Pyrimidine derivatives and their uses

Abstract

The present invention belongs to the field of chemical medicine and provides a compound represented by Formula I or a pharmaceutically acceptable salt thereof. The pyrimidine derivatives provided by the present invention, as SIKs inhibitors, provide new options for the preparation of anti-tumor drugs and / or drugs for treating inflammation and / or diabetes, etc.

Description

Technical Field

[0001] The present invention relates to pyrimidine derivatives and their preparation methods and uses, belonging to the field of chemical medicine. Background Art

[0002] Macrophages play different roles in immune responses because they have the innate physiological ability to adapt to the changing needs of the host. In response to infection or tissue damage, macrophages acquire an inflammatory phenotype characterized by the production of high levels of pro-inflammatory cytokines such as tumor necrosis factor α (TNF-α), interleukin (IL)-12, and IL-1. This state is commonly referred to as "classical activation" or M1 macrophages. This initial event triggers a series of processes to establish an immune response to clear the infection and help repair tissue damage. After the treatment is completed, the inflammation problem must be resolved. To this end, macrophages transform into a pro-inflammatory phenotype characterized by the production of high levels of anti-inflammatory cytokines, including IL-10 and IL-1 receptor antagonist (IL-1ra). Various factors, including apoptotic neutrophils, immune complexes, IL-10, and prostaglandin E2 (PGE2), have been shown to promote multiple but related anti-inflammatory and pro-inflammatory phenotypes of macrophages, which have previously been classified as M2 subtypes.

[0003] Salt-inducible kinases (SIKs) control a novel molecular switch that regulates macrophage polarization. Pharmacological inhibition of SIKs induces a macrophage phenotype characterized by the secretion of high levels of anti-inflammatory cytokines, including interleukin (IL)-10, and the secretion of extremely low levels of pro-inflammatory cytokines such as tumor necrosis factor α. Salt-inducible kinases (SIKs) inhibit the production of IL-10 by phosphorylating CRTC3 in macrophages. Pharmacological inhibition of SIKs promotes the dephosphorylation of CRTC3 at Ser62, Ser162, Ser329, and Ser370 sites, and these cells rapidly migrate to the nucleus, enhancing CREB-dependent gene transcription, including the gene transcription of IL-10. Further evidence shows that stimuli that elevate cAMP, including small molecule inhibitors of phosphodiesterase and the physiological agonist PGE2, also induce the production of IL-10 through a protein kinase A-dependent signaling pathway that interferes with the ability of SIKs to phosphorylate CRTC3. Therefore, MSKs and SIKs play a key role in macrophage CREB-dependent gene transcription, including the production of IL-10. Based on this, SIKs are attractive new drug targets for treating macrophage-driven diseases. Summary of the Invention

[0004] The object of the present invention is to provide a class of pyrimidine derivatives having SIKs kinase inhibitory activity or pharmaceutically acceptable salts thereof, and their structures are shown in Formula I:

[0005]

[0006] R 1 、R 2 、R 3 are independently selected from -H, deuterated hydrogen, halogen, -OH, -NO 2 、-CN, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 amido, n = 0-4;

[0007] R 7 is selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy;

[0008] R 8 is selected from H, C1-C8 alkyl, C1-C8 acyl, R 13 -S(=O) 2 -;

[0009] R 13 is selected from trifluoromethyl, p-tolyl, C1-C8 alkyl, C3-C8 cycloalkyl, C5-C8 bridged cycloalkyl;

[0010] R 4 is selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C5-C8 bridged cycloalkyl, substituted or unsubstituted 6-10-membered aryl; R 4 in which the substituents of the substitution are selected from C1-C8 alkoxy, halogen;

[0011] R 5 is selected from -H, deuterated hydrogen, halogen, -OH, -NO 2 、-CN, halogen-substituted or unsubstituted C1-C8 alkyl, halogen-substituted or unsubstituted C1-C8 alkoxy, C1-C8 amido,

[0012] R 9 is selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy;

[0013] R 10 is selected from H, C1-C8 alkyl, C1-C8 acyl, R 14 -S(=O) 2 -;

[0014] R 14 is selected from trifluoromethyl, p-tolyl, C1-C8 alkyl, C3-C8 cycloalkyl, C5-C8 bridged cycloalkyl;

[0015] R 6 is selected from -H, deuterated hydrogen, halogen, -OH, -NO2 、 -CN, halogen-substituted or unsubstituted C1-C8 alkyl, halogen-substituted or unsubstituted C1-C8 alkoxy, C1-C8 amido, q = 0 - 4;

[0016] R 11 is selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy;

[0017] R 12 is selected from H, C1-C8 alkyl, C1-C8 acyl, R 15 -S(=O) 2 -;

[0018] R 15 is selected from trifluoromethyl, p-tolyl, C1-C8 alkyl, C3-C8 cycloalkyl, C5-C8 bridged cycloalkyl;

[0019] R 5 and R 6 are not both H at the same time.

[0020] Wherein, in the above compounds, when R 5 is selected from then R 6 is selected from -H, deuterated hydrogen, halogen, -OH, -NO 2 、 -CN, halogen-substituted or unsubstituted C1-C8 alkyl, halogen-substituted or unsubstituted C1-C8 alkoxy, C1-C8 amido; when R 6 is selected from R 5 is selected from -H, deuterated hydrogen, halogen, -OH, -NO 2 、 -CN, halogen-substituted or unsubstituted C1-C8 alkyl, halogen-substituted or unsubstituted C1-C8 alkoxy, C1-C8 amido.

[0021] Wherein, in the above compounds, R 1 、 R 2 、 R 3 are independently selected from -H, deuterated hydrogen, halogen, -OH, -NO 2 、 -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 amido, n = 0 - 2; R 7 is selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy; R 8 is selected from H, C1-C6 alkyl, C1-C6 acyl, R 13 -S(=O) 2 -; R13 Selected from trifluoromethyl, p-tolyl, C1-C6 alkyl, C3-C6 cycloalkyl, C5-C6 bridged cycloalkyl.

[0022] Preferably, in the above compounds, R 1 , R 2 , R 3 are independently selected from -H, deuterated hydrogen, halogen, -OH, -NO 2 , -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 amido.

[0023] More preferably, in the above compounds, R 1 , R 2 , R 3 are independently selected from -H, halogen, C1-C4 alkyl, C1-C4 alkoxy.

[0024] Most preferably, in the above compounds, R 1 , R 2 , R 3 are independently selected from -H, Br, Cl, F, methyl, methoxy.

[0025] Among them, in the above compounds, R 4 is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C5-C8 bridged cycloalkyl, substituted or unsubstituted 6-10-membered aryl; R 4 in, the substituents of the substitution are selected from C1-C6 alkoxy, halogen.

[0026] Preferably, in the above compounds, R 4 is selected from substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C5 bridged cycloalkyl, substituted or unsubstituted 6-membered aryl; R 4 in, the substituents of the substitution are selected from C1-C4 alkoxy, halogen.

[0027] More preferably, in the above compounds, R 4 is selected from unsubstituted C1-C4 alkyl, halogen-substituted or unsubstituted C3-C6 cycloalkyl, unsubstituted C5 bridged cycloalkyl, C1-C4 alkoxy-substituted or unsubstituted 6-membered aryl.

[0028] Most preferably, in the above compounds, R 4 is selected from

[0029] Among them, in the above compounds, R 5 is selected from -H, deuterated hydrogen, halogen, -OH, -NO 2, -CN, halogen-substituted or unsubstituted C1-C6 alkyl, halogen-substituted or unsubstituted C1-C6 alkoxy, C1-C6 amido, p = 0 - 2; R 9 selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy; R 10 selected from H, C1-C6 alkyl, C1-C6 acyl, R 14 -S(=O) 2 -; R 14 selected from trifluoromethyl, p-tolyl, C1-C6 alkyl, C3-C6 cycloalkyl, C5-C6 bridged cycloalkyl.

[0030] Preferably, in the above compounds, R 5 selected from -H, halogen, -NO 2 , halogen-substituted or unsubstituted C1-C4 alkyl, halogen-substituted or unsubstituted C1-C4 alkoxy, C1-C4 amido, p = 0 - 2; R 9 selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy; R 10 selected from H, C1-C6 alkyl, C1-C6 acyl.

[0031] More preferably, in the above compounds, R 5 selected from -H, halogen, -NO 2 , halogen-substituted C1-C4 alkyl, unsubstituted C1-C4 alkoxy, R 9 selected from H; R 10 selected from H, C1-C4 alkyl.

[0032] Most preferably, in the above compounds, R 5 selected from H, F, Cl, Br, trifluoromethyl, methoxy, nitro.

[0033] Among them, in the above compounds, R 6 selected from -H, deuterated hydrogen, halogen, -OH, -NO 2 , -CN, halogen-substituted or unsubstituted C1-C6 alkyl, halogen-substituted or unsubstituted C1-C6 alkoxy, C1-C6 amido, q = 0 - 2; R 11 selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy; R 12 selected from H, C1-C6 alkyl, C1-C6 acyl, R 15 -S(=O) 2 -; R15 Selected from trifluoromethyl, p-tolyl, C1-C6 alkyl, C3-C6 cycloalkyl, C5-C6 bridged cycloalkyl.

[0034] Preferably, in the above compounds, R 6 is selected from -H, halogen, -NO 2 , halogen-substituted or unsubstituted C1-C4 alkyl, halogen-substituted or unsubstituted C1-C4 alkoxy, q = 0-2; R 11 is selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy; R 12 is selected from H, C1-C6 alkyl, C1-C6 acyl.

[0035] More preferably, in the above compounds, R 6 is selected from -H, When R 6 is , q = 0-1; when R 6 is q = 0; R 11 is selected from H; R 12 is selected from H, C1-C6 alkyl, C1-C6 acyl.

[0036] Most preferably, in the above compounds, R 6 is selected from H,

[0037] The present invention provides the structural formulas of some of the above pyrimidine derivatives as follows:

[0038]

[0039]

[0040]

[0041]

[0042] The present invention also provides analogs of the above pyrimidine compounds, and their structures are as follows:

[0043]

[0044] The present invention also provides pharmaceutically acceptable salts of the above-mentioned pyrimidine derivatives. The salts formed with acids refer to those obtained by the reaction of the free base of the parent compound with inorganic acids or organic acids. Inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, perchloric acid, etc. Organic acids include acetic acid, propionic acid, acrylic acid, oxalic acid, (D)- or (L)-malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, γ-hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, mandelic acid, succinic acid, malonic acid, etc.

[0045] As used herein, the term "pharmaceutically acceptable" means that within the scope of reasonable medical judgment, it is suitable for contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic reaction, etc., and can directly or indirectly provide the compounds or prodrugs of the compounds of the present invention when administered to the recipient.

[0046] The present invention also provides a pharmaceutically acceptable pharmaceutical composition of the above-mentioned pyrimidine derivatives, which is prepared by adding a pharmaceutically acceptable auxiliary component to the pyrimidine derivative or its salt represented by Formula I. The auxiliary components such as cyclodextrin, arginine or meglumine. The cyclodextrin is selected from α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, (C 1-4 alkyl)-α-cyclodextrin, (C 1-4 alkyl)-β-cyclodextrin, (C 1-4 alkyl)-γ-cyclodextrin, (hydroxy-C 1-4 alkyl)-α-cyclodextrin, (hydroxy-C 1-4 alkyl)-β-cyclodextrin, (hydroxy-C 1-4 alkyl)-γ-cyclodextrin, (carboxy-C 1-4 alkyl)-α-cyclodextrin, (carboxy-C 1-4 alkyl)-β-cyclodextrin, (carboxy-C 1-4 alkyl)-γ-cyclodextrin, carbohydrate ethers of α-cyclodextrin, carbohydrate ethers of β-cyclodextrin, carbohydrate ethers of γ-cyclodextrin, sulfobutyl ethers of α-cyclodextrin, sulfobutyl ethers of β-cyclodextrin and sulfobutyl ethers of γ-cyclodextrin. The auxiliary components also include a medically acceptable carrier, adjuvant or vehicle. Ion exchangers, alumina, aluminum stearate, lecithin can be used in the pharmaceutically acceptable pharmaceutical composition; buffering substances include phosphates, glycine, arginine, sorbic acid, etc.

[0047] The above-mentioned pharmaceutical composition can be in liquid form or solid form. Among them, the liquid form can be in the form of an aqueous solution. The solid form can be in the form of powder, granule, tablet or lyophilized powder. The pharmaceutical composition also contains water for injection, saline solution, glucose aqueous solution, saline for injection / infusion, glucose for injection / infusion, Ringer's solution or Ringer's solution containing lactate.

[0048] The present invention also provides the use of the above-mentioned pyrimidine derivative or its salt or pharmaceutical composition in the preparation of SIKs inhibitors.

[0049] The present invention also provides the use of the above-mentioned pyrimidine derivative or its salt or pharmaceutical composition in the preparation of drugs for treating inflammation, tumors, diabetes and / or other diseases.

[0050] In the above-mentioned uses, the tumors include: solid tumors, sarcomas, hematological cancers, and subtypes include breast cancer, ovarian cancer, prostate cancer, cervical cancer, testicular cancer, colon cancer, colorectal cancer, liver cancer, non-small cell lung cancer, squamous cell carcinoma, small cell lung cancer, gastric cancer, gastrointestinal stromal tumor, pancreatic cancer, bladder cancer, germ cell tumor, mast cell tumor, mastocytosis, glioblastoma, neuroblastoma, astrocytoma, melanoma, B-cell lymphoma, T-cell lymphoma, indolent lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, myeloma and / or myelodysplastic syndrome, etc.

[0051] In the above-mentioned uses, the inflammation includes: actinic keratosis, psoriasis, atopic dermatitis, psoriasis vulgaris, vitiligo, roseola and / or systemic lupus erythematosus, inflammatory bowel disease, rheumatoid arthritis, etc.

[0052] In the above-mentioned uses, the "other diseases" include but are not limited to the following: autoimmune diabetes, diabetic retinopathy, liver fibrosis, pulmonary fibrosis, renal fibrosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinocerebellar degeneration, atherosclerosis, anemia, sickle cell anemia, thalassemia, osteoarthritis, rheumatoid arthritis, malaria, trypanosomiasis, helminthiasis, protozoal infection, multiple sclerosis, lupus, asthma, allergic rhinitis and / or inflammatory bowel disease, etc.

[0053] Term definition:

[0054] The compounds and derivatives provided by the present invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) naming system.

[0055] The term "alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon-based group. C 1 ~C 6 Examples of alkyl include, but are not limited to, methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), isobutyl (C 4 ), n-pentyl (C 5 ), 3-pentyl (C 5 ), pentyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butyl (C 5 ), tert-pentyl (C 5 ) and n-hexyl (C 6 ).

[0056] The term "cycloalkyl" refers to a saturated cyclic hydrocarbon-based group that does not contain heteroatoms and can be a monocyclic structure or a polycyclic structure, such as: cyclopropyl (3-membered), cyclohexyl (6-membered).

[0057] The term "aryl" refers to a fully carbon monocyclic or fused-ring group having a conjugated π-electron system. An aryl can be a fully aromatic group, such as phenyl, naphthyl, anthracenyl, phenanthrenyl, pyrenyl, etc. The carbon atoms in the aryl can be substituted by heteroatoms selected from sulfur, oxygen, and / or nitrogen, such as thiophene, furan, pyrrole, pyridine, quinoline, indole, etc.

[0058] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), iodine (I).

[0059] The term "pharmaceutically acceptable" means that a carrier, vehicle, diluent, excipient, and / or the salts formed are generally chemically or physically compatible with the other components that make up a pharmaceutical dosage form and are physiologically compatible with the receptor.

[0060] The term "pharmaceutically acceptable salts" refers to the organic and inorganic salts of the compounds of the present invention, preferably inorganic salts and salts formed from pharmaceutically acceptable non-toxic acids, including but not limited to, inorganic acid salts formed by reacting with amino groups, such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, nitrate, organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, hydrochloride, oleate, stearate, ascorbate, formate, borate, camphorate, mesylate, esylate, tosylate, malate, etc.

[0061] The pharmaceutically acceptable auxiliary components described in the present invention refer to substances contained in the dosage form other than the active ingredient, such as cyclodextrin, arginine or meglumine. The cyclodextrin is selected from α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, (C 1-4 alkyl)-α-cyclodextrin, (C 1-4 alkyl)-β-cyclodextrin, (C 1-4 alkyl)-γ-cyclodextrin, (hydroxy-C 1-4 alkyl)-α-cyclodextrin, (hydroxy-C 1-4 alkyl)-β-cyclodextrin, (hydroxy-C 1-4 alkyl)-γ-cyclodextrin, (carboxy-C 1-4 alkyl)-α-cyclodextrin, (carboxy-C 1-4 alkyl)-β-cyclodextrin, (carboxy-C 1-4 alkyl)-γ-cyclodextrin, sugar ethers of α-cyclodextrin, sugar ethers of β-cyclodextrin, sugar ethers of γ-cyclodextrin, sulfobutyl ethers of α-cyclodextrin, sulfobutyl ethers of β-cyclodextrin and sulfobutyl ethers of γ-cyclodextrin. The auxiliary components also include pharmaceutically acceptable carriers, adjuvants or vehicles. Ion exchangers, alumina, aluminum stearate, lecithin can be used in the pharmaceutically acceptable pharmaceutical compositions; buffering substances include phosphates, glycine, arginine, sorbic acid, etc.

[0062] Advantages of the present invention:

[0063] The pyrimidine derivatives provided by the present invention as SIKs inhibitors provide new options for the preparation of anti-tumor drugs and / or drugs for treating inflammation and / or diabetes, etc. Detailed implementation manners

[0064] The preparation method of the pyrimidine derivatives of formula I in the present invention has the following synthetic route:

[0065]

[0066] Step 1: Add 10 g of ethyl 2,4-dichloro-5-pyrimidinecarboxylate into a 250 mL three-necked round-bottom flask, add 80 mL of acetonitrile and triethylamine (12.6 mL, 2 equiv), cool the reaction solution to 0 °C with an ice bath, and then add R 4 the corresponding amine (1.2 equiv) dropwise into the reaction solution within 30 minutes, and keep the temperature of the reaction solution below 40 °C during the dropping. After the dropping is completed, transfer it to room temperature and react for 3 hours. After the reaction is completed, pour the reaction solution into 240 mL of water, precipitate a pale yellowish-green precipitate, filter by suction, and wash the filter cake with water (100 mL × 2 times) to obtain the crude product c. The crude product is put into the next step without further purification.

[0067] Step 2: Lithium hydroxide (3.3 g, 3 equiv) was added into a 250 mL round-bottom flask, dissolved with 40 mL of water. The crude product c obtained in Step 1 was dissolved with 40 mL of tetrahydrofuran and added into the reaction solution. The reaction was carried out at room temperature with vigorous stirring for 4 - 6 hours. After the reaction was completed, 1 M hydrochloric acid was added to adjust the pH to 2 - 3, and a large amount of white precipitate was precipitated. The precipitate was filtered by suction, and the filter cake was washed with water (100 mL × 2 times) and dried at 80 °C to obtain 8.6 g of pure product d.

[0068] Step 3: The product d (5 g, 1 equiv) obtained in Step 2 was added into a 100 mL round-bottom flask, suspended with 30 mL of dichloromethane. 10 mL of thionyl chloride was added dropwise at 0 °C, and 5 drops of N,N-dimethylformamide were added. The reaction solution was heated to 60 °C and reacted for 2 - 4 hours. The reaction solution changed from a white suspension to a yellowish-brown clear liquid. The reaction solution was rotary evaporated to remove the excess thionyl chloride. After the reaction solution was rotary evaporated, it was dissolved with 30 mL of ethyl acetate, and the phase transfer catalyst Amlyst 15 (3 g) was added. The aromatic amine (1.5 equiv) was added dropwise, and the reaction was carried out at 50 °C overnight, generating a large amount of white precipitate. After the reaction was completed, 20 mL of methanol was added to dissolve the precipitate, and the phase transfer catalyst was removed by suction filtration. The product was purified by silica gel column chromatography to obtain pure product f.

[0069] Step 4: The product f (50 mg, 1.0 equiv) obtained in Step 3 and aniline (1.1 equiv) were added into a 25 mL round-bottom flask, and 4 mL of acetic acid was added. The reaction was carried out at 50 - 70 °C overnight. After the reaction was completed, the product was purified by silica gel column chromatography under reduced pressure to obtain the final product.

[0070] Synthetic routes of target compounds B1 - B24, B29 - B41, B46 - B73 and intermediates 6a, 6b:

[0071]

[0072] Reagents and conditions: (a) Et 3 N,CH 3 CN, 0 °C to r.t., 3 h; (b) LiOH, THF / H 2 O (V / V = 1 / 1), r.t., 4 - 6 h; (c) i. SOCl 2 , DMF, CH 2 Cl 2 , 60 °C, 2 - 4 h; ii. Aromatic amine, EA, 50 °C, overnight; (d) Aromatic amine, acetic acid, 50 - 70 °C, overnight.

[0073] Synthetic routes of target compounds B26 - B28, B43 - 44:

[0074]

[0075] Reagents and conditions: (a) TFA, DCM, r.t., 1 h; (b) Corresponding acid, HATU, Et 3 N, r.t. 2 h.

[0076]

[0077] Reagents and conditions: (a) K 2 CO 3 , DMSO, 80 °C, 2 h; (b) Zn, NH 4 Cl, EtOH / H 2 O, 80 °C, 2 h; or Pd / C, N 2 H 4 ·H 2 O, MeOH, r.t., 2 h.

[0078] Synthesis of Intermediate 3a (Ethyl 2-chloro-4-((2,4-dimethoxyphenyl)amino)pyrimidine-5-carboxylate)

[0079]

[0080] Add 10 g of ethyl 2,4-dichloropyrimidine-5-carboxylate to a 250 mL round-bottom flask, add 80 mL of acetonitrile and triethylamine (12.6 mL, 2.0 equiv). Cool the reaction mixture to 0 °C in an ice bath, then add 2,4-dimethoxyaniline (1.2 equiv) dropwise to the reaction mixture within 30 minutes, keeping the reaction temperature below 40 °C during the addition. After the addition, transfer the reaction mixture to room temperature and react for 3 hours. After the reaction is completed, pour the reaction mixture into 240 mL of water to precipitate a pale yellowish-green solid. Filter by suction, wash the filter cake with water (100 mL × 2) to obtain the crude product. Dissolve the crude product in ethyl acetate, dry over anhydrous sodium sulfate, filter by suction and distill under reduced pressure. Purify by silica gel column chromatography (70 - 95% dichloromethane / petroleum ether, adding 1% Et 3 N) to obtain Intermediate 3a. Yield: 81.2%. 1 H NMR (400 MHz, CDCl 3)δ10.62(s,1H),8.78(s,1H),8.31(d,J=8.7Hz,1H),6.59–6.50(m,2H),4.42(q,J=7.1Hz,2H),3.92(s,3H),3.82(s,3H),1.42(t,J=7.1Hz,3H).Exact mass calcd for C 15 H 17 ClN 3 O 4 [M+H] + :338.0908;found 338.0905。

[0081] Synthesis of Intermediate 3b (Ethyl 2-chloro-4-(cyclopropylamino)pyrimidine-5-carboxylate)

[0082]

[0083] The synthesis method is the same as that of 3a, only replacing 2,4-dimethoxyaniline with cyclopropylamine. Yield: 80.0%. 1 HNMR(400MHz,DMSO-d 6 )δ8.58(s,1H),8.29(d,J=3.2Hz,1H),4.28(q,J=7.1Hz,2H),2.92(tq,J=7.6,3.9Hz,1H),1.29(t,J=7.1Hz,3H),0.85–0.77(m,2H),0.66–0.56(m,2H).LC-MS:[M+H] + =242.4。

[0084] Synthesis of Intermediate 3c (Ethyl 2-chloro-4-(cyclobutylamino)pyrimidine-5-carboxylate)

[0085]

[0086] The synthesis method is the same as that of 3a, only replacing 2,4-dimethoxyaniline with cyclobutylamine. Yield: 78.6%. 1 HNMR(400MHz,DMSO-d 6)δ8.59(s,1H),8.47(d,J=7.1Hz,1H),4.57–4.45(m,1H),4.31(q,J=7.1Hz,2H),2.36–2.25(m,2H),2.03(tdd,J=12.2,9.7,2.8Hz,2H),1.72(tt,J=12.2,6.1Hz,2H),1.31(t,J=7.1Hz,3H).LC-MS:[M+H] + = 256.4。

[0087] Synthesis of Intermediate 3d (Ethyl 2-chloro-4-(methylamino)pyrimidine-5-carboxylate)

[0088]

[0089] The synthesis method is the same as that of 3a, only replacing 2,4-dimethoxyaniline with aqueous methylamine solution. Yield: 73.6%. 1 H NMR(400MHz,CDCl 3 )δ8.65(s,1H),8.36(s,1H),4.35(q,J=7.0Hz,2H),3.09(d,J=4.5Hz,3H),1.38(t,J=7.0Hz,3H).LC-MS:[M+H] + = 216.4。

[0090] Synthesis of Intermediate 3e (Ethyl 2-chloro-4-(cyclopentylamino)pyrimidine-5-carboxylate)

[0091]

[0092] The synthesis method is the same as that of 3a, only replacing 2,4-dimethoxyaniline with cyclopentylamine. Yield: 83.6%. 1 HNMR(400MHz,DMSO-d 6 )δ8.60(s,1H),8.35(d,J=7.2Hz,1H),4.36(dt,J=13.5,6.7Hz,1H),4.31(q,J=7.1Hz,2H),2.00(td,J=11.6,6.2Hz,2H),1.77–1.65(m,2H),1.61(ddd,J=12.8,7.9,4.4Hz,2H),1.51(td,J=12.1,6.1Hz,2H),1.32(t,J=7.1Hz,3H).LC-MS:[M+H] += 270.5.

[0093] Synthesis of Intermediate 3f (Ethyl 2-chloro-4-(cyclohexylamino)pyrimidine-5-carboxylate)

[0094]

[0095] The synthesis method is the same as that of 3a, only replacing 2,4-dimethoxyaniline with cyclohexylamine. Yield: 84.0%. 1 HNMR(400MHz,CDCl 3 ) δ 8.65(s, 1H), 8.44(d, J = 6.5Hz, 1H), 4.35(q, J = 7.1Hz, 2H), 4.19–4.07(m, 1H), 1.98(dd, J = 11.9, 3.0Hz, 2H), 1.80–1.70(m, 2H), 1.69–1.57(m, 1H), 1.54–1.40(m, 2H), 1.39(t, J = 7.1Hz, 3H), 1.35–1.19(m, 3H). LC-MS: [M+H] + = 284.5.

[0096] Synthesis of Intermediate 3g (Ethyl 4-(bicyclo[1.1.1]pentan-1-ylamino)-2-chloropyrimidine-5-carboxylate)

[0097]

[0098] The synthesis method is the same as that of 3a, only replacing 2,4-dimethoxyaniline with 1-bicyclo[1,1,1]pentanamine. Yield: 76.7%. 1 H NMR(400MHz, DMSO-d 6 ) δ 8.58(s, 1H), 8.47(d, J = 7.1Hz, 1H), 4.35(q, J = 7.1Hz, 2H), 2.18(s, 6H), 1.31(t, J = 7.1Hz, 3H). LC-MS: [M+H] + = 268.4.

[0099] Synthesis of Intermediate 3h (Ethyl 2-chloro-4-(isopropylamino)pyrimidine-5-carboxylate)

[0100]

[0101] The synthesis method is the same as that of 3a, except that 2,4-dimethoxyaniline is replaced with isopropylamine. Yield: 74.5%. 1 HNMR(400MHz,DMSO-d 6 )δ8.61(s,1H),8.24(d,J=7.4Hz,1H),4.31(q,J=7.3Hz,2H),4.23(dd,J=13.3,6.7Hz,1H),1.31(t,J=7.1Hz,3H),1.22(d,J=6.5Hz,2×3H).LC-MS:[M+H] + =244.4。

[0102] Synthesis of Intermediate 3i (Ethyl 2-chloro-4-((3,3-difluorocyclobutyl)amino)pyrimidine-5-carboxylate)

[0103]

[0104] The synthesis method is the same as that of 3a, except that 2,4-dimethoxyaniline is replaced with isopropylamine. Yield: 75.2%. 1 HNMR(400MHz,CDCl 3 )δ8.71(s,1H),8.61(s,1H),4.60–4.47(m,1H),4.38(q,J=7.1Hz,2H),3.21–3.05(m,2H),2.68–2.48(m,2H),1.40(t,J=7.1Hz,3H).LC-MS:[M+H] + =292.4。

[0105] Synthesis of Intermediate 4a (2-Chloro-4-((2,4-dimethoxyphenyl)amino)pyrimidine-5-carboxylic acid)

[0106]

[0107] Dissolve lithium hydroxide (142.1 mg, 4.0 equiv) in water (10 mL), add 10 mL of tetrahydrofuran, stir vigorously, then add Intermediate 3a (2.0 g, 1.0 equiv), and react at room temperature for 4 - 6 hours. Monitor the reaction by TLC. After the reaction is completed, adjust the pH to 2 - 4 with 1N hydrochloric acid, and a large amount of white precipitate is formed. Filter by suction to obtain the filter cake. Wash the filter cake with water and dry to obtain Intermediate 4a. Yield: >98.0%. 1 H NMR(400MHz,DMSO-d 6) δ 10.89 (s, 1H), 8.38 (s, 1H), 7.96 (d, J = 8.8 Hz, 1H), 6.66 (d, J = 2.6 Hz, 1H), 6.56 (dd, J = 8.8, 2.6 Hz, 1H), 3.82 (s, 3H), 3.77 (s, 3H). LC-MS: [M+H] + = 310.4.

[0108] Synthesis of Intermediate 4b (2-Chloro-4-(cyclopropylamino)pyrimidine-5-carboxylic acid)

[0109]

[0110] The synthesis method of Intermediate 4b is the same as that of 4a. Yield: >98.0%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.56 (s, 1H), 8.49 (d, J = 2.7 Hz, 1H), 2.90 (qd, J = 7.6, 4.0 Hz, 1H), 0.81 (q, J = 6.9 Hz, 2H), 0.64–0.56 (m, 2H). LC-MS: [M+H] + = 214.4.

[0111] Synthesis of Intermediate 4c (2-Chloro-4-(cyclobutylamino)pyrimidine-5-carboxylic acid)

[0112]

[0113] The synthesis method of Intermediate 4c is the same as that of 4a. Yield: >98.0%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.65 (d, J = 7.3 Hz, 1H), 8.56 (s, 1H), 4.53–4.43 (m, 1H), 2.34–2.25 (m, 2H), 2.05–1.93 (m, 2H), 1.75–1.66 (m, 2H). LC-MS: [M+H] + = 228.4.

[0114] Synthesis of Intermediate 4d (2-Chloro-4-(methylamino)pyrimidine-5-carboxylic acid)

[0115]

[0116] The synthesis method of intermediate 4d is the same as that of 4a. Yield: >98.0%. 1 H NMR(400MHz,CDCl 3 )δ8.62(s,1H),8.45(s,1H),3.05(d,J=5.0Hz,3H).LC-MS:[M+H] + =188.4。

[0117] Synthesis of intermediate 4e (2-Chloro-4-(cyclopentylamino)pyrimidine-5-carboxylic acid)

[0118]

[0119] The synthesis method of intermediate 4e is the same as that of 4a. Yield: >98.0%. 1 H NMR(400MHz,DMSO-d 6 )δ8.62–8.51(m,2H),4.40–4.27(m,1H),1.98(td,J=11.8,6.1Hz,2H),1.74–1.42(m,6H).LC-MS:[M+H] + =242.4。

[0120] Synthesis of intermediate 4f (2-Chloro-4-(cyclohexylamino)pyrimidine-5-carboxylic acid)

[0121]

[0122] The synthesis method of intermediate 4f is the same as that of 4a. Yield: >98.0%. 1 H NMR(400MHz,DMSO-d 6 )δ8.55(s,1H),8.53(d,J=7.3Hz,1H),3.95(dd,J=12.5,7.9Hz,1H),1.86(d,J=9.8Hz,2H),1.65(dd,J=9.0,3.7Hz,2H),1.54(d,J=12.1Hz,1H),1.42–1.21(m,5H).LC-MS:[M+H] + =256.4。

[0123] Synthesis of intermediate 4g (4-(Bicyclo[1.1.1]pentan-1-ylamino)-2-chloropyrimidine-5-carboxylic acid)

[0124]

[0125] The synthesis method of intermediate 4g is the same as that of 4a. Yield: >98.0%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.86 (s, 1H), 8.61 (s, 1H), 2.53 (s, 1H), 2.17 (s, 6H). LC-MS: [M+H] + = 240.4.

[0126] Synthesis of intermediate 4h (2-chloro-4-(isopropylamino)pyrimidine-5-carboxylic acid)

[0127]

[0128] The synthesis method of intermediate 4h is the same as that of 4a. Yield: >98.0%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.72 (s, 1H), 8.57 (d, J = 0.8 Hz, 1H), 8.43 (d, J = 7.6 Hz, 1H), 4.23 (dq, J = 13.3, 6.8 Hz, 1H), 1.21 (d, J = 6.5 Hz, 2×3H). LC-MS: [M+H] + = 216.5.

[0129] Synthesis of intermediate 4i (2-chloro-4-((3,3-difluorocyclobutyl)amino)pyrimidine-5-carboxylic acid)

[0130]

[0131] The synthesis method of intermediate 4i is the same as that of 4a. Yield: >98.0%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.81 (d, J = 6.0 Hz, 1H), 8.61 (t, J = 2.4 Hz, 1H), 4.48–4.33 (m, 1H), 3.08–2.90 (m, 2H), 2.90–2.71 (m, 2H). LC-MS: [M+H] + = 264.5.

[0132] Intermediate 5a

[0133] (Synthesis of (2-Chloro-4-((2,4-dimethoxyphenyl)amino)-N-(2,6-dimethylphenyl)p-yrimidine-5-carboxamide))

[0134]

[0135] Add intermediate 4a (1 g, 1.0 equiv) into a 50 mL round-bottom flask, suspend it with 10 mL of dichloromethane, add 3 mL of thionyl chloride dropwise at 0 °C, add 2 drops of N,N-dimethylformamide, heat the reaction solution to 60 °C and react for 2 - 4 hours. The reaction solution changes from a white suspension to a light brown-yellow clear liquid. Rotavaporize the reaction solution to remove the excess thionyl chloride and the solvent dichloromethane. After the reaction solution is rotavaporized, dissolve it with 10 mL of ethyl acetate, add the aromatic amine (1.5 equiv) dropwise, and react at 50 °C overnight to produce a large amount of white precipitate. After the reaction is completed, dissolve the precipitate with 20 mL of methanol, perform vacuum distillation, and purify it by silica gel column chromatography (50 - 100% DCM / PE, adding 1% of Et 3 N) to obtain intermediate 5a. Yield: 68.2%. 1 H NMR (400 MHz, CDCl 3 ) δ 11.10 (s, 1H), 8.86 (s, 1H), 8.22 (d, J = 8.9 Hz, 1H), 8.12 (s, 1H), 7.19–7.10 (m, 3H), 6.55 (dd, J = 8.9, 2.6 Hz, 1H), 6.50 (d, J = 2.6 Hz, 1H), 3.83 (d, J = 4.3 Hz, 3H), 3.82 (s, 3H), 2.29 (s, 2×3H). LC-MS: [M+H] + = 413.5.

[0136] (Synthesis of intermediate 5c (2-chloro-4-(cyclopentylamino)-N-(2,6-dimethylphenyl)pyrimidine-5-carboxamide))

[0137]

[0138] The synthesis method of intermediate 5c is the same as that of 5a. Yield: 66.4%. 1 H NMR (400 MHz, DMSO-d 6)δ9.99(s,1H),9.01(d,J=7.2Hz,1H),8.79(s,1H),7.14–7.08(m,3H),4.37–4.26(m,1H),2.16(s,2×3H),1.96(dt,J=11.6,5.7Hz,2H),1.62(ddd,J=13.0,12.4,6.5Hz,4H),1.48–1.40(m,2H).LC-MS:[M+H] + = 345.5。

[0139] Intermediate 5e

[0140] (Synthesis of 2-chloro-4-((3,3-difluorocyclobutyl)amino)-N-(2,6-dimethylphenyl)pyrimidine-5-carboxamide)

[0141]

[0142] The synthesis method of Intermediate 5e is the same as that of 5a. Yield: 65.6%. 1 H NMR(400MHz,DMSO-d 6 )δ10.02(s,1H),9.16(d,J=6.3Hz,1H),8.82(s,1H),7.19–7.07(m,3H),4.37(s,1H),3.06–2.91(m,2H),2.83–2.66(m,2H),2.18(s,2×3H).LC-MS:[M+H] + = 367.5。

[0143] Synthesis of Intermediate 5f (2-chloro-N-(2,6-dimethylphenyl)-4-(isopropylamino)pyrimidine-5-carboxamide)

[0144]

[0145] The synthesis method of Intermediate 5f is the same as that of 5a. Yield: 65.2%. 1 H NMR(400MHz,DMSO-d 6 )δ9.98(s,1H),8.86(d,J=7.6Hz,1H),8.80(s,1H),7.18–7.04(m,3H),4.19(dq,J=13.3,6.5Hz,1H),2.16(s,6H),1.18(d,J=6.5Hz,2×3H).LC-MS:[M+H]+ = 319.5.

[0146] Synthesis of Intermediate 5g (2-chloro-4-(cyclobutylamino)-N-(2,6-dimethylphenyl)pyrimidine-5-carboxamide)

[0147]

[0148] The synthesis method of Intermediate 5g is the same as that of 5a. Yield: 68.6%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.00 (s, 1H), 9.04 (d, J = 7.2 Hz, 1H), 8.77 (s, 1H), 7.12 (s, 3H), 4.46 (dq, J = 16.1, 8.0 Hz, 1H), 2.33–2.24 (m, 2H), 2.15 (s, 2×3H), 2.00–1.87 (m, 2H), 1.75–1.64 (m, 2H). LC-MS: [M+H] + = 331.5.

[0149] Synthesis of Intermediate 5h (2-chloro-4-(cyclopropylamino)-N-(2,6-dimethylphenyl)pyrimidine-5-carboxamide)

[0150]

[0151] The synthesis method of Intermediate 5h is the same as that of 5a. Yield: 64.6%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.98 (s, 1H), 8.91 (d, J = 3.6 Hz, 1H), 8.79 (s, 1H), 7.17–7.07 (m, 3H), 2.91 (dq, J = 7.6, 4.1 Hz, 1H), 2.15 (s, 2×3H), 0.79 (td, J = 7.0, 5.2 Hz, 2H), 0.60–0.53 (m, 2H). LC-MS: [M+H] + = 317.5.

[0152] Intermediate 5j

[0153] (2-chloro-N-(2-chloro-6-methylphenyl)-4-(cyclopropylamino)pyrimidine-5-carboxamide) Synthesis

[0154]

[0155] The synthesis method of intermediate 5j is the same as that of 5a. Yield: 66.1%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.28 (s, 1H), 8.86 (d, J = 3.8 Hz, 1H), 8.81 (s, 1H), 7.40 (dd, J = 6.9, 2.4 Hz, 1H), 7.32–7.24 (m, 2H), 2.97–2.88 (m, 1H), 2.21 (s, 3H), 0.82–0.75 (m, 2H), 0.60–0.53 (m, 2H). LC-MS: [M + H] + = 337.4.

[0156] Intermediate 5k

[0157] (N-(2-bromo-6-methylphenyl)-2-chloro-4-(cyclopropylamino)pyrimidine-5-carboxamide) synthesis

[0158]

[0159] The synthesis method of intermediate 5k is the same as that of 5a. Yield: 64.8%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.35 (s, 1H), 8.89 (s, 1H), 8.83 (s, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 7.5 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 2.92 (d, J = 3.2 Hz, 1H), 2.22 (s, 3H), 0.83–0.75 (m, 2H), 0.62–0.53 (m, 2H). LC-MS: [M + H] + = 381.5.

[0160] Intermediate 5l

[0161] (2-chloro-4-(cyclopropylamino)-N-(2-fluoro-6-methylphenyl)pyrimidine-5-carboxamide) synthesis

[0162]

[0163] The synthesis method of intermediate 5l is the same as that of 5a. Yield: 63.6%. 11H NMR (400 MHz, DMSO-d 6 ) δ 10.20 (s, 1H), 8.87 (s, 1H), 8.83 (s, 1H), 7.29–7.22 (m, 1H), 7.16–7.07 (m, 2H), 2.92 (d, J = 3.3 Hz, 1H), 2.22 (s, 3H), 0.83–0.74 (m, 2H), 0.61–0.52 (m, 2H). LC-MS: [M+H] + = 321.4。

[0164] Intermediate 5m

[0165] (Synthesis of 2-chloro-4-(cyclopropylamino)-N-(2-methoxy-6-methylphenyl)pyrimidine-5-carboxamide)

[0166]

[0167] The synthesis method of intermediate 5m is the same as that of 5a. Yield: 59.6%. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.94 (s, 1H), 8.80 (s, 1H), 7.19 (t, J = 7.9 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.86 (d, J = 7.6 Hz, 1H), 3.73 (s, 3H), 2.91 (dt, J = 10.9, 3.7 Hz, 1H), 2.13 (s, 3H), 0.82–0.72 (m, 2H), 0.61–0.51 (m, 2H). LC-MS: [M+H] + = 333.5。

[0168] (Synthesis of intermediate 5n (2-chloro-4-(cyclopropylamino)-N-(2,6-dimethoxyphenyl)pyrimidine-5-carboxamide))

[0169]

[0170] The synthesis method of intermediate 5n is the same as that of 5a. Yield: 55.7%. 1 1H NMR (400 MHz, DMSO-d 6)δ9.70(s,1H),9.01(s,1H),8.77(s,1H),7.26(t,J=8.4Hz,1H),6.72(s,1H),6.70(s,1H),3.73(s,2×3H),2.90(dd,J=6.8,3.6Hz,1H),0.82–0.74(m,2H),0.59–0.50(m,2H).LC-MS:[M+H] + = 349.5。

[0171] Intermediate 5o

[0172] (Synthesis of 2-chloro-N-(2-chloro-6-methoxyphenyl)-4-(cyclopropylamino)pyrimidine-5-carboxamide)

[0173]

[0174] The synthesis method of Intermediate 5o is the same as that of 5a. Yield: 55.2%. 1 H NMR(400MHz,DMSO-d 6 )δ10.16(s,1H),8.98(s,1H),8.81(s,1H),7.33(t,J=8.3Hz,1H),7.12(d,J=8.1Hz,1H),7.09(d,J=8.4Hz,1H),3.78(s,3H),2.92(ddd,J=11.1,7.3,3.9Hz,1H),0.83–0.71(m,2H),0.61–0.52(m,2H).LC-MS:[M+H] + = 353.5。

[0175] Synthesis of Intermediate 5p (2-chloro-4-(cyclopropylamino)-N-(2-fluorophenyl)pyrimidine-5-carboxamide)

[0176]

[0177] The synthesis method of Intermediate 5p is the same as that of 5a. Yield: 68.2%. 1 H NMR(400MHz,DMSO-d 6)δ 10.37 (s, 1H), 8.69 (d, J = 4.4 Hz, 1H), 8.67 (s, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.34–7.25 (m, 2H), 7.24–7.17 (m, 1H), 2.95–2.86 (m, 1H), 0.81–0.74 (m, 2H), 0.61–0.52 (m, 2H). LC-MS: [M + H] + = 307.5.

[0178] Synthesis of Intermediate 5q (2-chloro-4-(cyclopropylamino)-N-(2,6-difluorophenyl)pyrimidine-5-carboxamide)

[0179]

[0180] The synthesis method of Intermediate 5q is the same as that of 5a. Yield: 65.2%. 1 H NMR (400 MHz, DMSO-d 6 )δ 10.41 (s, 1H), 8.78 (s, 2H), 7.48–7.37 (m, 1H), 7.22 (t, J = 8.2 Hz, 2H), 2.92 (qd, J = 7.6, 3.9 Hz, 1H), 0.82–0.75 (m, 2H), 0.62–0.54 (m, 2H). LC-MS: [M + H] + = 325.5.

[0181] Synthesis of Intermediate 5r (2-chloro-N-(2-chloro-6-methylphenyl)-4-(cyclobutylamino)pyrimidine-5-carboxamide)

[0182]

[0183] The synthesis method of Intermediate 5r is the same as that of 5a. Yield: 64.3%. 1 H NMR (400 MHz, DMSO-d 6 )δ 10.28 (s, 1H), 9.03 (d, J = 7.2 Hz, 1H), 8.81 (s, 1H), 7.41 (dd, J = 6.9, 2.3 Hz, 1H), 7.28 (d, J = 7.0 Hz, 2H), 4.53–4.42 (m, 1H), 2.29 (dt, J = 8.9, 6.9 Hz, 2H), 2.22 (s, 3H), 2.00–1.92 (m, 2H), 1.74–1.67 (m, 2H). LC-MS: [M + H]+ = 351.4.

[0184] Synthesis of Intermediate 5s (N-(2-bromo-6-methylphenyl)-2-chloro-4-(cyclobutylamino)pyrimidine-5-carboxamide)

[0185]

[0186] The synthesis method of Intermediate 5s is the same as that of 5a. Yield: 61.2%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.34 (s, 1H), 9.04 (d, J = 6.4 Hz, 1H), 8.83 (s, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 7.5 Hz, 1H), 7.20 (t, J = 7.7 Hz, 1H), 4.55–4.40 (m, 1H), 2.35–2.26 (m, 2H), 2.24 (s, 3H), 2.03–1.89 (m, 2H), 1.76–1.65 (m, 2H). LC-MS: [M+H] + = 395.5.

[0187] Synthesis of Intermediate 5t (2-chloro-4-(cyclobutylamino)-N-(2-fluoro-6-methylphenyl)pyrimidine-5-carboxamide)

[0188]

[0189] The synthesis method of Intermediate 5t is the same as that of 5a. Yield: 62.6%. 1 H NMR (400 MHz, CDCl 3 ) δ 8.91 (d, J = 6.7 Hz, 1H), 8.55 (s, 1H), 7.92 (s, 1H), 7.20 (td, J = 8.0, 5.6 Hz, 1H), 7.06 (d, J = 7.7 Hz, 1H), 7.00 (t, J = 8.9 Hz, 1H), 4.69–4.56 (m, 1H), 2.40 (tdd, J = 7.3, 5.6, 3.4 Hz, 2H), 2.29 (s, 3H), 2.01–1.89 (m, 2H), 1.75 (qd, J = 9.3, 5.8 Hz, 2H). LC-MS: [M+H] + = 335.5.

[0190] Intermediate 5u

[0191] Synthesis of (2-chloro-4-(cyclobutylamino)-N-(2-methoxy-6-methylphenyl)pyrimidine-5-carboxamide)

[0192]

[0193] The synthesis method of intermediate 5u is the same as that of 5a. Yield: 57.6%. 1 H NMR(400MHz, DMSO-d 6 )δ9.86(s, 1H), 9.11(s, 1H), 8.78(s, 1H), 7.20(t, J = 7.9Hz, 1H), 6.92(d, J = 8.2Hz, 1H), 6.87(d, J = 7.6Hz, 1H), 4.53–4.40(m, 1H), 3.74(s, 3H), 2.36–2.23(m, 2H), 2.14(s, 3H), 2.04–1.87(m, 2H), 1.76–1.65(m, 2H). LC-MS: [M + H] + = 347.5

[0194] Synthesis of intermediate 5v (2-chloro-4-(cyclobutylamino)-N-(2,6-dimethoxyphenyl)pyrimidine-5-carboxamide)

[0195]

[0196] The synthesis method of intermediate 5v is the same as that of 5a. Yield: 55.7%. 1 H NMR(400MHz, DMSO-d 6 )δ9.66(s, 1H), 9.17(s, 1H), 8.75(s, 1H), 7.27(t, J = 8.4Hz, 1H), 6.72(d, J = 8.4Hz, 2H), 4.53–4.40(m, 1H), 3.74(s, 2×3H), 2.29(dd, J = 6.5, 3.4Hz, 2H), 2.02–1.88(m, 2H), 1.70(dt, J = 9.5, 4.4Hz, 2H). LC-MS: [M + H] + = 363.5

[0197] Intermediate 5w

[0198] Synthesis of (2-chloro-N-(2-chloro-6-methoxyphenyl)-4-(cyclobutylamino)pyrimidine-5-carboxamide)

[0199]

[0200] The synthesis method of intermediate 5w is the same as that of 5a. Yield: 59.6%. 1 H NMR(400MHz,DMSO-d 6 )δ10.14(s,1H),9.15(s,1H),8.78(s,1H),7.33(t,J=8.3Hz,1H),7.13(d,J=7.9Hz,1H),7.10(d,J=8.4Hz,1H),4.54–4.41(m,1H),3.79(s,3H),2.29(dd,J=6.5,3.5Hz,2H),2.01–1.90(m,2H),1.70(dt,J=9.5,4.4Hz,2H).LC-MS:[M+H] + =363.4。

[0201] Synthesis of intermediate 5x (2-chloro-4-(cyclobutylamino)-N-(2-fluorophenyl)pyrimidine-5-carboxamide)

[0202]

[0203] The synthesis method of intermediate 5x is the same as that of 5a. Yield: 69.6%. 1 H NMR(400MHz,DMSO-d 6 )δ10.35(s,1H),8.90(d,J=6.5Hz,1H),8.71(s,1H),7.54(t,J=7.8Hz,1H),7.36–7.27(m,2H),7.24(td,J=8.5,4.9Hz,1H),4.55–4.43(m,1H),2.34–2.24(m,2H),2.05–1.93(m,2H),1.76–1.65(m,2H).LC-MS:[M+H] + =321.5。

[0204] Synthesis of intermediate 5y (2-chloro-4-(cyclobutylamino)-N-(2,6-difluorophenyl)pyrimidine-5-carboxamide)

[0205]

[0206] The synthesis method of intermediate 5y is the same as that of 5a. Yield: 65.6%. 1 H NMR (400 MHz, CDCl 3 ) δ 8.79 (d, J = 7.1 Hz, 1H), 8.58 (s, 1H), 8.31 (s, 1H), 7.41 (d, J = 8.1 Hz, 2H), 7.26–7.19 (m, 1H), 4.70–4.54 (m, 1H), 2.47–2.35 (m, 2H), 2.03–1.88 (m, 2H), 1.83–1.69 (m, 2H). LC-MS: [M+H] + = 339.4.

[0207] Target product B1

[0208] (Synthesis of 4-((2,4-dimethoxyphenyl)amino)-N-(2,6-dimethylphenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0209]

[0210] Dissolve intermediate 5a (50 mg, 1.0 equiv) and 4-(4-methylpiperazin)aniline (1.1 equiv) in 2 mL of acetic acid, heat up to 50 to 90 °C, and react overnight. Monitor the reaction by TLC. After the reaction is completed, concentrate the reaction solution under reduced pressure and purify it by preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to obtain the target product B1. Yield: 72.8%, white powder. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.01 (s, 1H), 9.60 (s, 1H), 9.42 (s, 1H), 8.86 (s, 1H), 8.27 (s, 1H), 7.50 (s, 2H), 7.13 (s, 3H), 6.88 (d, J = 8.8 Hz, 2H), 6.62 (d, J = 2.3 Hz, 1H), 6.44 (d, J = 6.8 Hz, 1H), 3.78 (s, 3H), 3.76 (s, 3H), 3.17–3.03 (m, 4H), 2.49–2.43 (m, 4H), 2.22 (s, 3H), 2.20 (s, 2×3H). 13 C NMR (101 MHz, DMSO-d 6)δ165.66,160.24,157.60,146.89,135.92(2C),135.08,127.83(2C),126.75,121.99(2C),115.65(2C),103.96,98.55,55.96,55.30,54.68,48.73,45.76,18.15.Exact mass calcd for C 32 H 38 N 7 O 3 [M+H] + :568.3036; found 568.3036.

[0211] Target product B2

[0212] (Synthesis of 4-((2,4-dimethoxyphenyl)amino)-N-(2,6-dimethylphenyl)-2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0213]

[0214] The synthesis method is the same as that of target product B1. Yield: 64.5%, white powder. 1 H NMR(400MHz, DMSO-d 6 )δ10.88(s, 1H), 10.00(s, 1H), 9.74(s, 1H), 8.93(s, 1H), 8.15(s, 1H), 7.67(d, J = 15.0Hz, 1H), 7.46–7.38(dd, J = 7.5, 1.2Hz, 1H), 7.37–7.21(m, 3H), 6.94(t, J = 9.3Hz, 1H), 6.66(d, J = 2.5Hz, 1H), 6.49(dd, J = 8.9, 2.2Hz, 1H), 3.80(s, 3H), 3.78(s, 3H), 2.96(s, 4H), 2.47(s, 4H), 2.27(s, 3H), 2.22(s, 3H). 13 C NMR(101MHz, DMSO-d 6)δ165.75,159.84,159.34,156.84(d,J = 208.6Hz),156.28,153.39,151.07,138.90,134.93(d,J = 11.2Hz),134.54(d,J = 9.2Hz),133.76,132.57(2C),129.09,128.20,127.07(2C),118.95(d,J = 3.9Hz),115.97(d,J = 2.0Hz),108.28(d,J = 25.6Hz),104.16,98.64,55.92,55.31,54.79(2C),50.38(2C),45.82,18.35.Exact mass calcd for C 32 H 37 FN 7 O 3 [M + H] + :586.2942; found 586.2943。

[0215] Target product B3

[0216] (Synthesis of 4 - ((2,4 - dimethoxyphenyl)amino)-N-(2,6 - dimethylphenyl)-2 - ((4-(4 - ethylpiperazin - 1 - yl)phenyl)amino)pyrimidine - 5 - carboxamide)

[0217]

[0218] The synthesis method is the same as that of target product B1. Yield: 71.2%, white powder. 1 H NMR(400MHz, DMSO - d 6 )δ11.01(s, 1H), 9.60(s, 1H), 9.42(s, 1H), 8.85(s, 1H), 8.45–8.11(m, 1H), 7.49(d,J = 6.7Hz, 2H), 7.13(s, 3H), 6.88(d,J = 9.0Hz, 2H), 6.62(d,J = 2.6Hz, 1H), 6.44(d,J = 8.3Hz, 1H), 3.78(s, 3H), 3.76(s, 3H), 3.17–3.02(m, 4H), 2.37(q,J = 7.2Hz, 2H), 2.20(s, 2×3H), 1.03(t,J = 7.2Hz, 3H). 13 C NMR(101MHz, DMSO - d 6)δ165.71,160.28,159.22,157.64,155.78,147.01,135.96(2C),135.11,127.87(2C),126.80,122.06(2C),115.63(2C),104.00,98.58,55.99,55.34,52.48(2C),51.74,48.91(2C),18.17(2C),12.05.Exact mass calcd for C 33 H 40 N 7 O 3 [M+H] + :582.3193; found 582.3163.

[0219] Target product B4

[0220] (Synthesis of 4-(cyclohexylamino)-N-(2,6-dimethylphenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0221]

[0222] The synthesis method is the same as that of target product B1. Yield: 71.4%, white powder. 1 H NMR(400MHz, DMSO-d 6 )δ9.48(s, 1H), 9.31(s, 1H), 8.87(d, J = 7.1Hz, 1H), 8.73(s, 1H), 7.63(d, J = 8.6Hz, 2H), 7.09(s, 3H), 6.86(d, J = 8.9Hz, 2H), 3.99–3.88(m, 1H), 3.10–3.01(m, 4H), 2.47–2.40(m, 4H), 2.20(s, 3H), 2.15(s, 2×3H), 1.95(d, J = 9.2Hz, 2H), 1.68(dd, J = 8.9, 3.8Hz, 2H), 1.57(dd, J = 8.6, 3.7Hz, 1H), 1.38(dd, J = 23.2, 11.7Hz, 2H), 1.29–1.19(m, 3H). 13 C NMR(101MHz, DMSO-d 6)δ165.99,160.77,160.04,157.13,146.37,135.91(2C),135.20,132.61,127.77(2C),126.67,120.39(2C),115.79(2C),98.89,56.16,54.76(2C),48.89,45.83(2C),32.25(2C),24.45(2C),21.85,18.19(2C).LC-MS:[M+H] + = 514.5.

[0223] Target product B5

[0224] (Synthesis of 4-(cyclopentylamino)-N-(2,6-dimethylphenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0225]

[0226] The synthesis method is the same as that of target product B1. Yield: 69.7%, white powder.

[0227] Target product B6

[0228] (Synthesis of 4-(bicyclo[1.1.1]pentan-1-ylamino)-N-(2,6-dimethylphenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0229]

[0230] The synthesis method is the same as that of target product B1. Yield: 69.2%, white powder. 1 H NMR(400MHz, DMSO-d 6 )δ9.48(s, 1H), 9.32(s, 1H), 8.73(s, 1H), 8.69(d, J = 4.2Hz, 1H), 7.65(d, J = 8.7Hz, 2H), 7.09(s, 3H), 6.87(d, J = 9.0Hz, 2H), 3.06–3.03(m, 4H), 2.47–2.40(m, 5H), 2.21(s, 3H), 2.16(s, 2×3H), 2.10(s, 6H). LC-MS: [M+H] + = 498.5.

[0231] Target product B7

[0232] Synthesis of (4 - ((3,3 - difluorocyclobutyl)amino)-N-(2,6 - dimethylphenyl)-2 - ((4-(4 - methylpiperazin - 1 - yl)phenyl)amino)pyrimidine - 5 - carboxamide)

[0233]

[0234] The synthesis method is the same as that of target product B1. Yield: 65.1%, white powder. 1 H NMR(400MHz,DMSO - d 6 )δ9.58(s,1H),9.42(s,1H),9.10(s,1H),8.80(s,1H),7.59(d,J = 8.5Hz,2H),7.10(s,3H),6.89(d,J = 8.5Hz,2H),4.34(s,1H),3.12–3.05(m,4H),3.05–2.96(m,2H),2.60(qd,J = 14.6,6.6Hz,2H),2.48–2.41(m,4H),2.21(s,3H),2.17(s,2×3H). 13 C NMR(101MHz,DMSO - d 6 )δ165.55,161.21,159.97,157.12,146.52,135.83(2C),135.08,132.14,127.68(2C),126.62,120.80(2C),115.66(2C),54.69(2C),48.76(2C),45.75,43.83–41.37(m),36.38–33.85(m,2C),18.12(2C).LC - MS:[M + H] + = 522.4.

[0235] Target product B8

[0236] Synthesis of (N-(2,6 - dimethylphenyl)-4-(isopropylamino)-2 - ((4-(4 - methylpiperazin - 1 - yl)phenyl)amino)pyrimidine - 5 - carboxamide)

[0237]

[0238] The synthesis method is the same as that of target product B1. Yield: 64.2%, white powder. 1 H NMR(400MHz,DMSO-d 6 )δ9.49(s,1H),9.33(s,1H),8.80(d,J=6.7Hz,1H),8.75(s,1H),7.64(d,J=8.8Hz,2H),7.09(s,3H),6.87(d,J=9.0Hz,2H),4.22(tt,J=12.7,6.4Hz,1H),3.11–3.00(m,4H),2.48–2.39(m,4H),2.21(s,3H),2.16(s,2×3H),1.21(s,3H),1.20(s,3H). 13 C NMR(101MHz,DMSO-d 6 )δ165.87,160.76,160.02,157.01,146.26,135.82(2C),135.16,132.48,127.67(2C),126.55,120.35(2C),115.71(2C),54.72(2C),48.79(2C),45.77,41.48,22.48(2C),18.13(2C).LC-MS:[M+H] + =474.5。

[0239] Target product B9

[0240] (4-(cyclobutylamino)-N-(2,6-dimethylphenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide) synthesis

[0241]

[0242] The synthesis method is the same as that of target product B1. Yield: 71.2%, white powder. 1 H NMR(400MHz,DMSO-d 6)δ9.48(s,1H),9.33(s,1H),9.01(d,J=6.4Hz,1H),8.74(s,1H),7.64(d,J=8.8Hz,2H),7.10(s,3H),6.89(d,J=9.1Hz,2H),4.56–4.41(m,1H),3.13–2.97(m,4H),2.49–2.40(m,4H),2.39–2.31(m,2H),2.21(s,3H),2.16(s,2×3H),1.95–1.84(m,2H),1.79–1.67(m,2H). 13 C NMR(101MHz,DMSO-d 6 )δ165.78,160.54,160.02,157.06,146.36,135.86(2C),135.13,132.41,127.72(2C),126.63,120.46(2C),115.72(2C),98.82,54.77(2C),48.84(2C),45.83,45.17,30.70(2C),18.14(2C),15.09.Exact mass calcd for C 28 H 36 N 7 O[M+H] + :486.2981;found 486.2983。

[0243] Target product B10

[0244] (Synthesis of 4-(cyclopropylamino)-N-(2,6-dimethylphenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0245]

[0246] The synthesis method is the same as that of target product B1. Yield: 71.6%, white powder. 1 H NMR(400MHz,DMSO-d 6)δ9.49(s,1H),9.42(s,1H),8.87(s,1H),8.75(s,1H),7.78(s,2H),7.09(s,3H),6.88(d,J=9.0Hz,2H),3.09–3.01(m,4H),2.87(d,J=3.5Hz,1H),2.47–2.39(m,4H),2.21(s,3H),2.15(s,2×3H),0.82(q,J=6.3Hz,2H),0.57–0.47(m,2H). 13 C NMR(101MHz,DMSO-d 6 )δ165.69,162.86,159.93,156.84,146.23,135.84,135.10(2C),132.63,127.70(2C),126.62,120.25(2C),115.75(2C),99.09,54.76(2C),48.85(2C),45.82,23.53,18.13(2C),6.68(2C).Exact mass calcd for C 27 H 34 N 7 O[M+H] + :472.2825;found 472.2824。

[0247] Target product B11

[0248] (Synthesis of N-(2,6-dimethylphenyl)-4-(methylamino)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0249]

[0250] The synthesis method is the same as that of target product B1. Yield: 70.4%, white powder. 1 H NMR(400MHz,DMSO-d 6 )δ9.47(s,1H),9.32(s,1H),8.72(s,1H),8.69(d,J=4.2Hz,1H),7.66(d,J=8.7Hz,2H),7.09(s,3H),6.88(d,J=9.0Hz,2H),3.09–3.03(m,4H),2.94(d,J=4.7Hz,3H),2.47–2.40(m,4H),2.21(s,3H),2.16(s,2×3H).13 C NMR (101 MHz, DMSO-d 6 ) δ 165.65, 162.08, 160.05, 156.70, 146.25, 135.86 (2C), 135.20, 132.53, 127.69 (2C), 126.57, 120.47 (2C), 115.78 (2C), 99.91, 54.73 (2C), 48.83 (2C), 45.77, 27.24, 18.14 (2C). LC-MS: [M+H] + = 446.5。

[0251] Target product B12

[0252] (Synthesis of 4-(cyclobutylamino)-N-(2,6-dimethylphenyl)-2-((3-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0253]

[0254] The synthesis method is the same as that of target product B1. Yield: 70.3%, white powder. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.51 (s, 1H), 9.40 (s, 1H), 9.09 (d, J = 5.5 Hz, 1H), 8.76 (s, 1H), 7.59 (s, 1H), 7.25 (dd, J = 8.6, 1.8 Hz, 1H), 7.10 (s, 3H), 6.83 (d, J = 8.6 Hz, 1H), 4.60 (dq, J = 15.7, 7.9 Hz, 1H), 3.82 (s, 3H), 2.93 (s, 4H), 2.50 (s, 4H), 2.34 (dd, J = 16.1, 7.8 Hz, 2H), 2.25 (s, 3H), 2.16 (s, 2×3H), 1.97–1.83 (m, 2H), 1.77–1.61 (m, 2H). 13 C NMR (101 MHz, DMSO-d 6)δ165.71,160.49,159.92,157.05,151.87,145.84,135.81(2C),135.69,135.06,132.44,127.69(2C),126.61,117.92,112.81,104.32,55.21,54.90(2C),50.12(2C),45.66,44.96,30.84(2C),18.10(2C),14.95.LC-MS:[M+H] + = 516.5。

[0255] Target product B13

[0256] (Synthesis of 4-(cyclobutylamino)-N-(2,6-dimethylphenyl)-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0257]

[0258] The synthesis method is the same as that of target product B1. Yield: 72.5%, white powder. 1 H NMR(400MHz,DMSO-d 6 )δ9.50(s,1H),8.99(d,J = 6.6Hz,1H),8.71(s,1H),7.91(d,J = 6.5Hz,1H),7.84(s,1H),7.10(s,3H),6.63(d,J = 2.3Hz,1H),6.51(dd,J = 8.8,2.2Hz,1H),4.44(dq,J = 15.1,7.5Hz,1H),3.83(s,3H),3.18–3.08(m,4H),2.48–2.41(m,4H),2.36–2.27(m,2H),2.22(s,3H),2.16(s,2×3H),1.94–1.82(m,2H),1.75–1.66(m,2H). 13 C NMR(101MHz,DMSO-d 6)δ165.72,160.58,160.21,157.09,150.49,148.02,135.85(2C),135.07,127.71(2C),126.65,122.19,120.39,106.76,99.92,99.13,55.72,54.75(2C),48.76(2C),45.82,45.09,30.64(2C),18.11(2C),15.05.Exact mass calcd for C 29 H 38 N 7 O 2 [M+H] + :516.3087; found 516.3093.

[0259] Target product B14

[0260] (Synthesis of 4-(cyclobutylamino)-N-(2,6-dimethylphenyl)-2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0261]

[0262] The synthesis method is the same as that of target product B1. Yield: 74.6%, white powder. 1 H NMR(400MHz, DMSO-d 6 )δ9.63(s, 1H), 9.61(s, 1H), 9.07(d, J = 6.3Hz, 1H), 8.81(s, 1H), 7.87(d, J = 15.8Hz, 1H), 7.41(dd, J = 8.7, 1.6Hz 1H), 7.10(s, 3H), 6.97(t, J = 9.4Hz, 1H), 4.50(dd, J = 15.1, 7.6Hz, 1H), 3.00–2.91(m, 4H), 2.50–2.42(m, 4H), 2.42–2.33(m, 2H), 2.22(s, 3H), 2.17(s, 2×3H), 1.98–1.86(m, 2H). 13 C NMR(101MHz, DMSO-d 6)δ165.65,160.47,159.80,157.05,154.62(d, J = 241.8Hz),135.83(2C),135.60(d, J = 11.1Hz),135.06,134.04(d, J = 9.2Hz),127.71(2C),126.64,119.09(d, J = 4.3Hz),115.00,107.34(d, J = 26.4Hz),54.83(2C),50.41(d, J = 2.0Hz, 2C),45.83,45.34,30.59(2C),18.11(2C),15.13. Exact mass calcd for C 28 H 35 FN 7 O[M + H] + : 504.2887; found 504.2887。

[0263] Target product B15

[0264] (Synthesis of 4-(cyclobutylamino)-N-(2,6-dimethylphenyl)-2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0265]

[0266] The synthesis method is the same as that of target product B1. Yield: 57.6%, white powder. 1 H NMR(400MHz, DMSO-d 6 )δ9.65(s, 1H), 9.06(d, J = 6.5Hz, 1H), 8.80(s, 1H), 8.25(dd, J = 8.8, 6.4Hz, 1H), 8.00(s, 1H), 7.11(s, 3H), 7.05(dd, J = 10.3, 2.7Hz, 1H), 6.98(td, J = 8.6, 2.7Hz, 1H), 4.44(dq, J = 15.6, 7.9Hz, 1H), 2.85(t, J = 4.4Hz, 4H), 2.39–2.30(m, 2H), 2.25(s, 3H), 2.17(s, 2×3H), 1.97–1.89(m, 2H), 1.78–1.70(m, 2H). 13 C NMR(101MHz, DMSO-d 6)δ165.53,160.57,159.68,158.51(d,J = 254.2Hz),157.20,143.80(d,J = 8.2Hz),135.81(2C),134.96,130.03(d,J = 2.5Hz),127.69(2C),126.67,120.99,110.02(d,J = 22.1Hz),107.63(d,J = 23.3Hz),99.93,55.08(2C),51.06(2C),45.77,45.29,30.43(2C),18.07(2C),15.08.LC-MS:[M+H] + = 504.5。

[0267] Target product B16

[0268] (Synthesis of 4-(cyclobutylamino)-N-(2,6-dimethylphenyl)-2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0269]

[0270] The synthesis method is the same as that of target product B1. Yield: 74.6%, white powder. 1 H NMR(400MHz, DMSO-d 6 )δ9.66(s,1H),9.60(s,1H),9.06(d,J = 6.5Hz,1H),8.82(s,1H),8.25(s,1H),7.52(dd,J = 8.6,1.5Hz,1H),7.18–7.04(m,4H),4.50(dq,J = 15.6,7.8Hz,1H),2.93(s,4H),2.48(s,4H),2.44–2.35(m,2H),2.23(s,3H),2.17(s,2×3H),1.98–1.91(m,2H),1.79–1.68(m,2H). 13 C NMR(101MHz, DMSO-d 6)δ165.60,160.44,159.75,157.10,143.06,136.53,135.82(2C),135.04,127.69(2C),127.52,126.62,120.65,118.49,99.53,54.86(2C),51.01(2C),45.73,45.37,30.63(2C),18.12(2C),15.13.LC-MS:[M+H] + = 520.6。

[0271] Target product B17

[0272] (Synthesis of 4-(cyclobutylamino)-N-(2,6-dimethylphenyl)-2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0273]

[0274] The synthesis method is the same as that of target product B1. Yield: 57.6%, white powder. 1 H NMR(400MHz, DMSO-d 6 )δ9.64(s, 1H), 9.08(d, J = 6.5Hz, 1H), 8.80(s, 1H), 8.41(d, J = 8.0Hz, 1H), 8.20(s, 1H), 7.22(d, J = 7.8Hz, 1H), 7.15(t, J = 7.6Hz, 1H), 7.11(s, 3H), 7.00(t, J = 7.4Hz, 1H), 4.47(dt, J = 22.9, 7.7Hz, 3H), 2.83(t, J = 4.5Hz, 4H), 2.53(s, 4H), 2.42–2.33(m, 2H), 2.26(s, 3H), 2.17(s, 2×3H), 2.00–1.90(m, 2H), 1.78–1.71(m, 2H). 13 C NMR(101MHz, DMSO-d 6)δ165.49,160.57,159.54,157.14,141.37,135.80(2C),134.93,133.93,127.69(2C),126.68,124.41,122.22,120.32,118.76,55.34(2C),51.51(2C),45.82,45.38,30.43(2C),18.06(2C),15.10.LC-MS:[M+H] + = 486.5.

[0275] Target product B18

[0276] (Synthesis of 4-(cyclobutylamino)-N-(2,6-dimethylphenyl)-2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0277]

[0278] The synthesis method is the same as that of target product B1. Yield: 69.2%, white powder. 1 H NMR(400MHz, DMSO-d 6 )δ9.58(s, 1H), 9.41(s, 1H), 9.11(d, J = 7.1Hz, 1H), 8.79(s, 1H), 7.61(s, 1H), 7.18–7.06(m, 5H), 6.57(d, J = 7.2Hz, 1H), 4.60(td, J = 16.1, 8.0Hz, 1H), 3.19–3.09(m, 4H), 2.49–2.44(m, 4H), 2.34(dd, J = 16.4, 7.9Hz, 2H), 2.23(s, 3H), 2.17(s, 2×3H), 1.93(dd, J = 20.3, 10.4Hz, 2H), 1.76–1.62(m, 2H). 13 C NMR(101MHz, DMSO-d 6 )δ165.67, 160.44, 160.04, 157.08, 153.22, 151.50, 140.99, 135.78(2C), 135.05, 133.54, 128.73, 127.66(2C), 126.58, 110.53, 106.61, 54.75(2C), 48.47(2C), 45.80, 44.91, 30.81(2C), 18.09(2C), 14.90. LC-MS: [M+H]+ = 486.5.

[0279] Target product B19

[0280] Synthesis of (4-(cyclobutylamino)-N-(2,6-dimethylphenyl)-2-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0281]

[0282] The synthesis method is the same as that of target product B1. Yield: 76.8%, white powder. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.47 (s, 1H), 9.32 (s, 1H), 9.01 (d, J = 6.2 Hz, 1H), 8.74 (s, 1H), 7.63 (d, J = 8.8 Hz, 2H), 7.09 (s, 3H), 6.88 (d, J = 9.1 Hz, 2H), 4.49 (dd, J = 14.8, 7.3 Hz, 1H), 3.10–3.02 (m, 4H), 2.50–2.45 (m, 4H), 2.36 (dd, J = 14.3, 7.1 Hz, 2H), 2.30–2.38 (m, 2H), 2.16 (s, 2×3H), 1.95–1.82 (m, 2H), 1.68–1.77 (m, 2H), 1.02 (t, J = 7.2 Hz, 3H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 172.19, 165.76, 160.53, 160.00, 157.04, 146.37, 135.84 (2C), 135.11, 132.38, 127.69 (2C), 126.59, 120.45 (2C), 115.66 (2C), 52.44 (2C), 51.67, 48.91 (2C), 45.15, 30.68 (2C), 21.22, 18.12 (2C), 15.06, 11.99. Exact mass calcd for C 29 H 38 N 7 O [M+H] + : 500.3138; found 500.3141.

[0283] Target product B20

[0284] Synthesis of (4-(cyclobutylamino)-N-(2,6-dimethylphenyl)-2-((4-(4-ethylpiperazin-1-yl)-2-fluorophenyl)amino)pyrimidine-5-carboxamide)

[0285]

[0286] The synthesis method is the same as that of target product B1. Yield: 36.8%, white powder. 1 H NMR(400MHz,DMSO-d 6 )δ9.58(s,1H),9.06(d,J=6.5Hz,1H),8.77(s,1H),8.25(dd,J=8.8,6.3Hz,1H),8.00(s,1H),7.11(s,3H),7.05(dd,J=10.3,2.8Hz,1H),6.98(td,J=8.7,2.8Hz,1H),4.51–4.37(m,1H),2.91–2.82(m,4H),2.65–2.52(m,4H),2.41(dd,J=13.3,6.2Hz,2H),2.36–2.30(m,2H),2.17(s,2×3H),1.96–1.86(m,2H),1.75(dt,J=9.0,4.7Hz,2H),1.04(t,J=7.2Hz,3H).Exact mass calcd for C 29 H 37 FN 7 O[M+H] + :518.3044;found 518.3022.

[0287] Target product B21

[0288] Synthesis of (4-(cyclobutylamino)-N-(2,6-dimethylphenyl)-2-((4-(4-ethylpiperazin-1-yl)-2-fluorophenyl)amino)pyrimidine-5-carboxamide)

[0289]

[0290] The synthesis method is the same as that of target product B1. Yield: 81.8%, white powder. 1 H NMR(400MHz,DMSO-d 6)δ9.51(s,1H),9.36(s,1H),9.03(d,J=6.3Hz,1H),8.76(s,1H),7.67(d,J=8.8Hz,2H),7.10(s,3H),6.90(d,J=9.1Hz,2H),4.50(dq,J=15.2,7.6Hz,1H),3.73(dd,J=5.7,3.8Hz,4H),3.06–3.02(m,4H),2.41–2.30(m,2H),2.17(s,2×3H),1.91(ddd,J=11.1,9.4,2.0Hz,2H),1.74(dt,J=21.9,11.1Hz,2H). 13 C NMR(101MHz,DMSO-d 6 )δ165.77,160.54,160.01,157.07,146.33,135.84(2C),135.12,132.74,127.69(2C),126.60,120.45(2C),120.18,115.48(2C),98.88,66.22(2C),49.25(2C),45.17,30.68(2C),18.13(2C),15.08.Exactmass calcd for C 27 H 33 N 6 O 2 [M+H] + :473.2665;found 473.2660。

[0291] Target product B22

[0292] (Synthesis of 4-(cyclobutylamino)-N-(2,6-dimethylphenyl)-2-((3-morpholinophenyl)amino)pyrimidine-5-carboxamide)

[0293]

[0294] The synthesis method is the same as that of target product B1. Yield: 71.8%, white powder. 1 H NMR(400MHz,DMSO-d 6)δ9.54(s,1H),9.42(s,1H),9.09(d,J=7.0Hz,1H),8.78(s,1H),7.58(s,1H),7.19(d,J=8.2Hz,1H),7.14(d,J=8.0Hz,1H),7.10(s,3H),6.58(dd,J=8.0,1.2Hz,1H),4.66–4.52(m,1H),3.85–3.71(m,4H),3.14–3.07(m,4H),2.39–2.27(m,2H),2.17(s,2×3H),1.97–1.85(m,2H),1.78–1.61(m,2H). 13 C NMR(101MHz,DMSO-d 6 )δ165.68,160.46,160.08,157.05,151.58,141.06,135.80(2C),135.03,128.83,127.70(2C),126.64,110.92,109.29,106.40,99.20,66.23(2C),48.93(2C),44.95,30.83(2C),18.10(2C),14.94.Exact masscalcd for C 27 H 33 N 6 O 2 [M+H] + :473.2665;found 473.2647。

[0295] Target product B23

[0296] (Synthesis of 4-(cyclobutylamino)-N-(2,6-dimethylphenyl)-2-((4-(3-oxomorpholino)phenyl)amino)pyrimidine-5-carboxamide)

[0297]

[0298] The synthesis method is the same as that of target product B1. Yield: 76.9%, white powder. 1 H NMR(400MHz,DMSO-d 6)δ9.68(s,1H),9.60(s,1H),9.07(d,J=6.7Hz,1H),8.81(s,1H),7.85(d,J=8.9Hz,2H),7.31(d,J=8.9Hz,2H),7.10(s,3H),4.52(dd,J=15.4,7.8Hz,1H),4.19(s,2H),4.00–3.93(m,2H),3.75–3.66(m,2H),2.31–2.43(m,2H),2.17(s,2×3H),1.98–1.85(m,2H),1.81–1.70(m,2H). 13 C NMR(101MHz,DMSO-d 6 )δ165.98,165.63,160.49,159.96,157.06,138.73,135.82(2C),135.39,135.03,127.71(2C),126.65,125.70(2C),119.28(2C),99.63,67.79,63.58,49.25,45.23,30.64(2C),18.11(2C),15.06.Exact mass calcd for C 27 H 31 N 6 O 3 [M+H] + :487.2458;found 487.2417。

[0299] Target product B24

[0300] (Synthesis of 4-(cyclobutylamino)-N-(2,6-dimethylphenyl)-2-((4-(morpholinomethyl)phenyl)amino)pyrimidine-5-carboxamide)

[0301]

[0302] The synthesis method is the same as that of target product B1. Yield: 70.9%, white powder. 1 H NMR(400MHz,DMSO-d 6)δ9.55(s,2H),9.04(d,J=6.8Hz,1H),8.78(s,1H),7.76(d,J=8.5Hz,2H),7.21(d,J=8.5Hz,2H),7.10(s,3H),4.56–4.44(m,1H),3.57–3.55(m,4H),3.39(s,2H),2.42–2.29(m,6H),2.17(s,2×3H),1.96–1.86(m,2H),1.69–1.78(m,2H). 13 C NMR(101MHz,DMSO-d 6 )δ165.67,160.50,160.04,157.04,139.27,135.82(2C),135.04,130.87,129.16(2C),127.71(2C),126.66,119.02(2C),99.41,66.24(2C),62.18,53.17(2C),45.23,30.65(2C),18.13(2C),15.07.Exact mass calcd for C 28 H 35 N 6 O 2 [M+H] + :487.2821;found 487.2845。

[0303] Target product B25

[0304] (Synthesis of 4-(cyclobutylamino)-N-(2,6-dimethylphenyl)-2-((4-(piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0305]

[0306] The intermediate of compound B25 with Boc protection was generated by the same synthetic method as that of target product B1. Then, 2 mL of dichloromethane was added to the reaction solution, and 1 mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 2 hours, and the reaction was monitored by TLC. After the reaction was completed, distillation under reduced pressure was carried out, and the target product B25 was separated by silica gel column chromatography (DCM / MeOH = 97 / 3, adding 1% triethylamine). The total yield of the two steps was 70.4%, and it was a white powder. 1 H NMR(400MHz,DMSO-d 6)δ9.48(s,1H),9.35(s,1H),9.02(d,J=6.1Hz,1H),8.74(s,1H),7.64(d,J=8.7Hz,2H),7.10(s,3H),6.89(d,J=9.0Hz,2H),4.49(dq,J=15.4,7.7Hz,1H),3.12–2.99(m,4H),2.96–2.82(m,4H),2.35(dt,J=9.1,8.4Hz,2H),2.17(s,2×3H),1.96–1.84(m,2H),1.80–1.67(m,2H). 13 C NMR(101MHz,DMSO-d 6 )δ165.70,160.48,159.95,157.01,146.68,135.79(2C),135.08,132.51,127.65(2C),126.56,120.40(2C),115.80(2C),98.73,49.47(2C),45.69,45.18(2C),30.64(2C),18.08(2C),11.21.LC-MS:[M+H] + =472.5。

[0307] Target product B29

[0308] (Synthesis of 4-(cyclobutylamino)-N-(2,6-dimethylphenyl)-2-((4-(morpholinomethyl)phenyl)amino)pyrimidine-5-carboxamide)

[0309]

[0310] The synthesis method is the same as that of target product B1. Yield: 70.9%, white powder. 1 H NMR(400MHz,DMSO-d 6 )δ9.52(s,1H),9.45(s,1H),8.91(s,1H),8.76(s,1H),7.52(s,2H),7.09(s,3H),6.83(d,J=8.9Hz,1H),3.75(s,3H),3.03–2.89(m,5H),2.59(s,4H),2.31(s,3H),2.15(s,2×3H),0.79(q,J=6.5Hz,2H),0.56–0.49(m,2H). 13 C NMR(101MHz,DMSO-d 6)δ166.08,163.24,160.37,157.20,152.33,142.94,136.31,136.24(2C),136.03,135.46,128.13(2C),127.06,118.43,111.88,104.93,55.80,55.09(2C),50.22(2C),45.66,23.95,18.53(2C),7.11.LC-MS:[M+H] + = 502.5.

[0311] Target product B30

[0312] (Synthesis of 4-(cyclopropylamino)-N-(2,6-dimethylphenyl)-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0313]

[0314] The synthesis method is the same as that of target product B1. Yield: 75.2%, white powder. 1 H NMR(400MHz, DMSO-d 6 )δ9.51(s, 1H), 8.86(s, 1H), 8.72(s, 1H), 8.22(s, 1H), 7.83(s, 1H), 7.09(s, 3H), 6.64(d, J = 2.3Hz, 1H), 6.50(dd, J = 8.9, 2.3Hz, 1H), 3.85(s, 3H), 3.17–3.05(m, 4H), 2.90–2.81(m, 1H), 2.48–2.39(m, 4H), 2.22(s, 3H), 2.15(s, 2×3H), 0.82–0.74(m, 2H), 0.57–0.44(m, 2H). 13 C NMR(101MHz, DMSO-d 6 )δ165.59, 162.85, 159.92, 156.84, 147.62, 135.81(2C), 135.01, 127.69(2C), 126.63, 120.64, 106.85, 99.88, 99.51, 55.74, 54.75(2C), 48.78(2C), 45.82, 23.42, 18.09(2C), 6.61(2C). Exact mass calcd for C 28 H 36 N7 O 2 [M+H] + : 502.2930; found 502.2928.

[0315] Target product B31

[0316] Synthesis of (4-(cyclopropylamino)-N-(2,6-dimethylphenyl)-2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0317]

[0318] The synthesis method is the same as that of target product B1. Yield: 63.2%, white powder. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.70 (s, 1H), 9.55 (s, 1H), 8.91 (s, 1H), 8.79 (s, 1H), 8.07 (d, J = 15.3 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.09 (s, 3H), 6.96 (t, J = 9.4 Hz, 1H), 3.02–2.89 (m, 4H), 2.89–2.79 (m, 1H), 2.49–2.36 (m, 4H), 2.21 (s, 3H), 2.15 (s, 2×3H), 0.88–0.79 (m, 2H), 0.61–0.48 (m, 2H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 165.53, 162.82, 159.74, 156.82, 154.66 (d, J = 241.4 Hz), 135.81 (2C), 135.68, 134.99, 133.95 (d, J = 9.2 Hz), 127.71 (2C), 126.65, 119.10 (d, J = 4.0 Hz), 114.90, 107.35 (d, J = 26.7 Hz), 99.71, 54.83 (2C), 50.42 (d, J = 2.0 Hz, 2C), 45.83, 23.57, 18.10 (2C), 6.67 (2C). Exact mass calcd for C 27 H 33 FN 7 O[M+H] + : 490.2731; found 490.2728.

[0319] Target product B32

[0320] Synthesis of (4-(cyclopropylamino)-N-(2,6-dimethylphenyl)-2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0321]

[0322] The synthesis method is the same as that of target product B1. Yield: 56.6%, white powder. 1 H NMR(400MHz,DMSO-d 6 )δ9.62(s,1H),8.92(d,J=2.6Hz,1H),8.77(s,1H),8.65–8.49(m,1H),8.07(s,1H),7.10(s,3H),7.07(dd,J=10.3,2.9Hz,1H),6.97(td,J=8.7,2.8Hz,1H),2.85(d,J=4.3Hz,5H),2.61–2.50(m,4H),2.26(s,3H),2.15(s,2×3H),0.85–0.78(m,2H),0.56–0.49(m,2H). 13 C NMR(101MHz,DMSO-d 6 )δ194.72,165.41,162.90,158.85,158.23(d,J=255.9Hz),156.47,143.21(d,J=7.9Hz),135.80(2C),134.90,130.32(d,J=2.6Hz),127.71(2C),126.71,120.51,110.33(d,J=21.7Hz),107.77(d,J=23.7Hz),99.90(d,J=68.7Hz),55.13(2C),51.23(2C),45.78,23.45,18.06(2C),6.58(2C).LC-MS:[M+H] + =490.5。

[0323] Target product B33

[0324] Synthesis of (2 - ((3 - chloro - 4 - (4 - methylpiperazin - 1 - yl)phenyl)amino) - 4 - (cyclopropylamino) - N - (2,6 - dimethylphenyl)pyrimidine - 5 - carboxamide)

[0325]

[0326] The synthesis method is the same as that of target product B1. Yield: 69.6%, white powder. 1 H NMR(400MHz,DMSO - d 6 )δ9.72(s,1H),9.58(s,1H),8.93(s,1H),8.80(s,1H),8.35(s,1H),7.66(dd,J=8.7,1.9Hz,1H),7.11(s,1H),7.09(s,3H),2.91(s,4H),2.86(dd,J=6.5,3.3Hz,1H),2.46(s,3H),2.22(s,3H),2.15(s,2×3H),1.84(s,3H),0.94–0.84(m,2H),0.59–0.51(m,2H). 13 C NMR(101MHz,DMSO - d 6 )δ165.52,162.84,159.73,156.85,143.02,136.66,135.80(2C),134.99,127.70(2C),127.61,126.65,120.67,120.52,118.44,99.85,54.92(2C),51.08(2C),45.80,23.57,18.10(2C),6.70(2C).LC - MS:[M + H] + =506.5。

[0327] Target product B34

[0328] Synthesis of (4 - (cyclopropylamino) - N - (2,6 - dimethylphenyl) - 2 - ((4 - (4 - ethylpiperazin - 1 - yl)phenyl)amino)pyrimidine - 5 - carboxamide)

[0329]

[0330] The synthesis method is the same as that of target product B1. Yield: 75.4%, white powder. 11H NMR (400 MHz, DMSO-d 6 ) δ 9.48 (s, 1H), 9.42 (s, 1H), 8.86 (s, 1H), 8.74 (s, 1H), 7.79 (d, J = 6.7 Hz, 2H), 7.10 (s, 3H), 6.89 (d, J = 9.0 Hz, 2H), 3.09–3.01 (m, 4H), 2.86 (s, 2H), 2.38 (dd, J = 14.3, 7.1 Hz, 2H), 2.15 (s, 2×3H), 1.04 (t, J = 7.1 Hz, 3H), 0.82 (q, J = 6.4 Hz, 2H), 0.56–0.49 (m, 2H). LC-MS: [M+H] + = 486.5。

[0331] Target product B35

[0332] (Synthesis of 4-(cyclopropylamino)-N-(2,6-dimethylphenyl)-2-((4-(4-ethylpiperazin-1-yl)-2-fluorophenyl)amino)pyrimidine-5-carboxamide)

[0333]

[0334] The synthesis method is the same as that of target product B1. Yield: 40.6%, white powder. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 9.60 (s, 1H), 8.92 (d, J = 2.9 Hz, 1H), 8.77 (s, 1H), 8.62–8.50 (m, 1H), 8.07 (s, 1H), 7.10 (s, 3H), 7.09–7.04 (m, 1H), 6.97 (td, J = 8.7, 2.8 Hz, 1H), 2.86 (t, J = 4.1 Hz, 4H), 2.85 (m, 1H), 2.53–2.59 (m, 4H), 2.41 (q, J = 7.2 Hz, 3H), 2.15 (s, 2×3H), 1.04 (t, J = 6.5 Hz, 3H), 0.85–0.79 (m, 2H), 0.56–0.50 (m, 2H). LC-MS: [M+H] + = 504.5。

[0335] Target product B36

[0336] Synthesis of (4-(cyclopropylamino)-N-(2,6-dimethylphenyl)-2-((2-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0337]

[0338] The synthesis method is the same as that of target product B1. Yield: 42.7%, white powder. 1 H NMR(400MHz,DMSO-d 6 )δ9.59(s,1H),8.93(d,J=2.6Hz,1H),8.78(s,1H),8.68(d,J=8.0Hz,1H),8.29(s,1H),7.23(d,J=7.7Hz,1H),7.18–7.07(m,4H),7.03–6.96(m,1H),2.93–2.89(m,1H),2.86(t,J=4.2Hz,4H),2.61(s,4H),2.32(s,3H),2.16(s,2×3H),0.87–0.80(m,2H),0.58–0.52(m,2H). 13 CNMR(101MHz,DMSO-d 6 )δ165.38,162.90,159.46,156.90,141.00,135.79(2C),134.85,134.10,127.71(2C),126.71,124.67,122.05,120.37,118.73,100.20,55.20(2C),51.40(2C),45.57,23.48,18.05(2C),6.58(2C).LC-MS:[M+H] + =472.4。

[0339] Target product B37

[0340] Synthesis of (4-(cyclopropylamino)-N-(2,6-dimethylphenyl)-2-((3-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0341]

[0342] The synthesis method is the same as that of target product B1. Yield: 66.3%, white powder. 11H NMR (400 MHz, DMSO-d 6 ) δ 9.57 (s, 1H), 9.45 (s, 1H), 8.91 (d, J = 3.2 Hz, 1H), 8.78 (s, 1H), 7.60 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.14–7.06 (m, 4H), 6.54 (dd, J = 8.2, 1.7 Hz, 1H), 3.15–3.02 (m, 4H), 2.94 (td, J = 7.0, 3.6 Hz, 1H), 2.48–2.37 (m, 4H), 2.21 (s, 3H), 2.15 (s, 2×3H), 0.79 (q, J = 6.7 Hz, 2H), 0.58–0.50 (m, 2H). 13 13C NMR (101 MHz, DMSO-d 6 ) δ 165.60, 162.77, 160.07, 156.79, 151.49, 141.09, 135.78 (2C), 135.02, 128.78, 127.68 (2C), 126.61, 110.54, 109.21, 106.78, 99.54, 54.66 (2C), 48.45 (2C), 45.77, 23.56, 18.10 (2C), 6.63 (2C). LC-MS: [M+H] + = 472.4.

[0343] Target product B38

[0344] (Synthesis of 4-(cyclopropylamino)-N-(2,6-dimethylphenyl)-2-((4-morpholinophenyl)amino)pyrimidine-5-carboxamide)

[0345]

[0346] The synthesis method is the same as that of target product B1. Yield: 78.3%, white powder. 1 1H NMR (400 MHz, DMSO-d 6)δ9.50(s,1H),9.45(s,1H),8.87(d,J=2.4Hz,1H),8.76(s,1H),7.81(d,J=6.9Hz,2H),7.09(s,3H),6.89(d,J=9.1Hz,2H),3.76–3.70(m,4H),3.07–3.00(m,4H),2.91–2.83(m,1H),2.15(s,2×3H),0.82(q,J=6.7Hz,2H),0.57–0.49(m,2H). 13 C NMR(101MHz,DMSO-d 6 )δ165.64,162.82,159.90,156.81,146.17,135.80(2C),135.06,132.93,127.66(2C),126.57,120.25(2C),115.49(2C),99.18,66.19(2C),49.24(2C),23.49,18.09(2C),6.64(2C).LC-MS:[M+H] + =459.5。

[0347] Target product B39

[0348] (Synthesis of 4-(cyclopropylamino)-N-(2,6-dimethylphenyl)-2-((3-morpholinophenyl)amino)pyrimidine-5-carboxamide)

[0349]

[0350] The synthesis method is the same as that of target product B1. Yield: 67.4%, white powder. 1 H NMR(400MHz,DMSO-d 6 )δ9.58(s,1H),9.48(s,1H),8.92(d,J=3.0Hz,1H),8.80(s,1H),7.57(s,1H),7.46(d,J=8.0Hz,1H),7.13(t,J=8.2Hz,1H),7.09(s,3H),6.56(dd,J=8.1,1.5Hz,1H),3.74–3.71(m,4H),3.05(dd,J=10.9,6.6Hz,4H),2.94(td,J=7.0,3.6Hz,1H),2.16(s,2×3H),0.79(q,J=6.6Hz,2H),0.54(t,J=7.6Hz,2H). 1313C NMR (101 MHz, DMSO-d 6 ) δ 165.60, 162.77, 160.08, 156.79, 151.53, 141.16, 135.78 (2C), 135.02, 128.84, 127.67 (2C), 126.60, 110.88, 109.01, 106.50, 99.60, 66.14 (2C), 48.89 (2C), 23.55, 18.09 (2C), 6.64 (2C). LC-MS: [M+H] + = 459.4

[0351] Target product B40

[0352] (Synthesis of 4-(cyclopropylamino)-N-(2,6-dimethylphenyl)-2-((4-(3-oxomorpholino)phenyl)amino)pyrimidine-5-carboxamide)

[0353]

[0354] The synthesis method is the same as that of target product B1. Yield: 78.4%, white powder 1 1H NMR (400 MHz, DMSO-d 6 ) δ 9.75 (s, 1H), 9.56 (s, 1H), 8.91 (d, J = 2.8 Hz, 1H), 8.81 (s, 1H), 7.99 (d, J = 8.7 Hz, 2H), 7.29 (d, J = 8.8 Hz, 2H), 7.10 (s, 3H), 4.18 (s, 2H), 3.99–3.92 (m, 2H), 3.70 (t, J = 5.0 Hz, 2H), 2.93–2.84 (m, 1H), 2.16 (s, 2×3H), 0.83 (q, J = 6.6 Hz, 2H), 0.60–0.50 (m, 2H). 13 13C NMR (101 MHz, DMSO-d 6 ) δ 165.92, 165.50, 162.81, 159.90, 156.81, 138.83, 135.78 (2C), 135.28, 134.96, 127.68 (2C), 126.63, 125.67 (2C), 119.24 (2C), 99.89, 67.77, 63.55, 49.23, 23.56, 18.09 (2C), 6.63 (2C). LC-MS: [M+H] + = 473.4

[0355] Target product B41

[0356] Synthesis of (4-(cyclopropylamino)-N-(2,6-dimethylphenyl)-2-((4-(morpholinomethyl)phenyl)amino)pyrimidine-5-carboxamide)

[0357]

[0358] The synthesis method is the same as that of target product B1. Yield: 76.2%, white powder. 1 H NMR(400MHz,DMSO-d 6 )δ9.64(s,1H),9.56(s,1H),8.89(d,J=2.9Hz,1H),8.79(s,1H),7.91(d,J=8.2Hz,2H),7.20(d,J=8.4Hz,2H),7.09(s,3H),3.59–3.52(m,4H),3.38(s,2H),2.89(ddt,J=10.7,7.2,3.8Hz,1H),2.33(s,4H),2.15(s,2×3H),0.82(q,J=6.6Hz,2H),0.57–0.50(m,2H). 13 C NMR(101MHz,DMSO-d 6 )δ165.55,162.81,159.96,156.80,139.40,135.78(2C),134.99,130.68,129.14(2C),127.68(2C),126.62,118.86(2C),99.55,66.22(2C),62.18,53.16(2C),23.54,18.10(2C),6.64(2C).LC-MS:[M+H] + =473.4。

[0359] Target product B42

[0360] Synthesis of (4-(cyclopropylamino)-N-(2,6-dimethylphenyl)-2-((4-(piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0361]

[0362] The intermediate of Boc-protected compound B42 was generated by the synthesis method of the target product B1. Then, 2 mL of dichloromethane was added to the reaction solution, and 1 mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 2 hours. The reaction was monitored by TLC. After the reaction was completed, distillation under reduced pressure was carried out, and the target product B42 was separated by silica gel column chromatography (DCM / MeOH = 97 / 3, adding 1% triethylamine). The total yield of the two steps was 76.2%, and it was a white powder. 1 H NMR(400MHz,DMSO-d 6 )δ9.51(s,1H),9.49(s,1H),8.87(d,J=2.5Hz,1H),8.75(s,1H),7.84(d,J=7.4Hz,2H),7.09(s,3H),6.95(d,J=9.1Hz,2H),3.28–3.24(m,4H),3.24–3.19(m,4H),2.86(td,J=6.8,3.5Hz,1H),2.15(s,2×3H),0.85–0.79(m,2H),0.57–0.49(m,2H). 13 C NMR(101MHz,DMSO-d 6 )δ165.67,162.87,159.92,156.85,145.11,135.84(2C),135.07,133.75,127.72(2C),126.66,120.26(2C),116.59(2C),46.57(2C),43.01(2C),23.55,18.13(2C),6.68(2C).LC-MS:[M+H] + =458.5。

[0363] Target product B43

[0364] (2-((4-(4-(cyclopropanecarbonyl)piperazin-1-yl)phenyl)amino)-4-(cyclopropylamino)-N-(2,6-dimethylphenyl)pyrimidine-5-carboxamide) synthesis

[0365]

[0366] Dissolve B42 (50.0 mg, 1.0 equiv), cyclopropanecarboxylic acid (2.0 equiv) and HATU (62.3 mg, 1.5 equiv) in 5 mL of dichloromethane, add triethylamine (3.0 equiv), and react at room temperature for 2 hours. Monitor the reaction by TLC. After the reaction is completed, concentrate the reaction solution under reduced pressure and separate it by silica gel column chromatography to obtain the final product B43. Yield: 73.5%, white powder. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.49 (s, 1H), 9.45 (s, 1H), 8.86 (s, 1H), 8.74 (s, 1H), 7.81 (d, J = 6.8 Hz, 2H), 7.09 (s, 3H), 6.93 (d, J = 9.0 Hz, 2H), 3.80 (s, 2H), 3.60 (s, 2H), 3.09 (s, 2H), 3.02 (s, 2H), 2.91–2.82 (m, 1H), 2.15 (s, 2×3H), 2.04–1.95 (m, 1H), 0.86–0.80 (m, 2H), 0.73 (dd, J = 9.4, 6.4 Hz, 4H), 0.56–0.47 (m, 2H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 171.27, 165.73, 162.90, 159.97, 156.87, 146.03, 135.88 (2C), 135.10, 133.25, 127.77 (2C), 126.71, 120.30 (2C), 116.50 (2C), 99.27, 49.89, 49.28, 44.97, 41.67, 23.59, 18.14 (2C), 10.41, 7.15 (2C), 6.72 (2C). LC-MS: [M+H] + = 526.5.

[0367] Target product B44

[0368] (Synthesis of 2-((4-(4-(2-cyclopropylacetyl)piperazin-1-yl)phenyl)amino)-4-(cyclopropylamino)-N-(2,6-dimethylphenyl)pyrimidine-5-carboxamide)

[0369]

[0370] The synthesis method is the same as that of the target product B43. Yield: 76.2%, white powder. 1 H NMR (400 MHz, CDCl3 ) δ 8.93 (s, 1H), 8.46 (s, 1H), 7.77 (s, 1H), 7.72 (d, J = 8.5 Hz, 2H), 7.17–7.05 (m, 3H), 6.89 (d, J = 9.0 Hz, 2H), 3.85–3.71 (m, 2H), 3.69–3.54 (m, 2H), 3.16–3.03 (m, 4H), 2.91 (dt, J = 10.8, 3.6 Hz, 1H), 2.31 (d, J = 6.8 Hz, 2H), 2.24 (s, 2×3H), 1.08–1.02 (m, 1H), 0.84 (q, J = 6.8 Hz, 2H), 0.64–0.58 (m, 2H), 0.58–0.49 (m, 2H), 0.18 (q, J = 4.9 Hz, 2H). 13 C NMR (101 MHz, CDCl 3 ) δ 171.42, 165.71, 163.27, 158.24, 153.10, 146.98, 135.77 (2C), 133.68, 132.69, 128.42 (2C), 127.60, 121.06 (2C), 117.37 (2C), 100.10, 50.59, 50.11, 41.64, 40.38, 38.56, 23.98, 18.51 (2C), 7.40 (2C), 6.93 (2C), 4.67 (2C). LC-MS: [M + H] + = 540.5。

[0371] Target product B45

[0372] (Synthesis of 2 - ((4 - (4 - acetylpiperazin - 1 - yl)phenyl)amino) - 4 - (cyclopropylamino) - N - (2,6 - dimethylphenyl)pyrimidine - 5 - carboxamide)

[0373]

[0374] The synthesis method is the same as that of target product B43. Yield: 76.6%, white powder. 1 H NMR (400 MHz, CDCl 3)δ9.01(s,1H),8.51(s,1H),7.83(s,2H),7.62(d,J = 8.7Hz,2H),7.17–7.06(m,3H),6.90(d,J = 9.0Hz,2H),3.81–3.73(m,2H),3.66–3.57(m,2H),3.16–3.12(m,2H),3.11–3.07(m,2H),2.95–2.89(m,1H),2.24(s,2×3H),2.13(s,3H),0.85(q,J = 6.8Hz,2H),0.66–0.58(m,2H). 13 C NMR(101MHz,CDCl 3 )δ169.34,165.68,163.26,157.73,153.39,147.17,135.82(2C),133.65,132.26,128.45(2C),127.64,121.31(2C),117.40(2C),100.61,50.36,49.97,46.41,41.55,23.98,21.45,18.50(2C),6.95(2C).LC-MS:[M+H] + = 500.5。

[0375] Target product B46

[0376] (Synthesis of N-(2-chloro-6-methylphenyl)-4-(cyclopropylamino)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0377]

[0378] The synthesis method is the same as that of target product B1. Yield: 68.2%, white powder. 1 H NMR(400MHz,DMSO-d 6)δ9.74(s,1H),9.43(s,1H),8.76(d,J=2.4Hz,1H),8.74(s,1H),7.77(s,2H),7.36(dd,J=7.4,1.7Hz,1H),7.22(dd,J=13.1,5.4Hz,2H),6.88(d,J=9.1Hz,2H),3.07–3.03(m,4H),2.85(dt,J=7.7,4.1Hz,1H),2.46–2.42(m,4H),2.20(s,3H),2.19(s,3H),0.81(q,J=6.5Hz,2H),0.55–0.48(m,2H). 13 C NMR(101MHz,DMSO-d 6 )δ165.87,162.86,160.00,157.20,146.33,138.90,133.87,132.59,132.53,129.02,128.10,127.00,120.33,115.78,98.61,54.76,48.84,45.85,23.59,18.37,6.69.LC-MS:[M+H] + =492.4。

[0379] Target product B47

[0380] (Synthesis of N-(2-bromo-6-methylphenyl)-4-(cyclopropylamino)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0381]

[0382] The synthesis method is the same as that of target product B1. Yield: 65.4%, white powder. 1 H NMR(400MHz,DMSO-d 6)δ9.82(s,1H),9.48(s,1H),8.79(s,2H),7.79(d,J=4.4Hz,2H),7.52(d,J=7.7Hz,1H),7.29(d,J=7.5Hz,1H),7.15(t,J=7.8Hz,1H),6.88(d,J=9.1Hz,2H),3.09–3.02(m,4H),2.82–2.91(d,J=3.3Hz,1H),2.47–2.41(m,4H),2.21(s,3H),2.21(s,3H),0.82(q,J=6.5Hz,2H),0.56–0.49(m,2H). 13 C NMR(101MHz,DMSO-d 6 )δ165.72,162.82,159.93,157.19,146.24,139.04,135.34,132.52,130.09,129.56,128.51,123.80,120.26(2C),115.71(2C),54.73(2C),48.80(2C),45.81,23.52,18.63,6.64(2C).LC-MS:[M+H] + =537.4。

[0383] Target product B48

[0384] (Synthesis of 4-(cyclopropylamino)-N-(2-fluoro-6-methylphenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0385]

[0386] The synthesis method is the same as that of target product B1. Yield: 62.5%, white powder. 1 H NMR(400MHz,DMSO-d 6)δ9.64(s,1H),9.49(s,1H),8.80(s,1H),8.75(s,1H),7.79(s,2H),7.22(td,J=7.9,5.7Hz,1H),7.15–7.02(m,2H),6.88(d,J=9.1Hz,2H),3.14–2.98(m,4H),2.87(d,J=3.2Hz,1H),2.49–2.39(m,4H),2.21(s,2×3H),0.82(q,J=6.5Hz,2H),0.59–0.47(m,2H). 13 C NMR(101MHz,DMSO-d 6 )δ165.89,162.74,159.89,158.10(d,J=245.5Hz),157.23,146.24,138.27(d,J=2.1Hz),132.48,127.59(d,J=8.4Hz),125.67(d,J=2.2Hz),124.08(d,J=13.3Hz),120.20(2C),115.69(2C),113.06(d,J=21.3Hz),54.73(2C),48.80(2C),45.79,23.50,17.56(d,J=2.5Hz),6.63(2C).LC-MS:[M+H] + =476.4。

[0387] Target product B49

[0388] (Synthesis of 4-(cyclopropylamino)-N-(2-methoxy-6-methylphenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0389]

[0390] The synthesis method is the same as that of target product B1. Yield: 63.6%, white powder. 1 H NMR(400MHz,DMSO-d 6)δ9.42(s,1H),9.32(s,1H),8.87(d,J=2.2Hz,1H),8.73(s,1H),7.79(d,J=6.1Hz,2H),7.16(t,J=7.9Hz,1H),6.88(d,J=9.0Hz,3H),6.84(d,J=7.6Hz,1H),3.72(s,3H),3.11–3.00(m,4H),2.90–2.82(m,1H),2.47–2.41(m,4H),2.21(s,3H),2.13(s,3H),0.82(q,J=6.6Hz,2H),0.57–0.47(m,2H). 13 C NMR(101MHz,DMSO-d 6 )δ165.86,162.77,159.85,157.02,155.27,146.17,137.09,132.63,127.21,124.84,121.87,120.15(2C),115.73(2C),109.04,99.55,55.53,54.74(2C),48.84(2C),45.79,23.46,17.84,6.63(2C).LC-MS:[M+H] + =488.5。

[0391] Target product B50

[0392] (Synthesis of 4-(cyclopropylamino)-N-(2,6-dimethoxyphenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0393]

[0394] The synthesis method is the same as that of target product B1. Yield: 62.7%, white powder. 1 H NMR(400MHz,DMSO-d 6)δ9.39(s,1H),9.10(s,1H),8.91(d,J=3.0Hz,1H),8.70(s,1H),7.78(d,J=6.6Hz,2H),7.22(t,J=8.4Hz,1H),6.88(d,J=9.1Hz,2H),6.69(d,J=8.5Hz,2H),3.72(s,2×3H),3.09–3.03(m,4H),2.81–2.90(m,1H),2.47–2.41(m,4H),2.21(s,3H),0.81(q,J=6.6Hz,2H),0.55–0.47(m,2H). 13 C NMR(101MHz,DMSO-d 6 )δ165.87,162.75,159.80,157.10,156.26(2C),146.15,132.67,127.69,120.18(2C),115.75(2C),114.50,104.30(2C),99.56,55.73,55.69,54.75(2C),48.85(2C),45.80,23.44,6.63(2C).LC-MS:[M+H] + =504.5。

[0395] Target product B51

[0396] (Synthesis of N-(2-chloro-6-methoxyphenyl)-4-(cyclopropylamino)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0397]

[0398] The synthesis method is the same as that of target product B1. Yield: 61.4%, white powder. 1 H NMR(400MHz,DMSO-d 6)δ9.56(s,1H),9.47(s,1H),8.82(d,J=2.2Hz,1H),8.74(s,1H),7.79(d,J=5.5Hz,2H),7.30(t,J=8.3Hz,1H),7.10(d,J=8.1Hz,1H),7.06(d,J=8.3Hz,1H),6.88(d,J=9.1Hz,2H),3.77(s,3H),3.11–3.02(m,4H),2.82–2.91(m,1H),2.47–2.40(m,4H),2.21(s,3H),0.82(q,J=6.4Hz,2H),0.58–0.49(m,2H). 13 C NMR(101MHz,DMSO-d 6 )δ165.91,162.76,159.88,157.30,156.91,146.23,133.23,132.52,128.50,124.14,120.93,120.22(2C),115.71(2C),110.61,56.08,54.73(2C),48.81(2C),45.82,23.48,6.62(2C).LC-MS:[M+H] + =508.4。

[0399] Target product B52

[0400] (Synthesis of 4-(cyclopropylamino)-N-(2-fluorophenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0401]

[0402] The synthesis method is the same as that of target product B1. Yield: 61.5%, white powder. 1 H NMR(400MHz,DMSO-d 6 )δ9.92(s,1H),9.49(s,1H),8.74(s,1H),8.71(s,1H),7.78(s,2H),7.46(t,J=7.6Hz,1H),7.29–7.14(m,3H),6.88(d,J=9.0Hz,2H),3.05(s,4H),2.87(s,1H),2.43(s,4H),2.20(s,3H),0.89–0.79(m,2H),0.61–0.49(m,2H). 1313C NMR (101 MHz, DMSO-d 6 ) δ 165.89, 162.78, 159.91, 157.56, 156.16 (d, J = 246.7 Hz), 146.31, 132.49, 127.52 (2C), 126.88 (d, J = 6.4 Hz), 125.64 (d, J = 12.1 Hz), 124.27 (d, J = 3.2 Hz), 120.33 (2C), 115.83 (d, J = 15.7 Hz), 98.83, 54.76 (2C), 48.83 (2C), 45.85, 23.59, 6.72 (2C). LC-MS: [M+H] + = 462.5。

[0403] Target product B53

[0404] (Synthesis of 4-(cyclopropylamino)-N-(2,6-difluorophenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0405]

[0406] The synthesis method is the same as that of target product B1. Yield: 60.4%, white powder. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 9.55 (s, 1H), 8.77 (s, 1H), 8.73 (s, 1H), 7.80 (s, 2H), 7.44–7.32 (m, 1H), 7.18 (t, J = 8.1 Hz, 2H), 6.89 (d, J = 9.1 Hz, 2H), 3.12–3.03 (m, 4H), 2.88 (d, J = 3.4 Hz, 1H), 2.49–2.43 (m, 4H), 2.23 (s, 3H), 0.89–0.79 (m, 2H), 0.59–0.52 (m, 2H). 13 13C NMR (101 MHz, DMSO-d 6)δ165.94,162.71,159.91,158.27(dd,J=248.2,5.1Hz,2C),157.66,146.27,132.40,128.10(t,J=10.0Hz),120.32(2C),115.72(2C),114.65(t,J=16.9Hz),111.83(d,J=22.7Hz,2C),98.17,54.64(2C),48.69(2C),45.69,23.55,6.65(2C).LC-MS:[M+H] + = 480.4。

[0407] Target product B54

[0408] (Synthesis of N-(2-chloro-6-methylphenyl)-4-(cyclobutylamino)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0409]

[0410] The synthesis method is the same as that of target product B1. Yield: 66.4%, white powder. 1 H NMR(400MHz,DMSO-d 6 )δ9.75(s,1H),9.38(s,1H),8.94(d,J=5.9Hz,1H),8.76(s,1H),7.63(d,J=8.5Hz,2H),7.40–7.33(m,1H),7.30–7.18(m,2H),6.89(d,J=9.0Hz,2H),4.56–4.42(m,1H),3.13–2.99(m,4H),2.48–2.40(m,4H),2.34(d,J=4.5Hz,2H),2.21(s,3H),2.21(s,3H),1.96–1.84(m,2H),1.78–1.65(m,2H). 13 C NMR(101MHz,DMSO-d 6)δ165.97,160.54,160.08,157.45,146.45,138.91,133.92,132.62,132.32,129.02,128.10,127.01,120.57(2C),115.74(2C),98.41,54.76(2C),48.82(2C),45.84,45.24,30.68(2C),18.37,15.12.Exact mass calcd for C 27 H 33 ClN 7 O[M+H] + :506.2435;found 506.2422。

[0411] Target product B55

[0412] (Synthesis of N-(2-bromo-6-methylphenyl)-4-(cyclobutylamino)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0413]

[0414] The synthesis method is the same as that of target product B1. Yield: 63.8%, white powder. 1 H NMR(400MHz,DMSO-d 6 )δ9.75(s,1H),9.38(s,1H),8.94(d,J=5.9Hz,1H),8.76(s,1H),7.63(d,J=8.6Hz,2H),7.53(d,J=7.9Hz,1H),7.30(d,J=7.5Hz,1H),7.16(t,J=7.8Hz,1H),6.89(d,J=9.0Hz,2H),4.53–4.44(m,1H),3.10–3.04(m,4H),2.48–2.41(m,4H),2.35(d,J=4.0Hz,2H),2.23(s,3H),2.21(s,3H),1.96–1.81(m,2H),1.75(dd,J=9.3,5.1Hz,2H). 13 C NMR(101MHz,DMSO-d 6)δ165.82,160.52,160.05,157.38,146.41,139.07,135.34,132.29,130.13,129.61,128.56,123.83,120.49(2C),115.70(2C),99.57,54.73(2C),53.91,48.79(2C),45.80,30.65(2C),18.62(2C),15.08.LC-MS:[M+H] + = 550.4。

[0415] Target product B56

[0416] (Synthesis of N-(2-bromo-6-methylphenyl)-4-(cyclobutylamino)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0417]

[0418] The synthesis method is the same as that of target product B1. Yield: 62.9%, white powder. 1 H NMR(400MHz, DMSO-d 6 )δ9.65(s, 1H), 9.40(s, 1H), 8.95(d, J = 5.9Hz, 1H), 8.76(s, 1H), 7.64(d, J = 8.6Hz, 2H), 7.27–7.18(m, 1H), 7.13–7.04(m, 2H), 6.89(d, J = 9.0Hz, 2H), 4.56–4.42(m, 1H), 3.12–3.02(m, 4H), 2.48–2.41(m, 4H), 2.40–2.30(m, 2H), 2.22(s, 3H), 2.21(s, 3H), 1.97–1.87(m, 2H), 1.75(dd, J = 9.3, 5.1Hz, 2H). 13 C NMR(101MHz, DMSO-d 6)δ165.98,160.42,160.01,158.12(d, J = 245.7Hz),157.46,146.37,138.28,132.26,127.62(d, J = 8.9Hz),125.69(d, J = 3.3Hz),124.10(d, J = 13.7Hz),120.49(2C),115.67(2C),113.08(d, J = 20.3Hz),99.54,54.72(2C),48.77(2C),45.78,30.61(2C),21.63,17.57(d, J = 2.3Hz),15.05. LC-MS: [M+H] + = 490.5。

[0419] Target product B57

[0420] (Synthesis of 4-(cyclobutylamino)-N-(2-methoxy-6-methylphenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0421]

[0422] The synthesis method is the same as that of target product B1. Yield: 62.4%, white powder. 1 H NMR(400MHz, DMSO-d 6 )δ9.32(s, 1H), 9.31(s, 1H), 9.02(d, J = 6.4Hz, 1H), 8.72(s, 1H), 7.64(d, J = 8.7Hz, 2H), 7.18(dd, J = 14.5, 6.5Hz, 1H), 6.94–6.83(m, 4H), 4.49(dd, J = 15.2, 7.7Hz, 1H), 3.74(s, 3H), 3.11–3.04(m, 4H), 2.48–2.41(m, 4H), 2.35(d, J = 4.3Hz, 2H), 2.22(s, 3H), 2.14(s, 3H), 1.98–1.84(m, 2H), 1.79–1.69(m, 2H). 13 C NMR(101MHz, DMSO-d 6) δ 165.98, 160.46, 159.93, 157.29, 155.30, 146.32, 137.14, 132.44, 127.28, 124.85, 121.91, 120.38 (2C), 115.74 (2C), 109.06, 55.55, 54.78 (2C), 48.84 (2C), 45.86, 45.18, 30.70 (2C), 17.91, 15.12. LC-MS: [M+H] + = 502.5.

[0423] Target product B58

[0424] (Synthesis of 4-(cyclobutylamino)-N-(2,6-dimethoxyphenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0425]

[0426] The synthesis method is the same as that of target product B1. Yield: 61.9%, white powder. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.30 (s, 1H), 9.09 (s, 1H), 9.07 (d, J = 6.8 Hz, 1H), 8.70 (s, 1H), 7.63 (d, J = 8.7 Hz, 2H), 7.23 (t, J = 8.4 Hz, 1H), 6.89 (d, J = 9.0 Hz, 2H), 6.70 (d, J = 8.4 Hz, 2H), 4.48 (dq, J = 15.0, 7.5 Hz, 1H), 3.73 (s, 2×3H), 3.10–3.02 (m, 4H), 2.48–2.41 (m, 4H), 2.39–2.31 (m, 2H), 2.21 (s, 3H), 1.94–1.81 (m, 2H), 1.77–1.69 (m, 2H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 165.96, 160.43, 159.87, 157.33, 156.28 (2C), 146.26, 132.45, 127.71, 120.34 (2C), 115.71 (2C), 114.51, 104.29 (2C), 55.72 (2C), 54.74 (2C), 48.83 (2C), 45.81, 30.67 (2C), 15.09. LC-MS: [M+H] + = 518.5.

[0427] Target product B59

[0428] Synthesis of (N-(2-chloro-6-methoxyphenyl)-4-(cyclobutylamino)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0429]

[0430] The synthesis method is the same as that of target product B1. Yield: 62.5%, white powder. 1 H NMR(400MHz,DMSO-d 6 )δ9.54(s,1H),9.37(s,1H),8.97(d,J = 6.4Hz,1H),8.73(s,1H),7.63(d,J = 8.6Hz,2H),7.30(t,J = 8.3Hz,1H),7.11(d,J = 8.1Hz,1H),7.07(d,J = 8.4Hz,1H),6.89(d,J = 9.0Hz,2H),4.55–4.43(m,1H),3.78(s,3H),3.10–3.04(m,4H),2.48–2.42(m,4H),2.40–2.30(m,2H),2.22(s,3H),1.96–1.81(m,2H),1.77–1.68(m,2H). 13 C NMR(101MHz,DMSO-d 6 )δ166.00,159.97,159.52,157.52,156.93,146.36,133.26,132.30,128.53,124.16,120.95,120.40(2C),115.69(2C),110.62,99.55,56.07,54.73(2C),48.78(2C),45.80,30.62(2C),15.08.LC-MS:[M+H] + = 522.4

[0431] Target product B60

[0432] Synthesis of (4-(cyclobutylamino)-N-(2-fluorophenyl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0433]

[0434] The synthesis method is the same as that of target product B1. Yield: 62.1%, white powder. 1 H NMR(400MHz, DMSO-d 6 ) δ9.91(s, 1H), 9.42(s, 1H), 8.90(s, 1H), 8.70(s, 1H), 7.64(d, J = 8.5Hz, 2H), 7.48(t, J = 7.6Hz, 1H), 7.30–7.23(m, 2H), 7.23–7.15(m, 1H), 6.89(d, J = 9.0Hz, 2H), 4.54–4.49(m, 1H), 3.13–3.01(m, 4H), 2.48–2.41(m, 4H), 2.40–2.31(m, 2H), 2.21(s, 3H), 1.98–1.89(m, 2H), 1.78–1.68(m, 2H). 13 C NMR(101MHz, DMSO-d 6 ) δ165.94, 160.41, 158.67(d, J = 264.3Hz), 157.75, 154.90, 146.39, 132.26, 127.49(d, J = 1.4Hz), 126.81(d, J = 7.3Hz), 125.64(d, J = 12.4Hz), 124.24(d, J = 3.6Hz), 120.47(2C), 115.87, 115.67(2C), 98.47, 54.72(2C), 48.77(2C), 45.78, 45.22, 30.64(2C), 15.07. LC-MS: [M+H] + = 476.4.

[0435] Target product B61

[0436] (Synthesis of N-(2-bromo-6-methylphenyl)-4-(cyclobutylamino)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0437]

[0438] The synthesis method is the same as that of target product B1. Yield: 62.8%, white powder. 1 H NMR(400MHz, DMSO-d 6)δ 10.02 (s, 1H), 9.45 (s, 1H), 8.89 (d, J = 5.5 Hz, 1H), 8.78 (s, 1H), 7.63 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 8.1 Hz, 2H), 7.41–7.34 (m, 1H), 6.89 (d, J = 9.1 Hz, 2H), 4.56–4.43 (m, 1H), 3.12–3.03 (m, 4H), 2.48–2.41 (m, 4H), 2.40–2.30 (m, 2H), 2.21 (s, 3H), 1.97–1.88 (m, 2H), 1.75 (dd, J = 9.4, 5.0 Hz, 2H). LC-MS: [M+H] + = 493.5。

[0439] Target product B62

[0440] (Synthesis of N-(2-chloro-6-methylphenyl)-4-(cyclopropylamino)-2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0441]

[0442] The synthesis method is the same as that of target product B1. Yield: 57.2%, white powder. 1 H NMR (400 MHz, DMSO-d 6 )δ 9.81 (s, 1H), 9.75 (s, 1H), 8.84 (s, 1H), 8.80 (s, 1H), 8.07 (d, J = 15.3 Hz, 1H), 7.51 (dd, J = 8.7, 1.4 Hz, 1H), 7.38 (dd, J = 7.4, 1.7 Hz, 1H), 7.30–7.21 (m, 2H), 6.98 (t, J = 9.5 Hz, 1H), 3.02–2.90 (m, 4H), 2.86 (d, J = 3.4 Hz, 1H), 2.48–2.40 (m, 4H), 2.22 (s, 3H), 2.21 (s, 3H), 0.84 (q, J = 6.6 Hz, 2H), 0.61–0.53 (m, 2H). LC-MS: [M+H] + = 510.5。

[0443] Target product B63

[0444] (Synthesis of (4-(cyclopropylamino)-2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-N-(2-fluoro-6-methylphenyl)pyrimidine-5-carboxamide))

[0445]

[0446] The synthesis method is the same as that of the target product B1. Yield: 52.7%, white powder. 1 H NMR(400MHz, DMSO-d 6 ) δ 9.76(s, 1H), 9.67(s, 1H), 8.84(s, 1H), 8.78(s, 1H), 8.06(d, J = 15.4Hz, 1H), 7.51(d, J = 8.8Hz, 1H), 7.26–7.19(m, 1H), 7.13–7.03(m, 2H), 6.97(t, J = 9.4Hz, 1H), 2.95(s, 4H), 2.89–2.80(m, 1H), 2.45(s, 4H), 2.21(s, 3H), 2.21(s, 3H), 0.84(q, J = 6.3Hz, 2H), 0.61–0.53(m, 2H). 13 C NMR(101MHz, DMSO-d 6 ) δ 165.77, 162.72, 159.74, 157.25, 156.86, 155.82, 146.57, 138.26, 135.62, 134.29, 133.92, 133.83, 125.71(d, J = 2.2Hz), 123.97(d, J = 13.0Hz), 119.16(d, J = 2.5Hz), 114.93(d, J = 5.4Hz), 113.23(d, J = 7.7Hz), 100.25, 54.66(d, J = 4.4Hz, 2C), 50.19(2C), 45.57, 23.56, 17.55, 6.63(2C). LC-MS: [M + H] + = 494.4.

[0447] Target product B64

[0448] (Synthesis of (4-(cyclopropylamino)-N-(2,6-difluorophenyl)-2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide))

[0449]

[0450] The synthesis method is the same as that of target product B1. Yield: 40.8%, white powder. 1 H NMR(400MHz,DMSO-d 6 )δ9.98(s,1H),9.80(s,1H),8.80(s,1H),8.77(s,1H),8.06(d,J=14.3Hz,1H),7.50(d,J=8.6Hz,1H),7.41–7.33(m,1H),7.20–7.14(m,2H),6.96(t,J=9.4Hz,1H),2.94(s,4H),2.91–2.80(m,1H),2.45(s,4H),2.20(s,3H),0.86–0.79(m,2H),0.61–0.52(m,2H). 13 C NMR(101MHz,DMSO-d 6 )δ165.90,162.74,159.82,158.29(dd,J=248.4,5.1Hz,2C),157.73,154.65(d,J=241.4Hz),135.53(d,J=11.0Hz),134.14(d,J=9.4Hz),128.21(t,J=9.5Hz),119.13(d,J=1.6Hz),115.06,114.61(t,J=16.8Hz),111.89(dd,J=18.5,3.8Hz,2C),107.51(d,J=24.2Hz),99.60,54.80(2C),50.40(2C),45.82,23.65,6.70(2C).LC-MS:[M+H] + =498.4。

[0451] Target product B65

[0452] (Synthesis of N-(2-chloro-6-methylphenyl)-4-(cyclobutylamino)-2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0453]

[0454] The synthesis method is the same as that of target product B1. Yield: 42.3%, white powder. 11H NMR (400 MHz, DMSO-d 6 ) δ 9.81 (s, 1H), 9.66 (s, 1H), 8.98 (d, J = 6.1 Hz, 1H), 8.79 (s, 1H), 7.85 (d, J = 15.6 Hz, 1H), 7.43–7.33 (m, 2H), 7.31–7.19 (m, 2H), 6.97 (t, J = 9.4 Hz, 1H), 4.48 (dq, J = 15.3, 7.7 Hz, 1H), 3.03–2.88 (m, 4H), 2.49–2.41 (m, 4H), 2.40–2.32 (m, 2H), 2.22 (s, 3H), 2.21 (s, 3H), 1.98–1.87 (m, 2H), 1.79–1.66 (m, 2H). 13 13C NMR (101 MHz, DMSO-d 6 ) δ 165.84, 160.47, 159.89, 157.40, 154.64 (d, J = 241.7 Hz), 138.89, 135.49 (d, J = 11.0 Hz), 134.18 (d, J = 9.2 Hz), 133.81, 132.59, 129.04, 128.16, 127.03, 119.16 (d, J = 4.2 Hz), 115.12, 107.46 (d, J = 25.6 Hz), 99.11, 54.83 (2C), 50.42 (d, J = 1.9 Hz, 2C), 45.84, 45.40, 30.58 (2C), 18.34, 15.17. Exact mass calcd for C 27 H 32 FClN 7 O [M+H] + : 524.2341; found 524.2303。

[0455] Target product B66

[0456] (Synthesis of 4-(cyclobutylamino)-2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-N-(2-fluoro-6-methylphenyl)pyrimidine-5-carboxamide)

[0457]

[0458] The synthesis method is the same as that of target product B1. Yield: 44.6%, white powder. 1 1H NMR (400 MHz, DMSO-d6 )δ9.66(s,1H),9.65(s,1H),8.98(d,J=6.2Hz,1H),8.77(s,1H),7.85(d,J=15.7Hz,1H),7.40(dd,J=8.7,1.8Hz,1H),7.27–7.19(m,1H),7.15–7.06(m,2H),6.98(t,J=9.4Hz,1H),4.49(dq,J=15.5,7.6Hz,1H),2.96(s,4H),2.46(s,4H),2.42–2.31(m,2H),2.22(s,3H),2.22(s,3H),1.99–1.90(m,2H),1.80–1.68(m,2H). 13 C NMR(101MHz,DMSO-d 6 )δ165.84,160.32,159.79,158.08(d,J=245.6Hz),157.42,154.55(d,J=241.7Hz),138.24,135.43(d,J=10.9Hz),134.10(d,J=9.2Hz),127.70(d,J=9.0Hz),125.73(d,J=2.9Hz),123.97(d,J=13.2Hz),119.11(d,J=4.3Hz),115.01,113.11(d,J=20.6Hz),107.33(d,J=28.5Hz),54.80(2C),50.39(d,J=2.6Hz,2C),45.84,45.33,30.52(2C),17.59(d,J=2.5Hz),15.12.LC-MS:[M+H] + =508.4。

[0459] Target product B67

[0460] (Synthesis of 4-(cyclobutylamino)-N-(2,6-difluorophenyl)-2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0461]

[0462] The synthesis method is the same as that of target product B1. Yield: 41.6%, white powder. 1 H NMR(400MHz,DMSO-d 6)δ9.95(s,1H),9.71(s,1H),8.92(d,J=6.3Hz,1H),8.79(s,1H),7.84(d,J=15.6Hz,1H),7.44–7.31(m,2H),7.19(t,J=8.1Hz,2H),6.97(t,J=9.4Hz,1H),4.57–4.41(m,1H),2.96(s,4H),2.48(s,4H),2.41–2.30(m,2H),2.22(s,3H),2.00–1.87(m,2H),1.81–1.67(m,2H). 13 CNMR(101MHz,DMSO-d 6 )δ165.97,160.33,159.88,158.29(dd,J=248.4,5.1Hz,2C),157.92,154.59(d,J=241.6Hz),135.37(d,J=11.0Hz),134.20(d,J=9.2Hz),128.23(t,J=9.4Hz),119.15(d,J=1.5Hz),115.18(d,J=2.5Hz),114.60(t,J=16.8Hz),111.89(dd,J=18.0,5.9Hz,2C),107.51(d,J=26.8Hz),98.57,54.74(2C),50.30(2C),45.69,45.42,30.51(2C),15.15.LC-MS:[M+H] + =512.5。

[0463] Target product B68

[0464] (Synthesis of N-(2-chloro-6-methylphenyl)-4-(cyclopropylamino)-2-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0465]

[0466] The synthesis method is the same as that of target product B1. Yield: 61.8%, white powder. 1 H NMR(400MHz,DMSO-d 6)δ9.74(s,1H),9.43(s,1H),8.77(s,1H),8.74(s,1H),7.77(d,J=4.3Hz,2H),7.36(dd,J=7.4,1.7Hz,1H),7.28–7.19(m,2H),6.88(d,J=9.1Hz,2H),3.09–3.03(m,4H),2.91–2.82(m,1H),2.50–2.45(m,4H),2.36(q,J=7.2Hz,2H),2.19(s,3H),1.02(t,J=7.2Hz,3H),0.81(q,J=6.6Hz,2H),0.56–0.47(m,2H). 13 C NMR(101MHz,DMSO-d 6 )δ165.88,162.87,160.00,157.21,146.37,138.91,133.88,132.60,132.53,129.02,128.10,127.01,120.34(2C),115.75(2C),52.48(2C),51.72,48.93(2C),23.59,18.34,12.01,6.70(2C).LC-MS:[M+H] + =506.5。

[0467] Target product B69

[0468] (Synthesis of 4-(cyclopropylamino)-2-((4-(4-ethylpiperazin-1-yl)phenyl)amino)-N-(2-fluoro-6-methylphenyl)pyrimidine-5-carboxamide)

[0469]

[0470] The synthesis method is the same as that of target product B1. Yield: 57.8%, white powder. 1 H NMR(400MHz,DMSO-d 6)δ9.64(s,1H),9.43(s,1H),8.77(s,1H),8.74(s,1H),7.78(s,2H),7.21(dd,J=13.5,7.7Hz,1H),7.13–7.03(m,2H),6.88(d,J=8.9Hz,2H),3.07(s,4H),2.91–2.81(m,1H),2.53(s,4H),2.40(q,J=7.1Hz,2H),2.19(s,3H),1.02(t,J=7.1Hz,3H),0.86–0.75(m,2H),0.56–0.47(m,2H). 13 CNMR(101MHz,DMSO-d 6 )δ166.16,162.95,160.09,158.30(d,J=245.5Hz),157.42,146.40,138.48,132.69,127.89(d,J=8.4Hz),125.91(d,J=3.0Hz),124.20(d,J=13.4Hz),120.61,120.55(2C),115.96(2C),113.27(d,J=20.5Hz),52.38(2C),51.76,48.81(2C),23.70,17.74(d,J=2.3Hz),11.81,6.84(2C).LC-MS:[M+H] + =490.5。

[0471] Target product B70

[0472] (Synthesis of 4-(cyclopropylamino)-2-((4-(4-ethylpiperazin-1-yl)phenyl)amino)-N-(2-fluoro-6-methylphenyl)pyrimidine-5-carboxamide)

[0473]

[0474] The synthesis method is the same as that of target product B1. Yield: 58.3%, white powder. 1 H NMR(400MHz,DMSO-d 6)δ9.87(s,1H),9.54(s,1H),8.76(s,1H),8.73(s,1H),7.79(s,2H),7.42–7.32(m,1H),7.18(t,J=8.1Hz,2H),6.88(d,J=9.1Hz,2H),3.12–3.04(m,4H),2.92–2.84(m,1H),2.50(s,4H),2.38(q,J=7.2Hz,2H),1.03(t,J=7.2Hz,3H),0.87–0.78(m,2H),0.58–0.51(m,2H). 13 C NMR(101MHz,DMSO-d 6 )δ165.94,162.72,159.92,158.27(dd,J=248.3,5.2Hz,2C),157.65,146.32,132.38,128.09(t,J=8.9Hz),120.29(2C),115.67(2C),114.66(t,J=16.9Hz),111.82(dd,J=18.1,4.8Hz,2C),52.37(2C),51.64(2C),48.80,23.55,11.90,6.65(2C).LC-MS:[M+H] + =494.5。

[0475] Target product B71

[0476] (Synthesis of N-(2-chloro-6-methylphenyl)-4-(cyclobutylamino)-2-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide)

[0477]

[0478] The synthesis method is the same as that of target product B1. Yield: 56.4%, white powder. 1 H NMR(400MHz,DMSO-d 6)δ9.74(s,1H),9.40(s,1H),8.96(d,J=5.7Hz,1H),8.76(s,1H),7.64(d,J=8.6Hz,2H),7.42–7.34(m,1H),7.30–7.19(m,2H),6.90(d,J=9.0Hz,2H),4.43–4.56(m,1H),3.14–3.00(m,4H),2.45–2.50(m,4H),2.36(dd,J=14.2,7.0Hz,4H),2.22(s,3H),1.97–1.88(m,2H),1.69–1.79(m,2H),1.03(t,J=7.2Hz,3H). 13 C NMR(101MHz,DMSO-d 6 )δ165.87,160.47,160.01,157.37,146.42,138.84,133.87,132.55,132.24,128.94,128.01,126.93,120.45(2C),115.61(2C),100.42,52.44(2C),51.66,48.89(2C),45.12,30.62(2C),18.29,15.05,12.01.Exact mass calcd for C 28 H 35 ClN 7 O[M+H] + :520.2592;found 520.2557。

[0479] Target product B72

[0480] (Synthesis of 4-(cyclobutylamino)-2-((4-(4-ethylpiperazin-1-yl)phenyl)amino)-N-(2-fluoro-6-methylphenyl)pyrimidine-5-carboxamide)

[0481]

[0482] The synthesis method is the same as that of target product B1. Yield: 53.8%, white powder. 1 H NMR(400MHz,DMSO-d 6)δ9.63(s,1H),9.35(s,1H),8.93(d,J=6.2Hz,1H),8.73(s,1H),7.62(d,J=8.6Hz,2H),7.28–7.18(m,1H),7.14–7.06(m,2H),6.89(d,J=9.0Hz,2H),4.54–4.42(m,1H),3.14–3.02(m,4H),2.50–2.45(m,4H),2.36(dd,J=14.2,7.0Hz,4H),2.21(s,3H),1.97–1.88(m,2H),1.77–1.70(m,2H),1.02(t,J=7.2Hz,3H). 13 C NMR(101MHz,DMSO-d 6 )δ166.23,160.60,160.18,158.31(d,J=245.3Hz),157.63,146.64,138.48,132.37,127.87(d,J=9.0Hz),125.91(d,J=3.6Hz),124.22(d,J=13.2Hz),120.78(2C),115.85(2C),113.27(d,J=20.6Hz),98.63,52.52(2C),51.82,48.96(2C),45.39,30.79,17.72(d,J=2.4Hz),15.25,12.03(2C).LC-MS:[M+H] + =504.5。

[0483] Target product B73

[0484] Synthesis of 4-(cyclobutylamino)-N-(2,6-difluorophenyl)-2-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide

[0485]

[0486] The synthesis method is the same as that of target product B1. Yield: 62.9%, white powder. 1 H NMR(400MHz,DMSO-d 6)δ9.86(s,1H),9.45(s,1H),8.88(d,J=5.6Hz,1H),8.75(s,1H),7.63(d,J=8.3Hz,2H),7.45–7.32(m,1H),7.19(t,J=8.1Hz,2H),6.89(d,J=9.0Hz,2H),4.57–4.42(m,1H),3.14–3.01(m,4H),2.50(s,4H),2.37(q,J=7.2Hz,2H),2.37–2.29(m,2H),1.99–1.82(m,2H),1.79–1.67(m,2H),1.03(t,J=7.2Hz,3H). 13 C NMR(101MHz,DMSO-d 6 )δ166.04,160.38,160.04,158.29(dd,J=248.4,5.1Hz,2C),157.91,146.49,132.14,128.27–127.94(m),120.54(2C),115.63(2C),114.69(t,J=16.7Hz),111.84(dd,J=18.5,5.4Hz,2C),52.40(2C),51.66,48.83(2C),45.22,30.59(2C),15.08,11.95.LC-MS:[M+H] + =508.5。

[0487] Activity experiment

[0488] Experimental method: The experiments of SIK1, SIK2 and SIK3 kinase activities were provided by Eurofins. For the detailed experimental operations, please refer to the website https: / / www.eurofinsdiscoveryservices.com.

[0489] Each kinase was incubated with the corresponding compound in the specified reaction solution and other reagents (such as MOPS, EDTA, EAIYAAPFAKKK, magnesium acetate, etc.) (with different pH, concentrations and activities according to the specific requirements of different kinases). The reaction was initiated by adding the Mg(n) / ATP mixture. After incubating at room temperature for a specified period of time (as required), the reaction was terminated by adding phosphoric acid at a concentration of 0.5%. 10 μL of the terminated reaction solution was spotted onto a P30 filter pad and washed 4 times with 0.425% phosphoric acid for 4 minutes each time, then washed once with methanol, followed by drying and scintillation counting. The experimental results are shown in Table 1 and Table 2. In Table 1, “%Control” a"@1 μM" refers to the inhibition rate of a 1 μM compound. Taking compound B32 as an example, 111 (10 nM) and 101 (100 nM) respectively refer to the inhibition rates of compound B32 at concentrations of 10 nM and 100 nM.

[0490] Table 1 Inhibitory Activity of Compounds of the Present Invention against SIKs Kinases

[0491]

[0492]

[0493]

[0494]

[0495]

[0496] Table 2 IC of Some Compounds 50

[0497]

[0498] Pharmacokinetic Evaluation and Plasma Protein Binding Rate

[0499] Pharmacokinetic study. Experimental animals: male Sprague-Dawley rats (6 - 8 weeks old, body weight 270 - 325 g). There were 6 rats in each group, with a total of 8 groups. The test compounds were administered orally or intravenously at a concentration of 5 or 10 mg / kg. At consecutive time points: 0 min before dosing and 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h after dosing, approximately 0.2 mL of blood was collected. The collected blood was mixed with the anticoagulant tripotassium ethylenediaminetetraacetate (K3EDTA), centrifuged at 3500 rpm for 15 min, the supernatant plasma was collected, and stored at -40 °C for further analysis. Finally, the plasma samples were analyzed by LC / MS / MS (Waters Acquity UPLC system; Waters Quattro Premier XE), and the pharmacokinetic parameters were calculated using the non-compartmental method with WinNonlin software (ver 5.2, Pharsight, CA).

[0500] Plasma protein binding rate experiment. Cut a dialysis bag (10K) about 7 cm in length, boil it in deionized water for 20 minutes, wash it clean with deionized water and set aside; prepare human plasma with a compound concentration of 10 μM, take 1 mL and add it to the washed dialysis bag, and clamp both ends with clips; place the dialysis bag containing plasma into a dissolution apparatus, add 100 mL of PBS, and dialyze at 37 °C and 50 rpm for 8 h. After 8 h of dialysis, take 50 μL of plasma and 50 μL of PBS respectively, add 50 μL of blank PBS and plasma respectively, then add 200 μL of acetonitrile for treatment, centrifuge at 13000 rpm for 15 min, and take the supernatant for LC-MS / MS analysis. Plasma protein binding rate % = PBS free compound / (plasma bound compound + PBS free compound) * 100%. The results are shown in Table 3.

[0501] Table 3 Pharmacokinetic properties

[0502]

[0503]

[0504] Note: a Administered at 5 mg / kg (n = 6, mean ± SD), b Administered at 10 mg / kg (n = 6, mean ± SD).

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that, the structure of the compound is as shown in Formula I: R 1 selected from C1-C4 alkoxy groups; R 2 selected from -H; R 3 selected from halogen, C1-C4 alkyl groups, C1-C4 alkoxy groups; R 4 selected from R 5 selected from -H; R 6 Selected from q = 0; R 11 Selected from H; R 12 Selected from C1-C6 alkyl groups.

2. The compound according to claim 1, characterized in that, R 1 selected from methoxy; R 2 selected from -H; R 3 selected from Br, Cl, F, methyl, methoxy.

3. The compound according to claim 1, characterized in that, R 6 selected from 4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, the structural formula of the compound is as follows:

5. A compound or a pharmaceutically acceptable salt thereof, characterized in that, the structure of the compound is as shown in Formula I: R 1 selected from C1-C4 alkyl; R 2 selected from -H; R 3 selected from halogen, C1-C4 alkyl; R 4 selected from R 5 selected from p = 0; R 9 selected from H; R 10 selected from C1-C4 alkyl; R 6 Selected from -H.

6. The compound according to claim 5, characterized in that, R 1 selected from methyl; R 2 selected from -H; R 3 selected from Br, Cl, F, methyl.

7. The compound according to claim 5, characterized in that, R 5 selected from 8. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, characterized in that, the structural formula of the compound is as follows:

9. A pyrimidine derivative or a pharmaceutically acceptable salt thereof, characterized in that, the structural formula of the pyrimidine derivative is as follows:

10. A pharmaceutical composition, which is composed of the compound according to any one of claims 1 to 9 and a pharmaceutically acceptable salt thereof as active ingredients, and a pharmaceutically acceptable auxiliary ingredient is added.

11. Use of the compound according to any one of claims 1 to 9 and a pharmaceutically acceptable salt thereof in the preparation of SIKs inhibitors.

12. Use of the compound according to any one of claims 1 to 9 and a pharmaceutically acceptable salt thereof in the preparation of a drug for treating inflammation and / or tumor and / or diabetes.

13. Use of the pharmaceutical composition according to claim 10 in the preparation of SIKs inhibitors.

14. Use of the pharmaceutical composition according to claim 10 in the preparation of a drug for treating inflammation and / or tumor and / or diabetes.

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