WO2019196720A1 - Arginine methyltransferase inhibitor, pharmaceutical composition thereof and use thereof - Google Patents

Abstract

Disclosed are an arginine methyltransferase inhibitor, a pharmaceutical composition thereof and a use thereof. Specifically, disclosed are a compound represented by formula (I), a pharmaceutically acceptable salt, isomer, racemate, prodrug, co-crystal complex, hydrate or solvate thereof, a pharmaceutical composition thereof, and a use thereof in the preparation of a PRMT4 inhibitor or in the preparation of a drug for the treatment of cancer, inflammatory disease, autoimmune disease or diabetes.

Description

Arginine methyltransferase inhibitor and pharmaceutical composition thereof and use thereof Technical field

The invention relates to the technical field of chemical medicine, in particular to a kind of arginine methyltransferase inhibitor, a pharmaceutical composition thereof and use thereof.

Background technique

Epigenetics causes heritable changes in gene expression without altering the nucleotide sequence of the gene. It plays a very important role in many physiological and biochemical processes such as protein expression, cell proliferation, and cell cycle, and is closely related to the occurrence and development of various diseases. Post-translational modifications of histones are an important part of epigenetics.

Arginine methylation is a common histone post-translational modification that plays an important role in signal transduction, DNA repair, transcription, protein subcellular localization and RNA processing. Protein arginine methyltransferase Family (PRMTs) are a class of enzymes with methyltransferase activity. According to the different ways of catalyzing the methylation of arginine, the PRMTs family is mainly divided into three types. Type I (PRMT1, 2, 3, 4, 6, 8) catalyzes the formation of arginine monomethyl and asymmetric dimethylation, and type II PRMTs catalyze the formation of monomethyl and symmetrical arginine, Including PRMT5 and PRMT9, type III PRMTs with PRMT7 can only catalyze the formation of monomethylation.

PRMT4 (also known as coactivator-associated arginine methyltransferase 1, CARM1) asymmetrically dimethylated arginine residues of histones H3R2, H3R17, and H3R26, and can also methylate many non-groups. Protein substrates, such as CBP/P300, PABP1, HuR, CA150, SAP49, and the like. PRMT4 is also a coactivator of various tumor-associated proteins, such as p53, NF-κB, β-catenin, and ERα. PRMT4 has been reported to be highly expressed in breast cancer, colon cancer, bladder cancer, lung cancer, and is closely related to the occurrence of immune response, inflammation, and diabetes. PRMT4 is therefore considered to be a very potential therapeutic target.

Summary of the invention

In one aspect, the invention provides a compound of formula (I), a pharmaceutically acceptable salt, isomer, racemate, prodrug, co-crystal complex, hydrate or solvate thereof. Object,

among them:

R ₁ is hydrogen, C ₁ -C ₃ alkyl; preferably hydrogen or methyl;

R ₂ is hydrogen, C ₁ -C ₃ alkyl; preferably hydrogen or methyl;

More preferably, at least one of R ₁ and R ₂ is hydrogen;

R ₃ is hydrogen, C ₁ -C ₃ alkyl; preferably hydrogen or methyl;

R ₄ is hydrogen, halogen, C ₁ -C ₃ alkyl; preferably hydrogen, fluorine, chlorine or methyl;

R ₅ is hydrogen, halogen, C ₁ -C ₃ alkyl; preferably hydrogen, fluorine, chlorine or methyl;

X is N or CR ₆ ;

R ₆ is hydrogen, halogen, substituted or unsubstituted C ₁ -C ₃ alkyl substituted by one or more halogen, cyano or hydroxy; preferably hydrogen, chloro, fluoro, by one or more halogens, cyano or a substituted or unsubstituted C ₁ -C ₃ alkyl group of a hydroxy group; more preferably hydrogen, chlorine, fluorine, a substituted or unsubstituted methyl group substituted by one or more halogens, a cyano group or a hydroxy group or one or more halogens a substituted or unsubstituted ethyl group of a cyano group or a hydroxy group;

Y is N or CH;

L ₁ is -NH, -N(C ₁ -C ₃ alkyl)-, -O- or absent;

L ₂ is -NH, -N(C ₁ -C ₃ alkyl)-, -O- or absent;

R _{7 is} selected from substituted or unsubstituted saturated 3-10 membered cycloalkyl, substituted or unsubstituted saturated 3-10 membered heterocyclic group, substituted or unsubstituted C ₆ -C ₁₀ aryl group, substituted or unsubstituted a 5-12 membered heteroaryl, substituted or unsubstituted oxazabicyclo[3.2.1]octyl group, preferably selected from substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutane, Substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexane, substituted or unsubstituted cycloheptyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted nitrogen heterocycle Pentyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted oxetanyl, substituted or unsubstituted oxolyl, substituted or unsubstituted oxacyclohexane a substituted or unsubstituted thicyclic group, a substituted or unsubstituted thietane monooxide or a double oxide, a substituted or unsubstituted morpholinyl group, a substituted or unsubstituted piperazinyl group, Substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted thienyl, substituted or unsubstituted isoxazolyl, substituted Or unsubstituted oxazolyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted benzo Thienyl, substituted or unsubstituted quinolyl, substituted or unsubstituted isoquinolyl, substituted or unsubstituted fluorenyl, substituted or unsubstituted azaindolyl, substituted or unsubstituted tetrahydropyridyl a phenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted oxazabicyclo[3.2.1]octyl group; the substituted substituent is selected from a C ₁ -C ₆ alkyl group, 3- 8-membered cycloalkyl, halogen, hydroxy, amino (-NH ₂ ), cyano, nitro, hydroxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino, halogenated C ₁ -C ₆ alkyl , C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ alkylsulfinyl, C ₁ -C ₆ alkylcarbonyl And ₁ , 2 or 3 substituents of a C ₁ -C ₆ amide group; preferably selected from the group consisting of methyl, ethyl, fluoro, chloro, bromo, hydroxy, amino, cyano, nitro, trifluoromethyl, tri Fluoromethoxy, methoxy, ethoxy, methylsulfonyl, ethanesulfonyl , An acetyl group and a methoxyphenyl, 2 or 3 substituents;

R _{8 is} selected from H, halogen, substituted or unsubstituted C ₆ -C ₁₀ aryl or substituted or unsubstituted 5-12 membered heteroaryl, preferably selected from H, halogen, substituted or unsubstituted phenyl, substituted Or unsubstituted C ₁ -C ₆ alkylphenyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted thienyl, substituted or unsubstituted isoxazolyl, substituted Or unsubstituted oxazolyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted benzo Thienyl, substituted or unsubstituted quinolyl, substituted or unsubstituted isoquinolyl, substituted or unsubstituted fluorenyl, substituted or unsubstituted azaindolyl, substituted or unsubstituted piperidinyl a substituted or unsubstituted piperazinyl group, a substituted or unsubstituted morphinolinyl group, a substituted or unsubstituted thiomorpholinyl group, and a substituted or unsubstituted dihydropyrrolopyridyl group, wherein the substituted substituent is selected From: C ₁ -C ₆ alkyl, 3-8 membered cycloalkyl, halogen, hydroxy, amino, cyano, nitro, Hydroxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino, halogenated C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogenated C ₁ -C ₆ alkoxy, C _{1 1} , 2 or 3 substituents of -C ₆ alkylsulfonyl, C ₁ -C ₆ alkylsulfinyl, C ₁ -C ₆ alkylcarbonyl and C ₁ -C ₆ amido; preferably selected from the group consisting of Base, ethyl, fluorine, chlorine, bromine, hydroxyl, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, methylsulfonyl, ethylsulfonyl, acetyl And 1, 2 or 3 substituents of the methoxyphenyl group.

In one embodiment, R ₁ is methyl or H; and R ₂ is H.

In one embodiment, R ₃ is methyl or H; R ₄ is H; and R ₅ is H, fluoro, methyl or chloro.

In one embodiment, X is CR ₆ or N; R ₆ is methyl.

In one embodiment, Y is N or CH.

In one embodiment, L ₁ is -NH-, -NCH ₃ -, -O- or is absent.

In one embodiment, L ₂ is -NH-, -O- or is absent.

In one embodiment, R ₇ is tetrahydropyranyl, methoxyphenylpiperazinyl, phenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, fluorophenyl, chlorophenyl, Difluorophenyl, trifluoromethylpyridyl, dimethylisoxazolyl or morphinolinyl, methanesulfonyl piperazinyl, methanesulfonylpiperidinyl, thiomorpholinyl, methylpiperazinyl, Acetyl piperazinyl, cyclopropylpiperazinyl, dihydropyrrolopyridyl, oxazabicyclo[3.2.1]octyl; preferably tetrahydropyranyl, 1-(2-methoxy Phenyl) piperazinyl, phenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4- Chlorophenyl, 1,2-difluorophenyl, 2,4-difluorophenyl, 2-trifluoromethylpyridin-4-yl, 3,5-dimethylisoxazole-4-yl, morphine Orolinyl, 4-(methylsulfonyl)piperazin-1-yl, 1-(methylsulfonyl)piperidin-4-yl, 4-thiomorpholine-4,4-dioxy-1-yl, 4 -methylpiperazin-1-yl, 4-acetylpiperazin-1-yl, 4-cyclopropylpiperazin-1-yl or 6,7-dihydro-5H-pyrrolo[3,4-b Pyridine-6-yl, 3-chloro-4-fluorophenyl, 3-fluoro-4-chlorophenyl, indol-4-yl, 7-azaindole-5- , benzothiazol-5-yl, benzothiazole-6-yl, 1-methyl-1H-indazol-5-yl, 1-cyclopropyl-1H-pyrazol-4-yl, 3-cyclopropyl -1-methyl-1H-pyrazol-5-yl, isoindoline-2-yl, piperidinyl, benzyl, 8-oxa-3-azabicyclo[3.2.1] octyl Alk-3-yl, (S)-3-methylmorpholinyl, pyridin-4-yl.

In one embodiment, R ₈ is H, chloro, phenyl, benzyl, phenylmethylsulfonyl, pyridyl, trimethylpyrazolyl, dimethylpyrazolyl, methylbromopyrazolyl, Pyrimidinyl, methylpyrazolyl, fluorobenzyl, trifluoromethylphenyl, trifluoromethoxyphenyl, fluorophenyl, chlorophenyl, difluorophenyl, trifluoromethylpyridyl, aza Indenyl, fluorenyl, methoxyindenyl, difluoromethylbenzimidazolyl, aminopyrimidinyl, quinolyl, isoquinolyl, morphinolinyl, benzothienyl, phenol, two Methyl isoxazolyl, methanesulfonyl piperazinyl, methanesulfonylpiperidinyl, thiomorpholinyl, methylpiperazinyl, acetylpiperazinyl, cyclopropylpiperazinyl or dihydropyrrole Pyridyl; preferably H, chloro, phenyl, phenylmethylsulfonyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1,3,5-trimethylpyrazol-4-yl, 1,3-Dimethyl-1H-pyrazol-4-yl, 1-methyl-4-bromopyrazole-5-yl, 5-pyrimidinyl, 1-methylpyrazol-5-yl, 4- Fluorobenzyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl 1,2-difluorophenyl, 2,4-difluorophenyl, 2-trifluoromethylpyridin-4-yl, 7-azaindole-4-yl, 1H-indenyl, H-oxime Zin-4-yl, 7-methoxyindol-2-yl, 2-(difluoromethyl)-1H-benzo[D]imidazol-1-yl, 2-aminopyrimidin-5-yl, anthracene Ind-4-yl, quinoline-5-yl, isoquinolin-5-yl, morphinolinyl, benzothiophen-2-yl, phenol-3-yl, 3,5-dimethylisoxazole- 4-yl, 4-(methylsulfonyl)piperazin-1-yl, 1-(methylsulfonyl)piperidin-4-yl, 4-thiomorpholine-4,4-dioxy-1-yl, 4-methylpiperazin-1-yl, 4-acetylpiperazin-1-yl, 4-cyclopropylpiperazin-1-yl or 6,7-dihydro-5H-pyrrolo[3,4- b] Pyridine-6-yl, 4-hydroxyphenyl, 4-methoxyphenyl, 2-amino-4-trifluoromethylpyridin-5-yl.

In one embodiment, the compound of formula (I) is selected from the compounds represented by the following formula:

Wherein R ₁ , R ₃ , R ₄ , R ₅ , L ₁ , L ₂ , R ₇ and R ₈ have the same meanings as defined in claim 1.

In one embodiment, the compound of formula (I) is selected from the group consisting of:

The compounds of the invention may contain one or more asymmetric centers and thus may occur as racemates and single enantiomers, mixtures of diastereomers and single diastereomers. The scope of the invention includes all possible optical isomers and mixtures of diastereomers and pure or partially pure compounds.

The present invention includes free forms of the compounds of formula (I), as well as the pharmaceutically acceptable salts and stereoisomers thereof. The solubility of the free form in certain physical properties, such as in polar solvents, is somewhat different from its respective salt form, but the salts for the purposes of the invention are pharmaceutically equivalent to their respective free forms.

"C ₁ -C ₆ alkyl" means a straight or branched saturated hydrocarbon group having from 1 to 6 carbon atoms in the chain, and includes, without limitation, methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, sec-butyl, tert-butyl, and the like.

"C ₁ -C ₆ alkoxy" means a straight or branched alkyl-O- group having from 1 to 6 carbon atoms in the alkyl moiety, for example, methoxy, ethoxy, positive Propyloxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy.

"C ₁ -C ₆ alkylsulfonyl" means a straight or branched alkylsulfonyl group having from 1 to 6 carbon atoms in the alkyl moiety, for example, methylsulfonyl, ethylsulfonyl, N-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl or tert-butylsulfonyl.

"C ₁ -C ₆ alkylsulfinyl" means a straight or branched alkylsulfinyl group having from 1 to 6 carbon atoms in the alkyl moiety, for example, methylsulfinyl, ethyl Sulfonyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, isobutylsulfinyl or tert-butylsulfinyl.

"3-8 membered cycloalkyl" means a group containing one or more saturated and/or partially saturated rings, all of which are ring carbon atoms, including from 3 to 8 carbon atoms; for example, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptenyl, cycloheptatrienyl, cyclooctyl, indanyl, tetrahydronaphthyl, benzocycloheptyl and the like.

"3-8 membered heterocyclyl" means containing one or more saturated and/or partially saturated rings comprising from 3 to 8 ring atoms, wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(O) a hetero atom of m (wherein m is an integer of 0 to 2), and the remaining ring atoms are carbon; for example, propylene oxide, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl , thiomorpholinyl, homopiperazinyl.

"Halogen" means fluoro, chloro, bromo and iodo.

"C ₆ -C ₁₂ aryl" means an aromatic ring group containing 6 to 12 ring atoms but no hetero atom in the ring atom, preferably a 6-10 membered aryl group (ie, 6 to 10 carbon atoms) Aryl), such as phenyl, naphthyl.

The "5-12 membered heteroaryl group" means an aromatic ring group containing 5 to 12 ring atoms and having 1 to 4 hetero atoms in the ring atom as a ring member. The hetero atom can be selected from nitrogen, oxygen or sulfur. The heteroaryl group may be a monocyclic heteroaryl group having 5 to 7 ring atoms or a bicyclic heteroaryl group having 7 to 12 ring atoms. As long as one ring of the bicyclic heteroaryl group is a heteroaromatic ring, the other may be an aromatic ring or a non-aromatic ring, containing a hetero atom or a hetero atom. Further, the bicyclic heteroaryl group may be a concentric ring structure, a spiro ring structure, or a two heterocyclic ring directly connected. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, pyridyl, pyrimidinyl, furyl, thienyl, isoxazolyl, indolyl, and the like.

In a second aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the above formula (I), a pharmaceutically acceptable salt thereof, an isomer thereof, racemic One or more of a body, a prodrug, a co-crystal complex, a hydrate or a solvent compound as an active ingredient, and a pharmaceutically acceptable carrier.

By "therapeutically effective amount" is meant that the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects.

"Pharmaceutically acceptable salt" refers to a conventional non-toxic salt of the present invention formed by the basic present invention and an inorganic or organic acid form. Conventional non-toxic salts include inorganic acids such as, but not limited to, salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like; organic acids such as, but not limited to, acetic acid, propionic acid, succinic acid, lactic acid, malic acid Salt prepared from tartaric acid, maleic acid, salicylic acid, fumaric acid, methanesulfonic acid, oxalic acid, trifluoroacetic acid, ascorbic acid, toluenesulfonic acid and the like.

Since the acidic moiety, such as a carboxyl group, which is deprotonated in a compound under physiological conditions, can be an anion, such charged charge can be counterbalanced by a protonated or alkylated basic moiety, such as a tetravalent nitrogen atom, carried internally. Therefore, it should be noted that the compounds of the invention are potential internal salts and zwitterions.

"Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By "compatibility" it is meant herein that the components of the composition are capable of intermingling with the active ingredients of the present invention and with respect to each other without significantly reducing the efficacy of the active ingredients. Examples of pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid). , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as Tween

), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.

Preferably, the pharmaceutical composition further comprises other pharmaceutically acceptable therapeutic agents, in particular other anti-cancer drugs, anti-inflammatory drugs, anti-autoimmune drugs, anti-diabetic drugs or combinations thereof. The therapeutic agent includes, but is not limited to, a drug antitumor drug acting on the chemical structure of DNA such as cisplatin, an antitumor drug affecting nucleic acid synthesis such as methotrexate (MTX), 5-fluorouracil (5FU), etc., affecting nucleic acid transcription Anti-tumor drugs such as doxorubicin, epirubicin, aclarithromycin, phosfomycin, etc., antitumor drugs acting on tubulin synthesis such as paclitaxel, vinorelbine, etc., aromatase inhibitors such as ammonia Mitt, lantron, letrozole, ruined, etc., cell signaling pathway inhibitors such as epidermal growth factor receptor inhibitors Imatinib, Gefitinib, Erlotinib ), Lapatinib, etc.

The pharmaceutical compositions of the present invention may be in liquid, semi-solid or solid form, formulated in a manner suitable for the route of administration employed.

The pharmaceutical composition of the present invention can be administered by the following modes of administration: oral, parenteral, peritoneal, intravenous, transdermal, sublingual, intramuscular, rectal, buccal, liposome and the like.

In a third aspect, the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt, isomer, racemate, prodrug, co-crystal complex, hydrate or solvent thereof Use of a compound for the preparation of a medicament for use in a PRMT4 inhibitor or in the manufacture of a medicament for the treatment of cancer, inflammatory diseases, autoimmune diseases or diabetes.

The cancer includes, without limitation, bladder cancer, breast cancer, prostate cancer, pancreatic cancer, liver cancer, colon cancer, rectal cancer, cervical cancer, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocyte, Myeloblasts, angiosarcoma, astrocytoma, myelomonocytes, and promyelocytes), acute T cell leukemia, chondrosarcoma, chronic lymphocytic leukemia, chronic myeloid (granulocyte) leukemia, large cells Lymphoma, fibrosarcoma, testicular germ cell carcinoma, glioma, lymphoma (Hodgkin or non-Hodgkin type), multiple myeloma, lymphoma, myeloma, neuroblastoma, non-small cells Lung cancer, small cell lung cancer.

Non-limiting inflammatory diseases include pneumonia, sinusitis, encephalitis, meningitis, gastritis, enteritis, ulcerative colitis, idiopathic proctitis, conjunctivitis, otitis media, reflux esophagitis, nodular arteries inflammation.

Non-limiting autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis, organ transplant rejection, and multiple sclerosis.

DRAWINGS

1 is a graph showing the antitumor effect of Compound S20 in the pancreatic cancer ASPC1 nude mouse xenograft model in Test Example 2; FIG. 1A is a graph of tumor volume versus time; FIG. 1B is a graph comparing tumor weight at the end of the test. Figure 1C is a graph of mouse body weight versus time.

detailed description

In all examples, ¹ H NMR was recorded by a Varian Mercury-300 or Varian Mercury-400 NMR spectrometer with chemical shifts expressed in δ (ppm); mass spectrometry by Finnigan/MAT-95 (EI) and Finnigan LCQ/DECA and Micromass Recorded by Ultra Q-TOF (ESI) mass spectrometer; 200-300 mesh silica gel of Qingdao Ocean Chemical Co., Ltd. was used for compound separation.

In addition to the standard methods known in the literature or exemplified in the experimental procedures, the compounds of the invention can be prepared using the reactions shown in the schemes below. Accordingly, the following illustrative schemes are for illustrative purposes and are not limited to the listed compounds or any particular substituents. The number of substituents shown in the schemes does not necessarily have to correspond to the number used in the claims, and as is clear, it is shown that the monosubstituted linkages allow for multiple substituted compounds under the definition of formula (I) above.

When the compound of the formula (I) is a compound of the formula I-A, I-B, I-C or I-D, the boronic acid pinacol ester intermediate can be synthesized by the following route:

Among them, the meta-bromobenzaldehyde and 2-(N-Boc-N-methylamino)ethylamine are subjected to reductive amination to prepare the intermediate (II), and the free secondary amine is protected with Boc to obtain an intermediate (III). The intermediate (III) and the bis-pinacol borate are subjected to a Miyaura-Ishiyama-Hartwig Borylation to obtain the corresponding boronic acid pinacol ester intermediate (IV).

The preparation method of the compound represented by the general formula (I) of the present invention may be one of the following preparation methods:

When the compound represented by the formula (I) is a compound represented by the formula I-A, I-B or I-C, the target product can be obtained by the following route one,

Route one

The intermediate (V) is prepared by a nucleophilic substitution reaction of a trichloropyrimidine or a triazine with a corresponding secondary or primary amine, and then the intermediate (V) and the intermediate (IV) are reacted to form a Suzuki reaction. Body (VI);

When L ₂ is absent, the intermediate (VI) is reacted with the corresponding boronic acid or boronic acid pinacol ester compound via Suzuki to obtain the intermediate (VII), and then the Boc protecting group is removed to prepare the formula (VIII). compound of;

When L ₂ is -N- or -O-, the intermediate (VI) is substituted with the corresponding amine, alcohol or phenol to obtain the intermediate (IX), and then the Boc protecting group is removed to prepare the formula (X). The compound shown.

When the compound represented by the formula (I) is a compound represented by the formula I-D, the target product can be obtained by the following route 2;

Route two

Wherein 2,4,6-trichloropyridine is reacted with intermediate (IV) via Suzuki to prepare intermediate (XI), then intermediate (XI) with morpholine in lithium bistrimethylsilylamide and bistriphenyl The selective substitution reaction under the action of phosphine palladium dichloride gives the intermediate (XII), and the intermediate (XII) is reacted with the corresponding boronic acid or boronic acid pinacol ester to obtain the intermediate (XIII), and then the Boc is removed. A protecting group is prepared to give a compound of the formula (XIV).

When the compound represented by the formula (I) is a compound represented by the formula I-E, the target product can be obtained by the following route three;

Route three,

Among them, starting from the meta-bromo benzylamine, the intermediate (XV) is obtained by Boc protection, and the intermediate (XV) is reacted with the bis-pinacol borate to form a boronic acid pinacol ester intermediate ( XVI), the boronic acid pinacol ester intermediate (XVI) reacts with the intermediate (V) to obtain the intermediate (XVII), and the intermediate (XVII) is reacted with the corresponding boric acid or boronic acid pinacol ester via Suzuki to obtain an intermediate The intermediate (XVIII) is obtained by further removing the Boc protecting group, and the intermediate (XIX) and the protected amino aldehyde are subjected to reductive amination to obtain the intermediate (XX), followed by alkylation. The compound of the formula (XXII) can be prepared by reacting the intermediate (XXI) and then removing the Boc protecting group.

Abbreviations and symbols in the present invention:

Abbreviation/symbol	Chinese name
AcOH	acetic acid
MeOH	Methanol

NaBH 3 CN	Sodium cyanoborohydride
NaHCO 3	Sodium bicarbonate
THF	Tetrahydrofuran
(Boc) 2 O	Di-tert-butyl dicarbonate
(Bpin) 2	Double-linked pinacol borate
KOAc	Potassium acetate
DMSO	Dimethyl sulfoxide
Pd(dppf) 2 Cl 2 .CH 2 Cl 2	[1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex
EtOH	Ethanol
TEA	Triethylamine
Na 2 CO 3	Sodium carbonate
Dioxane	1,4-dioxane
H 2 O	water
Pd(PPh 3 ) 4	Tetratriphenylphosphine palladium
DMF	N,N-dimethylformamide
t-BuOK	Potassium tert-butoxide
HCl	Hydrogen chloride
Boc	Tert-butoxycarbonyl

Preparation Example 1 N1-Methyl-N2-(3-(5-methyl-4-(pyridin-4-yl)-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine- 2-yl)benzyl)ethane-1,2-diamine (S1)

Step 1. Synthesis of intermediate a

2,4,6-trichloro-5-methylpyrimidine (7.75 g, 39.3 mmol) was added to a round bottom flask, 100 mL of ethanol was dissolved, triethylamine (11 mL, 78.6 mmol) was added, and 4-amino was added under ice bath. Tetrahydropyran (3.77 g, 37.3 mmol), which was slowly warmed to room temperature overnight, was applied to the mixture and the mixture was applied to the title compound.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ4.73 (d, J = 6.9Hz, 1H), 4.38-4.21 (m, 1H), 4.06-3.95 (m, 2H), 3.55 (td, J = 11.8,2.1 Hz, 2H), 2.11 (s, 3H), 2.03 (ddd, J = 12.4, 4.1, 1.9 Hz, 2H), 1.62 - 1.45 (m, 2H).

Step 2. Synthesis of intermediate b

In a round bottom flask, m-bromobenzaldehyde (3.7 g, 20 mmol), 2-(N-Boc-N-methylamino)ethylamine was added, dissolved in 60 mL of methanol, and acetic acid (4.8 g, 80 mmol) was added and stirred under ice bath. After 15 min, sodium cyanoborohydride (2.52 g, 40 mmol) was added in portions, and the reaction was stirred for 1 hour in an ice-bath, and the mixture was stirred with saturated brine, and the mixture was evaporated and evaporated. After three times, it was dried over anhydrous sodium sulfate.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ7.59-7.49 (m, 2H), 7.37-7.18 (m, 2H), 3.90 (s, 2H), 3.40-3.15 (m, 4H), 2.87 (s, 3H ), 1.45 (s, 9H).

Step 3. Synthesis of intermediate c

Intermediate b (5.4 g, 16 mmol) was added to a round-bottomed flask, which was dissolved in EtOAc (EtOAc, EtOAc, EtOAc (EtOAc) The solid was removed, and the column was directly applied to the column, and the column was obtained to give Intermediate C as a colorless oil, 5.8 g, yield 82%.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ7.43-7.33 (m, 2H), 7.22-7.08 (m, 2H), 4.41 (d, J = 16.0Hz, 2H), 3.44-3.16 (m, 4H), 2.86 (d, J = 8.0 Hz, 3H), 1.53 - 1.39 (m, 18H).

Step 4. Synthesis of intermediate d

Intermediate c (1.37 g, 3.10 mmol), pinacol borate (850 mg, 3.35 mmol), potassium acetate (940 mg, 9.6 mmol), [1,1'-bis(diphenylphosphine) were added to a three-necked flask. ) ferrocene] palladium dichloride dichloromethane complex (78 mg, 0.096 mmol), protected with nitrogen, added 10 mL of dimethyl sulfoxide, reacted at 80 ° C for 4 hours, cooled with water, extracted with ethyl acetate, saturated brine The mixture was washed with water and dried over anhydrous sodium sulfate.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ7.71-7.61 (m, 2H), 7.38-7.27 (m, J = 7.3Hz, 2H), 4.58-4.32 (m, 2H), 3.31 (s, 4H), 2.84 (d, J = 13.7 Hz, 3H), 1.46 (d, J = 23.6 Hz, 19H).

Step 5. Synthesis of intermediate e

Intermediate a (528 mg, 2.0 mmol), intermediate d (1.2 g, 2.5 mmol), tetrakistriphenylphosphine palladium (115 mg, 0.1 mmol), sodium carbonate (428 mg, 4.0 mmol), and nitrogen were added to a three-neck flask. Protected, add 1,4-dioxane 12mL and 4mL of water, react at 70 ° C overnight, add water, add 2 times with ethyl acetate, wash twice with saturated brine, dry over anhydrous sodium sulfate, column chromatography to obtain intermediate , 380 mg as a white solid, 30% yield.

^{1 H NMR (300MHz, DMSO-} d 6) δ8.15 (d, J = 6.2Hz, 2H), 7.43 (d, J = 8.0Hz, 1H), 7.34 (s, 1H), 6.91 (d, J = 6.8 Hz, 1H), 4.46 (s, 2H), 4.32 (s, 1H), 3.92 (d, J = 12.0 Hz 2H), 3.47 (t, 3H), 2.77 (s, 3H), 2.15 (s, 3H) ), 1.86 (s, 2H), 1.66 (d, J = 9.0 Hz, 2H), 1.45-1.30 (m, 18H).

Step 6. Synthesis of intermediate f

Intermediate e (100 mg, 0.17 mmol), 4-pyridine boronic acid (42 mg, 0.34 mmol), tetratriphenylphosphine palladium (20 mg, 0.017 mmol), sodium carbonate (36 mg, 0.34 mmol), and nitrogen were added to a three-neck flask. After the addition, 1,4-dioxane 3 mL and 1 mL of water were added, and the reaction was carried out at 95 ° C overnight, and the mixture was combined with EtOAc. The product was 87 mg, yield 81%.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.78-8.68 (m, 3H), 8.32-8.25 (m, 2H), 7.57-7.52 (m, 2H), 7.49 (s, 1H), 4.66 (s, 1H ), 4.58-4.52 (m, 1H), 4.51-4.42 (m, 2H), 4.10 - 4.00 (m, 2H), 3.65 (t, J = 11.5 Hz, 2H), 3.42 - 3.16 (m, 4H), 2.84 (d, J = 17.2 Hz, 3H), 2.17 (d, J = 9.6 Hz, 2H), 2.09 (s, 3H), 1.68 - 1.54 (m, 2H), 1.49 - 1.34 (m, 18H).

Step 6. Synthesis of product S1

Add intermediate e (86mg, 0.14mmol) to a round bottom flask, add methanolic hydrochloric acid solution, stir at room temperature for 3 hours, spin dry the reaction solution, add ammonia gas methanol solution to the upper column, column chromatography to obtain S1, as a white solid The product was 55 mg in a yield of 93%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.71 (dd, J = 4.4, 1.6 Hz, 2H), 8.31 (s, 1H), 8.29 - 8.24 (m, 1H), 7.49 (dd, J = 4.4, 1.6 Hz, 2H), 7.37-7.41 (m, 2H), 4.69 (d, J = 7.2 Hz, 1H), 4.61 - 4.39 (m, 1H), 4.05 (dd, J = 8.2, 2.8 Hz, 2H), 3.85 (s, 2H), 3.63 (dd, J = 11.6, 9.9 Hz, 2H), 2.72 (ddd, J = 10.3, 6.8, 4.6 Hz, 4H), 2.38 (s, 3H), 2.17 (dd, J = 12.4) , 2.1 Hz, 2H), 2.08 (s, 3H), 1.98 (s, 2H), 1.62 (qd, J = 11.9, 4.4 Hz, 2H). MS m/z: 433.34 ([M+H] ⁺ ).

Preparation Example 2 N1-(3-(4-(3,5-Dimethylisothiazol-4-yl)-5-methyl-6-((tetrahydro-2H-pyran-4-yl)amino) Pyrimidine-2-yl)benzyl)-N2-methylethane-1,2-diamine (S2)

Similar to the preparation of Example 1, the product S2 was obtained by reacting the intermediate e with 3,5-dimethylisoxazole-4-boronic acid via Suzuki and then removing the protecting group.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.27-8.22 (m, 2H), 7.45-7.38 (m, 2H), 4.60 (d, J = 7.1Hz, 1H), 4.54-4.41 (m, 1H), 4.07 (dd, J = 8.3, 2.8), 3.89 (s, 2H), 3.66 (td, J = 11.7, 2.1 Hz, 2H), 2.87 (ddd, J = 10.3, 6.8, 4.6 Hz, 4H), (2.49 (s, 3H), 2.36 (s, 3H), 2.29 (s, 3H), 2.19 (dd, J = 12.6, 2.3 Hz, 2H), 1.98 (s, 3H), 1.64 (qd, J = 11.9, 4.4 Hz, 2H). MS m/z: 451.41 ([M+H] ⁺ ).

PREPARATIVE EXAMPLE 3 N1-Methyl-N2-(3-(5-methyl-4-(4-(methylsulfonyl)phenyl)-6-((tetrahydro-2H-pyran-4-yl)) Amino)pyrimidin-2-yl)benzyl)ethane-1,2-diamine (S3)

Similar to the preparation of Example 1, the product S3 was obtained by reacting the intermediate e with 4-methanesulfonylbenzeneboronic acid via Suzuki and then removing the protecting group.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.33 (s, 1H), 8.32-8.26 (m, 1H), 8.09-8.03 (m, 2H), 7.85-7.78 (d, J = 8.4Hz, 2H), 7.42 (d, J = 5.2 Hz, 2H), 4.71 (d, J = 7.2 Hz, 1H), 4.56 - 4.45 (m, 1H), 4.09 (dd, J = 8.3, 2.8), 3.88 (s, 2H) , 3.66 (td, J = 11.6, 2.0 Hz, 2H), 3.11 (s, 3H), 2.76 (ddd, J = 10.3, 6.8, 4.6 Hz, 4H), 2.47 (s, 3H), 2.32 (s, 2H) ), 2.21 (dd, J = 12.6, 2.3 Hz, 2H), 2.11 (s, 3H), 1.77 (qd, J = 11.9, 4.4 Hz, 2H). MS m/z: 510.39 ([M+H] ⁺ ).

PREPARATIVE EXAMPLE 4 N1-Methyl-N2-(3-(5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-6-((tetrahydro-2H-pyran)- 4-yl)amino)pyrimidin-2-yl)benzyl)ethane-1,2-diamine (S4)

Similar to the preparation of Example 1, the product S4 was obtained from the reaction of the intermediate e with 1-methyl-1H-pyrazole-5-boronic acid pinacol ester via Suzuki, followed by removal of the protecting group.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.28 (s, 1H), 8.27-8.23 (m, 1H), 7.52 (d, J = 1.9Hz, 1H), 7.44-7.38 (m, 2H), 6.36 ( d, J = 1.9 Hz, 1H), 4.74 (d, J = 7.2 Hz, 1H), 4.54 - 4.41 (m, 1H), 4.05 (dd, J = 8.3, 2.8 Hz, 2H), 3.99 (s, 3H) ), 3.85 (s, 2H), 3.63 (td, J = 11.6, 2.0 Hz, 2H), 2.84 (ddd, J = 10.3, 6.8, 4.6 Hz, 4H), 2.74 (s, 2H), 2.43 (s, 3H), 2.16 (dd, J = 12.6, 2.3 Hz, 2H), 2.08 (s, 3H), 1.62 (qd, J = 11.9, 4.4 Hz, 2H). MS m/z: 436.38 ([M+H] ⁺ ).

Preparation Example 5 N1-Methyl-N2-(3-(5-methyl-6-((tetrahydro-2H-pyran-4-yl)amino)-[4,5'-bipyrimidine]-2 -yl)benzyl)ethane-1,2-diamine (S5)

Similar to the preparation of Example 1, the product S5 was obtained by reacting the intermediate e with 5-boric acid pyrimidine via Suzuki and then removing the protecting group.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.26 (s, 1H), 9.00 (s, 2H), 8.31 (s, 1H), 8.29 - 8.24 (m, 1H), 7.44 - 7.39 (m, 2H), 4.72 (d, J = 7.2 Hz, 1H), 4.45-4.53 (m, 1H), 4.05 (dd, J = 8.1, 2.7 Hz, 2H), 3.85 (s, 2H), 3.63 (td, J = 11.7, 2.0 Hz, 2H), 2.75 (ddd, J = 10.3, 6.8, 4.6 Hz, 4H), 2.49 (s, 4H), 2.40 (s, 4H), 2.17 (dd, J = 12.5, 2.2 Hz, 2H), 2.14 (s, 3H), 1.62 (qd, J = 11.9, 4.4 Hz, 2H). MS m/z: 434.37 ([M+H] ⁺ ).

PREPARATIVE EXAMPLE 6 N1-(3-(4-(4-Bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-6-((tetrahydro-2H-pyran-4) -amino)amino)pyrimidin-2-yl)benzyl)-N2-methylethane-1,2-diamine (S6)

Similar to the preparation of Example 1, the intermediate e was reacted with 1-methyl-1H-pyrazole-5-boronic acid pinacol ester through Suzuki, followed by bromination with N-bromosuccinimide, and finally Deprotection affords product S6.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.27 (s, 1H), 8.24 (m, 1H), 7.51 (s, 1H), 7.45-7.37 (m, 2H), 4.75 (d, J = 7.1Hz, 1H), 4.57–4.39 (m, 1H), 4.05 (dd, J=8.1, 2.7 Hz, 2H), 3.88 (s, 3H), 3.85 (s, 2H), 3.64 (td, J=11.7, 2.0 Hz) , 2H), 3.25 (s, 2H), 2.81 (ddd, J = 10.3, 6.8, 4.6 Hz, 4H), 2.44 (s, 3H), 2.16 (dd, J = 12.5, 2.2 Hz, 2H), 2.02 ( s, 3H), 1.65 (qd, J = 11.9, 4.4 Hz, 2H). MS m/z: 514.36 ([M+H] ⁺ ).

Preparation Example 7 N1-(3-(4-(1,3-Dimethyl-1H-pyrazol-4-yl)-5-methyl-6-((tetrahydro-2H-pyran-4-) Amino)pyrimidin-2-yl)benzyl)-N2-methylethane-1,2-diamine (S7)

Similar to the preparation of Example 1, the product S7 was obtained from the reaction of the intermediate e with 1,3-dimethylpyrazole-4-boronic acid pinacol ester via Suzuki, followed by removal of the protecting group.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31 (s, 1H), 8.29 - 8.24 (m, 1H), 7.49 (s, 1H), 7.42 - 7.35 (m, 2H), 4.51 (d, J = 7.1 Hz, 1H), 4.50–4.38 (m, 1H), 4.05 (d, J = 11.1 Hz, 2H), 3.89 (s, 3H), 3.85 (s, 2H), 3.63 (td, J = 11.6, 2.0 Hz) , 2H), 2.73 (ddd, J = 10.3, 6.8, 4.6 Hz, 4H), 2.39 (s, 3H), 2.38 (s, 3H), 2.17 (dd, J = 12.5, 2.2 Hz, 2H), 2.08 ( s, 3H), 1.93 (s, 2H), 1.61 (qd, J = 11.9, 4.4 Hz, 2H). MS m/z: 450.44 ([M+H] ⁺ ).

PREPARATIVE EXAMPLE 8 N1-Methyl-N2-(3-(5-methyl-4-((tetrahydro-2H-pyran-4-yl)amino)-6-(1,3,5-trimethyl) -1H-pyrazol-4-yl)pyrimidin-2-yl)benzyl)ethane-1,2-diamine (S8)

Similar to the preparation of Example 1, the intermediate E was reacted with 1,3,5-trimethyl-1-hydro-pyrazole-4-boronic acid pinacol ester via Suzuki, and the protecting group was removed to obtain the product S8. .

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31 (s, 1H), 8.28 (m,, 1H), 7.38-7.43 (m, 2H), 4.55 (d, J = 7.1 Hz, 1H), 4.52 - 4.43 (m, 1H), 4.08 (dd, J = 8.1, 2.7 Hz, 2H), 3.87 (s, 2H), 3.79 (s, 3H), 3.67 (dd, J = 11.5, 9.9 Hz, 2H), 2.77 ( Ddd, J = 10.3, 6.8, 4.6 Hz, 4H), 2.41 (s, 3H), 2.25 (s, 3H), 2.22 (s, 3H), 2.21 (dd, J = 12.5, 2.2 Hz, 2H), 2.00 (s, 3H), 1.69 (qd, J = 11.9, 4.4 Hz, 2H). MS m/z: 464.40 ([M+H] ⁺ ).

PREPARATIVE EXAMPLE 9 N1-Methyl-N2-(3-(5-methyl-4-(pyridin-3-yl)-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine- 2-yl)benzyl)ethane-1,2-diamine (S9)

Similar to the preparation of Example 1, the product S9 was obtained by reacting the intermediate e with pyridine-3-boronic acid via Suzuki and then removing the protecting group.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.85 (dd, J = 2.2, 0.8 Hz, 1H), 8.67 (dd, J = 4.9, 1.7 Hz, 1H), 8.33 (s, 1H), 8.32 - 8.27 (m, 1H), 8.02–7.95 (m, 1H), 7.46–7.38 (m, 3H), 4.69 (d, J=7.2 Hz, 1H), 4.59–4.44 (m, 1H), 4.08 (dd, J) = 8.3, 2.8), 3.88 (s, 2H), 3.66 (td, J = 11.7, 2.1 Hz, 2H), 2.78 (ddd, J = 10.3, 6.8, 4.6 Hz, 4H), 2.62 (s, 2H), 2.43 (s, 3H), 2.20 (dd, J = 12.4, 2.2 Hz, 2H), 2.14 (s, 3H), 1.65 (qd, J = 11.9, 4.4 Hz, 2H). MS m/z: 433.41 ([ M+H] ⁺ ).

PREPARATIVE EXAMPLE 10 N1-Methyl-N2-(3-(5-methyl-4-(pyridin-2-yl)-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine- 2-yl)benzyl)ethane-1,2-diamine (S10)

Similar to the preparation of Example 1, the product S10 was obtained by reacting the intermediate e with pyridine-2-boronic acid via Suzuki and then removing the protecting group.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.67 (d, J = 4.9Hz, 1H), 8.34 (s, 1H), 8.31-8.28 (m, 1H), 7.94 (d, J = 7.8Hz, 1H) , 7.85 (td, J = 7.7, 1.8 Hz, 1H), 7.37-7.42 (m, 2H), 7.33 (ddd, J = 7.8, 4.9, 1.8 Hz, 1H), 4.69 (d, J = 7.3 Hz, 1H) ), 4.58–4.44 (m, 1H), 3.98 (dd, J=8.2, 2.8 Hz, 2H), 3.86 (s, 2H), 3.64 (td, J=11.5, 1.8 Hz, 2H), 3.39 (s, 2H), 2.84 (ddd, J = 10.3, 6.8, 4.6 Hz, 4H), 2.45 (s, 3H), 2.24 (s, 3H), 2.22 - 2.12 (dd, J = 12.4, 2.1 Hz, 2H), 1.61 (qd, J = 11.9, 4.3 Hz, 2H). MS m/z: 433.36 ([M+H] ⁺ ).

PREPARATIVE EXAMPLE 11 N1-(3-(4-(7-Methoxy-1H-indol-2-yl)-5-methyl-6-((tetrahydro-2H-pyran-4-yl)) Amino)pyrimidin-2-yl)benzyl)-N2-methylethane-1,2-diamine (S11)

Similar to the preparation of Example 1, the product S11 was obtained from the reaction of the intermediate e with 7-methoxy-H-indole-boronic acid pinacol ester via Suzuki, followed by removal of the protecting group.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ10.05 (s, 1H), 8.43 (s, 1H), 8.34 (dd, J = 6.7,2.0Hz, 1H), 7.48-7.40 (m, 2H), 7.28 ( d, J = 7.9 Hz, 1H), 7.05 (t, J = 7.8 Hz, 1H), 6.92 (s, 1H), 6.70 (d, J = 7.6 Hz, 1H), 4.68 (d, J = 7.1 Hz, 1H), 4.51–4.36 (m, 1H), 4.06 (dd, J=8.2, 2.8 Hz, 2H), 4.02 (s, 3H), 3.91 (s, 2H), 3.63 (td, J = 11.6, 1.9 Hz) , 2H), 2.88 (s, 2H), 2.81 (ddd, J = 10.3, 6.8, 4.6 Hz, 4H), 2.43 (s, 3H), 2.37 (s, 3H), 2.17 (dd, J = 12.5, 2.1 Hz, 2H), 1.61 (qd, J = 11.5, 4.4 Hz, 2H). MS m/z: 501.40 ([M+H] ⁺ )

PREPARATIVE EXAMPLE 12 N1-(3-(4-Chloro-5-methyl-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-2-yl)benzyl)-N2- Methyl ethane-1,2-diamine (S12)

Similar to the preparation of Example 1, the product S12 was obtained by directly removing the protecting group from the intermediate e.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.27 (s, 1H), 8.21. (d, J = 7.3 Hz, 1H), 7.45-7.37 (m, 2H), 4.58 (d, J = 7.1 Hz, 1H) , 4.42 (m, 1H), 4.05 (dd, J = 8.2, 2.8 Hz, 2H), 3.88 (s, 2H), 3.62 (td, J = 11.6, 1.9 Hz, 2H), 2.82 (ddd, J = 10.3) , 6.8, 4.6 Hz, 4H), 2.46 (s, 3H), 2.18 (s, 3H), 2.13 (dd, J = 12.5, 2.1 Hz, 2H), 2.07 (s, 2H), 1.60 (qd, J = 11.5, 4.4 Hz, 2H). MS m/z: 390.28 ([M+H] ⁺ ).

PREPARATIVE EXAMPLE 13 N1-Methyl-N2-(3-(5-methyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-6-((tetrahydro-2H-) Pyran-4-yl)amino)pyrimidin-2-yl)benzyl)ethane-1,2-diamine (S13)

Similar to the preparation of Example 1, the product S13 was obtained from the reaction of the intermediate e with 7-azaindole-4-boronic acid pinacol ester via Suzuki, followed by removal of the protecting group.

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.94 (s, 1H), 8.40 (d, J = 4.9 Hz, 1H), 8.33 (s, 1H), 8.32 - 8.27 (m, 1H), 7.43 - 7.34 ( m, 3H), 7.20 (d, J = 4.9 Hz, 1H), 6.44 (d, J = 3.5 Hz, 1H), 4.68 (d, J = 7.1 Hz, 1H), 4.57 - 4.40 (m, 1H), 4.08 (dd, J = 8.2, 2.8 Hz, 2H), 3.84 (s, 2H), 3.66 (td, J = 11.6, 1.9 Hz, 2H), 2.73 (ddd, J = 11.5, 7.1, 5.3 Hz, 4H) , 2.37 (s, 3H), 2.21 (dd, J = 12.5, 2.1 Hz, 2H), 2.02 (s, 3H), 1.71 - 1.53 (qd, J = 11.5, 4.4 Hz, 2H). MS m/z: 472.40 ([M+H] ⁺ ).

Preparation Example 14 N1-(3-(4-(1H-indol-4-yl)-5-methyl-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-2- Benzyl)-N2-methylethane-1,2-diamine (S14)

Similar to the preparation of Example 1, the product S14 was obtained from the reaction of the intermediate e with 4-pinaboronic acid pinacol ester via Suzuki, followed by removal of the protecting group.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.26 (s, 1H), 8.24 - 8.29 (m, 2H), 7.39 (t, J = 7.5 Hz, 1H), 7.30 (dd, J = 14.4, 7.7 Hz, 2H), 7.18 (t, J = 7.5 Hz, 1H), 7.14 (d, J = 6.0 Hz, 1H), 7.04 (d, J = 3.0 Hz, 1H), 6.39 (d, J = 3.0 Hz, 1H) , 4.63 (d, J = 7.2 Hz, 1H), 4.60 - 4.46 (m, 1H), 4.07 (dd, J = 8.2, 2.8 Hz, 2H), 3.71 (s, 2H), 3.66 (td, J = 11.6) , 1.9 Hz, 2H), 3.19 (s, 2H), 2.61 (ddd, J = 11.5, 7.1, 5.3 Hz, 4H), 2.25 (s, 3H), 2.19 (dd, J = 12.5, 2.1 Hz, 2H) , 2.00 (s, 3H), 1.64 (qd, J = 11.5, 4.4 Hz, 2H). MS m/z: 471.44 ([M+H] ⁺ ).

PREPARATIVE EXAMPLE 15 N1-(3-(4-(Benzo[b]thiophen-2-yl)-5-methyl-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine- 2-yl)benzyl)-N2-methylethane-1,2-diamine (S15)

Similar to the preparation of Example 1, the product S15 was obtained by reacting the intermediate e with benzothiophene-2-boronic acid via Suzuki and then removing the protecting group.

¹ H NMR (400MHz, CDCl ₃ ) δ 8.39 (s, 1H), 8.37 - 8.32 (m, 1H), 7.95-7.79 (m, 1H), 7.87 - 7.77 (m, 1H), 7.64 (s, 1H) ), 7.46-7.40 (m, 2H), 7.40 - 7.33 (m, 2H), 4.68 (d, J = 7.1 Hz, 1H), 4.58 - 4.41 (m, 1H), 4.06 (dd, J = 8.2, 2.8) Hz, 2H), 3.90 (s, 2H), 3.63 (td, J = 11.6, 1.9 Hz, 2H), 3.16 (s, 2H), 2.83 (ddd, J = 11.5, 6.8, 4.9 Hz, 4H), 2.45 (s, 3H), 2.36 (s, 3H), 2.17 (dd, J = 12.5, 2.1 Hz, 2H), 1.62 (qd, J = 11.6, 4.4 Hz, 2H). MS m/z: 488.38 ([M +H] ⁺ ).

PREPARATIVE EXAMPLE 16 N1-Methyl-N2-(3-(5-methyl-4-(quinolin-5-yl)-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine -2-yl)benzyl)ethane-1,2-diamine (S16)

Similar to the preparation of Example 1, the product S16 was obtained by reacting the intermediate e with 5-quinoline-boronic acid via Suzuki and then removing the protecting group.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.91 (dd, J = 4.2, 1.7 Hz, 1H), 8.30 - 8.22 (m, 2H), 8.17 (d, J = 8.5 Hz, 1H), 8.08 - 8.00 ( m, 1H), 7.77 (dd, J = 8.5, 7.1 Hz, 1H), 7.53 (dd, J = 7.0, 1.0 Hz, 1H), 7.37-7.40 (m 2H), 7.34 (dd, J = 8.5, 4.2 Hz, 1H), 4.67 (d, J = 7.2 Hz, 1H), 4.62 - 4.47 (m, 1H), 4.07 (dd, J = 8.2, 2.8 Hz, 2H), 3.78 (s, 2H), 3.66 (td) , J = 11.6, 1.9 Hz, 2H), 3.29 (s, 2H), 2.73 (ddd, J = 10.6, 6.8, 4.7 Hz, 4H), 2.35 (s, 3H), 2.21 (dd, J = 12.5, 2.1 Hz, 2H), 1.84 (s, 3H), 1.64 (qd, J = 11.6, 4.4 Hz, 2H). MS m/z: 483.41 ([M+H] ⁺ ).

PREPARATIVE EXAMPLE 17 N1-Methyl-N2-(3-(5-methyl-4-(isoquinolin-5-yl)-6-((tetrahydro-2H-pyran-4-yl)amino) Pyrimidin-2-yl)benzyl)ethane-1,2-diamine (S17)

Similar to the preparation of Example 1, the product S17 was obtained by reacting the intermediate e with 5-isoquinoline-boronic acid via Suzuki and then removing the protecting group.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ9.29 (s, 1H), 8.45 (d, J = 6.0Hz, 1H), 8.25 (t, J = 3.8Hz, 2H), 8.03 (dd, J = 7.6, 1.0 Hz, 1H), 7.74 - 7.65 (m, 2H), 7.49 (d, J = 6.0 Hz, 1H), 7.40 - 7.34 (m, 2H), 4.70 (d, J = 7.2 Hz, 1H), 4.61 - 4.45 (m, 1H), 4.07 (dd, J = 8.2, 2.8 Hz, 2H), 3.78 (s, 2H), 3.67 (td, J = 11.6, 1.9 Hz, 2H), 3.63 (s, 2H), 2.75 (ddd, J = 10.6, 6.8, 4.7 Hz, 4H), 2.36 (s, 3H), 2.21 (dd, J = 12.5, 2.1 Hz, 2H), 1.83 (s, 3H), 1.64 (qd, J = 11.6) , 4.4 Hz, 2H). MS m/z: 483.40 ([M+H] ⁺ ).

PREPARATIVE EXAMPLE 18 N1-(3-(4-(3,5-Dimethylisothiazol-4-yl)-5-methyl-6-(methyl(tetrahydro-2H-pyran-4-yl) Amino)pyrimidin-2-yl)benzyl)-N2-methylethane-1,2-diamine (S18)

Similar to the preparation of Example 1, product S18 was obtained by methylation of intermediate f with methyl iodide followed by removal of the protecting group.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.28 (s, 1H), 8.24 (d, J = 7.6 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.41 (t, J = 7.6 Hz) , 1H), 4.52–4.27 (m, 1H), 4.13 (dd, J=11.2, 4.2 Hz, 2H), 3.88 (s, 2H), 3.67 (s, 2H), 3.59 (td, J = 11.6, 1.9 Hz, 2H), 3.01 (s, 3H), 2.87 (ddd, J = 10.6, 6.8, 4.7 Hz, 4H), 2.49 (s, 3H), 2.40 (s, 3H), 2.32 (s, 3H), 2.10 (s, 3H), 2.01 (qd, J = 11.6, 4.4 Hz, 2H), 1.87 (dd, J = 12.5, 2.1 Hz, 2H). MS m/z: 465.42 ([M+H] ⁺ ).

Preparation Example 19 N1-(3-(4-(3,5-Dimethylisoxazol-4-yl)-6-(4-(2-methoxyphenyl)piperazin-1-yl)- 5-methylpyrimidin-2-yl)benzyl)-N2-methylethane-1,2-diamine (S19)

Similar to the preparation of Example 1, the product S19 was obtained from 4-(1-(2-methoxyphenyl))piperazine and 2,4,6-trichloro-5-methylpyrimidine as starting materials.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.41 - 8.31 (m, 2H), 7.48 - 7.40 (m, 2H), 7.09 - 7.04 (m, 1H), 7.02 (dd, J = 7.9, 1.8 Hz, 1H) ), 6.97 (dd, J = 7.2, 1.3 Hz, 1H), 6.95 - 6.90 (m, 1H), 3.93 (s, 3H), 3.89 (s, 2H), 3.79 (m, 4H), 3.34 - 3.22 ( m, 4H), 2.75 (ddd, J = 10.6, 6.8, 4.7 Hz, 4H), 2.42 (s, 3H), 2.41 (s, 3H), 2.34 (s, 3H), 2.17 (s, 3H). m/z: 542.40 ([M+H] ⁺ ).

Preparation Example 20 N1-(3-(4-(3,5-Dimethylisothiazol-4-yl)-5-methyl-6-(phenylamino)pyrimidin-2-yl)benzyl) -N2-methylethane-1,2-diamine (S20)

Similar to the preparation of Example 1, the product S20 was obtained from aniline and 2,4,6-trichloro-5-methylpyrimidine as a starting material.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.33 (s, 1H), 8.31-8.26 (m, 1H), 7.79 (dd, J = 8.6,1.0Hz, 2H), 7.52-7.39 (m, 4H), 7.24–7.11 (m, 1H), 6.71 (s, 1H), 3.88 (s, 2H), 2.76 (ddd, J = 10.6, 6.8, 4.7 Hz, 4H), 2.42 (s, 3H), 2.41 (s, 3H), 2.35 (s, 3H), 2.24 (s, 2H), 2.19 (s, 3H). MS m/z: 443.29 ([M+H] ⁺ ).

PREPARATIVE EXAMPLE 21 N1-(3-(4-(4-Cyclopropylpiperazin-1-yl)-6-(3,5-dimethylisoxazol-4-yl)-5-methylpyrimidine -2-yl)benzyl)-N2-methylethane-1,2-diamine (S21)

Similar to the preparation of Example 1, the product S21 was obtained from N-cyclopropylpiperazine and 2,4,6-trichloro-5-methylpyrimidine as starting materials.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.35 - 8.25 (m, 2H), 7.46 (d, J = 7.8 Hz, 1H), 7.40 (t, J = 7.8 Hz, 1H), 3.86 (s, 2H) , 3.52 (t, J = 4.4 Hz, 4H), 2.89 (ddd, J = 10.6, 6.8, 4.7 Hz, 4H), 2.78 (t, J = 4.4 Hz, 4H), 2.51 (s, 3H), 2.37 ( s, 3H), 2.31 (s, 3H), 2.13 (s3H), 1.64-1.72 (m, 1H), 0.55-0.40 (m, 4H). MS m/z: 476.30 ([M+H] ⁺ ).

Preparation Example 22 N1-(3-(4-(3,5-Dimethylisoxazol-4-yl)-5-methyl-6-morpholinopyrimidin-2-yl)benzyl)- N2-methylethane-1,2-diamine (S22)

Similar to the preparation of Example 1, the product S22 was obtained from morpholine and 2,4,6-trichloro-5-methylpyrimidine as a starting material.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.31 (s, 1H), 8.30-8.26 (m, 1H), 7.44-7.35 (m, 2H), 3.88 (t, J = 4.4Hz, 4H), 3.86 ( s, 2H), 3.54 (t, J = 4.4 Hz, 4H), 2.72 (ddd, J = 10.6, 6.8, 4.7 Hz, 4H), 2.39 (s, 3H), 2.37 (s, 3H), 2.29 (s ,3H),2.10(s,3H).MS m/z:437.25([M+H] ⁺ )

PREPARATIVE EXAMPLE 23 N1-Methyl-N2-(3-(5-methyl-4-phenoxy-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-2-yl) Benzyl)ethane-1,2-diamine (S23)

Similar to the preparation of Example 1, the product S23 was obtained by nucleophilic substitution of the intermediate e with phenol followed by removal of the protecting group.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.01 - 8.08 (m,, 2H), 7.38 (t, J = 8.4 Hz, 2H), 7.35-7.28 (dm, 2H), 7.21-7.14 (m, 3H) , 4.46 (d, J = 6.9 Hz, 1H), 4.37 - 4.45 (m, 1H), 4.05 (dd, J = 8.2, 2.8 Hz, 2H), 3.77 (s, 2H), 3.62 (td, J = 11.6) , 2.0 Hz, 2H), 2.73 (ddd, J = 10.6, 6.8, 4.7 Hz, 4H), 2.41 (s, 3H), 2.15 (dd, J = 12.5, 2.1 Hz, 2H), 2.09 (s, 3H) , 1.61 (qd, J = 11.6, 4.4 Hz, 2H). MS m/z: 448.26 ([M+H] ⁺ )

Preparation Example 24 N1-(3-(4-((4-fluorobenzyl)oxy)-5-methyl-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine- 2-yl)benzyl)-N2-methylethane-1,2-diamine (S24)

Similar to the preparation of Example 1, the product S24 was obtained by nucleophilic substitution of the intermediate e with 4-fluorobenzyl alcohol followed by removal of the protecting group.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.25-8.31 (m, 2H), 7.51-7.45 (m, 2H), 7.46-7.39 (m, 2H), 7.12-7.02 (m, 2H), 5.51 (s , 2H), 4.47 - 4.37 (m, 1H), 4.32 (d, J = 7.4 Hz, 1H), 4.05 (dd, J = 8.2, 2.9 Hz, 2H), 3.91 (s, 2H), 3.63 (td, J = 11.6, 2.0 Hz, 2H), 2.84 (ddd, J = 10.6, 6.8, 4.7 Hz, 4H), 2.47 (s, 3H), 2.14 (dd, J = 12.4, 2.1 Hz, 2H), 1.99 (s , 3H), 1.58 (ddd, J=qd, J=11.6, 4.4 Hz, 2H). MS m/z: 480.23 ([M+H] ⁺ )

Preparation Example 25 N1-(3-(4-(3,5-Dimethylisoxazol-4-yl)-5-methyl-6-(4-methylpiperazin-1-yl)pyrimidine- 2-yl)benzyl)-N2-methylethane-1,2-diamine (S25)

Similar to the preparation of Example 1, the product S25 was obtained from N-methylpiperazine and 2,4,6-trichloro-5-methylpyrimidine as starting materials.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.34 - 8.28 (m, 2H), 7.49-7.39 (m, 2H), 3.90 (s, 2H), 3.59 (t, J = 4.7 Hz, 4H), 2.87 ( Ddd, J = 10.6, 6.8, 4.7 Hz, 4H), 2.61 (t, J = 4.7 Hz, 4H), 2.51 (s, 3H), 2.38 (s, 3H), 2.37 (s, 3H), 2.30 (s ,3H),2.10(s,3H).MS m/z: 450.30([M+H] ⁺ )

PREPARATIVE EXAMPLE 26 N1-(3-(4-(3,5-Dimethylisoxazol-4-yl)-5-methyl-6-(5H-pyrrolo[3,4-b]pyridine- 6(7H)-yl)pyrimidin-2-yl)benzyl)-N2-methylethane-1,2-diamine (S26)

Similar to the preparation of Example 1, starting from 6,7-dihydro-5H-pyrrole[3,4-b]pyridine hydrochloride and 2,4,6-trichloro-5-methylpyrimidine. Product S26.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.50 (d, J = 4.2Hz, 1H), 8.35-8.29 (m, 2H), 7.69 (d, J = 7.5Hz, 1H), 7.36-7.45 (m, 2H), 7.20-7.27 (m, 1H), 5.24 (d, J = 13.9 Hz, 4H), 3.87 (s, 2H), 2.80 (ddd, J = 10.6, 6.8, 4.7 Hz, 4H), 2.43 (s) , 3H), 2.39 (s, 3H), 2.33 (s, 3H), 2.31 (s, 3H). MS m/z: 470.27 ([M+H] ⁺ ).

Preparation Example 27 N1-(3-(4-(3,5-Dimethylisoxazol-4-yl)-5-methyl-6-(4-(acetyl)piperazin-1-yl) Pyrimidin-2-yl)benzyl)-N2-methylethane-1,2-diamine (S27)

Similar to the preparation of Example 1, the product S27 was obtained from N-acetylpiperazine and 2,4,6-trichloro-5-methylpyrimidine as starting materials.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.31-8.25 (m, 2H), 7.46-7.36 (m, 2H), 3.86 (s, 2H), 3.79 (t, J = 4.8Hz, 2H), 3.72- 3.63 (m, 2H), 3.63-3.54 (m, 2H), 3.49 (t, J = 4.8 Hz, 2H), 3.10 (s, 2H), 2.78 (ddd, J = 10.6, 6.8, 4.7 Hz, 4H) , 2.43 (s, 3H), 2.37 (s, 3H), 2.29 (s, 3H), 2.16 (s, 3H), 2.13 (s, 3H). MS m/z: 478.28 ([M+H] ⁺ ) .

PREPARATIVE EXAMPLE 28 N1-(3-(4-(3,5-Dimethylisoxazol-4-yl)-5-methyl-6-(4-thiomorpholine-4,4-dioxide -1-yl)pyrimidin-2-yl)benzyl)-N2-methylethane-1,2-diamine (S28)

Similar to the preparation of Example 1, the product S28 was obtained starting from thiomorpholine-1,1-dioxide and 2,4,6-trichloro-5-methylpyrimidine.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.29 (s, 1H), 8.23 (d, J = 7.4Hz, 1H), 7.48-7.39 (m, 2H), 4.09 (t, J = 4.8Hz, 4H) , 3.87(s, 2H), 3.29 (t, J = 4.8 Hz, 4H), 2.74 (ddd, J = 10.6, 6.8, 4.7 Hz, 4H), 2.41 (s, 3H), 2.40 (s, 3H), 2.31 (s, 3H), 2.16 (s, 3H). MS m/z: 485.19 ([M+H] ⁺ ).

Preparation Example 29 N1-(3-(4-(3,5-Dimethylisoxazol-4-yl)-5-methyl-6-((1-(methylsulfonyl))piperidine-4- Amino)pyrimidin-2-yl)benzyl)-N2-methylethane-1,2-diamine (S29)

Similar to the preparation of Example 1, the product S29 was obtained from 1-methanesulfonyl-4-aminopiperidine and 2,4,6-trichloro-5-methylpyrimidine as starting materials.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.26 (s, 1H), 8.24-8.20 (m, 1H), 7.44-7.37 (m, 2H), 4.74 (d, J = 7.3Hz, 1H), 4.35- 4.45 (m, 1H), 3.90 (d, J = 12.2 Hz, 2H), 3.86 (s, 2H), 2.97 (td, J = 12.0, 2.3 Hz, 2H), 2.86 (s, 3H), 2.73 (ddd , J = 10.6, 6.8, 4.7 Hz, 4H), 2.40 (s, 3H), 2.36 (s, 3H), 2.36 - 2.30 (m, 4H), 2.30 (s, 3H), 1.99 (s, 3H), 1.72 (td, J = 12.1, 3.8 Hz, 2H). MS m/z: 528.26 ([M+H] ⁺ ).

Preparation Example 30 N1-(3-(4-(3,5-Dimethylisoxazol-4-yl)-5-methyl-6-(4-(methylsulfonyl)piperazin-1-yl) Pyrimidine-2-yl)benzyl)-N2-methylethane-1,2-diamine (S30)

Similar to the preparation of Example 1, the product S30 was obtained from N-methanesulfonylpiperazine and 2,4,6-trichloro-5-methylpyrimidine as starting materials.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.29 (s, 1H), 8.26 (dt, J = 7.5,1.5Hz, 1H), 7.46-7.37 (m, 2H), 3.86 (s, 2H), 3.65 ( t, J = 4.4 Hz, 4H), 3.41 (t, J = 4.4 Hz, 4H), 3.20 (s, 2H), 2.83 (s, 3H), 2.78 (ddd, J = 11.8, 5.9, 1.8 Hz, 4H) ), 2.43 (s, 3H), 2.37 (s, 3H), 2.29 (s, 3H), 2.11 (s, 3H). MS m/z: 514.25 ([M+H] ⁺ ).

Preparation Example 31 N1-(3-(4-(3,5-Dimethylisoxazol-4-yl)-6-((4-fluorophenyl)amino)-5-methylpyrimidin-2- Benzyl)-N2-methylethane-1,2-diamine (S31)

Similar to the preparation of Example 1, the product S31 was obtained from 4-fluoroaniline and 2,4,6-trichloro-5-methylpyrimidine as starting materials.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.27 (s, 1H), 8.21. (dt, J = 6.7, 1.9 Hz, 1H), 7.73 - 7.63 (m, 2H), 7.44 - 7.36 (m, 2H), 7.16–7.07 (m, 2H), 6.65 (s, 1H), 3.85 (s, 2H), 2.74 (ddd, J = 11.8, 5.9, 1.8 Hz, 4H), 2.40 (s, 3H), 2.39 (s, 3H), 2.32 (s, 2H), 2.22 (s, 3H), 2.16 (s, 3H). MS m/z: 461.21. ([M+H] ⁺ ).

Preparation Example 32 N1-(3-(4-(3,5-Dimethylisoxazol-4-yl)-6-((3-fluorophenyl)amino)-5-methylpyrimidin-2- Benzyl)-N2-methylethane-1,2-diamine (S32)

Similar to the preparation of Example 1, the product S32 was obtained from 3-fluoroaniline and 2,4,6-trichloro-5-methylpyrimidine as starting materials.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33 (s, 1H), 8.30 - 8.24 (m, 1H), 8.05 - 7.90 (m, 1H), 7.46 - 7.40 (m, 2H), 7.39 - 7.28 (m) , 2H), 6.85 (d, J = 2.3 Hz, 1H), 6.67 (s, 1H), 3.88 (s, 2H), 2.75 (ddd, J = 11.8, 5.9, 1.8 Hz, 4H, 4H), 2.40 ( s, 6H), 2.33 (s, 3H), 2.18 (s, 3H), 1.68 (s, 2H). MS m/z: 461.21. ([M+H] ⁺ ).

Preparation Example 33 N1-(3-(4-((4-Chlorophenyl)amino)-6-(3,5-dimethylisoxazol-4-yl)-5-methylpyrimidin-2- Benzyl)-N2-methylethane-1,2-diamine (S33)

Similar to the preparation of Example 1, the product S33 was obtained from 4-chloroaniline and 2,4,6-trichloro-5-methylpyrimidine as starting materials.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.29 (s, 1H), 8.27 - 8.20 (m, 1H), 7.77 - 7.67 (m, 2H), 7.45 - 7.35 (m, 4H), 6.66 (s, 1H) ), 3.86 (s, 2H), 2.72 (ddd, J = 11.8, 5.9, 1.8 Hz, 4H), 2.40 (s, 3H), 2.39 (s, 3H), 2.32 (s, 3H), 2.16 (s, 3H), 1.85 (s, 2H). MS m/z: 477.16 ([M+H] ⁺ ).

Preparation Example 34 N1-(3-(4-(3,5-Dimethylisoxazol-4-yl)-6-morpholino-1,3,5-triazin-2-yl)benzene Base)-N2-methylethane-1,2-diamine (S34)

Similar to the preparation of Example 1, the product S34 was obtained from morpholine and cyanuric chloride as starting materials.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.34 (s, 1H), 8.29 (d, J = 7.7 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.41 (t, J = 7.6 Hz) , 1H), 4.05-3.85 (m,, 4H), 3.86 (s, 2H), 3.82-3.75 (m, 4H), 2.84 (s, 3H), 2.72 (dtd, J = 7.8, 5.7, 1.1 Hz, 4H), 2.63 (s, 3H), 2.39 (s, 3H). MS m/z: 422.22 ([M+H] ⁺ ).

PREPARATIVE EXAMPLE 35 3-(4-(3-(((2-(methylamino)ethyl)amino)methyl)phenyl)-6-morpholino-1,3,5-triazine-2 -yl)phenol (S35)

Similar to the preparation of Example 1, starting from morpholine and cyanuric chloride, the intermediate was reacted with 3-hydroxybenzeneboronic acid via Suzuki, and the protecting group was removed to obtain product S35.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.51 (s, 1H), 8.33 (d, J = 7.6Hz, 1H), 8.04-7.95 (m, 2H), 7.42 (d, J = 7.6Hz, 1H) , 7.36 (t, J = 7.6 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.03 - 6.93 (m, 1H), 4.52 (s, 3H), 4.00 - 3.92 (m, 4H), 3.89 (s, 2H), 3.85 - 3.68 (m, 4H), 2.84 (dtd, J = 7.8, 5.7, 1.1 Hz, 4H), 2.45 (s, 3H). MS m/z: 421.22 ([M+H ] ⁺ ).

PREPARATIVE EXAMPLE 36 N1-(3-(4,6-Dimorpholino-1,3,5-triazin-2-yl)benzyl)-N2-methylethane-1,2-diamine (S36)

Similar to the preparation of Example 1, starting from morpholine and cyanuric chloride, the intermediate was nucleophilically substituted with the morpholine ring, and the protecting group was removed to obtain the product S36.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.29-8.24 (m, 2H), 7.45 (d, J = 7.5Hz, 1H), 7.38 (t, J = 7.5Hz, 1H), 4.00-3.82 (m, 8H), 3.86 (s, 3H), 3.81 - 3.68 (m, 8H), 2.72 (dtd, J = 7.8, 5.7, 1.1 Hz, 4H), 2.40 (s, 3H). MS m/z: 414.24 ([ M+H] ⁺ ).

PREPARATIVE EXAMPLE 37 N1-(3-(4-(1H-Indol-4-yl)-6-morpholino-1,3,5-triazin-2-yl)benzyl)-N2-A Ethylethane-1,2-diamine (S37)

Similar to the preparation of Example 1, starting from morpholine and cyanuric chloride, the intermediate was reacted with 4-pinaboronic acid pinacol ester via Suzuki, and then the protecting group was removed to obtain product S37.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ9.13 (s, 1H), 8.51 (dd, J = 8.9,2.9Hz, 2H), 8.45 (dd, J = 7.5,0.8Hz, 1H), 7.58 (d, J=2.9 Hz, 1H), 7.55–7.44 (m, 3H), 7.34–7.27 (m, 2H), 4.15–4.06 (m, 4H), 3.91 (s, 2H), 3.87–3.80 (m, 4H) , 2.77 (dtd, J = 7.8, 5.7, 1.1 Hz, 4H), 2.42 (s, 3H). MS m/z: 444.24 ([M+H] ⁺ ).

PREPARATIVE EXAMPLE 38 N1-(3-(4-(2-Aminopyrimidin-5-yl)-6-morpholino-1,3,5-triazin-2-yl)benzyl)-N2-A Ethylethane-1,2-diamine (S38)

Similar to the preparation of Example 1, starting from morpholine and cyanuric chloride, the intermediate was reacted with 2-aminopyrimidine-5-boronic acid pinacol ester via Suzuki, and the protecting group was removed to obtain product S38.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ9.36 (s, 2H), 8.49-8.35 (m, 2H), 7.53 (d, J = 7.7Hz, 1H), 7.45 (t, J = 7.6Hz, 1H) , 5.61 (s, 2H), 4.11-3.98 (m, 4H), 3.91 (s, 2H), 3.88 - 3.79 (m, 4H), 2.76 (dtd, J = 7.8, 5.7, 1.1 Hz, 4H), 2.42 (d, J = 6.7 Hz, 3H). MS m/z: 422.21. ([M+H] ⁺ ).

PREPARATIVE EXAMPLE 39 N1-(3-(4-(2-(Difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazine -2-yl)benzyl)-N2-methylethane-1,2-diamine (S39)

Similar to the preparation of Example 1, starting from morpholine and cyanuric chloride, the intermediate and 2-difluoromethyl-1H-benzimidazole were nucleophilically substituted, and then the protecting group was removed to obtain the product S39. .

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.46 (d, J = 8.1Hz, 1H), 8.33 (s, 1H), 8.27 (d, J = 7.8Hz, 1H), 7.88 (d, J = 7.7Hz , 1H), 7.68 (s, 0H), 7.57 - 7.51 (m, 1H), 7.48 - 7.36 (m, 3H), 4.15 - 4.07 (m, 2H), 3.94 - 3.90 (m, 2H), 3.88 (s , 2H), 3.86 - 3.79 (m, 4H), 2.77 (dtd, J = 7.8, 5.7, 1.1 Hz, 4H), 2.43 (s, 3H), 2.33 (s, 2H). MS m/z: 495.19 ( [M+H] ⁺ ).

PREPARATIVE EXAMPLE 40 N1-(3-(4-(1H-oxazol-4-yl)-6-morpholino-1,3,5-triazin-2-yl)benzyl)-N2-A Ethylethane-1,2-diamine (S40)

Similar to the preparation of Example 1, starting from morpholine and cyanuric chloride, the intermediate was reacted with 1-oxazol-4-boronic acid pinacol ester via Suzuki, and then the protecting group was removed to obtain product S40.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.01 (d, J = 0.8 Hz, 1H), 8.45 (dd, J = 11.2, 8.2 Hz, 3H), 7.60 (d, J = 8.3 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.45 (dt, J = 8.1, 7.0 Hz, 2H), 4.06 (s, 4H), 3.93 (s, 2H), 3.89 - 3.79 (m, 4H), 2.83 ( Dtd, J = 7.8, 5.7, 1.1 Hz, 4H), 2.46 (s, 3H). MS m/z: 445.21. ([M+H] ⁺ ).

PREPARATIVE EXAMPLE 41 N1-Methyl-N2-(3-(4-morpholino-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1,3,5-triazine -2-yl)benzyl)ethane-1,2-diamine (S41)

Similar to the preparation of Example 1, starting from morpholine and cyanuric chloride, the intermediate and 7-azaindole-4-boronic acid pinacol ester were reacted with Suzuki, and then the protective group was removed to obtain a product. S41.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ11.73 (s, 1H), 8.49 (dd, J = 5.7,3.6Hz, 3H), 8.26 (d, J = 5.1Hz, 1H), 7.59-7.53 (m, 2H), 7.49 (t, J = 7.9 Hz, 1H), 7.45 (d, J = 3.4 Hz, 1H), 4.15 - 4.06 (m, 4H), 3.95 (s, 2H), 3.89 - 3.83 (m, 4H) ), 2.85 (dtd, J = 7.8, 5.7, 1.1 Hz, 4H), 2.48 (s, 3H). MS m/z: 445.21. ([M+H] ⁺ ).

Preparation Example 42 N1-(3-(4-((3,4-difluorophenyl)amino)-6-(3,5-dimethylisothiazol-4-yl)-5-methylpyrimidine- 2-yl)benzyl)-N2-methylethane-1,2-diamine (S42)

Similar to the preparation of Example 1, the product S42 was obtained from 3,4-difluoroaniline and 2,4,6-trichloro-5-methylpyrimidine as starting materials.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.29 (s, 1H), 8.23 (dt, J = 6.6, 1.9 Hz, 1H), 8.00 (ddd, J = 12.7, 7.2, 2.5 Hz, 1H), 7.47– 7.37 (m, 2H), 7.27 - 7.22 (m, 1H), 7.18 (dd, J = 18.3, 8.7 Hz, 1H), 6.67 (s, 1H), 3.87 (s, 2H), 2.75 (dtd, J = 7.8, 5.7, 1.1 Hz, 4H), 2.41 (s, 3H), 2.39 (s, 3H), 2.32 (s, 3H), 2.17 (s, 3H). MS m/z: 479.2 ([M+H] ⁺ ).

PREPARATIVE EXAMPLE 43 N1-(3-(4-(3,5-Dimethylisothiazol-4-yl)-5-methyl-6-((2-(trifluoromethyl)pyridin-4-yl) Amino)pyrimidin-2-yl)benzyl)-N2-methylethane-1,2-diamine (S43)

Similar to the preparation of Example 1, the product S43 was obtained from 2-trifluoromethyl-4-aminopyrimidine and 2,4,6-trichloro-5-methylpyrimidine as starting materials.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.66 (d, J = 2.1Hz, 1H), 8.61 (d, J = 5.6Hz, 1H), 8.33-8.24 (m, 2H), 7.73 (dd, J = 5.6, 2.1 Hz, 1H), 7.46 (dt, J = 15.0, 7.5 Hz, 2H), 7.37 (s, 1H), 3.88 (s, 2H), 2.78 (dtd, J = 7.8, 5.7, 1.1 Hz, 4H) ), 2.41 (s, 3H), 2.39 (s, 3H), 2.31 (s, 3H), 2.25 (s, 3H). MS m/z: 512.2 ([M+H] ⁺ ).

PREPARATIVE EXAMPLE 44 N1-(3-(4-(3,5-Dimethylisothiazol-4-yl)-6-((2-fluorophenyl)amino)-5-methylpyrimidin-2-yl Benzyl)-N2-methylethane-1,2-diamine (S44)

Similar to the preparation of Example 1, the product S44 was obtained from 2-fluoroaniline and 2,4,6-trichloro-5-methylpyrimidine as starting materials.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.72 (td, J = 8.2,1.5Hz, 1H), 8.33 (s, 1H), 8.29-8.22 (m, 1H), 7.46-7.41 (m, 2H), 7.27 (t, 5.8 Hz, 1H), 7.18 (ddd, J = 11.2, 8.2, 1.4 Hz, 1H), 7.12-7.04 (m, 1H), 6.86 (d, J = 3.8 Hz, 1H), 3.88 (s) , 2H), 2.74 (dtd, J = 7.8, 5.7, 1.1 Hz, 4H), 2.41 (s, 3H), 2.40 (s, 3H), 2.33 (s, 3H), 2.20 (s, 3H). MS m /z: 461.2 ([M ⁺ H] ⁺ ).

PREPARATIVE EXAMPLE 45 N1-(3-(4-(3,5-Dimethylisothiazol-4-yl)-5-methyl-6-((4-(trifluoromethoxy)phenyl)amino) Pyrimidine-2-yl)benzyl)-N2-methylethane-1,2-diamine (S45)

Similar to the preparation of Example 1, the product S45 was obtained from 4-trifluoromethoxyaniline and 2,4,6-trichloro-5-methylpyrimidine as starting materials.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.29 (s, 1H), 8.23 (dt, J = 6.8,1.8Hz, 1H), 7.85-7.76 (m, 2H), 7.47-7.38 (m, 2H), 7.28 (d, J = 8.5 Hz, 2H), 6.71 (s, 1H), 3.86 (s, 2H), 2.76 (dtd, J = 7.8, 5.7, 1.1 Hz, 4H), 2.41 (s, 3H), 2.39 (s, 3H), 2.32 (s, 3H), 2.18 (s, 3H). MS m/z: 527.2 ([M+H] ⁺ ).

Preparation Example 46 N1-(3-(4-((2,4-difluorophenyl)amino)-6-(3,5-dimethylisothiazol-4-yl)-5-methylpyrimidine- 2-yl)benzyl)-N2-methylethane-1,2-diamine (S46)

Similar to the preparation of Example 1, the product S46 was obtained from 2,4-difluoroaniline and 2,4,6-trichloro-5-methylpyrimidine as starting materials.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.57 (td, J = 9.2,6.0Hz, 1H), 8.29 (s, 1H), 8.22 (dt, J = 6.5,2.0Hz, 1H), 7.50-7.38 ( m, 2H), 7.07 - 7.00 (m, 1H), 6.97 (ddd, J = 11.1, 8.3, 2.8 Hz, 1H), 6.68 (d, J = 2.8 Hz, 1H), 3.87 (s, 2H), 2.74 (dq, J=6.7, 4.8 Hz, 4H), 2.41 (s, 3H), 2.40 (s, 3H), 2.33 (s, 3H), 2.19 (s, 3H). MS m/z: 479.2 ([M +H] ⁺ ).

PREPARATIVE EXAMPLE 47 N1-(3-(4-(3,5-Dimethylisothiazol-4-yl)-5-methyl-6-((4-(trifluoromethyl)phenyl)amino) Pyrimidin-2-yl)benzyl)-N2-methylethane-1,2-diamine (S47)

Similar to the preparation of Example 1, the product S47 was obtained from 4-trifluoromethylaniline and 2,4,6-trichloro-5-methylpyrimidine as starting materials.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.31 (s, 1H), 8.25 (dt, J = 6.4,1.9Hz, 1H), 7.93 (d, J = 8.5Hz, 2H), 7.66 (d, J = 8.6 Hz, 2H), 7.47 - 7.37 (m, 2H), 6.97 (s, 1H), 3.86 (s, 2H), 2.75 (dq, J = 6.7, 4.8 Hz, 4H), 2.39 (s, 3H), 2.38 (s, 3H), 2.31 (s, 3H), 2.20 (s, 3H). MS m/z: 511.2 ([M+H] ⁺ ).

Preparation Example 48 5-methyl-2-(3-(((2-(methylamino)ethyl)ethyl)methyl)methyl)phenyl)-N4-phenyl-N6-(tetrahydro-2H-pyridyl)喃-4-yl)pyrimidine-4,6-diamine (S48)

Similar to the preparation of Example 1, the product S48 was obtained by reacting the intermediate e with aniline via Buchwald-Hartwig and then removing the protecting group.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.28 (s, 1H), 8.26 - 8.21 (m, 1H), 7.57 (d, J = 7.9 Hz, 2H), 7.42 - 7.31 (m, 4H), 7.03 ( t, J = 7.3 Hz, 1H), 6.28 (s, 1H), 4.49 - 4.39 (m, 1H), 4.27 (d, J = 7.3 Hz, 1H), 4.05 (d, J = 11.4 Hz, 2H), 3.86(s, 2H), 3.62 (dd, J = 11.6, 10.0 Hz, 2H), 2.75 (dq, J = 6.7, 4.8 Hz, 4H), 2.40 (s, 3H), 2.15 (dd, J = 12.6, 2.3 Hz, 2H), 1.96 (s, 3H), 1.57 (qd, J = 11.8, 4.3 Hz, 2H). MS m/z: 447.3 ([M+H] ⁺ ).

Preparation Example 49 5-methyl-2-(3-(((2-(methylamino)ethyl)amino)methyl)methyl)phenyl)-6-((tetrahydro-2H-pyran-4-) Amino)pyrimidine-4-phenol (S49)

Similar to the preparation of Example 1, the product S49 was obtained by hydrolysis of the intermediate e under a sodium hydroxide solution and then removing the protecting group.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.28 (s, 1H), 8.13 (d, J = 7.5Hz, 1H), 7.52-7.41 (m, 2H), 5.28 (s, 2H), 4.44-4.30 ( m,1H), 4.26 (d, J = 7.5 Hz, 1H), 4.02 (d, J = 11.2 Hz, 2H), 3.91 (s, 2H), 3.57 (dd, J = 11.6, 10.0 Hz, 2H), 2.74 (dq, J = 6.7, 4.8 Hz, 4H), 2.40 (s, 3H), 2.08 (dd, J = 12.6, 2.3 Hz, 2H), 1.97 (s, 3H), 1.58 (qd, J = 12.0, 4.4 Hz, 2H). MS m/z: 372.3 ([M+H] ⁺ ).

PREPARATIVE EXAMPLE 50 N1-(3-(4-(3,5-Dimethylisoxazol-4-yl)-5-methyl-6-((tetrahydro-2H-pyran-4-yl) Amino)pyrimidin-2-yl)-4-fluorobenzyl)-N2-methylethane-1,2-diamine (S50)

Similar to the preparation of Example 1, reductive amination of S50 was carried out from 3-bromo-4-fluorobenzaldehyde and 2-(N-Boc-N-methylamino)ethylamine as starting materials.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.87 (d, J = 7.2 Hz, 1H), 7.33 (s, 1H), 7.06 (t, J = 9.5 Hz, 1H), 4.63 (d, J = 6.8 Hz) , 1H), 4.43-4.33 (d, J = 5.9 Hz, 1H), 4.02 (d, J = 11.2 Hz, 2H), 3.79 (s, 2H), 3.57 (t, J = 11.5 Hz, 2H), 2.70 (dq, J=6.7, 4.8 Hz, 4H), 2.38 (s, 3H), 2.34 (s, 3H), 2.27 (s, 3H), 2.15 (d, J = 12.3 Hz, 2H), 1.97 (s, 3H), 1.59 (qd, J = 12.0, 4.4 Hz, 2H). MS m/z: 469.29 ([M+H]+).

Preparation Example 51 N1-(4-Chloro-3-(4-(3,5-dimethylisoxazol-4-yl)-5-methyl-6-((tetrahydro-2H-pyran-) 4-yl)amino)pyrimidin-2-yl)benzyl)-N2-methylethane-1,2-diamine (S51)

Similar to the preparation of Example 1, reductive amination was carried out from 3-bromo-4-chlorobenzaldehyde and 2-(N-Boc-N-methylamino)ethylamine as a starting material to obtain S51.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ7.64 (d, J = 2.2Hz, 1H), 7.40 (d, J = 8.2Hz, 1H), 7.30 (dd, J = 8.2,2.2Hz, 1H), 4.61 (d, J = 7.3 Hz, 1H), 4.50 - 4.29 (m, 1H), 4.02 (d, J = 10.3 Hz, 2H), 3.80 (s, 2H), 3.56 (td, J = 11.7, 2.0 Hz, 2H), 2.71 (dq, J=6.7, 4.8 Hz, 4H), 2.41 (s, 3H), 2.37 (s, 3H), 2.28 (s, 3H), 2.19–2.09 (m, 2H), 2.00 (s) , 3H), 1.58 (qd, J = 12.0, 4.4 Hz, 2H). MS m/z: 484.34 ([M+H]+).

PREPARATIVE EXAMPLE 52 N1-Methyl-N2-(3-(5-methyl-4-morpholino-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-2- Phenylmethyl)ethane-1,2-diamine (S52)

Similar to the preparation of Example 1, the intermediate e, and the 7-azaindole-4-boronic acid pinacol ester were obtained from morpholine and 2,4,6-trichloro-5-methylpyrimidine as starting materials. After Suzuki reaction, the protecting group is removed to obtain product S52.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ11.75 (s, 1H), 8.42 (ddd, J = 13.3,7.3,4.1Hz, 3H), 7.44 (t, J = 3.6Hz, 3H), 7.32-7.28 ( m,1H), 6.49 (d, J = 3.5 Hz, 1H), 3.96 - 3.91 (m, 4H), 3.89 (s, 2H), 3.68 - 3.53 (m, 4H), 2.77 (dt, J = 11.1, 5.2 Hz, 4H), 2.42 (s, 3H), 2.17 (s, 4H). MS m/z: 458.30 ([M+H]+).

Preparation Example 53 N1-(3-(4-(1H-indazol-4-yl)-5-methyl-6-morpholinopyrimidin-2-yl)benzyl)-N2-methylethane -1,2-diamine (S53)

Similar to the preparation of Example 1, the intermediate e was obtained from morpholine and 2,4,6-trichloro-5-methylpyrimidine as the starting material, and the 1-carbazole-4-boronic acid pinacol ester was passed through Suzuki. The reaction, and then removal of the protecting group, gives the product S53.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.43 (s, 1H), 8.39 (td, J = 4.8, 1.6 Hz, 1H), 8.17 (d, J = 0.9 Hz, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.39 (dd, J = 8.7, 6.7 Hz, 3H), 7.31 (d, J = 6.4 Hz, 1H), 3.93 - 3.89 (m, 4H), 3.88 (s, 2H), 3.62 - 3.53 (m, 4H), 2.77 (dq, J = 6.8, 5.1 Hz, 4H), 2.41 (s, 3H), 2.20 (s, 3H). MS m/z: 458.30 ([M+H]+).

PREPARATIVE EXAMPLE 54 N1-Methyl-N2-(3-(6-morpholino-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)benzyl Ethane-1,2-diamine (S54)

Step 1. Synthesis of intermediate g

2,4,6-trichloropyrimidine (1.10 g, 6.0 mmol), intermediate d (1.96 g, 4.0 mmol), palladium acetate (18 mg, 0.08 mmol), sodium carbonate (848 mg, 8.0 mmol) were added to a three-necked flask. Triphenylphosphine (42mg, 0.16mmol), protected with nitrogen, added 20mL of tetrahydrofuran and 10mL of water, reacted at 70 ° C overnight, cooled, extracted twice with ethyl acetate, washed twice with saturated brine, dried over anhydrous sodium sulfate, column Chromatography gave intermediate e as a colorless oil 1.5 g, yield 73%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (d, J = 23.8 Hz, 2H), 7.68 (d, J = 19.2 Hz, 1H), 7.50-7.40 (m, 2H), 4.58 - 4.46 (m, 2H), 3.55-3.40 (m, 4H), 2.87 (d, J = 6.9 Hz, 3H), 1.54-1.43m18H).

Step 2. Synthesis of intermediate h

Add intermediate h (1.50 g, 2.94 mmol) and bistriphenylphosphine palladium chloride (103 mg, 0.147 mmol) in a three-necked flask, dissolve with 20 mL of dry tetrahydrofuran, protect with nitrogen, cool to 0 ° C, add double three A solution of methylsilylamino lithium (2.5 mL, 3.24 mmol) and morpholine (256 mg, 2.94 mmol) in tetrahydrofuran (5 mL) was stirred for a half hour, quenched with water, ethyl acetate and washed with saturated sodium chloride After three times, it was dried over anhydrous sodium

_{^{1 H NMR (400MHz, CDCl 3}} ) δ7.85 (s, 2H), 7.45-7.30 (m, 2H), 6.75 (s, 1H), 4.60-4.45 (m, 2H), 3.86-3.79 (m, 4H ), 3.75-3.68 (m, 4H), 42-3.22 (d, J = 36.2 Hz, 5H), 2.87 (d, J = 10.6 Hz, 4H), 1.57-1.41 (m, 18H).

Step 3. Synthesis of intermediates i

Intermediate h (112 mg, 0.20 mmol), 7-azaindole-4-boronic acid pinacol ester (72 mg, 0.30 mmol), tetratriphenylphosphine palladium (23 mg, 0.02 mmol), carbonic acid were added to a three-necked flask. Sodium (43 mg, 0.40 mmol), nitrogen-protected, added 1,4-dioxane 3 mL and water 1 mL, reacted at 95 ° C overnight, cooled with water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate The intermediate i was obtained as a yellow oil (yield: 108 mg).

Step 4. Synthesis of product S54

Add intermediate i (108 mg, 0.17 mmol) to a round bottom flask, add methanolic hydrochloric acid solution, stir at room temperature for 3 hours, spin dry the reaction solution, add ammonia gas methanol solution to the upper column, and column chromatography to obtain S54 as a white solid. The product was 40 mg. ¹ H NMR (300MHz, CDCl ₃ ) δ 11.07 (s, 1H), 8.45 (d, J = 5.1 Hz, 1H), 8.20 (d, J = 5.1 Hz, 1H), 8.11 - 8.04 (m, 2H) , 7.47 (dd, J = 8.4, 4.0 Hz, 4H), 6.90 (s, 1H), 3.92 (s, 2H), 3.87-3.77 (m 8H), 2.80 (dq, J = 6.7, 4.8 Hz, 4H) , 2.44 (s, 3H). MS m/z: 444.28 ([M+H]+).

Preparation Example 55

N1-(3-(2-(1H-carbazol-4-yl)-6-morpholinopyrimidin-4-yl)benzyl)-N2-methylethane-1,2-diamine (S55 )

Analogously to the preparation of Example 54, intermediate i was reacted with 1-oxazol-4-boronic acid pinacol ester via Suzuki, and the protecting group was removed to give product S55.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.06 (d, J = 0.8 Hz, 1H), 8.37 (d, J = 6.6 Hz, 1H), 8.10-8.06 (dd, J = 7.2, 2.9 Hz, 2H) , 7.55 (d, J = 8.2 Hz, 1H), 7.49 - 7.40 (m, 3H), 6.83 (s, 1H), 3.93 (s, 2H), 3.90 - 3.73 (m, 8H), 2.80 (ddd, J =10.7, 6.9, 4.9 Hz, 4H). MS m/z: 444.28 ([M+H]+).

Preparation Example 56

N1-(3-(4-(3,5-Dimethylisoxazol-4-yl)-5-methyl-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine- 2-yl)benzyl)-N1,N2-dimethylethane-1,2-diamine (S56)

Step 1. Synthesis of intermediate j

To a round bottom flask was added m-bromobenzylamine (1.86 g, 10 mmol), which was dissolved in 100 mL of THF, sodium hydrogen carbonate (1.68 g, 20 mmol) was added, and di-tert-butyl dicarbonate (2.4 g, 11 mmol) was added with stirring at room temperature. After stirring overnight, the solution was stirred, EA was dissolved, and brine was washed three times with brine, dried over anhydrous sodium sulfate

Step 2. Synthesis of intermediate k

Add intermediate j (10 mmol), pinacol borate (2.67 g, 10.5 mmol), potassium acetate (2.9 g, 30 mmol), [1,1'-bis(diphenylphosphine) dioxin to a three-neck bottle. Iron] palladium dichloride dichloromethane complex (245mg, 0.3mmol), nitrogen protection, add dimethyl sulfoxide 15mL, react at 80 ° C for 4 hours, add water, ethyl acetate extraction, saturated brine wash, no The mixture was dried over sodium sulfate (MgSO4).

^{1 H NMR (400MHz, DMSO-} d 6) δ7.58 (s, 1H), 7.57-7.51 (m, 1H), 7.43 (t, J = 6.3Hz, 1H), 7.39-7.29 (m, 2H), 4.12 (d, J = 6.3 Hz, 2H), 1.40 (s, 9H), 1.30 (s, 12H).

Step 3. Synthesis of intermediate l

Intermediate a (300 mg, 1.15 mmol), intermediate k (496 mg, 1.49 mmol), tetrakistriphenylphosphine palladium (67 mg, 0.06 mmol), sodium carbonate (243 mg, 2.29 mmol) were added to a three-necked flask. Add 1,4-dioxane 12mL and 4mL of water, react at 70 ° C overnight, add water, add 2 times with ethyl acetate, wash twice with saturated brine, dry over anhydrous sodium sulfate, and obtain the intermediate e by column chromatography. It was 330 mg as a white solid, yield 67%.

^{1 H NMR (300MHz, DMSO-} d 6) δ8.14 (s, 1H), 8.10 (d, J = 7.6Hz, 1H), 7.40 (t, J = 7.7Hz, 2H), 7.35-7.27 (m, 1H), 6.88 (d, J = 7.3 Hz, 1H), 4.18 (d, J = 6.2 Hz, 2H), 3.56 - 3.40 (m, 2H), 2.14 (s, 3H), 1.88 (d, J = 11.7) Hz, 2H), 1.64 (qd, J = 12.00, 4.5 Hz, 2H), 1.39 (s, 9H).

Step 4. Synthesis of intermediate m

Intermediate 1 (200 mg, 0.46 mmol), 3,5-dimethylisoxazole-4-boronic acid (130 mg, 0.92 mmol), tetrakistriphenylphosphine palladium (54 mg, 0.05 mmol), carbonic acid were added to a three-necked flask. Sodium (98mg, 0.924mmol), with nitrogen protection, add 1,4-dioxane 6mL and water 2mL, react at 95 ° C overnight, add water, extract with ethyl acetate, wash with saturated brine, dry with anhydrous sodium sulfate, column Chromatography of intermediate f gave 172 mg (yield:ield:

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.28 (m, 2H), 7.42 (d, J = 7.9Hz, 1H), 7.38 (d, J = 7.7Hz, 1H), 4.97 (s, 1H), 4.70 (d, J = 7.2 Hz, 1H), 4.62 - 4.44 (m, 1H), 4.42 (d, J = 5.8 Hz, 2H), 4.16 - 4.02 (m, 2H), 3.67 (td, J = 11.7, 2.1 Hz, 2H), 2.38 (s, 3H), 2.32 (s, 3H), 2.20 (ddd, J = 12.3, 4.5, 2.2 Hz, 2H), 2.01 (s, 3H), 1.73 - 1.61 (m, 3H) , 1.47 (s, 9H).

Step 5. Synthesis of intermediate n

Add intermediate m (172 mg, 0.34 mmol) to a round bottom flask, add methanolic hydrochloric acid solution, stir at room temperature for 3 hours, spin dry the reaction solution, add ammonia methanol solution to the upper column, column chromatography to obtain intermediate n white solid The product was 120 mg in a yield of 87%.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.29-8.20 (m, 2H), 7.46-7.34 (m, 2H), 4.64 (d, J = 7.2Hz, 1H), 4.47 (dd, J = 11.0,4.1 Hz, 1H), 4.12–3.99 (m, 2H), 3.92 (s, 2H), 3.64 (td, J=11.7, 2.1 Hz, 2H), 2.36 (s, 3H), 2.29 (s, 3H), 2.18 (dd, J = 12.4, 2.2 Hz, 2H), 1.98 (s, 3H), 1.84 (s, 3H), 1.68 - 1.53 (m, 2H).

Step 6. Synthesis of intermediate o

Add n-Boc-(methylamino)ethylamine (44 mg, 0.26 mmol), acetic acid (58 mg, 0.97 mmol), and then stirred for 15 min. After adding sodium cyanoborohydride (31 mg, 0.48 mmol), the mixture was stirred for 30 minutes, and then the mixture was evaporated. 90%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.28 - 8.20 (m, 2H), 7.41 (dd, J = 4.8, 1.8 Hz, 2H), 4.62 (d, J = 7.2 Hz, 1H), 4.54 - 4.35 ( m,1H), 4.06 (dd, J=8.3, 2.9 Hz, 2H), 3.87 (s, 2H), 3.64 (td, J = 11.6, 1.8 Hz, 2H), 2.85 (s, 3H), 2.80 (t , J = 6.4 Hz, 2H), 2.35 (d, J = 3.6 Hz, 3H), 2.29 (s, 3H), 2.24 - 2.14 (m, 2H), 2.00 (d, J = 17.3 Hz, 4H), 1.63 (ddd, J = 23.8, 11.4, 4.4 Hz, 2H), 1.41 (s, 9H).

Step 7. Synthesis of intermediate p

Intermediate o (55 mg, 0.1 mmol) was added to a round bottom flask, and N,N-dimethylformamide was added and dissolved, and then N,N-diisopropylethylamine (19 mg, 0.15 mmol) and iodomethane (14 mg, 0,1 mmol) After stirring at room temperature overnight, ethyl acetate was added and the mixture was evaporated.

Step 8. Synthesis of product S56

The intermediate p (20 mg, 0.035 mmol) was added to a round bottom flask, and a methanolic solution of hydrochloric acid was added thereto, and the mixture was stirred at room temperature for 3 hours, and the reaction mixture was stirred, and the mixture was stirred with an ammonia methanol solution to obtain an intermediate n white solid. Product S56 12 mg, yield 73%.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.34-8.12 (m, 2H), 7.45-7.36 (m, 2H), 4.58 (d, J = 7.3Hz, 1H), 4.54-4.41 (m, 1H), 4.07 (d, J = 11.0 Hz, 2H), 3.64 (td, J = 11.6, 1.9 Hz, 2H), 3.58 (s, 2H), 2.62 (dq, J = 6.7, 4.8 Hz, 4H, 4H), 2.39 (s, 3H), 2.37 (s, 3H), 2.31 (s, 3H), 2.21 (s, 3H), 2.21 - 2.16 (m, 2H), 1.99 (s, 3H), 1.63 (qd, J = 11.8) , MS Hz, 465.18 ([M+H]+).

Preparation Example 57

N1-(3-(4-(3,5-Dimethylisoxazol-4-yl)-5-methyl-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine- 2-yl)benzyl)ethane-1,2-diamine (S57)

Similar to the preparation of Example 56, the intermediate m was reacted with N-Boc glyoxamine by reductive amination, and the protecting group was removed to give the product S57.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.34-8.19 (m, 2H), 7.48-7.35 (m, 2H), 4.67 (d, J = 7.1Hz, 1H), 4.55-4.38 (m, 1H), 4.07 (d, J = 11.2 Hz, 2H), 3.88 (s, 2H), 3.65 (dd, J = 11.5, 10.1 Hz, 2H), 2.79 (dq, J = 6.7, 4.8 Hz, 4H), 2.36 (s) , 3H), 2.32 (s, 3H), 2.30 (s, 3H), 2.19 (d, J = 10.4 Hz, 2H), 1.98 (d, J = 7.5 Hz, 3H), 1.64 (qd, J = 11.8, 4.3 Hz, 2H). MS m/z: 437.19 ([M+H]+).

Preparation Example 58

N1-(3-(4-(3,5-Dimethylisoxazol-4-yl)-5-methyl-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine- 2-yl)benzyl)-N1-methylethane-1,2-diamine (S58)

Similar to the preparation of Example 56, intermediate m was reacted with N-Boc glyoxalamine by reductive amination, alkylation under methyl iodide, and deprotection afforded product S58.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.34-8.19 (m, 2H), 7.48-7.35 (m, 2H), 4.67 (d, J = 7.1Hz, 1H), 4.55-4.38 (m, 1H), 4.07 (d, J = 11.2 Hz, 2H), 3.88 (s, 2H), 3.65 (dd, J = 11.5, 10.1 Hz, 2H), 2.79 (dt, J = 11.3, 5.4 Hz, 4H), 2.36 (s) , 3H), 2.32 (s, 3H), 2.30 (s, 3H), 2.19 (d, J = 10.4 Hz, 2H), 1.98 (d, J = 7.5 Hz, 3H), 1.64 (qd, J = 11.8, 4.3 Hz, 2H). MS m/z: 451.29 ([M+H]+).

Preparation Example 1-1

N1-methyl-N2-(3-(5-methyl-4-phenyl-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-2-yl)benzyl) Alkane-1,2-diamine (1-1)

Similarly to Preparation Example 1, the product 1-1 was obtained by reacting the intermediate e with phenylboronic acid via Suzuki and then removing the protecting group.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.35 (s, 1H), 8.33 - 8.28 (m, 1H), 7.62 - 7.56 (m, 2H), 7.50 - 7.41 (m, 3H), 7.41 - 7.38 (m) , 2H), 4.57 (d, J = 7.2 Hz, 1H), 4.54 - 4.43 (m, 1H), 4.11 - 4.01 (m, 2H), 3.86 (s, 2H), 3.65 (td, J = 11.6, 1.9 Hz, 2H), 2.81-2.76 (m, 2H), 2.73 - 2.68 (m, 2H), 2.40 (s, 3H), 2.19 (dd, J = 12.4, 2.1 Hz, 2H), 2.11 (s, 3H) , 1.62 (qd, J = 11.9, 4.3 Hz, 2H). HRMS (ESI): m/z [M+H] ⁺ calcd for C ₂₆ H ₃₄ N ₅ O 432.2758, found 432.2764.

Preparation Example 1-2

N1-methyl-N2-(3-(5-methyl-4-((tetrahydro-2H-pyran-4-yl)amino)-6-(4-(trifluoromethoxy)phenyl)) Pyrimidin-2-yl)benzyl)ethane-1,2-diamine (1-2)

Similar to Preparation Example 1, the product 1-2 was obtained by reacting the intermediate e with 4-trifluoromethoxyphenylboronic acid via Suzuki and then removing the protecting group.

H NMR (400MHz, CDCl ₃ ) δ 8.33 (s, 1H), 8.31-8.26 (m, 1H), 7.63 (d, J = 8.7 Hz, 2H), 7.43 - 7.37 (m, 2H), 7.31 (d) , J = 8.3 Hz, 2H), 4.61 (d, J = 7.2 Hz, 1H), 4.54 - 4.42 (m, 1H), 4.06 (d, J = 11.2 Hz, 2H), 3.86 (s, 2H), 3.64 (td, J = 11.6, 2.0 Hz, 2H), 2.80 - 2.74 (m, 2H), 2.73 - 2.65 (m, 2H), 2.39 (s, 3H), 2.19 (dd, J = 12.4, 2.0 Hz, 2H) ), 2.10 (s, 3H), 1.62 (qd, J = 11.8, 4.4 Hz, 2H). HRMS (ESI): m/z [M+H] ⁺ calcd for C ₂₇ H ₃₃ F ₃ N ₅ O ₂ 516.2581 , found 516.2592.

Preparation Examples 1-3

N1-(3-(4-((3-chloro-4-fluorophenyl)amino)-6-(3,5-dimethylisothiazol-4-yl)-5-methylpyrimidin-2-yl) Benzyl)-N2-methylethane-1,2-diamine (1-3)

Similarly to Preparation Example 1, the product 1-3 was obtained starting from 3-chloro-4-fluoroaniline and 2,4,6-trichloro-5-methylpyrimidine.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.30 (s, 1H), 8.27-8.22 (m, 1H), 8.15 (dd, J = 6.6,2.7Hz, 1H), 7.46-7.40 (m, 3H), 7.17 (t, J = 8.7 Hz, 1H), 6.65 (s, 1H), 3.87 (s, 2H), 2.77 (dd, J = 6.5, 4.6 Hz, 2H), 2.69 (dd, J = 6.7, 4.8 Hz) , 2H), 2.39 (s, 6H), 2.32 (s, 3H), 2.16 (s, 3H). MS m/z: 495.24 ([M+H]+).

Preparation Examples 1-4

N1-(3-(4-((3-fluoro-4-chlorophenyl)amino)-6-(3,5-dimethylisothiazol-4-yl)-5-methylpyrimidin-2-yl) Benzyl)-N2-methylethane-1,2-diamine (1-4)

Similarly to Preparation Example 1, the product 1-4 was obtained starting from 3-fluoro-4-chloroaniline and 2,4,6-trichloro-5-methylpyrimidine.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.31 (s, 1H), 8.28-8.23 (m, 1H), 8.05 (dd, J = 11.5,2.4Hz, 1H), 7.47-7.42 (m, 2H), 7.42–7.35 (m, 1H), 7.29 (dd, J=8.7, 1.6 Hz, 1H), 6.70 (s, 1H), 3.88 (s, 2H), 2.79 (dd, J = 6.4, 4.6 Hz, 2H) , 2.71 (dd, J = 6.7, 4.8 Hz, 2H), 2.40 (s, 3H), 2.40 (s, 3H), 2.32 (s, 3H), 2.18 (s, 3H). MS m/z: 495.25 ( [M+H]+).

Preparation Examples 1-5

N1-(3-(4-(4-Hydroxyphenyl)-5-methyl-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-2-yl)benzyl)- N2-methylethane-1,2-diamine (1-5)

Similarly to Preparation Example 1, the product 1-5 was obtained by reacting the intermediate e with 4-hydroxybenzeneboronic acid via Suzuki and then removing the protecting group.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.39 (s, 1H), 8.29 (d, J = 7.4Hz, 1H), 7.43 (d, J = 8.2Hz, 2H), 7.40-7.33 (m, 2H) , 6.81 (d, J = 8.2 Hz, 2H), 4.53 (d, J = 7.2 Hz, 1H), 4.48-4.40 (m, 1H), 4.05 (d, J = 11.7 Hz, 2H), 3.86 (s, 2H), 3.63 (t, J = 11.3 Hz, 2H), 2.83 - 2.77 (m, 2H), 2.72 - 2.67 (m, 2H), 2.38 (s, 3H), 2.16 (d, J = 12.5 Hz, 2H) ), 2.09 (s, 3H), 1.59 (qd, J = 11.9, 4.4 Hz, 2H). HRMS (ESI): m/z [M+H] ⁺ calcd for C ₂₆ H ₃₄ N ₅ O ₂ 448.2707,found 448.2715.

Preparation Examples 1-6

N1-(3-(4-(4-methoxyphenyl)-5-methyl-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-2-yl)benzyl) )-N2-methylethane-1,2-diamine (1-6)

Similarly to Preparation Example 1, the product 1-6 was obtained by reacting the intermediate e with 4-methoxybenzeneboronic acid via Suzuki and then removing the protecting group.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.35 (s, 1H), 8.34 - 8.28 (m, 1H), 7.59 - 7.53 (m, 2H), 7.42 - 7.35 (m, 2H), 6.98 (d, J) = 8.6 Hz, 2H), 4.55 (d, J = 7.2 Hz, 1H), 4.52 - 4.39 (m, 1H), 4.10 - 4.02 (m, 2H), 3.85 (s, 5H), 3.64 (dt, J = 11.6, 5.8 Hz, 2H), 2.80 - 2.74 (m, 2H), 2.73 - 2.65 (m, 2H), 2.39 (s, 3H), 2.18 (dd, J = 12.4, 1.8 Hz, 2H), 2.11 (s , 3H), 1.61 (qd, J = 11.9, 4.4 Hz, 2H). HRMS (ESI): m/z [M+H] ⁺ calcd for C ₂₇ H ₃₆ N ₅ O ₂ 462.2864, found 462.2865.

Preparation Examples 1-7

N1-(3-(4-(3,5-Dimethylisothiazol-4-yl)-5-methyl-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidine-2 -yl)-4-methylbenzyl)-N2-methylethane-1,2-diamine (1-7)

Similar to Preparation Example 1, reductive amination was carried out from 3-bromo-4-methylbenzaldehyde and 2-(N-Boc-N-methylamino)ethylamine as starting materials to give 1-7.

H NMR (400MHz, CDCl ₃ ) δ 7.61 (s, 1H), 7.29 (d, J = 7.7 Hz, 1H), 7.17 (dd, J = 7.7, 1.5 Hz, 1H), 4.65 (d, J = 7.5) Hz, 1H), 4.45–4.32 (m, 1H), 4.06–3.96 (m, 2H), 3.91 (s, 2H), 3.55 (td, J=11.7, 1.9 Hz, 2H), 2.60 (t, J= 5.5 Hz, 2H), 2.54 (t, J = 5.5 Hz, 2H), 2.36 (s, 3H), 2.35 (s, 3H), 2.32 (s, 3H), 2.24 (s, 3H), 2.11 (dd, J = 12.5, 2.3 Hz, 2H), 1.97 (s, 3H), 1.60 (qd, J = 11.5, 4.4 Hz, 2H). MS m/z: 465.28 ([M+H]+).

Preparation Examples 1-8

N1-(3-(4-(3,5-Dimethylisothiazol-4-yl)-6-((4-fluorophenyl)amino)-5-methylpyrimidin-2-yl)benzyl) )-N1,N2-dimethylethane-1,2-diamine (1-8)

Similarly to Preparation Example 56, the product 1-8 was obtained from 4-fluoroaniline and 2,4,6-trichloro-5-methylpyrimidine as starting materials.

¹ H NMR (400MHz, CHLOROFORM -d) δ8.26 (d, J = 1.9Hz, 1H), 8.24-8.20 (m, 1H), 7.74-7.67 (m, 2H), 7.40 (dd, J = 4.8, 1.8 Hz, 2H), 7.15 - 7.08 (m, 2H), 6.62 (s, 1H), 3.57 (s, 2H), 2.67 (dd, J = 6.6, 5.2 Hz, 2H), 2.55 (dd, J = 6.6 , 5.2 Hz, 2H), 2.39 (s, 3H), 2.36 (s, 3H), 2.32 (s, 3H), 2.21 (s, 3H), 2.16 (s, 3H). MS m/z: 475.35 ([ M+H]+).

Preparation Examples 1-9

N1-(3-(4-((1H-indol-4-yl)amino)-6-(3,5-dimethylisothiazol-4-yl)-5-methylpyrimidin-2-yl) Benzyl)-N2-methylethane-1,2-diamine (1-9)

Similarly to Preparation Example 1, the product 1-9 was obtained starting from 5-aminoindole and 2,4,6-trichloro-5-methylpyrimidine.

¹ H NMR (400MHz, CHLOROFORM -d) δ8.93 (s, 1H) , 8.31-8.26 (m, 2H), 8.02 (d, J = 7.4Hz, 1H), 7.39 (dd, J = 4.7,1.5Hz , 2H), 7.30 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 3.2 Hz, 1H), 6.90 (s, 1H), 6.52 (d, J = 3.2 Hz, 1H), 3.84 (s) , 2H), 2.76 (dd, J = 6.7, 4.7 Hz, 2H), 2.68 (dd, J = 6.6, 4.6 Hz, 2H), 2.42 (s, 3H), 2.39 (s, 3H), 2.35 (s, 3H), 2.24(s, 3H). MS m/z: 482.30 ([M+H]+).

Preparation Examples 1-10

N1-(3-(4-((1H-pyrrolo[2,3-b]pyridin-5-yl)amino)-6-(3,5-dimethylisothiazol-4-yl)-5- Methylpyrimidin-2-yl)benzyl)-N2-methylethane-1,2-diamine (1-10)

Similarly to Preparation Example 1, the product 1-10 was obtained starting from 5-amino-7-azaindole and 2,4,6-trichloro-5-methylpyrimidine.

¹ H NMR (400MHz, CHLOROFORM -d) δ8.61 (d, J = 2.3Hz, 1H), 8.32 (d, J = 2.4Hz, 1H), 8.29 (s, 1H), 8.25-8.20 (m, 1H ), 7.39-7.35 (m, 3H), 6.60 (s, 1H), 6.55 (d, J = 3.5 Hz, 1H), 3.83 (s, 2H), 2.77 (dd, J = 6.4, 4.4 Hz, 2H) , 2.69 (dd, J=6.6, 4.6 Hz, 2H), 2.42 (s, 3H), 2.40 (s, 3H), 2.35 (s, 3H), 2.21 (s, 3H). MS m/z: 483.33 ( [M+H]+).

Preparation Examples 1-11

N1-(3-(4-(Benzo[d]thiazol-5-ylamino)-6-(3,5-dimethylisothiazol-4-yl)-5-methylpyrimidin-2-yl) Benzyl)-N2-methylethane-1,2-diamine (1-11)

Similarly to Preparation Example 1, the product 1-11 was obtained starting from 1,3-benzothiazol-5-amine and 2,4,6-trichloro-5-methylpyrimidine.

¹ H NMR (400MHz, CHLOROFORM -d) δ9.06 (s, 1H) , 8.65 (d, J = 2.1Hz, 1H), 8.35 (s, 1H), 8.30-8.24 (m, 1H), 7.96 (d , J = 8.6 Hz, 1H), 7.82 (dd, J = 8.7, 2.2 Hz, 1H), 7.43 - 7.38 (m, 2H), 6.93 (s, 1H), 3.85 (s, 2H), 2.77 (dd, J=6.7, 4.7 Hz, 2H), 2.69 (dd, J=6.9, 4.9 Hz, 2H), 2.40 (s, 3H), 2.37 (s, 3H), 2.33 (s, 3H), 2.21 (s, 3H) ).MS m/z: 500.28 ([M+H]+).

Preparation Examples 1-12

N1-(3-(4-(benzo[d]thiazol-6-ylamino)-6-(3,5-dimethylisothiazol-4-yl)-5-methylpyrimidin-2-yl) Benzyl)-N2-methylethane-1,2-diamine (1-12)

Similarly to Preparation Example 1, the product 1-12 was obtained starting from 1,3-benzothiazol-6-amine and 2,4,6-trichloro-5-methylpyrimidine.

¹ H NMR (400 MHz, chloroform-d) δ 8.94 (s, 1H), 8.77 (d, J = 2.1 Hz, 1H), 8.33 (d, J = 1.9 Hz, 1H), 8.26 (dt, J = 6.6) , 2.0 Hz, 1H), 8.13 (d, J = 8.7 Hz, 1H), 7.64 (dd, J = 8.8, 2.2 Hz, 1H), 7.46 - 7.39 (m, 2H), 6.88 (s, 1H), 3.87 (s, 2H), 2.77 (dd, J = 6.7, 4.7 Hz, 2H), 2.68 (dd, J = 6.6, 4.7 Hz, 2H), 2.40 (s, 3H), 2.37 (s, 3H), 2.33 ( s, 3H), 2.21 (s, 3H). MS m / z: 500.31 ([M + H] +).

Preparation Examples 1-13

N1-(3-(4-(3,5-Dimethylisothiazol-4-yl)-5-methyl-6-((1-methyl-1H-indazol-5-yl)amino)pyrimidine -2-yl)benzyl)-N2-methylethane-1,2-diamine (1-13)

Analogously to Preparation Example 1, the product 1-13 was obtained starting from 5-amino-1-methyl-1H-carbazole and 2,4,6-trichloro-5-methylpyrimidine.

¹ H NMR (400MHz, CHLOROFORM -d) δ8.30 (s, 1H) 8.23 (dt, J = 7.0,1.9Hz, 1H), 8.13 (d, J = 1.9Hz, 1H), 8.00 (d, J = 0.9 Hz, 1H), 7.67 (dd, J = 8.9, 2.0 Hz, 1H), 7.47 - 7.42 (m, 1H), 7.41 - 7.35 (m, 2H), 6.69 (s, 1H), 3.85 (s, 2H) ), 2.78–2.73 (m, 2H), 2.69–2.65 (m, 2H), 2.41 (s, 3H), 2.37 (s, 3H), 2.34 (s, 3H), 2.19 (s, 3H). MS m /z:497.39([M+H]+).

Preparation Examples 1-14

N1-(3-(4-((1-cyclopropyl-1H-pyrazol-4-yl)amino)-6-(3,5-dimethylisothiazol-4-yl)-5-methyl Pyrimidin-2-yl)benzyl)-N2-methylethane-1,2-diamine (1-14)

Analogously to Preparation Example 1, the product 1-14 was obtained starting from 1-cyclopropylpyrazol-4-amine and 2,4,6-trichloro-5-methylpyrimidine.

¹ H NMR (400MHz, CHLOROFORM -d) δ8.29 (s, 1H) , 8.24 (ddd, J = 5.8,3.1,1.8Hz, 1H), 8.19 (s, 1H), 7.68 (d, J = 0.8Hz , 1H), 7.45-7.40 (m, 1H), 6.70 (s, 1H), 3.88 (s, 2H), 3.65 (tt, J = 7.3, 3.8 Hz, 1H), 2.79 - 2.74 (m, 2H), 2.71–2.66 (m, 2H), 2.38 (s, 3H), 2.36 (s, 3H), 2.30 (s, 3H), 2.14–2.09 (m, 6H), 1.21–1.16 (m, 2H), 1.08– 1.02 (m, 2H). MS m / z: 473.19 ([M + H] +).

Preparation Examples 1-15

N1-(3-(4-((3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)amino)-6-(3,5-dimethylisothiazol-4-yl)) -5-methylpyrimidin-2-yl)benzyl)-N2-methylethane-1,2-diamine (1-15)

Similar to Preparation Example 1, the product 1- was obtained from 3-cyclopropyl-1-methyl-1H-pyrazole-5-ammonia and 2,4,6-trichloro-5-methylpyrimidine as starting materials. 15.

¹ H NMR (400MHz, CHLOROFORM -d) δ8.20 (s, 1H) , 8.13 (dt, J = 7.5,1.6Hz, 1H), 7.43-7.32 (m, 2H), 6.48 (s, 1H), 5.97 (s, 1H), 3.83 (s, 2H), 3.72 (s, 3H), 2.74 (ddd, J = 6.5, 4.8, 1.2 Hz, 2H), 2.68 (ddd, J = 6.1, 4.9, 1.3 Hz, 2H ), 2.39 (d, J = 1.0 Hz, 6H), 2.31 (s, 3H), 2.15 (s, 3H), 1.95 (tt, J = 8.4, 5.0 Hz, 1H), 0.97 - 0.90 (m, 2H) , 0.79–0.69 (m, 2H). MS m/z: 487.21. ([M+H]+).

Preparation Examples 1-16

N1-(3-(4-(3,5-Dimethylisothiazol-4-yl)-6-((4-fluorophenyl)amino)-5-methylpyrimidin-2-yl)benzyl) )-N1-methylethane-1,2-diamine (1-16)

Similar to Preparation Example 56, starting from 4-fluoroaniline and 2,4,6-trichloro-5-methylpyrimidine, the intermediate and N-Boc glyoxalamine were subjected to reductive amination reaction, and then removed. The protecting group gives the product 1-17.

¹ H NMR (400MHz, CHLOROFORM -d) δ8.27 (d, J = 1.7Hz, 1H), 8.22 (dt, J = 6.7,2.0Hz, 1H), 7.73-7.67 (m, 2H), 7.44-7.37 (m, 2H), 7.16 - 7.09 (m, 2H), 6.61 (s, 1H), 3.57 (s, 2H), 2.78 (t, J = 5.9 Hz, 2H), 2.47 (t, J = 5.9 Hz, 2H), 2.39 (s, 3H), 2.32 (s, 3H), 2.22 (s, 3H), 2.16 (s, 3H). MS m/z: 461.10 ([M+H]+).

Preparation Example 1-17

N1-(3-(4-(3,5-Dimethylisothiazol-4-yl)-6-(isoindoline-2-yl)-5-methylpyrimidin-2-yl)benzene Base)-N2-methylethane-1,2-diamine (1-17)

Similarly to Preparation Example 1, the product 1-17 was obtained starting from isoindoline and 2,4,6-trichloro-5-methylpyrimidine.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.37-8.32 (m, 2H), 7.45-7.42 (m, 2H), 7.39-7.31 (m, 4H), 5.24 (s, 4H), 3.90 (s, 2H ), 2.82-2.77 (m, 2H), 2.75 - 2.69 (m, 2H), 2.43 (s, 3H), 2.42 (s, 3H), 2.36 (s, 3H), 2.35 (s, 3H). HRMS ( ESI): m/z [M+H] ⁺ calcd for C ₂₈ H ₃₃ N ₆ O 469.2710found 469.2703.

Preparation Examples 1-18

N1-methyl-N2-(3-(5-methyl-4-(phenylamino)-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrimidin-2- Benzo)phenyl)ethane-1,2-diamine (1-18)

Similar to Preparation Example 1, starting from aniline and 2,4,6-trichloro-5-methylpyrimidine, from the intermediate with 1,3,5-trimethylpyrazole-4-boronic acid The alcohol ester is subjected to a Suzuki reaction, and finally the protecting group is removed to give the product 1-18.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.34 (s, 1H), 8.32 - 8.27 (m, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.45-7.38 (m, 4H), 7.13 ( t, J = 7.4 Hz, 1H), 6.58 (s, 1H), 3.86 (s, 2H), 3.79 (s, 3H), 2.81 - 2.74 (m, 2H), 2.72 - 2.65 (m, 2H), 2.39 (s,3H), 2.27(s,3H), 2.24(s,3H), 2.16(s,3H).HRMS(ESI):m/z[M+H] ⁺ calcd for C ₂₇ H ₃₄ N ₇ 456.2870 .

Preparation Examples 1-19

N1-methyl-N2-(3-(5-methyl-4-(phenylamino)-6-(pyridin-3-yl)pyrimidin-2-yl)benzyl)ethane-1,2- Diamine (1-19)

Similar to Preparation Example 1, starting from aniline and 2,4,6-trichloro-5-methylpyrimidine, the intermediate was reacted with 3-pyridine boronate via Suzuki, and finally the protecting group was removed. Product 1-19.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.88 (d, J = 1.2 Hz, 1H), 8.69 (d, J = 4.8 Hz, 1H), 8.37 (s, 1H), 8.31 (t, J = 4.4 Hz) , 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.48 - 7.37 (m, 5H), 7.15 (t, J = 7.4 Hz, 1H), 6.68 (s, 1H), 3.86 (s, 2H), 2.81 - 2.74 (m, 2H), 2.72 - 2.65 (m, 2H), 2.39 (s, 3H), 2.29 (s, 3H). HRMS (ESI): m/z[M+H] ⁺ calcd for C ₂₆ H ₂₉ N ₆ 425.2448.

Preparation Examples 1-20

N1-(3-(4-(3,5-Dimethylisothiazol-4-yl)-5-methyl-6-(piperidin-1-yl)pyrimidin-2-yl)benzyl)- N2-methylethane-1,2-diamine (1-20)

Analogously to Preparation Example 1, the product 1-20 was obtained starting from piperidine and 2,4,6-trichloro-5-methylpyrimidine.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.36 - 8.27 (m, 2H), 7.46 - 7.34 (m, 2H), 3.87 (s, 2H), 3.48 (s, 4H), 2.82 - 2.74 (m, 2H) ), 2.72–2.67 (m, 2H), 2.40 (s, 3H), 2.38 (s, 3H), 2.31 (s, 3H), 2.09 (s, 3H), 1.73 (s, 6H). HRMS (ESI) :m/z[M+H] ⁺ calcd for C ₂₅ H ₃₅ N ₆ O 435.2867found 435.2873.

Preparation Example 1-21

N4-Benzyl-5-methyl-2-(3-((2-(methylamino)ethyl))amino)methyl)phenyl)-N6-(tetrahydro-2H-pyran-4 -yl)pyrimidine-4,6-diamine (1-21)

Similar to Preparation Example 1, the product 1-21 was obtained by subjecting the intermediate e to benzylamine by nucleophilic substitution reaction and then removing the protecting group.

¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.21 (s, 1H), 8.18 (t, J = 3.9 Hz, 1H), 7.38 (d, J = 7.6 Hz, 2H), 7.32 (d, J = 4.9 Hz, 2H), 7.26 (t, J = 7.5 Hz, 2H), 7.16 (t, J = 7.3 Hz, 1H), 4.75 (s, 2H), 4.41 - 4.31 (m, 1H), 3.97 (d, J = 11.7 Hz, 2H), 3.74 (s, 2H), 3.56 (t, J = 11.6 Hz, 2H), 2.71 - 2.60 (m, 4H), 2.30 (s, 3H), 2.01 (d, J = 11.6) Hz, 2H), 1.90 (s, 3H), 1.61 (qd, J = 12.1, 4.3 Hz, 2H). HRMS (ESI): m/z [M+H] ⁺ calcd for C ₂₇ H ₃₇ N ₆ O 461.3023 Found 461.3025.

Preparation Example 1-22

N1-(3-(4-(Benzyloxy)-5-methyl-6-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-2-yl)benzyl)-N2- Methyl ethane-1,2-diamine (1-22)

Similar to Preparation Example 1, the product 1-22 was obtained by subjecting the intermediate e to benzyl alcohol by a nucleophilic substitution reaction and then removing the protecting group.

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.29-8.24 (m, 2H), 7.49 (d, J = 7.4Hz, 2H), 7.43-7.34 (m, 4H), 7.31 (d, J = 7.4Hz, 1H), 5.53 (s, 2H), 4.45 - 4.35 (m, 1H), 4.31 (d, J = 11.4 Hz, 1H), 4.03 (d, J = 11.3 Hz, 2H), 3.87 (s, 2H), 3.61 (t, J = 10.9 Hz, 2H), 2.81-2.76 (m, 2H), 2.72 - 2.67 (m, 2H), 2.40 (s, 3H), 2.12 (d, J = 11.0 Hz, 2H), 1.98 (s, 4H), 1.57 (qd, J = 11.8, 4.3 Hz, 2H). HRMS (ESI): m/z [M+H] ⁺ calcd for C ₂₇ H ₃₆ N ₅ O ₂ 462.2864 found 462.2876.

Preparation Examples 1-23

N1-(3-(4-(6-Amino-4-(trifluoromethyl)pyridin-3-yl)-6-morpholino-1,3,5-triazin-2-yl)benzyl )-N2-methylethane-1,2-diamine (1-23)

Similar to Preparation Example 1, starting from morpholine and cyanuric chloride, the intermediate and 2-amino-4-trifluoromethyl-5-pyridineboronic acid pinacol ester were subjected to Suzuki reaction and then deprotected. The product 1-23 can be obtained.

¹ H NMR (400MHz, CHLOROFORM -d) δ8.90 (s, 1H) , 8.41 (s, 1H), 8.37 (dt, J = 7.8,1.5Hz, 1H), 7.50 (d, J = 7.6Hz, 1H ), 7.43 (t, J = 7.6 Hz, 1H), 6.82 (s, 1H), 5.24 (s, 2H), 4.01 (d, J = 38.8 Hz, 4H), 3.87 (s, 2H), 3.85 - 3.75 (m, 4H), 2.80–2.76 (m, 2H), 2.73–2.68 (m, 2H), 2.40 (s, 3H), 2.24 (s, 4H). MS m/z: 489.34 ([M+H] +).

Preparation Example 1-24

N1-(3-(2-(6-Amino-4-(trifluoromethyl)pyridin-3-yl)-6-morpholinopyrimidin-4-yl)benzyl)-N2-methylethane -1,2-diamine (1-24)

Analogously to Preparation Example 54, intermediate h was reacted with 2-amino-4-trifluoromethyl-5-pyridineboronic acid pinacol ester via Suzuki, and the protecting group was removed to give the product 1-24.

¹ H NMR (400MHz, CHLOROFORM -d) δ8.73 (s, 1H) , 8.02 (s, 1H), 7.94-7.89 (m, 1H), 7.45-7.36 (m, 2H), 6.81 (d, J = 19.7 Hz, 2H), 5.04 (s, 2H), 3.86 (s, 2H), 3.81 (dd, J = 6.0, 3.8 Hz, 5H), 3.74 (dt, J = 6.5, 2.7 Hz, 4H), 2.77 ( Dd, J = 6.5, 4.3 Hz, 2H), 2.70 (dd, J = 6.5, 4.3 Hz, 2H), 2.40 (s, 3H). MS m/z: 488.35 ([M+H]+).

Preparation Example 1-25

N1-(3-(6-(8-oxa-3-azabicyclo[3.2.1]octane-3-yl)-2-(1H-pyrrolo[2,3-b]pyridine-4 -yl)pyrimidin-4-yl)benzyl)-N2-methylethane-1,2-diamine (1-25)

Similar to the preparation of Example 54, intermediate g and 8-oxo-3-azabicyclo[3.2.1]octane were subjected to affinity substitution reaction and subsequent Suzuki reaction, and then the protecting group was removed to obtain product 1- 25.

¹ H NMR (400MHz, CHLOROFORM -d) δ10.99 (s, 1H) , 8.44 (d, J = 5.1Hz, 1H), 8.20 (d, J = 5.1Hz, 1H), 8.12-8.03 (m, 2H ), 7.51–7.42 (m, 4H), 6.84 (s, 1H), 4.59–4.54 (m, 2H), 4.15 (s, 2H), 3.91 (s, 2H), 3.35 (dd, J = 12.5, 2.6) Hz, 2H), 2.81 (td, J = 5.5, 1.4 Hz, 2H), 2.74 (td, J = 5.5, 1.4 Hz, 2H), 2.42 (s, 3H), 2.04 - 1.98 (m, 2H), 1.88 (d, J = 7.1 Hz, 2H). MS m/z: 470.40 ([M+H] ⁺ ).

Preparation Examples 1-26

N1-(3-(6-(8-oxa-3-azabicyclo[3.2.1]octane-3-yl)-2-(1H-indazol-4-yl)pyrimidin-4-yl Benzyl)-N2-methylethane-1,2-diamine (1-26)

Similar to the preparation of Example 54, the intermediate g was subjected to an affinity substitution reaction with 8-oxo-3-azabicyclo[3.2.1]octane, followed by a reaction with Suzuki 4-pyrazoleboronic acid pinacol ester, Removal of the protecting group provides product 1-26.

¹ H NMR (400 MHz, chloroform-d) δ 9.05 (d, J = 1.0 Hz, 1H), 8.36 (dd, J = 7.3, 0.9 Hz, 1H), 8.10 (d, J = 1.9 Hz, 1H), 8.04 (dt, J = 7.1, 1.9 Hz, 1H), 7.55 (dt, J = 8.3, 0.9 Hz, 1H), 7.49 - 7.40 (m, 3H), 6.78 (s, 1H), 4.54 (dd, J = 4.8, 2.4 Hz, 2H), 4.12 (s, 2H), 3.91 (s, 2H), 3.33 (dd, J = 12.5, 2.6 Hz, 2H), 2.83 (dd, J = 6.4, 4.3 Hz, 2H), 2.75 (dd, J = 6.4, 4.3 Hz, 2H), 2.42 (s, 3H), 2.05 - 1.93 (m, 2H), 1.86 (d, J = 7.0 Hz, 2H).

Preparation Example 1-27

N1-methyl-N2-(3-(6-(piperidin-1-yl)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)benzene Ethyl-1,2-diamine (1-27)

Analogously to the preparation of Example 54, intermediate g was reacted with piperidine by affinity substitution, followed by Suzuki reaction, followed by removal of the protecting group to give product 1-27.

¹ H NMR (400 MHz, chloroform-d) δ 11.00 (s, 1H), 8.47 (d, J = 5.0 Hz, 1H), 8.22 (d, J = 5.1 Hz, 1H), 8.11 - 8.03 (m, 2H) ), 7.49 (q, J = 3.4 Hz, 2H), 7.47 - 7.42 (m, 2H), 6.91 (s, 1H), 3.92 (s, 2H), 3.83 (t, J = 4.8 Hz, 4H), 2.81 (dd, J = 6.3, 4.3 Hz, 2H), 2.73 (dd, J = 6.9, 4.8 Hz, 2H), 2.42 (s, 3H), 2.80 - 2.66 (m, 6H). MS m/z: 442.28 ( [M+H]+).

Preparation Examples 1-28

(S)-N1-methyl-N2-(3-(6-(3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidine-4 -yl)benzyl)ethane-1,2-diamine (1-28)

Analogously to the preparation of Example 54, intermediate g was subjected to an affinity substitution reaction with 3-(S)-3-methylmorpholine, followed by a Suzuki reaction, followed by removal of the protecting group to give the product 1-28.

¹ H NMR (400MHz, CHLOROFORM -d) δ10.81 (s, 1H) , 8.47 (d, J = 5.1Hz, 1H), 8.22 (d, J = 5.1Hz, 1H), 8.10 (d, J = 2.1 Hz, 1H), 8.06 (dt, J = 7.1, 1.9 Hz, 1H), 7.52 - 7.44 (m, 4H), 6.87 (s, 1H), 4.61 (d, J = 7.5 Hz, 1H), 4.26 (d) , J = 13.1 Hz, 1H), 4.10 (dd, J = 11.4, 3.7 Hz, 1H), 3.93 (s, 2H), 3.88 (d, J = 11.4 Hz, 1H), 3.81 (dd, J = 11.3, 3.1 Hz, 1H), 3.67 (td, J = 11.9, 3.0 Hz, 1H), 3.47 - 3.38 (m, 1H), 2.82 (dd, J = 6.9, 4.8 Hz, 2H), 2.74 (dd, J = 6.3) , 4.2 Hz, 2H), 2.43 (s, 3H), 1.41 (d, J = 6.8 Hz, 3H). MS m/z: 458.48 ([M+H]+).

Preparation Examples 1-29

N1-methyl-N2-(3-(6-(pyridin-4-yl)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin-4-yl)benzyl Ethane-1,2-diamine (1-29)

Similar to the preparation of Example 54, the intermediate g and the 4-pyridine boronic acid were reacted with Suzuki, and then reacted with the 7-azaindole-4-boronic acid pinacol ester in the second step by Suzuki, and then the protective group was removed. Product 1-29 was obtained.

¹ H NMR (400MHz, CHLOROFORM -d) δ11.55 (s, 1H) , 8.83-8.78 (m, 2H), 8.44 (d, J = 5.1Hz, 1H), 8.30 (d, J = 5.1Hz, 1H ), 8.19–8.12 (m, 2H), 8.08–8.02 (m, 2H), 7.97 (s, 1H), 7.56–7.47 (m, 4H), 3.93 (s, 2H), 2.89–2.83 (m, 2H) ), 2.82–2.76 (m, 2H), 2.46 (s, 3H). MS m/z: 436.35 ([M+H]+).

Test Example 1

In vitro activity assay: The present invention uses the AlphaLISA detection technique to verify the ability of the compounds of the invention to inhibit PRMT4 protein.

First, the purpose of the experiment

The inhibitory activity of the compound of the present invention on the PRMT4 protein was determined.

Second, experimental reagents and instruments

Reagents: anti-histone H3R26 methylated antibody-conjugated acceptor beads, streptavidin donor microbeads, epigenetic buffer (5-fold concentration) (purchased from PerkinElmer), PRMT4 enzyme activity reagent Box (people CARM1) (purchased from Reaction Biology), SAM (purchased from Sigma).

TP-064 is a small molecule inhibitor of PRMT4 jointly developed by Takeda Pharmaceutical Co., Ltd. and SGC (Structural Genomics Consortium) Joint Research Center. Its structure is as follows. TP-064 is available from R&DSystem, https://www.rndsystems.com/cn/products/tp-064_6008#product_datasheets. Compound TP-064 was dissolved in DMSO and used for subsequent bioactivity comparison evaluation.

EZM2302 is a selective PRMT4 inhibitor developed by Epizyme and GlaxoSmithKline (GSK). It is also the fastest-promoting compound for PRMT4 target. The structure of the compound is as follows. (Compound EZM2302 was purchased from Selleck)

Instrument: Multi-label microplate analysis system (purchased from PerkinElmer Envision)

Third, the experimental steps

1. Dilute PRMT4 protein, S-adenosyl-L-methionine, PRMT4 inhibitor and histone H3 peptide (21-44) with epigenetic buffer;

2. The following reagents were sequentially added to a 384 microplate whiteboard;

-- 5 μL of PRMT4 inhibitor (2-fold concentration) or epigenetic buffer,

--2.5 μL of PRMT4 protein (4-fold concentration),

- Incubate at 37 ° C for 10 minutes,

- 2.5 μL histone H3 peptide (21-44) / S-adenosyl-L-methionine mixture (4 times concentration);

3. Seal the microplate and incubate for 60 minutes at room temperature;

4. Prepare a 1x concentration epigenetic buffer;

5. Prepare anti-histone H3R26 methylated antibody-conjugated acceptor beads (100 μg/mL) with 1× concentration of epigenetic buffer at a final concentration of 20 μg/mL;

6. Add 5 μL of 1-fold anti-histone H3R26 methylated antibody-conjugated acceptor beads and incubate for 60 minutes;

7. Prepare streptavidin donor microbeads (50 μg/mL) with 1× concentration of epigenetic buffer to a final concentration of 20 μg/mL;

8. Add 10 μL of diluted streptavidin donor beads and incubate for 30 minutes in the dark;

9. Microplate reader readings.

Two sets of holes were set in each group of experiments, and a blank control group was set up.

Using the binding rate (%) as the ordinate, the concentrations of PRMT4 protein, S-adenosyl-L-methionine, PRMT4 inhibitor and histone H3 peptide (21-44) were plotted on the abscissa, and the competition was drawn using Graphpad prism software. The inhibition curve was used, and the obtained regression equation was used to calculate the concentration (IC ₅₀ ) at which the compound had a binding rate to the PRMT4 protein of 50%.

Inhibition rate (%) = {[(positive control signal value - blank control signal value) - (test compound signal value - blank control signal value)] / (positive control signal value - blank control signal value)}

Table 1: Inhibitory activity of compounds on PRMT4

Compound number	IC 50 (nM)	Compound number	IC 50 (nM)
TP-064	A	S30	A
S1	A	S31	A
S2	A	S32	A
S3	A	S33	A
S4	A	S34	A
S5	A	S35	A
S6	A	S36	B
S7	A	S37	B
S8	A	S38	B
S9	A	S39	B
S10	A	S40	B
S11	B	S41	B
S12	B	S42	A
S13	A	S43	A
S14	B	S44	A
S15	B	S45	A
S16	A	S46	A
S17	A	S47	A
S18	A	S48	B
S19	A	S49	B
S20	A	S50	A
S21	A	S51	A
S22	A	S52	A
S23	C	S53	A
S24	B	S54	B
S25	B	S55	B
S26	A	S56	B
S27	B	S57	B
S28	A	S58	B
S29	A

Table 2: Inhibitory activity of compounds on PRMT4

Compound number	IC 50 (nM)	Compound number	IC 50 (nM)
TP-064	A	1-16	A
1-1	B	1-17	B
1-2	A	1-18	B
1-3	A	1-19	B
1-4	A	1-20	B
1-5	A	1-21	B
1-6	B	1-22	B
1-7	B	1-23	A
1-8	A	1-24	A
1-9	B	1-25	A

1-10	A	1-26	B
1-11	A	1-27	A
1-12	B	1-28	A
1-13	B	1-29	A
1-14	A	EZM2302	A
1-15	A

A<10nM; 10nM<B<50nM; 50nM<C<100nM;

Most of the compounds in Tables 1 and 2 (such as S1-S10, S13, S16-S22, S26, S28-S35, S42-S47, S50-S53, etc.) exhibited PRMT4 which was comparable or even superior to the positive control TP-064. Protein inhibitory activity. The results of molecular level activity data indicate that these compounds can effectively inhibit the protein arginine methyltransferase family PRMT4, which fully demonstrates the potential of these compounds to treat cancer, inflammatory diseases, autoimmune diseases, and diabetes.

Test Example 2

The antitumor efficacy of the test compound S20 on the pancreatic cancer ASPC1 nude mouse xenograft model.

Balb/C nude mice (6 weeks, female, purchased from Shanghai Lingchang Biotechnology Co., Ltd.) were purchased, and the animals were adapted for one week before the experiment. The ASPC1 cells were expanded in vitro, and the cells in the log phase were suspended in serum-free RPMI1640 medium, and 100 μL (4.0*10 ⁶ cells) of the cell suspension were injected into the anterior and posterior iliac crest. Animal experimental procedures are performed in accordance with the ethical guidelines for animal experiments. When the average tumor volume of the tumor-bearing mice reached 50-100 mm ³ , the mice were divided into three groups by random discrimination: solvent control group, positive drug EZM2302 100 mg/kg group and compound S20 100 mg/kg group, 7 mice in each group. . Continuous administration was started for 21 days after grouping, once a day, and the tumor volume was tested three times every three days and weighed. Tumor volume (TV) calculation formula: TV = 1/2 * a * b ² , where a, b represent length and width, respectively. The relative tumor volume (RTV) was calculated based on the measurement results. Tumor growth inhibition (TGI) was calculated based on the measurement results, and the calculation formula was: TGI = [1-RTV (experimental group) / RTV (control group)] * 100%.

The test results are shown in Figures 1 and 3.

Table 3 In vivo pharmacodynamics experimental data

Group	EZM2302 (100mg/kg)	S20 (100mg/kg)
TGI (%)	twenty three	52

In the pancreatic cancer ASPC1 nude mice xenograft model, the same dose of S20 can obtain significantly better than the positive drug EZM2302, while the body weight of the mice remained basically normal, and no obvious side effects were observed.

The embodiments are merely illustrative of several embodiments of the present invention, and the description thereof is to be considered as illustrative and not restrictive. It should be noted that a number of variations and modifications may be made by those skilled in the art without departing from the spirit of the present invention, which are within the scope of the present invention. Therefore, the scope of the invention should be determined by the appended claims.

Claims (10)

1. a compound of the formula (I), a pharmaceutically acceptable salt, isomer, racemate, prodrug, co-crystal complex, hydrate or solvate thereof,

   

   among them:

   R ₁ is hydrogen, C ₁ -C ₃ alkyl;

   R ₂ is hydrogen, C ₁ -C ₃ alkyl;

   R ₃ is hydrogen, C ₁ -C ₃ alkyl;

   R ₄ is hydrogen, halogen, C ₁ -C ₃ alkyl;

   R ₅ is hydrogen, halogen, C ₁ -C ₃ alkyl;

   X is N or CR ₆ ;

   R ₆ is hydrogen, halogen, substituted or unsubstituted C ₁ -C ₃ alkyl group substituted by one or more halogen, cyano or hydroxy;

   Y is N or CH;

   L ₁ is -NH, -N(C ₁ -C ₃ alkyl)-, -O- or absent;

   L ₂ is -NH, -N(C ₁ -C ₃ alkyl)-, -O- or absent;

   R _{7 is} selected from substituted or unsubstituted saturated 3-10 membered cycloalkyl, substituted or unsubstituted saturated 3-10 membered heterocyclic group, substituted or unsubstituted C ₆ -C ₁₀ aryl group, substituted or unsubstituted a 5-12 membered heteroaryl, substituted or unsubstituted oxazabicyclo[3.2.1]octyl group; the substituted substituent is selected from the group consisting of C ₁ -C ₆ alkyl groups, 3-8 membered rings Alkyl, halogen, hydroxy, amino, cyano, nitro, hydroxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino, halogenated C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy , halogenated C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ alkylsulfinyl, C ₁ -C ₆ alkylcarbonyl and C ₁ -C ₆ amido 1, 2 or 3 substituents;

   R _{8 is} selected from H, halogen, substituted or unsubstituted C ₆ -C ₁₀ aryl or substituted or unsubstituted 5-12 membered heteroaryl, the substituted substituent being selected from: C ₁ -C ₆ alkane Base, 3-8 membered cycloalkyl, halogen, hydroxy, amino, cyano, nitro, hydroxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino, halogenated C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ alkylsulfinyl, C ₁ -C ₆ alkylcarbonyl and ₁ , 2 or 3 substituents of the C ₁ -C ₆ amide group.
2. A compound of the formula (I), a pharmaceutically acceptable salt, an isomer, a racemate, a prodrug, a co-crystal complex, a hydrate or a solvate thereof, according to claim 1. among them,

   R ₁ is hydrogen or methyl;

   R ₂ is hydrogen or methyl;

   Preferably, at least one of R ₁ and R ₂ is hydrogen;

   R ₃ is hydrogen or methyl;

   R ₄ is hydrogen, fluorine, chlorine or methyl;

   R ₅ is hydrogen, fluorine, chlorine or methyl;

   X is N or CR ₆ ;

   R ₆ is hydrogen, chlorine, fluorine, substituted or unsubstituted C ₁ -C ₃ alkyl group substituted by one or more halogens, cyano groups or hydroxyl groups; preferably hydrogen, chlorine, fluorine, one or more halogens, cyanogen a substituted or unsubstituted methyl group of a hydroxy or hydroxy group or an ethyl group substituted or unsubstituted with one or more halogen, cyano or hydroxy groups;

   Y is N or CH;

   L ₁ is -NH, -N(C ₁ -C ₃ alkyl)-, -O- or absent;

   L ₂ is -NH, -N(C ₁ -C ₃ alkyl)-, -O- or absent;

   R _{7 is} selected from substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutane, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexane, substituted or unsubstituted cycloheptane Alkyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted oxetanyl , substituted or unsubstituted oxopentyl, substituted or unsubstituted oxacyclohexyl, substituted or unsubstituted thiacyclohexyl, substituted or unsubstituted thiacyclohexane monooxide Or a double oxide, a substituted or unsubstituted morpholinyl group, a substituted or unsubstituted piperazinyl group, a substituted or unsubstituted imidazolyl group, a substituted or unsubstituted pyrazolyl group, a substituted or unsubstituted thienyl group, a substituted or Unsubstituted isoxazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted carbazole , substituted or unsubstituted benzothienyl, substituted or unsubstituted quinolinyl, substituted Unsubstituted isoquinolyl, substituted or unsubstituted fluorenyl, substituted or unsubstituted azaindolyl, substituted or unsubstituted tetrahydropyranyl and substituted or unsubstituted phenyl, substituted or not Substituted oxazahebicyclo[3.2.1]octyl; the substituted substituent is selected from the group consisting of methyl, ethyl, fluoro, chloro, bromo, hydroxy, amino, cyano, nitro, trifluoro 1, 2 or 3 substituents of methyl, trifluoromethoxy, methoxy, ethoxy, methylsulfonyl, ethylsulfonyl, acetyl and methoxyphenyl;

   R _{8 is} selected from H, halogen, substituted or unsubstituted phenyl, substituted or unsubstituted C ₁ -C ₆ alkylphenyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or Unsubstituted thienyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted benzimidazolyl , substituted or unsubstituted oxazolyl, substituted or unsubstituted benzothienyl, substituted or unsubstituted quinolyl, substituted or unsubstituted isoquinolyl, substituted or unsubstituted fluorenyl, substituted or Unsubstituted azaindenyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted morphinolinyl, substituted or unsubstituted thiomorpholinyl and substituted or not a substituted dihydropyrrolopyridyl group selected from the group consisting of methyl, ethyl, fluoro, chloro, bromo, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy , methoxy, ethoxy, methanesulfonyl, ethylsulfonyl, acetyl and methoxyphenyl 1, 2, or 3 substituents.
3. The compound of the formula (I) according to claim 1 or 2, a pharmaceutically acceptable salt, isomer, racemate, prodrug, co-crystal complex, hydrate or solvate thereof And a compound represented by the formula (I) is selected from the group consisting of a compound represented by one of the following formulas:

   

   Wherein R ₁ , R ₃ , R ₄ , R ₅ , L ₁ , L ₂ , R ₇ and R ₈ are the same as defined in claim 1 or 2.
4. The compound of the formula (I) according to any one of claims 1 to 3, a pharmaceutically acceptable salt, isomer, racemate, prodrug, co-crystal complex, hydrated Or a solvate, wherein

   R ₇ is tetrahydropyranyl, methoxyphenylpiperazinyl, phenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, fluorophenyl, chlorophenyl, difluorophenyl, tri Fluoromethylpyridyl, dimethylisoxazolyl or morphinolyl, methanesulfonylpiperazinyl, methanesulfonylpiperidinyl, thiomorpholinyl, methylpiperazinyl, acetyl piperazinyl, Cyclopropyl piperazinyl or dihydropyrrolopyridyl;

   R ₈ is H, chloro, phenyl, benzyl, phenylmethylsulfonyl, pyridyl, trimethylpyrazolyl, dimethylpyrazolyl, methylbromopyrazolyl, pyrimidinyl, methylpyridyl Azyl, fluorobenzyl, trifluoromethylphenyl, trifluoromethoxyphenyl, fluorophenyl, chlorophenyl, difluorophenyl, trifluoromethylpyridyl, azaindole, anthracene , methoxyindenyl, difluoromethylbenzimidazolyl, aminopyrimidinyl, quinolyl, isoquinolinyl, morphinolinyl, benzothienyl, phenol, dimethylisoxazolyl , methanesulfonyl piperazinyl, methanesulfonyl piperidinyl, thiomorpholinyl, methyl piperazinyl, acetyl piperazinyl, cyclopropyl piperazinyl, dihydropyrrolopyridinyl or oxa nitrogen Heterobicyclo[3.2.1]octyl.
5. The compound of the formula (I) according to any one of claims 1 to 4, a pharmaceutically acceptable salt, isomer, racemate, prodrug, co-crystal complex, hydrated Or a solvate, wherein

   R ₇ is tetrahydropyranyl, 1-(2-methoxyphenyl)piperazinyl, phenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 2-fluorobenzene , 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 1,2-difluorophenyl, 2,4-difluorophenyl, 2-trifluoromethylpyridin-4-yl, 3,5-Dimethylisoxazole-4-yl, morphinolinyl, 4-(methylsulfonyl)piperazin-1-yl, 1-(methylsulfonyl)piperidin-4-yl, 4-sulfur Demorpholine-4,4-dioxy-1-yl, 4-methylpiperazin-1-yl, 4-acetylpiperazin-1-yl, 4-cyclopropylpiperazin-1-yl or 6 ,7-Dihydro-5H-pyrrolo[3,4-b]pyridine-6-yl, 3-chloro-4-fluorophenyl, 3-fluoro-4-chlorophenyl, indol-4-yl, 7 -azaindole-5-yl, benzothiazol-5-yl, benzothiazole-6-yl, 1-methyl-1H-indazol-5-yl, 1-cyclopropyl-1H-pyrazole 4-yl, 3-cyclopropyl-1-methyl-1H-pyrazol-5-yl, isoindoline-2-yl, piperidinyl, benzyl, 8-oxa-3-nitrogen Heterobicyclo[3.2.1]octane-3-yl, (S)-3-methylmorpholinyl, pyridin-4-yl;

   R ₈ is H, chloro, phenyl, phenylmethylsulfonyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1,3,5-trimethylpyrazol-4-yl, 1, 3-Dimethyl-1H-pyrazol-4-yl, 1-methyl-4-bromopyrazole-5-yl, 5-pyrimidinyl, 1-methylpyrazol-5-yl, 4-fluorobenzyl Base, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 1,2-di Fluorophenyl, 2,4-difluorophenyl, 2-trifluoromethylpyridin-4-yl, 7-azaindole-4-yl, 1H-indenyl, 1H-indazol-4-yl , 7-methoxyindol-2-yl, 2-(difluoromethyl)-1H-benzo[D]imidazol-1-yl, 2-aminopyrimidin-5-yl, indol-4-yl , quinoline-5-yl, isoquinolin-5-yl, morphinolinyl, benzothiophen-2-yl, phenol-3-yl, 3,5-dimethylisoxazole-4-yl, 4 -(Methanesulfonyl)piperazin-1-yl, 1-(methylsulfonyl)piperidin-4-yl, 4-thiomorpholine-4,4-dioxy-1-yl, 4-methylpiperidin Pyrazin-1-yl, 4-acetylpiperazin-1-yl, 4-cyclopropylpiperazin-1-yl or 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-6 -yl, 4-hydroxyphenyl, 4-methoxyphenyl, 2-amino-4-trifluoromethylpyridin-5-yl.
6. The compound of the formula (I) according to any one of claims 1 to 5, a pharmaceutically acceptable salt, isomer, racemate, prodrug, co-crystal complex thereof, hydrated Or a solvate, wherein

   R ₁ is methyl or H; R ₂ is H;

   R ₃ is methyl or H; R ₄ is H; R ₅ is H, fluorine or chlorine;

   X is CR ₆ or N; R ₆ is a methyl group;

   Y is N or CH;

   L ₁ is -NH-, -NCH ₃ -, -O- or absent;

   L ₂ is -NH-, -O- or absent.
7. The compound of the formula (I) according to any one of claims 1 to 6, a pharmaceutically acceptable salt, isomer, racemate, prodrug, co-crystal complex, hydrated Or a solvate wherein the compound of the formula (I) is selected from the group consisting of the following compounds:

   

   

   

   

   

   

   

   
8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) according to any one of claims 1 to 7, a pharmaceutically acceptable salt, isomer thereof, exogenous One or more of a polar body, a prodrug, a co-crystal complex, a hydrate or a solvent compound as an active ingredient, and a pharmaceutically acceptable carrier.
9. The compound of the formula (I) according to any one of claims 1 to 7, a pharmaceutically acceptable salt, isomer, racemate, prodrug, co-crystal complex, hydrate thereof Or a solvent compound or the pharmaceutical composition according to claim 8 for preparing a co-activator-associated arginine methyltransferase 1 inhibitor or for preparing a medicament for treating cancer, an inflammatory disease, an autoimmune disease or diabetes Use in.
10. The use according to claim 9, wherein the cancer comprises bladder cancer, breast cancer, prostate cancer, pancreatic cancer, liver cancer, colon cancer, rectal cancer, cervical cancer, acute leukemia, acute lymphocytic leukemia, acute myeloid Leukemia, acute T cell leukemia, chondrosarcoma, chronic lymphocytic leukemia, chronic myeloid granulocyte leukemia, large cell lymphoma, fibrosarcoma, testicular germ cell carcinoma, glioma, lymphoma, multiple myeloma, lymphoma , bone marrow cancer, neuroblastoma, non-small cell lung cancer and small cell lung cancer;

    The inflammatory diseases include pneumonia, sinusitis, encephalitis, meningitis, gastritis, enteritis, ulcerative colitis, idiopathic proctitis, conjunctivitis, otitis media, reflux esophagitis, and nodular arteritis;

    The autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis, organ transplant rejection, and multiple sclerosis.

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