive control well. 10 μL of 1x kinase buffer was added to the negative control well. After centrifugation at 1000 rpm for 30 seconds, the plate was incubated at room temperature for 10 minutes. A 5 / 3x final ATP and kinase substrate solution was prepared using 1x kinase buffer. The reaction was initiated by adding 15 μL of the 5 / 3x final ATP and substrate solution. The 384-well plate was centrifuged at 1000 rpm for 30 seconds, mixed thoroughly by shaking, and then incubated at room temperature for the indicated time. To terminate the kinase reaction, 30 μL of stop solution was added, centrifuged again at 1000 rpm for 30 seconds, and mixed thoroughly by shaking. The conversion rate was measured using a Caliper EZ Reader. The conversion inhibition rate (%) was calculated using the following formula: % Conversion Inhibition = (mean % positive control conversion - % sample conversion / (mean % positive control conversion - mean % negative control conversion). Negative control wells represent conversion readings from kinase buffer background wells, and positive control wells represent conversion readings from wells without compound inhibition. Dose-effect curves were fitted using log(inhibitor) vs. response (variable slope) in GraphPad Prism analysis software, with log concentration on the x-axis and % inhibition on the y-axis, to calculate IC50 values ​​for each compound. Calculation formula: y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50-x) × hillslope)), where x is the logarithm of the inhibitor concentration and y is the % inhibition rate.

[0311] Table 1 below shows the inhibition rates of CDK9 kinase activity of several compounds at 10 nM (inhibition rate range: A>50%, B: 25-49%).

[0312] [Table 1]

[0313] Table 2 below shows the IC of some compounds in the CDK9 kinase activity assay. 50 The range of IC 50 Range: A < 0.1 μM, B: 0.1-0.5 μM, C: 0.5-1 μM).

[0314] [Table 2]

[0315] As described in the kinase activity inhibition experiments above, the selective inhibition rates of CDK7, CDK9, JAK1, JAK2, JAK3, ITK, RET, TYK2, and LRRK2 kinases by several compounds at 10 nM were measured. The results are shown in Table 3 below (inhibition rate range: A > 50%, B: 25-49%, C: < 25%).

[0316] [Table 3] Biological measurement test example 2

[0317] The selectivity of the test compound against CDK kinases was detected. The test concentration of the compound was 0.1 μM, and the inhibition rate of the test compound against CDK kinases was detected in replicate wells mainly by HTRF and ADP-Glo ​​detection methods.

[0318] HTRF detection: 2x ATP / substrate and 2x kinase / metal ion solutions were prepared using kinase reaction buffer, and 25 nL of compound dilutions were transferred to a 384-well plate using an Echo 655. After centrifugation, 2.5 μL of 2x kinase / metal ion solution was added and incubated at 25°C for 10 minutes. After 10 minutes, 2.5 μL of 2x substrate / ATP solution was added to the 384-well plate and incubated at 25°C for 60 minutes. 2x kinase detection reagent (XL665 and antibody) was prepared using detection buffer, and 5 μL of kinase detection reagent was added per well to the 384-well plate and incubated at 25°C for 60 minutes. Fluorescence signals at 620 nm (Cryptate) and 665 nm (XL665) were read using a microplate reader, and the ratios were used to calculate the kinase activity inhibition rate of the compounds.

[0319] ADP-Glo ​​detection method: 2x ATP / substrate and 2x kinase / metal ion solutions were prepared using kinase reaction buffer, and 20 nL of compound dilutions were transferred to a 384-well plate using an Echo 655. After centrifugation, 2 μL of 2x kinase / metal ion solution was added and incubated at 25°C for 10 minutes. After 10 minutes, 2 μL of 2x substrate / ATP solution was added to the 384-well plate and incubated at 25°C for 60 minutes. 4 μL of ADP detection reagent was added per well and incubated at room temperature for 40 minutes. 10 μL of ADP detection reagent was added per well and incubated at room temperature for 40 minutes. The chemiluminescent signal was read using a microplate reader, and the compound inhibition rate against kinase activity was calculated.

[0320] Table 4 below shows the compound inhibition rate of compound 8 against CDK kinase activity at 0.1 uM (range: A>95%, B: 75-95%, C: 50-75%, D: <50%). [Table 4] Biological Test Example 3

[0321] The culture conditions for the cell lines used in the CDK9 cellular activity detection experiment are as follows: MV-4-11 cells: Cultured in IMDM medium containing 10% fetal bovine serum (containing 100 U / mL penicillin and 0.1 g / L streptomycin). HCC1187 cells: Cultured in RPMI-1640 medium containing 10% fetal bovine serum (containing 100 U / mL penicillin and 0.1 g / L streptomycin). Mia Paca-2 cells: cultured in DMEM containing 10% fetal bovine serum and 2.5% horse serum (containing 100 U / mL penicillin and 0.1 g / L streptomycin). A375 cells: Cultured in RPMI-1640 medium containing 10% fetal bovine serum (containing 100 U / mL penicillin and 0.1 g / L streptomycin). All of the above cell lines were cultured in a saturated humidity incubator at 37°C and 5% CO2.

[0322] Cell Treatment Protocol: MV-4-11, HCC1187, Mia Paca-2, and A375 cells were cultured to 80%-90% confluence, digested with trypsin, counted, and diluted to a specific cell density in complete medium. 100 μL of cells were seeded into a 96-well plate at a concentration of 100 μL per well. Complete medium was used as a background control and incubated overnight in a 37°C, 5% CO2, saturation humidity incubator. The following day, compounds were diluted to a final concentration of 200x with DMSO. 3 μL of the DMSO stock solution of the compound was added to 197 μL of complete medium. 50 μL of the diluted compound was added to each well of the cells and incubated for 72 hours in a 37°C, 5% CO2, saturation humidity incubator. After 72 hours, the culture plate was placed at room temperature to equilibrate, and 40 μL of CellTiter-Glo® Reagent was added to each well. The cells were then mixed on a shaker for 2 minutes to lyse the cells. The plate was incubated at room temperature for 60 minutes to stabilize the chemiluminescence signal, and the chemiluminescence signal was read using a PE EnVision microplate reader. The cell proliferation inhibition rate (Inh%) was calculated according to (DMSO wells - compound-treated wells) / (DMSO wells - background wells) × 100, and the cell proliferation IC was calculated by fitting using GraphPad Prism 5. 50 got the value.

[0323] Table 5 below shows the IC of some compounds in cellular activity assays. 50 The range is shown (IC 50 Range: A<0.25 μM, B: 0.25–1 μM, C: 1–5 μM, NT indicates not determined). [Table 5]

Claims

1. A compound represented by the following formula (I), or a meso form, racemic form, enantiomer, diastereomer, or pharmaceutically acceptable salt thereof: 【Chemistry 1】 [In the formula, X is H, C １ -C ３ Alkyl group, halogen, CF ３ , a carbamoyl group, a cyano group, and C １ -C ３ alkoxycarbonyl groups, L is a single bond, C ６ -C １０ aryl group, 5- to 12-membered heteroaryl group, C ３ -C ８ cycloalkyl groups, and 3- to 8-membered heterocyclyl groups (wherein ６ -C １０ aryl group, 5- to 12-membered heteroaryl group, C ３ -C ８ The cycloalkyl group and the 3- to 8-membered heterocyclyl group may optionally be one or more R １ further substituted with Ring A is C ６ -C １０ aryl group, 5- to 12-membered heteroaryl group, C ３ -C ８ cycloalkyl groups, and 3- to 8-membered heterocyclyl groups (wherein ６ -C １０ aryl group, 5- to 12-membered heteroaryl group, C ３ -C ８ The cycloalkyl group and the 3- to 8-membered heterocyclyl group may optionally be one or more R ２ further substituted with Y is a single bond or -CH ２ NR ３ -, wherein R ３ is H, C １ -C ３ Alkyl group, C １ -C ３ alkyl acyl groups, and Boc), However, at least one of L and Y is a single bond, Q is C ４ -C ５ Alkylene group, and C ４ -C ５ alkenylene groups, wherein one of said groups is -CH ２ The - unit is optionally an O atom, an S atom or an -NR ３ -, preferably Q is 【Chemistry 2】 selected from the group consisting of R １ and R ２ are each independently hydrogen, halogen, amino group, C １ -C ３ Alkylamino group, cyano group, oxo group, hydroxy group, C １ -C ３ Alkyl group, C １ -C ３ Alkoxy groups, 3- to 8-membered heterocyclyl groups, and C １ -C ３ a 3- to 8-membered heterocyclyl group substituted with an alkyl group;

2. The compound represented by formula (I) according to claim 1, wherein the compound represented by formula (I) has the structure of the following formula (II): or a meso form, racemic form, enantiomer, diastereomer, or pharmaceutically acceptable salt thereof. 【Transformation 3】 [In formula (II), X, Q, R ２ and R ３ is as defined in claim 1]

3. The compound represented by formula (I) according to claim 1, wherein the compound represented by formula (I) has the structure of the following formula (III), or a meso form, racemic form, enantiomer, diastereomer, or pharmaceutically acceptable salt thereof. 【Chemistry 4】 [In formula (III), X, Q, A and R １ is as defined in claim 1]

4. 4. The compound represented by formula (III) according to claim 3, or a meso form, racemic form, enantiomer, diastereomer or pharmaceutically acceptable salt thereof, wherein ring A is a benzene ring or a pyrazole ring.

5. The compound according to any one of claims 1 to 4, wherein the compound is selected from the group consisting of the following compounds: a meso form, a racemic form, an enantiomer, a diastereomer, or a pharmaceutically acceptable salt thereof: 【Chemistry 5-1】 【Chemistry 5-2】 【Chemistry 5-3】 【Chemistry 5-4】 【Transformation 5-5】

6. A pharmaceutical composition comprising the compound according to any one of claims 1 to 5, or its meso form, racemate, enantiomer, diastereomer, or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

7. Use of the compound according to any one of claims 1 to 5, or its meso form, racemate, enantiomer, diastereomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a disease or condition associated with CDK9 kinase imbalance, wherein the disease or condition associated with CDK9 kinase imbalance is preferably selected from the group consisting of solid tumors and hematopoietic malignancies.

8. The use according to claim 7, wherein the disease or condition associated with CDK9 kinase imbalance is selected from the group consisting of solid tumors and hematopoietic malignancies, preferably acute myeloid leukemia (AML), breast cancer, prostate cancer, hepatocellular carcinoma, and pancreatic cancer.

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