TW202322805A

TW202322805A - Heterocyclic compounds with cyclin-dependent kinase inhibition activity, a preparation method and medical use thereof

Info

Publication number: TW202322805A
Application number: TW111136383A
Authority: TW
Inventors: 閆旭; 陳振華; 劉國標; 谷曉成; 尚飛; 杜佩金
Original assignee: 大陸商中國醫藥研究開發中心有限公司
Priority date: 2021-09-29
Filing date: 2022-09-26
Publication date: 2023-06-16
Also published as: CN116390921A; WO2023051302A1

Abstract

The present invention relates to heterocyclic compounds with cyclin-dependent kinase inhibition activity, a preparation method and medical use thereof. Specifically, the present invention relates to the compound represented by the general formula (I), its preparation method, the pharmaceutical composition containing the same, and its use as a cyclin-dependent kinase (CDK) inhibitor in the prevention and/or treatment of abnormal cell growth such as cancer. The definition of each group in the general formula (I) is the same as that in the specification.

Description

具有細胞週期蛋白依賴性激酶抑制活性的雜環化合物及其製備方法和醫藥用途 Heterocyclic compound with cyclin-dependent kinase inhibitory activity, preparation method and medical use thereof

本發明屬於醫藥技術領域，具體關於一種嘧啶并吡啶類化合物、及其製備方法及含有其的醫藥組成物，以及其作為細胞週期蛋白依賴性激酶(CDK)抑制劑在治療異常細胞生長如癌症的藥物中的用途。本發明的化合物可以抑制細胞週期蛋白依賴性激酶CDK2/細胞週期蛋白E1(CCNE1)、CDK6/細胞週期蛋白D1、CDK4/細胞週期蛋白D3，因此可用於治療癌症，如HR+/HER2-轉移性乳腺癌、卵巢癌等。 The invention belongs to the technical field of medicine, and specifically relates to a pyrimidopyridine compound, a preparation method thereof, a pharmaceutical composition containing the same, and its use as a cyclin-dependent kinase (CDK) inhibitor in the treatment of abnormal cell growth such as cancer Uses in medicine. The compounds of the present invention can inhibit the cyclin-dependent kinases CDK2/cyclin E1 (CCNE1), CDK6/cyclin D1, CDK4/cyclin D3, and therefore can be used for the treatment of cancer, such as HR+/HER2- metastatic breast cancer, ovarian cancer, etc.

細胞週期蛋白依賴性激酶(CDK)屬於絲胺酸/蘇胺酸蛋白激酶家族，是調控細胞週期的關鍵蛋白。目前，已發現的CDK主要包括CDK1-15等，藉由與相應的細胞週期蛋白(cyclin)結合，形成穩定形式的CDK/cyclin複合物，來發揮作用。此外，細胞內含有內源性的CDK和CDK/cyclin複合物抑制因子(CKI)，這三者共同組成細胞週期的調控網絡，在細胞***的過程中受到嚴格控制。在許多癌細胞中均發現，CDK、細胞週期蛋白和CKI三者表達失控，且CDK/細胞週期蛋白複合物通常是過度表達。 Cyclin-dependent kinases (CDKs) belong to the serine/threonine protein kinase family and are key proteins in the regulation of the cell cycle. Currently, the discovered CDKs mainly include CDK1-15, etc., which play a role by combining with the corresponding cell cycle protein (cyclin) to form a stable form of CDK/cyclin complex. In addition, cells contain endogenous CDK and CDK/cyclin complex inhibitor (CKI), which together form a cell cycle regulatory network that is strictly controlled during cell division. control. In many cancer cells, it is found that the expression of CDK, cyclin and CKI is out of control, and the CDK/cyclin complex is usually overexpressed.

CDK4和CDK6的結構和功能十分相似，且都能與cyclin D的3種亞型(cyclinD1/D2/D3)結合，形成複合物，使包括視網膜母細胞瘤蛋白(Retinoblastoma protein,Rb)在內的一系列受質磷酸化，促使細胞週期進展。磷酸化的Rb蛋白釋放與其結合的轉錄因子E2F等，E2F激活並轉錄一系列基因，使細胞進入S期，開始DNA複製(Kato等人，Genes Dev，1993，7(3)，331-342；Dyson等人，Genes Dev，1998，12(15)，2245-2262)。CDK4/6的活性同時受INK4家族(包括p16^INK4A、p15^INK4B、p18^INK4C、p19^INK4D)的負性調控，INK4作為內源性抑制蛋白，可與CDK競爭性結合，抑制cyclin D-CDK4/6複合物的形成(Baker等人，Genes & Cancer，2012，3(11-12)，658-669)。 The structure and function of CDK4 and CDK6 are very similar, and they can combine with the three subtypes of cyclin D (cyclinD1/D2/D3) to form a complex, which makes the retinoblastoma protein (Retinoblastoma protein, Rb) Phosphorylation of a series of substrates promotes cell cycle progression. The phosphorylated Rb protein releases the transcription factor E2F bound to it, etc. E2F activates and transcribes a series of genes, making the cell enter the S phase and start DNA replication (Kato et al., Genes Dev, 1993, 7(3), 331-342; Dyson et al., Genes Dev, 1998, 12(15), 2245-2262). The activity of CDK4/6 is also negatively regulated by the INK4 family (including p16 ^INK4A , p15 ^INK4B , p18 ^INK4C , p19 ^INK4D ). As an endogenous inhibitory protein, INK4 can competitively bind with CDK and inhibit cyclin D-CDK4/6 Complex formation (Baker et al., Genes & Cancer, 2012, 3(11-12), 658-669).

然而，多數人類癌症中均發現，CyclinD-CDK4/6-p16-Rb通路出現異常持續激活，這會促使G1期快速發展，導致細胞異常增殖。其主要原因包括，基因重排或者基因擴增導致cyclin D1的過度表達(Bergsagel等人，Blood，2005，106(1)，296-303)；p16INK4a基因缺失、點突變、或者DNA甲基化導致p16INK4a失活(Ruas等人，Biochim Biophys Acta，1998，1378(2)，F115-177)；CDK4/6基因擴增或者點突變(Hamilton等人，Cancer Treatment Reviews，2016，45,129-138)。基於該通路的異常進行靶向干預，使得CDK4/6成為熱門的抗腫瘤靶點之一。 However, abnormal and persistent activation of the CyclinD-CDK4/6-p16-Rb pathway has been found in most human cancers, which can promote the rapid development of G1 phase and lead to abnormal cell proliferation. The main reasons include overexpression of cyclin D1 caused by gene rearrangement or gene amplification (Bergsagel et al., Blood, 2005, 106(1), 296-303); p16INK4a gene deletion, point mutation, or DNA methylation lead to p16INK4a inactivation (Ruas et al., Biochim Biophys Acta, 1998, 1378(2), F115-177); CDK4/6 gene amplification or point mutation (Hamilton et al., Cancer Treatment Reviews, 2016, 45, 129-138). Targeted intervention based on the abnormality of this pathway makes CDK4/6 one of the popular anti-tumor targets.

靶向CDK的治療中，進展最快的是選擇性CDK4/6抑制劑。第一代廣譜類CDK抑制劑Flavopiridol(Alvocidib)可同時抑制CDK1/2/4/6/7/9，但由於其嚴重的毒副作用，導致出現乏力、腹瀉、骨髓抑制等不良反應，最終未能成功應用於臨床(Senderowicz等人，Journal of Clinical Oncology，1998，16(9)，2986-2999)。目前有三款化合物Palbociclib、Ribociclib和Abemaciclib獲得FDA批准，用於晚期乳腺癌的一線或二線治療，還有一項藥物Lerociclib處於臨床開發階段。 Among the therapies targeting CDK, the fastest progress is the selective CDK4/6 inhibitor. Flavopiridol (Alvocidib), the first-generation broad-spectrum CDK inhibitor, can inhibit CDK1/2/4/6/7/9 at the same time, but due to its severe side effects, it may cause adverse reactions such as fatigue, diarrhea, and bone marrow suppression, and finally failed able It has been successfully applied clinically (Senderowicz et al., Journal of Clinical Oncology, 1998, 16(9), 2986-2999). Currently, three compounds, Palbociclib, Ribociclib and Abemaciclib, have been approved by the FDA for first-line or second-line treatment of advanced breast cancer, and one drug, Lerociclib, is in clinical development.

Palbociclib是FDA批准的首個CDK4/6抑制劑。它是一種口服的吡啶類化合物，藉由降低Rb蛋白的磷酸化，阻止細胞週期從G1期進入S期，抑制ER+乳腺癌細胞的增殖。多項大型、隨機、前瞻性的臨床研究已經證實Palbociclib聯合來曲唑或Fulvestrant能顯著延長患者無進展生存期，且安全性可靠(Cristofanilli等人，Lancet Oncol，2016，17(4)，425-439；Richard等人，Lancet Oncology，2015；Finn等人，N Engl J Med，2016，375(20)，1925-1936；Nicholas等人，N Engl J Med，2015，373(3)，209-219)。這些臨床試驗數據支持Palbociclib聯合芳香化酶抑制劑或氟維斯群作為標準的一線護理方案，治療ER+/HER2-絕經前或絕經後乳腺癌轉移的女性患者。 Palbociclib is the first CDK4/6 inhibitor approved by the FDA. It is an oral pyridine compound, which prevents the cell cycle from G1 phase to S phase by reducing the phosphorylation of Rb protein, and inhibits the proliferation of ER+ breast cancer cells. A number of large-scale, randomized, and prospective clinical studies have confirmed that Palbociclib combined with letrozole or Fulvestrant can significantly prolong the progression-free survival of patients with reliable safety (Cristofanilli et al., Lancet Oncol, 2016, 17(4), 425-439 ; Richard et al., Lancet Oncology, 2015; Finn et al., N Engl J Med, 2016, 375(20), 1925-1936; Nicholas et al., N Engl J Med, 2015, 373(3), 209-219) . These clinical trial data support the use of palbociclib in combination with an aromatase inhibitor or fulvestrant as a standard first-line care regimen for the treatment of ER+/HER2- premenopausal or postmenopausal women with metastatic breast cancer.

Ribociclib(Kisqali，LEE011)和Abemaciclib(Verzenio，LY2835219)均是口服可逆的CDK4/6抑制劑，能夠藉由抑制Rb磷酸化，引起G1期阻滯。Ribociclib對CDK4/6抑制的IC₅₀值分別為10nM和39nM，而對其他CDK家族成員敏感性較低(CDK1和CDK2的IC₅₀值均大於50mM)(Sherr等人，Cancer Discovery，2016，6(4)，353-367)。口服給藥1-4h後，血漿內能達到Cmax值；持續給藥8天後達到血液穩定狀態。Ribociclib與人血漿蛋白的結合率為70%，在體內能被CPY3A4(一種弱抑制劑)分解，主要產物是N-羥基和N-去甲基衍生物。Abemaciclib對CDK4/6激酶的選擇性更高，IC₅₀值分別為2nM和5nM，而對CDK1和CDK2抑制的IC₅₀值>500nM。Abemacielib是一種苯基嘧啶類化合物，結構上與Palbociclib和Ribociclib相近。Abemaciclib表現出更廣泛的抑制作用，同時能夠抑制Dyrk、PIM、HIPK和CAMK激酶家族(Ki<10nM)(Chen等人，Molecular Cancer Therapeutics，2016，15(10)，2273-2281)。體內藥物代謝數據顯示，口服給藥後的4-24小時內達到峰值，持續服用5天後達到穩態。Abemaciclib與人血漿蛋白的結合率約為96%，在體內能被CPY3A4分解，主要分解產物為N-脫乙基衍生物。氘原子的引入，使化合物具有更強的代謝穩定性，代謝穩定性提高了11-45%，表現為較高的半衰期。該藥物被批准，與Fluvestrant聯合治療ER+/HER2-晚期或轉移性乳腺癌。此外，在異種移植腫瘤中，Abemaciclib與吉西他濱聯用，也顯示出協同抗腫瘤活性，並且對多種類型腫瘤也具有抑制效果，包括套細胞淋巴瘤(MCL)、結直腸癌、肺癌、膠質母細胞瘤和急性髓細胞白血病(AML)。 Ribociclib (Kisqali, LEE011) and Abemaciclib (Verzenio, LY2835219) are oral reversible CDK4/6 inhibitors, which can cause G1 phase arrest by inhibiting Rb phosphorylation. The IC ₅₀ values of ribociclib for CDK4/6 inhibition are 10nM and 39nM, respectively, while the sensitivity to other CDK family members is low (the IC ₅₀ values of CDK1 and CDK2 are both greater than 50mM) (Sherr et al., Cancer Discovery, 2016, 6( 4), 353-367). After 1-4 hours of oral administration, the Cmax value can be reached in the plasma; after 8 days of continuous administration, the stable state of blood is reached. The binding rate of ribociclib to human plasma protein is 70%, and it can be decomposed by CPY3A4 (a weak inhibitor) in vivo, and the main products are N-hydroxyl and N-demethylated derivatives. Abemaciclib is more selective for CDK4/6 kinases with IC ₅₀ values of 2 nM and 5 nM, respectively, while for CDK1 and CDK2 inhibition with IC ₅₀ values >500 nM. Abemacielib is a phenylpyrimidine compound that is structurally related to palbociclib and ribociclib. Abemaciclib exhibited a broader inhibitory effect and was able to inhibit Dyrk, PIM, HIPK and CAMK kinase families (Ki<10nM) simultaneously (Chen et al., Molecular Cancer Therapeutics, 2016, 15(10), 2273-2281). In vivo drug metabolism data show that it reaches a peak within 4-24 hours after oral administration, and reaches a steady state after 5 days of continuous administration. The binding rate of Abemaciclib to human plasma protein is about 96%, and it can be decomposed by CPY3A4 in vivo, and the main decomposition product is N-deethyl derivative. The introduction of deuterium atoms makes the compound have stronger metabolic stability, and the metabolic stability is increased by 11-45%, which is manifested as a higher half-life. The drug is approved in combination with Fluvestrant for the treatment of ER+/HER2- advanced or metastatic breast cancer. In addition, in xenograft tumors, Abemaciclib combined with gemcitabine also showed synergistic antitumor activity, and also had inhibitory effects on various types of tumors, including mantle cell lymphoma (MCL), colorectal cancer, lung cancer, glioblastoma cancer and acute myeloid leukemia (AML).

儘管CDK4/6抑制劑聯合內分泌治療方法，能給特定類型乳腺癌患者帶來顯著臨床收益，但仍舊有部分患者是治療無效(10-20%)，且70-80%的腫瘤患者在治療12-36月後會發展為耐藥(Tripathy等人，Lancet Oncol，2018，19(7)，904-915)。CDK4/6治療耐藥的因素有多種，臨床前研究表明，包括Rb丟失、CCND1過表達、p16擴增、CCNE1-CDK2複合物過度激活(例如，CCNE1在乳腺癌和卵巢癌細胞系模型中高表達)、CDK2的旁路激活、CDK4/6活性增高、CDK7過表達等，這些均可能與CDK4/6治療耐藥相關(Taylor Harding等人，Oncotarget，2014，6(2)，696-714；Herrera-Abreu等人，Cancer Res，2016，76(8)，2301-2313)。 Although CDK4/6 inhibitors combined with endocrine therapy can bring significant clinical benefits to certain types of breast cancer patients, some patients are still ineffective (10-20%), and 70-80% of tumor patients are treated after 12 - Development of drug resistance after 36 months (Tripathy et al., Lancet Oncol, 2018, 19(7), 904-915). Several factors contribute to resistance to CDK4/6 therapy, and preclinical studies have shown that these include loss of Rb, overexpression of CCND1, amplification of p16, hyperactivation of the CCNE1-CDK2 complex (for example, CCNE1 is highly expressed in breast and ovarian cancer cell line models ), CDK2 bypass activation, increased CDK4/6 activity, CDK7 overexpression, etc., all of which may be related to CDK4/6 treatment resistance (Taylor Harding et al., Oncotarget, 2014, 6(2), 696-714; Herrera - Abreu et al., Cancer Res, 2016, 76(8), 2301-2313).

藉由生物標記物方法將乳腺癌患者分為不同亞組，不僅有助於區分從Palbociclib最大獲益的患者亞組，還有助於闡明可能導致CDK4/6聯合治療耐藥的機制。Palbociclib最近的III期臨床研究中發現，CCNE1(細胞週期蛋白E1)與治療抵抗密切相關(Turner等人，Journal of Clinical Oncology，2019，37(14)，1-11)。CCNE1 mRNA低表達的亞組人群，Palbociclib療效顯著。同時，對臨床治療中其它變量分析，CDK4、CDK6、cyclin D1、RB1的表達水平與Palbociclib的治療效果均無顯著關聯；該研究引起人們極大興趣，也證實CCNE1是Palbociclib的耐藥的生物標記物。 Dividing breast cancer patients into different subgroups by biomarker approach not only helps to distinguish the subgroup of patients who benefit the most from palbociclib, but also helps to clarify the possible causes of CDK4/6 combination therapy. Mechanisms of drug resistance. In the recent phase III clinical study of palbociclib, CCNE1 (cyclin E1) was found to be closely related to treatment resistance (Turner et al., Journal of Clinical Oncology, 2019, 37(14), 1-11). In subgroups with low CCNE1 mRNA expression, Palbociclib has a significant effect. At the same time, in the analysis of other variables in clinical treatment, the expression levels of CDK4, CDK6, cyclin D1, and RB1 were not significantly related to the therapeutic effect of Palbociclib; this study aroused great interest and confirmed that CCNE1 is a biomarker of Palbociclib resistance .

Cyclin E(細胞週期蛋白E)是由CCNE1編碼的蛋白，在G1中期開始表達，在G1-S期表達水平達到高峰後逐漸降解消失，其表達水平受E2F調控，藉由泛素化蛋白酶體降解(Mazumder等人，Current Cancer Drug Targets，2004，4(1)，65-75)。Cyclin E與CDK2結合，形成複合物，藉由磷酸化下游受質Rb、CDC6、NPAT和P107等使細胞進入DNA合成的S期；Cyclin E在維持染色體穩定，調控細胞紡錘體和中心體週期中具有重要作用；Cyclin E在多種惡性腫瘤中存在高表達，且CCNE1基因擴增或過表達還與多種腫瘤的預後差有關，如子宮內膜瘤、胃癌、卵巢癌(George等人，Clinical cancer research，2017，23(7)，1862-1874；Nakayama等人，Cancer，2010，116(11)，2621-2634；KENTARO等人，Int J Oncol，2015，48(2)，506-516；Ooi等人，Human Pathology，2016，S0046817716303082)等。 Cyclin E (Cyclin E) is a protein encoded by CCNE1, which begins to express in the middle of G1, and gradually degrades and disappears after the expression level reaches the peak in G1-S phase. (Mazumder et al., Current Cancer Drug Targets, 2004, 4(1), 65-75). Cyclin E binds to CDK2 to form a complex, and phosphorylates the downstream substrates Rb, CDC6, NPAT and P107 to make the cell enter the S phase of DNA synthesis; Cyclin E maintains chromosome stability and regulates the cell spindle and centrosome cycle It plays an important role; Cyclin E is highly expressed in a variety of malignant tumors, and CCNE1 gene amplification or overexpression is also related to the poor prognosis of a variety of tumors, such as endometrioma, gastric cancer, and ovarian cancer (George et al., Clinical cancer research , 2017, 23(7), 1862-1874; Nakayama et al., Cancer, 2010, 116(11), 2621-2634; KENTARO et al., Int J Oncol, 2015, 48(2), 506-516; Ooi et al. People, Human Pathology, 2016, S0046817716303082) etc.

CDK2藉由與伴侶蛋白相互作用並磷酸化激活，在細胞週期調控中發揮關鍵作用，並參與一系列生物學過程，例如DNA損傷、細胞內轉運、蛋白質降解、信號轉導、DNA和RNA代謝和轉譯等(Tadesse等人，Drug Discovery Today，2020，25(2)，406-413)。CDK2在大多數正常組織是低表達狀態(McCurdy等人，Oncogene，2016)。***期的細胞，CDK2是關鍵的細胞週期調節因子，從G1期晚期開始激活，持續表達整個S期。CDK2結合CCNE1或E2和Cyclin A2，被細胞週期蛋白複合物(CDK7、MAT1、細胞週期蛋白H)磷酸化激活，同時，可被CDC25A去磷酸化負調控。在G1後期，CDK2-cyclinE和CDK4/6-cyclin-D共同磷酸化Rb，使Rb釋放E2F，啟動細胞週期調控基因的轉錄。除Rb外，CDK2還可調節其他蛋白的磷酸化，使之與細胞週期聯繫起來。例如，CDK2-cyclin-E對Smad3的磷酸化限制了其轉錄活性，最終減緩了細胞週期進展(Matsuura等人，Nature，2004，430(6996)，226-231)。CDK2還能磷酸化複製前複合物蛋白，這些是啟動DNA合成所必需的。如CDC6，它是將微小染色體維持(MCM)蛋白裝載到DNA和MCM解旋酶蛋白上，並啟動DNA複製的必需蛋白(Chuang等人，Molecular Cell，2009，35(2)，206-216)。CDK2在調控中心體複製方面也起著重要作用，藉由靶向磷酸化中心體蛋白如核磷脂(Npm)和cp110，釋放中心粒，然後維持中心粒複製(Adon等人，Molecular & Cellular Biology，2010，30(3)，694-710；Hu等人，Cancer Research，2015，75(10)，2029-2038)。 CDK2 plays a key role in cell cycle regulation by interacting with chaperone proteins and phosphorylation activation, and participates in a series of biological processes, such as DNA damage, intracellular transport, protein degradation, signal transduction, DNA and RNA metabolism and Translation et al. (Tadesse et al., Drug Discovery Today, 2020, 25(2), 406-413). CDK2 is underexpressed in most normal tissues (McCurdy et al., Oncogene, 2016). In dividing cells, CDK2 is a key cell cycle regulator, Activated from late G1 phase, persistent expression throughout S phase. CDK2 binds CCNE1 or E2 and Cyclin A2, is activated by phosphorylation of cyclin complexes (CDK7, MAT1, cyclin H), and can be negatively regulated by CDC25A dephosphorylation. In late G1, CDK2-cyclinE and CDK4/6-cyclin-D co-phosphorylate Rb, causing Rb to release E2F and initiate the transcription of cell cycle regulatory genes. In addition to Rb, CDK2 also regulates the phosphorylation of other proteins, linking them to the cell cycle. For example, phosphorylation of Smad3 by CDK2-cyclin-E limits its transcriptional activity, ultimately slowing cell cycle progression (Matsuura et al., Nature, 2004, 430(6996), 226-231). CDK2 also phosphorylates prereplication complex proteins, which are required to initiate DNA synthesis. Such as CDC6, which is an essential protein for loading minichromosome maintenance (MCM) protein onto DNA and MCM helicase protein, and initiating DNA replication (Chuang et al., Molecular Cell, 2009, 35(2), 206-216) . CDK2 also plays an important role in regulating centrosome duplication by targeting phosphorylated centrosome proteins such as nucleophospholipid (Npm) and cp110, releasing centrioles and then maintaining centriole duplication (Adon et al., Molecular & Cellular Biology, 2010, 30(3), 694-710; Hu et al., Cancer Research, 2015, 75(10), 2029-2038).

CDK2的蛋白結構與大多數的蛋白激酶類似，折疊呈“雙葉狀”。體積較小的N-末端區主要由β-折疊構成，包括5個反平行結構的β-長鏈和一個C-螺旋。C-α螺旋含有序列PSTAIRE，是週期蛋白結合所必需的。較大的C-末端區域，富含α-螺旋，並包含激活片段(也稱為T-環(殘基145(天冬胺酸)-172(谷胺酸))和激活磷酸化位點Thr160。T-環結合受質的Ser/Thr(磷酸化受體)區域，進行磷酸化激活，發揮細胞週期調控作用。N-末端和C-末端由柔性鉸鏈區(殘基81(Glu)-84(His))連接，該區域形成一個深裂，即ATP結合位點(Pavletich等人，Journal of Molecular Biology，1999，287(5)，821-828；Malumbres等人，Chemical Reviews，2014，15(6)，122；Honda等人，Embo Journal，2005，24(3))。 The protein structure of CDK2 is similar to that of most protein kinases, and it is folded in a "double leaf shape". The smaller N-terminal region is mainly composed of β-sheets, including 5 long antiparallel β-strands and a C-helix. The C-alpha helix contains the sequence PSTAIRE and is required for cyclin binding. Larger C-terminal region, rich in α-helices, and contains the activation segment (also known as the T-loop (residues 145 (aspartate)-172 (glutamate)) and the activation phosphorylation site Thr160 The T-ring binds to the Ser/Thr (phosphorylated receptor) region of the substrate, activates phosphorylation, and plays a role in cell cycle regulation. The N-terminal and C-terminal are composed of a flexible hinge region (residues 81 (Glu)-84 (His)) junction, this region forms a deep cleft, the ATP binding site (Pavletich et al. People, Journal of Molecular Biology, 1999, 287(5), 821-828; Malumbres et al., Chemical Reviews, 2014, 15(6), 122; Honda et al., Embo Journal, 2005, 24(3)).

CDK2激活和抑制受到以下幾種機制調控：在沒有絲裂原信號時，CDK2處於非活性狀態。在G1期後期，CDK2活性開始升高，這是由於，首先，E2F介導的CCNE基因轉錄，其蛋白產物結合並激活CDK2；CDK2-cyclin E或A複合物的完全激活，需要CAK磷酸化Thr160位點；再者，Wee1和Myt1激酶能分別抑制Thr14和Tyr15位點的磷酸化，CDC25蛋白磷酸酶家族對這些殘基的去磷酸化可以使CDK2重新激活；此外，CDK抑制蛋白家族Cip和Kip，能結合CDK2使其失活，週期蛋白E和A可被泛素連接酶介導的泛素化過程所降解(Solomon等人，Journal of Medicinal Chemistry，2018)。 CDK2 activation and inhibition are regulated by several mechanisms: In the absence of mitogen signaling, CDK2 is inactive. In the late G1 phase, CDK2 activity begins to increase, which is due to, first, E2F-mediated transcription of the CCNE gene, and its protein product binds and activates CDK2; full activation of the CDK2-cyclin E or A complex requires phosphorylation of Thr160 by CAK Furthermore, Wee1 and Myt1 kinases can inhibit the phosphorylation of Thr14 and Tyr15 respectively, and the dephosphorylation of these residues by the CDC25 protein phosphatase family can reactivate CDK2; in addition, the CDK inhibitory protein family Cip and Kip , can bind to CDK2 to inactivate it, and cyclins E and A can be degraded by ubiquitin ligase-mediated ubiquitination (Solomon et al., Journal of Medicinal Chemistry, 2018).

CDK2還可結合細胞週期蛋白A，參與整個S期的進展，並調控DNA損傷修復。DNA損傷後，DNA損傷反應(DDR)使細胞阻滯在G1/S交界處，以修復受損的DNA，並維持子細胞的基因組保真度。研究發現，有兩種機制，均是藉由抑制CDK2蛋白磷酸化，使細胞維持在G1/S的DNA損傷檢查點，並阻止細胞增殖。首先，p53的積累導致p21Cip1/Waf1轉錄上調，隨後藉由抑制cyclin-D1-CDK4/6和cyclinE-CDK2，使細胞週期停滯(Shieh等人，Genes & Development，2000，14(3)，289-300)。第二個機制是靶向CDC25A進行降解，WEE1藉由持續抑制CDK2蛋白Thr14和Tyr15位置的磷酸化，從而阻止細胞進入S期(Mailand等人，Science，2000，288(5470)，1425-1429)。CDK2的靶蛋白，FOXO1在dsDNA斷裂觸發DNA損傷，從而誘導細胞凋亡中起著重要作用。DNA損傷誘導G1/S期阻滯時，CDK2不再磷酸化FOXO1，使FOXO1發揮轉錄活性，藉由上調多種促凋亡蛋白的表達(FasL、TRAIL和Bim)，促使細胞凋亡過程(Huang等人，Science，2006，314(5797)，294-297；Huang等人，Cell Cycle，2007，6(8)，902-906)。 CDK2 can also bind cyclin A, participate in the progression of the entire S phase, and regulate DNA damage repair. Following DNA damage, the DNA damage response (DDR) arrests cells at the G1/S junction to repair damaged DNA and maintain genomic fidelity in daughter cells. Studies have found that there are two mechanisms, both of which are to maintain cells at the G1/S DNA damage checkpoint and prevent cell proliferation by inhibiting CDK2 protein phosphorylation. First, the accumulation of p53 leads to the upregulation of p21Cip1/Waf1 transcription, followed by cell cycle arrest by inhibiting cyclin-D1-CDK4/6 and cyclinE-CDK2 (Shieh et al., Genes & Development, 2000, 14(3), 289- 300). The second mechanism is to target CDC25A for degradation. WEE1 prevents cells from entering the S phase by continuously inhibiting the phosphorylation of CDK2 protein Thr14 and Tyr15 (Mailand et al., Science, 2000, 288(5470), 1425-1429) . The target protein of CDK2, FOXO1, plays an important role in dsDNA breakage triggering DNA damage, thereby inducing apoptosis. When DNA damage induces G1/S phase arrest, CDK2 no longer phosphorylates FOXO1, allowing FOXO1 to exert transcriptional activity, and promotes cell apoptosis by up-regulating the expression of various pro-apoptotic proteins (FasL, TRAIL, and Bim) Process (Huang et al., Science, 2006, 314(5797), 294-297; Huang et al., Cell Cycle, 2007, 6(8), 902-906).

綜合以上，雖然CDK4/6抑制劑已成為特定類型乳腺癌的一線治療方案，但有些類型乳腺癌對CDK4/6抑制劑是天然的不敏感，如三陰性乳腺癌(TNBC)。另外在ER+Her2-的乳腺癌中也發現對CDK4/6耐藥現象。Cyclin E在多種惡性腫瘤中存在高表達，包括對CDK4/6抑制劑不敏感的腫瘤(TNBC)和卵巢癌等；CDK2與CyclinE形成的複合體，在CDK4/6耐藥中也發揮重要作用；靶向CDK2能夠延緩CDK4/6抑制劑分子產生的治療抵抗，對耐藥的患者進一步發揮療效；而在靶向CDK2/4/6來克服CDK4/6耐藥的化合物中，未見有獲批的藥物，僅有Pfizer的PF-06873600進入臨床II期研究。因此，開發選擇性高、藥物毒性低的CDK2/4/6抑制劑，來克服CDK4/6耐藥，是一個急需解決的問題。 In summary, although CDK4/6 inhibitors have become the first-line treatment for specific types of breast cancer, some types of breast cancer are naturally insensitive to CDK4/6 inhibitors, such as triple-negative breast cancer (TNBC). In addition, drug resistance to CDK4/6 was also found in ER+Her2- breast cancer. Cyclin E is highly expressed in a variety of malignant tumors, including tumors insensitive to CDK4/6 inhibitors (TNBC) and ovarian cancer; the complex formed by CDK2 and CyclinE also plays an important role in CDK4/6 drug resistance; Targeting CDK2 can delay the treatment resistance produced by CDK4/6 inhibitor molecules, and further exert curative effects on drug-resistant patients; however, no compounds targeting CDK2/4/6 to overcome CDK4/6 drug resistance have been approved Only Pfizer's PF-06873600 has entered Phase II clinical research. Therefore, it is an urgent problem to develop CDK2/4/6 inhibitors with high selectivity and low drug toxicity to overcome CDK4/6 drug resistance.

來自輝瑞PF-06873600的專利(US 2018/0044344 A1)數據顯示，在不同腫瘤類型的細胞系中，CCNE1在卵巢癌OVCAR3和乳腺癌HCC1806中具有較高的擴增頻率。因此，合成了一系列具有類藥性質的小分子CDK2/4/6抑制劑。藉由檢測對OVCAR3和HCC1806細胞的抑制水平，評估了CDK2抑制的效果；藉由檢測對MCF-7細胞的抑制水平，評估了CDK4/6抑制的效果。 Data from Pfizer's PF-06873600 patent (US 2018/0044344 A1) showed that among cell lines of different tumor types, CCNE1 had a higher amplification frequency in ovarian cancer OVCAR3 and breast cancer HCC1806. Therefore, a series of small molecule CDK2/4/6 inhibitors with drug-like properties were synthesized. By detecting the inhibition level of OVCAR3 and HCC1806 cells, the effect of CDK2 inhibition was evaluated; by detecting the inhibition level of MCF-7 cells, the effect of CDK4/6 inhibition was evaluated.

本發明人經過潛心研究，設計合成了一系列嘧啶并吡啶類化合物，其顯示出抑制細胞週期蛋白依賴性激酶(CDK)活性，可以被開發為治療和/或預防與CDK活性相關的疾病如癌症的藥物。 After painstaking research, the inventors have designed and synthesized a series of pyrimidopyridine compounds, which are shown to inhibit the activity of cyclin-dependent kinase (CDK), and can be developed to treat and/or prevent diseases related to CDK activity, such as cancer Drug.

因此，本發明的目的是提供一種通式(I)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽， Therefore, the object of the present invention is to provide a compound represented by general formula (I) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereoisomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

其中， in,

環A選自雜環基，該雜環基視需要進一步被選自鹵素、胺基、硝基、氰基、羥基、巰基、側氧基、烷基、烷氧基、鹵烷基、鹵烷氧基、環烷基、雜環基、芳基、雜芳基的一個或多個基團所取代； Ring A is selected from heterocyclic groups, which are further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, pendant oxy, alkyl, alkoxy, haloalkyl, haloalkane, if desired Substituted by one or more groups of oxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;

環B選自環烷基、雜環基、芳基和雜芳基； Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

R¹選自烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基，其中該烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基視需要進一步被選自鹵素、胺基、硝基、氰基、羥基、巰基、羧基、酯基、側氧基、烷基、烷氧基、鹵烷基、鹵烷氧基、烯基、炔基、環烷基、雜環基、芳基、雜芳基的一個或多個基團所取代； ^R is selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and Heteroaryl is optionally further selected from halogen, amine, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, pendant oxy, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl Substituted by one or more groups of radical, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

R²選自氫、烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基，其中該烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基視需要進一步被選自鹵素、胺基、硝基、氰基、羥基、巰基、羧基、酯基、側氧基、烷基、烷氧基、鹵烷基、鹵烷氧基、烯基、炔基、環烷基、雜環基、芳基、雜芳基的一個或多個基團所取代；或者， ^R is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amine, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, pendant oxy, alkyl, alkoxy, haloalkyl, haloalkoxy , alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl substituted by one or more groups; or,

R¹和R²與他們連接的氮原子和硫原子一起形成雜環基或雜芳基，該雜環基或雜芳基視需要進一步被選自鹵素、胺基、硝基、氰基、側氧基、羥基、巰基、羧基、酯基、烷基、烷氧基、鹵烷基、鹵烷氧基、烯基、炔基、環烷基、雜環基、芳基和雜芳基的一個或多個基團取代； R ¹ and R ² form a heterocyclic group or a heteroaryl group together with their attached nitrogen atom and sulfur atom, and the heterocyclic group or heteroaryl group is optionally further selected from halogen, amine group, nitro group, cyano group, pendant One of oxy, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl or multiple groups are substituted;

每個R³各自獨立地選自鹵素、胺基、硝基、氰基、羥基、巰基、烷基、烷氧基、環烷基、雜環基、芳基、雜芳基，該烷基、烷氧基、環烷基、雜環基、芳基、雜芳基視需要進一步被選自鹵素、胺基、硝基、氰基、羥基、巰基、羧基、酯基、側氧基、烷基、烷氧基、鹵烷基、鹵烷氧基、環烷基、雜環基、芳基、雜芳基的一個或多個基團所取代；或者， ^Each R is independently selected from halogen, amine, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, the alkyl, Alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally further selected from halogen, amine, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, side oxy, alkyl , alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are substituted by one or more groups; or,

任意兩個R³與他們連接的原子一起形成環烷基、雜環基、芳基和雜芳基，該環烷基、雜環基、芳基和雜芳基視需要進一步被選自鹵素、胺基、硝基、氰基、側氧基、羥基、巰基、羧基、酯基、烷基、烷氧基、鹵烷基、鹵烷氧基、烯基、炔基、環烷基、雜環基、芳基和雜芳基的一個或多個基團取代； Any ^two R together with the atoms they connect form cycloalkyl, heterocyclyl, aryl and heteroaryl, which cycloalkyl, heterocyclyl, aryl and heteroaryl are further selected from halogen, Amine, nitro, cyano, side oxy, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocycle One or more groups of radical, aryl and heteroaryl are substituted;

R⁴選自氫、鹵素、胺基、硝基、氰基、羥基、巰基、烷基、烷氧基、環烷基、雜環基、芳基、雜芳基、-C(O)R^a、-O(O)CR^a、-C(O)OR^a、-C(O)NR^aR^b、-NHC(O)R^a、-S(O)_mR^a、-S(O)_mNR^aR^b和-NHS(O)_mR^a，該烷基、烷氧基、環烷基、雜環基、芳基、雜芳基視需要進一步被選自鹵素、胺基、硝基、氰基、羥基、巰基、羧基、酯基、側氧基、烷基、烷氧基、鹵烷基、鹵烷氧基、環烷基、雜環基、芳基、雜芳基的一個或多個基團所取代； R ^is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O) ^Ra , -O(O)CR ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -NHC(O)R ^a , -S(O) _m R ^a , -S(O) _m NR ^a R ^b and -NHS(O) _m ^Ra , the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl are further selected from halogen, amino, nitro, One or more of cyano, hydroxyl, mercapto, carboxyl, ester, side oxy, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl replaced by a group;

R⁵選自氫、鹵素、胺基、硝基、氰基、羥基、巰基、烷基、烷氧基、醯基、環烷基、雜環基、芳基、雜芳基、-C(O)R^a、-O(O)CR^a、-C(O)OR^a、-C(O)NR^aR^b、-NHC(O)R^a、-S(O)_mR^a、-S(O)_mNR^aR^b和-NHS(O)_mR^a，該烷基、烷氧基、環烷基、雜環基、芳基、雜芳基視需要進一步被選自鹵素、胺基、硝基、氰基、羥基、巰基、羧基、酯基、側氧基、烷基、烷氧基、鹵烷基、鹵烷氧基、環烷基、雜環基、芳基、雜芳基的一個或多個基團所取代； ^R is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, acyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O )R ^a , -O(O)CR ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -NHC(O)R ^a , -S(O) _m R ^a , -S( O) _m NR ^a R ^b and -NHS (O) _m R ^a , the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl are further selected from halogen, amino, Nitro, cyano, hydroxyl, mercapto, carboxyl, ester, side oxy, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl Replaced by one or more groups;

R^a和R^b各自獨立地選自氫、鹵素、羥基、氰基、胺基、羧基、酯基、烷基、烷氧基、烯基、炔基、環烷基、雜環基、芳基和雜芳基，其中該烷基、烷氧基、烯基、炔基、環烷基、雜環基、芳基和雜芳基各自獨立地視需要進一步被選自鹵素、胺基、硝基、氰基、羥基、巰基、羧基、酯基、側氧基、烷基、烷氧基、烯基、炔基、環烷基、雜環基、芳基和雜芳基中的一個或多個基團取代； R ^a and R ^b are each independently selected from hydrogen, halogen, hydroxyl, cyano, amino, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, amino, nitro , cyano, hydroxyl, mercapto, carboxyl, ester, pendant oxy, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group substitution;

或者R^a和R^b與他們連接的原子一起形成環烷基或雜環基，該環烷基或雜環基視需要進一步被選自鹵素、胺基、硝基、氰基、側氧基、羥基、巰基、羧基、酯基、烷基、烷氧基、烯基、炔基、環烷基、雜環基、芳基和雜芳基中的一個或多個基團取代； Or R ^a and R ^b form a cycloalkyl or heterocyclic group together with the atoms they are connected to, and the cycloalkyl or heterocyclic group is further selected from halogen, amino, nitro, cyano, side oxygen, One or more of hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted;

m為0、1、2： m is 0, 1, 2:

p為0、1、2、3或4。 p is 0, 1, 2, 3 or 4.

在本發明的一個實施方案中，根據本發明所述的通式(I)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽， In one embodiment of the present invention, the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

其中， in,

環A選自3至12員單環雜環基、螺雜環基、稠雜環基或橋雜環基，較佳5至7員單環雜環基、7至10員螺雜環基、7至10員稠雜環基和7至10員橋雜環基，更佳吡咯烷基、哌啶基、哌嗪基，該雜環基視需要進一步被選自鹵素、胺基、硝基、氰基、羥基、巰基、側氧基、C₁-C₆烷基、C₁-C₆烷氧基、C₁-C₆鹵烷基、 C₁-C₆鹵烷氧基、C₃-C₆環烷基、5至7員雜環基、C₆-C₁₀芳基、5至10員雜芳基的一個或多個基團所取代。 Ring A is selected from 3 to 12 membered monocyclic heterocyclic groups, spiro heterocyclic groups, fused heterocyclic groups or bridged heterocyclic groups, preferably 5 to 7 membered monocyclic heterocyclic groups, 7 to 10 membered spiro heterocyclic groups, 7 to 10 membered condensed heterocyclic group and 7 to 10 membered bridged heterocyclic group, more preferably pyrrolidinyl, piperidinyl, piperazinyl, the heterocyclic group is further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, pendant oxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, C ₃ - One or more groups of C ₆ cycloalkyl, 5 to 7 membered heterocyclic group, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl are substituted.

在本發明的另一個實施方案中，根據本發明所述的通式(I)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽，其為通式(II)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽， In another embodiment of the present invention, the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by general formula (II) or stereoisomers, tautomers, mesomers, Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

其中，環B、R¹、R²、R³、R⁴、R⁵、p如通式(I)所定義。 Wherein, ring B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and p are as defined in general formula (I).

在本發明的另一個實施方案中，根據本發明該通式(I)或通式(II)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽， In another embodiment of the present invention, according to the present invention, the compound represented by the general formula (I) or general formula (II) or its stereoisomer, tautomer, mesomer, racemate , an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

其中， in,

環B選自C₃-C₇環烷基、4至7員雜環基、C₆-C₁₀芳基、5至10員雜芳基，更佳

、

、

、

、

、

。 Ring B is selected from C ₃ -C ₇ cycloalkyl, 4 to 7 membered heterocyclic group, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl, more preferably

,

.

在本發明的另一個實施方案中，根據本發明所述的通式(I)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽，其為通式(III)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽， In another embodiment of the present invention, the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (III) or Stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

其中， in,

其中，R¹、R²、R³、R⁴、R⁵、p如通式(I)所定義。 Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and p are as defined in general formula (I).

在本發明的另一個實施方案中，根據本發明所述的通式(I)、通式(II)或通式(III)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其前藥、或其可藥用鹽， In another embodiment of the present invention, the compound represented by general formula (I), general formula (II) or general formula (III) or its stereoisomers, tautomers, internal Racemate, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof,

其中， in,

每個R³各自獨立地選自鹵素、胺基、氰基、羥基、巰基、C₁-C₆烷基、C₁-C₆烷氧基、C₃-C₇環烷基、4至7員雜環基，該C₁-C₆烷基、C₁-C₆烷氧基、C₃-C₇環烷基、4至7員雜環基視需要進一步被選自鹵素、胺基、硝基、氰基、經基、巰基、羧基、酯基、側氧基、烷基、烷氧基、鹵烷基、鹵烷氧基、環烷基、雜環基、芳基、雜芳基的一個或多個基團所取代；較佳鹵素、羥基、C₁-C₆烷基、C₁-C₆鹵烷基； Each R ³ is independently selected from halogen, amine, cyano, hydroxyl, mercapto, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₇ cycloalkyl, 4 to 7 member heterocyclic group, the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₇ cycloalkyl, 4 to 7 member heterocyclic group are further selected from halogen, amino, Nitro, cyano, alkenyl, mercapto, carboxyl, ester, side oxy, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl Substituted by one or more groups; preferred halogen, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl;

p為0、1、2或3；較佳1或2。 p is 0, 1, 2 or 3; preferably 1 or 2.

在本發明的另一個實施方案中，根據本發明所述的通式(I)、通式(II)、或通式(III)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽， In another embodiment of the present invention, according to the present invention, the compound represented by general formula (I), general formula (II) or general formula (III) or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

其中， in,

R¹選自C₁-C₆烷基、C₂-C₆烯基、C₂-C₆炔基、C₃-C₆環烷基、5至7員雜環基、C₆-C₁₀芳基和5至10員雜芳基，較佳C₁-C₆烷基、C₃-C₆環烷基；較佳C₁-C₆烷基、C₃-C₆環烷基、5至7員雜環基； R ¹ is selected from C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 5 to 7 membered heterocyclyl, C ₆ -C ₁₀ Aryl and 5 to 10 membered heteroaryl, preferably C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl; preferably C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, 5 to 7-membered heterocyclyl;

該C₁-C₆烷基、C₂-C₆烯基、C₂-C₆炔基或C₃-C₆環烷基視需要進一步被選自鹵素、胺基、硝基、氰基、羥基、巰基、羧基、酯基、側氧基、C₁-C₆烷基、C₁-C₆烷氧基、C₂-C₆烯基、C₂-C₆炔基、C₃-C₆環烷基、5至7員雜環基、C₁-C₆鹵烷基、C₁-C₆烷氧基的一個或多個基團所取代； The C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₃ -C ₆ cycloalkyl is optionally further selected from halogen, amino, nitro, cyano, Hydroxy, mercapto, carboxyl, ester, side oxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 5 to 7-membered heterocyclic group, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy group substituted by one or more groups;

該5至7員雜環基、C₆-C₁₀芳基和5至10員雜芳基視需要進一步被選自鹵素、胺基、硝基、氰基、羥基、巰基、羧基、酯基、側氧基、C₁-C₆烷基、C₁-C₆烷氧基、C₂-C₆烯基、C₂-C₆炔基、C₃-C₆環烷基、5至7員雜環基、C₁-C₆鹵烷基、C₁-C₆烷氧基、C₆-C₁₀芳基、5至10員雜芳基的一個或多個基團取代。 The 5 to 7 membered heterocyclic group, C ₆ -C ₁₀ aryl group and 5 to 10 membered heteroaryl group are optionally further selected from halogen, amine, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, Pendant oxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 5 to 7 members Substitution by one or more groups of heterocyclic group, C ₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, C ₆ -C ₁₀ aryl group, 5 to 10 membered heteroaryl group.

在本發明的另一個實施方案中，根據本發明所述的通式(I)、通式(II)或通式(III)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽， In another embodiment of the present invention, the compound represented by general formula (I), general formula (II) or general formula (III) or its stereoisomers, tautomers, internal racemate, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

其中， in,

R²選自氫、C₁-C₆烷基、C₂-C₆烯基、C₂-C₆炔基、C₃-C₆環烷基、5至7員雜環基、C₆-C₁₀芳基和5至10員雜芳基，較佳氫、C₁-C₆烷基、C₃-C₆環烷基；較佳氫和C₁-C₆烷基； R ² is selected from hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 5 to 7 membered heterocyclyl, C ₆ - C ₁₀ aryl and 5 to 10 membered heteroaryl, preferably hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl; preferably hydrogen and C ₁ -C ₆ alkyl;

在本發明的另一個實施方案中，根據本發明所述的通式(I)、通式(II)或通式(III)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽，其中，R¹和R²與他們連接的氮原子和硫原子一起形成5至7員雜環基，該5至7員雜環基視需要進一步被選自鹵素、胺基、硝基、氰基、側氧基、羥基、巰基、羧基、酯基、C₁-C₆烷基、C₁-C₆烷氧基、C₂-C₆烯基、C₂-C₆炔基、C₃-C₆環烷基、5至7員雜環基、C₁-C₆鹵烷基、C₁-C₆烷氧基、C₆-C₁₀芳基、5至10員雜芳基的一個或多個基團取代。 In another embodiment of the present invention, the compound represented by general formula (I), general formula (II) or general formula (III) or its stereoisomers, tautomers, internal Racemate, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^and ^R are connected to their nitrogen atom and sulfur atom together form a 5 to 7-membered heterocyclic group, which is optionally further selected from the group consisting of halogen, amine, nitro, cyano, pendant oxy, hydroxyl, mercapto, carboxyl, ester, _C -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 5 to 7 membered heterocyclyl, C ₁ One or more groups of -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryl, 5 to 10 membered heteroaryl are substituted.

其中， in,

R⁴選自氫、鹵素、胺基、硝基、氰基、羥基、巰基、C₁-C₆烷基、C₁-C₆烷氧基、C₁-C₆鹵烷基、C₁-C₆鹵烷氧基，較佳氫、鹵素、C₁-C₆烷基、C₁-C₆烷氧基、C₁-C₆鹵烷基、C₁-C₆鹵烷氧基；較佳R⁴為氫或C₁-C₆烷基。 R ⁴ is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ - C ₆ haloalkoxy, preferably hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy; relatively Preferably R ⁴ is hydrogen or C ₁ -C ₆ alkyl.

其中， in,

R⁵選自氫、鹵素、胺基、硝基、氰基、羥基、巰基、C₁-C₆烷基、C₁-C₆烷氧基、C₁-C₆鹵烷基、C₁-C₆鹵烷氧基、-C(O)R^a，較佳氫、鹵素、C₁-C₆烷基、C₁-C₆烷氧基、C₁-C₆鹵烷基、C₁-C₆鹵烷氧基、-C(O)R^a； R ⁵ is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ - C ₆ haloalkoxy, -C(O) ^Ra , preferably hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ - C ₆ Haloalkoxy, -C(O)R ^a ;

R^a選自C₁-C₆烷基。 R ^a is selected from C ₁ -C ₆ alkyl groups.

本發明典型的化合物包括但不限於以下化合物： Typical compounds of the invention include, but are not limited to, the following compounds:

或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其前藥、或其可藥用鹽。 or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof, or prodrugs thereof, or pharmaceutically acceptable Salt.

本發明進一步提供一種根據本發明所述的通式(I)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其前藥、或其可藥用鹽的製備方法，其包括以下步驟： The present invention further provides a compound represented by general formula (I) according to the present invention or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers A method for preparing an enantiomer, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

在鹼的存在下，在催化劑存在下，化合物Ij與化合物Ia發生脫水反應得到通式(I)化合物；該鹼較佳三乙胺；該催化劑較佳三苯基二氯化磷； In the presence of a base, in the presence of a catalyst, compound Ij and compound Ia undergo a dehydration reaction to obtain a compound of general formula (I); the base is preferably triethylamine; the catalyst is preferably triphenylphosphine dichloride;

環A、環B、R¹、R²、R³、R⁴、R⁵、p如通式(I)所定義。 Ring A, ring B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and p are as defined in general formula (I).

本發明進一步提供一種根據本發明所述的通式(II)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其前藥、或其可藥用鹽的製備方法，其包括以下步驟： The present invention further provides a compound represented by general formula (II) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer A method for preparing an enantiomer, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

在鹼的存在下，在催化劑存在下，化合物IIj與化合物Ia發生脫水反應得到通式(II)化合物；該鹼較佳三乙胺；該催化劑較佳三苯基二氯化磷； In the presence of a base, in the presence of a catalyst, compound IIj and compound Ia undergo a dehydration reaction to obtain a compound of general formula (II); the base is preferably triethylamine; the catalyst is preferably triphenylphosphine dichloride;

環B、R¹、R²、R³、R⁴、R⁵、p如通式(II)所定義。 Ring B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and p are as defined in general formula (II).

本發明進一步提供一種根據本發明所述的通式(III)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其前藥、或其可藥用鹽的製備方法，其包括以下步驟： The present invention further provides a compound represented by general formula (III) according to the present invention or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers A method for preparing an enantiomer, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

在鹼的存在下，在催化劑存在下，化合物IIIj與化合物Ia發生脫水反應得到通式(III)化合物；該鹼較佳三乙胺；該催化劑較佳三苯基二氯化磷； In the presence of a base, in the presence of a catalyst, compound IIIj and compound Ia undergo a dehydration reaction to obtain a compound of general formula (III); the base is preferably triethylamine; the catalyst is preferably triphenylphosphine dichloride;

R¹、R²、R³、R⁴、R⁵、p如通式(III)所定義。 R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and p are as defined in general formula (III).

本發明還提供一種醫藥組成物，其包含本發明所述的通式(I)、通式(II)、或通式(III)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽，和藥學上可接受的載體或賦形劑。 The present invention also provides a pharmaceutical composition, which comprises the compound represented by the general formula (I), general formula (II) or general formula (III) of the present invention or its stereoisomers, tautomers, Mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

本發明的目的還在於提供根據本發明所述的通式(I)、通式(II)或通式(III)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽或包含其的醫藥組成物在製備細胞週期蛋白依賴性激酶(CDK)抑制劑中的用途。 The object of the present invention is also to provide the compound represented by general formula (I), general formula (II) or general formula (III) or its stereoisomer, tautomer, mesomer according to the present invention , racemate, Use of enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, in the preparation of cyclin-dependent kinase (CDK) inhibitors.

本發明的目的還在於提供根據本發明所述的通式(I)、通式(II)或通式(III)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽或包含其的醫藥組成物在製備抑制癌細胞增值、抑制癌細胞侵襲或誘導癌細胞凋亡的藥物中的用途。 The object of the present invention is also to provide the compound represented by general formula (I), general formula (II) or general formula (III) or its stereoisomer, tautomer, mesomer according to the present invention , racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it in the preparation of inhibiting cancer cell proliferation, inhibiting cancer cell invasion, or inducing Use in medicine for apoptosis of cancer cells.

本發明的目的還在於提供根據本發明所述的通式(I)、通式(II)或通式(III)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽或包含其的醫藥組成物在製備用於預防和/或治療與細胞週期蛋白-依賴性激酶活性相關的疾病的藥物中的用途，該疾病例如癌症，特別是與以細胞週期蛋白依賴性激酶CDK2/細胞週期蛋白E1(CCNE1)、CDK6/細胞週期蛋白D1、CDK4/細胞週期蛋白D3的擴增或過表達為特徵的癌症，更特別為乳腺癌如HR+/HER2-轉移性乳腺癌或卵巢癌。 The object of the present invention is also to provide the compound represented by general formula (I), general formula (II) or general formula (III) or its stereoisomer, tautomer, mesomer according to the present invention , racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it in the preparation for prevention and/or treatment of cyclin - Use in medicine for diseases associated with dependent kinase activity, such as cancer, in particular with cyclin-dependent kinases CDK2/cyclin E1 (CCNE1), CDK6/cyclin D1, CDK4/cell cycle Cancers, more particularly breast cancers such as HR+/HER2- metastatic breast or ovarian cancers, characterized by amplification or overexpression of protein D3.

本發明還涉及根據本發明所述的通式(I)、通式(II)或通式(III)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽或包含其的醫藥組成物，其用作CDK抑制劑。 The present invention also relates to the compound represented by general formula (I), general formula (II) or general formula (III) or its stereoisomers, tautomers, mesomers and racemates according to the present invention A rotamer, an enantiomer, a diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a CDK inhibitor.

本發明還涉及根據本發明所述的通式(I)、通式(II)或通式(III)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽或包含其的醫藥組成物，其用於抑制癌細胞增值、抑制癌細胞侵襲或誘導癌細胞凋亡。 The present invention also relates to the compound represented by general formula (I), general formula (II) or general formula (III) or its stereoisomers, tautomers, mesomers and racemates according to the present invention spinomers, enantiomers, The diastereoisomer, or its mixture, or its pharmaceutically acceptable salt, or a pharmaceutical composition containing it, is used for inhibiting cancer cell proliferation, inhibiting cancer cell invasion or inducing cancer cell apoptosis.

本發明還涉及根據本發明所述的通式(I)、通式(II)或通式(III)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽或包含其的醫藥組成物，其用作用於預防和/或治療與細胞週期蛋白-依賴性激酶活性相關的疾病，該疾病例如癌症，特別是與以細胞週期蛋白依賴性激酶CDK2/細胞週期蛋白E1(CCNE1)、CDK6/細胞週期蛋白D1、CDK4/細胞週期蛋白D3的擴增或過表達為特徵的癌症，更特別為乳腺癌如HR+/HER2-轉移性乳腺癌或卵巢癌的藥物。 The present invention also relates to the compound represented by general formula (I), general formula (II) or general formula (III) or its stereoisomers, tautomers, mesomers and racemates according to the present invention Rotary body, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, which is used for the prevention and/or treatment of cyclin-dependent Diseases associated with sex kinase activity, such as cancer, especially those associated with the amplification or hyperactivity of the cyclin-dependent kinases CDK2/cyclin E1 (CCNE1), CDK6/cyclin D1, CDK4/cyclin D3 Drugs in cancers characterized by expression, more particularly breast cancer such as HR+/HER2- metastatic breast or ovarian cancer.

本發明還涉及一種抑制CDK的方法，其包含向有需要的受試者施用有效量的根據本發明所述的通式(I)、通式(II)或通式(III)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽或包含其的醫藥組成物。 The present invention also relates to a method for inhibiting CDK, which comprises administering an effective amount of the compound represented by general formula (I), general formula (II) or general formula (III) according to the present invention to a subject in need or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof or containing them Pharmaceutical composition.

本發明還涉及一種抑制癌細胞增值、抑制癌細胞侵襲或誘導癌細胞凋亡的方法，其包含向有需要的受試者施用有效量的根據本發明所述的通式(I)、通式(II)或通式(III)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽或包含其的醫藥組成物。 The present invention also relates to a method for inhibiting cancer cell proliferation, inhibiting cancer cell invasion, or inducing cancer cell apoptosis, which comprises administering an effective amount of the general formula (I), general formula (II) or the compound represented by the general formula (III) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereoisomer, or A mixture, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it.

本發明還涉及一種預防和/或治療與細胞週期蛋白-依賴性激酶活性相關的疾病的方法，其包含向有需要的受試者施用有效量的根據本發明所述的通式(I)、通式(II)或通式(III)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽或包含其的醫藥組成物，該疾病例如癌症，特別是與以細胞週期蛋白依賴性激酶CDK2/細胞週期蛋白E1(CCNE1)、CDK6/細胞週期蛋白D1、CDK4/細胞週期蛋白D3的擴增或過表達為特徵的癌症，更特別為乳腺癌如HR+/HER2-轉移性乳腺癌或卵巢癌。 The present invention also relates to a method for preventing and/or treating diseases related to cyclin-dependent kinase activity, which comprises administering to a subject in need an effective amount of the general formula (I), The compound represented by general formula (II) or general formula (III) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or A pharmaceutically acceptable salt or a pharmaceutical composition comprising it, the disease such as cancer, especially with the cyclin-dependent kinase CDK2/cyclin E1 (CCNE1), CDK6/cyclin D1, CDK4/cyclin D3 Cancers characterized by amplification or overexpression of , more particularly breast cancer such as HR+/HER2- metastatic breast or ovarian cancer.

根據本發明所述的通式(I)、通式(II)或通式(III)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽或包含其的醫藥組成物可以與另外一種抗癌治療劑或抗癌治療方法同時、分開或相繼施用。 According to the compound represented by general formula (I), general formula (II) or general formula (III) or its stereoisomer, tautomer, mesoform, racemate, para Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same may be administered simultaneously, separately, or sequentially with another anticancer therapeutic agent or anticancer therapeutic method.

[發明的詳細說明] [Detailed description of the invention]

除非有相反陳述，在說明書和申請專利範圍中使用的術語具有下述含義。 Unless stated otherwise, the terms used in the specification and claims have the following meanings.

“烷基”是指飽和的一價脂族烴基，其包括具有指定碳原子數的直鏈和支鏈基團。烷基通常含有1-20個碳原子(C₁-C₂₀烷基)，較佳1至12個碳原子(C₁-C₁₂烷基)，更佳1至8個碳原子(C₁-C₈烷基)或1至6個碳原子(C₁-C₆烷基”)或1至4個碳原子(C₁-C₄烷基)。烷基的非限制性實例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、第二丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各種支鏈異構體等。烷基可以是取代的或非取代的，當被取代時，取代基可以在任何可使用的連接點上被取代。適用於烷基的視需要的取代基包括但不限於C₃-C₈環烷基、3-12員雜環基、C₆-C₁₂芳基和5-12員雜芳基、鹵素、=O(側氧基)、=S(硫基)、=N-CN、並且其中每個該C₃-C₈環烷基、3-12員雜環基、C₆-C₁₂芳基和5-12員雜芳基視需要被取代。烷基上的典型取代基包括鹵素、-OH、C₁-C₆烷氧基、-O-C₆-C₁₂芳基、-CN、=O、C₃-C₈環烷基、C₆-C₁₂芳基、5-12員雜芳基和3-12員雜環基；其中每個該C₃-C₈環烷基、C₆-C₁₂芳基、5-12員雜芳基和3-12員雜環基視需要被1-3個獨立地選自鹵素、-OH、=O、C₁-C₆烷基、C₁-C₆烷氧基、C₁-C₆鹵烷基、C₁-C₆羥基烷基、C₁-C₆烷氧基-C₁-C₆烷基、-CN、-NH₂、-NH(C₁-C₆烷基)和-N(C₁-C₆烷基)₂的取代基所取代。在一些實施方案中，烷基視需要被一個或多個取代基，較佳被1-3個取代基取代，該取代基獨立地選自鹵素、-OH、C₁-C₆烷氧基、-O-C₆-C₁₂芳基、-CN、=O、C₃-C₈環烷基、C₆-C₁₂芳基、5-12員雜芳基和3-12員雜環基。在其他實施方案中，烷基視需要被一個或多個取代基，較佳被1-3個取代基取代，該取代基獨立地選自鹵素、-OH、C₁-C₆烷氧基、-CN、C₃-C₈環烷基、3-12員雜環基、C₆-C₁₂芳基和5-12員雜芳基，其各自視需要含有1、2或3個選自O、N和S(O)x(其中x是0-2)的另外的雜原子；且其中每個該環烷基、雜環基、芳基或雜芳基視需要被1-3個獨立地選自鹵素、-OH、=O、C₁-C₆烷基、C₁-C₆烷氧基、C₁-C₆鹵烷基、C₁-C₆羥基烷基、C₁-C₆烷氧基-C₁-C₆烷基、-CN、-NH₂、-NH(C₁-C₆烷基)和-N(C₁-C₆烷基)₂的取代基所取代。 "Alkyl" means a saturated monovalent aliphatic hydrocarbon group including straight and branched chain groups having the indicated number of carbon atoms. Alkyl usually contains 1-20 carbon atoms (C ₁ -C ₂₀ alkyl), preferably 1 to 12 carbon atoms (C ₁ -C ₁₂ alkyl), more preferably 1 to 8 carbon atoms (C ₁ - C ₈ alkyl) or 1 to 6 carbon atoms (C ₁ -C ₆ alkyl") or 1 to 4 carbon atoms (C ₁ -C ₄ alkyl). Non-limiting examples of alkyl include methyl, Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, second-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethyl Propyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1 ,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl , 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3 -Methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3 -Dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethyl Hexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methylhexyl Base-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2 -Diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers, etc. Alkyl can be substituted or unsubstituted, When substituted, the substituents may be substituted at any available point of attachment. Optional substituents suitable for alkyl groups include, but are not limited to, C ₃ -C ₈ cycloalkyl, 3-12 membered heterocyclyl, C ₆ -C ₁₂ aryl and 5-12 membered heteroaryl, halogen, =O (side oxy), =S (thio), =N-CN, and each of the C ₃ -C ₈ cycloalkane radical, 3-12 membered heterocyclyl, C ₆ -C ₁₂ aryl and 5-12 membered heteroaryl are optionally substituted. Typical substituents on alkyl include halogen, -OH, C ₁ -C ₆ alkoxy Base, -OC ₆ -C ₁₂ aryl, -CN, =O, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₂ aryl, 5-12 membered heteroaryl and 3-12 membered heterocyclic group; Wherein each of the C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₂ aryl, 5-12 membered heteroaryl and 3-12 membered heterocyclic group is optionally selected from 1-3 independently selected from halogen, - OH, =O, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl, -CN, -NH ₂ , -NH(C ₁ -C ₆ alkyl) and -N(C ₁ -C ₆ alkyl) ₂ substituents. In some embodiments, the alkyl group is optionally substituted by one or more substituents, preferably 1-3 substituents independently selected from halogen, -OH, C ₁ -C ₆ alkoxy, -OC ₆ -C ₁₂ aryl, -CN, =O, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₂ aryl, 5-12 membered heteroaryl and 3-12 membered heterocyclic group. In other embodiments, the alkyl group is optionally substituted by one or more substituents, preferably 1-3 substituents independently selected from halogen, -OH, C ₁ -C ₆ alkoxy, -CN, C ₃ -C ₈ cycloalkyl, 3-12 membered heterocyclic group, C ₆ -C ₁₂ aryl and 5-12 membered heteroaryl, each of which optionally contains 1, 2 or 3 members selected from O , N, and S(O)x (where x is 0-2) additional heteroatoms; and wherein each of the cycloalkyl, heterocyclyl, aryl or heteroaryl groups is optionally represented by 1-3 independently selected from halogen, -OH, =O, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ Alkoxy-C ₁ -C ₆ alkyl, -CN, -NH ₂ , -NH(C ₁ -C ₆ alkyl) and -N(C ₁ -C ₆ alkyl) ₂ are substituted.

本文所述的視需要取代的烷基可以被一個或多個取代基取代，除非另有說明，否則這些取代基是獨立選擇的。在這種取代具有化學意義的程度上，取代基的總數可以等於烷基基團上的氫原子總數。視需要取代的烷基通常含有1至6個視需要的取代基，有時1至5個視需要的取代基，較佳1至4個視需要的取代基，或更佳1至3個視需要的取代基。特別地，除非另外指出，烷基可以被一個或多個(直至烷基基團上存在的氫原子總數)鹵素基團取代。因此，C₁-C₄烷基包括鹵烷基，特別是具有1至4個碳原子的氟烷基，例如三氟甲基或二氟乙基(即CF₃和-CH₂CHF₂)。 The optionally substituted alkyl groups described herein may be substituted with one or more substituents, which are independently selected unless otherwise stated. To the extent such substitution is chemically significant, the total number of substituents can be equal to the total number of hydrogen atoms on the alkyl group. Optionally substituted alkyl groups usually contain 1 to 6 optional substituents, sometimes 1 to 5 optional substituents, preferably 1 to 4 optional substituents, or more preferably 1 to 3 optional substituents. required substituents. In particular, unless otherwise indicated, an alkyl group may be substituted by one or more (up to the total number of hydrogen atoms present on the alkyl group) halo groups. Thus, C ₁ -C ₄ alkyl includes haloalkyl, especially fluoroalkyl having 1 to 4 carbon atoms, such as trifluoromethyl or difluoroethyl (ie CF ₃ and —CH ₂ CHF ₂ ).

術語“烯基”指由至少由兩個碳原子和至少一個碳-碳雙鍵組成的如上定義的烷基，例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。烯基可以是取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基。 The term "alkenyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3- -butenyl etc. Alkenyl may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio , alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio.

術語“炔基”指由至少由兩個碳原子和至少一個碳-碳三鍵組成的如上定義的烷基，例如乙炔基、丙炔基、丁炔基等。炔基可以是取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基。 The term "alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, eg ethynyl, propynyl, butynyl and the like. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio , alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio.

術語“環烷基”指飽和或部分不飽和單環或多環環狀烴取代基，環烷基環包含3至20個碳原子，較佳包含3至12個碳原子，更佳包含3至6個碳原子。單環環烷基的非限制性實例包括環丙基、環丁基、環戊基、環戊烯基、環己基、環己烯基、環己二烯基、環庚基、環庚三烯基、環辛基等；多環環烷基包括螺環、稠環和橋環的環烷基。 The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring contains 3 to 20 carbon atoms, preferably contains 3 to 12 carbon atoms, more preferably contains 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Base, cyclooctyl, etc.; polycyclic cycloalkyl includes spiro ring, fused ring and bridged ring cycloalkyl.

術語“螺環烷基”指5至20員的單環之間共用一個碳原子(稱螺原子)的多環基團，其可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統。較佳為6至14員，更佳為7至10員。根據環與環之間共用螺原子的數目將螺環烷基分為單螺環烷基、雙螺環烷基或多螺環烷基，較佳為單螺環烷基和雙螺環烷基。更佳為4員/4員、4員/5員、4員/6員、5員/5員或5員/6員單螺環烷基。螺環烷基的非限制性實例包括： The term "spirocycloalkyl" refers to a polycyclic group of 5 to 20 membered monocyclic rings sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has complete conjugation The π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of spiro atoms shared between the ring and the ring, the spirocycloalkyl group is divided into single spirocycloalkyl, double spirocycloalkyl or multi-spirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl . More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

術語“稠環烷基”指5至20員，系統中的每個環與體系中的其他環共享毗鄰的一對碳原子的全碳多環基團，其中一個或多個環可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統。較佳為6至14員，更佳為7至10員。根據組成環的數目可以分為雙環、三環、四環或多環稠環烷基，較佳為雙環或三環，更佳為5員/5員或5員/6員雙環烷基。稠環烷基的非限制性實例包括： The term "fused cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, each ring of which shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl. Non-limiting examples of fused cycloalkyl groups include:

術語“橋環烷基”指5至20員，任意兩個環共用兩個不直接連接的碳原子的全碳多環基團，其可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統。較佳為6至14員，更佳為7至10員。根據組成環的數目可以分為雙環、三環、四環或多環橋環烷基，較佳為雙環、三環或四環，更佳為雙環或三環。橋環烷基的非限制性實例包括： The term "bridged cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two non-directly attached carbon atoms, which may contain one or more double bonds, but none of the rings has a complete Conjugated π-electron systems. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

該環烷基環可以稠合於芳基、雜芳基或雜環烷基環上，其中與母體結構連接在一起的環為環烷基，非限制性實例包括茚滿基、四氫萘基、苯并環庚烷基等。環烷基可以是視需要取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、側氧基、羧基或羧酸酯基。 The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring where the ring bonded to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl , Benzocycloheptyl, etc. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio group, heterocycloalkylthio group, pendant oxy group, carboxyl group or carboxylate group.

術語“雜環基”指飽和或部分不飽和單環或多環環狀徑取代基，其包含3至20個環原子，其中一個或多個環原子為選自氮、氧或S(O)_m(其中m是整數0至2)的雜原子，但不包括-O-O-、-O-S-或-S-S-的環部分，其餘環原子為碳。較佳包含3至12個環原子，其中1~4個是雜原子；最佳包含3至8個環原子，其中1~3個是雜原子；最佳包含5至7個環原子，其中1~2或1~3個是雜原子。單環雜環基的非限制性實例包括吡咯烷基、咪唑烷基、四氫呋喃基、四氫噻吩基、二氫咪唑基、二氫呋喃基、二氫吡唑基、二氫吡咯基、哌啶基、哌嗪基、嗎啉基、硫嗎啉基、高哌嗪基、吡喃基等，較佳1,2,5-噁二唑基、吡喃基或嗎啉基。多環雜環基包括螺環、稠環和橋環的雜環基。 The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic ring radical substituent comprising 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2), but excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. Preferably contain 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; optimally contain 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; optimally contain 5 to 7 ring atoms, of which 1 ~2 or 1~3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably 1,2,5-oxadiazolyl, pyranyl or morpholinyl. Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.

術語“螺雜環基”指5至20員的單環之間共用一個原子(稱螺原子)的多環雜環基團，其中一個或多個環原子為選自氮、氧或S(O)_m(其中m是整數0至2)的雜原子，其餘環原子為碳。其可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統。較佳為6至14員，更佳為7至10員。根據環與環之間共用螺原子的數目將螺雜環基分為單螺雜環基、雙螺雜環基或多螺雜環基，較佳為單螺雜環基和雙螺雜環基。更佳為4員/4員、4員/5員、4員/6員、5員/5員或5員/6員單螺雜環基。螺雜環基的非限制性實例包括： The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group that shares one atom (called spiro atom) between 5 to 20-membered monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) _m (wherein m is an integer from 0 to 2), the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of shared spiro atoms between rings, spiroheterocyclyls are divided into single spiroheterocyclyls, double spiroheterocyclyls or polyspiroheterocyclyls, preferably single spiroheterocyclyls and double spiroheterocyclyls . More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiro heterocyclic group. Non-limiting examples of spiroheterocyclyls include:

術語“稠雜環基”指5至20員，系統中的每個環與體系中的其他環共享毗鄰的一對原子的多環雜環基團，一個或多個環可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統，其中一個或多個環原子為選自氮、氧或S(O)_m(其中m是整數0至2)的雜原子，其餘環原子為碳。較佳為6至14員，更佳為7至10員。根據組成環的數目可以分為雙環、三環、四環或多環稠雜環基，較佳為雙環或三環，更佳為5員/5員或5員/6員雙環稠雜環基。稠雜環基的非限制性實例包括： The term "fused heterocyclyl" refers to 5 to 20 membered polycyclic heterocyclic groups in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bond, but none of the rings has a fully conjugated π-electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) _m (where m is an integer from 0 to 2), and the remaining ring The atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups . Non-limiting examples of fused heterocyclic groups include:

術語“橋雜環基”指5至14員，任意兩個環共用兩個不直接連接的原子的多環雜環基團，其可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統，其中一個或多個環原子為選自氮、氧或S(O)_m(其中m是整數0至2)的雜原子，其餘環原子為碳。較佳為6至14員，更佳為7至10員。根據組成環的數目可以分為雙環、三環、四環或多環橋雜環基，較佳為雙環、三環或四環，更佳為雙環或三環。橋雜環基的非限制性實例包括： The term "bridged heterocyclyl" refers to a 5 to 14-membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete shared bond. A pi-electron system of a yoke wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

該雜環基環可以稠合於芳基、雜芳基或環烷基環上，其中與母體結構連接在一起的環為雜環基，其非限制性實例包括： The heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring where the ring bonded to the parent structure is a heterocyclyl, non-limiting examples of which include:

和

等。

and

wait.

雜環基可以是視需要取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、側氧基、羧基或羧酸酯基。 The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio group, heterocycloalkylthio group, pendant oxy group, carboxyl group or carboxylate group.

術語“芳基”指具有共軛的π電子體系的6至14員全碳單環或稠合多環(也就是共享毗鄰碳原子對的環)基團，較佳為6至10員，例如苯基和萘基。更佳苯基。該芳基環可以稠合於雜芳基、雜環基或環烷基環上，其中與母體結構連接在一起的環為芳基環，其非限制性實例包括： The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e. rings sharing adjacent pairs of carbon atoms) group having a conjugated pi electron system, preferably 6 to 10 members, e.g. phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, where the ring bonded to the parent structure is an aryl ring, non-limiting examples of which include:

芳基可以是取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、羧基或羧酸酯基。 Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio , alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, carboxyl or carboxylate.

術語“雜芳基”指包含1至4個雜原子、5至14個環原子的雜芳族體系，其中雜原子選自氧、硫和氮。雜芳基較佳為5至10員，含1至3個雜原子；更佳為5員或6員，含1至2個雜原子；較佳例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，較佳為咪唑基、噻唑基、吡唑基或嘧啶基、噻唑基；更佳吡唑基或噻唑基。該雜芳基環可以稠合於芳基、雜環基或環烷基環上，其中與母體結構連接在一起的環為雜芳基環，其非限制性實例包括： The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 members, containing 1 to 3 heteroatoms; more preferably 5 or 6 members, containing 1 to 2 heteroatoms; preferred examples are imidazolyl, furyl, thienyl, thiazolyl , pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; More preferably pyrazolyl or thiazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, where the ring bonded to the parent structure is a heteroaryl ring, non-limiting examples of which include:

雜芳基可以是視需要取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、羧基或羧酸酯基。 Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio group, heterocycloalkylthio group, carboxyl group or carboxylate group.

術語“烷氧基”指-O-(烷基)和-O-(環烷基)，其中烷基和環烷基的定義如上所述。烷氧基的非限制性實例包括：甲氧基、乙氧基、丙氧基、丁氧基、環丙氧基、環丁氧基、環戊氧基、環己氧基。烷氧基可以是視需要取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、羧基或羧酸酯基。 The term "alkoxy" refers to -O-(alkyl) and -O-(cycloalkyl), wherein alkyl and cycloalkyl are as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, Cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio group, heterocycloalkylthio group, carboxyl group or carboxylate group.

術語“鹵烷基”指被一個或多個鹵素取代的烷基，其中烷基如上所定義。 The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

術語“鹵烷氧基”指被一個或多個鹵素取代的烷氧基，其中烷氧基如上所定義。 The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy group is as defined above.

術語“羥基”指-OH基團。 The term "hydroxyl" refers to a -OH group.

術語“鹵素”指氟、氯、溴或碘。 The term "halogen" refers to fluorine, chlorine, bromine or iodine.

術語“胺基”指-NH₂。 The term "amino" refers to _-NH2 .

術語“氰基”指-CN。 The term "cyano" refers to -CN.

術語“硝基”指-NO₂。 The term "nitro" refers to _-NO2 .

術語“側氧基”指=O。 The term "side oxy" refers to =0.

術語“羧基”指-C(O)OH。 The term "carboxy" refers to -C(O)OH.

術語“巰基”指-SH。 The term "mercapto" refers to -SH.

術語“酯基”指-C(O)O(烷基)或-C(O)O(環烷基)，其中烷基和環烷基如上所定義。 The term "ester group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

術語“醯基”指含有-C(O)R基團的化合物，其中R為烷基、環烷基、雜環基、芳基、雜芳基。 The term "acyl" refers to compounds containing the group -C(O)R, where R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.

“視需要”或“視需要地”意味著隨後所描述的事件或環境可以但不必發生，該說明包括該事件或環境發生或不發生的場合。例如，“視需要被烷基取代的雜環基團”意味著烷基可以但不必須存在，該說明包括雜環基團被烷基取代的情形和雜環基團不被烷基取代的情形。 "Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes cases where the heterocycle group is substituted with an alkyl group and cases where the heterocycle group is not substituted with an alkyl group .

“取代的”指基團中的一個或多個氫原子，較佳為最多5個，更佳為1~3個氫原子彼此獨立地被相應數目的取代基取代。不言而喻，取代基僅處在它們的可能的化學位置，所屬技術領域具有通常知識者能夠在不付出過多努力的情況下確定(藉由實驗或理論)可能或不可能的取代。例如，具有游離氫的胺基或羥基與具有不飽和(如烯屬)鍵的碳原子結合時可能是不穩定的。 "Substituted" means that one or more hydrogen atoms in a group, preferably at most 5, more preferably 1 to 3 hydrogen atoms are independently substituted by a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amine or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.

“醫藥組成物”表示含有一種或多種本文所述化合物或其生理學上/可藥用的鹽或前體藥物與其他化學組分的混合物，以及其他組分例如生理學/可藥用的載體和賦形劑。醫藥組成物的目的是促進對生物體的給藥，利於活性成分的吸收進而發揮生物活性。 "Pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof and other chemical components, and other components such as a physiologically/pharmaceutically acceptable carrier and excipients. The purpose of the pharmaceutical composition is to promote the administration to the living body, facilitate the absorption of the active ingredient and thus exert the biological activity.

“可藥用鹽”是指本發明化合物的鹽，這類鹽用於哺乳動物體內時具有安全性和有效性，且具有應有的生物活性。 "Pharmaceutically acceptable salt" refers to the salt of the compound of the present invention, which is safe and effective when used in mammals, and has proper biological activity.

“癌症”是指任何惡性和/或侵襲性生長或腫瘤(由異常細胞生長引起)。癌症包括以形成它們的細胞類型命名的實體瘤，血液、骨髓或淋巴系統的癌症。實體瘤的實例包括肉瘤和癌。血液癌症包括但不限於白血病、淋巴瘤和骨髓瘤。癌症還包括起源於身體具體部位的原發性癌症，已經從其開始的部位擴散到身體的其它部位的轉移性癌症，緩解後從原始的原發性癌症的復發，以及第二原發性癌症(這是在具有與新的原發性癌症不同類型的先前癌症病史的人中的新的原發性癌症)。在本文提供的一些實施方案中，癌症可以選自乳腺癌、卵巢癌、膀胱癌、子宮癌、***癌、肺癌、食道癌、肝癌、胰腺癌和胃癌。在一些這種實施方案中，癌症的特徵在於CCNE1和/或CCNE2的擴增或過表達。 "Cancer" refers to any malignant and/or invasive growth or tumor (caused by abnormal cell growth). Cancers include solid tumors named for the type of cells that form them, cancers of the blood, bone marrow, or lymphatic system. Examples of solid tumors include sarcomas and carcinomas. Cancers of the blood include, but are not limited to, leukemias, lymphomas, and myelomas. Cancer also includes primary cancer that started in a specific part of the body, metastatic cancer that has spread from where it started to other parts of the body, recurrence from the original primary cancer after remission, and second primary cancer (This is a new primary cancer in a person with a history of previous cancer of a different type than the new primary cancer). In some embodiments provided herein, the cancer may be selected from breast cancer, egg Cancer of the breast, bladder, uterus, prostate, lung, esophagus, liver, pancreas, and stomach. In some such embodiments, the cancer is characterized by amplification or overexpression of CCNE1 and/or CCNE2.

本文所述的立體異構體可包括本發明化合物(包括表現出超過一種異構類型的化合物)的順式和反式異構體、光學異構體如(R)和(S)對映異構體、非對映異構體、幾何異構體、旋轉異構體、阻轉異構體、構象異構體和互變異構體；及其混合物(如外消旋體和非對映異構體對)。 Stereoisomers described herein may include cis and trans isomers, optical isomers such as (R) and (S) enantiomers of the compounds of the invention (including compounds exhibiting more than one isomeric type). isomers, diastereomers, geometric isomers, rotamers, atropisomers, conformers and tautomers; and mixtures thereof (such as racemates and diastereoisomers Construct pair).

本發明化合物可以表現出互變異構現象和結構異構現象。例如，化合物可以數種互變異構形式，包括烯醇和亞胺形式以及酮和烯胺形式，和幾何異構體及其混合物存在。所有這種互變異構形式都包括在本發明化合物的範圍內。互變異構體作為在溶液中的互變異構組的混合物存在。在固體形式中，通常一種互變異構體佔優勢。即使可以描述一種互變異構體，但本發明包括所提供的化合物的所有互變異構體。 The compounds of the present invention may exhibit tautomerism and structural isomerism. For example, compounds may exist in several tautomeric forms, including enol and imine forms and keto and enamine forms, and geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of the compounds of the present invention. Tautomers exist as a mixture of tautomeric sets in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present invention includes all tautomers of the provided compounds.

用於製備/分離單一的對映異構體的常規技術包括由合適的光學純的前體手性合成或利用例如手性高壓液相色譜(HPLC)或超臨界流體色譜(SFC)拆分外消旋體(或鹽或衍生物的外消旋體)。 Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution using, for example, chiral high pressure liquid chromatography (HPLC) or supercritical fluid chromatography (SFC). Racemate (or racemate of salt or derivative).

本文所述化合物的對映異構體純度可以用對映異構體過量(ee)來描述，其表示樣品以比另一種對映異構體更大的量含有一種對映異構體的程度。外消旋混合物的ee為0%，而單一的完全純的對映異構體的ee為100%。類似地，非對映異構體純度可以用非對映異構體過量(de)來描述。 The enantiomeric purity of the compounds described herein can be described in terms of enantiomeric excess (ee), which indicates the degree to which a sample contains one enantiomer in a greater amount than the other . The ee of a racemic mixture is 0%, while the ee of a single completely pure enantiomer is 100%. Similarly, diastereomeric purity can be described in terms of diastereomeric excess (de).

按照本發明所屬領域的常規方法，本發明通式(I)所示的化合物可以與鹼或者酸生成藥學上可接受的鹼式加成鹽或酸式加成鹽。該鹼包括無機鹼和有機鹼，可接受的有機鹼包括二乙醇胺、乙醇胺、N-甲基葡糖胺、三乙醇胺、胺丁三醇等，可接受的無機鹼包括氫氧化鋁、氫氧化鈣、氫氧化鉀、碳酸鈉和氫氧化鈉等。該酸包括無機酸和有機酸，可接受的無機酸包括鹽酸、硫酸、硝酸、磷酸、氫溴酸等。可接受的有機酸包括乙酸、三氟乙酸、甲酸、抗環血酸等。 According to conventional methods in the field to which the present invention belongs, the compound represented by the general formula (I) of the present invention can form a pharmaceutically acceptable base addition salt or acid addition salt with a base or an acid. The base includes inorganic bases and organic bases, and acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, Tromethamine, etc., acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. The acid includes inorganic acids and organic acids, and acceptable inorganic acids include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, and the like. Acceptable organic acids include acetic acid, trifluoroacetic acid, formic acid, ascorbic acid, and the like.

含活性成分的醫藥組成物可以是適用於口服的形式，例如片劑、糖錠劑、錠劑、水或油混懸液、可分散粉末或顆粒、乳液、硬或軟膠囊，或糖漿劑或酏劑。可按照本領域任何已知製備醫藥組成物的方法製備口服組成物，此類組成物可含有一種或多種選自以下的成分：甜味劑、矯味劑、著色劑和防腐劑，以提供悅目和可口的藥用製劑。片劑含有活性成分和用於混合的適宜製備片劑的無毒的可藥用的賦形劑。這些賦形劑可以是惰性賦形劑，如碳酸鈣、碳酸鈉、乳糖、磷酸鈣或磷酸鈉；造粒劑和崩解劑，例如微晶纖維素、交聯羧甲基纖維素鈉、玉米澱粉或藻酸；黏合劑，例如澱粉、明膠、聚乙烯吡咯烷酮或***膠；和潤滑劑，例如硬脂酸鎂、硬脂酸或滑石粉。這些片劑可以不包衣或可藉由掩蓋藥物的味道或在胃腸道中延遲崩解和吸收，因而在較長時間內提供緩釋作用的已知技術將其包衣。例如，可使用水溶性味道掩蔽物質，例如羥丙基甲基纖維素或羥丙基纖維素，或延長時間物質例如乙基纖維素、醋酸丁酸纖維素。 The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixir. Oral compositions can be prepared according to any method known in the art for the preparation of pharmaceutical compositions, and such compositions can contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives to provide pleasing and Tasty medicinal preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients can be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binders such as starch, gelatin, polyvinylpyrrolidone or acacia; and lubricants such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over a longer period of time. For example, water-soluble taste-masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or time-extending materials such as ethylcellulose, cellulose acetate butyrate may be used.

也可用其中活性成分與惰性固體稀釋劑例如碳酸鈣、磷酸鈣或高嶺土混合的硬明膠膠囊，或其中活性成分與水溶性載體例如聚乙二醇或油溶媒例如花生油、液體石蠟或橄欖油混合的軟明膠膠囊提供口服製劑。 Hard gelatin capsules in which the active ingredient is admixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or in which the active ingredient is admixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin, or olive oil may also be used. Soft gelatin capsules provide an oral formulation.

水混懸液含有活性物質和用於混合的適宜製備水混懸液的賦形劑。此類賦形劑是懸浮劑，例如羧基甲基纖維素鈉、甲基纖維素、羥丙基甲基纖維素、藻酸鈉、聚乙烯吡咯烷酮和***膠；分散劑或濕潤劑，可以是天然產生的磷脂例如卵磷脂，或烯化氧與脂肪酸的縮合產物，例如聚氧乙烯硬脂酸酯，或環氧乙烷與長鏈脂肪醇的縮合產物，例如十七碳亞乙基氧基鯨蠟醇(heptadecaethyleneoxy cetanol)，或環氧乙烷與由脂肪酸和己糖醇衍生的部分酯的縮合產物，例如聚環氧乙烷山梨醇單油酸酯，或環氧乙烷與由脂肪酸和己糖醇酐衍生的偏酯的縮合產物，例如聚環氧乙烷脫水山梨醇單油酸酯。水混懸液也可以含有一種或多種防腐劑例如尼泊金乙酯或尼泊金正丙酯、一種或多種著色劑、一種或多種矯味劑和一種或多種甜味劑，例如蔗糖、糖精或阿司帕坦。 Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, and acacia; dispersing or wetting agents, which may be natural phospholipids produced such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or Condensation products of ethylene oxide with long-chain fatty alcohols, such as heptadecaethyleneoxy cetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as Polyethylene oxide sorbitan monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene oxide sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propylparaben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or arginine. Spartan.

油混懸液可藉由使活性成分懸浮於植物油如花生油、橄欖油、芝麻油或椰子油，或礦物油例如液體石蠟中配製而成。油混懸液可含有增稠劑，例如蜂蠟、硬石蠟或鯨蠟醇。可加入上述的甜味劑和矯味劑，以提供可口的製劑。可藉由加入抗氧化劑例如丁羥茴醚或α-生育酚保存這些組成物。 Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening and flavoring agents as mentioned above may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants such as butylated hydroxyanisole or alpha-tocopherol.

藉由加入水，適用於製備水混懸液的可分散粉末和顆粒可以提供活性成分和用於混合的分散劑或濕潤劑、懸浮劑或一種或多種防腐劑。適宜的分散劑或濕潤劑和懸浮劑如上所述。也可加入其他賦形劑例如甜味劑、矯味劑和著色劑。藉由加入抗氧化劑例如抗壞血酸保存這些組成物。 Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives for admixture. Suitable dispersing or wetting agents and suspending agents are mentioned above. Other excipients, for example sweetening, flavoring and coloring agents, may also be added. These compositions are preserved by adding antioxidants such as ascorbic acid.

本發明的醫藥組成物也可以是水包油乳劑的形式。油相可以是植物油例如橄欖油或花生油，或礦物油例如液體石蠟或其混合物。適宜的乳化劑可以是天然產生的磷脂，例如大豆卵磷脂，和由脂肪酸和己糖醇酐衍生的酯或偏酯，例如山梨坦單油酸酯，和該偏酯和環氧乙烷的縮合產物，例如聚環氧乙烷山梨醇單油酸酯。乳劑也可以含有甜味劑、矯味劑、防腐劑和抗氧劑。可用甜味劑例如甘油、丙二醇、山梨醇或蔗糖配製的糖漿和酏劑。此類製劑也可含有緩和劑、防腐劑、著色劑和抗氧劑。 The pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as olive oil or arachis oil, or a mineral oil such as liquid paraffin or mixtures thereof. Suitable emulsifiers may be naturally occurring phospholipids, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of such partial esters with ethylene oxide , such as polyethylene oxide sorbitan monooleate. The emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.

本發明的醫藥組成物可以是無菌注射水溶液形式。可以使用的可接受的溶媒和溶劑有水、林格氏液和等滲氯化鈉溶液。無菌注射製劑可以是其中活性成分溶於油相的無菌注射水包油微乳。例如將活性成分溶於大豆油和卵磷脂的混合物中。然後將油溶液加入水和甘油的混合物中處理形成微乳。可藉由局部大量注射，將注射液或微乳注入患者的血流中。或者，最好按可保持本發明化合物恆定循環濃度的方式給予溶液和微乳。為保持這種恆定濃度，可使用連續靜脈內遞藥裝置。 The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous solutions. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then treated in a mixture of water and glycerol to form a microemulsion. The injection or microemulsion can be injected into the patient's bloodstream by local bolus injection. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the invention. To maintain this constant concentration, a continuous intravenous delivery device can be used.

本發明的醫藥組成物可以是用於肌內和皮下給藥的無菌注射水或油混懸液的形式。可按已知技術，用上述那些適宜的分散劑或濕潤劑和懸浮劑配製該混懸液。無菌注射製劑也可以是在無毒腸胃外可接受的稀釋劑或溶劑中製備的無菌注射溶液或混懸液，例如在1,3-丁二醇中製備的溶液。此外，可方便地用無菌固定油作為溶劑或懸浮介質。為此目的，可使用包括合成甘油單或二酯在內的任何調和固定油。此外，脂肪酸例如油酸也可以製備注射劑。 The pharmaceutical composition of the present invention may be in the form of sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension prepared in a non-toxic parenterally acceptable diluent or solvent, for example a solution in 1,3-butanediol. In addition, sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are prepared as injectables.

可按用於直腸給藥的栓劑形式給予本發明化合物。可藉由將藥物與在普通溫度下為固體但在直腸中為液體，因而在直腸中會溶化而釋放藥物的適宜的無刺激性賦形劑混合來製備這些醫藥組成物。此類物質包括可可脂、甘油明膠、氫化植物油、各種分子量的聚乙二醇和聚乙二醇的脂肪酸酯的混合物。 The compounds of this invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols.

所屬技術領域具有通常知識者熟知，藥物的給藥劑量依賴於多種因素，包括但並非限定於以下因素：所用特定化合物的活性、病人的年齡、病人的體重、病人的健康狀況、病人的行被、病人的飲食、給藥時間、給藥方式、***的速率、藥物的組合等。另外，最佳的治療方式如治療的模式、通式化合物的日用量或可藥用的鹽的種類可以根據傳統的治療方案來驗證。 It is well known to those skilled in the art that the dosage of the drug depends on various factors, including but not limited to the following factors: the activity of the specific compound used, the patient's age, the patient's body weight, the patient's health status, the patient's behavior, etc. , the patient's diet, administration time, administration method, excretion rate, drug combination, etc. In addition, the optimal treatment method such as the treatment mode, the daily dosage of the compound of the general formula or the type of pharmaceutically acceptable salt can be verified according to the traditional treatment plan.

本發明可以含有通式(I)所示的化合物，及其藥學上可接受的鹽、水合物或溶劑化物作為活性成分，與藥學上可接受的載體或賦型劑混合製備成組成物，並製備成臨床上可接受的劑型。本發明的衍生物可以與其他活性成分組合使用，只要它們不產生其他不利的作用，例如過敏反應等。本發明化合物可作為唯一的活性成分，也可以與其它治療與酪胺酸激酶活性相關的疾病的藥物聯合使用。聯合治療藉由將各個治療組分同時、分開或相繼給藥來實現。 The present invention may contain the compound represented by the general formula (I), and its pharmaceutically acceptable salt, hydrate or solvate as the active ingredient, mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition, and Prepared into clinically acceptable dosage forms. The derivatives of the present invention can be used in combination with other active ingredients as long as they do not produce other adverse effects such as allergic reactions and the like. The compound of the present invention can be used as the sole active ingredient, and can also be used in combination with other drugs for treating diseases related to tyrosine kinase activity. Combination therapy is achieved by the simultaneous, separate or sequential administration of the individual therapeutic components.

[本發明化合物的合成方法] [Synthetic method of the compound of the present invention]

為了完成本發明的目的，本發明採用如下合成方案製備本發明的通式(I)化合物。 In order to accomplish the object of the present invention, the present invention adopts the following synthetic scheme to prepare the compound of general formula (I) of the present invention.

本發明採用如下方案1製備本發明的通式(I)所示的化合物。 The present invention adopts the following Scheme 1 to prepare the compound represented by the general formula (I) of the present invention.

方案1 plan 1

步驟1：在極性非質子溶劑(如二氯甲烷)中，在適合的鹼(如三乙胺)存在的條件下，磺醯氯化合物發生反應得到磺醯胺化合物Ia； Step 1: In a polar aprotic solvent (such as dichloromethane), in the presence of a suitable base (such as triethylamine), the sulfonyl chloride compound reacts to obtain the sulfonamide compound Ia;

步驟2：在合適的溶劑中，在適合的還原劑存在下，4-氯-2-(甲硫基)嘧啶-5-羧酸乙酯發生還原反應得到化合物Ib；該溶劑例如四氫呋喃，該還原劑例如二異丁基氫化鋁； Step 2: In a suitable solvent, in the presence of a suitable reducing agent, 4-chloro-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester undergoes a reduction reaction to obtain Compound Ib; the solvent is such as tetrahydrofuran, and the reduction Agents such as diisobutylaluminum hydride;

步驟3：在合適的溶劑中，在適合的鹼的存在下，化合物Ib與化合物Ic反應得到化合物Id；該溶劑例如異丙醇，該鹼例如二異丙基乙胺，反應溫度可以為室溫至80℃之間； Step 3: In a suitable solvent, in the presence of a suitable base, compound Ib is reacted with compound Ic to obtain compound Id; the solvent is for example isopropanol, the base is for example diisopropylethylamine, and the reaction temperature can be room temperature to 80°C;

步驟4：在合適的溶劑中，在適合的氧化劑存在下，化合物Id發生氧化反應得到化合物Ie；該溶劑例如乙酸乙酯，該氧化劑例如二氧化錳，反應溫度可以在50℃至80℃之間； Step 4: In a suitable solvent, in the presence of a suitable oxidizing agent, compound Id is oxidized to obtain compound Ie; the solvent is, for example, ethyl acetate, and the oxidizing agent is, for example, manganese dioxide. The reaction temperature can be between 50°C and 80°C ;

步驟5：在合適的溶劑中，在適合的催化劑存在下，化合物Ie發生Aldol環化反應(參見VanderWel等人，J.Med.Chezn.2005，4S，2371)，得到化合物If；該溶劑例如四氫呋喃，該催化劑例如LHMDS，反應溫度可以為-20℃至室溫之間，反應在氮氣氛的條件下進行； Step 5: In a suitable solvent, in the presence of a suitable catalyst, compound Ie undergoes an Aldol cyclization reaction (see VanderWel et al., J.Med.Chezn.2005, 4S, 2371) to obtain compound If; the solvent such as tetrahydrofuran , the catalyst is such as LHMDS, the reaction temperature can be between -20°C and room temperature, and the reaction is carried out under a nitrogen atmosphere;

步驟6：在合適的溶劑中，在適合的氧化劑存在下，化合物If發生氧化反應得到化合物Ig；該溶劑特別為混合溶劑，如2-甲基四氫呋喃和水的混合溶劑，該氧化劑包括但不限於過硫酸氫鉀、間氯過氧苯甲酸等，過量的氧化劑有助於反應徹底進行，反應溫度可以為10℃至80℃之間； Step 6: In a suitable solvent, in the presence of a suitable oxidizing agent, compound If is oxidized to obtain compound Ig; the solvent is especially a mixed solvent, such as a mixed solvent of 2-methyltetrahydrofuran and water, and the oxidizing agent includes but is not limited to Potassium hydrogen persulfate, m-chloroperoxybenzoic acid, etc. Excessive oxidizing agents help the reaction to proceed completely, and the reaction temperature can be between 10°C and 80°C;

步驟7：在合適的溶劑中，在適合的鹼存在下，化合物Ig與化合物Ih發生反應得到化合物Ii；該溶劑例如異丙醇、2-甲基四氫呋喃，該鹼例如二異丙基乙胺，反應溫度可以在室溫至80℃之間； Step 7: In a suitable solvent, in the presence of a suitable base, Compound Ig reacts with Compound Ih to obtain Compound Ii; the solvent such as isopropanol, 2-methyltetrahydrofuran, the base such as diisopropylethylamine, The reaction temperature can be between room temperature and 80°C;

步驟8：在合適的溶劑中，在適當的酸的存在下，將化合物Ii脫保護得到化合物Ij；該溶劑例如二噁烷，該酸例如鹽酸，反應溫度典型地在室溫進行；進一步藉由如氫氧化鈉、氫氧化鉀的鹼將化合物游離； Step 8: In a suitable solvent, in the presence of a suitable acid, compound Ii is deprotected to obtain compound Ij; the solvent is such as dioxane, the acid is such as hydrochloric acid, and the reaction temperature is typically at room temperature; further by Alkali such as sodium hydroxide and potassium hydroxide will free the compound;

步驟9：在合適的溶劑中，在適當的鹼和催化劑的存在下，化合物Ij與化合物Ia發生脫水反應得到通式(I)化合物；該溶劑例如二氯甲烷，該鹼例如三乙胺，該催化劑例如三苯基二氯化磷；反應典型地在氮氣氛下反應進行；反應溫度典型地為0℃至室溫； Step 9: In a suitable solvent, in the presence of a suitable base and a catalyst, compound Ij is dehydrated with compound Ia to obtain a compound of general formula (I); the solvent is, for example, dichloromethane, the base is, for example, triethylamine, the Catalyst such as triphenylphosphine dichloride; the reaction is typically carried out under a nitrogen atmosphere; the reaction temperature is typically 0°C to room temperature;

其中，環A、環B、R¹、R²、R³、R⁴、R⁵、p如通式(I)所定義。 Wherein, ring A, ring B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and p are as defined in general formula (I).

本發明採用如下方案2製備本發明的通式(II)化合物。 The present invention adopts the following scheme 2 to prepare the compound of general formula (II) of the present invention.

方案2 Scenario 2

步驟7：在合適的溶劑中，在適合的鹼存在下，化合物Ig與化合物IIh發生反應得到化合物IIi；該溶劑例如異丙醇、2-甲基四氫呋喃，該鹼例如二異丙基乙胺，反應溫度可以在室溫至80℃之間； Step 7: In a suitable solvent, in the presence of a suitable base, compound Ig reacts with compound IIh to obtain compound IIi; the solvent such as isopropanol, 2-methyltetrahydrofuran, the base such as diisopropylethylamine, The reaction temperature can be between room temperature and 80°C;

步驟8：在合適的溶劑中，在適當的酸的存在下，將化合物IIi脫保護得到化合物IIj；該溶劑例如二噁烷，該酸例如鹽酸，反應溫度典型地在室溫進行；進一步藉由如氫氧化鈉、氫氧化鉀的鹼將化合物游離； Step 8: In a suitable solvent, in the presence of a suitable acid, compound IIi is deprotected to obtain compound IIj; the solvent is such as dioxane, the acid is such as hydrochloric acid, and the reaction temperature is typically at room temperature; further by Alkali such as sodium hydroxide and potassium hydroxide will free the compound;

步驟9：在合適的溶劑中，在適當的鹼和催化劑的存在下，化合物IIj與化合物Ia發生脫水反應得到通式(II)化合物；該溶劑例如二氯甲烷，該鹼例如三乙胺，該催化劑例如三苯基二氯化磷；反應典型地在氮氣氛下反應進行；反應溫度典型地為0℃至室溫； Step 9: In a suitable solvent, in the presence of a suitable base and a catalyst, compound IIj is dehydrated with compound Ia to obtain a compound of general formula (II); the solvent is, for example, dichloromethane, the base is, for example, triethylamine, the Catalyst such as triphenylphosphine dichloride; the reaction is typically carried out under a nitrogen atmosphere; the reaction temperature is typically 0°C to room temperature;

其中，環B、R¹、R²、R³、R⁴、R⁵、p如通式(II)所定義。 Wherein, ring B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and p are as defined in general formula (II).

本發明採用如下方案3製備本發明的通式(III)化合物。 The present invention adopts the following scheme 3 to prepare the compound of general formula (III) of the present invention.

方案3 Option 3

步驟2：在合適的溶劑中，在適合的還原劑存在下，4-氯-2-(甲硫基)略啶-5-羧酸乙酯發生還原反應得到化合物Ib；該溶劑例如四氫呋喃，該還原劑例如二異丁基氫化鋁； Step 2: In a suitable solvent, in the presence of a suitable reducing agent, 4-chloro-2-(methylthio)pyridine-5-carboxylic acid ethyl ester undergoes a reduction reaction to obtain Compound Ib; the solvent is such as tetrahydrofuran, the Reducing agents such as diisobutylaluminum hydride;

步驟3：在合適的溶劑中，在適合的鹼的存在下，化合物Ib與化合物IIIc反應得到化合物IIId；該溶劑例如異丙醇，該鹼例如二異丙基乙胺，反應溫度可以為室溫至80℃之間； Step 3: In a suitable solvent, in the presence of a suitable base, compound Ib is reacted with compound IIIc to obtain compound IIId; the solvent is for example isopropanol, the base is for example diisopropylethylamine, and the reaction temperature can be room temperature to 80°C;

步驟4：在合適的溶劑中，在適合的氧化劑存在下，化合物IIId發生氧化反應得到化合物IIIe；該溶劑例如乙酸乙酯，該氧化劑例如二氧化錳，反應溫度可以在50℃至80℃之間； Step 4: In a suitable solvent, in the presence of a suitable oxidizing agent, compound IIId is oxidized to obtain compound IIIe; the solvent is, for example, ethyl acetate, and the oxidizing agent is, for example, manganese dioxide. The reaction temperature can be between 50°C and 80°C ;

步驟5：在合適的溶劑中，在適合的催化劑存在下，化合物IIIe發生Aldol環化反應(參見VanderWel等人，J.Med.Chezn.2005，4S，2371)，得到化合物IIIf；該溶劑例如四氫呋喃，該催化劑例如LHMDS，反應溫度可以為-20℃至室溫之間，反應在氮氣氛的條件下進行； Step 5: In a suitable solvent, in the presence of a suitable catalyst, compound IIIe undergoes an Aldol cyclization reaction (see VanderWel et al., J.Med.Chezn.2005, 4S, 2371) to obtain compound IIIf; the solvent such as tetrahydrofuran , the catalyst is such as LHMDS, the reaction temperature can be between -20°C and room temperature, and the reaction is carried out under a nitrogen atmosphere;

步驟6：在合適的溶劑中，在適合的氧化劑存在下，化合物IIIf發生氧化反應得到化合物IIIg；該溶劑特別為混合溶劑，如2-甲基四氫呋喃和水的混合溶劑，該氧化劑包括但不限於過硫酸氫鉀、間氯過氧苯甲酸等，過量的氧化劑有助於反應徹底進行，反應溫度可以為10℃至80℃之間； Step 6: In a suitable solvent, in the presence of a suitable oxidizing agent, compound IIIf is oxidized to obtain compound IIIg; the solvent is especially a mixed solvent, such as a mixed solvent of 2-methyltetrahydrofuran and water, and the oxidizing agent includes but is not limited to Potassium hydrogen persulfate, m-chloroperoxybenzoic acid, etc. Excessive oxidizing agents help the reaction to proceed completely, and the reaction temperature can be between 10°C and 80°C;

步驟7：在合適的溶劑中，在適合的鹼存在下，化合物IIIg與化合物IIh發生反應得到化合物IIIi；該溶劑例如異丙醇、2-甲基四氫呋喃，該鹼例如二異丙基乙胺，反應溫度可以在室溫至80℃之間； Step 7: In a suitable solvent, in the presence of a suitable base, compound IIIg reacts with compound IIh to obtain compound IIIi; the solvent such as isopropanol, 2-methyltetrahydrofuran, the base such as diisopropylethylamine, The reaction temperature can be between room temperature and 80°C;

步驟8：在合適的溶劑中，在適當的酸的存在下，將化合物IIIi脫保護得到化合物IIIj；該溶劑例如二噁烷，該酸例如鹽酸，反應溫度典型地在室溫進行；進一步藉由如氫氧化鈉、氫氧化鉀的鹼將化合物游離； Step 8: In a suitable solvent, in the presence of a suitable acid, compound IIIi is deprotected to obtain compound IIIj; the solvent is such as dioxane, the acid is such as hydrochloric acid, and the reaction temperature is typically at room temperature; further by Alkali such as sodium hydroxide and potassium hydroxide will free the compound;

步驟9：在合適的溶劑中，在適當的鹼和催化劑的存在下，化合物IIIj與化合物Ia發生脫水反應得到通式(III)化合物；該溶劑例如二氯甲烷，該鹼例如三乙胺，該催化劑例如三苯基二氯化磷；反應典型地在氮氣氛下反應進行；反應溫度典型地為0℃至室溫； Step 9: In a suitable solvent, in the presence of a suitable base and a catalyst, compound IIIj is dehydrated with compound Ia to obtain a compound of general formula (III); the solvent is, for example, dichloromethane, the base is, for example, triethylamine, the Catalyst such as triphenylphosphine dichloride; the reaction is typically carried out under a nitrogen atmosphere; the reaction temperature is typically 0°C to room temperature;

其中，R¹、R²、R³、R⁴、R⁵、p如通式(III)所定義。 Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and p are as defined in general formula (III).

進一步藉由實施例來理解本發明的化合物及其製備，這些實施例說明了一些製備或使用該化合物的方法。然而，要理解的是，這些實施例並不限制本發明的範圍。現在已知的或進一步開發的本發明的變化被認為落入本文中描述的和要求保護的本發明範圍之內。 The compounds of the invention and their preparation are further understood by the examples, which illustrate some of the methods of making or using the compounds. However, it is to be understood that these examples do not limit the scope of the present invention. Variations of the invention now known or further developed are considered to fall within the scope of the invention described and claimed herein.

本發明化合物是利用便利的起始原料和通用的製備步驟來完成製備的。本發明給出了典型的或傾向性的反應條件，諸如反應溫度、時間、溶劑、壓力、反應物的莫耳比。但是除非特殊說明，其他反應條件也能採納。優化條件可能隨著具體的反應物或溶劑的使用而改變，但在通常情況下，反應優化步驟和條件都能得到確定。 The compounds of the present invention are prepared utilizing convenient starting materials and general preparative procedures. The present invention gives typical or preferred reaction conditions, such as reaction temperature, time, solvent, pressure, mole ratio of reactants. But unless otherwise specified, other reaction conditions can also be adopted. Optimum conditions may vary with specific reactants or solvents used, but in general, reaction optimization steps and conditions can be identified.

另外，本發明中可能用到了一些保護基團來保護某些官能團避免不必要的反應。適宜於各種官能團的保護基以及它們的保護或脫保護條件已經為所屬技術領域具有通常知識者廣泛熟知。例如T.W.Greene和G.M.Wuts的《有機製備中的保護基團》(第3版，Wiley,New York,1999和書中的引用文獻)詳細描述了大量的保護基團的保護或脫保護。 In addition, some protecting groups may be used in the present invention to protect certain functional groups from unnecessary reactions. Suitable protecting groups for various functional groups and their protection or deprotection conditions are widely known to those skilled in the art. Such as T.W.Greene and G.M.Wuts' "Protecting Groups in Organic Preparations" (3rd Edition, Wiley, New York, 1999 and citations therein) describes in detail the protection or deprotection of a large number of protecting groups.

化合物和中間體的分離和純化依據具體的需求採取適當的方法和步驟，例如過濾、萃取、蒸餾、結晶、管柱層析、製備薄層板色譜、製備高效液相色譜或上述方法的混合使用。其具體使用方法可參閱本發明描述的實例。當然，其他類似的分離和純化手段也是可以採用的。可以使用常規方法(包括物理常數和波譜數據)對其進行表徵。 The separation and purification of compounds and intermediates take appropriate methods and steps according to specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin-layer plate chromatography, preparative high-performance liquid chromatography or a combination of the above methods . For its specific usage method, please refer to the examples described in the present invention. Of course, other similar separation and purification means can also be used. They can be characterized using conventional methods, including physical constants and spectral data.

化合物的結構是藉由核磁共振(NMR)或/和質譜(MS)來確定的。NMR位移以10^-6(ppm)的單位給出。NMR的測定是用Brukerdps 300型核磁儀，測定溶劑為氘代二甲基亞碸(DMSO-d ₆)、氘代氯仿(CDCl₃)、氘代甲醇(CD₃OD)，內標為四甲基矽烷(TMS)。 Compound structures were determined by nuclear magnetic resonance (NMR) or/and mass spectroscopy (MS). NMR shifts are given in units of 10 ^-6 (ppm). The determination of NMR is carried out with Brukerdps 300 nuclear magnetic analyzer, and the determination solvents are deuterated dimethyl sulfide (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard is tetramethyl silane (TMS).

MS的測定用LC(Waters 2695)/MS(Quattro Premier xE)質譜儀(生產商：沃特世)(Photodiode Array Detector)。 LC (Waters 2695)/MS (Quattro Premier xE) mass spectrometer (manufacturer: Waters) (Photodiode Array Detector) was used for MS measurement.

製備液相色譜法使用lc6000高效液相色譜儀(生產商：創新通恒)。色譜管柱為DaisogelC18 10μm 100A(30mm×250mm)，流動相：乙腈/水。 The lc6000 high performance liquid chromatograph (manufacturer: Innovation Tongheng) was used for the preparative liquid chromatography. Chromatographic column is Daisogel C18 10 μm 100A (30mm×250mm), mobile phase: acetonitrile/water.

薄層層析矽膠板使用青島海洋化工GF254矽膠板，薄層色譜法(TLC)使用的矽膠板採用的規格是0.20mm~0.25mm，製備薄層層析分離純化產品採用的規格是0.5mm。 The thin-layer chromatography silica gel plate uses Qingdao Ocean Chemical GF254 silica gel plate. The specification of the silica gel plate used for thin-layer chromatography (TLC) is 0.20mm~0.25mm, and the specification used for the preparation of thin-layer chromatography separation and purification products is 0.5mm.

管柱層析一般使用青島海洋矽膠100~200目、200~300目和300~400目矽膠為載體。 Column chromatography generally uses Qingdao Marine silica gel 100-200 mesh, 200-300 mesh and 300-400 mesh silica gel as the carrier.

本發明的已知的起始原料可以採用或按照本領域已知的方法來合成，或可購買自網化商城、北京偶合、Sigma、百靈威、易世明、上海書亞、上海伊諾凱、安耐吉化學、上海畢得等公司。 The known starting materials of the present invention can be adopted or synthesized according to methods known in the art, or can be purchased from Wanghua Mall, Beijing Coupling, Sigma, Bailingwei, Yi Shiming, Shanghai Shuya, Shanghai Yinuokai, Anaiji Chemical, Shanghai Biide and other companies.

實施例中無特殊說明，反應能夠均在氮氣氛下進行。 Unless otherwise specified in the examples, the reactions can all be carried out under a nitrogen atmosphere.

氬氣氛或氮氣氛是指反應瓶連接一個約1L容積的氬氣或氮氣氣球。 Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.

反應溶劑，有機溶劑或惰性溶劑各自表述為使用的該溶劑在所描述的反應條件下不參與反應，包括如苯、甲苯、乙腈、四氫呋喃(THF)、二甲基甲醯胺(DMF)、氯仿、二氯甲烷、***、甲醇、氮-甲基吡咯碄酮(NMP)、吡啶等。實施例中無特殊說明，溶液是指水溶液。 Reaction solvents, organic solvents or inert solvents are each expressed as the solvent used does not participate in the reaction under the described reaction conditions, including such as benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform , dichloromethane, ether, methanol, nitrogen-methylpyrrolidinone (NMP), pyridine, etc. Unless otherwise specified in the examples, the solution refers to an aqueous solution.

本發明中所描述的化學反應一般在常壓下進行。反應溫度在-78℃至200℃之間。反應時間和條件為，例如，一個大氣壓下，-78℃至200℃之間，大約1至24小時內完成。如果反應過夜，則反應時間一般為16小時。實施例中無特殊說明，反應的溫度為室溫，為20℃~30℃。 The chemical reactions described in the present invention are generally carried out under normal pressure. The reaction temperature is between -78°C and 200°C. The reaction time and conditions are, for example, between -78°C and 200°C under one atmospheric pressure, and the reaction is completed within about 1 to 24 hours. If the reaction is overnight, the reaction time is generally 16 hours. Unless otherwise specified in the examples, the temperature of the reaction is room temperature, which is 20° C. to 30° C.

實施例中的反應進程的監測採用薄層色譜法(TLC)，反應所使用的展開劑的體系有：A：二氯甲烷和甲醇體系，B：石油醚和乙酸乙酯體系，C：丙酮，溶劑的體積比根據化合物的極性不同而進行調節。 The monitoring of the reaction process in the embodiment adopts thin layer chromatography (TLC), and the system of developing agent used in the reaction has: A: dichloromethane and methanol system, B: sherwood oil and ethyl acetate system, C: acetone, The volume ratio of the solvent is adjusted according to the polarity of the compound.

純化化合物採用的管柱層析的沖提劑的體系和薄層色譜法的展開劑體系包括：A：二氯甲烷和甲醇體系，B：石油醚和乙酸乙酯體系，溶劑的體積比根據化合物的極性不同而進行調節，也可以加入少量的三乙胺和三氟乙酸等鹼性或酸性試劑進行調節。 The eluent system of column chromatography and the developer system of thin-layer chromatography used for purifying compounds include: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, and the volume ratio of the solvent is based on the compound It can be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and trifluoroacetic acid.

除非另行定義，文中所使用的所有專業與科學用語與本領域熟練人員所熟悉的意義相同。此外，任何與所記載內容相似或均等的方法及材料皆可應用於本發明方法中。 Unless otherwise defined, all professional and scientific terms used herein have the same meanings as commonly understood by those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be applied to the method of the present invention.

根據本文提供的示例性程序及其所屬技術領域具有通常知識者已知的改變來製備本發明的化合物。 Compounds of the invention are prepared according to the exemplary procedures provided herein with modifications known to those of ordinary skill in the art.

縮略語 Acronym

Ac=乙醯基 Ac=acetyl

AcO或OAc=乙醯氧基 AcO or OAc = acetyloxy

ACN=乙腈 ACN = acetonitrile

aq=水溶液 aq=aqueous solution

Boc=第三丁氧基羰基 Boc=tertiary butoxycarbonyl

Bn=苄基 Bn=benzyl

DIPEA=二異丙基乙基胺 DIPEA = Diisopropylethylamine

DMAP=4-二甲胺基吡啶 DMAP=4-dimethylaminopyridine

DMF=N,N-二甲基甲醯胺 DMF=N,N-Dimethylformamide

DMSO=二甲亞碸 DMSO = dimethyl sulfoxide

DCM=二氯甲烷 DCM=dichloromethane

EA=乙酸乙酯 EA = ethyl acetate

EDTA=乙二胺四乙酸 EDTA=ethylenediaminetetraacetic acid

HPLC=高效液相色譜法 HPLC = high performance liquid chromatography

IC₅₀=抑制50%活性的濃度 IC ₅₀ = the concentration that inhibits 50% of the activity

LHMDS=六甲基二矽氮烷鋰鹽(雙(三甲基甲矽烷基)胺基鋰) LHMDS = lithium hexamethyldisilazane salt (lithium bis(trimethylsilyl)amide)

LC-MS=液相色譜-質普聯用 LC-MS = liquid chromatography - mass spectrometry

M+H⁺=母體化合物質量+一質子 M+H ⁺ = parent compound mass + a proton

Ms=甲磺醯基 Ms=methylsulfonyl

MS=質譜 MS = mass spectrometry

MsCl=甲基磺醯氯 MsCl=methylsulfonyl chloride

mCPBA=間氯過氧苯甲酸 mCPBA= m-chloroperoxybenzoic acid

NBS=N-溴丁二醯亞胺 NBS=N-Bromobutanediimide

NCS=N-氯丁二醯亞胺 NCS=N-Chlorobutanediimide

NIS=N-碘丁二醯亞胺 NIS=N-iodobutanediimide

NMR=核磁共振 NMR = nuclear magnetic resonance

OXONE=過硫酸氫鉀 OXONE=Potassium hydrogen persulfate

PE=石油醚 PE=petroleum ether

Pro=保護基 Pro=Protection base

TBS=第三丁基二甲基矽基 TBS = tertiary butyldimethylsilyl

TBHP=第三丁基過氧化氫 TBHP = tertiary butyl hydroperoxide

TEA=三乙胺 TEA=triethylamine

TFA=三氟乙酸 TFA=trifluoroacetic acid

THF=四氫呋喃 THF=tetrahydrofuran

[實施例] [Example]

實施例1：2-((1-(環丙烷磺醯亞胺基)哌啶-4-基)胺基)-8-(((1R,2R)-2-羥基-2-甲基環戊基)吡啶并[2,3-d]嘧啶-7(8H)-酮(1)的製備 Example 1: 2-((1-(cyclopropanesulfonylimino)piperidin-4-yl)amino)-8-(((1R,2R)-2-hydroxyl-2-methylcyclopentyl base) pyrido[2,3-d]pyrimidin-7(8H)-one (1)

步驟1：1-甲基-6-氧雜二環[3.1.0]己烷(1a)的製備 Step 1: Preparation of 1-methyl-6-oxabicyclo[3.1.0]hexane (1a)

於室溫，將1-甲基環戊-1-烯(112g，1366mmol)、DCM(4400mL)加到反應瓶中，然後將間氯過氧苯甲酸(496g，2049mmol，71%wt)分批加入瓶中，室溫攪拌反應過夜。反應結束後，加矽藻土抽濾，加入飽和碳酸氫鈉(2500mL)、10%硫代硫酸鈉(500mL)，有機相在低於20℃的水浴鍋中濃縮得到125g棕色油狀物的標題產物，直接用於下一步。 At room temperature, 1-methylcyclopent-1-ene (112g, 1366mmol), DCM (4400mL) were added to the reaction flask, and m-chloroperoxybenzoic acid (496g, 2049mmol, 71%wt) was added in batches Add to the bottle and stir the reaction overnight at room temperature. After the reaction was completed, add diatomaceous earth for suction filtration, add saturated sodium bicarbonate (2500mL), 10% sodium thiosulfate (500mL), and concentrate the organic phase in a water bath below 20°C to obtain 125g of brown oil. The product was used directly in the next step.

LCMS：m/z 99.07[M+H]⁺。 LCMS: m/z 99.07 [M+H] ⁺ .

步驟2：(±)-(1R*,2R*)-2-(苄基胺基)-1-甲基環戊-1-醇((±)1b)的製備 Step 2: Preparation of (±)-(1R*,2R*)-2-(benzylamino)-1-methylcyclopent-1-ol ((±)1b)

於室溫，向玻璃封管中裝入水(250mL)和苄胺(146g，1366mmol)，然後用氮氣吹掃5min，然後加入1-甲基-6-氧雜雙環[3.1.0]己烷(125g，粗品)。100℃加熱18h，此時觀察到兩相混合物。冷卻至室溫後，加入濃鹽酸水溶液(約12M，150mL)以使pH達到1。用乙酸乙酯(1500mL)萃出有機雜質。將酸性水層在冰水浴中冷卻，並使用5N氫氧化鈉水溶液調節pH至10。用乙酸乙酯(1200mL×3)萃取所得的兩相混合物，合併的有機相經無水硫酸鈉乾燥，過濾並減壓濃縮，得棕色油狀物。於80℃減壓濃縮5h，降至室溫，在石油醚中分散，過濾得到85.0g棕色固體狀的標題產物。 At room temperature, water (250mL) and benzylamine (146g, 1366mmol) were charged into a glass sealed tube, then purged with nitrogen for 5min, and then 1-methyl-6-oxabicyclo[3.1.0]hexane was added (125 g, crude). Heated at 100 °C for 18 h, at which point a biphasic mixture was observed. After cooling to room temperature, concentrated aqueous hydrochloric acid (about 12M, 150 mL) was added to bring the pH to 1. Organic impurities were extracted with ethyl acetate (1500 mL). The acidic aqueous layer was cooled in an ice-water bath, and the pH was adjusted to 10 using 5N aqueous sodium hydroxide solution. The resulting biphasic mixture was extracted with ethyl acetate (1200 mL×3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a brown oil. Concentrate under reduced pressure at 80° C. for 5 h, cool down to room temperature, disperse in petroleum ether, and filter to obtain 85.0 g of the title product as a brown solid.

LCMS：m/z 206.15[M+H]⁺。 LCMS: m/z 206.15 [M+H] ⁺ .

步驟3：(1R,2R)-2-(苄基胺基)-1-甲基環戊-1-醇(1c)的製備 Step 3: Preparation of (1R,2R)-2-(benzylamino)-1-methylcyclopent-1-ol (1c)

於室溫，在反應瓶中加入(±)-(1R*,2R*)-2-(苄基胺基)-1-甲基環戊-1-醇(85.0g，414mmol)和乙醇(600mL)，80℃加熱30min。向另一反應瓶中加入(R)-2-(3,5-二硝基苯甲醯胺基)-2-苯基乙酸(71.4g，207mmol)和乙醇(1200mL)，80℃加熱直至固體溶解，並繼續攪拌30min。將來自第一個反應瓶的醇的熱溶液以穩定流速倒入第二個反應瓶中熱的手性酸溶液中。反應混合物保持澄清約1min，然後開始沉澱。5min後，形成濃稠的白色懸浮液，但不妨礙攪拌。在80℃繼續攪拌4h，然後停止加熱並繼續攪拌混合物，同時逐漸冷卻至室溫過夜。過濾收集母液，濃縮得到45g棕色固體。將該棕色固體懸浮於1L分液漏斗中的水(250mL)和乙酸乙酯(500mL)中。加入鹽酸水溶液(4M，150mL，600mmol)並將混合物攪拌約30秒。獲得澄清的雙相混合物。分離各層，並將有機層用鹽酸水溶液(4M，100mL×3)進一步洗滌。合併酸性水層，在冰水浴中冷卻，加入氫氧化鈉水溶液(aq)，使pH達到10。在該pH下形成白色懸浮液。用飽和氯化鈉水溶液(250mL)稀釋，並用乙酸乙酯(1000mL×3)萃取。將合併的有機相經無水硫酸鈉乾燥，過濾並減壓濃縮，得到26.0g棕色固體狀的標題產物，直接用於下一步。 At room temperature, add (±)-(1R*,2R*)-2-(benzylamino)-1-methylcyclopent-1-ol (85.0g, 414mmol) and ethanol (600mL ), heated at 80°C for 30min. Add (R)-2-(3,5-dinitrobenzamido)-2-phenylacetic acid (71.4g, 207mmol) and ethanol (1200mL) to another reaction flask, heat at 80°C until solid Dissolve and continue stirring for 30min. Pour the hot solution of alcohol from the first reaction flask into the hot chiral acid solution in the second reaction flask at a steady flow rate. The reaction mixture remained clear for about 1 min and then started to precipitate. After 5 min, a thick white suspension formed but did not interfere with stirring. Stirring was continued at 80 °C for 4 h, then heating was stopped and the mixture was continued to stir while gradually cooling to room temperature overnight. The mother liquor was collected by filtration and concentrated to give 45 g of a brown solid. Suspend the brown solid in water (250 mL) and ethyl acetate (500 mL) in a 1 L separatory funnel. Aqueous hydrochloric acid (4M, 150 mL, 600 mmol) was added and the mixture was stirred for about 30 seconds. A clear biphasic mixture is obtained. The layers were separated, and the organic layer was further washed with aqueous hydrochloric acid (4M, 100 mL x 3). The acidic aqueous layers were combined, cooled in an ice-water bath, and aqueous sodium hydroxide solution (aq) was added to bring the pH to 10. At this pH a white suspension formed. Diluted with saturated aqueous sodium chloride (250 mL), and extracted with ethyl acetate (1000 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 26.0 g of the title product as a brown solid, which was used directly in the next step.

LCMS：m/z 206.15[M+H]⁺。 LCMS: m/z 206.15 [M+H] ⁺ .

步驟4：(1R,2R)-2-胺基-1-甲基環戊-1-醇(1d)的製備 Step 4: Preparation of (1R,2R)-2-amino-1-methylcyclopent-1-ol (1d)

於室溫，將20%氫氧化鈀碳(2.6g)加入到(1R,2R)-2-胺基-1-甲基環戊-1-醇(26.0g,127mmol)的異丙醇(250mL)溶液中，50℃在氫氣環境中攪拌16h。藉由矽藻土過濾除去催化劑，濾液濃縮得到15.0g紅棕色油狀物的標題產物，直接用於下一步。 At room temperature, 20% palladium hydroxide on carbon (2.6g) was added to (1R,2R)-2-amino-1-methylcyclopent-1-ol (26.0g, 127mmol) in isopropanol (250mL ) solution, stirred at 50°C for 16h in a hydrogen atmosphere. The catalyst was removed by filtration through celite, and the filtrate was concentrated to give 15.0 g of the title product as a reddish-brown oil, which was directly used in the next step.

LCMS：m/z 116.10[M+H]⁺。 LCMS: m/z 116.10 [M+H] ⁺ .

步驟5：(4-氯-2-(甲硫基)嘧啶-5-基)甲醇(1e)的製備 Step 5: Preparation of (4-chloro-2-(methylthio)pyrimidin-5-yl)methanol (1e)

於室溫，將4-氯-2-(甲硫基)嘧啶-5-羧酸乙酯(76.6g，330mmol)、四氫呋喃(3000mL)加入到反應瓶中，在氮氣氛下，於-78℃將二異丁基氫化鋁(990mL，1M四氫呋喃溶液，990mmol)慢慢滴加到反應瓶中，期間控制溫度不超過-60℃，攪拌反應過夜，期間允許溫度升至室溫。反應結束後，於0℃用飽和氯化銨溶液(1000mL)淬滅反應，加入濃鹽酸水溶液(約12M)以使pH達到2，收集有機相用飽和食鹽水(1000mL)洗滌，無水硫酸鈉乾燥，過濾並減壓濃縮，得到53.2g淡黃色固體狀的標題產物，直接用於下一步，收率：84.8%。 At room temperature, add ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (76.6g, 330mmol) and tetrahydrofuran (3000mL) into the reaction flask, under nitrogen atmosphere, at -78°C Diisobutylaluminum hydride (990 mL, 1M tetrahydrofuran solution, 990 mmol) was slowly added dropwise to the reaction flask while controlling the temperature not to exceed -60°C, and the reaction was stirred overnight, allowing the temperature to rise to room temperature during the reaction. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (1000 mL) at 0 °C, concentrated aqueous hydrochloric acid (about 12 M) was added to make the pH reach 2, the organic phase was collected, washed with saturated brine (1000 mL), and dried over anhydrous sodium sulfate , filtered and concentrated under reduced pressure to obtain 53.2 g of the title product as a pale yellow solid, which was directly used in the next step, yield: 84.8%.

LCMS：m/z 191[M+H]⁺。 LCMS: m/z 191 [M+H] ⁺ .

步驟6：(1R,2R)-2-((5-(羥甲基)-2-(甲硫基)嘧啶-4-基)胺基)-1-甲基環戊-1-醇(1f)的製備 Step 6: (1R,2R)-2-((5-(Hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)-1-methylcyclopent-1-ol (1f ) preparation

於室溫，將(4-氯-2-(甲硫基)嘧啶-5-基)甲醇(24.5g，129mmol)、(1R,2R)-2-胺基-1-甲基環戊-1-醇(15.0g，129mmol)、二異丙基乙胺(49.9g，387mmol)、異丙醇(200mL)加到500mL反應瓶中，於80℃攪拌反應過夜。反應結束後，減壓濃縮，殘餘物藉由管柱層析色譜法(沖提劑：二氯甲烷：甲醇=0-20：1)純化，得到25.0g白色固體狀的標題產物，收率：92.9%。 At room temperature, (4-chloro-2-(methylthio)pyrimidin-5-yl)methanol (24.5g, 129mmol), (1R,2R)-2-amino-1-methylcyclopent-1 - Alcohol (15.0g, 129mmol), diisopropylethylamine (49.9g, 387mmol), and isopropanol (200mL) were added to a 500mL reaction flask, and the reaction was stirred overnight at 80°C. After the reaction, it was concentrated under reduced pressure, and the residue was purified by column chromatography (eluant: dichloromethane: methanol = 0-20: 1) to obtain 25.0 g of the title product as a white solid, yield: 92.9%.

LCMS：m/z 270.12[M+H]⁺。 LCMS: m/z 270.12 [M+H] ⁺ .

步驟7：4-(((1R,2R)-2-羥基-2-甲基環戊基)胺基)-2-(甲硫基)嘧啶-5-甲醛(1g)的製備 Step 7: Preparation of 4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)-2-(methylthio)pyrimidine-5-carbaldehyde (1 g)

於室溫，將(1R,2R)-2-((5-(羥甲基)-2-(甲硫基)嘧啶-4-基)胺基)-1-甲基環戊-1-醇(25.0g，92.9mmol)、二氧化錳(161g，1858mmol)、乙酸乙酯(600mL)加到反應瓶中，於50℃攪拌反應過夜。反應結束後，過濾除去固體，濾液濃縮後藉由管柱層析色譜法(沖提劑：二氯甲烷：甲醇=0-20：1)純化，得到19.0g白色固體狀的標題產物，收率：76.6%。 At room temperature, (1R,2R)-2-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)-1-methylcyclopent-1-ol (25.0g, 92.9mmol), manganese dioxide (161g, 1858mmol), ethyl acetate (600mL) were added to the reaction flask, and the reaction was stirred overnight at 50°C. After the reaction, the solid was removed by filtration, and the filtrate was concentrated and purified by column chromatography (eluent: dichloromethane:methanol=0-20:1) to obtain 19.0 g of the title product as a white solid, yield : 76.6%.

LCMS：m/z 268.10[M+H]⁺。 LCMS: m/z 268.10 [M+H] ⁺ .

步驟8：8-((1R,2R)-2-羥基-2-甲基環戊基)-2-(甲硫基)吡啶并[2,3-d]嘧啶-7(8H)-酮(1h)的製備 Step 8: 8-((1R,2R)-2-Hydroxy-2-methylcyclopentyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one ( 1h) Preparation

於室溫，將4-(((1R,2R)-2-羥基-2-甲基環戊基)胺基)-2-(甲硫基)嘧啶-5-甲醛(13.4g，50.2mmol)、四氫呋喃(250mL)和乙酸乙酯(13.1mL，126mmol)加入到三口瓶中，甲醇-冰浴中冷卻至-5℃，在氮氣氛下，緩慢地加入六甲基矽胺基鋰(151mL，1.0M四氫呋喃溶液，151mmol)。期間允許溫度逐漸升至室溫並過夜。將得到的紅色溶液在冰水浴中冷卻至約3℃，然後緩慢地加入乙醇(88mL，1506mmol)。將混合物在冰浴中攪拌1h，然後移去冷卻浴，使溶液升至室溫，繼續攪拌1h。減壓除去溶劑，將殘餘物用水(100mL)和飽和氯化鈉水溶液(100mL)稀釋，水層用乙酸乙酯(400mL×3)萃取，將合併的有機相經無水硫酸鈉乾燥，過濾並減壓濃縮。得到17.0g棕色固體狀的標題產物，直接用於下一步。 At room temperature, 4-(((1R,2R)-2-hydroxyl-2-methylcyclopentyl)amino)-2-(methylthio)pyrimidine-5-carbaldehyde (13.4g, 50.2mmol) , tetrahydrofuran (250mL) and ethyl acetate (13.1mL, 126mmol) were added to a three-necked flask, cooled to -5°C in a methanol-ice bath, and slowly added hexamethylsilyl lithium (151mL, 1.0M tetrahydrofuran solution, 151 mmol). The temperature was allowed to gradually rise to room temperature overnight. The resulting red solution was cooled to about 3°C in an ice-water bath, then ethanol (88 mL, 1506 mmol) was added slowly. The mixture was stirred in an ice bath for 1 h, then the cooling bath was removed and the solution Warm up to room temperature and continue stirring for 1h. The solvent was removed under reduced pressure, the residue was diluted with water (100 mL) and saturated aqueous sodium chloride (100 mL), the aqueous layer was extracted with ethyl acetate (400 mL×3), the combined organic phases were dried over anhydrous sodium sulfate, filtered and reduced Concentrate under pressure. This gave 17.0 g of the title product as a brown solid which was used directly in the next step.

LCMS：m/z 292.10[M+H]⁺。 LCMS: m/z 292.10 [M+H] ⁺ .

步驟9：8-((1R,2R)-2-羥基-2-甲基環戊基)-2-(甲基磺醯基)吡啶并[2,3-d]嘧啶-7(8H)-酮(1i)的製備 Step 9: 8-((1R,2R)-2-Hydroxy-2-methylcyclopentyl)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidine-7(8H)- Preparation of ketone (1i)

於室溫，將8-((1R,2R)-2-羥基-2-甲基環戊基)-2-(甲硫基)吡啶并[2,3-d]嘧啶-7(8H)-酮(17.0g，粗品)、過硫酸氫鉀(76.9g，125mmol)、2-甲基四氫呋喃(250mL)、水(60mL)加入到反應瓶中，室溫攪拌4h。將溶液在水浴中冷卻，用水(100mL)和飽和氯化鈉水溶液(100mL)稀釋並用乙酸乙酯(500mL×3)萃取。合併的有機相經無水硫酸鈉乾燥，過濾並減壓濃縮。殘餘物藉由管柱層析色譜法(沖提劑：石油醚：乙酸乙酯=1：1-1)純化，得到10.8g泡沫狀棕色固體物的標題產物，收率：66.6%。 At room temperature, 8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(methylthio)pyrido[2,3-d]pyrimidine-7(8H)- Add ketone (17.0 g, crude product), potassium persulfate (76.9 g, 125 mmol), 2-methyltetrahydrofuran (250 mL), and water (60 mL) into the reaction flask, and stir at room temperature for 4 h. The solution was cooled in a water bath, diluted with water (100 mL) and saturated aqueous sodium chloride (100 mL) and extracted with ethyl acetate (500 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 1:1-1) to obtain 10.8 g of the title product as a foamy brown solid, yield: 66.6%.

LCMS：m/z 306.09[M-18]⁺。 LCMS: m/z 306.09 [M-18] ⁺ .

步驟10：4-((8-((1R,2R)-2-羥基-2-甲基環戊基)-7-側氧基-7,8-二氫吡啶并[2,3-d]嘧啶-2-基)胺基)哌啶-1-羧酸第三丁酯(1j)的製備 Step 10: 4-((8-((1R,2R)-2-Hydroxy-2-methylcyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-d] Preparation of tert-butyl pyrimidin-2-yl)amino)piperidine-1-carboxylate (1j)

於室溫，將8-((1R,2R)-2-羥基-2-甲基環戊基)-2-(甲基磺醯基)吡啶并[2,3-d]嘧啶-7(8H)-酮(3.80g，11.8mmol)和4-胺基哌啶-1-羧酸第三丁酯(2.82g，14.2mmol)、二異丙基乙胺(3.05g，23.6mmol)、2-甲基四氫呋喃(50mL)加入到反應瓶中，60℃攪拌反應過夜。冷卻至室溫後，加入乙酸乙酯(200mL)、水(50mL)和飽和碳酸氫鈉水溶液(50mL)。有機相經無水硫酸鈉乾燥，過濾並減壓濃縮。殘餘物藉由管柱層析色譜法(沖提劑：二氯甲烷：甲醇=0-5%)純化，得到4.55g黃色泡沫固體狀的標題產物，收率：87.1%。 At room temperature, 8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidine-7(8H )-ketone (3.80g, 11.8mmol) and tertiary butyl 4-aminopiperidine-1-carboxylate (2.82g, 14.2mmol), diisopropylethylamine (3.05g, 23.6mmol), 2- Methyltetrahydrofuran (50 mL) was added into the reaction flask, and the reaction was stirred overnight at 60°C. After cooling to room temperature, ethyl acetate (200 mL), water (50 mL) and saturated aqueous sodium bicarbonate (50 mL) were added. The organic phase was dried over anhydrous sodium sulfate, Filter and concentrate under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane: methanol = 0-5%) to obtain 4.55 g of the title product as a yellow foamy solid, yield: 87.1%.

步驟11：8-((1R,2R)-2-羥基-2-甲基環戊基)-2-(哌啶-4-基胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(1k)的製備 Step 11: 8-((1R,2R)-2-Hydroxy-2-methylcyclopentyl)-2-(piperidin-4-ylamino)pyrido[2,3-d]pyrimidine-7( Preparation of 8H)-ketone (1k)

於室溫，將4-((8-((1R,2R)-2-羥基-2-甲基環戊基)-7-側氧基-7,8-二氫吡啶并[2,3-d]嘧啶-2-基)胺基)哌啶-1-羧酸第三丁酯(3.63g，8.20mmol)加入到10mL鹽酸的二噁烷溶液中，攪拌反應2h，有黃色固體析出，減壓濃縮。於0℃，殘餘物中加入氫氧化鈉(aq)以使pH達到10，加入二氯甲烷(200mL×3)，收集有機相，減壓濃縮，得到2.57g黃色固體狀的標題產物，直接用於下一步。 At room temperature, 4-((8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-7-oxo-7,8-dihydropyrido[2,3- d] pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (3.63g, 8.20mmol) was added in 10mL of hydrochloric acid dioxane solution, stirred for 2h, a yellow solid was precipitated, and Concentrate under pressure. At 0°C, sodium hydroxide (aq) was added to the residue to bring the pH to 10, dichloromethane (200 mL×3) was added, the organic phase was collected and concentrated under reduced pressure to obtain 2.57 g of the title product as a yellow solid, which was directly used in in the next step.

LCMS：m/z 314.19[M+H]⁺。 LCMS: m/z 314.19 [M+H] ⁺ .

步驟12：N-(第三丁基二甲基甲矽烷基)環丙烷磺醯胺(11)的製備 Step 12: Preparation of N-(tert-butyldimethylsilyl)cyclopropanesulfonamide (11)

於室溫，在氮氣氛下，將環丙烷磺醯胺(2.42g，20.0mmol)、三乙胺(4.04g，40.0mmol)、四氫呋喃(40mL)加入到反應瓶中，攪拌10min後，緩慢加入第三丁基二甲基氯矽烷(3.60g，24.0mmol)、二甲胺基吡啶(254mg，2.00mmol)，30℃攪拌反應16h，有固體析出，減壓濃縮，殘餘物中加入乙酸乙酯(50mL×3)和水(30mL)，收集有機相，水層用乙酸乙酯(30mL×3)萃取，將合併的有機相經無水硫酸鈉乾燥，過濾並減壓濃縮，殘餘物藉由管柱層析色譜法(沖提劑：石油醚：乙酸乙酯=0-20%)純化，得到3.27g白色固體的標題產物，收率：69.6%。 At room temperature, under a nitrogen atmosphere, cyclopropanesulfonamide (2.42g, 20.0mmol), triethylamine (4.04g, 40.0mmol), tetrahydrofuran (40mL) were added to the reaction flask, stirred for 10min, and then slowly added Tertiary butyldimethylsilyl chloride (3.60g, 24.0mmol), dimethylaminopyridine (254mg, 2.00mmol), stirred and reacted at 30°C for 16h, solids were precipitated, concentrated under reduced pressure, and ethyl acetate was added to the residue (50mL×3) and water (30mL), the organic phase was collected, the aqueous layer was extracted with ethyl acetate (30mL×3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, the residue was collected by tube Purified by column chromatography (eluant: petroleum ether: ethyl acetate = 0-20%) to obtain 3.27 g of the title product as a white solid, yield: 69.6%.

LCMS：m/z 236.11[M+H]⁺。 LCMS: m/z 236.11 [M+H] ⁺ .

步驟13：2-((1-(環丙烷磺醯亞胺基)哌啶-4-基)胺基)-8-(((1R,2R)-2-羥基-2-甲基環戊基)吡啶并[2,3-d]嘧啶-7(8H)-酮(1)的製備 Step 13: 2-((1-(cyclopropanesulfonimino)piperidin-4-yl)amino)-8-(((1R,2R)-2-hydroxy-2-methylcyclopentyl ) Preparation of pyrido[2,3-d]pyrimidin-7(8H)-one (1)

於室溫，在氮氣氛下，將三苯基二氯化磷(1.83g，5.50mmol)的二氯甲烷溶液(6mL)冷卻到0℃，加入三乙胺(808mg，8.00mmol)，攪拌15min後，加入化合物N-(第三丁基二甲基甲矽烷基)環丙烷磺醯胺(1.18g,5.00mmol)，攪拌20min後加入化合物1k(343mg，1.00mmol)，加畢緩慢升至室溫，於室溫攪拌反應16h。加入飽和氯化銨溶液(1mL)淬滅反應，收集有機相，減壓濃縮，所得殘餘物藉由管柱層析色譜法(沖提劑：乙酸乙酯：甲醇=0-10%)純化，再用製備液相色譜法分離(色譜管柱型號：Daisogei 30mm*250mm，C18，10um，100A，流動相：乙腈/水，梯度：30%-80%)，得71.0mg白色固體狀標題化合物，收率15.9%。 At room temperature, under a nitrogen atmosphere, a dichloromethane solution (6 mL) of triphenylphosphine dichloride (1.83 g, 5.50 mmol) was cooled to 0°C, triethylamine (808 mg, 8.00 mmol) was added, and stirred for 15 min Finally, compound N-(tertiary butyldimethylsilyl) cyclopropanesulfonamide (1.18g, 5.00mmol) was added, and compound 1k (343mg, 1.00mmol) was added after stirring for 20min. Warm, the reaction was stirred at room temperature for 16h. The reaction was quenched by adding saturated ammonium chloride solution (1 mL), the organic phase was collected, concentrated under reduced pressure, and the resulting residue was purified by column chromatography (eluant: ethyl acetate: methanol = 0-10%), Separation by preparative liquid chromatography (column model: Daisogei 30mm*250mm, C18, 10um, 100A, mobile phase: acetonitrile/water, gradient: 30%-80%), to obtain 71.0 mg of the title compound as a white solid, Yield 15.9%.

LCMS：m/z 447.21[M+H]⁺。 LCMS: m/z 447.21 [M+H] ⁺ .

¹H NMR(300MHz,CDCl₃)δ 8.45(s,1H),7.50(d,J=8.9Hz,1H),6.43(d,J=9.4Hz,1H),5.76(s,1H),3.96(s,3H),3.01(t,J=10.7Hz,2H),2.73(s,1H),2.37(ddd,J=12.6,8.0,4.7Hz,1H),2.16(s,4H),1.91-1.77(m,2H),1.67(s,6H),1.36(s,3H),1.21(dd,J=4.5,2.7Hz,2H),0.99(t,J=8.1Hz,2H)。 ¹ H NMR (300MHz, CDCl ₃ )δ 8.45(s,1H),7.50(d,J=8.9Hz,1H),6.43(d,J=9.4Hz,1H),5.76(s,1H),3.96( s,3H),3.01(t,J=10.7Hz,2H),2.73(s,1H),2.37(ddd,J=12.6,8.0,4.7Hz,1H),2.16(s,4H),1.91-1.77 (m,2H),1.67(s,6H),1.36(s,3H),1.21(dd,J=4.5,2.7Hz,2H),0.99(t,J=8.1Hz,2H).

實施例2：2-((1-(環丙烷磺醯亞胺基)哌啶-4-基)胺基)-6-(二氟甲基)-8-((1R,2R)-2-羥基-2-甲基環戊基)吡啶并[2,3-d]嘧啶-7(8H)-酮(2)的製備 Example 2: 2-((1-(cyclopropanesulfonimino)piperidin-4-yl)amino)-6-(difluoromethyl)-8-((1R,2R)-2- Preparation of Hydroxy-2-methylcyclopentyl)pyrido[2,3-d]pyrimidin-7(8H)-one (2)

步驟1：2-((1-(環丙烷磺醯亞胺基)哌啶-4-基)胺基)-6-(二氟甲基)-8-((1R,2R)-2-羥基-2-甲基環戊基)吡啶并[2,3-d]嘧啶-7(8H)-酮(2)的製備 Step 1: 2-((1-(cyclopropanesulfonimino)piperidin-4-yl)amino)-6-(difluoromethyl)-8-((1R,2R)-2-hydroxyl Preparation of -2-methylcyclopentyl)pyrido[2,3-d]pyrimidin-7(8H)-one (2)

於室溫，將雙(((二氟甲基)亞磺醯基)氧基)鋅(59.0mg，0.200mmol)、氯化亞鐵(6.35mg，0.050mmol)的水溶液(1mL)滴加到2-((1-(環丙烷磺醯亞胺基)哌啶-4-基)胺基)-8-(((1R,2R)-2-羥基-2-甲基環戊基)吡啶并[2,3-d]嘧啶-7(8H)-酮(44.6mg，0.100mmol)、TFA(11.4mg，0.100mmol)的DMSO溶液(6mL)中。將TBHP(51.2mg，70%wt水溶液，0.400mmol)稀釋為1mL的水溶液，然後加入0.2mL稀釋後的TBHP，20℃反應2h；再次加入0.2mL稀釋後的TBHP，20℃反應2h；再次加入0.2mL稀釋後的TBHP，20℃反應過夜；最後加入0.2mL稀釋後的TBHP，20℃反應2h。將反應溶液倒入10%乙二胺四乙酸(10mL)中，並用乙酸乙酯(20mL×3)萃取。合併的有機相減壓濃縮，殘餘物用製備薄層色譜法(展開劑：二氯甲烷：甲醇=20：1)純化，並用製備液相色譜法分離(色譜管柱型號：Daisogei 30mm*250mm，C18，10um，100A，流動相：乙腈/水，梯度：30%-80%)，得10.1mg白色固體狀的標題化合物，收率20.4%。 At room temperature, an aqueous solution (1 mL) of bis(((difluoromethyl)sulfinyl)oxy)zinc (59.0 mg, 0.200 mmol), ferrous chloride (6.35 mg, 0.050 mmol) was added dropwise to 2-((1-(cyclopropanesulfonylimino)piperidin-4-yl)amino)-8-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)pyrido [2,3-d]pyrimidin-7(8H)-one (44.6mg, 0.100mmol), TFA (11.4mg, 0.100mmol) in DMSO solution (6mL). TBHP (51.2mg, 70%wt aqueous solution, 0.400mmol) was diluted to 1mL aqueous solution, then added 0.2mL diluted TBHP, reacted at 20°C for 2h; added 0.2mL diluted TBHP again, reacted at 20°C for 2h; added 0.2mL diluted TBHP again, reacted overnight at 20°C ;Finally add 0.2mL of diluted TBHP, and react for 2h at 20°C.The reaction solution is poured into 10% ethylenediaminetetraacetic acid (10mL), and extracted with ethyl acetate (20mL×3).The combined organic phase is concentrated under reduced pressure , the residue was purified by preparative thin-layer chromatography (developing solvent: methylene chloride:methanol=20:1), and separated by preparative liquid chromatography (chromatographic column model: Daisogei 30mm*250mm, C18, 10um, 100A, mobile Phase: acetonitrile/water, gradient: 30%-80%), 10.1 mg of the title compound was obtained as a white solid, yield 20.4%.

LCMS：m/z 497.21[M+H]⁺。 LCMS: m/z 497.21 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.55(s,1H),7.87(s,1H),6.79(t,J=55.2Hz,1H),5.75(s,1H),3.96(d,J=34.2Hz,3H),3.16-2.92(m,2H),2.72(s,1H),2.48(d,J=57.2Hz,4H),2.27-2.03(m,4H),1.98-1.84(m,2H),1.72(s,3H),1.36(s,3H),1.33-1.22(m,2H),1.14-1.04(m,2H)。 ¹ H NMR (400MHz, CDCl ₃ )δ 8.55(s,1H),7.87(s,1H),6.79(t,J=55.2Hz,1H),5.75(s,1H),3.96(d,J=34.2 Hz,3H),3.16-2.92(m,2H),2.72(s,1H),2.48(d,J=57.2Hz,4H),2.27-2.03(m,4H),1.98-1.84(m,2H) ,1.72(s,3H),1.36(s,3H),1.33-1.22(m,2H),1.14-1.04(m,2H).

實施例3：8-環戊基-2-(((1-(環丙烷磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(3)的製備 Example 3: 8-cyclopentyl-2-(((1-(cyclopropanesulfonimino)piperidin-4-yl)amino)pyrido[2,3-d]pyrimidine-7(8H )-The preparation of ketone (3)

步驟1：(4-(環戊基胺基)-2-(甲硫基)嘧啶-5-基)甲醇(3a)的製備 Step 1: Preparation of (4-(cyclopentylamino)-2-(methylthio)pyrimidin-5-yl)methanol (3a)

於室溫，將(4-氯-2-(甲硫基)嘧啶-5-基)甲醇(1e)(4.66g，20.0mmol)、環戊胺(2.04g，24.0mmol)、三乙胺(6.06g，60.0mmol)、四氫呋喃(50mL)加入250mL反應瓶中，室溫攪拌反應過夜。反應結束後，減壓濃縮，加入乙酸乙酯(100mL×3)和水(70mL)，收集有機相，減壓濃縮得到5.10g淡黃色固體狀的標題產物，直接用於下一步。 At room temperature, (4-chloro-2-(methylthio)pyrimidin-5-yl)methanol (1e) (4.66g, 20.0mmol), cyclopentylamine (2.04g, 24.0mmol), triethylamine ( 6.06g, 60.0mmol), tetrahydrofuran (50mL) were added into a 250mL reaction flask, and the reaction was stirred overnight at room temperature. After the reaction was completed, it was concentrated under reduced pressure, ethyl acetate (100 mL×3) and water (70 mL) were added, the organic phase was collected, concentrated under reduced pressure to obtain 5.10 g of the title product as a light yellow solid, which was directly used in the next step.

LCMS：m/z 240.11[M+H]⁺。 LCMS: m/z 240.11 [M+H] ⁺ .

步驟2：4-(環戊基胺基)-2-(甲硫基)嘧啶-5-甲醛(3b)的製備 Step 2: Preparation of 4-(cyclopentylamino)-2-(methylthio)pyrimidine-5-carbaldehyde (3b)

於室溫，將(4-(環戊基胺基)-2-(甲硫基)嘧啶-5-基)甲醇(13.4g，粗品)、二氧化錳(76.9g,884mmol)、乙酸乙酯(310mL)加到1L反應瓶中，於50℃攪拌反應過夜。反應結束後，過濾除去固體，濾液濃縮後藉由管柱層析色譜法(沖提劑：石油醚：乙酸乙酯=0-20%)純化，得到9.37g黃色油狀的標題產物，收率：89.4%。 At room temperature, (4-(cyclopentylamino)-2-(methylthio)pyrimidin-5-yl)methanol (13.4g, crude product), manganese dioxide (76.9g, 884mmol), ethyl acetate (310 mL) was added to a 1L reaction flask, and the reaction was stirred overnight at 50°C. After the reaction was finished, the solid was removed by filtration, and the filtrate was concentrated by column chromatography (washing Extracting agent: petroleum ether: ethyl acetate = 0-20%) purification, to obtain 9.37g of the title product in the form of yellow oil, yield: 89.4%.

LCMS：m/z 238.09[M+H]⁺。 LCMS: m/z 238.09 [M+H] ⁺ .

步驟3：8-環戊基-2-(甲硫基)吡啶并[2,3-d]嘧啶-7(8H)-酮(3c)的製備 Step 3: Preparation of 8-cyclopentyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (3c)

於室溫，將4-(環戊基胺基)-2-(甲硫基)嘧啶-5-甲醛(11.8g，49.8mmol)、四氫呋喃(250mL)和乙酸乙酯(11.0g，125mmol)加入到1L三口瓶中，甲醇-冰浴中冷卻至-5℃，在氮氣氛下，緩慢地加入六甲基矽胺基鋰(150mL,1.0M四氫呋喃溶液，150mmol)，期間允許溫度逐漸升至室溫並攪拌過夜。將得到的紅色溶液在冰水浴中冷卻至約3℃，然後緩慢地加入乙醇(200mL)。將混合物在冰浴中攪拌1h，然後移去冷卻浴，使溶液升至室溫，繼續攪拌1h。減壓濃縮，將殘餘物用水(100mL)和飽和氯化鈉水溶液(100mL)稀釋，水層用乙酸乙酯(500mL×3)萃取，將合併的有機相經無水硫酸鈉乾燥，過濾並減壓濃縮。殘餘物藉由管柱層析色譜法(沖提劑：石油醚：乙酸乙酯=0-40%)純化，得到11.0g黃色固體物的標題產物，收率：84.6%。 Add 4-(cyclopentylamino)-2-(methylthio)pyrimidine-5-carbaldehyde (11.8 g, 49.8 mmol), tetrahydrofuran (250 mL) and ethyl acetate (11.0 g, 125 mmol) at room temperature Into a 1L three-necked flask, cooled to -5°C in a methanol-ice bath, and slowly added lithium hexamethylsilylamide (150mL, 1.0M tetrahydrofuran solution, 150mmol) under a nitrogen atmosphere, allowing the temperature to gradually rise to room temperature Warm and stir overnight. The resulting red solution was cooled to about 3°C in an ice-water bath, then ethanol (200 mL) was added slowly. The mixture was stirred in an ice bath for 1 h, then the cooling bath was removed, the solution was allowed to warm to room temperature, and stirring was continued for 1 h. Concentrate under reduced pressure, dilute the residue with water (100 mL) and saturated aqueous sodium chloride solution (100 mL), extract the aqueous layer with ethyl acetate (500 mL×3), dry the combined organic phases over anhydrous sodium sulfate, filter and reduce pressure concentrate. The residue was purified by column chromatography (eluant: petroleum ether: ethyl acetate = 0-40%) to obtain 11.0 g of the title product as a yellow solid, yield: 84.6%.

LCMS：m/z 262.09[M+H]⁺。 LCMS: m/z 262.09 [M+H] ⁺ .

步驟4：8-環戊基-2-(甲基磺醯基)吡啶并[2,3-d]嘧啶-7(8H)-酮(3d)的製備 Step 4: Preparation of 8-cyclopentyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (3d)

於室溫，將8-環戊基-2-(甲硫基)吡啶并[2,3-d]嘧啶-7(8H)-酮(11.0g，42.2mmoI)、過硫酸氫鉀(64.8g，105mmol)、2-甲基四氫呋喃(200mL)、水(40mL)加入到1L反應瓶中，於室溫攪拌反應過夜。過濾，濾餅用乙酸乙酯(100mL×3)沖洗，收集濾液，加入乙酸乙酯(200mL)和水(100mL)，將合併的有機相經無水硫酸鈉乾燥，過濾並減壓濃縮。殘餘物藉由管柱層析色譜法(沖提劑：石油醚：乙酸乙酯=0-100%)純化，得到8.37g黃棕色固體物的標題產物，收率：67.7%。 At room temperature, 8-cyclopentyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (11.0g, 42.2mmol), potassium persulfate (64.8g , 105mmol), 2-methyltetrahydrofuran (200mL), water (40mL) were added into a 1L reaction flask, and the reaction was stirred overnight at room temperature. Filtration, the filter cake was washed with ethyl acetate (100mL×3), the filtrate was collected, ethyl acetate (200mL) and water (100mL) were added, and the combined The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 0-100%) to obtain 8.37 g of the title product as a yellow-brown solid, yield: 67.7%.

LCMS：m/z 294.08[M+H]⁺。 LCMS: m/z 294.08 [M+H] ⁺ .

步驟5：4-((8-環戊基-7-側氧基-7,8-二氫吡啶并[2,3-d]嘧啶-2-基)胺基)哌啶-1-羧酸第三丁酯(3e)的製備 Step 5: 4-((8-Cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidine-1-carboxylic acid Preparation of tertiary butyl ester (3e)

於室溫，將8-環戊基-2-(甲基磺醯基)吡啶并[2,3-d]嘧啶-7(8H)-酮(4.40g，15.0mmol)、4-胺基哌啶-1-羧酸第三丁酯(3.60g,18.0mmol)、二異丙基乙胺(3.87g，30.0mmol)、四氫呋喃(75mL)加入到反應瓶中，60℃攪拌反應過夜。冷卻至室溫後，加入乙酸乙酯(100mL×3)和水(100mL)。有機相經無水硫酸鈉乾燥，過濾並減壓濃縮。殘餘物藉由管柱層析色譜法(沖提劑：二氯甲烷：甲醇=0-5%)純化，得到5.80g黃色泡沫固體狀的標題產物，收率：93.6%。 At room temperature, 8-cyclopentyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (4.40g, 15.0mmol), 4-aminopiper Pyridine-1-carboxylic acid tert-butyl ester (3.60g, 18.0mmol), diisopropylethylamine (3.87g, 30.0mmol), tetrahydrofuran (75mL) were added into the reaction flask, and the reaction was stirred at 60°C overnight. After cooling to room temperature, ethyl acetate (100 mL×3) and water (100 mL) were added. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane: methanol = 0-5%) to obtain 5.80 g of the title product as a yellow foamy solid, yield: 93.6%.

LCMS：m/z 414.24[M+H]⁺。 LCMS: m/z 414.24 [M+H] ⁺ .

步驟6：8-環戊基-2-(哌啶-4-基胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(3f)的製備 Step 6: Preparation of 8-cyclopentyl-2-(piperidin-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (3f)

於室溫，將4-((8-環戊基-7-側氧基-7,8-二氫吡啶并[2,3-d]嘧啶-2-基)胺基)哌啶-1-羧酸第三丁酯(4.13g，10.0mmol)加入到10mL鹽酸的二噁烷溶液中，攪拌反應2h，有黃色固體析出，減壓濃縮。於0℃，殘餘物中加入氫氧化鈉(aq)以使pH達到10，加入二氯甲烷(200mL×3)，收集有機相，減壓濃縮，得到2.42g黃色固體物的標題產物，直接用於下一步。 At room temperature, 4-((8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidine-1- Tertiary butyl carboxylate (4.13 g, 10.0 mmol) was added to 10 mL of hydrochloric acid in dioxane, stirred for 2 h, a yellow solid precipitated out, and concentrated under reduced pressure. At 0°C, sodium hydroxide (aq) was added to the residue to bring the pH to 10, dichloromethane (200 mL×3) was added, the organic phase was collected and concentrated under reduced pressure to obtain 2.42 g of the title product as a yellow solid, which was directly used in in the next step.

LCMS：m/z 314.19[M+H]⁺。 LCMS: m/z 314.19 [M+H] ⁺ .

步驟7：8-環戊基-2-(((1-(環丙烷磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(3)的製備 Step 7: 8-Cyclopentyl-2-(((1-(cyclopropanesulfonimino)piperidin-4-yl)amino)pyrido[2,3-d]pyrimidine-7(8H) - Preparation of ketone (3)

於室溫，在氮氣氛下，將三苯基二氯化磷(1.82g,5.50mmol)的二氯甲烷溶液(20mL)冷卻到0℃，加入三乙胺(909mg,9.00mmol)，攪拌15min後，加入化合物N-(第三丁基二甲基甲矽烷基)環丙烷磺醯胺(1l)(690mg,5.00mmol)，攪拌20min後，加入化合物(8-環戊基-2-(哌啶-4-基胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(313mg,1.00mmol)，加畢緩慢升至室溫，攪拌反應16h。加入飽和氯化銨溶液(5mL)淬滅反應，收集有機相，減壓濃縮，所得殘餘物藉由管柱層析色譜法(沖提劑：乙酸乙酯：甲醇=0-10%)純化，得384mg淡黃色固體產物，取60mg用製備液相色譜法分離(色譜管柱型號：Daisogei 30mm*250mm，C18，10um，100A，流動相：乙腈/水，梯度：30%-80%)，得48.0mg白色固體標題化合物，收率80.0%。 At room temperature, under a nitrogen atmosphere, a solution of triphenylphosphine dichloride (1.82g, 5.50mmol) in dichloromethane (20mL) was cooled to 0°C, triethylamine (909mg, 9.00mmol) was added, and stirred for 15min Afterwards, the compound N-(tert-butyldimethylsilyl)cyclopropanesulfonamide ( 1l ) (690mg, 5.00mmol) was added, and after stirring for 20min, the compound (8-cyclopentyl-2-(piper Pyridin-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (313mg, 1.00mmol), slowly warmed up to room temperature after addition, and stirred for 16h. Add saturated ammonium chloride solution (5mL) quenched the reaction, collected the organic phase, concentrated under reduced pressure, and the resulting residue was purified by column chromatography (eluant: ethyl acetate: methanol = 0-10%) to obtain 384 mg of a light yellow solid product , 60mg was separated by preparative liquid chromatography (column model: Daisogei 30mm*250mm, C18, 10um, 100A, mobile phase: acetonitrile/water, gradient: 30%-80%), and 48.0mg of the title compound was obtained as a white solid , yield 80.0%.

LCMS：m/z 417.20[M+H]⁺。 LCMS: m/z 417.20 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.40(s,1H),7.44-7.40(d,J=16Hz,1H),6.39-6.36(d,J=12Hz,1H),5.87-5.82(m,1H),4.02(s,1H),3.88(s,2H),3.11-3.06(m,2H),2.40-2.34(m,3H),2.14-2.03(m,6H),1.84(s,2H),1.68(s,4H),1.23-1.20(m,2H),1.00-0.97(m,2H)。 ¹ H NMR (400MHz, CDCl ₃ ) δ 8.40(s,1H),7.44-7.40(d,J=16Hz,1H),6.39-6.36(d,J=12Hz,1H),5.87-5.82(m,1H ),4.02(s,1H),3.88(s,2H),3.11-3.06(m,2H),2.40-2.34(m,3H),2.14-2.03(m,6H),1.84(s,2H), 1.68 (s, 4H), 1.23-1.20 (m, 2H), 1.00-0.97 (m, 2H).

實施例4：8-((1R,2R)-2-羥基-2-甲基環戊基)-2-(((1-(N-甲基環丙烷磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(4)的製備 Example 4: 8-((1R,2R)-2-hydroxyl-2-methylcyclopentyl)-2-(((1-(N-methylcyclopropanesulfonimido)piperidine-4 Preparation of -yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (4)

步驟1：N-甲基丙烷-1-磺醯胺(4a)的製備 Step 1: Preparation of N-methylpropane-1-sulfonamide (4a)

於室溫，將環丙烷磺醯氯(1.43g，10.0mmol)、四氫呋喃(5mL)加入到玻璃封管中，降溫至0℃，加入三乙胺(4.04g，40.0mmol)、甲胺水溶液(5mL)，室溫攪拌反應16h。減壓濃縮，殘餘物中加入乙酸乙酯(50mL×3)和水(30mL)，收集有機相，水層用乙酸乙酯(30mL×3)萃取，將合併的有機相經無水硫酸鈉乾燥，過濾並減壓濃縮，殘餘物藉由管柱層析色譜法(沖提劑：石油醚：乙酸乙酯=0-50%)純化，得到1.26g白油狀物的標題產物，收率：92.0%。 At room temperature, cyclopropanesulfonyl chloride (1.43g, 10.0mmol) and tetrahydrofuran (5mL) were added into a sealed glass tube, cooled to 0°C, triethylamine (4.04g, 40.0mmol) and methylamine aqueous solution ( 5 mL), stirred at room temperature for 16 h. Concentrate under reduced pressure, add ethyl acetate (50mL×3) and water (30mL) to the residue, collect the organic phase, extract the aqueous layer with ethyl acetate (30mL×3), dry the combined organic phase over anhydrous sodium sulfate, Filtration and concentration under reduced pressure, the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 0-50%) to obtain 1.26 g of the title product as a white oil, yield: 92.0 %.

LCMS：m/z 138.08[M+H]⁺。 LCMS: m/z 138.08 [M+H] ⁺ .

步驟2：8-((1R,2R)-2-羥基-2-甲基環戊基)-2-(((1-(N-甲基環丙烷磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(4)的製備 Step 2: 8-((1R,2R)-2-Hydroxy-2-methylcyclopentyl)-2-(((1-(N-methylcyclopropanesulfonimido)piperidine-4- base)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (4)

與實施例1的步驟13的製備方法相同，除了用N-甲基丙烷-1-磺醯胺代替N-(第三丁基二甲基甲矽烷基)環丙烷磺醯胺，製得標題化合物。 The same preparation method as in step 13 of Example 1, except that N-(tertiary butyldimethylsilyl) cyclopropanesulfonamide is replaced with N-methylpropane-1-sulfonylamide to obtain the title compound .

LCMS：m/z 461.23[M+H]⁺。 LCMS: m/z 461.23 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.46(s,1H),7.50(d,J=8.5Hz,1H),6.44(d,J=9.2Hz,1H),5.77(s,1H),4.03(s,1H),3.82(s,2H),3.17-2.99(m,2H),2.73(s,4H),2.17(d,J=13.5Hz,6H),2.02(s,1H),1.84(dd,J=13.9,6.0Hz,2H),1.67(d,J=9.0Hz,3H),1.36(s,3H),1.26(s,2H),1.12(s,1H),1.04(s,1H)。 ¹ H NMR (400MHz, CDCl ₃ )δ 8.46(s,1H),7.50(d,J=8.5Hz,1H),6.44(d,J=9.2Hz,1H),5.77(s,1H),4.03( s,1H),3.82(s,2H),3.17-2.99(m,2H),2.73(s,4H),2.17(d,J=13.5Hz,6H),2.02(s,1H),1.84(dd ,J=13.9,6.0Hz,2H),1.67(d,J=9.0Hz,3H),1.36(s,3H),1.26(s,2H),1.12(s,1H),1.04(s,1H) .

實施例5：6-(二氟甲基)-8-(((1R,2R)-2-羥基-2-甲基環戊基)-2-(((1-(N-甲基環丙烷磺醯亞胺基))哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(5)的製備 Example 5: 6-(difluoromethyl)-8-(((1R,2R)-2-hydroxyl-2-methylcyclopentyl)-2-(((1-(N-methylcyclopropane Preparation of sulfimido))piperidin-4-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (5)

與實施例2的製備方法相同，除了用化合物4代替化合物1，製得標題化合物。 The title compound was prepared in the same manner as in Example 2, except that Compound 4 was used instead of Compound 1.

LCMS：m/z 511.22[M+H]⁺。 LCMS: m/z 511.22 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.55(s,1H),7.86(s,1H),6.79(t,J=55.2Hz,1H),5.73(s,1H),4.05(d,J=44.6Hz,1H),3.78(s,2H),3.16-2.90(m,2H),2.70(s,3H),2.47(s,1H),2.15(d,J=13.1Hz,3H),1.86(s,6H),1.67(s,3H),1.36(s,3H),1.20(d,J=3.8Hz,2H),0.99(dd,J=19.7,6.3Hz,2H)。 ¹ H NMR (400MHz, CDCl ₃ )δ 8.55(s,1H),7.86(s,1H),6.79(t,J=55.2Hz,1H),5.73(s,1H),4.05(d,J=44.6 Hz,1H),3.78(s,2H),3.16-2.90(m,2H),2.70(s,3H),2.47(s,1H),2.15(d,J=13.1Hz,3H),1.86(s ,6H),1.67(s,3H),1.36(s,3H),1.20(d,J=3.8Hz,2H),0.99(dd,J=19.7,6.3Hz,2H).

實施例6：8-環戊基-2-(((8-(環丙烷磺醯亞胺基)-8-氮雜雙[3.2.1]辛-3-基]胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(6)的製備 Example 6: 8-cyclopentyl-2-(((8-(cyclopropanesulfonimido)-8-azabis[3.2.1]oct-3-yl]amino)pyrido[2 ,3-d] Preparation of pyrimidin-7(8H)-one (6)

與實施例3的製備方法相同，除了用2-((8-氮雜雙環[3.2.1]辛-3-基)胺代替步驟1中的環戊胺，製得標題化合物。 The title compound was prepared in the same manner as in Example 3, except that 2-((8-azabicyclo[3.2.1]oct-3-yl)amine was used instead of cyclopentylamine in Step 1.

LCMS：m/z 443.22[M+H]⁺。 LCMS: m/z 443.22 [M+H] ⁺ .

¹HNMR(400MHz,CDCl₃)δ 8.37(s,1H),7.42(d,J=9.3Hz,1H),6.38(d,J=9.3Hz,1H),5.89-5.77(m,1H),4.38(s,1H),4.33-4.22(m,2H),2.63-2.29(m,7H),2.23(d,J=9.2Hz,2H),2.13(dd,J=15.7,6.7Hz,2H),2.02(dd,J=15.4,12.1Hz,4H),1.91-1.78(m,2H),1.73-1.62(m,2H),1.23(dq,J=11.5,5.7Hz,2H),1.07-0.99(m,1H),0.96(dd,J=7.5,2.1Hz,1H)。 ¹ HNMR(400MHz, CDCl ₃ ) δ 8.37(s,1H),7.42(d,J=9.3Hz,1H),6.38(d,J=9.3Hz,1H),5.89-5.77(m,1H),4.38 (s,1H),4.33-4.22(m,2H),2.63-2.29(m,7H),2.23(d,J=9.2Hz,2H),2.13(dd,J=15.7,6.7Hz,2H), 2.02(dd,J=15.4,12.1Hz,4H),1.91-1.78(m,2H),1.73-1.62(m,2H),1.23(dq,J=11.5,5.7Hz,2H),1.07-0.99( m, 1H), 0.96 (dd, J=7.5, 2.1Hz, 1H).

實施例7：8-環戊基-2-(((1-(丙-2-基磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(7)的製備 Example 7: 8-cyclopentyl-2-(((1-(propan-2-ylsulfonimido)piperidin-4-yl)amino)pyrido[2,3-d]pyrimidine- Preparation of 7(8H)-ketone (7)

步驟1：N-(第三丁基二甲基甲矽烷基)丙烷-2-磺醯胺(7a)的製備 Step 1: Preparation of N-(tert-butyldimethylsilyl)propane-2-sulfonamide (7a)

與實施例1的步驟12的方法相同，除了用丙烷-2-磺醯胺代替環丙烷磺醯胺，製得標題化合物。 The title compound was obtained in the same manner as in Step 12 of Example 1, except that propane-2-sulfonamide was used instead of cyclopropanesulfonamide.

步驟2：8-環戊基-2-(((1-(丙-2-基磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮的製備 Step 2: 8-Cyclopentyl-2-(((1-(propan-2-ylsulfonimino)piperidin-4-yl)amino)pyrido[2,3-d]pyrimidine-7 Preparation of (8H)-ketone

與實施例3的製備方法相同，除了用N-(第三丁基二甲基甲矽烷基)丙烷-2-磺醯胺(7a)代替N-(第三丁基二甲基甲矽烷基)環丙烷磺醯胺(11)，製得標題化合物。 The preparation method is the same as that of Example 3, except that N-(tert-butyldimethylsilyl) is replaced by N-(tert-butyldimethylsilyl) propane-2-sulfonamide (7a) Cyclopropanesulfonamide (11), the title compound was obtained.

LCMS：m/z 419.22[M+H]⁺。 LCMS: m/z 419.22 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.39(s,1H),7.42-7.40(d,J=8Hz,1H),6.38-6.35(d,J=12Hz,1H),5.88-5.79(m,1H),4.03(s,1H),3.94(s,2H),3.30-3.23(m,1H),3.11-3.06(m,2H),2.37(s,2H),2.17-2.11(m,2H),2.03(s,3H),1.86-1.84(m,3H),1.69-1.58(m,4H),1.41-1.36(m,6H)。 ¹ H NMR (400MHz, CDCl ₃ ) δ 8.39(s,1H),7.42-7.40(d,J=8Hz,1H),6.38-6.35(d,J=12Hz,1H),5.88-5.79(m,1H ),4.03(s,1H),3.94(s,2H),3.30-3.23(m,1H),3.11-3.06(m,2H),2.37(s,2H),2.17-2.11(m,2H), 2.03 (s, 3H), 1.86-1.84 (m, 3H), 1.69-1.58 (m, 4H), 1.41-1.36 (m, 6H).

實施例8：8-環戊基-2-(((1-(丙基磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(8)的製備 Example 8: 8-cyclopentyl-2-(((1-(propylsulfonimino)piperidin-4-yl)amino)pyrido[2,3-d]pyrimidine-7(8H )- Preparation of ketone (8)

步驟1：N-(第三丁基二甲基甲矽烷基)丙烷-1-磺醯胺(8a)的製備 Step 1: Preparation of N-(tert-butyldimethylsilyl)propane-1-sulfonamide (8a)

與實施例1的步驟12的方法相同，除了用丙烷-1-磺醯胺代替環丙烷磺醯胺，製得標題化合物。 The title compound was obtained in the same manner as in Step 12 of Example 1, except that propane-1-sulfonamide was used instead of cyclopropanesulfonamide.

與實施例3的製備方法相同，除了用N-(第三丁基二甲基甲矽烷基)丙烷-1-磺醯胺(8a)代替N-(第三丁基二甲基甲矽烷基)環丙烷磺醯胺(11)，製得標題化合物。 The same preparation method as in Example 3, except that N-(tertiary butyldimethylsilyl) is replaced by N-(tertiary butyldimethylsilyl) propane-1-sulfonamide (8a) Cyclopropanesulfonamide (11), the title compound was obtained.

LCMS：m/z 419.22[M+H]⁺。 LCMS: m/z 419.22 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.39(s,1H),7.42-7.40(d,J=8Hz,1H),6.38-6.35(d,J=12Hz,1H),5.86-5.82(m,1H),4.01(s,1H),3.87(s,2H),2.99-2.86(m,3H),2.85-2.81(m,1H),2.01(s,2H),1.93-1.91(m,2H),1.89(s,2H),1.87-1.85(m,5H),1.68-1.62(m,5H),1.09-1.06(t,J=12Hz,3H)。 ¹ H NMR (400MHz, CDCl ₃ ) δ 8.39(s,1H),7.42-7.40(d,J=8Hz,1H),6.38-6.35(d,J=12Hz,1H),5.86-5.82(m,1H ),4.01(s,1H),3.87(s,2H),2.99-2.86(m,3H),2.85-2.81(m,1H),2.01(s,2H),1.93-1.91(m,2H), 1.89(s, 2H), 1.87-1.85(m, 5H), 1.68-1.62(m, 5H), 1.09-1.06(t, J=12Hz, 3H).

實施例9：8-環戊基-2-(((1-(N-甲基丙基磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(9)的製備 Example 9: 8-cyclopentyl-2-(((1-(N-methylpropylsulfonimido)piperidin-4-yl)amino)pyrido[2,3-d]pyrimidine Preparation of -7(8H)-ketone (9)

步驟1：N-甲基丙烷-1-磺醯胺(9a)的製備 Step 1: Preparation of N-methylpropane-1-sulfonamide (9a)

與實施例4的步驟1的方法相同，除了用丙烷-1-磺醯氯代替環丙烷磺醯氯，製得標題化合物。 The title compound was obtained in the same manner as in Step 1 of Example 4, except that propane-1-sulfonyl chloride was used instead of cyclopropanesulfonyl chloride.

與實施例3的製備方法相同，除了用N-甲基丙烷-1-磺醯胺(9a)代替N-(第三丁基二甲基甲矽烷基)環丙烷磺醯胺(11)，製得標題化合物。 The preparation method is the same as that of Example 3, except that N-(tert-butyldimethylsilyl) cyclopropanesulfonamide (11) is replaced with N-methylpropane-1-sulfonamide (9a), the preparation The title compound was obtained.

LCMS：m/z 432.23[M+H]⁺。 LCMS: m/z 432.23 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.39(s,1H),7.43-7.40(d,J=12Hz,1H),6.38-6.35(d,J=12Hz,1H),5.87-5.78(m,1H),4.02(s,1H),3.82-3.71(s,2H),3.03-2.81(m,4H),2.69(s,3H),2.36-2.16(m,5H),2.03(m,2H),1.96-1.84(m,4H),1.68-1.64(m,4H),1.08-1.03(m,3H)。 ¹ H NMR (400MHz, CDCl ₃ ) δ 8.39(s,1H),7.43-7.40(d,J=12Hz,1H),6.38-6.35(d,J=12Hz,1H),5.87-5.78(m,1H ),4.02(s,1H),3.82-3.71(s,2H),3.03-2.81(m,4H),2.69(s,3H),2.36-2.16(m,5H),2.03(m,2H), 1.96-1.84 (m, 4H), 1.68-1.64 (m, 4H), 1.08-1.03 (m, 3H).

實施例10：8-環戊基-6-(二氟甲基)-2-(((1-(N-甲基丙基磺醯亞胺基)哌啶-4-基)胺基)吡啶基[2,3-d]嘧啶-7(8H)-酮(10)的製備 Example 10: 8-cyclopentyl-6-(difluoromethyl)-2-(((1-(N-methylpropylsulfonimido)piperidin-4-yl)amino)pyridine Preparation of [2,3-d]pyrimidin-7(8H)-one (10)

與實施例2的製備方法相同，除了用化合物9代替化合物1，製得標題化合物。 The title compound was prepared in the same manner as in Example 2, except that Compound 9 was used instead of Compound 1.

LCMS：m/z 483.1[M+H]⁺。 LCMS: m/z 483.1 [M+H] ⁺ .

¹HNMR(300MHz,CDCl₃)δ 8.51(s,1H),7.80(s,1H),6.99-6.62(m,1H),5.88-5.82(m,1H),4.05(s,1H),3.79(s,2H),3.02-2.98(m,4H),2.70(s,3H),2.18(m,5H),2.04(m,2H),1.92-1.88(m,4H),1.69(s,4H),1.09-1.04(m,3H)。 ¹ HNMR (300MHz, CDCl ₃ ) δ 8.51(s,1H),7.80(s,1H),6.99-6.62(m,1H),5.88-5.82(m,1H),4.05(s,1H),3.79( s,2H),3.02-2.98(m,4H),2.70(s,3H),2.18(m,5H),2.04(m,2H),1.92-1.88(m,4H),1.69(s,4H) ,1.09-1.04(m,3H).

實施例11：8-((1R,2R)-2-羥基-2-甲基環戊基)-2-(((1-(S-甲基磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(11)的製備 Example 11: 8-((1R,2R)-2-Hydroxy-2-methylcyclopentyl)-2-(((1-(S-methylsulfonimino)piperidin-4-yl )amino)pyrido[2,3-d]pyrimidin-7(8H)-one (11) preparation

步驟1：N-(第三丁基二甲基甲矽烷基)甲磺醯胺(11a)的製備 Step 1: Preparation of N-(tert-butyldimethylsilyl)methanesulfonamide (11a)

與實施例1的步驟12的方法相同，除了用甲磺醯胺代替環丙烷磺醯胺，製得標題化合物。 The title compound was obtained in the same manner as in Step 12 of Example 1, except that methanesulfonamide was used instead of cyclopropanesulfonamide.

其餘步驟與實施例1的步驟相同，除了用N-(第三丁基二甲基甲矽烷基)甲磺醯胺(11a)代替實施例1步驟13的N-(第三丁基二甲基甲矽烷基)環丙烷磺醯胺(11)，製得標題化合物。 All the other steps are the same as those in Example 1, except that N-(tertiary butyldimethylsilyl) methanesulfonamide (11a) is used to replace the N-(tertiary butyldimethylsilyl) in step 13 of Example 1 Silyl)cyclopropanesulfonamide (11) to obtain the title compound.

LCMS：m/z 421.19[M+H]⁺。 LCMS: m/z 421.19 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.45(s,1H),7.50(d,J=8.2Hz,1H),6.44(d,J=9.1Hz,1H),5.76(s,1H),3.94(d,J=42.8Hz,3H),2.87(d,J=7.0Hz,5H),2.73(s,1H),2.18(s,3H),1.99-1.78(m,6H),1.68(s,3H),1.36(s,3H)。 ¹ H NMR (400MHz, CDCl ₃ ) δ 8.45(s,1H),7.50(d,J=8.2Hz,1H),6.44(d,J=9.1Hz,1H),5.76(s,1H),3.94( d,J=42.8Hz,3H),2.87(d,J=7.0Hz,5H),2.73(s,1H),2.18(s,3H),1.99-1.78(m,6H),1.68(s,3H ), 1.36(s,3H).

實施例12：6-(二氟甲基)-8-(((1R,2R)-2-羥基-2-甲基環戊基)-2-((1-(S-甲基磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(12)的製備 Example 12: 6-(difluoromethyl)-8-(((1R,2R)-2-hydroxyl-2-methylcyclopentyl)-2-((1-(S-methylsulfonyl Preparation of amino)piperidin-4-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (12)

與實施例2的製備方法相同，除了用化合物11代替化合物1，製得標題化合物。 The title compound was prepared in the same manner as in Example 2, except that Compound 11 was used instead of Compound 1.

LCMS：m/z 471.19[M+H]⁺。 LCMS: m/z 471.19 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.55(s,1H),7.87(s,1H),6.79(t,J=55.2Hz,1H),5.75(s,1H),3.90(s,3H),2.88(s,3H),2.71(s,1H),2.19(s,4H),1.77(d,J=53.5Hz,10H),1.36(s,3H)。 ¹ H NMR (400MHz, CDCl ₃ )δ 8.55(s,1H),7.87(s,1H),6.79(t,J=55.2Hz,1H),5.75(s,1H),3.90(s,3H), 2.88(s,3H),2.71(s,1H),2.19(s,4H),1.77(d,J=53.5Hz,10H),1.36(s,3H).

實施例13：8-環戊基-2-(((1-(S-甲基磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(13)的製備 Example 13: 8-cyclopentyl-2-(((1-(S-methylsulfonimino)piperidin-4-yl)amino)pyrido[2,3-d]pyrimidine-7 Preparation of (8H)-ketone (13)

與實施例3的製備方法相同，除了用N-(第三丁基二甲基甲矽烷基)甲磺醯胺(11a)代替步驟7中的N-(第三丁基二甲基甲矽烷基)環丙烷磺醯胺(11)，製得標題化合物。 The preparation method is the same as in Example 3, except that N-(tertiary butyldimethylsilyl) methanesulfonamide (11a) is used to replace N-(tertiary butyldimethylsilyl) in step 7 ) cyclopropanesulfonamide (11) to obtain the title compound.

LCMS：m/z 391.18[M+H]⁺。 LCMS: m/z 391.18 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.39(s,1H),7.44-7.41(d,J=12Hz,1H),6.40-6.37(d,J=12Hz,1H),5.90-5.78(m,1H),4.03(s,1H),3.85(s,2H),2.95(s,2H),2.86(s,3H),2.35-2.19(m,6H),2.03(s,2H),1.87-1.84(m,2H),1.70(s,4H)。 ¹ H NMR (400MHz, CDCl ₃ ) δ 8.39(s,1H),7.44-7.41(d,J=12Hz,1H),6.40-6.37(d,J=12Hz,1H),5.90-5.78(m,1H ),4.03(s,1H),3.85(s,2H),2.95(s,2H),2.86(s,3H),2.35-2.19(m,6H),2.03(s,2H),1.87-1.84( m,2H), 1.70(s,4H).

實施例14：2-((1-(N,S-二甲基磺醯亞胺基)哌啶-4-基)胺基)-8-(((1R,2R)-2-羥基-2-甲基環戊基)吡啶并[2,3-d]嘧啶-7(8H)-酮(14)的製備 Example 14: 2-((1-(N,S-dimethylsulfonylimino)piperidin-4-yl)amino)-8-(((1R,2R)-2-hydroxy-2 Preparation of -methylcyclopentyl)pyrido[2,3-d]pyrimidin-7(8H)-one (14)

步驟1：N-甲基甲磺醯胺(14a)的製備 Step 1: Preparation of N-methylmethylsulfonamide (14a)

與實施例4的步驟1的方法相同，除了用甲磺醯氯代替環丙烷磺醯氯，製得標題化合物。 The title compound was obtained in the same manner as in Step 1 of Example 4, except that methanesulfonyl chloride was used instead of cyclopropanesulfonyl chloride.

其餘步驟與實施例1的步驟相同，除了用N-甲基甲磺醯胺(14a)代替實施例1步驟13的N-(第三丁基二甲基甲矽烷基)環丙烷磺醯胺(11)，製得標題化合物。 All the other steps are identical to the steps of Example 1, except that N-(tertiary butyldimethylsilyl) cyclopropanesulfonamide (14a) replaces the N-(tertiary butyldimethylsilyl) cyclopropanesulfonamide ( 11), the title compound was prepared.

LCMS：m/z 435.21[M+H]⁺。 LCMS: m/z 435.21 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.45(s,1H),7.53-7.46(m,1H),6.44(d,J=9.2Hz,1H),5.76(s,1H),4.02(s,1H),3.87-3.67(m,2H),2.94(s,6H),2.72(s,1H),2.69(d,J=1.1Hz,3H),2.28-1.97(m,5H),1.90-1.80(m,2H),1.68(d,J=9.0Hz,3H),1.36(s,3H)。 ¹ H NMR (400MHz, CDCl ₃ )δ 8.45(s,1H),7.53-7.46(m,1H),6.44(d,J=9.2Hz,1H),5.76(s,1H),4.02(s,1H ),3.87-3.67(m,2H),2.94(s,6H),2.72(s,1H),2.69(d,J=1.1Hz,3H),2.28-1.97(m,5H),1.90-1.80( m,2H), 1.68(d,J=9.0Hz,3H), 1.36(s,3H).

實施例15：6-(二氟甲基)-2-(((1-(N,S-二甲基磺醯亞胺基)哌啶-4-基)胺基)-8-((1R,2R)-2-羥基-2-甲基環戊基)吡啶并[2,3-d]嘧啶-7(8H)-酮(15)的製備 Example 15: 6-(difluoromethyl)-2-(((1-(N,S-dimethylsulfonylimino)piperidin-4-yl)amino)-8-((1R ,2R)-2-Hydroxy-2-methylcyclopentyl)pyrido[2,3-d]pyrimidin-7(8H)-one (15)

與實施例2的製備方法相同，除了用化合物14代替化合物1，製得標題化合物。 The title compound was prepared in the same manner as in Example 2, except that Compound 14 was used instead of Compound 1.

LCMS：m/z 485.21[M+H]⁺。 LCMS: m/z 485.21 [M+H] ⁺ .

¹HNMR(400MHz,CDCl₃)δ 8.55(s,1H),7.87(s,1H),6.79(t,J=55.2Hz,1H),5.70(s,1H),4.05(d,J=46.6Hz,1H),3.78(d,J=18.8Hz,2H),2.90(s,5H),2.69(d,J=1.2Hz,4H),2.29-1.95(m,6H),1.86(dd,J=13.2,6.1Hz,2H),1.70(s,3H),1.36(s,3H)。 ¹ HNMR(400MHz, CDCl ₃ ) δ 8.55(s,1H),7.87(s,1H),6.79(t,J=55.2Hz,1H),5.70(s,1H),4.05(d,J=46.6Hz ,1H),3.78(d,J=18.8Hz,2H),2.90(s,5H),2.69(d,J=1.2Hz,4H),2.29-1.95(m,6H),1.86(dd,J= 13.2, 6.1Hz, 2H), 1.70(s, 3H), 1.36(s, 3H).

實施例16：8-環戊基-2-(((1-(N,S-二甲基磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(16)的製備 Example 16: 8-cyclopentyl-2-(((1-(N,S-dimethylsulfonimino)piperidin-4-yl)amino)pyrido[2,3-d] Preparation of pyrimidin-7(8H)-one (16)

與實施例3的製備方法相同，除了用N-甲基甲磺醯胺(14a)代替步驟7中的N-(第三丁基二甲基甲矽烷基)環丙烷磺醯胺(11)，製得標題化合物。 The preparation method is the same as that of Example 3, except that N-(tertiary butyldimethylsilyl) cyclopropanesulfonamide (11) in step 7 is replaced with N-methylmethanesulfonamide (14a), The title compound was obtained.

LCMS：m/z 405.203[M+H]⁺。 LCMS: m/z 405.203 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.39(s,1H),7.4-7.41(d,J=12Hz,1H),6.39-6.36(d,J=12Hz,1H),5.90-5.78(m,1H),4.02(s,1H),3.80-3.67(s,2H),2.96-2.92(m,2H),2.69(s,3H),2.37-2.18(m,5H),2.03(m,2H),1.87-1.84(m,2H),1.68(m,4H)。 ¹ H NMR (400MHz, CDCl ₃ ) δ 8.39(s,1H),7.4-7.41(d,J=12Hz,1H),6.39-6.36(d,J=12Hz,1H),5.90-5.78(m,1H ),4.02(s,1H),3.80-3.67(s,2H),2.96-2.92(m,2H),2.69(s,3H),2.37-2.18(m,5H),2.03(m,2H), 1.87-1.84(m,2H),1.68(m,4H).

實施例17：8-環戊基-6-(二氟甲基)-2-(((1-(S-甲基磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(17)的製備 Example 17: 8-cyclopentyl-6-(difluoromethyl)-2-(((1-(S-methylsulfonyl imino)piperidin-4-yl)amino)pyrido[ Preparation of 2,3-d]pyrimidin-7(8H)-one (17)

與實施例2的製備方法相同，除了用化合物13代替化合物1，製得標題化合物。 The title compound was prepared in the same manner as in Example 2, except that Compound 13 was used instead of Compound 1.

LCMS：m/z 441.18[M+H]⁺。 LCMS: m/z 441.18 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.51(s,1H),7.79(s,1H),6.80(t,J=55.3Hz,1H),6.11(s,0.5H),5.94-5.73(m,1H),5.30(s,0.5H),4.06(s,1H),3.84(s,2H),3.01(s,1H),2.90(s,3H),2.62(s,2H),2.27(d,J=55.8Hz,4H),2.02(d,J=13.3Hz,2H),1.87(s,2H),1.70(s,4H)。 ¹ H NMR (400MHz, CDCl ₃ )δ 8.51(s,1H),7.79(s,1H),6.80(t,J=55.3Hz,1H),6.11(s,0.5H),5.94-5.73(m, 1H),5.30(s,0.5H),4.06(s,1H),3.84(s,2H),3.01(s,1H),2.90(s,3H),2.62(s,2H),2.27(d, J=55.8Hz, 4H), 2.02(d, J=13.3Hz, 2H), 1.87(s, 2H), 1.70(s, 4H).

實施例18：8-環戊基-6-(二氟甲基)-2-(((1-(N,S-甲基磺醯亞胺基))哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(18)的製備 Example 18: 8-Cyclopentyl-6-(difluoromethyl)-2-(((1-(N,S-methylsulfonylimino))piperidin-4-yl)amino) Preparation of pyrido[2,3-d]pyrimidin-7(8H)-one (18)

與實施例2的製備方法相同，除了用化合物16代替化合物1，製得標題化合物。 The title compound was prepared in the same manner as in Example 2, except that Compound 16 was used instead of Compound 1.

LCMS：m/z 455.20[M+H]⁺。 LCMS: m/z 455.20 [M+H] ⁺ .

¹HNMR(400MHz,CDCl₃)δ 8.51(s,1H),7.79(s,1H),6.80(t,J=55.3Hz,1H),6.00-5.73(m,1H),4.05(s,1H),3.76(s,2H),2.96(s,5H),2.71(s,3H),2.35(s,2H),2.22(s,3H),2.04(s,2H),1.86(s,2H),1.69(s,4H)。 ¹ HNMR(400MHz, CDCl ₃ )δ 8.51(s,1H),7.79(s,1H),6.80(t,J=55.3Hz,1H),6.00-5.73(m,1H),4.05(s,1H) ,3.76(s,2H),2.96(s,5H),2.71(s,3H),2.35(s,2H),2.22(s,3H),2.04(s,2H),1.86(s,2H), 1.69(s,4H).

實施例19：8-環戊基-2-(((1-(N-甲基環丙烷磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(3)的製備 Example 19: 8-cyclopentyl-2-(((1-(N-methylcyclopropanesulfonimino)piperidin-4-yl)amino)pyrido[2,3-d]pyrimidine Preparation of -7(8H)-one (3)

與實施例3的製備方法相同，除了用N-甲基丙烷-1-磺醯胺(4a)代替N-(第三丁基二甲基甲矽烷基)環丙烷磺醯胺(11)，製得標題化合物。 The preparation method is the same as that of Example 3, except that N-(tert-butyldimethylsilyl) cyclopropanesulfonamide (11) is replaced with N-methylpropane-1-sulfonamide (4a), The title compound was obtained.

LCMS：m/z 431.23[M+H]⁺。 LCMS: m/z 431.23 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.40(s,1H),7.41(d,J=9.3Hz,1H),6.37(d,J=9.3Hz,1H),5.84(p,J=9.0Hz,1H),5.41(s,1H),4.05(s,1H),3.78(s,2H),3.07(t,J=11.3Hz,2H),2.72(s,3H),2.55(d,J=2.9Hz,1H),2.37(s,2H),2.19(t,J=12.8Hz,2H),2.03(s,2H),1.90-1.80(m,2H),1.69(s,4H),1.33-1.16(m,2H),1.01(dd,J=22.1,9.7Hz,2H)。 ¹ H NMR (400MHz, CDCl ₃ )δ 8.40(s,1H),7.41(d,J=9.3Hz,1H),6.37(d,J=9.3Hz,1H),5.84(p,J=9.0Hz, 1H),5.41(s,1H),4.05(s,1H),3.78(s,2H),3.07(t,J=11.3Hz,2H),2.72(s,3H),2.55(d,J=2.9 Hz,1H),2.37(s,2H),2.19(t,J=12.8Hz,2H),2.03(s,2H),1.90-1.80(m,2H),1.69(s,4H),1.33-1.16 (m,2H),1.01(dd,J=22.1,9.7Hz,2H).

實施例20：8-環戊基-2-(((1-(環丙烷磺醯亞胺基)哌啶-4-基)胺基)-6-(二氟甲基)吡啶并[2,3-d]嘧啶-7(8H)-酮(20)的製備 Example 20: 8-cyclopentyl-2-(((1-(cyclopropanesulfonimino)piperidin-4-yl)amino)-6-(difluoromethyl)pyrido[2, 3-d] Preparation of pyrimidin-7(8H)-one (20)

與實施例2的製備方法相同，除了用化合物3代替化合物1，製得標題化合物。 The title compound was prepared in the same manner as in Example 2, except that Compound 3 was used instead of Compound 1.

LCMS：m/z 467.20[M+H]⁺。 LCMS: m/z 467.20 [M+H] ⁺ .

¹HNMR(400MHz,CDCl₃)δ 8.49(s,1H),7.79(s,1H),6.80(t,J=55.3Hz,1H),5.85(p,J=8.9Hz,1H),4.05(s,1H),3.88(s,2H),3.09(s,2H),2.50(s,2H),2.43(ddd,J=12.8,8.1,4.9Hz,3H),2.18(s,2H),2.04(s,2H),1.87(s,2H),1.70(s,4H),1.28-1.18(m,2H),1.02(dd,J=9.9,8.3Hz,2H)。 ¹ HNMR(400MHz, CDCl ₃ ) δ 8.49(s,1H),7.79(s,1H),6.80(t,J=55.3Hz,1H),5.85(p,J=8.9Hz,1H),4.05(s ,1H),3.88(s,2H),3.09(s,2H),2.50(s,2H),2.43(ddd,J=12.8,8.1,4.9Hz,3H),2.18(s,2H),2.04( s,2H),1.87(s,2H),1.70(s,4H),1.28-1.18(m,2H),1.02(dd,J=9.9,8.3Hz,2H).

實施例21：8-環戊基-6-(二氟甲基)-2-(((1-(N-甲基丙基磺醯亞胺基)哌啶丁-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(21)的製備 Example 21: 8-cyclopentyl-6-(difluoromethyl)-2-(((1-(N-methylpropylsulfonimido)piperidin-4-yl)amino) Preparation of pyrido[2,3-d]pyrimidin-7(8H)-one (21)

與實施例2的製備方法相同，除了用化合物19代替化合物1，製得標題化合物。 The title compound was prepared in the same manner as in Example 2, except that Compound 19 was used instead of Compound 1.

LCMS：m/z 481.21[M+H]⁺。 LCMS: m/z 481.21 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.52(s,1H),7.79(s,1H),6.80(t,J=55.3Hz,1H),5.90-5.79(m,1H),5.45(d,J=98.8Hz,1H),4.07(s,1H),3.81(s,2H),3.09(s,2H),2.74(s,3H),2.67(s,1H),2.37(s,2H),2.21(t,J=13.5Hz,2H),2.04(s,2H),1.87(s,2H),1.69(s,4H),1.32-1.21(m,2H),1.15-0.95(m,2H)。 ¹ H NMR (400MHz, CDCl ₃ )δ 8.52(s,1H),7.79(s,1H),6.80(t,J=55.3Hz,1H),5.90-5.79(m,1H),5.45(d,J =98.8Hz,1H),4.07(s,1H),3.81(s,2H),3.09(s,2H),2.74(s,3H),2.67(s,1H),2.37(s,2H),2.21 (t, J=13.5Hz, 2H), 2.04(s, 2H), 1.87(s, 2H), 1.69(s, 4H), 1.32-1.21(m, 2H), 1.15-0.95(m, 2H).

實施例22：8-(2-甲基環戊基)-2-((1-(S-甲基磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(22-P1和22-P2)的製備 Example 22: 8-(2-methylcyclopentyl)-2-((1-(S-methylsulfonimino)piperidin-4-yl)amino)pyrido[2,3- d] Preparation of pyrimidin-7(8H)-one (22-P1 and 22-P2)

與實施例3的製備方法相同，除了用2-甲基環戊烷-1-胺鹽酸鹽代替環戊胺和用N-(第三丁基二甲基甲矽烷基)甲磺醯胺(11a)代替N-(第三丁基二甲基甲矽烷基)環丙烷磺醯胺(11)，製得標題化合物。藉由管柱層析色譜法(沖提劑：乙酸乙酯：甲醇=0-10%)純化，再用製備液相色譜法分離得到化合物22-P1和22-P2。 The same preparation method as in Example 3, except that cyclopentylamine is replaced with 2-methylcyclopentane-1-amine hydrochloride and N-(tertiary butyldimethylsilyl) methanesulfonamide ( 11a) Instead of N-(tert-butyldimethylsilyl)cyclopropanesulfonamide (11), the title compound was obtained. By column chromatography (elution agent: Ethyl acetate: methanol = 0-10%) purification, and then separated by preparative liquid chromatography to obtain compounds 22-P1 and 22-P2.

LCMS：m/z 405.20[M+H]⁺。 LCMS: m/z 405.20 [M+H] ⁺ .

單一構型化合物22-P1(較短保留時間)： Single configuration compound 22-P1 (shorter retention time):

製備液相色譜法：色譜管柱：Daisogei 30mm×250mm，C18，10um，100A，流動相：乙腈/水，梯度：30%-80%。 Preparative liquid chromatography: chromatographic column: Daisogei 30mm×250mm, C18, 10um, 100A, mobile phase: acetonitrile/water, gradient: 30%-80%.

¹H NMR(400MHz,CDCl₃)δ 8.38(s,1H),7.43(d,J=9.3Hz,1H),6.40(d,J=9.3Hz,1H),5.41(d,J=9.1Hz,1H),4.01(d,J=3.4Hz,1H),3.84(s,2H),3.04-2.89(m,2H),2.87(s,3H),2.41(s,4H),2.18(d,J=8.7Hz,2H),2.11-1.97(m,2H),1.96-1.85(m,1H),1.83-1.60(m,3H),1.33(dd,J=20.2,9.7Hz,1H),0.94(d,J=6.6Hz,3H)。 ¹ H NMR (400MHz, CDCl ₃ )δ 8.38(s,1H),7.43(d,J=9.3Hz,1H),6.40(d,J=9.3Hz,1H),5.41(d,J=9.1Hz, 1H), 4.01(d, J=3.4Hz, 1H), 3.84(s, 2H), 3.04-2.89(m, 2H), 2.87(s, 3H), 2.41(s, 4H), 2.18(d, J =8.7Hz,2H),2.11-1.97(m,2H),1.96-1.85(m,1H),1.83-1.60(m,3H),1.33(dd,J=20.2,9.7Hz,1H),0.94( d, J=6.6Hz, 3H).

單一構型化合物22-P2(較長保留時間)： Single configuration compound 22-P2 (longer retention time):

¹H NMR(400MHz,CDCl₃)δ 8.37(s,1H),7.42(d,J=9.3Hz,1H),6.37(d,J=9.2Hz,1H),5.92(dd,J=17.3,9.7Hz,1H),4.14-3.98(m,1H),3.82(s,2H),3.01(s,2H),2.87(s,3H),2.69(s,3H),2.37(td,J=10.1,5.0Hz,1H),2.19(s,2H),2.12-1.97(m,1H),1.98-1.83(m,3H),1.71(s,2H),1.57(dd,J=19.0,8.4Hz,1H),0.79(d,J=7.1Hz,3H)。 ¹ H NMR (400MHz, CDCl ₃ )δ 8.37(s,1H),7.42(d,J=9.3Hz,1H),6.37(d,J=9.2Hz,1H),5.92(dd,J=17.3,9.7 Hz,1H),4.14-3.98(m,1H),3.82(s,2H),3.01(s,2H),2.87(s,3H),2.69(s,3H),2.37(td,J=10.1, 5.0Hz,1H),2.19(s,2H),2.12-1.97(m,1H),1.98-1.83(m,3H),1.71(s,2H),1.57(dd,J=19.0,8.4Hz,1H ),0.79(d,J=7.1Hz,3H).

實施例23：8-(2,2-二甲基環戊基)-2-((1-(S-甲基磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(23)的製備 Example 23: 8-(2,2-Dimethylcyclopentyl)-2-((1-(S-methylsulfonylimino)piperidin-4-yl)amino)pyrido[2 ,3-d] Preparation of pyrimidin-7(8H)-one (23)

與實施例3的製備方法相同，除了用2,2-二甲基環戊胺代替環戊胺和用N-(第三丁基二甲基甲矽烷基)甲磺醯胺(11a)代替N-(第三丁基二甲基甲矽烷基)環丙烷磺醯胺(11)，製得標題化合物。 The preparation method is the same as that of Example 3, except that 2,2-dimethylcyclopentylamine is used instead of cyclopentylamine and N-(tert-butyldimethylsilyl) methanesulfonamide (11a) is used instead of N -(tert-butyldimethylsilyl)cyclopropanesulfonamide (11) to obtain the title compound.

LCMS：m/z 419.20[M+H]+。 LCMS: m/z 419.20 [M+H]+.

¹H NMR(400MHz,CDCl₃)δ 8.39(s,1H),7.44-7.41(d,J=12Hz,1H),6.40-6.37(d,J=12Hz,1H),5.90-5.78(m,1H),4.03(s,1H),3.85(s,2H),2.95(s,2H),2.86(s,3H),2.62-2.20(m,2H),2.09-1.98(m,6H),1.67-1.50(m,3H),1.50(s,1H),1.16(s,3H),0.85(s,3H)。 ¹ H NMR (400MHz, CDCl ₃ ) δ 8.39(s,1H),7.44-7.41(d,J=12Hz,1H),6.40-6.37(d,J=12Hz,1H),5.90-5.78(m,1H ),4.03(s,1H),3.85(s,2H),2.95(s,2H),2.86(s,3H),2.62-2.20(m,2H),2.09-1.98(m,6H),1.67- 1.50(m,3H),1.50(s,1H),1.16(s,3H),0.85(s,3H).

實施例24：2-((1-(S-甲基磺醯亞胺基)哌啶-4-基)胺基)-8-(四氫呋喃-3-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(24)的製備 Example 24: 2-((1-(S-Methylsulfonimino)piperidin-4-yl)amino)-8-(tetrahydrofuran-3-yl)pyrido[2,3-d] Preparation of pyrimidin-7(8H)-one (24)

與實施例3的製備方法相同，除了用四氫呋喃-3-胺代替環戊胺和用N-(第三丁基二甲基甲矽烷基)甲磺醯胺(11a)代替N-(第三丁基二甲基甲矽烷基)環丙烷磺醯胺(11)，製得標題化合物。 The same preparation method as in Example 3, except that tetrahydrofuran-3-amine is used instead of cyclopentylamine and N-(tert-butyldimethylsilyl) methanesulfonamide (11a) is used instead of N-(tert-butyl dimethylsilyl)cyclopropanesulfonamide (11) to obtain the title compound.

LCMS：m/z 393.16[M+H]⁺。 LCMS: m/z 393.16 [M+H] ⁺ .

¹HNMR(400MHz,CDCl₃)δ 8.41(s,1H),7.45(d,J=9.4Hz,1H),6.40(d,J=9.3Hz,1H),6.25-6.07(m,1H),4.41-4.06(m,3H),3.98(t,J=8.7Hz,1H),3.88(s,2H),2.94(s,2H),2.87(s,3H),2.56(s,1H),2.17(d,J=4.3Hz,6H),1.76-1.54(m,2H)。 ¹ HNMR(400MHz, CDCl ₃ )δ 8.41(s,1H),7.45(d,J=9.4Hz,1H),6.40(d,J=9.3Hz,1H),6.25-6.07(m,1H),4.41 -4.06(m,3H),3.98(t,J=8.7Hz,1H),3.88(s,2H),2.94(s,2H),2.87(s,3H),2.56(s,1H),2.17( d,J=4.3Hz,6H),1.76-1.54(m,2H).

實施例25：2-((1-(S-甲基磺醯亞胺基)哌啶-4-基)胺基)-8-(螺[2.4]庚-4-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(25)的製備 Example 25: 2-((1-(S-Methylsulfonimino)piperidin-4-yl)amino)-8-(spiro[2.4]hept-4-yl)pyrido[2, 3-d] Preparation of pyrimidin-7(8H)-one (25)

與實施例3的製備方法相同，除了用螺[2.4]庚-4-胺代替環戊胺和用N-(第三丁基二甲基甲矽烷基)甲磺醯胺(11a)代替N-(第三丁基二甲基甲矽烷基)環丙烷磺醯胺(11)，製得標題化合物。 The preparation method is the same as that of Example 3, except that cyclopentylamine is replaced by spiro[2.4]hept-4-amine and N-(tert-butyldimethylsilyl)methanesulfonamide (11a) is replaced by N- (tert-butyldimethylsilyl)cyclopropanesulfonamide (11) to obtain the title compound.

LCMS：m/z 417.20[M+H]⁺。 LCMS: m/z 417.20 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.36(s,1H),7.41(d,J=9.4Hz,1H),6.38(d,J=9.1Hz,1H),5.80(t,J=8.1Hz,1H),4.00(s,1H),3.80(s,2H),3.03(d,J=11.5Hz,2H),2.87(s,3H),2.75-2.31(m,4H),2.10(dd,J=26.9,18.9Hz,4H),1.85(s,1H),1.69(s,2H),1.38(s,1H),0.60(s,2H),0.49(s,1H),0.25-0.06(m,1H)。 ¹ H NMR (400MHz, CDCl ₃ )δ 8.36(s,1H),7.41(d,J=9.4Hz,1H),6.38(d,J=9.1Hz,1H),5.80(t,J=8.1Hz, 1H),4.00(s,1H),3.80(s,2H),3.03(d,J=11.5Hz,2H),2.87(s,3H),2.75-2.31(m,4H),2.10(dd,J =26.9,18.9Hz,4H),1.85(s,1H),1.69(s,2H),1.38(s,1H),0.60(s,2H),0.49(s,1H),0.25-0.06(m, 1H).

實施例26：8-環戊基-6-甲基-2-((1-(S-甲基磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(26)的製備 Example 26: 8-cyclopentyl-6-methyl-2-((1-(S-methylsulfonimino)piperidin-4-yl)amino)pyrido[2,3-d ] Preparation of pyrimidin-7(8H)-one (26)

與實施例3的製備方法相同，除了用丙酸乙酯代替乙酸乙酯和用N-(第三丁基二甲基甲矽烷基)甲磺醯胺(11a)代替N-(第三丁基二甲基甲矽烷基)環丙烷磺醯胺(11)，製得標題化合物。 The same preparation method as in Example 3, except that ethyl propionate is used instead of ethyl acetate and N-(tert-butyldimethylsilyl) methanesulfonamide (11a) is used to replace N-(tert-butyl Dimethylsilyl)cyclopropanesulfonamide (11) to obtain the title compound.

LCMS：m/z 405.20[M+H]⁺。 LCMS: m/z 405.20 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.32(s,1H),7.30(d,J=1.1Hz,1H),5.87(p,J=8.9Hz,1H),4.09-4.00(m,1H),3.81(s,2H),3.00(d,J=5.1Hz,2H),2.86(s,3H),2.49(s,2H),2.33(s,2H),2.22-2.12(m,5H),2.05(s,2H),1.91-1.80(m,2H),1.77-1.61(m,4H)。 ¹ H NMR (400MHz, CDCl ₃ )δ 8.32(s,1H),7.30(d,J=1.1Hz,1H),5.87(p,J=8.9Hz,1H),4.09-4.00(m,1H), 3.81(s,2H),3.00(d,J=5.1Hz,2H),2.86(s,3H),2.49(s,2H),2.33(s,2H),2.22-2.12(m,5H),2.05 (s, 2H), 1.91-1.80 (m, 2H), 1.77-1.61 (m, 4H).

實施例27：8-環戊基-5,6-二甲基-2-((1-(S-甲基磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(27)的製備 Example 27: 8-cyclopentyl-5,6-dimethyl-2-((1-(S-methylsulfonimino)piperidin-4-yl)amino)pyrido[2, 3-d] Preparation of pyrimidin-7(8H)-one (27)

步驟1：1-(4-(環戊胺基)-2-(甲硫基)嘧啶-5-基)-1-乙醇(27a)的製備 Step 1: Preparation of 1-(4-(cyclopentylamino)-2-(methylthio)pyrimidin-5-yl)-1-ethanol (27a)

於室溫，將4-(環戊胺基)-2-(甲硫基)嘧啶-5-甲醛(3b)(929mg，3.70mmol)、THF(30mL)加入到三口瓶中，冷卻至-75℃，氮氣氛下，緩慢地加入甲基溴化鎂(3.7mL，1.0M THF溶液，3.70mmol)，期間允許溫度逐漸升至室溫並攪拌過夜。降溫到0℃，加入水(10mL)淬滅反應，收集有機相，減壓濃縮。殘餘物藉由管柱層析色譜法(沖提劑：石油醚：乙酸乙酯=0-75%)純化，得到740mg白色固體的標題產物，收率：75.0%。 At room temperature, add 4-(cyclopentylamino)-2-(methylthio)pyrimidine-5-carbaldehyde (3b) (929 mg, 3.70 mmol), THF (30 mL) into a three-necked flask, and cool to -75 Under nitrogen atmosphere, methylmagnesium bromide (3.7 mL, 1.0 M in THF, 3.70 mmol) was added slowly, allowing the temperature to gradually rise to room temperature and stirring overnight. Cool down to 0°C, add water (10 mL) to quench the reaction, collect the organic phase and concentrate under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 0-75%) to obtain 740 mg of the title product as a white solid, yield: 75.0%.

LCMS：m/z 254.14[M+H]⁺。 LCMS: m/z 254.14 [M+H] ⁺ .

步驟2：1-(4-(環戊胺基)-2-(甲硫基)嘧啶-5-基)-1-乙酮(27b)的製備 Step 2: Preparation of 1-(4-(cyclopentylamino)-2-(methylthio)pyrimidin-5-yl)-1-ethanone (27b)

於室溫，將1-(4-(環戊胺基)-2-(甲硫基)嘧啶-5-基)-1-乙醇(27a)(740mg,2.77mmol)、二氧化錳(4.54g,55.4mmol)、乙酸乙酯(10mL)加到反應瓶中，50℃攪拌反應過夜。反應結束後，過濾除去固體，濾液濃縮後藉由管柱層析色譜法(沖提劑：石油醚：乙酸乙酯=0-20%)純化，得到700mg淡黃色固體的標題產物，收率：95.4%。 At room temperature, 1-(4-(cyclopentylamino)-2-(methylthio)pyrimidin-5-yl)-1-ethanol (27a) (740mg, 2.77mmol), manganese dioxide (4.54g , 55.4mmol), ethyl acetate (10mL) were added to the reaction flask, and the reaction was stirred overnight at 50°C. After the reaction, the solid was removed by filtration, and the filtrate was concentrated and purified by column chromatography (eluant: petroleum ether: ethyl acetate = 0-20%) to obtain 700 mg of the title product as a light yellow solid, yield: 95.4%.

LCMS：m/z 252.14[M+H]⁺。 LCMS: m/z 252.14 [M+H] ⁺ .

其餘步驟與實施例3的製備方法相同，除了用1-(4-(環戊胺基)-2-(甲硫基)嘧啶-5-基)-1-乙酮(27b)代替4-(環戊基胺基)-2-(甲硫基)嘧啶-5-甲醛(3b)，用丙酸乙酯代替乙酸乙酯，和用N-(第三丁基二甲基甲矽烷基)甲磺醯胺(11a)代替N-(第三丁基二甲基甲矽烷基)環丙烷磺醯胺(11)，製化合物27。 The remaining steps are the same as the preparation method of Example 3, except that 4-( Cyclopentylamino)-2-(methylthio)pyrimidine-5-carbaldehyde (3b), with ethyl propionate instead of ethyl acetate, and with N-(tert-butyldimethylsilyl)methyl Compound 27 was prepared by replacing N-(tert-butyldimethylsilyl)cyclopropanesulfonamide (11) with sulfonamide (11a).

LCMS：m/z 419.22[M+H]⁺。 LCMS: m/z 419.22 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.53(s,1H),5.89(p,J=8.9Hz,1H),4.02(td,J=13.7,7.0Hz,1H),3.83(s,2H),2.97(t,J=10.3Hz,2H),2.86(s,3H),2.82-2.36(m,2H),2.34(s,5H),2.24-2.13(m,SH),2.10-1.99(m,2H),1.83(dt,J=11.4,8.4Hz,2H),1.68(dd,J=10.2,5.7Hz,4H)。 ¹ H NMR (400MHz, CDCl ₃ )δ 8.53(s,1H),5.89(p,J=8.9Hz,1H),4.02(td,J=13.7,7.0Hz,1H),3.83(s,2H), 2.97(t,J=10.3Hz,2H),2.86(s,3H),2.82-2.36(m,2H),2.34(s,5H),2.24-2.13(m,SH),2.10-1.99(m, 2H), 1.83 (dt, J=11.4, 8.4Hz, 2H), 1.68 (dd, J=10.2, 5.7Hz, 4H).

實施例28：6-乙醯基-8-環戊基-2-(((1-(S-甲基磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(28)的製備 Example 28: 6-Acetyl-8-cyclopentyl-2-(((1-(S-methylsulfonimino)piperidin-4-yl)amino)pyrido[2,3 -d] Preparation of pyrimidin-7(8H)-one (28)

步驟1：4-((6-碘-8-環戊基-7-側氧基-7,8-二氫吡啶并[2,3-d]嘧啶-2-基)胺基)哌啶-1-羧酸第三丁酯(28a)的製備 Step 1: 4-((6-iodo-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidine- Preparation of tert-butyl 1-carboxylate (28a)

於室溫，將4-((8-環戊基-7-側氧基-7,8-二氫吡啶并[2,3-d]嘧啶-2-基)胺基)哌啶-1-羧酸第三丁酯(3e)(149mg，0.36mmol)、NIS(122mg，0.55mmol)、對甲苯磺酸(6.24mg，0.036mmol)、乙腈(2mL)加入到反應瓶中，室溫攪拌反應過夜。減壓濃縮，殘餘物中加入EtOAc(10mL×3)和水(5mL)。有機相經無水硫酸鈉乾燥，過濾，減壓濃縮，殘餘物藉由管柱層析色譜法(沖提劑：石油醚：乙酸乙酯=0-40%)純化，得到164mg黃色固體物的標題產物，收率：84.7%。 At room temperature, 4-((8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidine-1- Tertiary butyl carboxylate (3e) (149mg, 0.36mmol), NIS (122mg, 0.55mmol), p-toluenesulfonic acid (6.24mg, 0.036mmol), and acetonitrile (2mL) were added to the reaction flask, and the reaction was stirred at room temperature overnight. It was concentrated under reduced pressure, and EtOAc (10 mL×3) and water (5 mL) were added to the residue. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 0-40%) to obtain 164 mg of the title as a yellow solid Product, yield: 84.7%.

LCMS：m/z 540.15[M+H]⁺。 LCMS: m/z 540.15 [M+H] ⁺ .

步驟2：4-(((8-環戊基-6-(1-乙氧基乙烯基)-7-側氧基-7,8-二氫吡啶并[2,3-d]嘧啶-2-基)胺基)哌啶-1-羧酸第三丁酯(28b)的製備 Step 2: 4-(((8-cyclopentyl-6-(1-ethoxyvinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2 Preparation of -yl)amino)piperidine-1-carboxylic acid tert-butyl ester (28b)

於室溫，將4-((6-碘-8-環戊基-7-側氧基-7,8-二氫吡啶并[2,3-d]嘧啶-2-基)胺基)哌啶-1-羧酸第三丁酯(28a)(296mg，0.55mmol)、三丁基(1-乙氧基乙烯基)錫烷(299mg，0.825mmol)、四三苯基膦鈀(76.3mg，0.066mmol)、甲苯(5mL)加入到反應瓶中，回流攪拌反應過夜。冷卻至室溫後，減壓濃縮，殘餘物中加入EtOAc(20mL×3)和水(10mL)。有機相經無水硫酸鈉乾燥，過濾，減壓濃縮，殘餘物藉由管柱層析色譜法(沖提劑：石油醚：乙酸乙酯=0-40%)純化，得到160mg淡黃色固體物的標題產物，收率：63.8%。 At room temperature, 4-((6-iodo-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piper Pyridine-1-carboxylic acid tert-butyl ester (28a) (296mg, 0.55mmol), tributyl (1-ethoxyvinyl) stannane (299mg, 0.825mmol), tetrakistriphenylphosphine palladium (76.3mg , 0.066mmol), toluene (5mL) were added to the reaction flask, and the reaction was stirred under reflux overnight. After cooling to room temperature, concentrated under reduced pressure, the residue EtOAc (20 mL x 3) and water (10 mL) were added to it. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by column chromatography (eluant: petroleum ether: ethyl acetate = 0-40%) to obtain 160 mg of a light yellow solid The title product, yield: 63.8%.

LCMS：m/z 484.28[M+H]⁺/456.25[M+H]⁺。 LCMS: m/z 484.28[M+H] ⁺ /456.25[M+H] ⁺ .

步驟3：6-乙醯基-8-環戊基-2-(哌啶-4-基胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(28c)的製備 Step 3: Preparation of 6-acetyl-8-cyclopentyl-2-(piperidin-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (28c)

於室溫，將4-(((8-環戊基-6-(1-乙氧基乙烯基)-7-側氧基-7,8-二氫吡啶并[2,3-d]嘧啶-2-基)胺基)哌啶-1-羧酸第三丁酯(28b)(160mg，0.350mmol)加入到2mL鹽酸的二噁烷溶液中，攪拌反應2h。有黃色固體析出，減壓濃縮，得到黃色固體。加入碳酸鉀(276mg，2.00mmol)，加入水(5mL)，攪拌反應2h。加入二氯甲烷(10mL×3)，收集有機相，減壓濃縮，得到93mg淡黃色固體物的標題產物，直接用於下一步。 At room temperature, 4-(((8-cyclopentyl-6-(1-ethoxyvinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine -2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (28b) (160mg, 0.350mmol) was added to 2mL hydrochloric acid in dioxane solution, stirred for 2h. A yellow solid was precipitated, and the pressure was reduced Concentrate to obtain a yellow solid.Add potassium carbonate (276mg, 2.00mmol), add water (5mL), and stir for 2h.Add dichloromethane (10mL×3), collect the organic phase, and concentrate under reduced pressure to obtain 93mg of a light yellow solid The title product was used directly in the next step.

LCMS：m/z 356.20[M+H]⁺。 LCMS: m/z 356.20 [M+H] ⁺ .

其餘步驟與實施例3的製備方法相同，除了用6-乙醯基-8-環戊基-2-(哌啶-4-基胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(28c)代替8-環戊基-2-(哌啶-4-基胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(3f)，用N-(第三丁基二甲基甲矽烷基)甲磺醯胺(11a)代替N-(第三丁基二甲基甲矽烷基)環丙烷磺醯胺(11)，製得化合物28。 The remaining steps are the same as the preparation method of Example 3, except that 6-acetyl-8-cyclopentyl-2-(piperidin-4-ylamino)pyrido[2,3-d]pyrimidine-7( 8H)-one (28c) instead of 8-cyclopentyl-2-(piperidin-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (3f), with N- Compound 28 was obtained by replacing N-(tert-butyldimethylsilyl)cyclopropanesulfonamide (11) with (tert-butyldimethylsilyl)methanesulfonamide (11a).

LCMS：m/z 433.19[M+H]⁺。 LCMS: m/z 433.19 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.56(s,1H),8.24(s,1H),6.03(s,0.6H),5.90-5.81(m,1H),5.39(s,0.4H),4.06(s,1H),3.85(s,2H),3.03(d,J=34.2Hz,3H),2.91(s,3H),2.70(s,3H),2.35(m,2H),2.20(s,2H),2.03(d,J=17.0Hz,2H),1.87(s,2H),1.72(s,4H)。 ¹ H NMR (400MHz, CDCl ₃ )δ 8.56(s,1H),8.24(s,1H),6.03(s,0.6H),5.90-5.81(m,1H),5.39(s,0.4H),4.06 (s,1H),3.85(s,2H),3.03(d,J=34.2Hz,3H),2.91(s,3H),2.70(s,3H),2.35(m,2H),2.20(s, 2H), 2.03(d, J=17.0Hz, 2H), 1.87(s, 2H), 1.72(s, 4H).

實施例29：6-乙醯基-8-環戊基-5-甲基-2-(((1-(S-甲基磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(29)的製備 Example 29: 6-Acetyl-8-cyclopentyl-5-methyl-2-(((1-(S-methylsulfonimino)piperidin-4-yl)amino)pyridine Preparation of [2,3-d]pyrimidin-7(8H)-one (29)

步驟1：4-((6-溴-8-環戊基-5-甲基-7-側氧基-7,8-二氫吡啶并[2,3-d]嘧啶-2-基)胺基)哌啶-1-羧酸第三丁酯(29a)的製備 Step 1: 4-((6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amine Base) preparation of piperidine-1-carboxylic acid tert-butyl ester (29a)

於室溫，將4-胺基哌啶-1-羧酸第三丁酯(2.52g,12.0mmol)、甲苯(10mL)加入到反應瓶中，氮氣氛下，降至0℃，加入雙(三甲基甲矽烷基)胺基鋰(1M在THF中，12mL，12.0mmol)，攪拌反應20分鐘，加入化合物6-溴-2-氯-8-環戊基-5-甲基吡啶并[2,3-d]嘧啶-7(8H)-酮(1.03g,3.00mmol)(商品化試劑CAS：1016636-76-2)，攪拌反應過夜。減壓濃縮，殘餘物中加入EtOAc(20mL×3)和水(10mL)。有機相經無水硫酸鈉乾燥，過濾，減壓濃縮。殘餘物藉由管柱層析色譜法(沖提劑：石油醚：乙酸乙酯=0-40%)純化，得到620mg淡黃色固體物的標題產物，收率：40.9%。 At room temperature, tertiary butyl 4-aminopiperidine-1-carboxylate (2.52g, 12.0mmol) and toluene (10mL) were added to the reaction flask, and under a nitrogen atmosphere, the temperature was lowered to 0°C, and bis( Lithium trimethylsilyl)amide (1M in THF, 12mL, 12.0mmol), stirred for 20 minutes, compound 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[ 2,3-d] Pyrimidin-7(8H)-one (1.03g, 3.00mmol) (commercial reagent CAS: 1016636-76-2), stirred overnight. It was concentrated under reduced pressure, and EtOAc (20 mL×3) and water (10 mL) were added to the residue. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 0-40%) to obtain 620 mg of the title product as a light yellow solid, yield: 40.9%.

LCMS：m/z 506.17[M+H]⁺。 LCMS: m/z 506.17 [M+H] ⁺ .

其餘步驟與實施例28的製備方法相同，除了用4-((6-溴-8-環戊基-5-甲基-7-側氧基-7,8-二氫吡啶并[2,3-d]嘧啶-2-基)胺基)哌啶-1-羧酸第三丁酯(29a)代替4-((6-碘-8-環戊基-7-側氧基-7,8-二氫吡啶并[2,3-d]嘧啶-2-基)胺基)哌啶-1-羧酸第三丁酯(28a)，製得化合物29。 The remaining steps are the same as the preparation method of Example 28, except that 4-((6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3 -d]pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (29a) instead of 4-((6-iodo-8-cyclopentyl-7-oxo-7,8 -Dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (28a), compound 29 was prepared.

LCMS：m/z 447.21[M+H]⁺。 LCMS: m/z 447.21 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.63(s,1H),6.35(s,0.6H),5.88-5.75(m,1H),5.21(s,0.4H),4.05(s,1H),3.82(s,2H),3.01(s,3H),2.88(s,3H),2.53(s,3H),2.33(s,5H),2.19(s,2H),2.02(s,2H),1.85(s,2H),1.69(s,4H)。 ¹ H NMR (400MHz, CDCl ₃ )δ 8.63(s,1H),6.35(s,0.6H),5.88-5.75(m,1H),5.21(s,0.4H),4.05(s,1H),3.82 (s,2H),3.01(s,3H),2.88(s,3H),2.53(s,3H),2.33(s,5H),2.19(s,2H),2.02(s,2H),1.85( s,2H), 1.69(s,4H).

實施例30：8-環戊基-2-(((1-(1-氧化-4,5-二氫-3H-1λ⁶-異噻唑-1-基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(30)的製備 Example 30: 8-Cyclopentyl-2-(((1-(1-oxido-4,5-dihydro-3H-1λ ⁶ -isothiazol-1-yl)piperidin-4-yl)amino ) Preparation of pyrido[2,3-d]pyrimidin-7(8H)-one (30)

與實施例3的製備方法相同，除了用異噻唑烷1,1-二氧化物代替N-(第三丁基二甲基甲矽烷基)環丙烷磺醯胺(11)，製得化合物30。 The preparation method was the same as in Example 3, except that N-(tert-butyldimethylsilyl)cyclopropanesulfonylamide (11) was replaced by isothiazolidine 1,1-dioxide to prepare compound 30.

LCMS：m/z 417.20[M+H]⁺。 LCMS: m/z 417.20 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.39(s,1H),7.41(d,J=9.3Hz,1H),6.37(d,J=9.2Hz,1H),5.83(p,J=8.9Hz,1H),4.06(s,1H),3.77(s,3H),3.05(s,4H),2.51-2.32(m,4H),2.27-2.11(m,4H),2.03(s,3H),1.92-1.79(m,3H),1.70(s,5H),1.26(s,3H)。 ¹ H NMR (400MHz, CDCl ₃ )δ 8.39(s,1H),7.41(d,J=9.3Hz,1H),6.37(d,J=9.2Hz,1H),5.83(p,J=8.9Hz, 1H),4.06(s,1H),3.77(s,3H),3.05(s,4H),2.51-2.32(m,4H),2.27-2.11(m,4H),2.03(s,3H),1.92 -1.79(m,3H),1.70(s,5H),1.26(s,3H).

實施例31：6-甲基-8-(2-甲基環戊基)-2-((1-(S-甲基磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(31)的製備 Example 31: 6-Methyl-8-(2-methylcyclopentyl)-2-((1-(S-methylsulfonimino)piperidin-4-yl)amino)pyrido Preparation of [2,3-d]pyrimidin-7(8H)-one (31)

與實施例22的製備方法相同，除了用丙酸乙酯代替乙酸乙酯，製得化合物31。 Compound 31 was prepared in the same manner as in Example 22, except that ethyl propionate was used instead of ethyl acetate.

LCMS：m/z 419.20[M+H]⁺。 LCMS: m/z 419.20 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.32(s,1H),7.30(d,J=9.3Hz,1H),6.40(d,J=9.3Hz,1H),4.04(d,J=3.4Hz,1H),3.84(s,2H),2.97-2.96(m,2H),2.86(s,3H),2.62(s,1H),2.40(s,1H),2.09-1.64(m,11H),1.56(s,1H),1.32-1.26(m,2H),0.93-0.76(m,3H)。 ¹ H NMR (400MHz, CDCl ₃ )δ 8.32(s,1H),7.30(d,J=9.3Hz,1H),6.40(d,J=9.3Hz,1H),4.04(d,J=3.4Hz, 1H),3.84(s,2H),2.97-2.96(m,2H),2.86(s,3H),2.62(s,1H),2.40(s,1H),2.09-1.64(m,11H),1.56 (s, 1H), 1.32-1.26 (m, 2H), 0.93-0.76 (m, 3H).

實施例32：5,6-二甲基-8-(2-甲基環戊基)-2-(((1-(S-甲基磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(32)的製備 Example 32: 5,6-Dimethyl-8-(2-methylcyclopentyl)-2-(((1-(S-methylsulfonimino)piperidin-4-yl)amine base) pyrido[2,3-d]pyrimidin-7(8H)-one (32)

與實施例27的製備方法相同，除了用4-((2-甲基環戊基)胺基)-2-(甲硫基)嘧啶-5-甲醛(22b)代替4-(環戊胺基)-2-(甲硫基)嘧啶-5-甲醛(3b)，製得標題化合物。 The preparation method is the same as that of Example 27, except that 4-((2-methylcyclopentyl)amino)-2-(methylthio)pyrimidine-5-carbaldehyde (22b) is used instead of 4-(cyclopentylamino) )-2-(methylthio)pyrimidine-5-carbaldehyde (3b) to give the title compound.

LCMS：m/z 433.23[M+H]⁺。 LCMS: m/z 433.23 [M+H] ⁺ .

¹HNMR(400MHz,CDCl₃)δ 8.51(s,1H),5.98(dd,J=17.2,9.7Hz,1H),4.02(dd,J=10.6,6.8Hz,1H),3.82(s,2H),2.99(s,2H),2.86(s,3H),2.68(d,J=7.4Hz,1H),2.39-2.29(m,4H),2.24-2.13(m,5H),1.97(m,5H),1.61(m,3.5H),1.30(m,0.5H),0.93(d,J=6.6Hz,0.7H),0.77(d,J=7.1Hz,2.3H)。 ¹ HNMR(400MHz, CDCl ₃ )δ 8.51(s,1H),5.98(dd,J=17.2,9.7Hz,1H),4.02(dd,J=10.6,6.8Hz,1H),3.82(s,2H) ,2.99(s,2H),2.86(s,3H),2.68(d,J=7.4Hz,1H),2.39-2.29(m,4H),2.24-2.13(m,5H),1.97(m,5H ),1.61(m,3.5H),1.30(m,0.5H),0.93(d,J=6.6Hz,0.7H),0.77(d,J=7.1Hz,2.3H).

實施例33：6-(二氟甲基)-8-(2-甲基環戊基)-2-(((1-(S-甲基磺醯亞胺基)哌啶-4-基)胺基]吡啶并[2,3-d]嘧啶-7(8H)-酮(33-P1和33-P2)的製備 Example 33: 6-(Difluoromethyl)-8-(2-methylcyclopentyl)-2-(((1-(S-methylsulfonimino)piperidin-4-yl) Preparation of amino]pyrido[2,3-d]pyrimidin-7(8H)-one (33-P1 and 33-P2)

步驟1：6-(二氟甲基)-8-(2-甲基環戊基)-2-(((1-(甲基磺醯亞胺基)哌啶丁-4-基)胺基]吡啶并[2,3-d]嘧啶-7(8H)-酮(33-P1和33-P2)的製備 Step 1: 6-(Difluoromethyl)-8-(2-methylcyclopentyl)-2-(((1-(methylsulfonimino)piperidin-4-yl)amino Preparation of ]pyrido[2,3-d]pyrimidin-7(8H)-one (33-P1 and 33-P2)

於室溫，反應瓶中加入二氟甲烷亞磺酸鈉(172mg，1.25mmol)、水(3mL)、二甲基亞碸(15mL)，室溫攪拌25分鐘，加入8-(2-甲基環戊基)-2-((1-(S-甲基磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(202mg，0.50mmol)、氯化亞鐵(10.2mg，0.08mmol)。取過氧化第三丁醇(64.0mg，70%wt水溶液，0.50mmol)，用DMSO稀釋為1mL，，滴加到反應體系中，室溫攪拌過夜。將反應溶液倒入10%EDTA(30mL)中，並用EtOAc(50mL×3)萃取。合併有機相，用製備薄層色譜法(展開劑：二氯甲烷：甲醇=20：1)純化，並用製備液相色譜法分離，得到化合物33-P1(10.0mg)和33-P2(24.5mg)。 At room temperature, add sodium difluoromethanesulfinate (172mg, 1.25mmol), water (3mL), dimethylsulfoxide (15mL) into the reaction flask, stir at room temperature for 25 minutes, add 8-(2-methyl Cyclopentyl)-2-((1-(S-methylsulfonimido)piperidin-4-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one ( 202mg, 0.50mmol), ferrous chloride (10.2mg, 0.08mmol). Take tertiary butanol peroxide (64.0mg, 70%wt aqueous solution, 0.50mmol), dilute to 1mL with DMSO, add dropwise to the reaction system, and stir overnight at room temperature. The reaction solution was poured into 10% EDTA (30 mL), and extracted with EtOAc (50 mL×3). The organic phases were combined, purified by preparative thin-layer chromatography (developing solvent: dichloromethane:methanol=20:1), and separated by preparative liquid chromatography to obtain compounds 33-P1 (10.0mg) and 33-P2 (24.5mg ).

單一構型化合物33-P1(較短保留時間) Single configuration compound 33-P1 (shorter retention time)

LCMS：m/z 455.54[M+H]⁺。 LCMS: m/z 455.54 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.49(s,1H),7.79(s,1H),6.79(t,J=55.3Hz,1H),5.94(dd,J=17.2,9.7Hz,1H),4.04(s,1H),3.85(s,2H),2.97(s,2H),2.87(s,3H),2.68(d,J=44.8Hz,1H),2.47-2.28(m,2H),2.21(s,2H),2.06(dd,J=10.8,7.4Hz,1H),1.92(dd,J=18.9,9.6Hz,3H),1.77-1.55(m,3H),0.79(d,J=7.1Hz,3H)。 ¹ H NMR (400MHz, CDCl ₃ )δ 8.49(s,1H),7.79(s,1H),6.79(t,J=55.3Hz,1H),5.94(dd,J=17.2,9.7Hz,1H), 4.04(s,1H),3.85(s,2H),2.97(s,2H),2.87(s,3H),2.68(d,J=44.8Hz,1H),2.47-2.28(m,2H),2.21 (s,2H),2.06(dd,J=10.8,7.4Hz,1H),1.92(dd,J=18.9,9.6Hz,3H),1.77-1.55(m,3H),0.79(d,J=7.1 Hz, 3H).

單一構型化合物33-P2(較長保留時間) Single configuration compound 33-P2 (longer retention time)

LCMS：m/z 455.54[M+H]⁺。 LCMS: m/z 455.54 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.49(s,1H),7.79(s,1H),6.79(t,J=55.3Hz,1H),5.94(dd,J=17.2,9.7Hz,1H),4.04(s,1H),3.85(s,2H),2.97(s,2H),2.87(s,3H), 2.68(d,J=44.8Hz,1H),2.47-2.28(m,2H),2.21(s,2H),2.06(dd,J=10.8,7.4Hz,1H),1.92(dd,J=18.9,9.6Hz,3H),1.77-1.55(m,3H),0.79(d,J=7.1Hz,3H).)。 ¹ H NMR (400MHz, CDCl ₃ )δ 8.49(s,1H),7.79(s,1H),6.79(t,J=55.3Hz,1H),5.94(dd,J=17.2,9.7Hz,1H), 4.04(s,1H),3.85(s,2H),2.97(s,2H),2.87(s,3H), 2.68(d,J=44.8Hz,1H),2.47-2.28(m,2H),2.21 (s,2H),2.06(dd,J=10.8,7.4Hz,1H),1.92(dd,J=18.9,9.6Hz,3H),1.77-1.55(m,3H),0.79(d,J=7.1 Hz,3H).).

實施例34：6-乙醯基-5-甲基-8-(2-甲基環戊基)-2-(((1-(S-甲基磺醯亞胺基)哌啶基-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(34)的製備 Example 34: 6-Acetyl-5-methyl-8-(2-methylcyclopentyl)-2-(((1-(S-methylsulfonimino)piperidinyl-4 Preparation of -yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (34)

步驟1：4-(((5-甲基-8-(2-甲基環戊基)-7-側氧基-7,8-二氫吡啶并[2,3-d]嘧啶-2-基)胺基)哌啶-1-羧酸第三丁酯(34c)的製備 Step 1: 4-(((5-methyl-8-(2-methylcyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2- Base) amino) piperidine-1-carboxylate tert-butyl ester (34c)

與實施例27中化合物27e的製備方法相同，除了用1-(4-((2-甲基環戊基)胺基)-2-(甲硫基)嘧啶-5-基)乙-1-酮(32b)代替1-(4-(環戊胺基)-2-(甲硫基)嘧啶-5-基)-1-乙酮(27b)和用乙酸乙酯代替丙酸乙酯，製得化合物34c。 The preparation method is the same as that of compound 27e in Example 27, except that 1-(4-((2-methylcyclopentyl)amino)-2-(methylthio)pyrimidin-5-yl)ethane-1- Ketone (32b) in place of 1-(4-(cyclopentylamino)-2-(methylthio)pyrimidin-5-yl)-1-ethanone (27b) and ethyl acetate in place of ethyl propionate, prepared Compound 34c was obtained.

其餘步驟與實施例28的相同，除了用4-(((5-甲基-8-(2-甲基環戊基)-7-側氧基-7,8-二氫吡啶并[2,3-d]嘧啶-2-基)胺基)第三丁基-1-羧酸第三丁酯 (34c)代替4-((8-環戊基-7-側氧基-7,8-二氫吡啶并[2,3-d]嘧啶-2-基)胺基)哌啶-1-羧酸第三丁酯(3e)，製得化合物34。 The remaining steps are the same as in Example 28, except that 4-(((5-methyl-8-(2-methylcyclopentyl)-7-oxo-7,8-dihydropyrido[2, 3-d] pyrimidin-2-yl) amino) tertiary butyl-1-carboxylic acid tertiary butyl ester (34c) instead of 4-((8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidine-1-carboxy Acid tert-butyl ester (3e) to obtain compound 34.

LCMS：m/z 461.21[M+H]⁺。 LCMS: m/z 461.21 [M+H] ⁺ .

¹H NMR(400MHz,CDCl3)δ 8.60(s,1H),6.38(s,0.5H),6.01-5.83(m,1H),5.41(m,0.5H),4.04(s,1H),3.81(s,2H),3.01(s,2H),2.88(s,3H),2.69(d,J=11.5Hz,1H),2.52(d,J=7.0Hz,3H),2.37-2.27(m,4H),2.19(s,2H),2.10-1.93(m,2H),1.90(d,J=8.2Hz,2H),1.71(m,3H),1.32(dd,J=19.8,9.6Hz,1H),0.94(d,J=6.6Hz,1H),0.80(d,J=7.1Hz,2H)。 ¹ H NMR (400MHz, CDCl3) δ 8.60(s,1H),6.38(s,0.5H),6.01-5.83(m,1H),5.41(m,0.5H),4.04(s,1H),3.81( s,2H),3.01(s,2H),2.88(s,3H),2.69(d,J=11.5Hz,1H),2.52(d,J=7.0Hz,3H),2.37-2.27(m,4H ),2.19(s,2H),2.10-1.93(m,2H),1.90(d,J=8.2Hz,2H),1.71(m,3H),1.32(dd,J=19.8,9.6Hz,1H) ,0.94(d,J=6.6Hz,1H),0.80(d,J=7.1Hz,2H).

實施例35：6-乙醯基-8-(2-甲基環戊基)-2-(((1-(S-甲基磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(35)的製備 Example 35: 6-Acetyl-8-(2-methylcyclopentyl)-2-(((1-(S-methylsulfonylimino)piperidin-4-yl)amino) Preparation of pyrido[2,3-d]pyrimidin-7(8H)-one (35)

與實施例28的製備方法相同，除了用4-(((8-(2-甲基環戊基)-7-側氧基-7,8-二氫吡啶并[2,3-d]嘧啶-2-基)胺基)哌啶-1-羧酸第三丁酯(22e)代替4-((8-環戊基-7-側氧基-7,8-二氫吡啶并[2,3-d]嘧啶-2-基)胺基)哌啶-1-羧酸第三丁酯(3e)，製得化合物35。 The same preparation method as in Example 28, except that 4-(((8-(2-methylcyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine -2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (22e) instead of 4-((8-cyclopentyl-7-oxo-7,8-dihydropyrido[2, 3-d] pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (3e) to give compound 35.

LCMS：m/z 447.19[M+H]⁺。 LCMS: m/z 447.19 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.53(s,1H),8.23(s,1H),6.18(d,J=22.3Hz,0.5H),5.92(dd,J=17.8,9.4Hz,1H),5.41(d,J=24.1Hz,0.5H),4.07(s,1H),3.85(s,2H),3.00(d,J=11.5Hz,2H),2.92(s,4H),2.68(s,3H),2.55-2.28(m,1H),2.20(s,2H),2.02(m,4H),1.67(d,J=51.4Hz,3H),1.30(d,J=29.8Hz,1H),0.95(d,J=6.5Hz,1H),0.80(d,J=7.0Hz,2H)。 ¹ H NMR (400MHz, CDCl ₃ )δ 8.53(s,1H),8.23(s,1H),6.18(d,J=22.3Hz,0.5H),5.92(dd,J=17.8,9.4Hz,1H) ,5.41(d,J=24.1Hz,0.5H),4.07(s,1H),3.85(s,2H),3.00(d,J=11.5Hz,2H),2.92(s,4H),2.68(s ,3H),2.55-2.28(m,1H),2.20(s,2H),2.02(m,4H),1.67(d,J=51.4Hz,3H),1.30(d,J=29.8Hz,1H) ,0.95(d,J=6.5Hz,1H),0.80(d,J=7.0Hz,2H).

實施例36：8-環戊基-2-(((1-(噻吩-2-磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(36)的製備 Example 36: 8-Cyclopentyl-2-(((1-(thiophene-2-sulfonimino)piperidin-4-yl)amino)pyrido[2,3-d]pyrimidine-7 Preparation of (8H)-ketone (36)

步驟1：N-(第三丁基二甲基甲矽烷基)噻吩-2-磺醯胺(36a)的製備 Step 1: Preparation of N- (tert-butyldimethylsilyl)thiophene-2-sulfonamide (36a)

與實施例1的步驟12的方法相同，除了用噻吩-2-磺醯胺代替環丙烷磺醯胺，製得標題化合物。 The title compound was obtained in the same manner as in Step 12 of Example 1, except that thiophene-2-sulfonamide was used instead of cyclopropanesulfonamide.

其餘步驟與實施例3的製備方法相同，除了用N-(第三丁基二甲基甲矽烷基)噻吩-2-磺醯胺(36a)代替N-(第三丁基二甲基甲矽烷基)環丙烷磺醯胺(11)，製得化合物36。 All the other steps are the same as the preparation method of Example 3, except that N-(tert-butyldimethylsilyl)thiophene-2-sulfonamide (36a) is used instead of N-(tert-butyldimethylsilyl) base) cyclopropanesulfonamide (11) to obtain compound 36.

LCMS：m/z 459.18[M+H]⁺。 LCMS: m/z 459.18 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.33(s,1H),7.72-7.50(m,2H),7.40(d,J=9.3Hz,1H),7.22-7.11(m,1H),6.39(d,J=6.9Hz,1H),5.92-5.64(m,1H),4.02-381(m,1H),3.74(s,2H),2.91-2.54(m,2H),2.30(s,2H),2.20-2.07(m,2H),1.94(s,2H),1.85-1.76(m,3H),1.71(d,J=15.6Hz,2H),1.64(dd,J=10.3,5.3Hz,3H)。 ¹ H NMR (400MHz, CDCl ₃ )δ 8.33(s,1H),7.72-7.50(m,2H),7.40(d,J=9.3Hz,1H),7.22-7.11(m,1H),6.39(d ,J=6.9Hz,1H),5.92-5.64(m,1H),4.02-381(m,1H),3.74(s,2H),2.91-2.54(m,2H),2.30(s,2H), 2.20-2.07(m,2H),1.94(s,2H),1.85-1.76(m,3H),1.71(d,J=15.6Hz,2H),1.64(dd,J=10.3,5.3Hz,3H) .

實施例37：6-氟-8-(2-甲基環戊基)-2-((1-(S-甲基磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(37)的製備 Example 37: 6-Fluoro-8-(2-methylcyclopentyl)-2-((1-(S-methylsulfonimino)piperidin-4-yl)amino)pyrido[ Preparation of 2,3-d]pyrimidin-7(8H)-one (37)

與實施例22的製備方法相同，除了用2-氟乙酸乙酯代替乙酸乙酯，製得化合物37。 Compound 37 was prepared in the same manner as in Example 22, except that ethyl acetate was replaced with ethyl 2-fluoroacetate.

LCMS：m/z 423.20[M+H]⁺。 LCMS: m/z 423.20 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.39(s,1H),7.18(d,J=7.8Hz,1H),5.97(d,J=7.9Hz,1H),4.02(d,J=7.1Hz,1H),3.85(s,2H),2.92(m,7H),2.70(s,1H),2.38(tdd,J=14.3,8.6,5.2Hz,1H),2.27-2.14(m,2H),2.09(m,1H),1.92(m,3H),1.81-1.49(m,3H),0.95(d,J=6.6Hz,0.4H),0.80(d,J=7.1Hz,2.7H)。 ¹ H NMR(400MHz,CDCl ₃ )δ 8.39(s,1H),7.18(d, J =7.8Hz,1H),5.97(d, J =7.9Hz,1H),4.02(d, J =7.1Hz, 1H),3.85(s,2H),2.92(m,7H),2.70(s,1H),2.38(tdd, J =14.3,8.6,5.2Hz,1H),2.27-2.14(m,2H),2.09 (m,1H),1.92(m,3H),1.81-1.49(m,3H),0.95(d, J =6.6Hz,0.4H),0.80(d, J =7.1Hz,2.7H).

實施例38：6-氯-8-(2-甲基環戊基)-2-((1-(甲基磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(38)的製備 Example 38: 6-Chloro-8-(2-methylcyclopentyl)-2-((1-(methylsulfonimino)piperidin-4-yl)amino)pyrido[2, 3-d] Preparation of pyrimidin-7(8H)-one (38)

步驟1：4-(((6-氯-8-(2-甲基環戊基)-7-側氧基-7,8-二氫吡啶并[2,3-d]嘧啶-2-基)胺基)哌啶-1-羧酸第三丁酯(38a)的製備 Step 1: 4-(((6-chloro-8-(2-methylcyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl )amino)piperidine-1-carboxylate tertiary butyl ester (38a) preparation

於室溫，將4-(((8-(2-甲基環戊基)-7-側氧基-7,8-二氫吡啶并[2,3-d]嘧啶-2-基)胺基)哌啶-1-羧酸第三丁酯(22e)(341mg，0.80mmol)、NCS(128mg，0.96mmol)、2-甲基四氫呋喃(10mL)加入到反應瓶中，60℃攪拌反應過夜。減壓濃縮，殘餘物中加入EtOAc(20mL×3)和水(10mL)。有機相經無水硫酸鈉乾燥，過濾，減壓濃縮。殘餘物藉由管柱層析色譜法(沖提劑：石油醚：乙酸乙酯=0-50%)純化，得到0.32g黃色固體物的標題產物，收率：86.0%。 At room temperature, 4-(((8-(2-methylcyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amine Base) tert-butyl piperidine-1-carboxylate (22e) (341mg, 0.80mmol), NCS (128mg, 0.96mmol), 2-methyltetrahydrofuran (10mL) were added to the reaction flask, and the reaction was stirred overnight at 60°C Concentrated under reduced pressure, EtOAc (20mL×3) and water (10mL) were added to the residue. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (elution solvent: Petroleum ether: ethyl acetate = 0-50%) was purified to obtain 0.32 g of the title product as a yellow solid, yield: 86.0%.

LCMS：m/z 462.15[M+H]⁺。 LCMS: m/z 462.15 [M+H] ⁺ .

其餘步驟與實施例3的製備方法相同，除了用4-(((6-氯-8-(2-甲基環戊基)-7-側氧基-7,8-二氫吡啶并[2,3-d]嘧啶-2-基)胺基)哌啶-1-羧酸第三丁酯(38a)代替4-((8-環戊基-7-側氧基-7,8-二氫吡啶并[2,3-d]嘧啶-2-基)胺基)哌啶-1-羧酸第三丁酯(3e)，用N-(第三丁基二甲基甲矽烷基)甲磺醯胺(11a)代替N-(第三丁基二甲基甲矽烷基)環丙烷磺醯胺(11)，製得化合物38。 The remaining steps are the same as the preparation method of Example 3, except that 4-(((6-chloro-8-(2-methylcyclopentyl)-7-oxo-7,8-dihydropyrido[2 ,3-d]pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (38a) instead of 4-((8-cyclopentyl-7-oxo-7,8-di Hydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (3e), with N-(tert-butyldimethylsilyl)methyl Compound 38 was obtained by replacing N-(tert-butyldimethylsilyl)cyclopropanesulfonamide (11) with sulfonamide (11a).

LCMS：m/z 439.20[M+H]⁺。 LCMS: m/z 439.20 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.38(s,1H),7.66(d,J=9.3Hz,1H),6.02(d,J=9.3Hz,1H),4.01(d,J=3.4Hz,1H),3.84(s,2H),3.04-2.92(m,3H),2.91(s,3H),2.64-2.36(m,1H),2.19-2.00(m,4H),1.83-1.60(m,3H),1.60-1.56(m,3H),0.80(d,J=6.6Hz,3H)。 ¹ H NMR (400MHz, CDCl ₃ )δ 8.38(s,1H),7.66(d,J=9.3Hz,1H),6.02(d,J=9.3Hz,1H),4.01(d,J=3.4Hz, 1H),3.84(s,2H),3.04-2.92(m,3H),2.91(s,3H),2.64-2.36(m,1H),2.19-2.00(m,4H),1.83-1.60(m, 3H), 1.60-1.56(m, 3H), 0.80(d, J=6.6Hz, 3H).

實施例39：6-異丙基-8-(2-甲基環戊基)-2-(((1-(S-甲基磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(39)的製備 Example 39: 6-Isopropyl-8-(2-methylcyclopentyl)-2-(((1-(S-methylsulfonimino)piperidin-4-yl)amino) Preparation of pyrido[2,3-d]pyrimidin-7(8H)-one (39)

步驟1：4-(((6-溴-8-(2-甲基環戊基)-7-側氧基-7,8-二氫吡啶并[2,3-d]嘧啶-2-基)胺基)哌啶-1-羧酸第三丁酯(39a)的製備 Step 1: 4-(((6-bromo-8-(2-methylcyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl )amino)piperidine-1-carboxylate tertiary butyl ester (39a) preparation

於室溫，將4-(((8-(2-甲基環戊基)-7-側氧基-7,8-二氫吡啶并[2,3-d]嘧啶-2-基)胺基)哌啶-1-羧酸第三丁酯(22e)(854mg，2.00mmol)、NBS(391.0mg，2.20mmol)、2-甲基四氫呋喃(20mL)加入到反應瓶中，60℃攪拌反應過夜。減壓濃縮，殘餘物中加入EtOAc(20mL×3)和水(10mL)。有機相經無水硫酸鈉乾燥，過濾，減壓濃縮。殘餘物藉由管柱層析色譜法(沖提劑：石油醚：乙酸乙酯=0-50%)純化，得到0.95g黃色固體物的標題產物，收率：93.0%。 At room temperature, 4-(((8-(2-methylcyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amine Base) piperidine-1-carboxylic acid tert-butyl ester (22e) (854mg, 2.00mmol), NBS (391.0mg, 2.20mmol), 2-methyltetrahydrofuran (20mL) were added to the reaction flask, and the reaction was stirred at 60°C Overnight.Concentrate under reduced pressure, add EtOAc (20mL×3) and water (10mL) to the residue. The organic phase is washed with anhydrous sodium sulfate Dry, filter and concentrate under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 0-50%) to obtain 0.95 g of the title product as a yellow solid, yield: 93.0%.

LCMS：m/z 507.15[M+H]⁺。 LCMS: m/z 507.15 [M+H] ⁺ .

步驟2：4-((8-(2-甲基環戊基)-7-側氧基-6-(丙-1-烯-2-基)-7,8-二氫吡啶并[2,3-d]嘧啶-2-基)胺基)哌啶-1-羧酸第三丁酯(39b)的製備 Step 2: 4-((8-(2-methylcyclopentyl)-7-oxo-6-(prop-1-en-2-yl)-7,8-dihydropyrido[2, 3-d] Preparation of pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (39b)

於室溫，將4-(((6-溴-8-(2-甲基環戊基)-7-側氧基-7,8-二氫吡啶并[2,3-d]嘧啶-2-基)胺基)哌啶-1-羧酸第三丁酯(39a)(405mg，0.8mmol)、異丙烯硼酸酯(268.0mg，1.60mmol)、四三苯基膦鈀(124mg,0.08mmol)、磷酸鉀(508mg,2.40mmol)、二噁烷：水(15mL：3mL)加入到反應瓶中，回流攪拌反應過夜。冷卻至室溫後，減壓濃縮，殘餘物中加入EtOAc(20mL×3)和水(10mL)。有機相經無水硫酸鈉乾燥，過濾，減壓濃縮。得到373mg黑色油狀物的粗品標題產物，直接用於下一步。 At room temperature, 4-(((6-bromo-8-(2-methylcyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2 -yl)amino)piperidine-1-carboxylic acid tert-butyl ester (39a) (405mg, 0.8mmol), isopropenyl borate (268.0mg, 1.60mmol), tetrakistriphenylphosphine palladium (124mg, 0.08 mmol), potassium phosphate (508mg, 2.40mmol), dioxane: water (15mL: 3mL) were added to the reaction flask, and the reaction was stirred at reflux overnight. After cooling to room temperature, concentrated under reduced pressure, EtOAc (20mL ×3) and water (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude title product of 373 mg black oil was obtained, which was directly used in the next step.

LCMS：m/z 468.28[M+H]⁺。 LCMS: m/z 468.28 [M+H] ⁺ .

步驟3：4-(((6-異丙基-8-(2-甲基環戊基)-7-側氧基-7,8-二氫吡啶并[2,3-d]嘧啶-2-基)胺基)哌啶-1-羧酸第三丁酯(39c)的製備 Step 3: 4-(((6-isopropyl-8-(2-methylcyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-2 Preparation of -yl)amino)piperidine-1-carboxylic acid tert-butyl ester (39c)

於室溫，將4-((8-(2-甲基環戊基)-7-側氧基-6-(丙-1-烯-2-基)-7,8-二氫吡啶并[2,3-d]嘧啶-2-基)胺基)哌啶-1-羧酸第三丁酯(39b)(373mg，0.80mmol)、鈀碳(37.0mg)、甲醇(15mL)加入到反應瓶中，氫氣氛下，50℃攪拌反應過夜。冷卻至室溫後，減壓濃縮，殘餘物中加入EtOAc(20mL×3)和水(10mL)。有機相經無水硫酸鈉乾燥，過濾，減壓濃縮，得到180mg油狀物的粗品標題產物，直接用於下一步。 At room temperature, 4-((8-(2-methylcyclopentyl)-7-oxo-6-(prop-1-en-2-yl)-7,8-dihydropyrido[ 2,3-d]pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (39b) (373 mg, 0.80 mmol), palladium on carbon (37.0 mg), methanol (15 mL) were added to the reaction In the bottle, under a hydrogen atmosphere, the reaction was stirred at 50°C overnight. After cooling to room temperature, it was concentrated under reduced pressure, and EtOAc (20 mL×3) and water (10 mL) were added to the residue. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 180 mg of the crude title product as an oil, which was used directly in the next step.

LCMS：m/z 470.28[M+H]⁺。 LCMS: m/z 470.28 [M+H] ⁺ .

其餘步驟與實施例3的製備方法相同，除了用4-(((6-異丙基-8-(2-甲基環戊基)-7-側氧基-7,8-二氫吡啶并[2,3-d]嘧啶-2-基)胺基)哌啶-1-羧酸第三丁酯(39c)代替4-((8-環戊基-7-側氧基-7,8-二氫吡啶并[2,3-d]嘧啶-2-基)胺基)哌啶-1-羧酸第三丁酯(3e)，用N-(第三丁基二甲基甲矽烷基)甲磺醯胺(11a)代替N-(第三丁基二甲基甲矽烷基)環丙烷磺醯胺(11)，製得化合物39。 The remaining steps are the same as the preparation method of Example 3, except that 4-(((6-isopropyl-8-(2-methylcyclopentyl)-7-oxo-7,8-dihydropyrido [2,3-d]pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (39c) instead of 4-((8-cyclopentyl-7-oxo-7,8 -dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (3e), with N-(tert-butyldimethylsilyl ) methanesulfonamide (11a) instead of N-(tert-butyldimethylsilyl)cyclopropanesulfonamide (11) to obtain compound 39.

LCMS：m/z 447.19[M+H]⁺。 LCMS: m/z 447.19 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.36(s,1H),7.27(s,1H),6.18(d,J=22.3Hz,1H),5.92(dd,J=17.8,9.4Hz,1H),4.07(s,1H),3.85(s,2H),3.19(d,J=11.5Hz,1H),2.92(s,2H),2.86(s,3H),2.55-2.28(m,1H),2.20(s,2H),2.15-2.02(m,5H),1.67(d,J=51.4Hz,3H),1.20-1.19(m,6H),0.76(d,J=7.0Hz,3H)。 ¹ H NMR (400MHz, CDCl ₃ )δ 8.36(s,1H),7.27(s,1H),6.18(d,J=22.3Hz,1H),5.92(dd,J=17.8,9.4Hz,1H), 4.07(s,1H),3.85(s,2H),3.19(d,J=11.5Hz,1H),2.92(s,2H),2.86(s,3H),2.55-2.28(m,1H),2.20 (s, 2H), 2.15-2.02 (m, 5H), 1.67 (d, J=51.4Hz, 3H), 1.20-1.19 (m, 6H), 0.76 (d, J=7.0Hz, 3H).

實施例40：8-環丁基-2-(((1-(S-甲基磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(40)的製備 Example 40: 8-Cyclobutyl-2-(((1-(S-methylsulfonimino)piperidin-4-yl)amino)pyrido[2,3-d]pyrimidine-7 Preparation of (8H)-ketone (40)

與實施例3的製備方法相同，除了用環丁胺代替環戊胺和用N-(第三丁基二甲基甲矽烷基)甲磺醯胺(11a)代替N-(第三丁基二甲基甲矽烷基)環丙烷磺醯胺(11)，製得化合物40。 The same preparation method as in Example 3, except that cyclopentylamine is used instead of cyclopentylamine and N-(tert-butyldimethylsilyl) methanesulfonamide (11a) is used to replace N-(tert-butyldi Methylsilyl)cyclopropanesulfonamide (11) to obtain compound 40.

LCMS：m/z 377.20[M+H]⁺。 LCMS: m/z 377.20 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.35(s,1H),7.41(d,J=9.4Hz,1H),6.39(d,J=9.1Hz,1H),5.81-5.68(m,1H),4.12(s,1H),3.81(s,2H),3.32-2.51(m,9H),2.35(s,2H),2.26-2.14(m,2H),2.06-1.83(m,2H),1.74(s,2H)。 ¹ H NMR (400MHz, CDCl ₃ )δ 8.35(s,1H),7.41(d,J=9.4Hz,1H),6.39(d,J=9.1Hz,1H),5.81-5.68(m,1H), 4.12(s,1H),3.81(s,2H),3.32-2.51(m,9H),2.35(s,2H),2.26-2.14(m,2H),2.06-1.83(m,2H),1.74( s, 2H).

實施例41：8-(3,3-二氟環丁基)-2-((1-(S-甲基磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(41)的製備 Example 41: 8-(3,3-Difluorocyclobutyl)-2-((1-(S-methylsulfonimino)piperidin-4-yl)amino)pyrido[2, 3-d] Preparation of pyrimidin-7(8H)-one (41)

與實施例3的製備方法相同，除了用3,3-二氟環丁-1-胺鹽酸鹽代替環戊胺和用N-(第三丁基二甲基甲矽烷基)甲磺醯胺(11a)代替N-(第三丁基二甲基甲矽烷基)環丙烷磺醯胺(11)，製得化合物41。 The same preparation method as in Example 3, except that cyclopentylamine is replaced with 3,3-difluorocyclobutan-1-amine hydrochloride and N-(tertiary butyldimethylsilyl) methanesulfonamide (11a) replaces N-(tert-butyldimethylsilyl)cyclopropanesulfonamide (11) to obtain compound 41.

LCMS：m/z 413.15[M+H]⁺。 LCMS: m/z 413.15 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.42(s,1H),7.45(d,J=9.3Hz,1H),6.38(d,J=9.3Hz,1H),5.88(s,1H),4.12(s,1H),3.90(t,J=13.9Hz,4H),2.91(d,J=11.2Hz,4H),2.86(d,J=9.6Hz,3H),2.17(s,2H),1.97(d,J=27.6Hz,2H),1.72-1.56(m,2H)。 ¹ H NMR (400MHz, CDCl ₃ ) δ 8.42(s,1H),7.45(d,J=9.3Hz,1H),6.38(d,J=9.3Hz,1H),5.88(s,1H),4.12( s,1H),3.90(t,J=13.9Hz,4H),2.91(d,J=11.2Hz,4H),2.86(d,J=9.6Hz,3H),2.17(s,2H),1.97( d, J=27.6Hz, 2H), 1.72-1.56(m, 2H).

實施例42：8-(3,3-二甲基環丁基)-2-((1-(S-甲基磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(42)的製備 Example 42: 8-(3,3-Dimethylcyclobutyl)-2-((1-(S-methylsulfonylimino)piperidin-4-yl)amino)pyrido[2 ,3-d] Preparation of pyrimidin-7(8H)-one (42)

與實施例3的製備方法相同，除了用3,3-二甲基環丁胺鹽酸鹽代替環戊胺和用N-(第三丁基二甲基甲矽烷基)甲磺醯胺(11a)代替N-(第三丁基二甲基甲矽烷基)環丙烷磺醯胺(11)，製得化合物42。 The preparation method is the same as in Example 3, except that cyclopentylamine is replaced with 3,3-dimethylcyclobutylamine hydrochloride and N-(tertiary butyldimethylsilyl) methanesulfonamide (11a ) instead of N-(tert-butyldimethylsilyl)cyclopropanesulfonamide (11) to obtain compound 42.

LCMS：m/z 405.20[M+H]⁺。 LCMS: m/z 405.20 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.36(s,1H),7.40(d,J=9.4Hz,1H),6.35(d,J=9.3Hz,1H),5.67(s,1H),4.15-3.99(m,1H),3.84(s,2H),2.99(s,2H),2.88(m,5H),2.56(s,2H),2.19(ddd,J=23.5,14.1,6.6Hz,4H),1.70(s,2H),1.27(d,J=4.0Hz,6H)。 ¹ H NMR (400MHz, CDCl ₃ )δ 8.36(s,1H),7.40(d,J=9.4Hz,1H),6.35(d,J=9.3Hz,1H),5.67(s,1H),4.15- 3.99(m,1H),3.84(s,2H),2.99(s,2H),2.88(m,5H),2.56(s,2H),2.19(ddd,J=23.5,14.1,6.6Hz,4H) ,1.70(s,2H),1.27(d,J=4.0Hz,6H).

實施例43：8-((1R,2R)-2-羥基環戊基)-2-((1-(S-甲基磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(43)的製備 Example 43: 8-((1R,2R)-2-Hydroxycyclopentyl)-2-((1-(S-methylsulfonimino)piperidin-4-yl)amino)pyrido Preparation of [2,3-d]pyrimidin-7(8H)-one (43)

與實施例3的製備方法相同，除了用(1R,2R)-2-胺基環戊醇鹽酸鹽代替環戊胺和用N-(第三丁基二甲基甲矽烷基)甲磺醯胺(11a)代替N-(第三丁基二甲基甲矽烷基)環丙烷磺醯胺(11)，製得化合物43。 The preparation method is the same as that of Example 3, except that cyclopentylamine is replaced by ( 1R,2R )-2-aminocyclopentyl alcohol hydrochloride and N-(tert-butyldimethylsilyl) methanesulfonyl Amine (11a) instead of N-(tert-butyldimethylsilyl)cyclopropanesulfonamide (11) affords compound 43.

LCMS：m/z 407.20[M+H]⁺。 LCMS: m/z 407.20 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.45(s,1H),7.50(d,J=9.3Hz,1H),6.44(d,J=9.2Hz,1H),5.82(dd,J=16.0,9.4Hz,1H),4.38(dd,J=10.6,4.5Hz,1H),4.00(s,1H),3.84(s,2H),2.98(s,2H),2.88(s,3H),2.69(s,1H),2.40(s,2H),2.14(ddd,J=16.5,13.1,8.4Hz,3H),2.01(dd,J=12.2,7.1Hz,2H),1.88-1.40(m,5H)。 ¹ H NMR (400MHz, CDCl ₃ )δ 8.45(s,1H),7.50(d,J=9.3Hz,1H),6.44(d,J=9.2Hz,1H),5.82(dd,J=16.0,9.4 Hz,1H),4.38(dd,J=10.6,4.5Hz,1H),4.00(s,1H),3.84(s,2H),2.98(s,2H),2.88(s,3H),2.69(s ,1H),2.40(s,2H),2.14(ddd,J=16.5,13.1,8.4Hz,3H),2.01(dd,J=12.2,7.1Hz,2H),1.88-1.40(m,5H).

實施例44：8-((1R,2S)-2-羥基環戊基)-2-((1-(S-甲基磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(44)的製備 Example 44: 8-((1R,2S)-2-Hydroxycyclopentyl)-2-((1-(S-methylsulfonimino)piperidin-4-yl)amino)pyrido Preparation of [2,3-d]pyrimidin-7(8H)-one (44)

與實施例3的製備方法相同，除了用(1S,2R)-2-胺基環戊醇鹽酸鹽代替環戊胺和用N-(第三丁基二甲基甲矽烷基)甲磺醯胺(11a)代替N-(第三丁基二甲基甲矽烷基)環丙烷磺醯胺(11)，製得化合物44。 The preparation method is the same as in Example 3, except that ( 1S,2R )-2-aminocyclopentanol hydrochloride is used instead of cyclopentylamine and N-(tertiary butyldimethylsilyl) methanesulfonyl Amine (11a) instead of N-(tert-butyldimethylsilyl)cyclopropanesulfonamide (11) affords compound 44.

LCMS：m/z 407.20[M+H]⁺。 LCMS: m/z 407.20 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.45(s,1H),7.51(d,J=9.3Hz,1H),6.43(d,J=9.2Hz,1H),5.82(td,J=9.4,6.9Hz,1H),4.38(dd,J=11.0,4.5Hz,1H),4.01(s,1H),3.85(s,2H),2.98(d,J=20.4Hz,2H),2.89(s,4H),2.70(d,J=10.0Hz,2H),2.15(ddd,J=20.4,8.3,4.1Hz,3H),2.00(dt,J=11.2,5.6Hz,2H),1.78(d,J=17.1Hz,1H),1.75-1.54(m,3H)。 ¹ H NMR (400MHz, CDCl ₃ )δ 8.45(s,1H),7.51(d, J =9.3Hz,1H),6.43(d, J =9.2Hz,1H),5.82(td, J =9.4,6.9 Hz,1H),4.38(dd, J =11.0,4.5Hz,1H),4.01(s,1H),3.85(s,2H),2.98(d, J =20.4Hz,2H),2.89(s,4H ),2.70(d, J =10.0Hz,2H),2.15(ddd, J =20.4,8.3,4.1Hz,3H),2.00(dt, J =11.2,5.6Hz,2H),1.78(d, J = 17.1Hz, 1H), 1.75-1.54(m, 3H).

實施例45：8-((1R,3R)-3-羥基環戊基)-2-((1-(S-甲基磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(45)的製備 Example 45: 8-(( 1R,3R )-3-Hydroxycyclopentyl)-2-((1-(S-methylsulfonimino)piperidin-4-yl)amino)pyrido Preparation of [2,3-d]pyrimidin-7(8H)-one (45)

與實施例3的製備方法相同，除了用(1R,3R)-2-胺基環戊醇鹽酸鹽代替環戊胺和用N-(第三丁基二甲基甲矽烷基)甲磺醯胺(11a)代替N-(第三丁基二甲基甲矽烷基)環丙烷磺醯胺(11)，製得化合物45。 The preparation method is the same as that of Example 3, except that cyclopentylamine is replaced by ( 1R,3R )-2-aminocyclopentyl alcohol hydrochloride and N-(tert-butyldimethylsilyl) methanesulfonyl Amine (11a) instead of N-(tert-butyldimethylsilyl)cyclopropanesulfonamide (11) affords compound 45.

LCMS：m/z 407.20[M+H]⁺。 LCMS: m/z 407.20 [M+H] ⁺ .

實施例46：8-((1R,3S)-3-羥基環戊基)-2-((1-(S-甲基磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(46)的製備 Example 46: 8-((1R,3S)-3-Hydroxycyclopentyl)-2-((1-(S-methylsulfonimino)piperidin-4-yl)amino)pyrido Preparation of [2,3-d]pyrimidin-7(8H)-one (46)

與實施例3的製備方法相同，除了用(1S,3R)-3-胺基環戊醇鹽酸鹽代替環戊胺和用N-(第三丁基二甲基甲矽烷基)甲磺醯胺(11a)代替N-(第三丁基二甲基甲矽烷基)環丙烷磺醯胺(11)，製得化合物46。 The preparation method is the same as that of Example 3, except that cyclopentylamine is replaced by ( 1S,3R )-3-aminocyclopentanol hydrochloride and N-(tert-butyldimethylsilyl)methanesulfonyl Amine (11a) in place of N-(tert-butyldimethylsilyl)cyclopropanesulfonamide (11) affords compound 46.

LCMS：m/z 407.10[M+H]⁺。 LCMS: m/z 407.10 [M+H] ⁺ .

¹HNMR(400MHz,CDCl₃)δ 8.47(s,1H),7.51(d,J=9.3Hz,1H),6.40(d,J=9.3Hz,1H),6.04(ddd,J=13.8,9.5,4.8Hz,1H),5.35(s,1H),4.34(t,J=4.4Hz,1H),4.05(s,1H),3.85(s,2H),2.95(s,2H),2.86(s,3H),2.61-2.46(m,1H),2.33(ddd,J=14.8, 12.0,5.7Hz,2H),2.26-2.17(m,2H),2.13(s,1H),2.06(dd,J=13.3,6.9Hz,2H),1.91(dt,J=12.2,8.1Hz,1H),1.68(s,3H)。 ¹ HNMR(400MHz, CDCl ₃ )δ 8.47(s,1H),7.51(d,J=9.3Hz,1H),6.40(d,J=9.3Hz,1H),6.04(ddd,J=13.8,9.5, 4.8Hz,1H),5.35(s,1H),4.34(t,J=4.4Hz,1H),4.05(s,1H),3.85(s,2H),2.95(s,2H),2.86(s, 3H),2.61-2.46(m,1H),2.33(ddd,J=14.8, 12.0,5.7Hz,2H),2.26-2.17(m,2H),2.13(s,1H),2.06(dd,J= 13.3,6.9Hz,2H),1.91(dt,J=12.2,8.1Hz,1H),1.68(s,3H).

實施例47：8-(3,3-二氟環戊基)-2-(((1-(S-甲基磺醯亞胺基)哌啶丁-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(47)的製備 Example 47: 8-(3,3-Difluorocyclopentyl)-2-(((1-(S-methylsulfonylimino)piperidin-4-yl)amino)pyrido[ Preparation of 2,3-d]pyrimidin-7(8H)-one (47)

與實施例3的製備方法相同，除了用3,3-二氟環戊胺鹽酸鹽代替環戊胺和用N-(第三丁基二甲基甲矽烷基)甲磺醯胺(11a)代替N-(第三丁基二甲基甲矽烷基)環丙烷磺醯胺(11)，製得化合物47。 The preparation method is the same as that of Example 3, except that cyclopentylamine is replaced with 3,3-difluorocyclopentylamine hydrochloride and N-(tertiary butyldimethylsilyl) methanesulfonamide (11a) Instead of N-(tert-butyldimethylsilyl)cyclopropanesulfonamide (11), compound 47 was prepared.

LCMS：m/z 427.20[M+H]⁺。 LCMS: m/z 427.20 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.42(s,1H),7.46(d,J=9.4Hz,1H),6.40(d,J=8.9Hz,1H),6.09(dd,J=18.3,9.1Hz,1H),4.16-4.02(m,1H),3.87(s,2H),3.16(d,J=36.7Hz,1H),2.96(s,2H),2.89(s,3H),2.86-2.44(m,4H),2.31(d,J=11.3Hz,1H),2.25-2.06(m,4H),1.69(d,J=10.0Hz,2H)。 ¹ H NMR (400MHz, CDCl ₃ )δ 8.42(s,1H),7.46(d,J=9.4Hz,1H),6.40(d,J=8.9Hz,1H),6.09(dd,J=18.3,9.1 Hz,1H),4.16-4.02(m,1H),3.87(s,2H),3.16(d,J=36.7Hz,1H),2.96(s,2H),2.89(s,3H),2.86-2.44 (m,4H),2.31(d,J=11.3Hz,1H),2.25-2.06(m,4H),1.69(d,J=10.0Hz,2H).

實施例48：8-(3,3-二甲基環戊基)-2-(((1-(S-甲基磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(48)的製備 Example 48: 8-(3,3-Dimethylcyclopentyl)-2-(((1-(S-methylsulfonylimino)piperidin-4-yl)amino)pyrido[ Preparation of 2,3-d]pyrimidin-7(8H)-one (48)

與實施例3的製備方法相同，除了用3,3-二甲基環戊烷-1-胺代替環戊胺和用N-(第三丁基二甲基甲矽烷基)甲磺醯胺(11a)代替N-(第三丁基二甲基甲矽烷基)環丙烷磺醯胺(11)，製得化合物48。 The preparation method is the same as that of Example 3, except that cyclopentylamine is replaced with 3,3-dimethylcyclopentane-1-amine and N-(tertiary butyldimethylsilyl) methanesulfonamide ( 11a) Instead of N-(tert-butyldimethylsilyl)cyclopropanesulfonamide (11), compound 48 was prepared.

LCMS：m/z 419.20[M+H]⁺。 LCMS: m/z 419.20 [M+H] ⁺ .

實施例49：8-(3-甲基環戊基)-2-((1-(S-甲基磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(49)的製備 Example 49: 8-(3-Methylcyclopentyl)-2-((1-(S-methylsulfonimino)piperidin-4-yl)amino)pyrido[2,3- d] Preparation of pyrimidin-7(8H)-one (49)

步驟1：N-苄基-3-甲基環戊烷-1-胺(49a)的製備 Step 1: Preparation of N-benzyl-3-methylcyclopentane-1-amine (49a)

於室溫，將3-甲基環戊酮(10.0g,101.9mmol)、DCM(200mL)、苄胺(9.84g,91.7mmol)、乙酸(10.0mL)依次加入至反應瓶中，室溫攪拌1.5小時。分批加入三乙醯氧基硼氫化鈉(43.2g,203.8mmol)，室溫攪拌過夜。將反應液濃縮後再次以DCM稀釋，以飽和NaOH水溶液調節PH至10，水相以DCM萃取，合併有機相後濃縮得25.0g粗品黃色油狀標題產物，直接用於下一步。 At room temperature, 3-methylcyclopentanone (10.0g, 101.9mmol), DCM (200mL), benzylamine (9.84g, 91.7mmol), acetic acid (10.0mL) were sequentially added to the reaction flask, stirred at room temperature 1.5 hours. Sodium triacetyloxyborohydride (43.2 g, 203.8 mmol) was added in portions and stirred overnight at room temperature. The reaction solution was concentrated and then diluted with DCM again. The pH was adjusted to 10 with saturated NaOH aqueous solution. The aqueous phase was extracted with DCM. The organic phases were combined and concentrated to obtain 25.0 g of the title product as a crude yellow oil, which was directly used in the next step.

LCMS：m/z 190.15[M+H]⁺。 LCMS: m/z 190.15 [M+H] ⁺ .

步驟2：3-甲基環戊胺鹽酸鹽(49b)的製備 Step 2: Preparation of 3-methylcyclopentylamine hydrochloride (49b)

於室溫，將N-苄基-3-甲基環戊烷-1-胺(25.0g，粗品)、異丙醇(200mL)加入至反應瓶中，氮氣氛下加入氫氧化鈀碳(3.00g)。置換氫氣，45℃反應過夜。反應結束後過濾，濾液降溫至5℃，滴加鹽酸二噁烷溶液(4.0M，50mL)，室溫攪拌過夜。反應液減壓濃縮，得17.9g紅褐色固體粗品，直接用於下一步。 At room temperature, N-benzyl-3-methylcyclopentane-1-amine (25.0 g, crude product) and isopropanol (200 mL) were added to the reaction flask, and palladium hydroxide on carbon (3.00 g). The hydrogen gas was replaced, and the reaction was carried out overnight at 45°C. After the reaction was completed, it was filtered, and the temperature of the filtrate was lowered to 5° C., a dioxane hydrochloride solution (4.0 M, 50 mL) was added dropwise, and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure to obtain 17.9 g of crude reddish-brown solid, which was directly used in the next step.

LCMS：m/z 100.10[M+H]⁺。 LCMS: m/z 100.10 [M+H] ⁺ .

其餘步驟與實施例3的製備方法相同，除了用3-甲基環戊胺鹽酸鹽(49b)代替環戊胺和用N-(第三丁基二甲基甲矽烷基)甲磺醯胺(11a)代替N-(第三丁基二甲基甲矽烷基)環丙烷磺醯胺(11)，製得標題化合物。 All the other steps are the same as the preparation method of Example 3, except that cyclopentylamine is replaced with 3-methylcyclopentylamine hydrochloride (49b) and N-(tertiary butyldimethylsilyl) methanesulfonamide (11a) in place of N-(tert-butyldimethylsilyl)cyclopropanesulfonamide (11) gave the title compound.

LCMS：m/z 405.20[M+H]⁺。 LCMS: m/z 405.20 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.37(s,1H),7.41(d,J=9.3,1H),6.38(d,J=9.1,1H),5.90(ddd,J=14.6,13.6,7.2,1H),4.17-3.96(m,1H),3.83(s,2H),3.00(d,J=20.9,2H),2.86(s,3H),2.78-2.50(m,2H),2.40(s,2H),2.28-2.05(m,3H),2.05-1.97(m,1H),1.97-1.81(m,2H),1.70(d,J=8.4,2H),1.50(s,1H),1.26(s,1H),1.10(dd,J=31.4,6.5,3H)。 ¹ H NMR (400MHz, CDCl ₃ )δ 8.37(s,1H),7.41(d,J=9.3,1H),6.38(d,J=9.1,1H),5.90(ddd,J=14.6,13.6,7.2 ,1H),4.17-3.96(m,1H),3.83(s,2H),3.00(d,J=20.9,2H),2.86(s,3H),2.78-2.50(m,2H),2.40(s ,2H),2.28-2.05(m,3H),2.05-1.97(m,1H),1.97-1.81(m,2H),1.70(d,J=8.4,2H),1.50(s,1H),1.26 (s,1H),1.10(dd,J=31.4,6.5,3H).

實施例50：8-環己基-2-(((1-(S-甲基磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(50)的製備 Example 50: 8-cyclohexyl-2-(((1-(S-methylsulfonimino)piperidin-4-yl)amino)pyrido[2,3-d]pyrimidine-7( Preparation of 8H)-ketone (50)

與實施例3的製備方法相同，除了用環己胺代替環戊胺和用N-(第三丁基二甲基甲矽烷基)甲磺醯胺(11a)代替N-(第三丁基二甲基甲矽烷基)環丙烷磺醯胺(11)，製得化合物50。 The same preparation method as in Example 3, except that cyclopentylamine is used instead of cyclopentylamine and N-(tert-butyldimethylsilyl) methanesulfonamide (11a) is used to replace N-(tert-butyldi Methylsilyl)cyclopropanesulfonamide (11) to obtain compound 50.

LCMS：m/z 405.20[M+H]⁺。 LCMS: m/z 405.20 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.36(s,1H),7.40(d,J=9.3Hz,1H),6.38(s,1H),5.32(t,J=12.2Hz,1H),4.02(s,1H),3.86(s,2H),2.97(s,2H),2.86(s,3H),2.68(d, J=11.4Hz,4H),2.22(t,J=8.8Hz,2H),1.90(d,J=12.2Hz,2H),1.69(s,5H),1.34(d,J=55.9Hz,3H)。 ¹ H NMR (400MHz, CDCl ₃ ) δ 8.36(s,1H),7.40(d,J=9.3Hz,1H),6.38(s,1H),5.32(t,J=12.2Hz,1H),4.02( s,1H),3.86(s,2H),2.97(s,2H),2.86(s,3H),2.68(d, J=11.4Hz,4H),2.22(t,J=8.8Hz,2H), 1.90(d,J=12.2Hz,2H),1.69(s,5H),1.34(d,J=55.9Hz,3H).

實施例51：6-(二氟甲基)-2-((1-(S-甲基磺醯亞胺基)哌啶-4-基)胺基)-8-(螺[2.4]庚-4-基)吡啶并[2,3-d]嘧啶-7-(8H)-酮(51)的製備 Example 51: 6-(Difluoromethyl)-2-((1-(S-methylsulfonimino)piperidin-4-yl)amino)-8-(spiro[2.4]hept- Preparation of 4-yl)pyrido[2,3-d]pyrimidin-7-(8H)-one (51)

與實施例33的製備方法相同，除了用2-((1-(S-甲基磺醯亞胺基)哌啶-4-基)胺基)-8-(螺[2.4]庚-4-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(25)代替8-(2-甲基環戊基)-2-((1-(S-甲基磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(22)，製得化合物51。 The same preparation method as in Example 33, except that 2-((1-(S-methylsulfonylimino)piperidin-4-yl)amino)-8-(spiro[2.4]hept-4- Base) pyrido[2,3-d]pyrimidin-7(8H)-one (25) instead of 8-(2-methylcyclopentyl)-2-((1-(S-methylsulfonyl imide yl)piperidin-4-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (22) to obtain compound 51.

LCMS：m/z 433.23[M+H]⁺。 LCMS: m/z 433.23 [M+H] ⁺ .

¹H NMR(400MHz,CDCl₃)δ 8.39(s,1H),7.66(s,1H),5.99(dd,J=16.8,9.7Hz,1H),4.04(s,1H),3.84(s,2H),3.05(d,J=26.6Hz,3H),2.91(s,3H),2.64(s,1H),2.36(dtd,J=17.4,7.1,3.3Hz,1H),2.26-2.15(m,2H),2.14-2.06(m,1H),2.03-1.84(m,3H),1.81-1.44(m,4H),0.79(d,J=7.1Hz,3H)。 ¹ H NMR (400MHz, CDCl ₃ )δ 8.39(s,1H),7.66(s,1H),5.99(dd,J=16.8,9.7Hz,1H),4.04(s,1H),3.84(s,2H ),3.05(d,J=26.6Hz,3H),2.91(s,3H),2.64(s,1H),2.36(dtd,J=17.4,7.1,3.3Hz,1H),2.26-2.15(m, 2H), 2.14-2.06(m, 1H), 2.03-1.84(m, 3H), 1.81-1.44(m, 4H), 0.79(d, J=7.1Hz, 3H).

實施例52：6-氯-2-((1-(S-甲基磺醯亞胺基)哌啶-4-基)胺基)-8-(螺[2.4]庚-4-基)吡啶[2,3-d]嘧啶-7(8H))-酮(52)的製備 Example 52: 6-Chloro-2-((1-(S-methylsulfonimino)piperidin-4-yl)amino)-8-(spiro[2.4]hept-4-yl)pyridine Preparation of [2,3-d]pyrimidin-7(8H))-one (52)

與實施例38的製備方法相同，除了用4-(((7-側氧基-8-(螺[2.4]庚基-4-基]-7,8-二氫吡啶并[2,3-d]嘧啶-2-基)胺基]胺基)哌啶-1-甲酸第三丁酯(25e)代替4-(((8-(2-甲基環戊基)-7-側氧基-7,8-二氫吡啶并[2,3-d]嘧啶-2-基)胺基)哌啶-1-羧酸第三丁酯(22e)，製得化合物52。 The same preparation method as in Example 38, except that 4-(((7-oxo-8-(spiro[2.4]heptyl-4-yl]-7,8-dihydropyrido[2,3- d] pyrimidin-2-yl) amino] amino) piperidine-1-carboxylic acid tert-butyl ester (25e) instead of 4-(((8-(2-methylcyclopentyl)-7-side oxy -7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (22e), to obtain compound 52.

LCMS：m/z 451.20[M+H]⁺。 LCMS: m/z 451.20 [M+H] ⁺ .

實施例53：8-環戊基-6-(二氟甲基)-2-(((1-(噻吩-2-磺醯亞胺基))哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(53)的製備 Example 53: 8-Cyclopentyl-6-(difluoromethyl)-2-(((1-(thiophene-2-sulfonimino))piperidin-4-yl)amino)pyrido Preparation of [2,3-d]pyrimidin-7(8H)-one (53)

與實施例33的製備方法相同，除了用8-環戊基-2-(((1-(噻吩-2-磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(36)代替8-(2-甲基環戊基)-2-((1-(S- 甲基磺醯亞胺基)哌啶-4-基)胺基)吡啶并[2,3-d]嘧啶-7(8H)-酮(22)，製得標題化合物。 The same preparation method as in Example 33, except that 8-cyclopentyl-2-(((1-(thiophene-2-sulfonyl imino)piperidin-4-yl)amino)pyrido[2, 3-d] pyrimidin-7(8H)-one (36) instead of 8-(2-methylcyclopentyl)-2-((1-(S- Methylsulfonylimino)piperidin-4-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (22), yielding the title compound.

LCMS：m/z 509.15[M+H]⁺。 LCMS: m/z 509.15 [M+H] ⁺ .

¹H NMR(400MHz,CDCl3)δ 8.45(s,1H),7.77(s,1H),7.59(dd,J=19.5,3.7Hz,2H),7.22-7.12(m,1H),6.78(t,J=55.2Hz,1H),5.78(s,1H),3.92(s,2H),3.73(s,1H),2.79(s,2H),2.58(s,1H),2.30(s,2H),2.14(s,2H),1.97(d,J=28.0Hz,2H),1.84(dd,J=12.7,6.9Hz,2H),1.77(d,J=19.3Hz,2H),1.72-1.51(m,3H)。 ¹ H NMR (400MHz, CDCl3) δ 8.45(s,1H),7.77(s,1H),7.59(dd,J=19.5,3.7Hz,2H),7.22-7.12(m,1H),6.78(t, J=55.2Hz,1H),5.78(s,1H),3.92(s,2H),3.73(s,1H),2.79(s,2H),2.58(s,1H),2.30(s,2H), 2.14(s,2H),1.97(d,J=28.0Hz,2H),1.84(dd,J=12.7,6.9Hz,2H),1.77(d,J=19.3Hz,2H),1.72-1.51(m ,3H).

[生物學測試] [biological test]

試驗例1：本發明化合物對CDK2/4/6的抑制活性 Test Example 1: Inhibitory activity of compounds of the present invention on CDK2/4/6

(1)CDK2/CyclinE1激酶活性抑制 (1) CDK2/CyclinE1 kinase activity inhibition

使用ADP-Glo激酶測定試劑盒(Promega，貨號V9102)檢測待測化合物對CDK2/CyclinE1激酶的抑制活性。在激酶反應中，激酶將受質磷酸化，同時消耗ATP，殘留ATP，能被Ultra-Glo^TM螢光素酶轉化成光，發光信號與激酶活性正相關，檢測這種發光信號值，即可反應出激酶活性。 ADP-Glo Kinase Assay Kit (Promega, Cat. No. V9102) was used to detect the inhibitory activity of the test compound on CDK2/CyclinE1 kinase. In the kinase reaction, the kinase phosphorylates the substrate and consumes ATP at the same time, and the remaining ATP can be converted into light by Ultra-Glo ^TM luciferase. The luminescent signal is positively correlated with the kinase activity, and the value of this luminescent signal can be detected. Reflects kinase activity.

試驗方法 experiment method

首先，將待測化合物在DMSO(Sigma，貨號D8418)中溶解，然後稀釋為200nM濃度，設定試驗起始濃度100nM，3倍稀釋，10個梯度。用Echo 550在384孔反應板中(Greiner，貨號784075)加入5μl稀釋後的化合物和2.5μl CDK2/Cyclin E1激酶(Carna，貨號04-165)，用封板膜封住板子，1000rpm離心1分鐘，25℃孵育10分鐘。再向反應板中加入2.5μl Histone H1蛋白(SignalChem，貨號H10-54N)和ATP(Promega，貨號V910B)的混合液，1000rpm離心1分鐘，25℃孵育反應60分鐘。吸取5μl的ADP-Glo試劑(Promega，貨號V9102)到反應板中，瞬時離心後，孵育40分鐘。最後加入10μl的檢測試劑到反應板中，孵育40分鐘。使用Envision2104多功能讀板機(PerkinElmer，型號Oct-04)讀取相對螢光單員(relative luminescence unit，RLU)值。RLU值大小用於表徵酶與受質反應程度。實驗數據採用GraphPad prism 6.0軟件進行非線性擬合公式計算化合物IC₅₀值： First, the compound to be tested was dissolved in DMSO (Sigma, product number D8418), and then diluted to a concentration of 200 nM, and the initial concentration of the test was set at 100 nM, with 3-fold dilution and 10 gradients. Add 5 μl of the diluted compound and 2.5 μl of CDK2/Cyclin E1 kinase (Carna, catalog number 04-165) to the 384-well reaction plate (Greiner, Cat. No. 784075) with Echo 550, seal the plate with a sealing film, and centrifuge at 1000 rpm for 1 minute , and incubate at 25°C for 10 minutes. Add 2.5 μl of a mixture of Histone H1 protein (SignalChem, Cat. No. H10-54N) and ATP (Promega, Cat. No. V910B) to the reaction plate, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C for 60 minutes. Pipette 5 μl of ADP-Glo reagent (Promega, Cat. No. V9102) into the reaction plate, centrifuge briefly, and incubate for 40 minutes. Finally, 10 μl of detection reagent was added to the reaction plate and incubated for 40 minutes. Use Envision2104 multifunctional plate reader (PerkinElmer, model Oct-04) to read relative luminescence unit (relative luminescence unit, RLU) value. The RLU value is used to characterize the degree of reaction between the enzyme and the substrate. The experimental data was calculated using GraphPad prism 6.0 software for nonlinear fitting formula to calculate the compound IC ₅₀ value:

Y=Bottom+(Top-Bottom)/(1+10^((LogIC₅₀-X)×HillSlope))。 Y=Bottom+(Top-Bottom)/(1+10^((LogIC ₅₀ -X)×HillSlope)).

X為化合物濃度對數值，Y為抑制的百分比，Bottom最小抑制百分比，Top為最大抑制百分比，HillSlope為曲線斜率。 X is the logarithmic value of the compound concentration, Y is the percentage of inhibition, Bottom is the minimum percentage of inhibition, Top is the maximum percentage of inhibition, and HillSlope is the slope of the curve.

(2)CDK6/CyclinD1激酶活性抑制 (2) CDK6/CyclinD1 kinase activity inhibition

使用ADP-Glo激酶測定試劑盒(Promega，貨號V9102)檢測待測化合物對CDK6/CyclinD1激酶的抑制活性。 ADP-Glo Kinase Assay Kit (Promega, Cat. No. V9102) was used to detect the inhibitory activity of the test compound on CDK6/CyclinD1 kinase.

試驗方法 experiment method

首先，將待測化合物溶解在DMSO(Sigma，貨號D8418)中，設定試驗起始濃度1000nM，3倍稀釋，10個梯度。用Echo 550在384孔反應板中(Greiner，貨號784075)加入5μl稀釋後的化合物和2.5μl CDK6/CyclinD1激酶(ThermoFisher，貨號PV4401)，用封板膜封住板子，瞬時離心30s，孵育10分鐘。再向反應板中加入2.5μl Histone H1蛋白(SignalChem，貨號H10-54N)和ATP(Promega，貨號V910B)的混合液，1000g離心30s，25℃孵育反應60分鐘。再加入5μl的ADP-Glo試劑(Promega，貨號V9102)到反應板中，瞬時離心後，孵育40分鐘。最後加入10μl的檢測試劑到反應板中，孵育40分鐘。使用Envision 2104多功能讀板機(PerkinElmer，型號Oct-04)讀取RLU值。RLU 值大小用於表徵酶與受質反應程度。實驗數據採用GraphPad prism 6.0軟件進行非線性擬合公式計算化合物的IC₅₀值： First, the compound to be tested was dissolved in DMSO (Sigma, Cat. No. D8418), and the initial concentration of the test was set to 1000 nM, with 3-fold dilution and 10 gradients. Add 5 μl of the diluted compound and 2.5 μl of CDK6/CyclinD1 kinase (ThermoFisher, catalog number PV4401) to the 384-well reaction plate (Greiner, catalog number 784075) with Echo 550, seal the plate with a sealing film, centrifuge briefly for 30 seconds, and incubate for 10 minutes . Add 2.5 μl of a mixture of Histone H1 protein (SignalChem, Cat. No. H10-54N) and ATP (Promega, Cat. No. V910B) to the reaction plate, centrifuge at 1000 g for 30 s, and incubate at 25° C. for 60 minutes. Add 5 μl of ADP-Glo reagent (Promega, Cat. No. V9102) to the reaction plate, centrifuge briefly, and incubate for 40 minutes. Finally, 10 μl of detection reagent was added to the reaction plate and incubated for 40 minutes. RLU values were read using an Envision 2104 multi-function plate reader (PerkinElmer, model Oct-04). The RLU value is used to characterize the degree of reaction between the enzyme and the substrate. The experimental data was calculated using GraphPad prism 6.0 software for nonlinear fitting formula to calculate the IC ₅₀ value of the compound:

X為化合物濃度對數值，Y為抑制的百分比，Bottom最小抑制百分比，Top為最大抑制百分比，HillSlope為曲線斜率。(3)CDK4/CyclinD3激酶活性抑制 X is the logarithmic value of the compound concentration, Y is the percentage of inhibition, Bottom is the minimum percentage of inhibition, Top is the maximum percentage of inhibition, and HillSlope is the slope of the curve. (3) CDK4/CyclinD3 kinase activity inhibition

使用ADP-Glo激酶測定試劑盒(Promega，貨號V9102)檢測待測化合物對CDK4/CyclinD3激酶的抑制活性。 ADP-Glo Kinase Assay Kit (Promega, Cat. No. V9102) was used to detect the inhibitory activity of the test compound on CDK4/CyclinD3 kinase.

試驗方法 experiment method

首先，將待測化合物溶解在DMSO(Sigma，貨號D8418)中，設定試驗起始濃度1000nM，3倍稀釋，10個梯度。用Echo 550在384孔反應板中(Greiner，貨號784075)，加入5μl稀釋後的化合物和2.5μl CDK4/CyclinD3激酶(Carna，貨號04-105)，用封板膜封住板子，瞬時離心30s，孵育10分鐘。再向反應板中加入2.5μl Histone H1蛋白(SignalChem，貨號H10-54N)和ATP(Promega，貨號V910B)的混合液，1000g離心30s，25℃孵育反應1h。再加入5μl的ADP-Glo試劑(Promega，貨號V9102)到反應板中，瞬時離心後，孵育40分鐘。最後加入10μl的檢測試劑到反應板中，孵育40分鐘。使用Envision 2104多功能讀板機(PerkinElmer，型號Oct-04)讀取RLU值。RLU值大小用於表徵酶與受質反應程度。實驗數據採用GraphPad prism 6.0軟件進行非線性擬合公式計算化合物的IC₅₀值： First, the compound to be tested was dissolved in DMSO (Sigma, Cat. No. D8418), and the initial concentration of the test was set to 1000 nM, with 3-fold dilution and 10 gradients. Add 5 μl of the diluted compound and 2.5 μl of CDK4/CyclinD3 kinase (Carna, catalog number 04-105) to a 384-well reaction plate (Greiner, Cat. No. 784075) with Echo 550, seal the plate with a sealing film, and centrifuge briefly for 30 s. Incubate for 10 minutes. Then add 2.5 μl of a mixture of Histone H1 protein (SignalChem, Cat. No. H10-54N) and ATP (Promega, Cat. No. V910B) to the reaction plate, centrifuge at 1000 g for 30 s, and incubate at 25° C. for 1 h. Add 5 μl of ADP-Glo reagent (Promega, Cat. No. V9102) to the reaction plate, centrifuge briefly, and incubate for 40 minutes. Finally, 10 μl of detection reagent was added to the reaction plate and incubated for 40 minutes. RLU values were read using an Envision 2104 multi-function plate reader (PerkinElmer, model Oct-04). The RLU value is used to characterize the degree of reaction between the enzyme and the substrate. The experimental data was calculated using GraphPad prism 6.0 software for nonlinear fitting formula to calculate the IC ₅₀ value of the compound:

本發明化合物對CDK2、CDK6和CDK4激酶抑制的IC₅₀值如下表1所示。 The IC ₅₀ values of the compounds of the present invention for the inhibition of CDK2, CDK6 and CDK4 kinases are shown in Table 1 below.

表1本發明化合物對CDK2、CDK6和CDK4激酶抑制的IC₅₀值

Table 1 The compounds of the present invention inhibit the _IC50 values of CDK2, CDK6 and CDK4 kinases

結論：從表1可以看出，本發明化合物具有良好的CDK2/4/6激酶抑制活性。 Conclusion: It can be seen from Table 1 that the compound of the present invention has good CDK2/4/6 kinase inhibitory activity.

試驗例2：本發明化合物對CDK2/4/6途徑的細胞學抑制水平 Test Example 2: The level of cytological inhibition of CDK2/4/6 pathway by the compound of the present invention

(1)OVCAR3和HCC1806細胞增殖試驗 (1) OVCAR3 and HCC1806 cell proliferation assay

藉由細胞增殖實驗，檢測待測化合物對卵巢癌細胞系OVCAR3和乳腺癌細胞系HCC1806的抑制水平，根據檢測指標IC₅₀，篩選候選化合物。 The inhibitory level of the compound to be tested on ovarian cancer cell line OVCAR3 and breast cancer cell line HCC1806 was detected by cell proliferation experiments, and candidate compounds were screened according to the detection index IC ₅₀ .

OVCAR3和HCC1806細胞株(均購買自南京科佰生物公司，ATCC編號分別為ATCC® HTB-161^TM和ATCC® CRL-2335^TM)培養於RPMI1640(Gibco，C11875500BT)，加入10%的FBS(Gbico，10099141)和雙抗(1%的青黴素和鏈黴素，Gibco公司，15140-122)。5,000個OVCAR3或HCC1806細胞接種在白色透明底96孔(Nunc，249944)/384孔板中(Corning，3570)，置於37℃，5%的培養箱內過夜。第二天，加入待測化合物，化合物用DMSO溶解，稀釋，試驗起始濃度從10mM開始，3倍稀釋，設置10個濃度梯度，每個梯度3個複孔。將細胞板放置培養箱中，37℃，5% CO₂共培養7天。使用CELL Titer-GLO發光法，檢測總的ATP含量來測定細胞增殖水平。將384孔板細胞取出，室溫平衡30min；每孔加入30μL CTG(CTG，Promega，貨號G7572)，振盪混勻，室溫孵育10min；多功能酶標儀(Biotek，型號Cytation 3)讀取螢光值。GraphPad Prism 6.0軟件分析不同濃度下化合物反應的Log值來測定增殖抑制的IC₅₀。 OVCAR3 and HCC1806 cell lines (both purchased from Nanjing Kebai Biological Company, ATCC numbers ATCC® HTB-161 ^TM and ATCC® CRL-2335 ^TM respectively) were cultured in RPMI1640 (Gibco, C11875500BT), adding 10% FBS (Gbico, 10099141) and double antibody (1% penicillin and streptomycin, Gibco, 15140-122). 5,000 OVCAR3 or HCC1806 cells were seeded in a white transparent bottom 96-well (Nunc, 249944)/384-well plate (Corning, 3570), and placed in a 5% incubator at 37°C overnight. The next day, add the compound to be tested, dissolve the compound with DMSO, and dilute it. The initial concentration of the test starts from 10 mM, and it is diluted 3 times. Set up 10 concentration gradients, and each gradient has 3 replicate wells. Place the cell plate in an incubator at 37°C, 5% CO ₂ for 7 days. Using the CELL Titer-GLO luminescence method, the total ATP content was detected to determine the level of cell proliferation. Take out the cells from the 384-well plate, and equilibrate at room temperature for 30 minutes; add 30 μL of CTG (CTG, Promega, Cat. No. G7572) to each well, shake and mix, and incubate at room temperature for 10 minutes; light value. GraphPad Prism 6.0 software analyzed the Log value of the compound response at different concentrations to determine the IC ₅₀ of proliferation inhibition.

(2)MCF7細胞增殖試驗 (2) MCF7 cell proliferation assay

人乳腺癌細胞(MCF7細胞)(購自ATCC，編號為HTB-22)培養於EMEM培養基中(ATCC，30-2003)，加入10% FBS(Gbico，10099141)。待細胞生長至70~80%的匯合度，消化細胞，製備細胞懸液。接種細胞在384孔板中(Corning，3570)，500個/孔，置於37℃，5%的培養箱內過夜。第二天加入待測化合物，化合物用DMSO溶解，稀釋，試驗起始濃度從10mM開始，3倍稀釋，設置10個濃度梯度，每個梯度3個複孔。將細胞板放置培養箱中，37℃，5% CO₂共培養7天。使用CELL Titer-GLO發光法，檢測總的ATP含量來測定細胞增殖水平，室溫平衡30min；每孔加入20μL CTG(CTG，Promega，貨號 G7572)，振盪混勻，室溫孵育10min；多功能酶標儀(Biotek，型號Cytation 3)讀取螢光值。GraphPad Prism 6.0軟件分析不同濃度下化合物反應的Log值來測定增殖抑制的IC₅₀。 Human breast cancer cells (MCF7 cells) (purchased from ATCC, number HTB-22) were cultured in EMEM medium (ATCC, 30-2003) with 10% FBS (Gbico, 10099141). When the cells grow to 70-80% confluence, digest the cells and prepare the cell suspension. Cells were seeded in a 384-well plate (Corning, 3570), 500 cells/well, and placed in a 5% incubator at 37°C overnight. The next day, the compound to be tested was added, and the compound was dissolved in DMSO, diluted, and the initial concentration of the test was 10 mM, diluted 3 times, and 10 concentration gradients were set, with 3 replicate wells for each gradient. Place the cell plate in an incubator at 37°C, 5% CO ₂ for 7 days. Use the CELL Titer-GLO luminescence method to detect the total ATP content to determine the cell proliferation level, and equilibrate at room temperature for 30 minutes; add 20 μL CTG (CTG, Promega, catalog number G7572) to each well, shake and mix, and incubate at room temperature for 10 minutes; Fluorescence values were read with a standard reader (Biotek, model Cytation 3). GraphPad Prism 6.0 software analyzed the Log value of the compound response at different concentrations to determine the IC ₅₀ of proliferation inhibition.

本發明化合物對OVCAR3，HCC1806和MCF-7細胞抑制的IC₅₀值如下表2所示。 The IC ₅₀ values of the compounds of the present invention for the inhibition of OVCAR3, HCC1806 and MCF-7 cells are shown in Table 2 below.

表2本發明化合物對OVCAR3、HCC1806和MCF-7細胞抑制的IC₅₀值

Table 2 The compounds of the present invention inhibit the _IC50 values of OVCAR3, HCC1806 and MCF-7 cells

結論：從表2可以看出，本發明化合物對OVCAR3、HCC1806和MCF-7細胞增殖具有顯著抑制作用。 Conclusion: It can be seen from Table 2 that the compound of the present invention has a significant inhibitory effect on the proliferation of OVCAR3, HCC1806 and MCF-7 cells.

試驗例3：本發明化合物的小鼠藥物代謝動力學實驗 Test example 3: mouse pharmacokinetic experiment of the compound of the present invention

實驗動物選用7-8週齡雄性ICR小鼠，購自北京維通利華實驗動物技術有限公司，飼養於SPF環境，溫度20~26℃，每日溫差不超過4℃，相對濕度40~70%RH，每日12h/12h交替照明。實驗動物經過3-5天的適應期，其中口服給藥動物於實驗前1天禁食過夜(>12h)，不禁水。 The experimental animals were male ICR mice aged 7-8 weeks, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., and raised in an SPF environment with a temperature of 20-26°C, a daily temperature difference of no more than 4°C, and a relative humidity of 40-70%. RH, 12h/12h alternate lighting every day. The experimental animals went through an adaptation period of 3-5 days, and the animals administered orally were fasted overnight (>12h) one day before the experiment, without water.

每個待測化合物分為iv(靜脈給藥)和po(灌胃)組(n=6)，劑量設為iv 1mg/kg、p.o 10mg/kg。靜脈組和灌胃組溶媒均為3%DMSO+97%(20% HP-β-CD溶液)。化合物溶液配製流程如下：先用DMSO溶解化合物，配成10mg/mL的儲液；取100μL儲液，用20%的HP-β-CD定容至5mL，得到濃度為0.2mg/mL的靜脈給藥溶液；取100μL的儲液，加入溶媒定容至5mL，渦旋，使分散均勻，得到化合物濃度為1mg/mL的灌胃給藥溶液。 Each compound to be tested was divided into iv (intravenous administration) and po (gastric administration) groups (n=6), and the dose was set as iv 1mg/kg, p.o 10mg/kg. Both the intravenous group and intragastric group were 3% DMSO+97% (20% HP-β-CD solution). The compound solution preparation process is as follows: dissolve the compound in DMSO first, and prepare a 10 mg/mL stock solution; take 100 μL of the stock solution, and dilute it to 5 mL with 20% HP-β-CD to obtain a concentration of 0.2 mg/mL for intravenous administration. Drug solution; take 100 μL of the stock solution, add solvent to make it up to 5 mL, vortex to disperse evenly, and obtain an intragastric administration solution with a compound concentration of 1 mg/mL.

給藥前稱量體重，藉由眼靜脈叢採血方式，採集0.1mL血樣加入肝素鈉抗凝管中，防止凝血。每個受試化合物6隻靜脈給藥，6隻口服給藥，並於給藥後2h給予食物。樣品採集時間點為，灌胃組：給藥前及給藥後5min、15min、30min、1h、2h、4h；靜脈組：給藥前及給藥後5min、15min、30min、1h、2h、4h。動物採血分成2部分分別進行，採用交叉時間點採血，同1隻小鼠最多設5個採血點。在取血60min內，用Sorvall ST 8R高速低溫離心機以3000rpm離心10min，取上層血漿，凍存到-20℃冰箱內，備用。使用LC-MS/MS的分析方法檢測樣品中化合物濃度。採用MAS Studio(V1.3.1 stable)軟件計算並得到化合物在小鼠體內的血藥濃度-時間曲線，以及主要的PK參數：AUC_0-t、C_max、T_max、T_1/2和F%。F%=(AUC_po×劑量_iv)/(AUC_iv×劑量_po)×100%。 Body weight was weighed before administration, and 0.1 mL blood samples were collected by means of blood collection from the ophthalmic venous plexus and added to heparin sodium anticoagulant tubes to prevent coagulation. Each test compound was administered intravenously to 6 rats, and 6 rats were given oral administration, and food was given 2 hours after administration. The time points of sample collection are: gavage group: 5min, 15min, 30min, 1h, 2h, 4h before administration and after administration; intravenous group: 5min, 15min, 30min, 1h, 2h, 4h before administration and after administration . Animal blood collection was divided into two parts, and cross-time point blood collection was adopted, and a maximum of 5 blood collection points were set for one mouse. Within 60 minutes of blood collection, centrifuge at 3,000 rpm for 10 minutes with a Sorvall ST 8R high-speed low-temperature centrifuge, take the upper layer of plasma, and store it in a -20°C refrigerator for later use. The concentration of the compound in the sample was detected by the analytical method of LC-MS/MS. MAS Studio (V1.3.1 stable) software was used to calculate and obtain the plasma concentration-time curve of the compound in mice, as well as the main PK parameters: AUC _0-t , C _max , T _max , T _1/2 and F% . F%=(AUC _po ×dose _iv )/(AUC _iv ×dose _po )×100%.

本發明化合物對小鼠的藥物代謝動力學參數如下表3所示。 The pharmacokinetic parameters of the compounds of the present invention on mice are shown in Table 3 below.

表3本發明化合物的小鼠藥物代謝動力學參數

The mouse pharmacokinetic parameter of table 3 compound of the present invention

結論：從表3可以看出，本發明化合物在小鼠的藥物代謝動力學實驗中具有較好的性質。 Conclusion: As can be seen from Table 3, the compounds of the present invention have good properties in the pharmacokinetic experiments of mice.

Claims

一種通式(I)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽， A compound represented by general formula (I) or its stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereoisomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof,

其中， in,

R⁴選自氫、鹵素、胺基、硝基、氰基、羥基、巰基、烷基、烷氧基、環烷基、雜環基、芳基、雜芳基、-C(O)R^a、-O(O)CR^a、-C(O)OR^a、-C(O)NR^aR^b、-NHC(O)R^a、-S(O)_mR^a、-S(O)_mNR^aR^b和-NHS(O)_mR^a，該烷基、烷氧基、環烷基、雜環基、芳基、雜芳基視需要進一步被選自鹵素、胺基、硝基、氰基、羥基、巰基、羧基、酯基、側氧基、烷基、烷氧基、鹵烷基、鹵烷氧基、環烷基、雜環基、芳基、雜芳基的一個或多個基團所取代； ^R is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O) ^Ra , -O(O)CR ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -NHC(O)R ^a , -S(O) _m R ^a , -S(O) _m NR ^a R ^b and -NHS(O) _m ^Ra , the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl are further selected from halogen, amino, nitro, One or more of cyano, hydroxyl, mercapto, carboxyl, ester, side oxy, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl replaced by a group;

m為0、1、2； m is 0, 1, 2;

p為0、1、2、3或4。 p is 0, 1, 2, 3 or 4.

如請求項1所述的通式(I)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽， The compound represented by the general formula (I) as described in Claim 1 or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers , or a mixture thereof, or a pharmaceutically acceptable salt thereof,

其中， in,

如請求項1或2所述的通式(I)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽，其為通式(II)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽， The compound represented by the general formula (I) as described in Claim 1 or 2 or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (II) or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

其中，環B、R¹、R²、R³、R⁴、R⁵、p如請求項1所定義。 Wherein, ring B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and p are as defined in Claim 1.

如請求項1至3中任一項所述的通式(I)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽， The compound represented by the general formula (I) or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

其中， in,

、

、

、

、

、

,

.

如請求項1至4中任一項所述的通式(I)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽，其為通式(III)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽， The compound represented by the general formula (I) or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, Diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by general formula (III) or stereoisomers thereof, Tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

其中，R¹、R²、R³、R⁴、R⁵、p如請求項1所定義。 Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and p are as defined in Claim 1.

如請求項1至5中任一項所述的通式(I)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽， The compound represented by the general formula (I) or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

其中， in,

每個R³各自獨立地選自鹵素、胺基、氰基、羥基、巰基、C₁-C₆烷基、C₁-C₆烷氧基、C₃-C₇環烷基、4至7員雜環基，該C₁-C₆烷基、C₁-C₆烷氧基、C₃-C₇環烷基、4至7員雜環基視需要進一步被選自鹵素、胺基、硝基、氰基、羥基、巰基、羧基、酯基、側氧基、烷基、烷氧基、鹵烷基、鹵烷氧基、環烷基、雜環基、芳基、雜芳基的一個或多個基團所取代；較佳鹵素、羥基、C₁-C₆烷基、C₁-C₆鹵烷基； Each R ³ is independently selected from halogen, amine, cyano, hydroxyl, mercapto, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₇ cycloalkyl, 4 to 7 member heterocyclic group, the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₇ cycloalkyl, 4 to 7 member heterocyclic group are further selected from halogen, amino, Nitro, cyano, hydroxyl, mercapto, carboxyl, ester, side oxy, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl Substituted by one or more groups; preferably halogen, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl;

p為0、1、2或3；較佳1或2。 p is 0, 1, 2 or 3; preferably 1 or 2.

如請求項1至6中任一項所述的通式(I)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽， The compound represented by the general formula (I) or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

其中， in,

如請求項1至7中任一項所述的通式(I)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽， The compound represented by the general formula (I) as described in any one of claim items 1 to 7 or its stereoisomer, tautomer, mesoform, racemate, enantiomer, Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

其中， in,

如請求項1至6中任一項所述的通式(I)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽，其中，R¹和R²與他們連接的氮原子和硫原子一起形成5至7員雜環基，該5至7員雜環基視需要進一步被選自鹵素、胺基、硝基、氰基、側氧基、羥基、巰基、羧基、酯基、C₁-C₆烷基、C₁-C₆烷氧基、C₂-C₆烯基、C₂-C₆炔基、C₃-C₆環烷基、5至7員雜環基、C₁-C₆鹵烷基、C₁-C₆烷氧基、C₆-C₁₀芳基、5至10員雜芳基的一個或多個基團取代。 The compound represented by the general formula (I) or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein, R ¹ and R ² form a 5 to 7-membered heterocyclic group together with the nitrogen atom and sulfur atom to which they are attached, and the 5 to 7 member The heterocyclic group is optionally further selected from the group consisting of halogen, amine, nitro, cyano, pendant oxy, hydroxyl, mercapto, carboxyl, ester, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₂ -C ₆ alkenyl _, C ₂ -C 6 alkynyl, C ₃ -C ₆ cycloalkyl, 5 to 7 membered heterocyclyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy , C ₆ -C ₁₀ aryl, 5- to 10-membered heteroaryl are substituted by one or more groups.

如請求項1至9中任一項所述的通式(I)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽， The compound represented by the general formula (I) as described in any one of claim items 1 to 9 or its stereoisomer, tautomer, mesoform, racemate, enantiomer, Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

其中， in,

如請求項1至10中任一項所述的通式(I)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽， The compound represented by the general formula (I) or its stereoisomers, tautomers, mesomers, racemates, enantiomers, Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

其中， in,

R⁵選自氫、鹵素、胺基、氰基、羥基、巰基、C₁-C₆烷基、C₁-C₆烷氧基、乙醯基、C₁-C₆鹵烷基、C₁-C₆鹵烷氧基、-C(O)R^a，較佳氫、鹵素、C₁-C₆烷基、C₁-C₆烷氧基、C₁-C₆鹵烷基、C₁-C₆鹵烷氧基、-C(O)R^a； ^R is selected from hydrogen, halogen, amino, cyano, hydroxyl, mercapto, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, acetyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, -C(O) ^Ra , preferably hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, -C(O)R ^a ;

R^a選自C₁-C₆烷基。 R ^a is selected from C ₁ -C ₆ alkyl groups.

如請求項1至11中任一項所述的通式(I)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽，其中該化合物選自： The compound represented by the general formula (I) as described in any one of claims 1 to 11 or its stereoisomer, tautomer, mesoform, racemate, enantiomer, Diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein the compound is selected from:

一種如請求項1至12中任一項所述的通式(I)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽的製備方法，其包括以下步驟： A compound represented by the general formula (I) as described in any one of claims 1 to 12 or its stereoisomers, tautomers, mesoforms, racemates, enantiomers , a diastereoisomer, or a mixture thereof, or a method for preparing a pharmaceutically acceptable salt thereof, comprising the following steps:

環A、環B、R¹、R²、R³、R⁴、R⁵、p如請求項1至12中任一項所定義。 Ring A, Ring B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and p are as defined in any one of claims 1 to 12.

一種醫藥組成物，其包含如請求項1至12中任一項所述的通式(I)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽和藥學上可接受的載體或賦形劑。 A pharmaceutical composition, which comprises the compound represented by the general formula (I) as described in any one of claims 1 to 12 or its stereoisomers, tautomers, mesoforms, racemates , enantiomers, diastereomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

一種如請求項1至12中任一項所述的通式(I)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽或如請求項14所述的醫藥組成物在製備細胞週期蛋白依賴性激酶(CDK)抑制劑中的用途。 A compound represented by the general formula (I) as described in any one of claims 1 to 12 or its stereoisomers, tautomers, mesoforms, racemates, enantiomers , diastereoisomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in Claim 14 in the preparation of a cyclin-dependent kinase (CDK) inhibitor.

一種如請求項1至12中任一項所述的通式(I)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽或如請求項14所述的醫藥組成物在製備抑制癌細胞增值、抑制癌細胞侵襲或誘導癌細胞凋亡的藥物中的用途。 A compound represented by the general formula (I) as described in any one of claims 1 to 12 or its stereoisomers, tautomers, mesoforms, racemates, enantiomers , diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition as described in Claim 14 in the preparation of drugs for inhibiting cancer cell proliferation, inhibiting cancer cell invasion, or inducing cancer cell apoptosis the use of.

一種如請求項1至12中任一項所述的通式(I)所示的化合物或其立體異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用鹽或如請求項14所述的醫藥組成物在製備用於預防和/或治療與細胞週期蛋白-依賴性激酶活性相關的疾病的藥物中的用途，該疾病例如癌症，特別是與以細胞週期蛋白依賴性激酶CDK2/細胞週期蛋白E1(CCNE1)、CDK6/細胞週期蛋白D1、CDK4/細胞週期蛋白D3的擴增或過表達為特徵的癌症，更特別為乳腺癌如HR+/HER2-轉移性乳腺癌或卵巢癌。 A compound represented by the general formula (I) as described in any one of claims 1 to 12 or its stereoisomers, tautomers, mesoforms, racemates, enantiomers , diastereoisomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in Claim 14 in the preparation of the drug for the prevention and/or treatment of cyclin-dependent kinase activity-related Use in the medicine of diseases, such as cancer, especially in connection with amplification or hyperactivity of cyclin-dependent kinases CDK2/cyclin E1 (CCNE1), CDK6/cyclin D1, CDK4/cyclin D3 Cancers characterized by expression, more particularly breast cancers such as HR+/HER2- metastatic breast or ovarian cancers.

如請求項15至17中任一項所述的用途，其中該藥物可以與另外一種抗癌治療劑或抗癌治療方法同時、分開或相繼施用。 The use according to any one of claims 15 to 17, wherein the drug can be administered simultaneously, separately or sequentially with another anticancer therapeutic agent or anticancer therapeutic method.