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CN115703760A - 2,4-disubstituted pyrimidines cyclin dependent kinase inhibitor and preparation method and application thereof - Google Patents

️Fri Feb 17 2023

2,4-disubstituted pyrimidines cyclin dependent kinase inhibitor and preparation method and application thereof Download PDF

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Publication number

CN115703760A

CN115703760A CN202110927556.5A CN202110927556A CN115703760A CN 115703760 A CN115703760 A CN 115703760A CN 202110927556 A CN202110927556 A CN 202110927556A CN 115703760 A CN115703760 A CN 115703760A Authority

China

Prior art keywords

group

alkyl

ring atoms

aryl

nitro

Prior art date

2021-08-11

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Granted

Application number

CN202110927556.5A

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Chinese (zh)

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CN115703760B (en

Inventor

方浩

吕明君

侯旭奔

杨新颖

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Shandong University

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Shandong University

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2021-08-11

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2021-08-11

Publication date

2023-02-17

2021-08-11 Application filed by Shandong University filed Critical Shandong University

2021-08-11 Priority to CN202110927556.5A priority Critical patent/CN115703760B/en

2023-02-17 Publication of CN115703760A publication Critical patent/CN115703760A/en

2024-05-31 Application granted granted Critical

2024-05-31 Publication of CN115703760B publication Critical patent/CN115703760B/en

Status Active legal-status Critical Current

2041-08-11 Anticipated expiration legal-status Critical

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-1 2,4-disubstituted pyrimidines Chemical class 0.000 title claims abstract description 128
238000002360 preparation method Methods 0.000 title claims abstract description 52
229940043378 cyclin-dependent kinase inhibitor Drugs 0.000 title claims description 7
239000002875 cyclin dependent kinase inhibitor Substances 0.000 title claims description 6
229940126074 CDK kinase inhibitor Drugs 0.000 title claims 2
102100034770 Cyclin-dependent kinase inhibitor 3 Human genes 0.000 title claims 2
101000945639 Homo sapiens Cyclin-dependent kinase inhibitor 3 Proteins 0.000 title claims 2
150000001875 compounds Chemical class 0.000 claims abstract description 97
102000003903 Cyclin-dependent kinases Human genes 0.000 claims abstract description 21
108090000266 Cyclin-dependent kinases Proteins 0.000 claims abstract description 21
239000002532 enzyme inhibitor Substances 0.000 claims abstract description 13
229940125532 enzyme inhibitor Drugs 0.000 claims abstract description 12
125000001424 substituent group Chemical group 0.000 claims description 25
125000003118 aryl group Chemical group 0.000 claims description 24
125000006413 ring segment Chemical group 0.000 claims description 24
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 22
125000005842 heteroatom Chemical group 0.000 claims description 21
229910052757 nitrogen Inorganic materials 0.000 claims description 21
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
125000000217 alkyl group Chemical group 0.000 claims description 20
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 18
238000006243 chemical reaction Methods 0.000 claims description 16
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
125000004093 cyano group Chemical group *C#N 0.000 claims description 15
150000003839 salts Chemical class 0.000 claims description 15
125000001072 heteroaryl group Chemical group 0.000 claims description 14
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
229910052736 halogen Inorganic materials 0.000 claims description 11
150000002367 halogens Chemical class 0.000 claims description 11
125000000753 cycloalkyl group Chemical group 0.000 claims description 10
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
125000005843 halogen group Chemical group 0.000 claims description 9
229910052717 sulfur Inorganic materials 0.000 claims description 9
125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 7
125000002619 bicyclic group Chemical group 0.000 claims description 7
125000002950 monocyclic group Chemical group 0.000 claims description 7
125000002757 morpholinyl group Chemical group 0.000 claims description 7
239000008194 pharmaceutical composition Substances 0.000 claims description 7
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 6
XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 6
ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 6
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 claims description 6
SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 6
229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
229910052760 oxygen Inorganic materials 0.000 claims description 5
125000003386 piperidinyl group Chemical group 0.000 claims description 5
125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 4
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
125000003545 alkoxy group Chemical group 0.000 claims description 4
125000003277 amino group Chemical group 0.000 claims description 4
239000003937 drug carrier Substances 0.000 claims description 4
229910052739 hydrogen Inorganic materials 0.000 claims description 4
239000001257 hydrogen Substances 0.000 claims description 4
239000000546 pharmaceutical excipient Substances 0.000 claims description 4
125000005936 piperidyl group Chemical group 0.000 claims description 4
125000004076 pyridyl group Chemical group 0.000 claims description 4
125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
229910052731 fluorine Inorganic materials 0.000 claims description 3
125000001153 fluoro group Chemical group F* 0.000 claims description 3
125000002541 furyl group Chemical group 0.000 claims description 3
125000002883 imidazolyl group Chemical group 0.000 claims description 3
YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 3
238000007911 parenteral administration Methods 0.000 claims description 3
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
125000004193 piperazinyl group Chemical group 0.000 claims description 3
235000011056 potassium acetate Nutrition 0.000 claims description 3
LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
125000000168 pyrrolyl group Chemical group 0.000 claims description 3
125000000335 thiazolyl group Chemical group 0.000 claims description 3
125000001544 thienyl group Chemical group 0.000 claims description 3
BMQDAIUNAGXSKR-UHFFFAOYSA-N (3-hydroxy-2,3-dimethylbutan-2-yl)oxyboronic acid Chemical compound CC(C)(O)C(C)(C)OB(O)O BMQDAIUNAGXSKR-UHFFFAOYSA-N 0.000 claims description 2
125000004642 (C1-C12) alkoxy group Chemical group 0.000 claims description 2
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 2
239000004593 Epoxy Substances 0.000 claims description 2
CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 2
125000003368 amide group Chemical group 0.000 claims description 2
239000003153 chemical reaction reagent Substances 0.000 claims description 2
SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 2
125000001041 indolyl group Chemical group 0.000 claims description 2
UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
125000001624 naphthyl group Chemical group 0.000 claims description 2
125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims description 2
125000003226 pyrazolyl group Chemical group 0.000 claims description 2
SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 2
GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 claims description 2
SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims 2
239000003560 cancer drug Substances 0.000 claims 1
125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims 1
206010028980 Neoplasm Diseases 0.000 abstract description 8
239000003814 drug Substances 0.000 abstract description 7
201000011510 cancer Diseases 0.000 abstract description 5
229940079593 drug Drugs 0.000 abstract description 3
238000005481 NMR spectroscopy Methods 0.000 description 74
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 62
238000003786 synthesis reaction Methods 0.000 description 44
239000000543 intermediate Substances 0.000 description 35
230000015572 biosynthetic process Effects 0.000 description 34
238000000034 method Methods 0.000 description 21
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 20
210000004027 cell Anatomy 0.000 description 17
150000002576 ketones Chemical class 0.000 description 16
108091007914 CDKs Proteins 0.000 description 11
108010024986 Cyclin-Dependent Kinase 2 Proteins 0.000 description 11
102100036239 Cyclin-dependent kinase 2 Human genes 0.000 description 11
230000002401 inhibitory effect Effects 0.000 description 11
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
239000007787 solid Substances 0.000 description 10
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
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102000016736 Cyclin Human genes 0.000 description 4
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Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明公开了一种2,4‑二取代嘧啶类细胞周期蛋白依赖性激酶酶抑制剂及其制备方法和应用。所述的化合物具有如下通式(I)所示的结构。本发明还提供该类化合物的制备方法以及在制备预防或治疗癌症药物中的应用。

The invention discloses a 2,4-disubstituted pyrimidine type cell cyclin-dependent kinase enzyme inhibitor, a preparation method and application thereof. The compound has the structure shown in the following general formula (I). The invention also provides the preparation method of the compound and its application in the preparation of drugs for preventing or treating cancer.

Description

2,4-二取代嘧啶类细胞周期蛋白依赖性激酶酶抑制剂及其制备方法和应用2,4-disubstituted pyrimidine class cyclin-dependent kinase inhibitors and preparation thereof preparation methods and applications

技术领域technical field

本发明涉及一种2,4-二取代嘧啶类细胞周期蛋白依赖性激酶酶抑制剂及其制备方法、药物组合物与医药用途，属于医药技术领域。The invention relates to a 2,4-disubstituted pyrimidine cyclin-dependent kinase enzyme inhibitor, a preparation method, a pharmaceutical composition and a medical application, belonging to the technical field of medicine.

背景技术Background technique

细胞周期蛋白依赖性激酶，简称CDK，属于丝氨酸/苏氨酸激酶家族。目前为止，已有20个CDK亚型被发现。文献证实，CDK不仅在调控细胞周期中起重要作用，也在细胞转录过程中发挥重要作用。大多肿瘤细胞中都可观察到CDK的过表达，或内源性CDK抑制剂的缺失。Cyclin-dependent kinases, referred to as CDKs, belong to the serine/threonine kinase family. So far, 20 CDK subtypes have been discovered. Literature has confirmed that CDK not only plays an important role in regulating the cell cycle, but also plays an important role in the process of cell transcription. Overexpression of CDKs, or loss of endogenous CDK inhibitors, can be observed in most tumor cells.

CDK有三个重要的功能域：第一个功能域是ATP的结合部位和该酶的活性部分；第二功能域是调节亚基，Cyclin的结合部位，只有在Cyclin与CDK形成这种二聚体的时候，它才能够被激活；第三个功能域是负性调控因子也就是内源性CDK抑制剂的结合部位。CDK has three important functional domains: the first functional domain is the binding site of ATP and the active part of the enzyme; the second functional domain is the regulatory subunit, the binding site of Cyclin, only when Cyclin and CDK form this dimer It can be activated only when it is active; the third functional domain is the binding site of the negative regulator, which is the endogenous CDK inhibitor.

有丝分裂信号刺激时，Cyclin D开始表达，结合并激活CDK4/6。CDK4/6/Cyclin D复合物可磷酸化RB蛋白从而释放出E2F因子。CDK2/CyclinE复合物可进一步磷酸化RB蛋白至其完全磷酸化状态，进而促使细胞由G1期向S期转化。在S期时，CDK2还与cyclin A结合维持RB蛋白的磷酸化状态，确保DNA的复制。CDK1与Cyclin A和B分别参与S期向G2期以及G2期向M期的转变。When stimulated by mitotic signals, Cyclin D is expressed, binds and activates CDK4/6. CDK4/6/Cyclin D complex can phosphorylate RB protein to release E2F factor. The CDK2/CyclinE complex can further phosphorylate RB protein to its fully phosphorylated state, thereby promoting the transition of cells from G1 phase to S phase. In S phase, CDK2 also binds to cyclin A to maintain the phosphorylation state of RB protein and ensure DNA replication. CDK1 and Cyclin A and B are involved in the transition from S phase to G2 phase and from G2 phase to M phase, respectively.

不同亚型的CDK具有不同的功能，例如，CDK4/6通过与Cyclin D结合在G1-S期起作用，主要作用是磷酸化RB蛋白，释放E2F因子，促进FoxM1的累积。CDK2在G1-S期起作用，主要是确保DNA的复制。CDK1在G2-M期起作用。CDK5通过与非周期蛋白p35和p39结合，在G1-S期起作用，主要与神经元的存活有关。而CDK7/8/9/11主要参与细胞的转录过程。Different subtypes of CDKs have different functions. For example, CDK4/6 acts in the G1-S phase by combining with Cyclin D. The main function is to phosphorylate RB protein, release E2F factors, and promote the accumulation of FoxM1. CDK2 works in the G1-S phase, mainly to ensure the replication of DNA. CDK1 functions in the G2-M phase. CDK5 plays a role in the G1-S phase by combining with non-cycling proteins p35 and p39, and is mainly related to the survival of neurons. CDK7/8/9/11 is mainly involved in the transcription process of cells.

至今，美国FDA已经批准了三个细胞周期蛋白依赖性激酶酶抑制剂上市：Palbociclib(PD 0332991)、Ribociclib(LEE011)和Abemaciclib(LY2835219)。其中，Palbociclib与来曲唑联用，Ribociclib和芳香酶抑制剂联用均用于治疗雌激素受体(ER)阳性、人表皮生长因子受体2(HER2)阴性的绝经后妇女转移性乳腺癌。而Abemaciclib疗法有两种，一种是与氟维司群(fulvestrant)联用治疗接受内分泌治疗后出现恶化的HR阳性、HER2阴性的晚期转移性乳腺癌女性患者；另外一种是作为单一疗法治疗接受内分泌治疗后恶化以及化疗前的HR阳性、HER2阴性的晚期转移性乳腺癌成年患者。So far, the US FDA has approved three cyclin-dependent kinase inhibitors: Palbociclib (PD 0332991), Ribociclib (LEE011) and Abemaciclib (LY2835219). Among them, the combination of palbociclib and letrozole, and the combination of ribociclib and aromatase inhibitors are all used to treat metastatic breast cancer in postmenopausal women who are estrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) negative . There are two types of Abemaciclib therapy, one is combined with fulvestrant (fulvestrant) to treat women with HR-positive, HER2-negative advanced metastatic breast cancer who have deteriorated after receiving endocrine therapy; the other is used as monotherapy. Adult patients with HR-positive, HER2-negative advanced metastatic breast cancer who have progressed after endocrine therapy and before chemotherapy.

发明内容Contents of the invention

针对现有技术的不足，本发明提供了一种2,4-二取代嘧啶类细胞周期蛋白依赖性激酶酶抑制剂，本发明还提供该化合物的制备方法和应用。Aiming at the deficiencies of the prior art, the invention provides a 2,4-disubstituted pyrimidine type cell cycle protein-dependent kinase inhibitor, and the invention also provides a preparation method and application of the compound.

本发明的技术方案如下：Technical scheme of the present invention is as follows:

一、2,4-二取代嘧啶类细胞周期蛋白依赖性激酶酶抑制剂1. 2,4-disubstituted pyrimidines cyclin-dependent kinase inhibitors

一种2,4-二取代嘧啶类细胞周期蛋白依赖性激酶酶抑制剂，是具有通式I结构的化合物，以及其立体异构体、药学上可接受的盐；A 2,4-disubstituted pyrimidine-type cyclin-dependent kinase enzyme inhibitor, which is a compound with the structure of general formula I, as well as its stereoisomers and pharmaceutically acceptable salts;

通式I中，R₂代表氢或被1-3个取代基取代或者未被取代的的C₁-C₁₂烷基、C₁-C₁₂烷氧基、C₃-C₁₄环烷基、C₆-C₁₅芳基、C₆-C₁₅芳基C₁-C₆烷基、C₃-C₁₄杂芳基、C₃-C₁₄杂芳基C₁-C₆烷基，所述的取代基选自羟基、卤素、烷基、三氟甲基、氰基、硝基、胍基、氨基、磺酰氨基、哌嗪基、哌啶基、吗啉基、羧基、硝基、叔丁氧羰基、含有5或6个环原子的单环芳基或具有8-15个环原子的双环芳基、含有1-2个杂原子的环原子数为5-6的单杂环基，所述杂原子独立地选自O、S、N或氧化的S或N；In general formula I, R ₂ represents hydrogen or substituted or unsubstituted C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkoxy, C ₃ -C ₁₄ cycloalkyl, C ₆ -C ₁₅ aryl, C ₆ -C ₁₅ aryl C ₁ -C ₆ alkyl, C ₃ -C ₁₄ heteroaryl, C ₃ -C ₁₄ heteroaryl C ₁ -C ₆ alkyl, the The substituents are selected from hydroxyl, halogen, alkyl, trifluoromethyl, cyano, nitro, guanidino, amino, sulfonylamino, piperazinyl, piperidinyl, morpholinyl, carboxyl, nitro, tertiary Butoxycarbonyl, a monocyclic aryl group with 5 or 6 ring atoms or a bicyclic aryl group with 8-15 ring atoms, a monoheterocyclic group with 5-6 ring atoms containing 1-2 heteroatoms, The heteroatoms are independently selected from O, S, N or oxidized S or N;

通式I中，R₃代表卤素、羟基、烷基、三氟甲基、氰基、硝基、胍基、氨基、羧基、环氧基、C₁-C₁₂烷基、C_3-C₆环烷基；In general formula I, R ₃ represents halogen, hydroxyl, alkyl, trifluoromethyl, cyano, nitro, guanidino, amino, carboxyl, epoxy, C ₁ -C ₁₂ alkyl, C _{3 -C} ₆ Cycloalkyl;

通式I中，X代表CH或者氮。In the general formula I, X represents CH or nitrogen.

根据本发明优选的，通式I中：Preferably according to the present invention, in general formula I:

R₁为氢原子、被1-3个取代基取代或者未被取代的C_1-C₁₂烷基、C_3-C₁₄环烷基、C_6-C₁₀芳基、C₃-C₉杂芳基，所述的取代基选自氰基、卤素、硝基、羧基、甲基、三氟甲基、胍基或、氨基、磺酰氨基、哌嗪基、吗啉基、哌啶基；R ₁ is a hydrogen atom, substituted by 1-3 substituents or unsubstituted C _1- C ₁₂ alkyl, C _3- C ₁₄ cycloalkyl, C _6- C ₁₀ aryl, C ₃ -C ₉ hetero Aryl, the substituent is selected from cyano, halogen, nitro, carboxyl, methyl, trifluoromethyl, guanidine or, amino, sulfonylamino, piperazinyl, morpholinyl, piperidinyl;

R₂代表氢原子、被1-3个取代基取代或者未被取代的C₃-C₈环烷基、含有6-7个环原子的单环芳基或具有8-15个环原子的双环芳基、含有1-2个杂原子的环原子数为5-6的单杂环芳基或含有1-4个杂原子环原子数为8-15的双杂环芳基，所述杂原子独立地选自O、S、N或氧化的S或N，所述的取代基选自羟基、氰基、硝基、卤素、C₁-C₆烷基、C₁-C₆卤烷基、C₁-C₆烷氧基、含有5或6个环原子的单环芳基、含有1-2个杂原子的环原子数为5-6的单杂环芳基；R ₂ represents a hydrogen atom, a C ₃ -C ₈ cycloalkyl group substituted by 1-3 substituents or unsubstituted, a monocyclic aryl group containing 6-7 ring atoms or a bicyclic group having 8-15 ring atoms Aryl, a monoheterocyclic aryl group with 5-6 ring atoms containing 1-2 heteroatoms or a biheterocyclic aryl group with 8-15 ring atoms containing 1-4 heteroatoms, the heteroatoms independently selected from O, S, N or oxidized S or N, and the substituents are selected from hydroxyl, cyano, nitro, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, monocyclic aryl group containing 5 or 6 ring atoms, monoheterocyclic aryl group containing 1-2 heteroatoms with 5-6 ring atoms;

R₃代表氢原子、卤素原子、羟基、烷基、三氟甲基、氰基、硝基、胍基、氨基、羧基、C₁-C₆烷基；R ₃ represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group, a trifluoromethyl group, a cyano group, a nitro group, a guanidine group, an amino group, a carboxyl group, and a C ₁ -C ₆ alkyl group;

X代表CH或者氮。X represents CH or nitrogen.

根据本发明进一步优选的，通式I中：Further preferred according to the present invention, in general formula I:

R₁代表氢原子，被1-3个取代基取代或者未被取代的C₁-C₆烷基，C₃-C₈环烷基，苯基，萘基，吲哚基，呋喃基，吡喃基，吡啶基，哌啶基，喹啉基，嘌呤基，嘧啶基，吡咯基，吡唑基，噻唑基，咪唑基或者噻吩基；所述的取代基选自卤素原子，羟基，氨基，C₁-C₆烷基，氰基，硝基或者C₃-C₆环烷基；R ₁ represents a hydrogen atom, substituted by 1-3 substituents or unsubstituted C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, phenyl, naphthyl, indolyl, furyl, pyryl pyryl, pyridyl, piperidyl, quinolinyl, purinyl, pyrimidyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl or thienyl; the substituent is selected from halogen atoms, hydroxyl, amino, C ₁ -C ₆ alkyl, cyano, nitro or C ₃ -C ₆ cycloalkyl;

R₂代表氢原子，被1-3个取代基取代或者未被取代的氨基、酰胺基、二甲氨基、磺酰基或者含有1-2个杂原子的六元杂环基，其中所述取代基选自卤素原子，羟基，氨基，C₁-C₆烷基，氰基，硝基，或者叔丁氧羰基，所述的杂原子为N或者O；R ₂ represents a hydrogen atom, substituted or unsubstituted amino, amido, dimethylamino, sulfonyl, or six-membered heterocyclic group containing 1-2 heteroatoms, wherein the substituent Selected from halogen atoms, hydroxyl, amino, C ₁ -C ₆ alkyl, cyano, nitro, or tert-butoxycarbonyl, and the heteroatom is N or O;

R₃代表氢原子、卤素原子，羟基，三氟甲基，氰基，氨基，羧基或者硝基；R ₃ represents a hydrogen atom, a halogen atom, a hydroxyl group, a trifluoromethyl group, a cyano group, an amino group, a carboxyl group or a nitro group;

X代表CH或者氮。X represents CH or nitrogen.

根据本发明，更进一步优选的，通式I中：According to the present invention, more preferably, in general formula I:

R₁代表C₁-C₆烷基，C₃-C₆环烷基；R ₁ represents C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl;

R₂代表被1-3个取代基取代或者未被取代的吡啶基、哌啶基、哌嗪基、吗啉基、二甲氨基、甲磺酰基,所述取代基选自甲基，乙基，或者叔丁氧羰基；R ₂ represents substituted or unsubstituted pyridyl, piperidyl, piperazinyl, morpholinyl, dimethylamino, methylsulfonyl, said substituents are selected from methyl, ethyl , or tert-butoxycarbonyl;

R₃代表氟原子或者氢原子；R ₃ represents a fluorine atom or a hydrogen atom;

X代表CH或者氮原子。X represents CH or nitrogen atom.

上述通式I化合物，最优选为如下之一：The above-mentioned compound of general formula I is most preferably one of the following:

以上优选化合物，后面的括号内的编号是对应于下面反应路线及表1中的化合物结构的编号。For the above preferred compounds, the numbers in the brackets behind are the numbers corresponding to the compound structures in the following reaction schemes and Table 1.

发明详述Detailed description of the invention

本文中所用的术语和定义含义如下：The terms and definitions used in this document have the following meanings:

本发明所述的“卤素原子”包括氟原子、氯原子、溴原子、碘原子；The "halogen atom" mentioned in the present invention includes fluorine atom, chlorine atom, bromine atom and iodine atom;

本发明所述“C_1-10烷基”指含有1～10个碳原子的烷烃部分去除一个氢原子衍生的直链或支链的烷基，如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基、新戊基、1-乙基丙基、正己基、异己基、2-甲基戊基、3-甲基戊基、4-甲基戊基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,2-二甲基丁基、2,3-二甲基丁基、3,3-二甲基丁基、1-乙基丁基、2-乙基丁基、1,1,2-三甲基丙基、1,2,2-三甲基丙基、1-乙基-1-甲基丙基，1-乙基-2-甲基丙基，庚基，辛基，壬基和癸基。优选C_1-6烷基，更优选C_1-4烷基，术语“C_1-6烷基”、“C1-4烷基”指上述实例中的含有1～6个、1～4个碳原子的具体实例；The "C _1-10 alkyl" in the present invention refers to a linear or branched alkyl group derived from an alkane containing 1 to 10 carbon atoms by removing one hydrogen atom, such as methyl, ethyl, n-propyl, iso Propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl , 1,2-dimethylpropyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 ,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3 ,3-Dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl 1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl, octyl, nonyl and decyl. Preferably C _1-6 alkyl, more preferably C _1-4 alkyl, the terms "C _1-6 alkyl" and "C1-4 alkyl" refer to those containing 1 to 6, 1 to 4 carbons in the above examples A concrete instance of an atom;

本发明所述的“C_3-8环烷基”是指3～8个碳原子的烷烃部分去除一个氢原子衍生的环状烷基，如环丙基、环丁基、1-甲基环丁基、环戊基、环己基、环庚基、环辛基等。优选C_4-7环烷基、C_4-6环烷基和C_5-6环烷基；The "C _3-8 cycloalkyl group" in the present invention refers to a cyclic alkyl group derived from an alkane with 3 to 8 carbon atoms by removing one hydrogen atom, such as cyclopropyl, cyclobutyl, 1-methylcycloalkyl, etc. Butyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. Preferred are C _4-7 cycloalkyl, C _4-6 cycloalkyl and C _5-6 cycloalkyl;

所述“单杂环基”的实例有：环氧乙烷基、二氧杂环丙烷基、硫杂环丙烷基、氮杂环丙烷基、2H-氮杂环丙烷基、二氮杂环丙烷基、3H-二氮杂环丙烯基、氧氮杂环丙烷基、氧杂环丁烷基、1,2-二氧杂环丁烷基、硫杂环丁烷基、1,2-二硫杂环丁烯基、氮杂环丁烷基、1,2-二氮杂环丁烷基、氮杂环丁二烯基、1,2-二氮杂环丁烯基、呋喃基、四氢呋喃基、噻吩基、2,5-二氢噻吩基、四氢噻吩基、吡咯基、二氢吡咯基、吡咯烷基、1,3-二氧杂环戊烷基、1,3-二氧杂环戊烯-2-酮基、1,2-二硫杂环戊烯基、1,3-二硫杂环戊烷基、咪唑基、4,5-二氢咪唑基、咪唑烷基、吡唑基、4,5-二氢吡唑基、吡唑烷基、噁唑基、4,5-二氢噁唑基、异噁唑基、4,5-二氢异噁唑基、2,3-二氢异噁唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、噻唑基、4,5-二氢噻唑基、异噻唑基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,3,4-噻二唑基、1,2,3-三唑基、1,2,4-三唑基、四唑基、2H-吡喃基、2H-吡喃-2-酮基、3,4-二氢-2H-吡喃基、4H-吡喃基、四氢吡喃基、4H-吡喃-4-酮基、吡啶基、2-吡啶酮基、4-吡啶酮基、哌啶基、1,4-二氧杂环己二烯基、1,4-二硫杂环己二烯基、1,4-氧硫杂环己二烯基、1,4-二氧杂环己烷基、1,3-二氧杂环己烷基、1,3-氧硫杂环己烷基、2H-1,2-噁嗪基、4H-1,2-噁嗪基、6H-1,2-噁嗪基、2H-1,3-噁嗪基、4H-1,3-噁嗪基、6H-1,3-噁嗪基、2H-1,4-噁嗪基、4H-1,4-噁嗪基、5,6-二氢-4H-1,3-噁嗪基、吗啉基、2H-1,3-噻嗪基、4H-1,3-噻嗪基、5,6-二氢-4H-1,3-噻嗪基、6H-1,3-噻嗪基、2H-1,4-噻嗪基、4H-1,4-噻嗪基、哒嗪基、嘧啶基、吡嗪基、哌嗪基、1,2,3-三嗪基、1,2,4-三嗪基、1,3,5-三嗪基、1,2,4,5-四嗪基、氧杂环庚三烯基、硫杂环庚三烯基、1,4-二氧杂环辛三烯基、氮杂环庚三烯基、1,2-二氮杂环庚三烯基、1,3-二氮杂环庚三烯基、1,4-二氮杂环庚三烯基、氮杂环辛四烯基、1,4-二氢-1,4-二氮杂环辛三烯基等；Examples of the "monoheterocyclic group" include: oxiranyl, dioxirane, thiiridine, aziridine, 2H-aziridine, diaziridine Base, 3H-diaziridyl, oxaziridine, oxetanyl, 1,2-dioxetanyl, thietanyl, 1,2-dithio Heterobutenyl, azetidinyl, 1,2-diazetidinyl, azetidinyl, 1,2-diazetidinyl, furyl, tetrahydrofuryl , thienyl, 2,5-dihydrothienyl, tetrahydrothienyl, pyrrolyl, dihydropyrrolyl, pyrrolidinyl, 1,3-dioxolyl, 1,3-dioxane Penten-2-onyl, 1,2-dithiolanyl, 1,3-dithiolanyl, imidazolyl, 4,5-dihydroimidazolyl, imidazolidinyl, pyrazole Base, 4,5-dihydropyrazolyl, pyrazolidinyl, oxazolyl, 4,5-dihydrooxazolyl, isoxazolyl, 4,5-dihydroisoxazolyl, 2,3 -Dihydroisoxazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, thiazolyl, 4,5-dihydrothiazolyl, isothiazolyl, 1,2, 3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetra Azolyl, 2H-pyranyl, 2H-pyran-2-onyl, 3,4-dihydro-2H-pyranyl, 4H-pyranyl, tetrahydropyranyl, 4H-pyran-4 - Keto, pyridyl, 2-pyridinyl, 4-pyridinyl, piperidinyl, 1,4-dioxinyl, 1,4-dithianyl, 1 ,4-oxathione, 1,4-dioxanyl, 1,3-dioxanyl, 1,3-oxathione, 2H- 1,2-oxazinyl, 4H-1,2-oxazinyl, 6H-1,2-oxazinyl, 2H-1,3-oxazinyl, 4H-1,3-oxazinyl, 6H- 1,3-oxazinyl, 2H-1,4-oxazinyl, 4H-1,4-oxazinyl, 5,6-dihydro-4H-1,3-oxazinyl, morpholinyl, 2H -1,3-thiazinyl, 4H-1,3-thiazinyl, 5,6-dihydro-4H-1,3-thiazinyl, 6H-1,3-thiazinyl, 2H-1, 4-thiazinyl, 4H-1,4-thiazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl , 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, oxepinyl, thiepinyl, 1,4-dioxahinyl Base, azepine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, nitrogen Heterocyclooctatraenyl, 1,4-dihydro-1,4-diazacyclooctatrienyl, etc.;

“芳基”是指含有芳香环的取代基，如苯基或苄基，其可选地与环烷基稠合，所述环烷基优选地具有4-7个环原子，更优选具有5-6个环原子。优选的芳基含有5-15个碳原子；"Aryl" means a substituent containing an aromatic ring, such as phenyl or benzyl, optionally fused to a cycloalkyl group, preferably having 4-7 ring atoms, more preferably 5 - 6 ring atoms. Preferred aryl groups contain 5-15 carbon atoms;

“杂芳基”是芳香杂环，可以是单环或双环基团。他们含有芳杂基含有一个或多个杂原子，优选为1-3个杂原子、甚至更优选1-2个杂原子，所述杂原子独立地选自O、S和N。“芳基烷基”是指C₁-C₄亚烷基连接的芳基；"Heteroaryl" is an aromatic heterocycle, which may be a monocyclic or bicyclic group. They contain heteroaryl containing one or more heteroatoms, preferably 1-3 heteroatoms, even more preferably 1-2 heteroatoms, independently selected from O, S and N. "Arylalkyl" means a C ₁ -C ₄ alkylene-linked aryl group;

“芳基烷基”是指C₁-C₄亚烷基连接的芳基；"Arylalkyl" means a C ₁ -C ₄ alkylene-linked aryl group;

“芳基烷基”是指C₁-C₄亚烷基连接的杂芳基；"Arylalkyl" means a C ₁ -C ₄ alkylene linked heteroaryl;

“烯基”，单独或联合地，文中所指为直链烃或支链烃，其含有2-6个，优选为2-4个碳原子；并且含有1-2个碳碳双键，优选为1个碳碳双键；"Alkenyl", alone or in combination, refers to a straight chain hydrocarbon or a branched chain hydrocarbon, which contains 2-6, preferably 2-4 carbon atoms; and contains 1-2 carbon-carbon double bonds, preferably is a carbon-carbon double bond;

“烷氧基”，表示基团―O―烷基；"Alkoxy" means the group -O-alkyl;

本发明所述“0-4的整数”是指0、1、2、3、4；The "integer of 0-4" in the present invention refers to 0, 1, 2, 3, 4;

本发明的通式I所示化合物可以通过公知的方法制成药学上可接受的盐，该盐是指式I所示化合物与酸或碱混合制成的盐；The compound shown in the general formula I of the present invention can be made into a pharmaceutically acceptable salt by known methods, and the salt refers to a salt prepared by mixing the compound shown in the formula I with an acid or a base;

适宜的酸加成盐是由形成无毒盐的酸形成。具有代表性的酸加成盐包括但不限于乙酸盐、己二酸盐、藻酸盐、柠檬酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、碳酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、碳酸盐、柠檬酸盐、二葡糖酸盐(digluconate)、甘油磷酸盐、半硫酸盐(hemisulfate)、庚酸盐、己酸盐、甲酸盐、富马酸盐、葡萄糖酸盐、葡萄糖醛酸盐、谷氨酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐(isethionate)、乳酸盐、马来酸盐、苹果酸盐、丙二酸盐、甲磺酸盐、烟酸盐、2-萘磺酸盐、烟酸盐(nicotinate)、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、扑酸盐、果胶酸盐(pectinate)、过硫酸盐、3-苯基丙酸盐、苦味酸盐(picrate)、三甲基乙酸盐(pivalate)、丙酸盐、蔗糖盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、磷酸盐、磷酸氢盐、磷酸二氢盐、对甲苯磺酸盐、三氟乙酸盐及十一酸盐；Suitable acid addition salts are formed from acids which form non-toxic salts. Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, carbonate Hydrogen salt, butyrate, camphorate, camphorsulfonate, carbonate, citrate, digluconate, glycerophosphate, hemisulfate, heptanoate, caproic acid Salt, formate, fumarate, gluconate, glucuronate, glutamate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), Lactate, maleate, malate, malonate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate salt, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionic acid salt, sucrose salt, stearate, succinate, sulfate, tartrate, thiocyanate, phosphate, hydrogen phosphate, dihydrogen phosphate, p-toluene sulfonate, trifluoroacetate and monoacid;

碱加成盐可在化合物的最后分离和纯化过程中，通过使含有羧酸的部分与适当的碱(如但不限于药用可接受的金属阳离子的氢氧化物、碳酸盐或碳酸氢盐)或者与氨或有机伯胺、仲胺或叔胺反应原位制备。药用可接受的盐包括但不限于基于碱金属或碱土金属的阳离子，如但不限于锂、钠、钾、钙、镁和铝盐等，以及非毒性季氨和胺阳离子，包括铵、四甲基铵、四乙基铵、甲胺、二甲胺、三甲胺、三乙胺、二乙胺、乙胺等。其它可用于形成碱加成盐的代表性有机胺包括乙二胺、乙醇胺、二乙醇胺、哌啶、哌嗪等；Base addition salts can be prepared during the final isolation and purification of the compound by reacting the carboxylic acid-containing moiety with a suitable base such as, but not limited to, the hydroxide, carbonate or bicarbonate salt of a pharmaceutically acceptable metal cation. ) or prepared in situ by reacting with ammonia or organic primary, secondary or tertiary amines. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals, such as, but not limited to, lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like, as well as non-toxic quaternary ammonium and amine cations, including ammonium, tetra Methylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, etc. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like;

本文中的“立体异构体”是指本发明化合物或其生理上的衍生物所有可能的立体异构体的形式。除非特别指出，本发明中涉及的化合物的化学命名包括所有可能的立体化学形式的混合物，所属混合物包含基本结构分子的所有对映体和非对映体，以及基本纯净的化合物单个异构体形式，即其中含有低于10％，优选低于5％，特别是低于2％，最优选低于1％的其它异构体。本发明类肽化合物各种立体异构体形式均明显包含于本发明的范围内；"Stereoisomer" herein refers to all possible stereoisomer forms of the compound of the present invention or its physiological derivatives. Unless otherwise indicated, the chemical designations of the compounds referred to in the present invention include mixtures of all possible stereochemical forms including all enantiomers and diastereomers of the basic structural molecule, as well as the substantially pure individual isomeric forms of the compounds , that is, it contains less than 10%, preferably less than 5%, especially less than 2%, most preferably less than 1% of other isomers. The various stereoisomeric forms of the peptoid compounds of the present invention are clearly included within the scope of the present invention;

通式I化合物还能以其它被保护的形式或衍生物的形式存在，这些形式对本领域技术人员而言是显而易见的，均应该包含于本发明的范围内；The compound of general formula I can also exist in other protected forms or derivative forms, which are obvious to those skilled in the art and should be included within the scope of the present invention;

如上所述的取代基自身还可被一个或多个取代基取代。这样的取代基包括在C.Hansch和A.Leo,Substituent Constants for Correlation Analysis in Chemistryand Biology(1979)中列出的那些取代基；优选的取代基包括烷基、烯基、烷氧基、羟基、硝基、氨基、氨基烷基、氰基、卤素、羧基、硫基、芳基、环烷基、杂芳基、杂环烷基、亚氨基、羟烷基、芳基氧基、芳基烷基及其结合；The substituents mentioned above may themselves be substituted by one or more substituents. Such substituents include those listed in C. Hansch and A. Leo, Substituent Constants for Correlation Analysis in Chemistry and Biology (1979); preferred substituents include alkyl, alkenyl, alkoxy, hydroxy, Nitro, amino, aminoalkyl, cyano, halogen, carboxy, thio, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, imino, hydroxyalkyl, aryloxy, arylalkane bases and their combinations;

本发明化合物可以用本领域已知的方法制成任何药物制剂，以口服、肠胃外、直肠或经肺给药等方式施用于需要这种治疗的患者，用于口服给药时，可制成常规的固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等，也可制成口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。制成口服制剂时，可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。用于肠胃外给药时，可制成注射剂，包括注射液、注射用无菌粉末与注射用浓溶液。制成注射剂时，可采用现有制药领域中的常规方法生产，配制注射剂时，可以不加入附加剂，也可根据药物的性质加入适宜的附加剂。用于直肠给药时，可制成栓剂等。用于经肺给药时，可制成吸入剂或喷雾剂等；The compound of the present invention can be made into any pharmaceutical preparation by methods known in the art, and administered to patients in need of such treatment by oral, parenteral, rectal or pulmonary administration, etc. When used for oral administration, it can be prepared Conventional solid preparations, such as tablets, capsules, pills, granules, etc., can also be made into oral liquid preparations, such as oral solutions, oral suspensions, syrups, etc. When making oral preparations, suitable fillers, binders, disintegrants, lubricants and the like can be added. For parenteral administration, it can be made into injections, including injection liquid, sterile powder for injection and concentrated solution for injection. When making injections, it can be produced by conventional methods in the existing pharmaceutical field. When preparing injections, no additives can be added, and suitable additives can also be added according to the properties of the medicine. For rectal administration, it can be made into suppositories and the like. When used for administration through the lungs, it can be made into inhalants or sprays, etc.;

本发明化合物的施用量和施用频率可以根据临床医生或药师的判断考虑例如以下的一些因素而作出调整：患者的年龄、健康状况和大小，以及待治疗病征的严重性。一般而言，本发明化合物的总日服剂量范围为每天约0.1至约2000mg，尽管必要时会有变化，这取决于治疗目的、患者和施用途径。在一个实施方案中，剂量为约1至约200mg/天，以单一剂量或以2-4个分离剂量给药。在另一个实施方案中，剂量为约10至约2000mg/天，以单一剂量或以2-4个分离剂量给药。在另一个实施方案中，剂量为约100至约2000mg/天，以单一剂量或以2-4个分离剂量给药。在又另一个实施方案中，剂量为约500至约2000mg/天，以单一剂量或以2-4个分离剂量给药。本发明的化合物、其药学上可接受的盐、酯或溶剂化物或它们的前药或异构体与其它治疗活性物质联合使用时，它们同时、分开或依次给药，可制成单一给药方式的药物组合物。联合使用的其它治疗活性物质的用药量可基于临床上所用的量，并可根据给药对象、给药途径、疾病、组合等适当选择。对其它治疗活性物质的给药形式没有特殊限制，只要在给药时将本发明的化合物和其它治疗活性物质组合即可。The amount and frequency of administration of the compounds of the present invention may be adjusted according to the judgment of the clinician or pharmacist taking into account factors such as the age, health and size of the patient, and the severity of the condition being treated. In general, the total daily dosage of the compounds of this invention will range from about 0.1 to about 2000 mg per day, although variations may be necessary, depending on the purpose of treatment, patient and route of administration. In one embodiment, the dosage is from about 1 to about 200 mg/day, administered in a single dose or in 2-4 divided doses. In another embodiment, the dosage is from about 10 to about 2000 mg/day, administered in a single dose or in 2-4 divided doses. In another embodiment, the dosage is from about 100 to about 2000 mg/day, administered in a single dose or in 2-4 divided doses. In yet another embodiment, the dosage is from about 500 to about 2000 mg/day, administered in a single dose or in 2-4 divided doses. When the compounds of the present invention, their pharmaceutically acceptable salts, esters or solvates, or their prodrugs or isomers are used in combination with other therapeutically active substances, they are administered simultaneously, separately or sequentially, and can be made into a single administration way of pharmaceutical compositions. The dosage of other therapeutically active substances to be used in combination can be based on the amount used clinically, and can be appropriately selected according to the subject of administration, administration route, disease, combination and the like. There are no particular restrictions on the form of administration of the other therapeutically active substance, as long as the compound of the present invention is combined with the other therapeutically active substance at the time of administration.

“药物组合物(pharmaceutical composition)”是指含有治疗上显著量的活性药剂的制备物，其以适于给予患者的形式被制备。因此，所述制备物不含有这样量的任何一种组分或多种组分，即，适当谨慎的医疗实施者发现所述制备物不适于给予普通对象。在许多情况下，这种药物组合物是无菌制备物。"Pharmaceutical composition" refers to a preparation containing a therapeutically significant amount of an active agent prepared in a form suitable for administration to a patient. Accordingly, the preparations do not contain any component or components in such amounts that a reasonably prudent practitioner of medicine would find the preparations unsuitable for administration to ordinary subjects. In many instances, such pharmaceutical compositions are prepared sterile.

本发明中所涉及的“室温”具体的温度范围是25-30℃。The specific temperature range of "room temperature" involved in the present invention is 25-30°C.

二、2,4-二取代嘧啶类细胞周期蛋白依赖性激酶酶抑制剂的制备方法Two, the preparation method of 2,4-disubstituted pyrimidine class cyclin-dependent kinase enzyme inhibitor

一种2,4-二取代嘧啶类细胞周期蛋白依赖性激酶酶抑制剂的制备方法，步骤如下：A preparation method of a 2,4-disubstituted pyrimidine class cyclin-dependent kinase enzyme inhibitor, the steps are as follows:

化合物A33-A70的合成路线如下：The synthetic route of compound A33-A70 is as follows:

试剂和条件：a)叔丁醇钾,乙二醇二甲醚,室温反应30分钟；碳酸钾，70℃反应8小时；b)联硼酸频那醇酯，醋酸钾，[1,1'-双(二苯基膦基)二茂铁]二氯化钯,二甲基亚砜,80℃反应8h；c)碳酸钾，[1,1'-双(二苯基膦基)二茂铁]二氯化钯，二氧六环，水，80℃反应8小时；d)三乙胺，二甲基亚砜，110℃反应6小时；e)钯碳，甲醇，室温反应10小时；f)双(三甲基硅基)氨基锂，甲苯，室温搅拌10分钟，室温反应1小时。Reagents and conditions: a) potassium tert-butoxide, ethylene glycol dimethyl ether, react at room temperature for 30 minutes; potassium carbonate, react at 70°C for 8 hours; b) pinacol borate, potassium acetate, [1,1'- Bis(diphenylphosphino)ferrocene]palladium dichloride, dimethyl sulfoxide, 80℃ for 8h; c) Potassium carbonate, [1,1'-bis(diphenylphosphino)ferrocene ] palladium dichloride, dioxane, water, 80 ℃ reaction 8 hours; d) triethylamine, dimethyl sulfoxide, 110 ℃ reaction 6 hours; e) palladium carbon, methanol, room temperature reaction 10 hours; f ) Lithium bis(trimethylsilyl)amide, toluene, stirred at room temperature for 10 minutes, and reacted at room temperature for 1 hour.

合成路线中目标化合物A33-A70的结构式如下表1所示：The structural formulas of the target compounds A33-A70 in the synthetic route are shown in Table 1 below:

表1目标化合物的结构式The structural formula of table 1 target compound

所述化合物的具体操作步骤将在实施例中详细说明。The specific operation steps of the compound will be described in detail in the examples.

本领域的技术人员可以对上述步骤进行变动以增加收率，他们可以根据本领域的基本知识设计合成路线，如选择反应物、反应溶剂、反应温度，也可以通过使用各种保护基以避免副反应的发生从而提高收率，这些常规的保护方法可以参见例如T.GreenProtecting Groups in Organic Synthesis。Those skilled in the art can change the above-mentioned steps to increase the yield, and they can design synthetic routes according to the basic knowledge in this field, such as selecting reactants, reaction solvents, and reaction temperature, and can also avoid side effects by using various protecting groups. The reaction occurs to increase the yield. For these conventional protection methods, see, for example, T.GreenProtecting Groups in Organic Synthesis.

三、2,4-二取代嘧啶类细胞周期蛋白依赖性激酶酶抑制剂的应用3. Application of 2,4-disubstituted pyrimidine cyclin-dependent kinase inhibitors

本发明的化合物是细胞周期蛋白依赖性激酶(CDKs)抑制剂，因此可以用于治疗疾病，其中潜在的病理学(至少部分地)由CDK2等亚型介导。治疗的疾病包括存在细胞增殖、细胞凋亡或分化障碍的其它疾病，例如癌症、与动脉粥样硬化有关的血管平滑肌增生、手术后血管狭窄、再狭窄和子宫内膜异位；感染，包括病毒感染，例如DNA病毒，RNA病毒和真菌感染；自身免疫疾病，例如牛皮癣、炎症，如类风湿性关节炎、狼疮、Ⅰ型糖尿病、糖尿病性肾病、多发性硬化和肾小球性肾炎；器官移植排斥，包括宿主对移植物的疾病。The compounds of the invention are inhibitors of cyclin-dependent kinases (CDKs) and are therefore useful in the treatment of diseases in which the underlying pathology is (at least in part) mediated by subtypes such as CDK2. Diseases treated include other diseases in which there are disorders of cell proliferation, apoptosis or differentiation such as cancer, vascular smooth muscle hyperplasia associated with atherosclerosis, postoperative vascular stenosis, restenosis and endometriosis; infections, including viral Infections, such as DNA viruses, RNA viruses, and fungal infections; autoimmune diseases, such as psoriasis, inflammation, such as rheumatoid arthritis, lupus, type 1 diabetes, diabetic nephropathy, multiple sclerosis, and glomerulonephritis; organ transplantation Rejection, including host-to-graft disease.

本发明进一步提供可用于制备治疗异常细胞增殖、例如癌症的药物的式Ⅰ化合物。本发明进一步治疗异常细胞增殖、例如选自下组的癌症的方法：乳腺、卵巢、子宫颈、前列腺、睾丸、食道、胃、皮肤、肺、骨、结肠、胰腺、甲状腺、胆道、颊腔与咽(口)、唇、舌、口腔、咽、小肠、结肠-直肠、大肠、直肠、脑与中枢神经系统的癌症、胶质母细胞瘤、成神经细胞瘤、角化棘肉瘤、表皮样瘤、大细胞癌、腺癌、腺瘤、滤泡癌、未分化的癌、乳头状癌、精原细胞瘤、黑瘤、肉瘤、膀胱癌、肝癌、肾癌、骨髓障碍、淋巴障碍、何杰金氏病、毛发细胞癌和白血病，该方法包含给予需要这类治疗的受治疗者治疗有效量的式Ⅰ化合物或其药学上可接受的盐。The present invention further provides compounds of formula I useful for the preparation of medicaments for the treatment of abnormal cell proliferation, such as cancer. The present invention is further a method of treating abnormal cell proliferation, such as a cancer selected from the group consisting of breast, ovary, cervix, prostate, testis, esophagus, stomach, skin, lung, bone, colon, pancreas, thyroid, biliary tract, buccal cavity and Cancers of the pharynx (mouth), lips, tongue, oral cavity, pharynx, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid tumor , large cell carcinoma, adenocarcinoma, adenoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer, kidney cancer, bone marrow disorder, lymphoid disorder, He Jie King's disease, hair cell carcinoma and leukemia, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

本发明的治疗方法包括将本发明的化合物(如通式I中的结构)或其药学上可接受的盐和药学上可接受的载体、稀释剂或赋形剂，施用给由此需要的受试者。本发明的各个实施方案包括通过将有效量的本发明的化合物或其药学上可接受的盐施用给由此需要的受试者来治疗上述障碍或疾病中的任一种的方法。The treatment method of the present invention comprises administering the compound of the present invention (such as the structure in general formula I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient to a subject in need thereof tester. Various embodiments of the invention include methods of treating any of the aforementioned disorders or diseases by administering to a subject in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

本发明的化合物对CDKs和其他激酶的抑制活性，本发明化合物也是有用的研究工具，用于体内和体外研究这些激酶的作用机理。The compounds of the present invention have inhibitory activity against CDKs and other kinases, and the compounds of the present invention are also useful research tools for studying the mechanism of action of these kinases in vivo and in vitro.

此外，本发明还包括一种适于口服给予哺乳动物的药物组合物，包含上述通式I的任一化合物，药学上可接受的载体，任选包含一种或多种药学上可接受的赋形剂。In addition, the present invention also includes a pharmaceutical composition suitable for oral administration to mammals, comprising any compound of the above general formula I, a pharmaceutically acceptable carrier, optionally comprising one or more pharmaceutically acceptable excipients Forming agent.

此外，本发明还包括一种适用于胃肠外给予哺乳动物的药物组合物，包括上述通式I的任一化合物，药学上可接受的载体，任选包含一种或多种药学上可接受的赋形剂。In addition, the present invention also includes a pharmaceutical composition suitable for parenteral administration to mammals, comprising any compound of the above-mentioned general formula I, a pharmaceutically acceptable carrier, optionally containing one or more pharmaceutically acceptable excipients.

进行抑酶活性和细胞活性两方面测试来评价化合物在体外的生物活性。The enzyme inhibitory activity and cell activity tests were carried out to evaluate the biological activity of the compound in vitro.

具体实施方式Detailed ways

下面结合实施例对本发明做进一步的说明，但不限于此。The present invention will be further described below in conjunction with the examples, but not limited thereto.

实施例1. 1-异丙基-5-溴-吡啶-2(1H)-酮(3)的合成Example 1. Synthesis of 1-isopropyl-5-bromo-pyridin-2(1H)-one (3)

将化合物1(11g)溶于乙二醇二甲醚(100ml)中，加入叔丁醇钾(7.07g)，室温搅拌30分钟，再分别加入碳酸钾(8.7g)和溴代异丙烷(11.8ml)，于90℃反应8h；反应结束后硅藻土过滤，经硅胶柱纯化，旋干得白色固体10g，产率73％；¹H NMR(400MHz,Chloroform-d)δ7.41(d,J＝2.6Hz,1H),7.31(dd,J＝9.6,2.7Hz,1H),6.49(d,J＝9.6Hz,1H),5.22(hept,J＝6.8Hz,1H),1.36(d,J＝6.8Hz,6H).Compound 1 (11g) was dissolved in ethylene glycol dimethyl ether (100ml), potassium tert-butoxide (7.07g) was added, stirred at room temperature for 30 minutes, potassium carbonate (8.7g) and bromoisopropane (11.8 ml), reacted at 90°C for 8h; after the reaction was completed, it was filtered with diatomaceous earth, purified by silica gel column, and spin-dried to obtain 10g of white solid with a yield of 73%; ¹ H NMR (400MHz, Chloroform-d) δ7.41(d, J=2.6Hz, 1H), 7.31(dd, J=9.6, 2.7Hz, 1H), 6.49(d, J=9.6Hz, 1H), 5.22(hept, J=6.8Hz, 1H), 1.36(d, J＝6.8Hz,6H).

化合物4-6参照化合物3的方法进行合成。Compounds 4-6 were synthesized according to the method of compound 3.

1-异丙基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-2(1H)-酮(7)的合成1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (7) Synthesis

将化合物3(10g)，联硼酸频那醇酯(17g)，醋酸钾(13.5g)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(1.68g)加入二甲基亚砜中(100ml)，于氮气保护下90℃反应10h；反应结束后，加入10eq的水，用乙酸乙酯萃取，无水硫酸镁干燥，经硅胶柱纯化，旋干得白色固体8g，产率66％；¹H NMR(400MHz,Chloroform-d)δ7.77(d,J＝1.6Hz,1H),7.56(dd,J＝9.1,1.9Hz,1H),6.51(d,J＝9.0Hz,1H),5.26(hept,J＝6.8Hz,1H),1.39(d,J＝6.9Hz,6H),1.31(s,12H).Compound 3 (10g), pinacol diboronate (17g), potassium acetate (13.5g) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.68g) Add dimethyl sulfoxide (100ml), and react at 90°C for 10h under the protection of nitrogen; after the reaction, add 10eq of water, extract with ethyl acetate, dry over anhydrous magnesium sulfate, purify through a silica gel column, spin dry to obtain white Solid 8g, yield 66%; ¹ H NMR (400MHz, Chloroform-d) δ7.77(d, J=1.6Hz, 1H), 7.56(dd, J=9.1, 1.9Hz, 1H), 6.51(d, J＝9.0Hz, 1H), 5.26(hept, J＝6.8Hz, 1H), 1.39(d, J＝6.9Hz, 6H), 1.31(s, 12H).

化合物8-10参照化合物7的方法进行合成。Compounds 8-10 were synthesized according to the method of compound 7.

1-异丙基-5-(2-氯嘧啶-4-基)吡啶-2(1H)-酮(11)的合成Synthesis of 1-isopropyl-5-(2-chloropyrimidin-4-yl)pyridin-2(1H)-one (11)

将2,4-二氯嘧啶(14.1g)，化合物7(3g)，碳酸钾(3.9g)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.35g)加入二氧六环和水(30ml，二氧六环：水＝4:1)的混合溶剂中，于氮气保护下90^℃反应10h；反应结束后，加入二氯甲(50ml)，水洗一次，无水硫酸镁干燥，经硅胶柱纯化，旋干得0.73g棕色固体，产率31；¹H NMR(400MHz,Chloroform-d)δ8.57(d,J＝5.3Hz,1H),8.50(d,J＝2.3Hz,1H),7.85(dd,J＝9.6,2.4Hz,1H),7.38(d,J＝5.3Hz,1H),6.66(d,J＝9.6Hz,1H),5.30(hept,J＝6.9Hz,1H),1.47(d,J＝6.8Hz,6H).2,4-dichloropyrimidine (14.1 g), compound 7 (3 g), potassium carbonate (3.9 g) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.35 g) Add dioxane and water (30ml, dioxane: water = 4:1) in a mixed solvent, react at 90 ^°C for 10h under nitrogen protection; after the reaction, add dichloromethane (50ml), wash with water Once, dried over anhydrous magnesium sulfate, purified by silica gel column, and spin-dried to obtain 0.73g brown solid, yield 31; ¹ H NMR (400MHz, Chloroform-d) δ8.57 (d, J=5.3Hz, 1H), 8.50 (d,J=2.3Hz,1H),7.85(dd,J=9.6,2.4Hz,1H),7.38(d,J=5.3Hz,1H),6.66(d,J=9.6Hz,1H),5.30 (hept,J=6.9Hz,1H),1.47(d,J=6.8Hz,6H).

化合物12-18参照化合物11的方法进行合成。Compounds 12-18 were synthesized according to the method of compound 11.

2-硝基-5-(哌啶-1-基)吡啶(21)的合成Synthesis of 2-nitro-5-(piperidin-1-yl)pyridine (21)

将哌啶(7.3ml)，化合物19(8.1g)和三乙胺(14ml)加入DMSO(80ml)中，110℃反应8h；反应结束后，加入5eq的水，抽滤得7g黄色固体，产率84％；¹H NMR(400MHz,Chloroform-d)δ8.14(d,J＝9.2Hz,1H),8.11(d,J＝3.0Hz,1H),7.16(dd,J＝9.2,3.1Hz,1H),3.47(m,4H),1.72(m,6H).Add piperidine (7.3ml), compound 19 (8.1g) and triethylamine (14ml) into DMSO (80ml), react at 110°C for 8h; after the reaction, add 5eq of water, and filter with suction to obtain 7g of yellow solid, product Yield 84%; ¹ H NMR (400MHz, Chloroform-d) δ8.14(d, J=9.2Hz, 1H), 8.11(d, J=3.0Hz, 1H), 7.16(dd, J=9.2, 3.1Hz ,1H),3.47(m,4H),1.72(m,6H).

化合物22-25参照化合物21的方法进行合成。Compounds 22-25 were synthesized according to the method of compound 21.

5-(哌啶-1-基)-2-氨基吡啶(26)的合成Synthesis of 5-(piperidin-1-yl)-2-aminopyridine (26)

将化合物21(6g)和Pd/C(1.2g)加入甲醇(80ml)中，氢气条件下室温搅拌10h；反应结束后，用硅藻土抽滤，旋干，用乙酸乙酯重结晶得4.2g粉色固体，产率82％；¹H NMR(400MHz,Chloroform-d)δ7.79(d,J＝2.7Hz,1H),7.18(dd,J＝8.8,2.9Hz,1H),6.47(d,J＝8.8Hz,1H),4.15(s,2H),3.04–2.92(m,4H),1.71(m,4H),1.54(m,2H).Compound 21 (6g) and Pd/C (1.2g) were added to methanol (80ml), and stirred at room temperature under hydrogen for 10h; g pink solid, yield 82%; ¹ H NMR (400MHz, Chloroform-d) δ7.79(d, J=2.7Hz, 1H), 7.18(dd, J=8.8, 2.9Hz, 1H), 6.47(d ,J＝8.8Hz,1H),4.15(s,2H),3.04–2.92(m,4H),1.71(m,4H),1.54(m,2H).

化合物27-30参照化合物26的方法进行合成。Compounds 27-30 were synthesized according to the method of compound 26.

1-异丙基-5-(2-(5-(哌啶-1-基)吡啶-2-基)氨基嘧啶-4-基)-吡啶-2(1H)-酮的合成(A33)Synthesis of 1-isopropyl-5-(2-(5-(piperidin-1-yl)pyridin-2-yl)aminopyrimidin-4-yl)-pyridin-2(1H)-one (A33)

将化合物26(0.53g)加入甲苯(10-ml)中，氮气保护下加入双(三甲基硅基)氨基锂，室温搅拌10min后加入化合物11(0.5g)，室温搅拌1h；反应结束后，加入饱和碳酸氢钠溶液，用二氯甲烷萃取，减压蒸除溶剂，用甲醇重结晶，得淡黄色固体0.39g，产率50％；m.p.221-223℃；¹H NMR(400MHz,Chloroform-d)δ8.47(d,J＝5.2Hz,1H),8.44(d,J＝2.3Hz,1H),8.24(d,J＝9.1Hz,1H),8.12(s,1H),8.06(d,J＝2.4Hz,1H),7.88(dd,J＝9.5,2.5Hz,1H),7.33(dd,J＝9.1,2.9Hz,1H),6.92(d,J＝5.3Hz,1H),6.65(d,J＝9.5Hz,1H),5.32(hept,J＝6.8Hz,1H),3.20–3.06(m,4H),1.75(m,4H),1.59(m,2H),1.46(d,J＝6.8Hz,6H)；¹³C NMR(101MHz,Chloroform-d)δ162.13,159.28,158.76,145.76,144.04,137.14,136.13,134.11,126.65,120.16,116.26,113.04,106.12,51.29,47.09,25.79,24.02,22.13.Add compound 26 (0.53g) to toluene (10-ml), add bis(trimethylsilyl)amide lithium under nitrogen protection, stir at room temperature for 10min, add compound 11 (0.5g), stir at room temperature for 1h; after the reaction , added saturated sodium bicarbonate solution, extracted with dichloromethane, evaporated the solvent under reduced pressure, and recrystallized with methanol to obtain 0.39 g of a light yellow solid, with a yield of 50%; mp221-223°C; ¹ H NMR (400MHz, Chloroform- d) δ8.47(d, J=5.2Hz, 1H), 8.44(d, J=2.3Hz, 1H), 8.24(d, J=9.1Hz, 1H), 8.12(s, 1H), 8.06(d ,J=2.4Hz,1H),7.88(dd,J=9.5,2.5Hz,1H),7.33(dd,J=9.1,2.9Hz,1H),6.92(d,J=5.3Hz,1H),6.65 (d, J=9.5Hz, 1H), 5.32(hept, J=6.8Hz, 1H), 3.20–3.06(m, 4H), 1.75(m, 4H), 1.59(m, 2H), 1.46(d, J＝6.8Hz, 6H); ¹³ C NMR (101MHz, Chloroform-d) δ162.13, 159.28, 158.76, 145.76, 144.04, 137.14, 136.13, 134.11, 126.65, 120.16, 116.26, 113.04, 106.12, 271.09, 57.09 24.02, 22.13.

化合物34-38，41-46，49-54，57-62参照化合物26的方法进行合成。Compounds 34-38, 41-46, 49-54, 57-62 were synthesized according to the method of compound 26.

1-异丙基-5-(2-(5-(哌嗪-1-基)吡啶-2-基)氨基嘧啶-4-基)-吡啶-2(1H)-酮的合成(A35)Synthesis of 1-isopropyl-5-(2-(5-(piperazin-1-yl)pyridin-2-yl)aminopyrimidin-4-yl)-pyridin-2(1H)-one (A35)

将化合物38(0.49g)加入5ml饱和氯化氢乙酸乙酯溶液，室温下搅拌过夜，抽滤得固体得黄色固体0.21g。产率50％；m.p.228-230℃；¹H NMR(400MHz,DMSO-d6)δ11.71(s,1H),9.73(s,2H),8.71(d,J＝2.3Hz,1H),8.64(d,J＝5.7Hz,1H),8.21(dd,J＝9.6,2.5Hz,1H),8.08(d,J＝9.2Hz,1H),8.03(d,J＝2.3Hz,1H),7.83–7.73(m,2H),6.59(d,J＝9.6Hz,1H),5.11(hept,J＝6.6Hz,1H),3.46(m,4H),3.24(m,4H),1.42(d,J＝6.8Hz,6H)；¹³C NMR(101MHz,DMSO-d6)δ161.47,161.00,159.62,159.16,145.96,143.73,137.03,135.78,125.52,119.58,115.72,114.03,106.78,50.31,47.44,45.98,21.82.Compound 38 (0.49 g) was added into 5 ml of saturated ethyl hydrogen chloride solution, stirred overnight at room temperature, and the solid was obtained by suction filtration to obtain 0.21 g of a yellow solid. Yield 50%; mp228-230°C; ¹ H NMR (400MHz, DMSO-d6) δ11.71(s, 1H), 9.73(s, 2H), 8.71(d, J=2.3Hz, 1H), 8.64( d,J=5.7Hz,1H),8.21(dd,J=9.6,2.5Hz,1H),8.08(d,J=9.2Hz,1H),8.03(d,J=2.3Hz,1H),7.83– 7.73(m,2H),6.59(d,J=9.6Hz,1H),5.11(hept,J=6.6Hz,1H),3.46(m,4H),3.24(m,4H),1.42(d,J =6.8Hz,6H); ¹³ C NMR (101MHz,DMSO-d6)δ161.47,161.00,159.62,159.16,145.96,143.73,137.03,135.78,125.52,119.58,115.72,114.03,106.78,547.34,2 .

化合物43，51，59参照化合物35的方法进行合成。Compounds 43, 51, and 59 were synthesized according to the method of compound 35.

1-异丙基-5-(2-(4-(二甲基氨基)苯基)氨基嘧啶-4-基)-吡啶-2(1H)-酮的合成(A39)Synthesis of 1-isopropyl-5-(2-(4-(dimethylamino)phenyl)aminopyrimidin-4-yl)-pyridin-2(1H)-one (A39)

将化合物11(0.5g)，化合物31(0.41g)，对甲苯磺酸(1g)加入10ml正丁醇中，110℃下搅拌8h，加饱和碳酸氢钠溶液淬灭，用二氯甲烷萃取，无水硫酸镁干燥，减压蒸除溶剂，用甲醇重结晶得0.36g黄色固体。产率52％；m.p.183-185℃；¹H NMR(400MHz,Chloroform-d)δ8.44(d,J＝2.3Hz,1H),8.35(d,J＝5.2Hz,1H),7.85(dd,J＝9.5,2.5Hz,1H),7.46(d,J＝8.9Hz,2H),6.98(s,1H),6.82(d,J＝5.2Hz,1H),6.77(d,J＝8.9Hz,2H),6.63(d,J＝9.5Hz,1H),5.30(hept,J＝6.8Hz,1H),2.94(s,6H),1.44(d,J＝6.8Hz,6H)；¹³C NMR(101MHz,Chloroform-d)δ162.19,161.01,160.65,158.89,147.49,136.12,134.15,129.24,122.40,120.00,116.32,113.28,105.12,47.04,41.17,22.10.Compound 11 (0.5g), compound 31 (0.41g), and p-toluenesulfonic acid (1g) were added to 10ml of n-butanol, stirred at 110°C for 8h, quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, Dry over anhydrous magnesium sulfate, evaporate the solvent under reduced pressure, and recrystallize from methanol to obtain 0.36 g of a yellow solid. Yield 52%; mp183-185°C; ¹ H NMR (400MHz, Chloroform-d) δ8.44(d, J=2.3Hz, 1H), 8.35(d, J=5.2Hz, 1H), 7.85(dd, J=9.5,2.5Hz,1H),7.46(d,J=8.9Hz,2H),6.98(s,1H),6.82(d,J=5.2Hz,1H),6.77(d,J=8.9Hz, 2H), 6.63(d, J=9.5Hz, 1H), 5.30(hept, J=6.8Hz, 1H), 2.94(s, 6H), 1.44(d, J=6.8Hz, 6H); ¹³ C NMR ( 101MHz, Chloroform-d) δ162.19, 161.01, 160.65, 158.89, 147.49, 136.12, 134.15, 129.24, 122.40, 120.00, 116.32, 113.28, 105.12, 47.04, 41.17, 22.10.

化合物40，47，48，55，56，63-70参照化合物35的方法进行合成。Compounds 40, 47, 48, 55, 56, 63-70 were synthesized according to the method of compound 35.

实施例2. 1-异丙基-5-(2-(5-吗啉代吡啶-2-基)氨基嘧啶-4-基)-吡啶-2(1H)-酮的合成(A34)Example 2. Synthesis of 1-isopropyl-5-(2-(5-morpholinopyridin-2-yl)aminopyrimidin-4-yl)-pyridin-2(1H)-one (A34)

中间体和目标化合物制备方法如实施例1。产率62％；m.p.>250℃；¹H NMR(400MHz,Chloroform-d)δ8.48(d,J＝5.2Hz,1H),8.43(d,J＝2.3Hz,1H),8.29(d,J＝9.1Hz,1H),8.14(s,1H),8.05(d,J＝2.7Hz,1H),7.89(dd,J＝9.5,2.4Hz,1H),7.32(dd,J＝9.1,2.9Hz,1H),6.94(d,J＝5.3Hz,1H),6.66(d,J＝9.5Hz,1H),5.34(hept,J＝6.8Hz,1H),3.97-3.83(m,4H),3.26–3.06(m,4H),1.46(d,J＝6.8Hz,6H)；¹³C NMR(101MHz,Chloroform-d)δ162.12,161.20,159.22,158.75,146.50,142.91,136.47,136.13,134.11,125.97,120.21,116.21,113.09,106.32,66.80,49.93,47.09,22.15.The preparation methods of intermediates and target compounds are as in Example 1. Yield 62%; mp>250°C; ¹ H NMR (400MHz, Chloroform-d) δ8.48(d, J=5.2Hz, 1H), 8.43(d, J=2.3Hz, 1H), 8.29(d, J=9.1Hz, 1H), 8.14(s, 1H), 8.05(d, J=2.7Hz, 1H), 7.89(dd, J=9.5, 2.4Hz, 1H), 7.32(dd, J=9.1, 2.9 Hz,1H),6.94(d,J=5.3Hz,1H),6.66(d,J=9.5Hz,1H),5.34(hept,J=6.8Hz,1H),3.97-3.83(m,4H), 3.26–3.06(m,4H),1.46(d,J=6.8Hz,6H); ¹³ C NMR(101MHz,Chloroform-d)δ162.12,161.20,159.22,158.75,146.50,142.91,136.47,136.13,134.11,125.97 ,120.21,116.21,113.09,106.32,66.80,49.93,47.09,22.15.

实施例3. 1-异丙基-5-(2-(5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基嘧啶-4-基)-吡啶-2(1H)-酮的合成(A36)Example 3. 1-isopropyl-5-(2-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)aminopyrimidin-4-yl)-pyridine-2(1H) -Synthesis of ketones (A36)

中间体和目标化合物制备方法如实施例1。产率40％；m.p.228-230℃；¹H NMR(400MHz,Chloroform-d)δ8.46(d,J＝5.3Hz,1H),8.43(d,J＝2.4Hz,1H),8.26(d,J＝9.1Hz,1H),8.04(d,J＝2.8Hz,1H),7.92(s,1H),7.88(dd,J＝9.5,2.5Hz,1H),7.33(dd,J＝9.1,2.9Hz,1H),6.93(d,J＝5.3Hz,1H),6.66(d,J＝9.5Hz,1H),5.33(hept,J＝6.8Hz,1H),3.25-3.14(m,4H),2.67-2.57(m,4H),2.37(s,3H),1.46(d,J＝6.8Hz,6H)；¹³C NMR(101MHz,Chloroform-d)δ162.12,161.19,159.19,158.72,146.05,143.05,136.72,136.08,134.13,126.15,120.20,116.14,113.04,106.28,54.98,49.74,47.08,46.19,22.15.The preparation methods of intermediates and target compounds are as in Example 1. Yield 40%; mp228-230°C; ¹ H NMR (400MHz, Chloroform-d) δ8.46(d, J=5.3Hz, 1H), 8.43(d, J=2.4Hz, 1H), 8.26(d, J=9.1Hz, 1H), 8.04(d, J=2.8Hz, 1H), 7.92(s, 1H), 7.88(dd, J=9.5, 2.5Hz, 1H), 7.33(dd, J=9.1, 2.9 Hz,1H),6.93(d,J=5.3Hz,1H),6.66(d,J=9.5Hz,1H),5.33(hept,J=6.8Hz,1H),3.25-3.14(m,4H), 2.67-2.57(m,4H),2.37(s,3H),1.46(d,J=6.8Hz,6H); ¹³ C NMR(101MHz,Chloroform-d)δ162.12,161.19,159.19,158.72,146.05,143.05, 136.72, 136.08, 134.13, 126.15, 120.20, 116.14, 113.04, 106.28, 54.98, 49.74, 47.08, 46.19, 22.15.

实施例4. 1-异丙基-5-(2-(5-(4-乙基哌嗪-1-基)吡啶-2-基)氨基嘧啶-4-基)-吡啶-2(1H)-酮的合成(A37)Example 4. 1-isopropyl-5-(2-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)aminopyrimidin-4-yl)-pyridine-2(1H) -Synthesis of ketones (A37)

中间体和目标化合物制备方法如实施例1。产率45％；m.p.215-217℃；¹H NMR(400MHz,Chloroform-d)δ8.46(d,J＝5.3Hz,1H),8.43(d,J＝2.4Hz,1H),8.26(d,J＝9.1Hz,1H),8.05(d,J＝2.8Hz,1H),7.95(s,1H),7.88(dd,J＝9.5,2.5Hz,1H),7.33(dd,J＝9.1,2.9Hz,1H),6.93(d,J＝5.3Hz,1H),6.66(d,J＝9.5Hz,1H),5.33(hept,J＝6.7Hz,1H),3.28-3.13(m,4H),2.73-2.59(m,4H),2.50(q,J＝7.2Hz,2H),1.46(d,J＝6.8Hz,6H),1.14(t,J＝7.2Hz,3H)；¹³C NMR(101MHz,Chloroform-d)δ162.11,161.16,159.24,158.75,146.14,143.07,136.73,136.10,134.12,126.11,120.19,116.20,113.08,106.21,52.70,52.36,49.80,47.07,22.14,12.04.The preparation methods of intermediates and target compounds are as in Example 1. Yield 45%; mp215-217°C; ¹ H NMR (400MHz, Chloroform-d) δ8.46(d, J=5.3Hz, 1H), 8.43(d, J=2.4Hz, 1H), 8.26(d, J=9.1Hz, 1H), 8.05(d, J=2.8Hz, 1H), 7.95(s, 1H), 7.88(dd, J=9.5, 2.5Hz, 1H), 7.33(dd, J=9.1, 2.9 Hz,1H),6.93(d,J=5.3Hz,1H),6.66(d,J=9.5Hz,1H),5.33(hept,J=6.7Hz,1H),3.28-3.13(m,4H), 2.73-2.59(m, 4H), 2.50(q, J=7.2Hz, 2H), 1.46(d, J=6.8Hz, 6H), 1.14(t, J=7.2Hz, 3H); ¹³ C NMR (101MHz , Chloroform-d) δ 162.11, 161.16, 159.24, 158.75, 146.14, 143.07, 136.73, 136.10, 134.12, 126.11, 120.19, 116.20, 113.08, 106.21, 52.70, 52.36, 442.10.40, 2

实施例5. 4-(6-(4-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)嘧啶-2-基)氨基吡啶-3-基)哌嗪-1-羧酸叔丁酯的合成(A38)Example 5. 4-(6-(4-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)pyrimidin-2-yl)aminopyridin-3-yl)piper Synthesis of tert-butylazine-1-carboxylate (A38)

中间体和目标化合物制备方法如实施例1。产率51％；m.p.220-222℃；¹H NMR(400MHz,Chloroform-d)δ8.45(d,J＝5.3Hz,1H),8.43(d,J＝2.4Hz,1H),8.28(d,J＝9.0Hz,1H),8.02(d,J＝2.8Hz,1H),7.88(dd,J＝9.5,2.5Hz,1H),7.82(s,1H),7.33(dd,J＝9.1,2.9Hz,1H),6.94(d,J＝5.3Hz,1H),6.66(d,J＝9.5Hz,1H),5.34(hept,J＝6.8Hz,1H),3.68-3.49(m,4H),3.19-2.99(m,4H),1.49(s,9H),1.46(d,J＝6.8Hz,6H)；¹³C NMR(101MHz,Chloroform-d)δ162.11,161.27,159.11,158.69,154.64,146.54,143.03,137.39,136.04,134.15,126.96,120.24,116.05,112.97,106.44,80.05,50.11,47.10,28.44,22.15.The preparation methods of intermediates and target compounds are as in Example 1. Yield 51%; mp220-222°C; ¹ H NMR (400MHz, Chloroform-d) δ8.45(d, J=5.3Hz, 1H), 8.43(d, J=2.4Hz, 1H), 8.28(d, J=9.0Hz, 1H), 8.02(d, J=2.8Hz, 1H), 7.88(dd, J=9.5, 2.5Hz, 1H), 7.82(s, 1H), 7.33(dd, J=9.1, 2.9 Hz,1H),6.94(d,J=5.3Hz,1H),6.66(d,J=9.5Hz,1H),5.34(hept,J=6.8Hz,1H),3.68-3.49(m,4H), 3.19-2.99(m,4H),1.49(s,9H),1.46(d,J=6.8Hz,6H); ¹³ C NMR(101MHz,Chloroform-d)δ162.11,161.27,159.11,158.69,154.64,146.54, 143.03, 137.39, 136.04, 134.15, 126.96, 120.24, 116.05, 112.97, 106.44, 80.05, 50.11, 47.10, 28.44, 22.15.

实施例6. 1-异丙基-5-(2-(4-(甲磺酰基)苯基)氨基嘧啶-4-基)-吡啶-2(1H)-酮的合成(A40)Example 6. Synthesis of 1-isopropyl-5-(2-(4-(methylsulfonyl)phenyl)aminopyrimidin-4-yl)-pyridin-2(1H)-one (A40)

中间体和目标化合物制备方法如实施例1。产率61％；m.p.248-250℃；¹H NMR(400MHz,Chloroform-d)δ8.49(d,J＝5.3Hz,1H),8.43(d,J＝2.4Hz,1H),7.91(m,5H),7.53(s,1H),7.04(d,J＝5.3Hz,1H),6.68(d,J＝9.5Hz,1H),5.40-5.29(hept,J＝6.8Hz,1H),3.07(s,3H),1.48(d,J＝6.8Hz,6H)；¹³C NMR(101MHz,Chloroform-d)δ162.06,161.57,159.29,158.77,144.69,135.96,134.35,132.99,128.72,120.42,118.40,115.72,107.48,47.26,44.87,22.17.The preparation methods of intermediates and target compounds are as in Example 1. Yield 61%; mp248-250°C; ¹ H NMR (400MHz, Chloroform-d) δ8.49(d, J=5.3Hz, 1H), 8.43(d, J=2.4Hz, 1H), 7.91(m, 5H), 7.53(s, 1H), 7.04(d, J=5.3Hz, 1H), 6.68(d, J=9.5Hz, 1H), 5.40-5.29(hept, J=6.8Hz, 1H), 3.07( s,3H),1.48(d,J=6.8Hz,6H); ¹³ C NMR(101MHz,Chloroform-d)δ162.06,161.57,159.29,158.77,144.69,135.96,134.35,132.99,128.72,120.42,118.42,115.7 ,107.48,47.26,44.87,22.17.

实施例7. 1-异丙基-5-(2-(5-(哌啶-1-基)吡啶-2-基)氨基-5-氟嘧啶-4-基)-吡啶-2(1H)-酮的合成(A41)Example 7. 1-isopropyl-5-(2-(5-(piperidin-1-yl)pyridin-2-yl)amino-5-fluoropyrimidin-4-yl)-pyridine-2(1H) -Synthesis of ketones (A41)

中间体和目标化合物制备方法如实施例1。产率52％；m.p.218-220℃；¹H NMR(400MHz,Chloroform-d)δ8.42(d,J＝2.3Hz,1H),8.33(d,J＝3.9Hz,1H),8.13(d,J＝9.2Hz,1H),8.13(dd,J＝9.6,2.3Hz,1H),8.04(d,J＝2.8Hz,1H),8.03(s,1H),7.34(dd,J＝9.1,2.9Hz,1H),6.67(d,J＝9.6Hz,1H),5.34(hept,J＝6.8Hz,1H),3.17–3.05(m,4H),1.75(m,4H),1.59(m,2H),1.44(d,J＝6.8Hz,6H)；¹³C NMR(101MHz,Chloroform-d)δ161.70,155.51,151.28,148.77,148.39,146.78,146.51,145.74,144.03,137.58,137.19,136.43,126.72,120.29,113.35,112.35,51.26,47.12,25.79,24.02,22.10。The preparation methods of intermediates and target compounds are as in Example 1. Yield 52%; mp218-220°C; ¹ H NMR (400MHz, Chloroform-d) δ8.42(d, J=2.3Hz, 1H), 8.33(d, J=3.9Hz, 1H), 8.13(d, J=9.2Hz, 1H), 8.13(dd, J=9.6, 2.3Hz, 1H), 8.04(d, J=2.8Hz, 1H), 8.03(s, 1H), 7.34(dd, J=9.1, 2.9 Hz,1H),6.67(d,J=9.6Hz,1H),5.34(hept,J=6.8Hz,1H),3.17–3.05(m,4H),1.75(m,4H),1.59(m,2H ), 1.44 (d, J=6.8Hz, 6H); ¹³ C NMR (101MHz, Chloroform-d) δ161.70, 155.51, 151.28, 148.77, 148.39, 146.78, 146.51, 145.74, 144.03, 137.58, 137.19, 136.473, 12 120.29, 113.35, 112.35, 51.26, 47.12, 25.79, 24.02, 22.10.

实施例8. 1-异丙基-5-(2-(5-吗啉代吡啶-2-基)氨基-5-氟嘧啶-4-基)-吡啶-2(1H)-酮的合成(A42)Example 8. Synthesis of 1-isopropyl-5-(2-(5-morpholinopyridin-2-yl)amino-5-fluoropyrimidin-4-yl)-pyridin-2(1H)-one ( A42)

中间体和目标化合物制备方法如实施例1。产率49％；m.p.225-227℃；¹H NMR(400MHz,DMSO-d6)δ9.72(s,1H),8.56(d,J＝3.8Hz,1H),8.51(d,J＝2.2Hz,1H),8.06(dd,J＝9.6,2.0Hz,1H),8.03(d,J＝2.2Hz,1H),8.01(d,J＝3.3Hz,1H),7.42(dd,J＝9.2,2.8Hz,1H),6.57(d,J＝9.6Hz,1H),5.09(hept,J＝6.7Hz,1H),3.85–3.65(m,4H),3.19–3.01(m,4H),1.37(d,J＝6.8Hz,6H)；¹³C NMR(101MHz,Chloroform-d)δ161.68,155.42,151.33,148.81,148.43(d,J＝9.0Hz),146.78,146.51,142.89,137.52,137.47,136.60,136.51,136.48,126.05,120.34,113.29,112.40,66.79,49.91,47.13,22.10.The preparation methods of intermediates and target compounds are as in Example 1. Yield 49%; mp225-227°C; ¹ H NMR (400MHz, DMSO-d6) δ9.72(s, 1H), 8.56(d, J=3.8Hz, 1H), 8.51(d, J=2.2Hz, 1H), 8.06(dd, J=9.6, 2.0Hz, 1H), 8.03(d, J=2.2Hz, 1H), 8.01(d, J=3.3Hz, 1H), 7.42(dd, J=9.2, 2.8 Hz, 1H), 6.57(d, J=9.6Hz, 1H), 5.09(hept, J=6.7Hz, 1H), 3.85–3.65(m, 4H), 3.19–3.01(m, 4H), 1.37(d , J＝6.8Hz, 6H); ¹³ C NMR (101MHz, Chloroform-d) δ161.68, 155.42, 151.33, 148.81, 148.43 (d, J＝9.0Hz), 146.78, 146.51, 142.89, 137.52, 137.47, 136.60, 136.51 ,136.48,126.05,120.34,113.29,112.40,66.79,49.91,47.13,22.10.

实施例9. 1-异丙基-5-(2-(5-(哌嗪-1-基)吡啶-2-基)氨基-5-氟嘧啶-4-基)-吡啶-2(1H)-酮的合成(A43)Example 9. 1-isopropyl-5-(2-(5-(piperazin-1-yl)pyridin-2-yl)amino-5-fluoropyrimidin-4-yl)-pyridine-2(1H) -Synthesis of ketones (A43)

中间体和目标化合物制备方法如实施例1。产率50％；m.p.>250℃；¹H NMR(400MHz,DMSO-d6)δ12.09(s,1H),9.75(s,2H),8.78(d,J＝3.2Hz,1H),8.61–8.51(m,1H),8.34–8.22(m,1H),8.08(d,J＝10.3Hz,1H),8.02–7.91(m,1H),7.82(d,J＝9.6Hz,1H),6.62(d,J＝9.6Hz,1H),5.09(hept,J＝6.7Hz,1H),3.48(m,4H),3.25(m,4H),1.39(d,J＝6.7Hz,6H)；¹³C NMR(101MHz,Chloroform-d)δ161.68,155.39,154.64,151.33,148.82,148.48,148.39,146.75,146.53,142.90,137.52,137.44,136.60,136.48,127.06,120.34,113.27,113.21,112.36,80.05,50.08,47.14,28.44,22.10.The preparation methods of intermediates and target compounds are as in Example 1. Yield 50%; mp>250°C; ¹ H NMR (400MHz, DMSO-d6) δ12.09(s, 1H), 9.75(s, 2H), 8.78(d, J=3.2Hz, 1H), 8.61– 8.51(m,1H),8.34–8.22(m,1H),8.08(d,J=10.3Hz,1H),8.02–7.91(m,1H),7.82(d,J=9.6Hz,1H),6.62 (d, J=9.6Hz, 1H), 5.09(hept, J=6.7Hz, 1H), 3.48(m, 4H), 3.25(m, 4H), 1.39(d, J=6.7Hz, 6H); ¹³ C NMR(101MHz,Chloroform-d)δ161.68,155.39,154.64,151.33,148.82,148.48,148.39,146.75,146.53,142.90,137.52,137.44,136.60,136.48,127.06,120.34,113.27,113.21,112.36,80.05,50.08 , 47.14, 28.44, 22.10.

实施例10. 1-异丙基-5-(2-(5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基-5-氟嘧啶-4-基)-吡啶-2(1H)-酮的合成(A44)Example 10. 1-isopropyl-5-(2-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino-5-fluoropyrimidin-4-yl)-pyridine- Synthesis of 2(1H)-Kones (A44)

中间体和目标化合物制备方法如实施例1。产率58％；m.p.235-237℃；¹H NMR(400MHz,Chloroform-d)δ8.46–8.39(d,J＝2.2Hz,1H),8.34(d,J＝3.8Hz,1H),8.23–8.08(m,3H),8.05(d,J＝2.8Hz,1H),7.34(dd,J＝9.0,2.8Hz,1H),6.68(d,J＝9.6Hz,1H),5.41–5.27(hept,J＝6.8Hz,1H),3.29–3.10(m,4H),2.71–2.54(m,4H),2.37(s,3H),1.44(d,J＝6.8Hz,6H)；¹³C NMR(101MHz,Chloroform-d)δ161.69,155.40,148.83,148.43,146.73,146.47,146.07,143.03,137.53,137.47,136.74,136.58,136.47,126.23,120.32,113.28,112.37,54.97,49.71,47.13,46.18,22.10.The preparation methods of intermediates and target compounds are as in Example 1. Yield 58%; mp235-237°C; ¹ H NMR (400MHz, Chloroform-d) δ8.46–8.39 (d, J=2.2Hz, 1H), 8.34 (d, J=3.8Hz, 1H), 8.23– 8.08(m,3H),8.05(d,J=2.8Hz,1H),7.34(dd,J=9.0,2.8Hz,1H),6.68(d,J=9.6Hz,1H),5.41–5.27(hept , J＝6.8Hz, 1H), 3.29–3.10(m, 4H), 2.71–2.54(m, 4H), 2.37(s, 3H), 1.44(d, J＝6.8Hz, 6H); ¹³ C NMR ( 101MHz,Chloroform-d)δ161.69,155.40,148.83,148.43,146.73,146.47,146.07,143.03,137.53,137.47,136.74,136.58,136.47,126.23,120.32,113.28,112.37,54.97,49.71,47.13,46.18,22.10.

实施例11. 1-异丙基-5-(2-(5-(4-乙基哌嗪-1-基)吡啶-2-基)氨基-5-氟嘧啶-4-基)-吡啶-2(1H)-酮的合成(A45)Example 11. 1-isopropyl-5-(2-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)amino-5-fluoropyrimidin-4-yl)-pyridine- Synthesis of 2(1H)-Kones (A45)

中间体和目标化合物制备方法如实施例1。产率22％；m.p.212-214℃；¹H NMR(400MHz,Chloroform-d)δ8.42(d,J＝2.2Hz,1H),8.33(d,J＝3.9Hz,1H),8.20–8.11(m,2H),8.05(m,2H),7.34(dd,J＝9.1,2.9Hz,1H),6.67(d,J＝9.6Hz,1H),5.34(hept,J＝6.8Hz,1H),3.26–3.14(m,4H),2.71–2.59(m,4H),2.50(q,J＝7.2Hz,2H),1.44(d,J＝6.8Hz,6H),1.14(t,J＝7.2Hz,3H)；¹³C NMR(101MHz,Chloroform-d)δ161.69,155.44,146.73,146.45,146.06,143.13,137.53,137.47,136.73,136.58,136.46,126.17,120.32,113.21,112.38,52.69,52.36,49.76,47.13,22.09,12.03.The preparation methods of intermediates and target compounds are as in Example 1. Yield 22%; mp212-214°C; ¹ H NMR (400MHz, Chloroform-d) δ8.42(d, J=2.2Hz, 1H), 8.33(d, J=3.9Hz, 1H), 8.20–8.11( m,2H),8.05(m,2H),7.34(dd,J=9.1,2.9Hz,1H),6.67(d,J=9.6Hz,1H),5.34(hept,J=6.8Hz,1H), 3.26–3.14(m,4H),2.71–2.59(m,4H),2.50(q,J=7.2Hz,2H),1.44(d,J=6.8Hz,6H),1.14(t,J=7.2Hz ,3H)； ¹³ C NMR(101MHz,Chloroform-d)δ161.69,155.44,146.73,146.45,146.06,143.13,137.53,137.47,136.73,136.58,136.46,126.17,120.32,113.21,112.38,52.69,52.36,49.76, 47.13, 22.09, 12.03.

实施例12. 4-(6-(4-(1-异丙基-6-氧代-1,6-二氢吡啶-3-基)-5-氟嘧啶-2-基)氨基吡啶-3-基)哌嗪叔丁基-1-羧酸叔丁酯的合成(A46)Example 12. 4-(6-(4-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoropyrimidin-2-yl)aminopyridine-3 -Synthesis of piperazine tert-butyl-1-carboxylate tert-butyl ester (A46)

中间体和目标化合物制备方法如实施例1。产率21％；m.p.225-227℃；¹H NMR(400MHz,DMSO-d6)δ9.74(s,1H),8.56(d,J＝3.8Hz,1H),8.51(d,J＝2.3Hz,1H),8.09–7.99(m,3H),7.44(dd,J＝9.2,2.8Hz,1H),6.57(d,J＝9.6Hz,1H),5.09(hept,J＝6.8Hz,1H),3.48(m,4H),3.07(m,4H),1.43(s,9H),1.37(d,J＝6.8Hz,6H).¹³C NMR(101MHz,DeuteriumOxide)δ162.84,152.84,149.74,145.25,144.98,142.57,141.36,138.40,138.26,136.42,120.28,119.04,116.22,113.27,49.45,45.16,42.76,20.84.The preparation methods of intermediates and target compounds are as in Example 1. Yield 21%; mp225-227°C; ¹ H NMR (400MHz, DMSO-d6) δ9.74(s, 1H), 8.56(d, J=3.8Hz, 1H), 8.51(d, J=2.3Hz, 1H), 8.09–7.99(m, 3H), 7.44(dd, J＝9.2, 2.8Hz, 1H), 6.57(d, J＝9.6Hz, 1H), 5.09(hept, J＝6.8Hz, 1H), 3.48(m,4H),3.07(m,4H),1.43(s,9H),1.37(d,J=6.8Hz,6H). ¹³ C NMR(101MHz,Deuterium Oxide)δ162.84,152.84,149.74,145.25,144.98 ,142.57,141.36,138.40,138.26,136.42,120.28,119.04,116.22,113.27,49.45,45.16,42.76,20.84.

实施例13. 1-异丙基-5-(2-(4-(二甲基氨基)苯基)氨基-5-氟嘧啶-4-基)-吡啶-2(1H)-酮的合成(A47)Example 13. Synthesis of 1-isopropyl-5-(2-(4-(dimethylamino)phenyl)amino-5-fluoropyrimidin-4-yl)-pyridin-2(1H)-one ( A47)

中间体和目标化合物制备方法如实施例1。产率97％；m.p.185-187^℃；¹H NMR(400MHz,Chloroform-d)δ8.41(d,J＝2.1Hz,1H),8.22(d,J＝4.0Hz,1H),8.12(dd,J＝9.6,2.3Hz,1H),7.41(d,J＝8.9Hz,2H),6.88(s,1H),6.77(d,J＝8.9Hz,2H),6.64(d,J＝9.6Hz,1H),5.32(hept,J＝6.8Hz,1H),2.94(s,6H),1.42(d,J＝6.8Hz,6H)；¹³C NMR(101MHz,Chloroform-d)δ161.77,157.02,151.04,148.36,147.52,146.92,146.66,137.70,137.63,136.44,136.33,129.25,122.17,120.12,113.52,113.46,113.31,47.06,41.13,22.08.The preparation methods of intermediates and target compounds are as in Example 1. Yield 97%; mp185-187 ^°C ; ¹ H NMR (400MHz, Chloroform-d) δ8.41(d, J=2.1Hz, 1H), 8.22(d, J=4.0Hz, 1H), 8.12(dd, J=9.6,2.3Hz,1H),7.41(d,J=8.9Hz,2H),6.88(s,1H),6.77(d,J=8.9Hz,2H),6.64(d,J=9.6Hz, 1H), 5.32(hept, J=6.8Hz, 1H), 2.94(s, 6H), 1.42(d, J=6.8Hz, 6H); ¹³ C NMR(101MHz, Chloroform-d) δ161.77, 157.02, 151.04, 148.36, 147.52, 146.92, 146.66, 137.70, 137.63, 136.44, 136.33, 129.25, 122.17, 120.12, 113.52, 113.46, 113.31, 47.06, 41.13, 22.08.

实施例14. 1-异丙基-5-(2-(4-(甲磺酰基)苯基)氨基-5-氟嘧啶-4-基)-吡啶-2(1H)-酮的合成(A48)Example 14. Synthesis of 1-isopropyl-5-(2-(4-(methylsulfonyl)phenyl)amino-5-fluoropyrimidin-4-yl)-pyridin-2(1H)-one (A48 )

中间体和目标化合物制备方法如实施例1。产率47％；m.p.226-228^℃；¹H NMR(400MHz,Chloroform-d)δ8.43(J＝2.1Hz,1H),8.37(d,J＝3.7Hz,1H),8.14(dd,J＝9.6,2.1Hz,1H),7.92(d,J＝8.7Hz,2H),7.85(d,J＝8.8Hz,2H),7.56(s,1H),6.70(d,J＝9.6Hz,1H),5.35(hept,J＝6.6Hz,1H),3.07(s,3H),1.46(d,J＝6.8Hz,6H)；¹³C NMR(101MHz,Chloroform-d)δ161.64,155.21,151.86,149.11,146.70,146.44,144.51,137.31,137.25,136.88,136.76,133.08,128.84,120.54,117.91,112.75,47.30,44.85,22.12.The preparation methods of intermediates and target compounds are as in Example 1. Yield 47%; mp226-228 ^℃ ; ¹ H NMR (400MHz, Chloroform-d) δ8.43 (J = 2.1Hz, 1H), 8.37 (d, J = 3.7Hz, 1H), 8.14 (dd, J = 9.6,2.1Hz,1H),7.92(d,J=8.7Hz,2H),7.85(d,J=8.8Hz,2H),7.56(s,1H),6.70(d,J=9.6Hz,1H) ,5.35(hept,J=6.6Hz,1H),3.07(s,3H),1.46(d,J=6.8Hz,6H); ¹³ C NMR(101MHz,Chloroform-d)δ161.64,155.21,151.86,149.11, 146.70, 146.44, 144.51, 137.31, 137.25, 136.88, 136.76, 133.08, 128.84, 120.54, 117.91, 112.75, 47.30, 44.85, 22.12.

实施例15. 1-环戊基-5-(2-(5-(哌啶-1-基)吡啶-2-基)氨基嘧啶-4-基)-吡啶-2(1H)-酮的合成(A49)Example 15. Synthesis of 1-cyclopentyl-5-(2-(5-(piperidin-1-yl)pyridin-2-yl)aminopyrimidin-4-yl)-pyridin-2(1H)-one (A49)

中间体和目标化合物制备方法如实施例1。产率47％；m.p.220-222℃；¹H NMR(400MHz,Chloroform-d)δ8.49–8.46(d,J＝5.3Hz,1H),8.47–8.44(d,J＝1.6Hz,1H),8.22(d,J＝9.0Hz,1H),8.05(d,J＝2.8Hz,1H),8.02(s,1H),7.85(dd,J＝9.5,1.6Hz,1H),7.32(dd,J＝9.0,2.7Hz,1H),6.91(d,J＝5.3Hz,1H),6.64(d,J＝9.5Hz,1H),5.38(m,1H),3.22–3.02(m,4H),2.26(m,2H),1.94(m,2H),1.78(m,8H),1.59(m,2H)；¹³C NMR(101MHz,Chloroform-d)δ162.69,161.08,159.25,158.78,145.67,144.04,137.21,136.01,134.94,126.50,119.94,116.14,113.00,106.12,56.74,51.26,32.70,25.79,24.62,24.03。The preparation methods of intermediates and target compounds are as in Example 1. Yield 47%; mp220-222°C; ¹ H NMR (400MHz, Chloroform-d) δ8.49–8.46 (d, J=5.3Hz, 1H), 8.47–8.44 (d, J=1.6Hz, 1H), 8.22(d,J=9.0Hz,1H),8.05(d,J=2.8Hz,1H),8.02(s,1H),7.85(dd,J=9.5,1.6Hz,1H),7.32(dd,J =9.0,2.7Hz,1H),6.91(d,J=5.3Hz,1H),6.64(d,J=9.5Hz,1H),5.38(m,1H),3.22–3.02(m,4H),2.26 (m,2H),1.94(m,2H),1.78(m,8H),1.59(m,2H); ¹³ C NMR(101MHz,Chloroform-d)δ162.69,161.08,159.25,158.78,145.67,144.04,137.21 , 136.01, 134.94, 126.50, 119.94, 116.14, 113.00, 106.12, 56.74, 51.26, 32.70, 25.79, 24.62, 24.03.

实施例16. 1-环戊基-5-(2-(5-吗啉代吡啶-2-基)氨基嘧啶-4-基)-吡啶-2(1H)-酮的合成(A50)Example 16. Synthesis of 1-cyclopentyl-5-(2-(5-morpholinopyridin-2-yl)aminopyrimidin-4-yl)-pyridin-2(1H)-one (A50)

中间体和目标化合物制备方法如实施例1。产率66％；m.p.>250℃；¹H NMR(400MHz,Chloroform-d)δ8.47(d,J＝5.3Hz,1H),8.45(d,J＝2.3Hz,1H),8.28(d,J＝9.1Hz,1H),8.17(s,1H),8.05(d,J＝2.7Hz,1H),7.86(dd,J＝9.5,2.4Hz,1H),7.31(dd,J＝9.1,2.8Hz,1H),6.93(d,J＝5.3Hz,1H),6.65(d,J＝9.5Hz,1H),5.38(p,J＝7.6Hz,1H),3.96–3.82(m,4H),3.22–3.06(m,4H),2.29(m,2H),1.94(m,2H),1.80(m,4H).¹³C NMR(101MHz,Chloroform-d)δ162.68,161.13,159.20,158.78,146.49,142.89,136.51,136.04,134.92,125.86,119.96,116.15,113.09,106.29,66.79,56.76,49.90,32.69,24.62.The preparation methods of intermediates and target compounds are as in Example 1. Yield 66%; mp>250°C; ¹ H NMR (400MHz, Chloroform-d) δ8.47(d, J=5.3Hz, 1H), 8.45(d, J=2.3Hz, 1H), 8.28(d, J=9.1Hz, 1H), 8.17(s, 1H), 8.05(d, J=2.7Hz, 1H), 7.86(dd, J=9.5, 2.4Hz, 1H), 7.31(dd, J=9.1, 2.8 Hz,1H),6.93(d,J=5.3Hz,1H),6.65(d,J=9.5Hz,1H),5.38(p,J=7.6Hz,1H),3.96–3.82(m,4H), 3.22–3.06(m,4H),2.29(m,2H),1.94(m,2H),1.80(m,4H). ¹³ C NMR(101MHz,Chloroform-d)δ162.68,161.13,159.20,158.78,146.49, 142.89, 136.51, 136.04, 134.92, 125.86, 119.96, 116.15, 113.09, 106.29, 66.79, 56.76, 49.90, 32.69, 24.62.

实施例17. 1-环戊基-5-(2-(5-(哌嗪-1-基)吡啶-2-基)氨基嘧啶-4-基)-吡啶-2(1H)-酮的合成(A51)Example 17. Synthesis of 1-cyclopentyl-5-(2-(5-(piperazin-1-yl)pyridin-2-yl)aminopyrimidin-4-yl)-pyridin-2(1H)-one (A51)

中间体和目标化合物制备方法如实施例1。产率75％；m.p.>250℃；¹H NMR(400MHz,DMSO-d6)δ12.03(s,1H),9.72(s,2H),8.74–8.60(m,2H),8.20(m,2H),8.01(d,J＝2.6Hz,1H),7.79(d,J＝5.8Hz,1H),7.72(d,J＝9.5Hz,1H),6.59(d,J＝9.5Hz,1H),5.19–5.05(m,1H),3.48(s,4H),3.25(m,4H),2.08(m,2H),1.88(m,4H),1.70(m,2H)；¹³C NMR(101MHz,Deuterium Oxide)δ163.18,161.63,155.92,155.78,142.47,141.29,137.01,136.33,134.95,121.24,118.56,115.86,115.31,109.38,58.98,44.94,42.74,31.84,23.69.The preparation methods of intermediates and target compounds are as in Example 1. Yield 75%; mp>250℃; ¹ H NMR (400MHz, DMSO-d6) δ12.03(s,1H),9.72(s,2H),8.74–8.60(m,2H),8.20(m,2H ),8.01(d,J=2.6Hz,1H),7.79(d,J=5.8Hz,1H),7.72(d,J=9.5Hz,1H),6.59(d,J=9.5Hz,1H), 5.19–5.05(m,1H),3.48(s,4H),3.25(m,4H),2.08(m,2H),1.88(m,4H),1.70(m,2H); ¹³ C NMR(101MHz, Deuterium Oxide) δ163.18, 161.63, 155.92, 155.78, 142.47, 141.29, 137.01, 136.33, 134.95, 121.24, 118.56, 115.86, 115.31, 109.38, 58.98, 464.94, 42.894, 23

实施例18. 1-环戊基-5-(2-(5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基嘧啶-4-基)-吡啶-2(1H)-酮的合成(A52)Example 18. 1-cyclopentyl-5-(2-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)aminopyrimidin-4-yl)-pyridine-2(1H) -Synthesis of Ketones (A52)

中间体和目标化合物制备方法如实施例1。产率33％；m.p.241-243℃；¹H NMR(400MHz,Chloroform-d)δ8.48(d,J＝5.3Hz,1H),8.46(d,J＝2.4Hz,1H),8.31(s,1H),8.25(d,J＝9.1Hz,1H),8.08(d,J＝2.8Hz,1H),7.85(dd,J＝9.5,2.5Hz,1H),7.32(dd,J＝9.1,2.9Hz,1H),6.92(d,J＝5.3Hz,1H),6.64(d,J＝9.5Hz,1H),5.38(m,1H),3.28–3.09(m,4H),2.71–2.54(m,4H),2.37(s,3H),2.29(m,2H),1.94(m,2H),1.79(m,4H).¹³C NMR(101MHz,Chloroform-d)δ162.67,159.22,158.77,146.07,143.02,136.80,135.98,134.94,126.01,120.08,116.09,113.03,106.21,56.89,54.98,49.73,46.17,32.64,24.61.The preparation methods of intermediates and target compounds are as in Example 1. Yield 33%; mp241-243°C; ¹ H NMR (400MHz, Chloroform-d) δ8.48(d, J=5.3Hz, 1H), 8.46(d, J=2.4Hz, 1H), 8.31(s, 1H), 8.25(d, J=9.1Hz, 1H), 8.08(d, J=2.8Hz, 1H), 7.85(dd, J=9.5, 2.5Hz, 1H), 7.32(dd, J=9.1, 2.9 Hz,1H),6.92(d,J=5.3Hz,1H),6.64(d,J=9.5Hz,1H),5.38(m,1H),3.28–3.09(m,4H),2.71–2.54(m ,4H),2.37(s,3H),2.29(m,2H),1.94(m,2H),1.79(m,4H). ¹³ C NMR(101MHz,Chloroform-d)δ162.67,159.22,158.77,146.07, 143.02, 136.80, 135.98, 134.94, 126.01, 120.08, 116.09, 113.03, 106.21, 56.89, 54.98, 49.73, 46.17, 32.64, 24.61.

实施例19. 1-环戊基-5-(2-(5-(4-乙基哌嗪-1-基)吡啶-2-基)氨基嘧啶-4-基)-吡啶-2(1H)-酮的合成(A53)Example 19. 1-cyclopentyl-5-(2-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)aminopyrimidin-4-yl)-pyridine-2(1H) -Synthesis of ketones (A53)

中间体和目标化合物制备方法如实施例1。产率51％；m.p.225-227℃；¹H NMR(400MHz,Chloroform-d)δ8.45(m,2H),8.24(d,J＝9.1Hz,1H),8.05(d,J＝2.8Hz,1H),7.93(s,1H),7.85(dd,J＝9.5,2.5Hz,1H),7.32(dd,J＝9.1,2.9Hz,1H),6.92(d,J＝5.3Hz,1H),6.64(d,J＝9.5Hz,1H),5.38(m,1H),3.27–3.13(m,4H),2.72–2.59(m,4H),2.50(q,J＝7.2Hz,2H),2.29(m,2H),1.94(m,2H),1.80(m,4H),1.14(t,J＝7.2Hz,3H).；¹³C NMR(101MHz,Chloroform-d)δ162.66,159.22,158.78,146.09,143.08,136.82,135.98,134.94,125.96,119.96,116.11,113.03,106.19,56.74,52.70,52.36,49.78,32.69,24.62,12.03.The preparation methods of intermediates and target compounds are as in Example 1. Yield 51%; mp225-227°C; ¹ H NMR (400MHz, Chloroform-d) δ8.45(m, 2H), 8.24(d, J=9.1Hz, 1H), 8.05(d, J=2.8Hz, 1H),7.93(s,1H),7.85(dd,J=9.5,2.5Hz,1H),7.32(dd,J=9.1,2.9Hz,1H),6.92(d,J=5.3Hz,1H), 6.64(d,J=9.5Hz,1H),5.38(m,1H),3.27–3.13(m,4H),2.72–2.59(m,4H),2.50(q,J=7.2Hz,2H),2.29 (m,2H),1.94(m,2H),1.80(m,4H),1.14(t,J=7.2Hz,3H).; ¹³ C NMR(101MHz,Chloroform-d)δ162.66,159.22,158.78,146.09 ,143.08,136.82,135.98,134.94,125.96,119.96,116.11,113.03,106.19,56.74,52.70,52.36,49.78,32.69,24.62,12.03.

实施例20. 4-(6-(4-(1-环戊基-6-氧代-1,6-二氢吡啶-3-基)嘧啶-2-基)氨基吡啶-3-基)哌嗪-1-羧酸叔丁酯的合成(A54)Example 20. 4-(6-(4-(1-cyclopentyl-6-oxo-1,6-dihydropyridin-3-yl)pyrimidin-2-yl)aminopyridin-3-yl)piper Synthesis of tert-butylazine-1-carboxylate (A54)

中间体和目标化合物制备方法如实施例1。产率82％；m.p.226-228℃；¹H NMR(400MHz,DMSO-d6)δ9.57(s,1H),8.58(d,J＝2.1Hz,1H),8.48(d,J＝5.3Hz,1H),8.14(dd,J＝9.5,2.3Hz,1H),8.09(d,J＝9.1Hz,1H),8.03(d,J＝2.7Hz,1H),7.43(dd,J＝9.0,2.8Hz,1H),7.34(d,J＝5.3Hz,1H),6.52(d,J＝9.5Hz,1H),5.20–5.09(m,1H),3.48(m,4H),3.08(m,4H),2.08(m,2H),1.94–1.65(m,6H),1.43(s,9H)；¹³C NMR(101MHz,Chloroform-d)δ162.70,161.17,159.15,158.77,154.65,146.66,142.93,137.43,136.03,134.94,126.87,119.98,116.12,113.03,106.37,80.08,56.78,50.08,32.70,28.44,24.62.The preparation methods of intermediates and target compounds are as in Example 1. Yield 82%; mp226-228°C; ¹ H NMR (400MHz, DMSO-d6) δ9.57(s, 1H), 8.58(d, J=2.1Hz, 1H), 8.48(d, J=5.3Hz, 1H), 8.14(dd, J=9.5, 2.3Hz, 1H), 8.09(d, J=9.1Hz, 1H), 8.03(d, J=2.7Hz, 1H), 7.43(dd, J=9.0, 2.8 Hz,1H),7.34(d,J=5.3Hz,1H),6.52(d,J=9.5Hz,1H),5.20–5.09(m,1H),3.48(m,4H),3.08(m,4H ),2.08(m,2H),1.94–1.65(m,6H),1.43(s,9H); ¹³ C NMR(101MHz,Chloroform-d)δ162.70,161.17,159.15,158.77,154.65,146.66,142.93,137.43 ,136.03,134.94,126.87,119.98,116.12,113.03,106.37,80.08,56.78,50.08,32.70,28.44,24.62.

实施例21. 1-环戊基-5-(2-(4-(二甲基氨基)苯基)氨基嘧啶-4-基)-吡啶-2(1H)-酮的合成(A55)Example 21. Synthesis of 1-cyclopentyl-5-(2-(4-(dimethylamino)phenyl)aminopyrimidin-4-yl)-pyridin-2(1H)-one (A55)

中间体和目标化合物制备方法如实施例1。产率68％；m.p.190-190℃；¹H NMR(400MHz,Chloroform-d)δ8.47(d,J＝2.2Hz,1H),8.35(d,J＝5.2Hz,1H),7.82(dd,J＝9.5,2.5Hz,1H),7.45(m,2H),7.15(s,1H),6.81(d,J＝5.3Hz,1H),6.76(m,2H),6.61(d,J＝9.5Hz,1H),5.36(m,1H),2.94(s,6H),2.23(m,2H),1.91(m,2H),1.75(m,4H)；¹³C NMR(101MHz,Chloroform-d)δ162.76,160.94,160.64,158.89,147.41,136.01,134.97,129.27,122.37,119.74,116.25,113.21,105.03,56.67,41.12,32.62,24.56.The preparation methods of intermediates and target compounds are as in Example 1. Yield 68%; mp 190-190°C; ¹ H NMR (400MHz, Chloroform-d) δ8.47(d, J=2.2Hz, 1H), 8.35(d, J=5.2Hz, 1H), 7.82(dd, J=9.5,2.5Hz,1H),7.45(m,2H),7.15(s,1H),6.81(d,J=5.3Hz,1H),6.76(m,2H),6.61(d,J=9.5 Hz,1H),5.36(m,1H),2.94(s,6H),2.23(m,2H),1.91(m,2H),1.75(m,4H); ¹³ C NMR(101MHz,Chloroform-d) δ162.76, 160.94, 160.64, 158.89, 147.41, 136.01, 134.97, 129.27, 122.37, 119.74, 116.25, 113.21, 105.03, 56.67, 41.12, 32.62, 24.56.

实施例22. 1-环戊基-5-(2-(4-(甲磺酰基)苯基)氨基嘧啶-4-基)-吡啶-2(1H)-酮的合成(A56)Example 22. Synthesis of 1-cyclopentyl-5-(2-(4-(methylsulfonyl)phenyl)aminopyrimidin-4-yl)-pyridin-2(1H)-one (A56)

中间体和目标化合物制备方法如实施例1。产率51％；m.p.>250℃；¹H NMR(400MHz,Chloroform-d)δ8.48(d,J＝5.3Hz,1H),8.45(d,J＝2.5Hz,1H),7.90(m,3H),7.87(dd,J＝9.6,2.5Hz,1H),7.70(d,J＝8.7Hz,1H),7.56(s,1H),7.03(d,J＝5.3Hz,1H),6.66(d,J＝9.4Hz,1H),5.37(m,1H),3.07(s,3H),2.28(m,2H),1.94(m,2H),1.77(m,4H)；¹³C NMR(101MHz,Chloroform-d)δ162.62,161.56,159.24,158.81,144.59,135.86,135.16,133.10,128.73,120.23,118.48,115.62,107.48,57.00,44.87,32.67,24.55.The preparation methods of intermediates and target compounds are as in Example 1. Yield 51%; mp>250°C; ¹ H NMR (400MHz, Chloroform-d) δ8.48(d, J=5.3Hz, 1H), 8.45(d, J=2.5Hz, 1H), 7.90(m, 3H), 7.87(dd, J=9.6, 2.5Hz, 1H), 7.70(d, J=8.7Hz, 1H), 7.56(s, 1H), 7.03(d, J=5.3Hz, 1H), 6.66( d, J＝9.4Hz, 1H), 5.37(m, 1H), 3.07(s, 3H), 2.28(m, 2H), 1.94(m, 2H), 1.77(m, 4H); ¹³ C NMR (101MHz , Chloroform-d) δ162.62, 161.56, 159.24, 158.81, 144.59, 135.86, 135.16, 133.10, 128.73, 120.23, 118.48, 115.62, 107.48, 57.00, 44.87, 32.67, 24.55.

实施例23. 1-环戊基-5-(2-(5-(哌啶-1-基)吡啶-2-基)氨基-5-氟嘧啶-4-基)-吡啶-2(1H)-酮的合成(A57)Example 23. 1-cyclopentyl-5-(2-(5-(piperidin-1-yl)pyridin-2-yl)amino-5-fluoropyrimidin-4-yl)-pyridine-2(1H) -Synthesis of ketones (A57)

中间体和目标化合物制备方法如实施例1。产率47％；m.p.226-228℃；¹H NMR(400MHz,Chloroform-d)δ8.44(d,J＝2.2Hz,1H),8.32(d,J＝3.9Hz,1H),8.13(d,J＝9.1Hz,1H),8.13(dd,J＝9.6,2.2Hz,1H),8.04(d,J＝2.9Hz,1H),8.01(s,1H),7.33(dd,J＝9.1,2.9Hz,1H),6.66(d,J＝9.6Hz,1H),5.38(m,1H),3.17–3.06(m,4H),2.27(m,2H),1.92(m,2H),1.75(m,8H),1.59(m,2H)；¹³C NMR(101MHz,Chloroform-d)δ162.26,155.47,151.28,148.57,146.53,145.68,144.03,137.53,137.47,137.32,137.21,126.62,120.05,113.27,112.34,56.87,51.24,32.65,25.78,24.47,24.02。The preparation methods of intermediates and target compounds are as in Example 1. Yield 47%; mp226-228°C; ¹ H NMR (400MHz, Chloroform-d) δ8.44(d, J=2.2Hz, 1H), 8.32(d, J=3.9Hz, 1H), 8.13(d, J=9.1Hz, 1H), 8.13(dd, J=9.6, 2.2Hz, 1H), 8.04(d, J=2.9Hz, 1H), 8.01(s, 1H), 7.33(dd, J=9.1, 2.9 Hz,1H),6.66(d,J＝9.6Hz,1H),5.38(m,1H),3.17–3.06(m,4H),2.27(m,2H),1.92(m,2H),1.75(m ,8H),1.59(m,2H); ¹³ C NMR(101MHz,Chloroform-d)δ162.26,155.47,151.28,148.57,146.53,145.68,144.03,137.53,137.47,137.32,137.21,126.67,4113.25 , 56.87, 51.24, 32.65, 25.78, 24.47, 24.02.

实施例24. 1-环戊基-5-(2-(5-吗啉代吡啶-2-基)氨基-5-氟嘧啶-4-基)-吡啶-2(1H)-酮的合成(A58)Example 24. Synthesis of 1-cyclopentyl-5-(2-(5-morpholinopyridin-2-yl)amino-5-fluoropyrimidin-4-yl)-pyridin-2(1H)-one ( A58)

中间体和目标化合物制备方法如实施例1。产率90％；m.p.>250℃；¹H NMR(400MHz,DMSO-d6)δ9.73(s,1H),8.55(d,J＝3.9Hz,1H),8.47(d,J＝2.3Hz,1H),8.07(dd,J＝9.5,2.0Hz,1H),8.04–8.00(d,J＝9.0Hz,1H),7.98(s,1H),7.41(dd,J＝9.0,2.8Hz,1H),6.56(d,J＝9.6Hz,1H),5.15(m,1H),3.82–3.71(m,4H),3.14–3.04(m,4H),2.12(m,2H),1.84(m,2H),1.71(m,4H)；¹³C NMR(101MHz,Chloroform-d)δ162.27,155.35,151.37,148.86,148.44,146.75,146.49,146.38,142.94,137.49,137.41,137.27,136.51,126.00,120.11,112.40,66.79,56.90,49.89,32.66,24.47.The preparation methods of intermediates and target compounds are as in Example 1. Yield 90%; mp>250℃; ¹ H NMR (400MHz, DMSO-d6) δ9.73(s, 1H), 8.55(d, J=3.9Hz, 1H), 8.47(d, J=2.3Hz, 1H), 8.07(dd, J=9.5, 2.0Hz, 1H), 8.04–8.00(d, J=9.0Hz, 1H), 7.98(s, 1H), 7.41(dd, J=9.0, 2.8Hz, 1H ),6.56(d,J＝9.6Hz,1H),5.15(m,1H),3.82–3.71(m,4H),3.14–3.04(m,4H),2.12(m,2H),1.84(m, 2H),1.71(m,4H); ¹³ C NMR(101MHz,Chloroform-d)δ162.27,155.35,151.37,148.86,148.44,146.75,146.49,146.38,142.94,137.49,137.41,137.27,1126.501, 112.40, 66.79, 56.90, 49.89, 32.66, 24.47.

实施例25. 1-环戊基-5-(2-(5-(哌嗪-1-基)吡啶-2-基)氨基-5-氟嘧啶-4-基)-吡啶-2(1H)-酮的合成(A59)Example 25. 1-cyclopentyl-5-(2-(5-(piperazin-1-yl)pyridin-2-yl)amino-5-fluoropyrimidin-4-yl)-pyridine-2(1H) -Synthesis of ketones (A59)

中间体和目标化合物制备方法如实施例1。产率98％；m.p.>250℃；¹H NMR(400MHz,DMSO-d6)δ12.14(s,1H),9.83(s,2H),8.76(d,1H),8.49(d,1H),8.31(dd,J＝9.1Hz,1H),8.07(d,J＝9.5Hz,1H),7.99(d,1H),7.82(d,J＝9.5Hz,1H),6.60(d,J＝9.6Hz,1H),5.12(m,1H),3.51(m,4H),3.26(m,4H),2.11(m,2H),1.78(m,4H)；¹³C NMR(101MHz,Deuterium Oxide)δ163.10,152.72,152.07,149.64,149.52,145.20,144.92,142.35,141.35,138.90,138.76,138.39,138.35,136.27,120.14,118.94,116.19,112.87,58.99,45.07,42.75,31.92,23.71.The preparation methods of intermediates and target compounds are as in Example 1. Yield 98%; mp>250℃; ¹ H NMR (400MHz, DMSO-d6) δ12.14(s,1H),9.83(s,2H),8.76(d,1H),8.49(d,1H), 8.31(dd, J=9.1Hz, 1H), 8.07(d, J=9.5Hz, 1H), 7.99(d, 1H), 7.82(d, J=9.5Hz, 1H), 6.60(d, J=9.6 Hz,1H),5.12(m,1H),3.51(m,4H),3.26(m,4H),2.11(m,2H),1.78(m,4H); ¹³ C NMR(101MHz,Deuterium Oxide)δ163 .10,152.72,152.07,149.64,149.52,145.20,144.92,142.35,141.35,138.90,138.76,138.39,138.35,136.27,120.14,118.94,116.19,112.87,58.99,45.07,42.75,31.92,23.71.

实施例26. 1-环戊基-5-(2-(5-(4-甲基哌嗪-1-基)吡啶-2-基)氨基-5-氟嘧啶-4-基)-吡啶-2(1H)-酮的合成(A60)Example 26. 1-cyclopentyl-5-(2-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino-5-fluoropyrimidin-4-yl)-pyridine- Synthesis of 2(1H)-Kones (A60)

中间体和目标化合物制备方法如实施例1。产率32％；m.p.238-240℃；1H NMR(400MHz,Chloroform-d)δ8.43(d,J＝2.2Hz,1H),8.33(d,J＝3.9Hz,1H),8.19–8.09(m,3H),8.05(d,J＝2.9Hz,1H),7.33(dd,J＝9.1,2.9Hz,1H),6.66(d,J＝9.6Hz,1H),5.38(m,1H),3.25–3.13(m,4H),2.67–2.55(m,4H),2.37(s,3H),2.26(m,2H),1.91(m,2H),1.80(m,4H)；¹³C NMR(101MHz,Chloroform-d)δ162.66,162.23,161.12,159.23,158.77,146.14,143.00,137.95,136.84,136.84,135.99,134.93,126.14,126.01,120.07,119.96,116.11,113.04,112.37,106.19,56.75,54.98,49.70,46.17,32.69,24.61.The preparation methods of intermediates and target compounds are as in Example 1. Yield 32%; mp238-240°C; 1H NMR (400MHz, Chloroform-d) δ8.43(d, J=2.2Hz, 1H), 8.33(d, J=3.9Hz, 1H), 8.19–8.09(m ,3H),8.05(d,J=2.9Hz,1H),7.33(dd,J=9.1,2.9Hz,1H),6.66(d,J=9.6Hz,1H),5.38(m,1H),3.25 –3.13(m,4H),2.67–2.55(m,4H),2.37(s,3H),2.26(m,2H),1.91(m,2H),1.80(m,4H); ¹³ C NMR (101MHz ,Chloroform-d)δ162.66,162.23,161.12,159.23,158.77,146.14,143.00,137.95,136.84,136.84,135.99,134.93,126.14,126.01,120.07,119.96,116.11,113.04,112.37,106.19,56.75,54.98,49.70 ,46.17,32.69,24.61.

实施例27. 1-环戊基-5-(2-(5-(4-乙基哌嗪-1-基)吡啶-2-基)氨基-5-氟嘧啶-4-基)-吡啶-2(1H)-酮的合成(A61)Example 27. 1-cyclopentyl-5-(2-(5-(4-ethylpiperazin-1-yl)pyridin-2-yl)amino-5-fluoropyrimidin-4-yl)-pyridine- Synthesis of 2(1H)-Kones (A61)

中间体和目标化合物制备方法如实施例1。产率43％；m.p.218-220℃；¹H NMR(400MHz,Chloroform-d)δ8.43(d,J＝2.1Hz,1H),8.34(d,J＝3.9Hz,1H),8.31(s,1H),8.16(d,J＝9.1Hz,1H),8.12(dd,J＝9.6,2.3Hz,1H),8.08(d,J＝2.8Hz,1H),7.33(dd,J＝9.1,2.9Hz,1H),6.66(d,J＝9.6Hz,1H),5.38(m,1H),3.29–3.09(m,4H),2.71–2.57(m,4H),2.50(q,J＝7.2Hz,2H),2.27(m,2H),1.91(m,2H),1.77(m,4H),1.14(t,J＝7.2Hz,3H).¹³C NMR(101MHz,Chloroform-d)δ162.24,155.43,151.33,148.82,148.39,146.77,146.51,146.04,143.09,137.49,137.38,137.23,136.78,126.09,120.08,113.23,112.35,56.89,52.69,52.36,49.74,32.65,24.47,12.02.The preparation methods of intermediates and target compounds are as in Example 1. Yield 43%; mp218-220°C; ¹ H NMR (400MHz, Chloroform-d) δ8.43(d, J=2.1Hz, 1H), 8.34(d, J=3.9Hz, 1H), 8.31(s, 1H), 8.16(d, J=9.1Hz, 1H), 8.12(dd, J=9.6, 2.3Hz, 1H), 8.08(d, J=2.8Hz, 1H), 7.33(dd, J=9.1, 2.9 Hz,1H),6.66(d,J=9.6Hz,1H),5.38(m,1H),3.29–3.09(m,4H),2.71–2.57(m,4H),2.50(q,J=7.2Hz ,2H),2.27(m,2H),1.91(m,2H),1.77(m,4H),1.14(t,J=7.2Hz,3H). ¹³ C NMR(101MHz,Chloroform-d)δ162.24,155.43 , 151.33,148.82,148.39,146.77,146.51,146.04,143.09,137.38,137.23,136.78,126.08, 113.23.35,52.49.74,49.74,2.74,2.74,2.74,2.74,2.74,2.74,2.74,2.74,2.74,2.74,2.74,2.74,2.74,2.74,2.74,2.74,2.74,49.74,49.74,49.74,49.74,49.74,49.7.

实施例28. 4-(6-(4-(1-环戊基-6-氧代-1,6-二氢吡啶-3-基)-5-氟嘧啶-2-基)氨基吡啶-3-基)哌嗪叔丁基-1-羧酸叔丁酯的合成(A62)Example 28. 4-(6-(4-(1-cyclopentyl-6-oxo-1,6-dihydropyridin-3-yl)-5-fluoropyrimidin-2-yl)aminopyridine-3 -Synthesis of piperazine tert-butyl-1-carboxylate tert-butyl ester (A62)

中间体和目标化合物制备方法如实施例1。产率26％；m.p.236-238℃；¹H NMR(400MHz,DMSO-d6)δ9.76(s,1H),8.56(d,J＝3.9Hz,1H),8.47(d,J＝2.2Hz,1H),8.06(dd,J＝9.4,2.0Hz,1H),8.03(d,J＝2.8Hz,1H),8.00(d,J＝9.1Hz,1H),7.43(dd,J＝9.1,3.0Hz,1H),6.56(d,J＝9.6Hz,1H),5.15(m,1H),3.48(m,4H),3.07(m,4H),2.11(m,2H),1.83(m,2H),1.71(m,4H),1.43(s,9H)；¹³C NMR(101MHz,Chloroform-d)δ162.23,155.40,154.64,151.34,148.83,148.37,146.71,146.54,142.90,137.47,126.98,120.11,113.22,112.34,80.06,56.89,50.07,32.66,28.44,24.47The preparation methods of intermediates and target compounds are as in Example 1. Yield 26%; mp236-238°C; ¹ H NMR (400MHz, DMSO-d6) δ9.76(s, 1H), 8.56(d, J=3.9Hz, 1H), 8.47(d, J=2.2Hz, 1H), 8.06(dd, J=9.4, 2.0Hz, 1H), 8.03(d, J=2.8Hz, 1H), 8.00(d, J=9.1Hz, 1H), 7.43(dd, J=9.1, 3.0 Hz,1H),6.56(d,J=9.6Hz,1H),5.15(m,1H),3.48(m,4H),3.07(m,4H),2.11(m,2H),1.83(m,2H ),1.71(m,4H),1.43(s,9H); ¹³ C NMR(101MHz,Chloroform-d)δ162.23,155.40,154.64,151.34,148.83,148.37,146.71,146.54,142.90,137.47,126.91,120. 113.22, 112.34, 80.06, 56.89, 50.07, 32.66, 28.44, 24.47

实施例29. 1-环戊基-5-(2-(4-(二甲基氨基)苯基)氨基-5-氟嘧啶-4-基)-吡啶-2(1H)-酮的合成(A63)Example 29. Synthesis of 1-cyclopentyl-5-(2-(4-(dimethylamino)phenyl)amino-5-fluoropyrimidin-4-yl)-pyridin-2(1H)-one ( A63)

中间体和目标化合物制备方法如实施例1。产率57％；m.p.180-182℃；¹H NMR(400MHz,Chloroform-d)δ8.43(d,J＝2.0Hz,1H),8.21(d,J＝4.0Hz,1H),8.11(dd,J＝9.6,2.2Hz,1H),7.40(d,J＝8.9Hz,2H),6.97(s,1H),6.76(d,J＝8.9Hz,2H),6.62(d,J＝9.6Hz,1H),5.36(m,1H),2.94(s,6H),2.23(m,2H),1.89(m,2H),1.75(m,4H)；¹³C NMR(101MHz,Chloroform-d)δ162.35,157.01,151.01,148.51,148.07,147.49,146.97,146.71,137.68,137.61,137.18,137.07,129.26,122.15,119.85,113.27,56.82,41.10,32.60,24.43.The preparation methods of intermediates and target compounds are as in Example 1. Yield 57%; mp 180-182°C; ¹ H NMR (400MHz, Chloroform-d) δ8.43(d, J=2.0Hz, 1H), 8.21(d, J=4.0Hz, 1H), 8.11(dd, J=9.6,2.2Hz,1H),7.40(d,J=8.9Hz,2H),6.97(s,1H),6.76(d,J=8.9Hz,2H),6.62(d,J=9.6Hz, 1H),5.36(m,1H),2.94(s,6H),2.23(m,2H),1.89(m,2H),1.75(m,4H); ¹³ C NMR(101MHz,Chloroform-d)δ162. 35,157.01,151.01,148.51,148.07,147.49,146.97,146.71,137.68,137.61,137.18,137.07,129.26,122.15,119.85,113.27,56.82,41.10,242.63,

实施例30. 1-环戊基-5-(2-(4-(甲磺酰基)苯基)氨基-5-氟嘧啶-4-基)-吡啶-2(1H)-酮的合成(A64)Example 30. Synthesis of 1-cyclopentyl-5-(2-(4-(methylsulfonyl)phenyl)amino-5-fluoropyrimidin-4-yl)-pyridin-2(1H)-one (A64 )

中间体和目标化合物制备方法如实施例1。产率44％；m.p.224-226℃；¹H NMR(400MHz,Chloroform-d)δ8.44(d,J＝2.0Hz,1H),8.36(d,J＝3.8Hz,1H),8.13(dd,J＝9.6,2.3Hz,1H),7.91(d,J＝8.8Hz,2H),7.83(d,J＝8.8Hz,2H),7.47(s,1H),6.68(d,J＝9.6Hz,1H),5.37(m,1H),3.07(s,3H),2.27(m,2H),1.92(m,2H),1.77(m,4H)；¹³C NMR(101MHz,Chloroform-d)δ162.22,155.25,151.83,149.30,148.88,146.70,146.44,144.58,137.68,137.55,137.29,137.23,133.02,128.80,120.32,117.98,112.75,57.12,44.85,32.64,24.43.The preparation methods of intermediates and target compounds are as in Example 1. Yield 44%; mp224-226°C; ¹ H NMR (400MHz, Chloroform-d) δ8.44(d, J=2.0Hz, 1H), 8.36(d, J=3.8Hz, 1H), 8.13(dd, J=9.6,2.3Hz,1H),7.91(d,J=8.8Hz,2H),7.83(d,J=8.8Hz,2H),7.47(s,1H),6.68(d,J=9.6Hz, 1H),5.37(m,1H),3.07(s,3H),2.27(m,2H),1.92(m,2H),1.77(m,4H); ¹³ C NMR(101MHz,Chloroform-d)δ162. 22, 155.25, 151.83, 149.30, 148.88, 146.70, 146.44, 144.58, 137.68, 137.55, 137.29, 137.23, 133.02, 128.80, 120.32, 117.98, 112.75, 57.12, 424.64

实施例31. 1-甲基-5-(2-(4-(二甲基氨基)苯基)氨基嘧啶-4-基)-吡啶-2(1H)-酮的合成(A65)Example 31. Synthesis of 1-methyl-5-(2-(4-(dimethylamino)phenyl)aminopyrimidin-4-yl)-pyridin-2(1H)-one (A65)

中间体和目标化合物制备方法如实施例1。产率58％；m.p.℃；¹H NMR(400MHz,Chloroform-d)δ8.35(d,J＝5.2Hz,1H),8.28(d,J＝2.4Hz,1H),7.93(dd,J＝9.5,2.5Hz,1H),7.43(d,J＝8.9Hz,2H),6.91(s,1H),6.81(d,J＝5.3Hz,1H),6.78(d,J＝8.9Hz,2H),6.65(d,J＝9.5Hz,1H),3.65(s,3H),2.95(s,6H)；The preparation methods of intermediates and target compounds are as in Example 1. Yield 58%; mp°C; ¹ H NMR (400MHz, Chloroform-d) δ8.35(d, J=5.2Hz, 1H), 8.28(d, J=2.4Hz, 1H), 7.93(dd, J= 9.5,2.5Hz,1H),7.43(d,J=8.9Hz,2H),6.91(s,1H),6.81(d,J=5.3Hz,1H),6.78(d,J=8.9Hz,2H) ,6.65(d,J=9.5Hz,1H),3.65(s,3H),2.95(s,6H);

实施例32. 1-甲基-5-(2-(4-(二甲基氨基)苯基)氨基-5-氟嘧啶-4-基)-吡啶-2(1H)-酮的合成(A66)Example 32. Synthesis of 1-methyl-5-(2-(4-(dimethylamino)phenyl)amino-5-fluoropyrimidin-4-yl)-pyridin-2(1H)-one (A66 )

中间体和目标化合物制备方法如实施例1。产率53％；m.p.℃；¹H NMR(400MHz,Chloroform-d)δ8.32(d,J＝2.2Hz,1H),8.22(d,J＝3.9Hz,1H),8.19(dd,J＝9.7,2.4Hz,2H),7.39(d,J＝8.9Hz,2H),6.87(s,1H),6.78(d,J＝8.9Hz,2H),6.66(d,J＝9.6Hz,1H),3.65(s,3H),2.95(s,6H).The preparation methods of intermediates and target compounds are as in Example 1. Yield 53%; mp°C; ¹ H NMR (400MHz, Chloroform-d) δ8.32(d, J=2.2Hz, 1H), 8.22(d, J=3.9Hz, 1H), 8.19(dd, J= 9.7,2.4Hz,2H),7.39(d,J=8.9Hz,2H),6.87(s,1H),6.78(d,J=8.9Hz,2H),6.66(d,J=9.6Hz,1H) ,3.65(s,3H),2.95(s,6H).

实施例33. 1-异丁基-5-(2-(4-(二甲基氨基)苯基)氨基嘧啶-4-基)-吡啶-2(1H)-酮的合成(A67)Example 33. Synthesis of 1-isobutyl-5-(2-(4-(dimethylamino)phenyl)aminopyrimidin-4-yl)-pyridin-2(1H)-one (A67)

中间体和目标化合物制备方法如实施例1。产率51％；m.p.℃；¹H NMR(400MHz,Chloroform-d)δ8.35(d,J＝5.2Hz,1H),8.22(d,J＝2.5Hz,1H),7.90(dd,J＝9.5,2.6Hz,1H),7.44(d,J＝8.9Hz,2H),6.90(s,1H),6.81(d,J＝5.3Hz,1H),6.77(d,J＝9.0Hz,2H),6.64(d,J＝9.5Hz,1H),3.84(d,J＝7.4Hz,2H),2.94(s,6H),2.24(m,1H),1.00(d,J＝6.7Hz,6H).The preparation methods of intermediates and target compounds are as in Example 1. Yield 51%; mp°C; ¹ H NMR (400MHz, Chloroform-d) δ8.35 (d, J=5.2Hz, 1H), 8.22 (d, J=2.5Hz, 1H), 7.90 (dd, J= 9.5,2.6Hz,1H),7.44(d,J=8.9Hz,2H),6.90(s,1H),6.81(d,J=5.3Hz,1H),6.77(d,J=9.0Hz,2H) ,6.64(d,J=9.5Hz,1H),3.84(d,J=7.4Hz,2H),2.94(s,6H),2.24(m,1H),1.00(d,J=6.7Hz,6H) .

实施例34. 1-异丁基-5-(2-(4-(甲磺酰基)苯基)氨基嘧啶-4-基)-吡啶-2(1H)-酮的合成(A68)Example 34. Synthesis of 1-isobutyl-5-(2-(4-(methylsulfonyl)phenyl)aminopyrimidin-4-yl)-pyridin-2(1H)-one (A68)

中间体和目标化合物制备方法如实施例1。产率56％；m.p.℃；¹H NMR(400MHz,Chloroform-d)δ8.42(d,J＝5.3Hz,1H),8.17(d,J＝2.4Hz,1H),7.98–7.76(m,5H),7.39(s,1H),6.96(d,J＝5.3Hz,1H),6.61(d,J＝9.5Hz,1H),3.80(d,J＝7.4Hz,2H),3.00(s,3H),2.19(m,1H),0.95(d,J＝6.7Hz,6H).The preparation methods of intermediates and target compounds are as in Example 1. Yield 56%; mp°C; ¹ H NMR (400MHz, Chloroform-d) δ8.42(d, J=5.3Hz, 1H), 8.17(d, J=2.4Hz, 1H), 7.98–7.76(m, 5H), 7.39(s, 1H), 6.96(d, J=5.3Hz, 1H), 6.61(d, J=9.5Hz, 1H), 3.80(d, J=7.4Hz, 2H), 3.00(s, 3H),2.19(m,1H),0.95(d,J＝6.7Hz,6H).

实施例35. 1-异丁基-5-(2-(4-(二甲基氨基)苯基)氨基-5-氟嘧啶-4-基)-吡啶-2(1H)-酮的合成(A69)Example 35. Synthesis of 1-isobutyl-5-(2-(4-(dimethylamino)phenyl)amino-5-fluoropyrimidin-4-yl)-pyridin-2(1H)-one ( A69)

中间体和目标化合物制备方法如实施例1。产率61％；m.p.℃；¹H NMR(400MHz,Chloroform-d)δ8.24(d,J＝2.3Hz,1H),8.21(d,J＝3.9Hz,1H),8.15(dd,J＝9.6,2.4Hz,1H),7.39(d,J＝8.9Hz,2H),6.85(s,1H),6.77(d,J＝8.9Hz,2H),6.65(d,J＝9.6Hz,1H),3.83(d,J＝7.4Hz,2H),2.94(s,6H),2.22(m,1H),0.99(d,J＝6.7Hz,6H).The preparation methods of intermediates and target compounds are as in Example 1. Yield 61%; mp°C; ¹ H NMR (400MHz, Chloroform-d) δ8.24(d, J=2.3Hz, 1H), 8.21(d, J=3.9Hz, 1H), 8.15(dd, J= 9.6,2.4Hz,1H),7.39(d,J=8.9Hz,2H),6.85(s,1H),6.77(d,J=8.9Hz,2H),6.65(d,J=9.6Hz,1H) ,3.83(d,J=7.4Hz,2H),2.94(s,6H),2.22(m,1H),0.99(d,J=6.7Hz,6H).

实施例36. 1-异丁基-5-(2-(4-(甲磺酰基)苯基)氨基-5-氟嘧啶-4-基)-吡啶-2(1H)-酮的合成(A70)Example 36. Synthesis of 1-isobutyl-5-(2-(4-(methylsulfonyl)phenyl)amino-5-fluoropyrimidin-4-yl)-pyridin-2(1H)-one (A70 )

中间体和目标化合物制备方法如实施例1。产率19％；m.p.℃；¹H NMR(400MHz,Chloroform-d)δ8.36(d,J＝3.7Hz,1H),8.27(d,J＝2.3Hz,1H),8.16(dd,J＝9.7,2.4Hz,1H),7.91(d,J＝8.7Hz,2H),7.83(d,J＝8.8Hz,2H),7.47(s,1H),6.70(d,J＝9.7Hz,1H),3.86(d,J＝7.4Hz,2H),3.07(s,3H),2.24(m,1H),1.01(d,J＝6.7Hz,6H).The preparation methods of intermediates and target compounds are as in Example 1. Yield 19%; mp°C; ¹ H NMR (400MHz, Chloroform-d) δ8.36(d, J=3.7Hz, 1H), 8.27(d, J=2.3Hz, 1H), 8.16(dd, J= 9.7,2.4Hz,1H),7.91(d,J=8.7Hz,2H),7.83(d,J=8.8Hz,2H),7.47(s,1H),6.70(d,J=9.7Hz,1H) ,3.86(d,J=7.4Hz,2H),3.07(s,3H),2.24(m,1H),1.01(d,J=6.7Hz,6H).

目标化合物活性评价Activity evaluation of target compounds

实验例1、目标化合物对细胞周期蛋白依赖性激酶抑制试验Experimental Example 1. Cyclin-dependent Kinase Inhibition Test of Target Compounds

术语说明：Terminology Explanation:

mM：毫摩尔/升。mM: millimole/liter.

μM：微摩尔/升。μM: micromole/liter.

IC₅₀：半数抑制浓度。IC ₅₀ : half inhibitory concentration.

1.[材料]Kinase-Glo Plus发光激酶测定试剂盒，CDK2/Cyclin 2A蛋白，96孔板1. [Materials] Kinase-Glo Plus Luminescent Kinase Assay Kit, CDK2/Cyclin 2A protein, 96-well plate

2.[方法]按照试剂盒的使用说明书进行实验准备：2. [Method] Prepare the experiment according to the instruction manual of the kit:

参考文献方法进行CDK2酶抑制剂的测试。所有酶促反应均在30℃下进行40分钟。50μL反应混合物包含40mM Tris、10mM MgCl₂、0.1mg/mL BSA、1mM DTT、10μM ATP、0.2μg/mL，CDK2/Cyclin 2A和100uM底物，pH 7.4。使用DMSO配置不同浓度的待测化合物，然后将5μL稀释液加入50μL反应混合物中，所有反应中DMSO的最终浓度不超过1％。化合物对CDK2的抑制活性使用Kinase-Glo Plus发光激酶测定试剂盒进行测定。通过量化激酶反应后溶液中剩余的ATP量来测量激酶活性。使用GraphPad Prism软件，使用归一化剂量反应拟合的非线性回归计算IC₅₀值。实验结果见表2。The CDK2 enzyme inhibitor test was carried out according to the reference method. All enzymatic reactions were performed at 30°C for 40 minutes. The 50 μL reaction mixture contained 40 mM Tris, 10 mM MgCl ₂ , 0.1 mg/mL BSA, 1 mM DTT, 10 μM ATP, 0.2 μg/mL, CDK2/Cyclin 2A and 100 uM substrate, pH 7.4. Different concentrations of test compounds were prepared in DMSO, then 5 μL of the dilution was added to 50 μL of the reaction mixture, and the final concentration of DMSO in all reactions did not exceed 1%. The inhibitory activity of compounds on CDK2 was determined using Kinase-Glo Plus Luminescent Kinase Assay Kit. Kinase activity is measured by quantifying the amount of ATP remaining in solution after the kinase reaction. _IC50 values were calculated using nonlinear regression with normalized dose-response fit using GraphPad Prism software. The experimental results are shown in Table 2.

表2.目标化合物对CDK2体外抑制实验结果Table 2. Results of in vitro inhibition experiments of target compounds on CDK2

^aIC₅₀或100nM浓度下的抑制率，表中数值为三次试验结果的平均值。 ^a IC ₅₀ or inhibition rate at 100nM concentration, the value in the table is the average value of three test results.

从表2中可以看出，实施例的化合物表现出不同程度的CDK2抑制剂活性，其中化合物A39，A40，A47，A48，A55，A56，A63和A64表现出比已知CDK2选择性抑制剂Roscovitine更优的抑制活性。As can be seen from Table 2, the compounds of the examples show different degrees of CDK2 inhibitory activity, wherein compounds A39, A40, A47, A48, A55, A56, A63 and A64 show a higher level of activity than the known CDK2 selective inhibitor Roscovitine Better inhibitory activity.

实验例2.目标化合物抑制细胞增殖的活性试验(In vitro)Experimental example 2. Activity test of target compound inhibiting cell proliferation (In vitro)

术语说明：Terminology Explanation:

MDA-MB-231：人乳腺癌细胞株。MDA-MB-231: human breast cancer cell line.

KG1：白血病细胞株。KG1: leukemia cell line.

BxPC3：胰腺癌癌细胞株。BxPC3: pancreatic cancer cell line.

A549：肺癌细胞株。A549: lung cancer cell line.

HepG2：肝癌细胞株。HepG2: liver cancer cell line.

Roscovitine:也称Seliciclib，是已知的选择性CDK2抑制剂，在本实验中用作阳性药物。Roscovitine: also known as Seliciclib, is a known selective CDK2 inhibitor used as a positive drug in this experiment.

IC₅₀：半数抑制浓度。IC ₅₀ : half inhibitory concentration.

μM：微摩尔/升。μM: micromole/liter.

选取代表性化合物进行体外抑制癌细胞增殖的活性试验：Select representative compounds for in vitro activity test of inhibiting cancer cell proliferation:

1.[材料]MDA-MB-231，KG1，K562和PC-3细胞株，四甲基偶氮唑蓝MTT，10％胎牛血清，96孔板。1. [Materials] MDA-MB-231, KG1, K562 and PC-3 cell lines, MTT tetramethylazoblue, 10% fetal bovine serum, 96-well plate.

2.[方法]2. [Method]

细胞培养肿瘤细胞株采用常规培养。实验时均用对数生长期细胞。Cell culture Tumor cell lines were cultured conventionally. Cells in logarithmic growth phase were used in the experiments.

细胞生长检测(MTT法)将肿瘤细胞悬液调整至3×10⁴/mL(悬浮细胞调整至4×10⁴/mL)，分别接种于96孔板(100μL/孔)，3000个细胞/孔(悬浮细胞4000个细胞/孔)。铺板9h后，每孔中加入100μL含不同浓度化合物的培养基，每个浓度设三个复孔，不加细胞的孔读数时作空白，加细胞不加化合物的孔作化合物空白孔，SAHA作化合物阳性对照。于37℃，5％CO₂中孵育48h，每孔加入10μL 0.5％的MTT染色液，继续孵育。4h后，2500rpm，离心30min，然后抛弃板孔中培养基，每孔加入150μL DMSO，37℃恒温震摇5-10min。酶标仪上于570nm处测定每孔的吸光度OD值，细胞生长抑制率按下式计算：Cell growth assay (MTT method) Tumor cell suspension adjusted to 3×10 ⁴ /mL (suspension cells adjusted to 4×10 ⁴ /mL), respectively inoculated in 96-well plates (100 μL/well), 3000 cells/well (Suspension cells 4000 cells/well). 9 hours after plating, add 100 μL of medium containing different concentrations of compounds to each well, and set up three replicate wells for each concentration. The wells without cells are used as blank when reading, the wells with cells and no compounds are used as compound blank wells, and the wells with SAHA are used as blank wells. Compound positive control. Incubate for 48 hours at 37°C in 5% CO ₂ , add 10 μL of 0.5% MTT staining solution to each well, and continue to incubate. After 4 hours, centrifuge at 2500 rpm for 30 minutes, discard the culture medium in the plate wells, add 150 μL DMSO to each well, and shake at a constant temperature of 37° C. for 5-10 minutes. Measure the absorbance OD value of each well at 570nm on a microplate reader, and the cell growth inhibition rate is calculated according to the following formula:

基于不同抑制剂浓度下的抑制率，运用Graphpad Prism拟合获得IC₅₀值。实验结果见表3。Based on the inhibition rate at different inhibitor concentrations, the _IC50 value was obtained by Graphpad Prism fitting. The experimental results are shown in Table 3.

表3.代表性化合物的抗肿瘤细胞增殖活性Table 3. Anti-tumor cell proliferation activity of representative compounds

结果表明，实施例的化合物具有抗MDA-MB-231、A549、KG1、BxPC3和HepG2肿瘤活性。The results show that the compounds of the examples have anti-MDA-MB-231, A549, KG1, BxPC3 and HepG2 tumor activity.

综上可知，实施例的化合物具有非常好的细胞周期蛋白依赖性激酶抑制活性和抑制肿瘤细胞增殖的作用，可用于制备治疗癌症的药物。In summary, the compounds of the examples have very good cyclin-dependent kinase inhibitory activity and tumor cell proliferation inhibitory effect, and can be used to prepare drugs for treating cancer.

Claims (8)

1.一种2,4-二取代嘧啶类细胞周期蛋白依赖性激酶酶抑制剂，是具有通式I结构的化合物，以及其立体异构体、药学上可接受的盐；1. A 2,4-disubstituted pyrimidine-type cyclin-dependent kinase enzyme inhibitor, which is a compound with the structure of general formula I, and its stereoisomers and pharmaceutically acceptable salts;

通式I中，R₁代表氢原子、被1-3个取代基取代或者未被取代的烷基、烷氧基、环烷基、C₆-C₁₅芳基、C₆-C₁₅芳基C₁-C₆烷基、C₃-C₁₄杂芳基、C₃-C₁₄杂芳基C₁-C₆烷基，所述的取代基选自羟基、氰基、硝基、卤素、C₁-C₆烷基、C₁-C₆卤烷基、C₁-C₆烷氧基、C₃-C₈环烷基、含有5或6个环原子的单环芳基或具有8-15个环原子的双环芳基、含有1-2个杂原子的环原子数为5-6的单杂环基；In general formula I, R ₁ represents a hydrogen atom, substituted or unsubstituted alkyl, alkoxy, cycloalkyl, C ₆ -C ₁₅ aryl, C ₆ -C ₁₅ aryl C ₁ -C ₆ alkyl, C ₃ -C ₁₄ heteroaryl, C ₃ -C ₁₄ heteroaryl C ₁ -C ₆ alkyl, the substituents are selected from hydroxyl, cyano, nitro, halogen, C ₁ _-C ₆ alkyl, C ₁ -C 6 haloalkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkyl, monocyclic aryl containing 5 or 6 ring atoms or having 8 - a bicyclic aryl group with 15 ring atoms, a monoheterocyclic group with 5-6 ring atoms containing 1-2 heteroatoms; 通式I中，R₂代表氢或被1-3个取代基取代或者未被取代的的C₁-C₁₂烷基、C₁-C₁₂烷氧基、C₃-C₁₄环烷基、C₆-C₁₅芳基、C₆-C₁₅芳基C₁-C₆烷基、C₃-C₁₄杂芳基、C₃-C₁₄杂芳基C₁-C₆烷基，所述的取代基选自羟基、卤素、烷基、三氟甲基、氰基、硝基、胍基、氨基、磺酰氨基、哌嗪基、哌啶基、吗啉基、羧基、硝基、叔丁氧羰基、含有5或6个环原子的单环芳基或具有8-15个环原子的双环芳基、含有1-2个杂原子的环原子数为5-6的单杂环基，所述杂原子独立地选自O、S、N或氧化的S或N；In general formula I, R ₂ represents hydrogen or substituted or unsubstituted C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkoxy, C ₃ -C ₁₄ cycloalkyl, C ₆ -C ₁₅ aryl, C ₆ -C ₁₅ aryl C ₁ -C ₆ alkyl, C ₃ -C ₁₄ heteroaryl, C ₃ -C ₁₄ heteroaryl C ₁ -C ₆ alkyl, the The substituents are selected from hydroxyl, halogen, alkyl, trifluoromethyl, cyano, nitro, guanidino, amino, sulfonylamino, piperazinyl, piperidinyl, morpholinyl, carboxyl, nitro, tertiary Butoxycarbonyl, a monocyclic aryl group with 5 or 6 ring atoms or a bicyclic aryl group with 8-15 ring atoms, a monoheterocyclic group with 5-6 ring atoms containing 1-2 heteroatoms, The heteroatoms are independently selected from O, S, N or oxidized S or N; 通式I中，R₃代表卤素、羟基、烷基、三氟甲基、氰基、硝基、胍基、氨基、羧基、环氧基、C₁-C₁₂烷基、C_3-C₆环烷基；In general formula I, R ₃ represents halogen, hydroxyl, alkyl, trifluoromethyl, cyano, nitro, guanidino, amino, carboxyl, epoxy, C ₁ -C ₁₂ alkyl, C _{3 -C} ₆ Cycloalkyl; 通式I中，X代表CH或者氮。In the general formula I, X represents CH or nitrogen. 2.如权利要求1所述的一种2,4-二取代嘧啶类细胞周期蛋白依赖性激酶酶抑制剂，其特征在于，通式I中：2. a kind of 2,4-disubstituted pyrimidine class cyclin-dependent kinase enzyme inhibitor as claimed in claim 1, is characterized in that, in general formula I: R₁为氢原子、被1-3个取代基取代或者未被取代的C₁-C₁₂烷基、C₃-C₁₄环烷基、C₆-C₁₀芳基、C₃-C₉杂芳基，所述的取代基选自氰基、卤素、硝基、羧基、甲基、三氟甲基、胍基或、氨基、磺酰氨基、哌嗪基、吗啉基、哌啶基；R ₁ is a hydrogen atom, substituted by 1-3 substituents or unsubstituted C ₁ -C ₁₂ alkyl, C ₃ -C ₁₄ cycloalkyl, C ₆ -C ₁₀ aryl, C ₃ -C ₉ hetero Aryl, the substituent is selected from cyano, halogen, nitro, carboxyl, methyl, trifluoromethyl, guanidine or, amino, sulfonylamino, piperazinyl, morpholinyl, piperidinyl; R₂代表氢原子、被1-3个取代基取代或者未被取代的C₃-C₈环烷基、含有6-7个环原子的单环芳基或具有8-15个环原子的双环芳基、含有1-2个杂原子的环原子数为5-6的单杂环芳基或含有1-4个杂原子环原子数为8-15的双杂环芳基，所述杂原子独立地选自O、S、N或氧化的S或N，所述的取代基选自羟基、氰基、硝基、卤素、C₁-C₆烷基、C₁-C₆卤烷基、C₁-C₆烷氧基、含有5或6个环原子的单环芳基、含有1-2个杂原子的环原子数为5-6的单杂环芳基；R ₂ represents a hydrogen atom, a C ₃ -C ₈ cycloalkyl group substituted by 1-3 substituents or unsubstituted, a monocyclic aryl group containing 6-7 ring atoms or a bicyclic group having 8-15 ring atoms Aryl, a monoheterocyclic aryl group with 5-6 ring atoms containing 1-2 heteroatoms or a biheterocyclic aryl group with 8-15 ring atoms containing 1-4 heteroatoms, the heteroatoms independently selected from O, S, N or oxidized S or N, and the substituents are selected from hydroxyl, cyano, nitro, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, monocyclic aryl group containing 5 or 6 ring atoms, monoheterocyclic aryl group containing 1-2 heteroatoms with 5-6 ring atoms; R₃代表氢原子、卤素原子、羟基、烷基、三氟甲基、氰基、硝基、胍基、氨基、羧基、C₁-C₆烷基；R ₃ represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group, a trifluoromethyl group, a cyano group, a nitro group, a guanidine group, an amino group, a carboxyl group, and a C ₁ -C ₆ alkyl group; X代表CH或者氮。X represents CH or nitrogen. 3.如权利要求2所述的一种2,4-二取代嘧啶类细胞周期蛋白依赖性激酶酶抑制剂，其特征在于，通式I中：R₁代表氢原子，被1-3个取代基取代或者未被取代的C₁-C₆烷基，C₃-C₈环烷基，苯基，萘基，吲哚基，呋喃基，吡喃基，吡啶基，哌啶基，喹啉基，嘌呤基，嘧啶基，吡咯基，吡唑基，噻唑基，咪唑基或者噻吩基；所述的取代基选自卤素原子，羟基，氨基，C₁-C₆烷基，氰基，硝基或者C₃-C₆环烷基；3. a kind of 2,4-disubstituted pyrimidine class cyclin-dependent kinase enzyme inhibitors as claimed in claim 2, is characterized in that, in general formula I: _R represents hydrogen atom, is substituted by 1-3 Substituted or unsubstituted C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, phenyl, naphthyl, indolyl, furyl, pyranyl, pyridyl, piperidyl, quinoline Base, purinyl, pyrimidinyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl or thienyl; the substituent is selected from halogen atom, hydroxyl, amino, C ₁ -C ₆ alkyl, cyano, nitro group or C ₃ -C ₆ cycloalkyl; R₂代表氢原子，被1-3个取代基取代或者未被取代的氨基、酰胺基、二甲氨基、磺酰基或者含有1-2个杂原子的六元杂环基，其中所述取代基选自卤素原子，羟基，氨基，C₁-C₆烷基，氰基，硝基，或者叔丁氧羰基，所述的杂原子为N或者O；R ₂ represents a hydrogen atom, substituted or unsubstituted amino, amido, dimethylamino, sulfonyl, or six-membered heterocyclic group containing 1-2 heteroatoms, wherein the substituent Selected from halogen atoms, hydroxyl, amino, C ₁ -C ₆ alkyl, cyano, nitro, or tert-butoxycarbonyl, and the heteroatom is N or O; R₃代表氢原子、卤素原子，羟基，三氟甲基，氰基，氨基，羧基或者硝基；R ₃ represents a hydrogen atom, a halogen atom, a hydroxyl group, a trifluoromethyl group, a cyano group, an amino group, a carboxyl group or a nitro group; X代表CH或者氮。X represents CH or nitrogen. 4.如权利要求3所述的一种2,4-二取代嘧啶类细胞周期蛋白依赖性激酶酶抑制剂，其特征在于，通式I中：4. a kind of 2,4-disubstituted pyrimidine class cyclin-dependent kinase enzyme inhibitor as claimed in claim 3, is characterized in that, in general formula I: R₁代表C₁-C₆烷基，C₃-C₆环烷基；R ₁ represents C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl; R₂代表被1-3个取代基取代或者未被取代的吡啶基、哌啶基、哌嗪基、吗啉基、二甲氨基、甲磺酰基,所述取代基选自甲基，乙基，或者叔丁氧羰基；R ₂ represents substituted or unsubstituted pyridyl, piperidyl, piperazinyl, morpholinyl, dimethylamino, methylsulfonyl, said substituents are selected from methyl, ethyl , or tert-butoxycarbonyl; R₃代表氟原子或者氢原子；R ₃ represents a fluorine atom or a hydrogen atom; X代表CH或者氮原子。X represents CH or a nitrogen atom. 5.如权利要求4所述的一种2,4-二取代嘧啶类细胞周期蛋白依赖性激酶酶抑制剂，其特征在于，为如下化合物之一：5. A 2,4-disubstituted pyrimidine cyclin-dependent kinase enzyme inhibitor as claimed in claim 4, characterized in that it is one of the following compounds:

6.如权利要求5所述的一种2,4-二取代嘧啶类细胞周期蛋白依赖性激酶酶抑制剂的制备方法，合成路线如下：6. the preparation method of a kind of 2,4-disubstituted pyrimidine class cyclin-dependent kinase enzyme inhibitor as claimed in claim 5, the synthetic route is as follows:

试剂和条件：a)叔丁醇钾,乙二醇二甲醚,室温反应30分钟；碳酸钾，70℃反应8小时；b)联硼酸频那醇酯，醋酸钾，[1,1'-双(二苯基膦基)二茂铁]二氯化钯,二甲基亚砜,80℃反应8h；c)碳酸钾，[1,1'-双(二苯基膦基)二茂铁]二氯化钯，二氧六环，水，80℃反应8小时；d)三乙胺，二甲基亚砜，110℃反应6小时；e)钯碳，甲醇，室温反应10小时；f)双(三甲基硅基)氨基锂，甲苯，室温搅拌10分钟，室温反应1小时；Reagents and conditions: a) potassium tert-butoxide, ethylene glycol dimethyl ether, react at room temperature for 30 minutes; potassium carbonate, react at 70°C for 8 hours; b) pinacol borate, potassium acetate, [1,1'- Bis(diphenylphosphino)ferrocene]palladium dichloride, dimethyl sulfoxide, 80℃ for 8h; c) Potassium carbonate, [1,1'-bis(diphenylphosphino)ferrocene ] palladium dichloride, dioxane, water, 80 ℃ reaction 8 hours; d) triethylamine, dimethyl sulfoxide, 110 ℃ reaction 6 hours; e) palladium carbon, methanol, room temperature reaction 10 hours; f ) Lithium bis(trimethylsilyl)amide, toluene, stirred at room temperature for 10 minutes, and reacted at room temperature for 1 hour; 合成路线中R₁、R₂、R₃如下所示：R ₁ , R ₂ , and R ₃ in the synthetic route are as follows:

7.如权利要求1-5任一所述的2,4-二取代嘧啶类细胞周期蛋白依赖性激酶酶抑制剂在制备癌症药物中的应用。7. Use of the 2,4-disubstituted pyrimidine cyclin-dependent kinase enzyme inhibitor according to any one of claims 1-5 in the preparation of cancer drugs. 8.一种适于口服或胃肠外给药的药物组合物，包含权利要求1-5任一所述的2,4-二取代嘧啶类细胞周期蛋白依赖性激酶酶抑制剂和一种或多种药学上可接受的载体或赋形剂。8. A pharmaceutical composition suitable for oral or parenteral administration, comprising the 2,4-disubstituted pyrimidine cyclin-dependent kinase inhibitor of any one of claims 1-5 and one or Various pharmaceutically acceptable carriers or excipients.

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CN115703760A - 2,4-disubstituted pyrimidines cyclin dependent kinase inhibitor and preparation method and application thereof - Google Patents

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