TW202346307A - Preparation and application of wee1 kinase inhibitor - Google Patents

Preparation and application of wee1 kinase inhibitor Download PDF

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TW202346307A
TW202346307A TW112108797A TW112108797A TW202346307A TW 202346307 A TW202346307 A TW 202346307A TW 112108797 A TW112108797 A TW 112108797A TW 112108797 A TW112108797 A TW 112108797A TW 202346307 A TW202346307 A TW 202346307A
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compound
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amino
pyrimidine
esi
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梁永宏
許志勇
曾兆森
熊方均
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大陸商藥雅科技（上海）有限公司
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems

Abstract

Disclosed are a preparation and application of a Wee1 kinase inhibitor, particularly relating to a compound as shown in formula (I) or formula (II) and a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the compound and/or the pharmaceutically acceptable salt thereof, and a use of the compound or the pharmaceutically acceptable salt thereof in the application of a medicament for the treatment or prevention of Wee1 kinase-associated diseases, especially tumors, wherein the compound is in a class of heterocyclic compounds. Also disclosed is a preparation method for the pharmaceutical composition of the compound or the pharmaceutically acceptable salt thereof. Substituents in the general formula (I) or formula (II) are the same as those defined in the description.

Description

Wee1激酶抑制劑的製備及其應用Preparation and application of Wee1 kinase inhibitors

本發明屬涉及藥物化學領域，更具體而言，涉及具有Wee1激酶抑制作用的新化合物，及其製備方法和該類化合物在抗腫瘤藥物製備中的用途。The present invention relates to the field of medicinal chemistry, and more specifically, to new compounds with Wee1 kinase inhibitory effects, preparation methods thereof and uses of such compounds in the preparation of anti-tumor drugs.

Wee-1蛋白激酶是細胞週期檢查點中重要的負調控蛋白。細胞週期檢查點包括G1(細胞靜息期)到S期(DNA合成期)轉變的G1期檢查點，G2(細胞***準備期)到M(細胞***期)期轉變的G2期檢查點以及M期metaphase(細胞***期中期)到anaphase(細胞***期後期)轉變的紡錘體檢查點。Wee-1蛋白激酶在G2期檢查點中發揮了重要的作用。細胞進入M期依賴於CDK1激酶活性，Wee-1通過磷酸化CDK1蛋白的Tyr15，抑制CDK1的活性，阻止細胞進入M期(細胞***期)。而Polo kinase激酶磷酸化Wee-1，啟動Wee-1蛋白的降解，促進細胞進入M期。由此可見，Wee-1激酶活性決定了G2檢查點的活性，進而調節細胞G2到M期的轉變[Cell Cycle, 2013, 12(19): 3159-64.]。Wee-1 protein kinase is an important negative regulatory protein in cell cycle checkpoints. Cell cycle checkpoints include the G1 phase checkpoint at the transition from G1 (cell resting phase) to S phase (DNA synthesis phase), the G2 phase checkpoint at the transition from G2 (cell division preparation phase) to M (cell division phase), and the M phase checkpoint. The spindle checkpoint transitions from metaphase (mid phase of cell division) to anaphase (late phase of cell division). Wee-1 protein kinase plays an important role in the G2 phase checkpoint. Cell entry into the M phase depends on CDK1 kinase activity. Wee-1 inhibits the activity of CDK1 by phosphorylating Tyr15 of the CDK1 protein, preventing cells from entering the M phase (cell division phase). Polo kinase phosphorylates Wee-1, initiates the degradation of Wee-1 protein, and promotes cells to enter M phase. It can be seen that Wee-1 kinase activity determines the activity of G2 checkpoint, thereby regulating the transition of cells from G2 to M phase [Cell Cycle, 2013, 12(19): 3159-64.].

當細胞的DNA受到損傷時，G1期、S期和G2期檢查延遲細胞進入***期，為細胞進入***之前修復損傷的DNA爭取了時間，從而保證了基因組的完整性。G1期檢查點的關鍵調控因數P53在很多惡性腫瘤細胞中是突變形式(PNAS, 2007, 104(10): 3753-3758)。P53功能缺陷的腫瘤細胞，在DNA受到損傷時，不能將細胞週期阻滯在G1期，因此更加依賴於G2期檢查點。針對DNA損傷，G2期檢查點通過平行且互相聯繫的兩條路徑抑制CDK1的磷酸化，從而延遲細胞進入***期。根據DNA損傷類型，共濟失調性毛細血管擴張症變異(ATM)蛋白激酶或者共濟失調性毛細血管擴張相關(ATR)蛋白激酶被啟動(Oncotarget, 2016, 7(31): 49902-49916)。When a cell's DNA is damaged, the G1, S and G2 phase checks delay the cell's entry into the division phase, buying time for the cell to repair the damaged DNA before it enters division, thereby ensuring the integrity of the genome. P53, a key regulatory factor of the G1 phase checkpoint, is mutated in many malignant tumor cells (PNAS, 2007, 104(10): 3753-3758). Tumor cells with deficient P53 function cannot arrest the cell cycle in the G1 phase when their DNA is damaged, and therefore are more dependent on the G2 phase checkpoint. In response to DNA damage, the G2 phase checkpoint inhibits the phosphorylation of CDK1 through two parallel and interconnected pathways, thereby delaying cells from entering the division phase. Depending on the type of DNA damage, ataxia telangiectasia variant (ATM) protein kinase or ataxia telangiectasia-related (ATR) protein kinase is activated (Oncotarget, 2016, 7(31): 49902-49916).

因此，抑制G2期檢查點，可以選擇性的殺傷腫瘤細胞。而Wee-1激酶活性在G2期檢查點中的重要作用，提示Wee-1激酶決定了DNA損傷後腫瘤細胞的修復或死亡，抑制Wee-1活性可以促進DNA損傷後未修復的腫瘤細胞進入M期，誘發凋亡[Curr Clin Pharmacol,2010.5(3): 186-91]。Therefore, inhibiting the G2 phase checkpoint can selectively kill tumor cells. The important role of Wee-1 kinase activity in the G2 phase checkpoint suggests that Wee-1 kinase determines the repair or death of tumor cells after DNA damage. Inhibiting Wee-1 activity can promote the entry of unrepaired tumor cells after DNA damage into M stage, inducing apoptosis [Curr Clin Pharmacol, 2010.5(3): 186-91].

WEE1在很多惡性腫瘤中過表達，比如肝癌、乳腺癌、惡性膠質瘤、黑色素瘤、成人和兒童腦瘤。其中一部分腫瘤細胞G1檢查點異常，如果抑制WEE1活性會導致G2期檢查點故障，此時帶有沒有修復的損傷DNA的細胞會持續進行***，最終***致死。(Molecular Cancer Therapeutics, 2013, 12(12): 2675-2684.)無論通過嘧啶衍生物(PD0166285)或者小干擾RNA敲低方式，抑制WEE1的活性都會使卵巢癌、結腸癌、宮頸癌、骨肉瘤、惡性膠質瘤和肺癌細胞對放射和拓撲異構酶抑制產生的DNA損傷更敏感。因此，WEE1抑制劑單藥和聯合用藥都具有廣闊的發展空間(Cancer Biology&Therapy, 2010, 9(7): 523-525)。WEE1 is overexpressed in many malignant tumors, such as liver cancer, breast cancer, malignant glioma, melanoma, and brain tumors in adults and children. Some of the tumor cells have abnormal G1 checkpoints. If WEE1 activity is inhibited, it will lead to G2 checkpoint failure. At this time, cells with unrepaired damaged DNA will continue to divide and eventually divide and die. (Molecular Cancer Therapeutics, 2013, 12(12): 2675-2684.) Whether through pyrimidine derivatives (PD0166285) or small interfering RNA knockdown, inhibiting the activity of WEE1 will cause ovarian cancer, colon cancer, cervical cancer, and osteosarcoma. , malignant glioma and lung cancer cells are more sensitive to DNA damage produced by radiation and topoisomerase inhibition. Therefore, WEE1 inhibitors have broad room for development both as single agents and in combination (Cancer Biology & Therapy, 2010, 9(7): 523-525).

AstraZeneca的Wee1抑制劑AZD1775已進入臨床II期，有超過30項的臨床實驗正在開發，並已顯示出良好的治療效果。目前，相關的Wee1抑制劑專利主要有：WO2007126122，WO2008133866，WO2011034743，WO2013039854，WO2018090939，WO2018133829，WO2019011228，WO2019037678，WO2019085933，WO2019173082，WO2020083404，WO2020192581，WO2020221358，WO2021043152。但是，目前尚無上市的該靶點產品。因此，開發更高效抑制該靶點的抑制劑是具有十分重要意義。AstraZeneca's Wee1 inhibitor AZD1775 has entered clinical phase II, with more than 30 clinical trials under development and has shown good therapeutic effects. At present, the relevant Wee1 inhibitor patents mainly include: WO2007126122, WO2008133866, WO2011034743, WO2013039854, WO2018090939, WO2018133829, WO2019011228, WO2019037678, WO2019085933, WO201 9173082, WO2020083404, WO2020192581, WO2020221358, WO2021043152. However, there are currently no products targeting this target on the market. Therefore, it is of great significance to develop inhibitors that inhibit this target more efficiently.

一種具有通式(I)所示的化合物、其立體異構體、可藥用的鹽、多晶型物或異構體，其中通式(I)所示的化合物結構如下： (I) 其中， 每個L 1在每次出現時獨立地選自鍵、O、NH、CH 2、CO或S； 每個L 2在每次出現時獨立地選自鍵、O、NH、CH 2、CO或S； 每個X 1、X 2在每次出現時獨立地選自N或CR 9； 當a為單鍵時，X 3選NR 1或者NH； 當a為雙鍵時，X 3選N； 每個環B在每次出現時獨立地選自3-8元雜環，所述3-8元雜環在每次出現時獨立地包含1、2、3或4個選自N、O、或S的雜原子；每個B在每次出現時獨立地可選地被1、2、3、4、5或6個R 11取代或不取代； 每個Ar 1在每次出現時獨立地選自苯基、萘基、5元雜芳基、6元雜芳基、7元雜芳基、8元雜芳基、9元雜芳基或10元雜芳基，每個雜芳基在每次出現時獨立地包含1、2、3或4個選自N、O、或S的雜原子；每個Ar 1在每次出現時獨立地可選地被1、2、3、4、5或6個R 12取代或不取代； 每個Ar 2在每次出現時獨立地選自苯基、萘基、5元雜芳基、6元雜芳基、7元雜芳基、8元雜芳基、9元雜芳基或10元雜芳基，每個雜芳基在每次出現時獨立地包含1、2、3或4個選自N、O、或S的雜原子；每個Ar 2在每次出現時獨立地可選地被1、2、3、4、5或6個R 13取代或不取代； 每個R 10在每次出現時獨立地選自氘、-C 1-6烷基、-C 1-6亞烷基-(鹵素) 1-3、C 1-6雜烷基、-C 1-6亞烷基-(OR 6) 1-3、-C 1-6亞烷基-NR 6R 7、-C(=O)R 6、-C(=O)OR 6、-OC(=O)R 6、-C(=O)NR 6R 7或-C 3-6碳環基；每個R 9獨立地可選地被1、2、3、4、5或6個選自氘、鹵素、-C 1-6烷基、-C 1-6烷氧基、氧代、-OR 6、-NR 6R 7、-CN、-C(=O)R 6、-C(=O)OR 6、-OC(=O)R 6、-C(=O)NR 6R 7、-NR 6C(=O)R 7或-S(O) 2NR 6R 7的取代基取代或不取代； 每個R 9、R 11、R 12、R 13在每次出現時獨立地選自氘、鹵素、氧代、-C 1-6烷基、-C 1-6亞烷基-(鹵素) 1-3、C 1-6雜烷基、-CN、-OR 6、-C 1-6亞烷基-(OR 6) 1-3、-O-C 1-6亞烷基-(鹵素) 1-3、-SR 6、-S-C 1-6亞烷基-(鹵素) 1-3、-NR 6R 7、-C 1-6亞烷基-NR 6R 7、-C(=O)R 6、-C(=O)OR 6、-OC(=O)R 6、-C(=O)NR 6R 7、-NR 6C(=O)R 7、-S(O) 2NR 6R 7或-C 3-6碳環基；每個R 9、R 11、R 12、R 13獨立地可選地被1、2、3、4、5或6個選自氘、鹵素、-C 1-6烷基、-C 1-6烷氧基、氧代、-OR 6、-NR 6R 7、-CN、-C(=O)R 6、-C(=O)OR 6、-OC(=O)R 6、-C(=O)NR 6R 7、-NR 6C(=O)R 7或-S(O) 2NR 6R 7的取代基取代或不取代； 每個R 1在每次出現時獨立地選自 、 、 或者 、-C 1-6烷基、-C 2-6烯基、-C 2-炔基、-C 1-6亞烷基-(鹵素) 1-3、C 1-6雜烷基、-CN、-OR 6、-C 1-6亞烷基-(OR 6) 1-3、-O-C 1-6亞烷基-(鹵素) 1-3、-SR 6、-S-C 1-6亞烷基-(鹵素) 1-3、-NR 6R 7、-C 1-6亞烷基-NR 6R 7、-C(=O)R 6、-C(=O)OR 6、-OC(=O)R 6、-C(=O)NR 6R 7、-NR 6C(=O)R 7、-S(O) 2NR 6R 7、-C 3-6碳環基、3-8元雜環；3-8元雜環在每次出現時獨立地包含1、2、3或4個選自N、O、或S的雜原子；每個R 1獨立地可選地被1、2、3、4、5或6個選自氘、鹵素、-C 1-6烷基、-C 1-6烷氧基、氧代、-OR 6、-NR 6R 7、-CN、-C(=O)R 6、-C(=O)OR 6、-OC(=O)R 6、-C(=O)NR 6R 7、-NR 6C(=O)R 7或-S(O) 2NR 6R 7的取代基取代或不取代； 其中： 每個L 3在每次出現時獨立地選自鍵、O、NH、C 1-6烷基、CO、OC 1-6烷基、NHC 1-6烷基或S； 每個環A是C 3-10碳環，所述的 和 可以連接在所述環A的相同的碳原子上或不同的原子上； 每個R 2是-OR 6、-NR 6R 7、-SR 6、-S(=O)R 6、-S(=O) 2R 6、5-10元雜芳基或3-10元雜環基，每個雜環基和雜芳基在每次出現時獨立地包含1、2、3或4個選自N、O、S、S=O或S(=O) 2的雜原子，每個R3在每次出現時獨立地可選地被1、2、3、4、5或6個R 19取代或不取代； 每個R 3和R 4在每次出現時獨立地選自氘、氫、鹵素、-C 1-6烷基、、-C 2-6烯基、-C 2-6炔基、氧代、-OR 6、-NR 6R 7、-CN、-C(=O)R 6、-C(=O)OR 6、-OC(=O)R 6、-C(=O)NR 6R 7、-NR 6C(=O)R 7或-S(O) 2NR 6R 7或-C 3-10碳環基、每個雜環基和雜芳基在每次出現時獨立地包含1、2、3或4個選自N、0、S、S=0或S(=O) 2的雜原子；每個R 3和R 4在每次出現時獨立地可選地被1、2、3、4、5或6個選自氘、鹵素、氧代、-C 1-6烷基、-C 1-6烷氧基、氧代、-OR 6、-NR 6R 7、-CN、-C(=O)R 6、-C(=O)OR 6、-OC(=O)R 6、-C(=O)NR 6R 7、-NR 6C(=O)R 7或-S(O) 2NR 6R 7的取代基取代或不取代； 每個R 5在每次出現時獨立地選自氘、鹵素、氧代、-C 1-6烷基、-C 1-6亞烷基-(鹵素) 1-3、C 1-6雜烷基、-CN、-OR 6、-C 1-6亞烷基-(OR 6) 1-3、-O-C 1-6亞烷基-(鹵素) 1-3、-SR 6、-S-C 1-6亞烷基-(鹵素) 1-3、-NR 6R 7、-C 1-6亞烷基-NR 6R 7、-C(=O)R 6、-C(=O)OR 6、-OC(=O)R 6、-C(=O)NR 6R 7、-NR 6C(=O)R 7、-S(O) 2NR 6R 7或-C 3-6碳環基，每個雜環基和雜芳基在每次出現時獨立地包含1、2、3或4個選自N、O、S、S=O或S(=O) 2的雜原子；每個R 3和R 4在每次出現時獨立地可選地被1、2、3、4、5或6個選自氘、鹵素、氧代、-C 1-6烷基、-C 1-6烷氧基、氧代、-OR 6、-NR 6R 7、-CN、-C(=O)R 6、-C(=O)OR 6、-OC(=O)R 6、-C(=O)NR 6R 7、-NR 6C(=O)R 7或-S(O) 2NR 6R 7的取代基取代或不取代； 每個Ar 3在每次出現時獨立地選自苯基、萘基、5元雜芳基、6元雜芳基、7元雜芳基、8元雜芳基、9元雜芳基或10元雜芳基，每個雜芳基在每次出現時獨立地包含1、2、3或4個選自N、O、或S的雜原子；每個Ar 3在每次出現時獨立地可選地被1、2、3、4、5或6個R 13取代或不取代； 每個R 13在每次出現時獨立地選自氘、鹵素、氧代、-C 1-6烷基、-C 1-6亞烷基-(鹵素) 1-3、C 1-6雜烷基、-CN、-OR 6、-C 1-6亞烷基-(OR 6) 1-3、-O-C 1-6亞烷基-(鹵素) 1-3、-SR 6、-S-C 1-6亞烷基-(鹵素) 1-3、-NR 6R 7、-C1-6亞烷基-NR 6R 7、-C(=O)R 6、-C(=O)OR 6、-OC(=O)R 6、-C(=O)NR 6R 7、-NR 6C(=O)R 7、-S(O) 2NR 6R 7或-C 3-6碳環基；每個R 12獨立地可選地被1、2、3、4、5或6個選自氘、鹵素、-C 1-6烷基、-C 1-6烷氧基、氧代、-OR 6、-NR 6R 7、-CN、-C(=O)R 6、-C(=O)OR 6、-OC(=O)R 6、-C(=O)NR 6R 7、-NR 6C(=O)R 7或-S(O) 2NR 6R 7的取代基取代或不取代； 每個R 6和R 7在每次出現時獨立地選自氫或-C1-6烷基，每個R 6和R 7獨立地可選地被1、2、3、4、5或6個R 8取代或不取代；或R 7和R 7與它們共同連接的N原子一起形成3-10元雜環，所述的3-10元雜環可進一步包含1、2、3或4個選自N、O、S、S(=O)或S(=O)2的雜原子，且所述的3-10元雜環獨立地可選地被1、2、3、4、5或6個R 8取代或不取代； 每個R 8在每次出現時獨立地選自氘、鹵素、氧代、-C 1-6烷基、-C 1-6亞烷基-(鹵素) 1-3、C 1-6雜烷基、-CN、-O-C 1-6亞烷基-(鹵素) 1-3、-SC 1 -6烷基、-S-C 1-6亞烷基-(鹵素) 1-3、-NC 1-6C 1-6、-C 1-6亞烷基-NC 1-6烷基C 1-6烷基、-C(=O)C 1-6烷基、-C(=O)OC 1-6烷基、-OC(=O)C 1-6烷基、-C(=O)NC 1-6烷基C 1-6烷基、-NC 1-6烷基C(=O)C 1-6烷基、-S(O) 2NC 1-6烷基C 1-6烷基或-C 3-6碳環基； n選自0、1、2、3、4、5或6； s選自0、1、2、3、4、5或6； p選自0、1、2、3、4、5或6； q選自0、1、2、3、4、5或6。 A compound represented by general formula (I), its stereoisomer, pharmaceutically acceptable salt, polymorph or isomer, wherein the structure of the compound represented by general formula (I) is as follows: (I) wherein each L 1 is independently selected at each occurrence from bond, O, NH, CH 2 , CO, or S; each L 2 is independently selected at each occurrence from bond, O, NH, CH 2 , CO or S; Each X 1 , Select N for A heteroatom from N, O, or S; each B at each occurrence is independently optionally substituted or unsubstituted by 1, 2, 3, 4, 5, or 6 R 11 ; each Ar 1 at each occurrence Each occurrence is independently selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl or 10-membered heteroaryl. Each heteroaryl group independently contains 1, 2, 3 or 4 heteroatoms selected from N, O, or S at each occurrence; each Ar 1 at each occurrence is optionally optionally replaced by 1, 2 , 3, 4, 5 or 6 R 12 substituted or unsubstituted; Each Ar 2 is independently selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl at each occurrence Aryl, 8-membered heteroaryl, 9-membered heteroaryl or 10-membered heteroaryl, each heteroaryl group independently contains 1, 2, 3 or 4 selected from N, O, or S at each occurrence of heteroatoms; each Ar 2 is independently optionally substituted at each occurrence with 1, 2, 3, 4, 5 or 6 R 13 or not; each R 10 is independently optionally substituted at each occurrence From deuterium, -C 1-6 alkyl, -C 1-6 alkylene-(halogen) 1-3 , C 1-6 heteroalkyl, -C 1-6 alkylene-(OR 6 ) 1- 3. -C 1-6 alkylene-NR 6 R 7 , -C(=O)R 6 , -C(=O)OR 6 , -OC(=O)R 6 , -C(=O)NR 6 R 7 or -C 3-6 carbocyclyl; each R 9 is independently optionally selected from 1, 2, 3, 4, 5 or 6 deuterium, halogen, -C 1-6 alkyl, - C 1-6 alkoxy, oxo, -OR 6 , -NR 6 R 7 , -CN, -C(=O)R 6 , -C(=O)OR 6 , -OC(=O)R 6 , -C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 or -S(O) 2 NR 6 R 7 substituents are substituted or unsubstituted; each R 9 , R 11 , R 12. R 13 is independently selected from deuterium, halogen, oxo, -C 1-6 alkyl, -C 1-6 alkylene-(halogen) 1-3 , C 1-6 heteroalkyl at each occurrence. Base, -CN, -OR 6 , -C 1-6 alkylene -(OR 6 ) 1-3 , -OC 1-6 alkylene -(halogen) 1-3 , -SR 6 , -SC 1- 6alkylene- (halogen) 1-3 , -NR 6 R 7 , -C 1-6alkylene -NR 6 R 7 , -C(=O)R 6 , -C(=O)OR 6 , -OC(=O)R 6 , -C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 , -S(O) 2 NR 6 R 7 or -C 3-6 carbocyclic group ; Each R 9 , R 11 , R 12 , R 13 is independently optionally selected from 1, 2, 3, 4, 5 or 6 deuterium, halogen, -C 1-6 alkyl, -C 1- 6Alkoxy , oxo, -OR 6 , -NR 6 R 7 , -CN, -C(=O)R 6 , -C(=O)OR 6 , -OC(=O)R 6 , -C The substituents of (=O)NR 6 R 7 , -NR 6 C(=O)R 7 or -S(O) 2 NR 6 R 7 may or may not be substituted; each R 1 is independently selected on each occurrence. since , , or , -C 1-6 alkyl, -C 2-6 alkenyl, -C 2- alkynyl, -C 1-6 alkylene-(halogen) 1-3 , C 1-6 heteroalkyl, -CN , -OR 6 , -C 1-6 alkylene-(OR 6 ) 1-3 , -OC 1-6 alkylene-(halogen) 1-3 , -SR 6 , -SC 1-6 alkylene -(halogen) 1-3 , -NR 6 R 7 , -C 1-6 alkylene -NR 6 R 7 , -C(=O)R 6 , -C(=O)OR 6 , -OC(= O)R 6 , -C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 , -S(O) 2 NR 6 R 7 , -C 3-6 carbocyclic group, 3-8 3-8 membered heterocycle; 3-8 membered heterocycle independently contains 1, 2, 3 or 4 heteroatoms selected from N, O, or S at each occurrence; each R 1 is independently optionally replaced by 1, 2, 3, 4, 5 or 6 selected from deuterium, halogen, -C 1-6 alkyl, -C 1-6 alkoxy, oxo, -OR 6 , -NR 6 R 7 , -CN, - C(=O)R 6 , -C(=O)OR 6 , -OC(=O)R 6 , -C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 or -S (O) 2 NR 6 R 7 substituents may or may not be substituted; where: Each L 3 at each occurrence is independently selected from bond, O, NH, C 1-6 alkyl, CO, OC 1-6 Alkyl, NHC 1-6 alkyl or S; each ring A is a C 3-10 carbocyclic ring, the and Can be connected to the same carbon atom or different atoms of the ring A; each R 2 is -OR 6 , -NR 6 R 7 , -SR 6 , -S(=O)R 6 , -S( =O) 2 R 6 , 5-10 membered heteroaryl or 3-10 membered heterocyclyl, each heterocyclyl and heteroaryl independently contain 1, 2, 3 or 4 selected from heteroatoms of N, O, S, S=O or S(=O) 2 , with each R3 independently optionally substituted at each occurrence by 1, 2, 3, 4, 5 or 6 R 19 or Unsubstituted; Each R3 and R4 at each occurrence is independently selected from deuterium, hydrogen, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, Oxo, -OR 6 , -NR 6 R 7 , -CN, -C(=O)R 6 , -C(=O)OR 6 , -OC(=O)R 6 , -C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 or -S(O) 2 NR 6 R 7 or -C 3-10 carbocyclyl, each heterocyclyl and heteroaryl are independent on each occurrence Ground contains 1, 2, 3 or 4 heteroatoms selected from N, 0, S, S = 0 or S(=O); each R and R are independently optionally substituted on each occurrence 1, 2, 3, 4, 5 or 6 selected from deuterium, halogen, oxo, -C 1-6 alkyl, -C 1-6 alkoxy, oxo, -OR 6 , -NR 6 R 7 , -CN, -C(=O)R 6 , -C(=O)OR 6 , -OC(=O)R 6 , -C(=O)NR 6 R 7 , -NR 6 C(=O) The substituents of R 7 or -S(O) 2 NR 6 R 7 may or may not be substituted; each R 5 at each occurrence is independently selected from deuterium, halogen, oxo, -C 1-6 alkyl, - C 1-6 alkylene-(halogen) 1-3 , C 1-6 heteroalkyl, -CN, -OR 6 , -C 1-6 alkylene-(OR 6 ) 1-3 , -OC 1 -6 alkylene-(halogen) 1-3 , -SR 6 , -SC 1-6 alkylene-(halogen) 1-3 , -NR 6 R 7 , -C 1-6 alkylene-NR 6 R 7 , -C(=O)R 6 , -C(=O)OR 6 , -OC(=O)R 6 , -C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 , -S(O) 2 NR 6 R 7 or -C 3-6 carbocyclyl, each heterocyclyl and heteroaryl independently contains 1, 2, 3 or 4 selected from N at each occurrence , O, S, S=O or S(=O) 2 heteroatoms; each R 3 and R 4 is independently optionally selected by 1, 2, 3, 4, 5 or 6 on each occurrence From deuterium, halogen, oxo, -C 1-6 alkyl, -C 1-6 alkoxy, oxo, -OR 6 , -NR 6 R 7 , -CN, -C(=O)R 6 , -C(=O)OR 6 , -OC(=O)R 6 , -C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 or -S(O) 2 NR 6 R 7 The substituents are substituted or unsubstituted; each Ar 3 at each occurrence is independently selected from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl , 9-membered heteroaryl or 10-membered heteroaryl, each heteroaryl independently containing 1, 2, 3 or 4 heteroatoms selected from N, O, or S at each occurrence; each Ar 3 independently optionally substituted or unsubstituted by 1, 2, 3, 4, 5 or 6 R 13 at each occurrence; Each R 13 at each occurrence is independently selected from deuterium, halogen, oxo, -C 1-6 alkyl, -C 1-6 alkylene-(halogen) 1-3 , C 1-6 heteroalkyl, -CN, -OR 6 , -C 1-6 alkylene-(OR 6 ) 1-3 , -OC 1-6 alkylene-(halogen) 1-3 , -SR 6 , -SC 1-6 alkylene-(halogen) 1-3 , -NR 6 R 7 , -C1 -6alkylene-NR 6 R 7 , -C(=O)R 6 , -C(=O)OR 6 , -OC(=O)R 6 , -C(=O)NR 6 R 7 , - NR 6 C(=O)R 7 , -S(O) 2 NR 6 R 7 or -C 3-6 carbocyclyl; each R 12 is independently optionally replaced by 1, 2, 3, 4, 5 or 6 are selected from deuterium, halogen, -C 1-6 alkyl, -C 1-6 alkoxy, oxo, -OR 6 , -NR 6 R 7 , -CN, -C(=O)R 6 , -C(=O)OR 6 , -OC(=O)R 6 , -C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 or -S(O) 2 NR 6 R 7 The substituents are substituted or unsubstituted; Each R 6 and R 7 are independently selected from hydrogen or -C1-6 alkyl at each occurrence, and each R 6 and R 7 are independently optionally substituted by 1, 2, 3, 4, 5 or 6 R 8 are substituted or unsubstituted; or R 7 and R 7 together with the N atoms to which they are connected form a 3-10 membered heterocycle, and the 3-10 membered heterocycle may further include 1 , 2, 3 or 4 heteroatoms selected from N, O, S, S (=O) or S (=O)2, and the 3-10 membered heterocyclic ring is independently optionally replaced by 1, 2 , 3, 4, 5 or 6 R 8 substituted or unsubstituted; Each R 8 is independently selected from deuterium, halogen, oxo, -C 1-6 alkyl, -C 1-6 substituent at each occurrence Alkyl-(halogen) 1-3 , C 1-6 heteroalkyl, -CN, -OC 1-6 Alkylene-(halogen) 1-3 , -SC 1 -6 alkyl, -SC 1-6 Alkylene-(halogen) 1-3 , -NC 1-6 C 1-6 , -C 1-6 alkylene-NC 1-6 alkyl C 1-6 alkyl, -C(=O)C 1-6 alkyl, -C(=O)OC 1-6 alkyl, -OC(=O)C 1-6 alkyl, -C(=O)NC 1-6 alkylC 1-6 alkyl , -NC 1-6 alkyl C(=O)C 1-6 alkyl, -S(O) 2 NC 1-6 alkyl C 1-6 alkyl or -C 3-6 carbocyclic group; select n from 0, 1, 2, 3, 4, 5 or 6; s is selected from 0, 1, 2, 3, 4, 5 or 6; p is selected from 0, 1, 2, 3, 4, 5 or 6; q Choose from 0, 1, 2, 3, 4, 5 or 6.

在一些實施方式中，每個R 1選自如下結構： In some embodiments, each R is selected from the following structures:

在一些實施方式中，式(I)所述的化合物或者其異構體、溶劑合物或其前體，或它們的藥學上可接受的鹽選自以下化合物、其異構體、溶劑合物或其前體，或它們的藥學上可接受的鹽： 。 In some embodiments, the compound described in formula (I) or its isomer, solvate or precursor thereof, or their pharmaceutically acceptable salt is selected from the following compounds, its isomers, solvates or their precursors, or their pharmaceutically acceptable salts: .

一種具有通式(II)所示的化合物、其立體異構體、可藥用的鹽、多晶型物或異構體，其中通式(II)所示的化合物結構如下： (II) 其中， 每個L 1在每次出現時獨立地選自鍵、O、NH、CH 2、CO或S； 每個L 2在每次出現時獨立地選自鍵、O、NH、CH 2、CO或S； 每個X 1、X 2在每次出現時獨立地選自N或C； 每個R 1在每次出現時獨立地選自氘、-C 1-6烷基、-C 1-6烯基、-C 1-6炔基、苯基、6元雜芳基、-C 1-6亞烷基-(鹵素) 1-3、-C 1-6亞烯基-(鹵素) 1-3、-C 1-6亞炔基-(鹵素) 1-3、C 1-6雜烷基、-C 1-6亞烷基-NR 6R 7、-C(=O)R 6、-C(=O)OR 6、-OC(=O)R 6、-C(=O)NR 6R 7、-NR 6C(=O)R 7、-S(O) 2NR 6R 7或-C 3-6碳環基；每個R 1獨立地可選地被1、2、3、4、5或6個選自氘、鹵素、-C 1-6烷基、-C 1-6烷氧基、氧代、-OR 6、-NR 6R 7、-CN、-C(=O)R 6、-C(=O)OR 6、-OC(=O)R 6、-C(=O)NR 6R 7、-NR 6C(=O)R 7或-S(O) 2NR 6R 7的取代基取代或不取代； 每個R 2在每次出現時獨立地選自苯基、萘基、6元雜芳基、9元雜芳基或10元雜芳基每個雜芳基在每次出現時獨立地包含1、2、3或4個選自N、O、或S的雜原子；每個Ar 2在每次出現時獨立地可選地被1、2、3、4、5或6個R 8取代或不取代； 每個環B在每次出現時獨立地選自3-8元雜環，所述3-8元雜環在每次出現時獨立地包含1、2、3或4個選自N、O、或S的雜原子；每個B在每次出現時獨立地可選地被1、2、3、4、5或6個R 9取代或不取代； 每個Ar 2在每次出現時獨立地選自苯基、萘基、5元雜芳基、6元雜芳基、7元雜芳基、8元雜芳基、9元雜芳基或10元雜芳基，每個雜芳基在每次出現時獨立地包含1、2、3或4個選自N、O、或S的雜原子；每個Ar 2在每次出現時獨立地可選地被1、2、3、4、5或6個R 10取代或不取代； 每個R 8、R 9、R 10在每次出現時獨立地選自氘、鹵素、氧代、-C 1-6烷基、-C 1-6亞烷基-(鹵素) 1-3、C 1-6雜烷基、-CN、-OR 6、-C 1-6亞烷基-(OR 6) 1-3、-O-C 1-6亞烷基-(鹵素) 1-3、-SR 6、-S-C 1-6亞烷基-(鹵素) 1-3、-NR 6R 7、-C 1-6亞烷基-NR 6R 7、-C(=O)R 6、-C(=O)OR 6、-OC(=O)R 6、-C(=O)NR 6R 7、-NR 6C(=O)R 7、-S(O) 2NR 6R 7或-C 3-6碳環基； 每個R 6和R 7在每次出現時獨立地選自氫或-C 1-6烷基、-C 1-6亞烷基-(鹵素) 1-3、C 1-6雜烷基、-CN。 A compound represented by general formula (II), its stereoisomer, pharmaceutically acceptable salt, polymorph or isomer, wherein the structure of the compound represented by general formula (II) is as follows: (II) wherein each L 1 is independently selected at each occurrence from bond, O, NH, CH 2 , CO, or S; each L 2 is independently selected at each occurrence from bond, O, NH, CH 2 , CO or S; Each X 1 , X 2 is independently selected from N or C at each occurrence; each R 1 is independently selected from deuterium, -C 1-6 alkyl, -C 1-6 alkenyl, -C 1-6 alkynyl, phenyl, 6-membered heteroaryl, -C 1-6 alkylene-(halogen) 1-3 , -C 1-6 alkenylene- (Halogen) 1-3 , -C 1-6 alkynylene-(halogen) 1-3 , C 1-6 heteroalkyl, -C 1-6 alkylene-NR 6 R 7 , -C(=O )R 6 , -C(=O)OR 6 , -OC(=O)R 6 , -C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 , -S(O) 2 NR 6 R 7 or -C 3-6 carbocyclyl; each R 1 is independently optionally selected from 1, 2, 3, 4, 5 or 6 deuterium, halogen, -C 1-6 alkyl, -C 1-6 alkoxy, oxo, -OR 6 , -NR 6 R 7 , -CN, -C(=O)R 6 , -C(=O)OR 6 , -OC(=O)R 6 , -C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 or -S(O) 2 NR 6 R 7 substituents are substituted or unsubstituted; each R 2 appears in each occurrence is independently selected from phenyl, naphthyl, 6-membered heteroaryl, 9-membered heteroaryl or 10-membered heteroaryl. Each heteroaryl group independently contains 1, 2, 3 or 4 choices at each occurrence. A heteroatom from N, O, or S; each Ar on each occurrence is independently optionally substituted or unsubstituted by 1, 2, 3, 4, 5, or 6 R; each ring B in Each occurrence is independently selected from a 3-8 membered heterocycle, which at each occurrence independently contains 1, 2, 3 or 4 heteroatoms selected from N, O, or S ; Each B at each occurrence is independently optionally substituted or unsubstituted by 1, 2, 3, 4, 5 or 6 R 9 ; Each Ar 2 at each occurrence is independently selected from phenyl, Naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl or 10-membered heteroaryl, each heteroaryl group is independent on each occurrence contains 1, 2, 3, or 4 heteroatoms selected from N, O, or S; each Ar 2 is independently optionally replaced by 1, 2, 3, 4, 5, or 6 R at each occurrence 10 is substituted or unsubstituted; each R 8 , R 9 , R 10 is independently selected from deuterium, halogen, oxo, -C 1-6 alkyl, -C 1-6 alkylene-( Halogen) 1-3 , C 1-6 heteroalkyl, -CN, -OR 6 , -C 1-6 alkylene-(OR 6 ) 1-3 , -OC 1-6 alkylene-(halogen) 1-3 , -SR 6 , -SC 1-6 alkylene-(halogen) 1-3 , -NR 6 R 7 , -C 1-6 alkylene-NR 6 R 7 , -C(=O) R 6 , -C(=O)OR 6 , -OC(=O)R 6 , -C(=O)NR 6 R 7 , -NR 6 C(=O)R 7 , -S(O) 2 NR 6 R 7 or -C 3-6 carbocyclyl; each R 6 and R 7 at each occurrence are independently selected from hydrogen or -C 1-6 alkyl, -C 1-6 alkylene-(halogen ) 1-3 , C 1-6 heteroalkyl, -CN.

在一些實施方式中，式(I)所述的化合物或者其異構體、溶劑合物或其前體，或它們的藥學上可接受的鹽選自以下化合物、其異構體、溶劑合物或其前體，或它們的藥學上可接受的鹽： 。 In some embodiments, the compound described in formula (I) or its isomer, solvate or precursor thereof, or their pharmaceutically acceptable salt is selected from the following compounds, its isomers, solvates or their precursors, or their pharmaceutically acceptable salts: .

本發明的另一個目的是一種藥物組合物，其含有藥理上可接受的賦形劑或載體，以及本發明的式(1A)或式(1B)所示的化合物、其異構體或其藥學上可接受的鹽作為活性成分。Another object of the present invention is a pharmaceutical composition, which contains pharmaceutically acceptable excipients or carriers, as well as the compound represented by formula (1A) or formula (1B) of the present invention, its isomer or its pharmaceutical composition. Acceptable salts as active ingredients.

本發明的再一個目的提供了本發明的上述化合物、其異構體或其藥學上可接受鹽用於製備治療由Wee1介導的相關疾病的藥物中的應用。Another object of the present invention provides the use of the above-mentioned compounds of the present invention, isomers thereof or pharmaceutically acceptable salts thereof for preparing drugs for treating related diseases mediated by Wee1.

某些化學術語certain chemical terms

除非有相反陳述，否則下列用在說明書和申請專利範圍中的術語。Unless stated to the contrary, the following terms are used in the specification and claims.

具有下述含義在本文中使用的表示方式“C x-y”表示碳原子數的範圍、其中x和y均為整數，例如C 3-8環烷基表示具有3-8個碳原子的環烷基，即具有3、4、5、6、7或8個碳原子的環烷基。還應理解，“C 3-8”還包含其中的任意亞範圍、例如C 3-7、C 3-6、C 4-7、C 4-6、C 5-6等。 The expression " C , that is, a cycloalkyl group with 3, 4, 5, 6, 7 or 8 carbon atoms. It should also be understood that "C 3-8 " also includes any subrange therein, such as C 3-7 , C 3-6 , C 4-7 , C 4-6 , C 5-6 , etc.

“烷基”指含有1至20個碳原子，例如1至18個碳原子、1至12個碳原子、1至8個碳原子、1至6個碳原子或1至4個碳原子的直鏈或支鏈的烴基基團。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、叔丁基、仲丁基、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、1,3-二甲基丁基和2-乙基丁基。所述烷基可以是取代的或未取代的。"Alkyl" refers to a straight group containing 1 to 20 carbon atoms, such as 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Chain or branched hydrocarbyl groups. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl -2-Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2dimethylbutyl, 2,2-dimethylbutyl, 1 ,3-dimethylbutyl and 2-ethylbutyl. The alkyl group may be substituted or unsubstituted.

“烯基”指含有至少一個碳碳雙鍵和通常2至20個碳原子例如2至8個碳原子、2至6個碳原子或2至4個碳原子的直鏈或支鏈的烴基基團。烯基的非限制性實例包括乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、2-甲基-2-丙烯基、1，4-戊二烯基和1，4-丁二烯基。所述烯基可以是取代的或未取代的。"Alkenyl" refers to a straight or branched chain hydrocarbyl group containing at least one carbon-carbon double bond and usually 2 to 20 carbon atoms, such as 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. group. Non-limiting examples of alkenyl groups include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1 , 4-pentadienyl and 1,4-butadienyl. The alkenyl group may be substituted or unsubstituted.

“炔基”指含有至少一個碳碳三鍵和通常2至20個碳原子，例如2至8個碳原子、2至6個碳原子或2至4個碳原子的直鏈或支鏈的烴基基團。炔基的非限制性實例包括乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基和3-丁炔基。所述炔基可以是取代的或未取代的。"Alkynyl" refers to a straight or branched hydrocarbon group containing at least one carbon-carbon triple bond and usually 2 to 20 carbon atoms, such as 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. group. Non-limiting examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl and 3-butynyl. The alkynyl group may be substituted or unsubstituted.

“環烷基”指含有3至14個碳環原子的飽和環形烴基取代基。環烷基可以是單碳環，通常含有3至7個碳環原子。單環環烷基的非限制性實例包括環丙基、環丁基、環戊基、環己基和環庚基。環烷基可選擇地可以是稠合到一起的雙或三環、如十氫萘基、所述環烷基可以是取代的或未取代的。"Cycloalkyl" refers to a saturated cyclic hydrocarbyl substituent containing 3 to 14 carbon ring atoms. Cycloalkyl groups can be single carbocyclic rings, usually containing 3 to 7 carbon ring atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyl groups may optionally be bi- or tricyclic rings fused together, such as decalinyl, which may be substituted or unsubstituted.

“雜環基”、“雜環烷基”、“雜環”是指穩定的3-18元單價非芳香環，包括2-12個碳原子，1-6個選自氮、氧和硫的雜原子。除非另作說明，雜環基基團可以是單環、雙環、三環或四環系統，其可能包含稠環、螺環或橋環系統，雜環基上的氮、碳或硫可選擇性的被氧化，氮原子可選擇性的被季銨化，雜環基可以部分或完全飽和。雜環基可以通過環上的碳原子或雜原子與分子的其餘部分通過一個單鍵連接。包含稠環的雜環基中可以包含一個或多個芳環或雜芳環，只要與分子的其餘部分連接的是非芳香環上的原子。為了本申請，雜環基優選的是一個穩定的4-11元單價非芳香單環或二環，其包含1-3個選自氮、氧和硫的雜原子，更優選的是一個穩定的4-8元單價非芳香單環，其包含1-3個選自氮、氧和硫的雜原子。雜環基的非限制性實例包括氮雜環庚烷基、氮雜環丁基、十氫異喹啉基、二氫呋喃基、二氫吲哚基、二氧戊烷基、1,1-二氧-硫代嗎啉基、咪唑烷基、咪唑啉基、異噻唑烷基、異惡唑烷基、嗎啉基、八氫吲哚基、八氫異吲哚基、惡嗪基、呱嗪基、呱啶基、4-呱啶酮基、吡喃基、吡唑烷基、吡咯烷基、喹嗪基、奎寧環基、四氫呋喃基、四氫吡喃基等。"Heterocyclyl", "heterocycloalkyl" and "heterocycle" refer to a stable 3-18 membered monovalent non-aromatic ring, including 2-12 carbon atoms, 1-6 selected from nitrogen, oxygen and sulfur. heteroatoms. Unless otherwise stated, the heterocyclyl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may contain fused, spiro or bridged ring systems, and the nitrogen, carbon or sulfur on the heterocyclyl group may be optional. is oxidized, the nitrogen atom can be selectively quaternized, and the heterocyclyl group can be partially or fully saturated. A heterocyclyl group can be connected to the rest of the molecule by a single bond through a carbon atom or a heteroatom in the ring. Heterocyclyl groups containing fused rings may contain one or more aromatic or heteroaromatic rings as long as the atoms attached to the remainder of the molecule are non-aromatic rings. For the purposes of this application, the heterocyclyl group is preferably a stable 4-11 membered monovalent non-aromatic monocyclic or bicyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4-8 membered monovalent non-aromatic monocyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclyl include azepanyl, azetidinyl, decahydroisoquinolyl, dihydrofuryl, indolyl, dioxolanyl, 1,1- Dioxy-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, phosphonium Azinyl, pyridinyl, 4-pyridinonyl, pyranyl, pyrazolidinyl, pyrrolidinyl, quinuclidinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, etc.

“螺雜環基”指5至20元，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。這些可以含有一個或多個雙鍵，但沒有一個環具有完全共扼的電子系統優選為6至14元，更優選為7至10元。根據環與環之間共用螺原子的數目將螺環烷基分為單螺雜環基、雙螺雜環基或多螺雜環基，優選為單螺環烷基和雙螺環烷基。更優選為4元/4元、4元/5元、4元/6元、5元/5元或5元/6元單螺環基。螺雜環基的非限制性實施例包含： "Spiroheterocyclyl" refers to a polycyclic heterocyclic group with 5 to 20 members, sharing one atom (called a spiro atom) between the single rings, in which one or more ring atoms are selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated electron system. Preferably, the electron system is from 6 to 14 members, more preferably from 7 to 10 members. According to the number of shared spiro atoms between the rings, the spirocycloalkyl group is divided into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a polyspiroheterocyclyl group, and is preferably a single spirocycloalkyl group and a double spirocycloalkyl group. 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 monospirocyclic group. Non-limiting examples of spiroheterocyclyl include:

“稠雜環基”指5至20元，系統中的每個環與體系中的其他環共用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。優選為6至14元，更優選為7至10元。根據組成環的數目可以分為雙環、三環、四環或多環稠雜環烷基，優選為雙環或三環，更優選為5元/5元或5元/6元雙環稠雜環基。稠雜環基的非限制性實施例包含： "Condensed heterocyclic group" refers to a polycyclic heterocyclic group with 5 to 20 members. Each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more bis bonds, but none of the rings has a fully conjugated π-electron system in which one or more ring atoms are selected from nitrogen, oxygen, or heteroatoms of S(O) m (where m is an integer 0 to 2), and the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocycloalkyl groups. . Non-limiting examples of fused heterocyclyl groups include:

“芳基”或“芳香基”指含有6至14個碳原子的芳香族單環或稠合多環基團，優選為6至10元，例如苯基和萘基，更優選為苯基。所述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。"Aryl" or "aryl" refers to an aromatic monocyclic or fused polycyclic group containing 6 to 14 carbon atoms, preferably 6 to 10 members, such as phenyl and naphthyl, more preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, where the ring attached to the parent structure is the aryl ring.

“雜芳基”或“雜芳香基”是指5-16元環狀系統，其包含1-15個碳原子，優選的1-10個碳原子，1-4個選自氮，氧和硫的雜原子，至少一個芳香環。除非另作說明，雜芳基可以是單環、雙環、三環或四環系統，其可能包含稠環或橋環系統，只要與分子其他部分的連接點為芳環原子，雜芳環上的氮原子、碳原子和硫原子可以透擇性的被氧化，氮原子可選擇性的被季銨化。為了本發明，雜芳基優選的為穩定的4-11元單芳香環，其包含1-3個選自氮、氧和硫的雜原子，更優選的為穩定的5-8元單芳香環，其包含1-3個選自選自氮、氧和硫的雜原子。雜芳基的非限定性實例包括吖啶基、氮雜卓基、苯並咪唑基、苯並吲哚基、苯並二氧芑基、苯並二惡茂基、苯並呋喃酮基、苯並呋喃基、苯並萘並呋喃基、苯並吡喃酮基、苯並吡喃基、苯並吡唑基、苯並噻二唑基、苯並噻唑基、苯並***基、呋喃基、咪唑基、吲唑基、吲哚基、惡唑基、嘌呤基、吡嗪基、吡唑基、噠嗪基、吡啶基、嘧啶基、吡咯基、喹唑啉基、喹啉基、奎寧基、四唑基，噻二唑基、噻唑基、噻吩基、三嗪基，***基等。本申請中，雜芳基優選為5-8元雜芳基，其包含1-3選自選自氮、氧和硫的雜原子，更優選為吡啶基、嘧啶基、噻唑基。所述雜芳基可以是取代的或未取代的。"Heteroaryl" or "heteroaryl" refers to a 5-16 membered ring system containing 1-15 carbon atoms, preferably 1-10 carbon atoms, 1-4 selected from nitrogen, oxygen and sulfur of heteroatoms and at least one aromatic ring. Unless otherwise stated, a heteroaryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may contain fused or bridged ring systems, as long as the point of attachment to the rest of the molecule is an aromatic ring atom, and the heteroaryl ring Nitrogen atoms, carbon atoms and sulfur atoms can be selectively oxidized, and nitrogen atoms can be selectively quaternized. For the purposes of the present invention, the heteroaryl group is preferably a stable 4-11 membered monoaromatic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, and more preferably a stable 5-8 membered monoaromatic ring. , which contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Non-limiting examples of heteroaryl groups include acridinyl, azepinyl, benzimidazolyl, benzindolyl, benzodioxanyl, benzodioxenyl, benzofuranonyl, benzo Furyl, benzonaphthofuryl, benzopyranone, benzopyranyl, benzopyrazolyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, furanyl, Imidazolyl, indazolyl, indolyl, oxazolyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinine base, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, etc. In this application, the heteroaryl group is preferably a 5-8 membered heteroaryl group, which contains 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, and is more preferably a pyridyl, pyrimidinyl or thiazolyl group. The heteroaryl group may be substituted or unsubstituted.

“鹵素”指氟、氯、溴或碘。"Halogen" means fluorine, chlorine, bromine or iodine.

“羥基”指-OH，“氨基”指-NH 2，“醯胺基”指-NHCO-，“氰基”指-CN，“硝基”指-CN，“異氰基”指-NC，“三氟甲基”指-CF 3。 "Hydroxy" refers to -OH, "amino" refers to -NH 2 , "amide group" refers to -NHCO-, "cyano" refers to -CN, "nitro" refers to -CN, "isocyano" refers to -NC, "Trifluoromethyl" refers to -CF3 .

本文單獨或作為其他成分的一部分使用的術語“雜原子”或“雜”是指除碳和氫之外的原子，雜原子獨立地選自氧、氮、硫、磷、矽、硒和錫，但不限於這些原子，在出現兩個或更多雜原子的實施方案中，所述兩個或更多雜原子可彼此相同，或者所述兩個或更多雜原子中的一些或全部此不同。The term "heteroatom" or "hetero" as used herein alone or as part of other ingredients refers to atoms other than carbon and hydrogen independently selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and tin, Without being limited to these atoms, in embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as each other, or some or all of the two or more heteroatoms may be different. .

本文單獨或組合使用的術語“稠”或“稠環”是指兩個或更多個環共用一個或更多個鍵的環狀結構。The term "fused" or "fused ring" as used herein alone or in combination refers to a cyclic structure in which two or more rings share one or more bonds.

本文單獨或組合使用的術語“螺”或“螺環”是指兩個或更多個環共用一個或更多個原子的環狀結構。The term "spiro" or "spirocycle" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more atoms.

“任選”或“任選地”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地場合例如，“任選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 may but need not occur, and the description includes instances where the event or circumstance does or does not occur. For example, "heterocyclyl optionally substituted by alkyl" "Group" means that an alkyl group may but does not have to be present, and this description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group.

“取代的”指基團中的一個或多個原子，較佳為5個、更佳為1~3個原子彼此獨立地被相應數目的取代基取代。不言而喻，取代基處在它們的可能的化學位置本領域技術人員能夠在不付出過多努力的情況下確定(通過實驗或理論)可能或不可能的取代。例如，具有游離的胺基或羥基與具有不飽和(如烯烴)鍵的碳原子結合時可能是不穩定的。所述取代基包括但不限於羥基、胺基、鹵素、氰基、C 1-6烷基、C 1-6烷氧基、C 2-6烯基、C 2-6炔基、C 3-8環烷基等。 "Substituted" means that one or more atoms in the group, preferably 5, more preferably 1 to 3 atoms, are independently substituted by a corresponding number of substituents. It goes without saying that the substituents are in their possible chemical positions. The person skilled in the art is able to determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, having a free amine or hydroxyl group may be unstable when bonded to a carbon atom with an unsaturated (eg, olefinic) bond. The substituents include but are not limited to hydroxyl, amine, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 8 Cycloalkyl etc.

“藥物組合物”指含有一種或多種本文所述的化合物或其可藥用的鹽或前藥以及其他分例如可藥用的載體和賦形劑的組合物。藥物組合物的目的是促對生物體的給藥、利於活性成分的吸收進而發揮生物活性。"Pharmaceutical composition" refers to a composition containing one or more compounds described herein, or a pharmaceutically acceptable salt or prodrug thereof, together with other ingredients such as pharmaceutically acceptable carriers and excipients. The purpose of pharmaceutical compositions is to facilitate administration to living organisms, facilitate the absorption of active ingredients, and thereby exert biological activity.

“異構體”指具有相同分子式但其原子結合的性質或順序或其原子的空間排列不同的化合物稱為“異構體”、其原子空間排列不同的異構體稱為“立體異構體”。立體異構體包括光學異構體、幾何異構體和構象異構體。本發明的化合物可以以光學異構體形式存在。根據手性碳原子周圍取代基的構型，這些光學異構體是“R”或“S”構型。光學異構體包括對映異構體和非對映異構體、製備和分離光學異構體的方法是本領域中已知的。"Isomers" refers to compounds that have the same molecular formula but different properties or order of the combination of atoms or the spatial arrangement of the atoms are called "isomers", and isomers with different spatial arrangements of the atoms are called "stereoisomers" ". Stereoisomers include optical isomers, geometric isomers and conformational isomers. The compounds of the present invention may exist as optical isomers. Depending on the configuration of the substituents surrounding the chiral carbon atom, these optical isomers are in the "R" or "S" configuration. Optical isomers include enantiomers and diastereomers, and methods of preparing and separating optical isomers are known in the art.

本發明的化合物也可以存在幾何異構體。本發明考慮由碳-碳雙鍵、碳-氮雙鍵、環烷基或雜環基團周的取代基的分佈所產生的各種幾何異構體和其混合物。碳-碳雙鍵或碳-氮鍵周圍的取代基指定為Z或E構型、環烷基或雜環周圍的取代基指定為順式或反式構型。The compounds of the present invention may also exist as geometric isomers. The present invention contemplates various geometric isomers and mixtures thereof resulting from the distribution of substituents around carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl or heterocyclic groups. Substituents around a carbon-carbon double bond or a carbon-nitrogen bond are designated as the Z or E configuration, and substituents around a cycloalkyl or heterocycle are designated as the cis or trans configuration.

本發明的化合物還可能顯示互變異構現象，例如酮-烯醇互變異構。The compounds of the present invention may also exhibit tautomerism, such as keto-enol tautomerism.

應該理解，本發明包括任何互變異構或立體異構形式和其混合物、並且不僅限於化合物的命名或化學結式中所使用的任何一個互變異構或立體異構形式。It should be understood that the present invention includes any tautomeric or stereoisomeric form and mixtures thereof and is not limited to any one tautomeric or stereoisomeric form used in the nomenclature or chemical formula of the compound.

“同位素”是在本發明化合物中出現的原子的所有同位素。同位素包括具有相同原子序數但不同質量數的那些原子。適合併入本發明化合物中的同位素的實例是氫、碳、氮、氧、磷、氟和氯，分別例如但不限於 2H、 3H、 13C、 14C、 15N、 18O、 31P、 32P、 35S、 18F和 36Cl。本發明的同位素標記化合物通常可通過本域技術人員已知的傳統技術或通過與所附實施例中描的那些類似的方法使用適當的同位素標記的試劑代替非同位素標記的劑制。這樣的化合物具有各種潛在用途、例如作為測定生物活性中的標樣和試劑。在穩定同位素的情況下，這樣的化合物具有有利地改變生物、藥理學或藥代動力學性質的潛力。 "Isotopes" are all isotopes of atoms present in the compounds of the invention. Isotopes include those atoms that have the same atomic number but different mass numbers. Examples of isotopes suitable for incorporation into the compounds of the present invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 31 respectively. P, 32 P, 35 S, 18 F and 36 Cl. Isotopically labeled compounds of the present invention can generally be formulated by conventional techniques known to those skilled in the art or by methods similar to those described in the accompanying examples using appropriate isotopically labeled reagents in place of non-isotopically labeled formulations. Such compounds have a variety of potential uses, such as as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds have the potential to beneficially modify biological, pharmacological or pharmacokinetic properties.

“前藥”是指本發明的化合物可以以前藥的形式給予。前藥是指在活體內的生理條件下例如通過氧化、還原、水解等(它們各自利用酶或在沒有酶參與下進行)轉化成本發明的生物活性化合物的衍生物。前藥的實例是下述化合物：其中本發明的化合物中的胺基被醯化、烷基化或磷酸化，例如二十烷醯基胺基、丙胺醯胺基、新戊醯氧基甲基胺基、或其中羥基被醯化、烷基化、磷酸化或轉化成硼酸鹽，例如乙醯氧基、棕櫚醯氧基、新戊醯氧基、琥珀醯氧基、富馬醯氧基、丙胺醯氧基、或其中羧基被酯化或醯胺化，或其中巰基與選擇性地向靶和/或向細胞的胞質溶膠遞送藥物的載體分子，例如肽形成二硫橋鍵、這些化合物可以由本發明的化合物根據公知方法製備。"Prodrug" means that the compound of the invention can be administered in the form of a prodrug. Prodrugs refer to derivatives that are converted into bioactive compounds of the present invention under physiological conditions in vivo, such as through oxidation, reduction, hydrolysis, etc. (each of which is performed using enzymes or without the participation of enzymes). Examples of prodrugs are compounds in which the amine group in the compound of the invention is chelated, alkylated or phosphorylated, for example eicosylamide, propylamineamide, neopentyloxymethyl Amino group, or in which the hydroxyl group is chelated, alkylated, phosphorylated or converted to a borate, such as acetyloxy, palmityloxy, pivalyloxy, succinyloxy, fumaryloxy, These compounds are propylamine acyloxy groups, or in which the carboxyl group is esterified or amidated, or in which the sulfhydryl group forms a disulfide bridge with a carrier molecule, such as a peptide, that selectively delivers the drug to the target and/or to the cytosol of the cell. It can be prepared from the compound of the present invention according to known methods.

“可藥用的鹽”或者“藥學上可接受的”是指由可藥用的鹼或酸，包括無機鹼或酸和有機鹼或酸製成的。在本發明的化合物含有一個或多個酸性或鹼性基團的情況下，本發明還包含它們相應的可藥用鹽。因此，含有酸性基團的本發明的化合物可以以鹽形式存在並可根據本發明使用，例如作為鹼金屬鹽、鹼土金屬鹽或作為銨鹽。這樣的鹽的更確切實例包括鈉鹽、鉀鹽、鈣鹽、鎂鹽或與胺或有機胺，例如伯胺、仲胺、叔胺、環胺等，例如氨、異丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、乙醇胺、二環己胺、乙二胺、嘌呤、呱嗪、呱啶、膽鹼和咖啡因等特別優選的有機鹼為異丙胺、二乙胺、乙醇胺、三甲胺、二環己胺、膽鹼和咖啡因的鹽。含有鹼性基團的本發明的化合物可以鹽形式存在並可根據本發明以它們與無機或有機酸的加成的形式使用。合適的酸的實例包括鹽酸、氫溴酸、磷酸、硫酸、磷酸、甲磺酸、對甲苯磺酸、萘二磺酸、草酸、乙酸、酒石酸、乳酸、水楊酸、苯甲酸、甲酸、丙酸、特戊酸、丙二酸、琥珀酸、庚二酸、富馬酸、馬來酸、蘋果酸、胺基磺酸、苯基丙酸、葡糖酸、抗壞血酸、異煙酸、檸檬酸、己二酸和本領域技術人員已知的其他酸。如果本發明的化合物在分子中同時含有酸性和鹼性基團，本發明除所提到的鹽形式外還包括內鹽或內銨鹽。各鹽通過本領域技術人員已知的常規方法獲得，例如通過在溶劑或分散劑中使這些與有機或無機酸或鹼接觸或通過與其它鹽陰離子交換或陽離子交換。"Pharmaceutically acceptable salts" or "pharmaceutically acceptable" refers to those made from pharmaceutically acceptable bases or acids, including inorganic bases or acids and organic bases or acids. Where the compounds of the invention contain one or more acidic or basic groups, the invention also encompasses their corresponding pharmaceutically acceptable salts. Compounds of the invention which contain acidic groups can therefore be present in the form of salts and can be used according to the invention, for example as alkali metal salts, alkaline earth metal salts or as ammonium salts. More specific examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with amines or organic amines, such as primary, secondary, tertiary, cyclic amines, etc., such as ammonia, isopropylamine, trimethylamine, dimethylamine, etc. Particularly preferred organic bases such as ethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purine, prazine, piridine, choline and caffeine are isopropylamine, diamine, etc. Salts of ethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. The compounds of the invention which contain basic groups can exist in the form of salts and can be used according to the invention in the form of their addition to inorganic or organic acids. Examples of suitable acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid Acid, pivalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid , adipic acid and other acids known to those skilled in the art. If the compounds according to the invention contain both acidic and basic groups in the molecule, the invention also includes, in addition to the salt forms mentioned, internal salts or betaine salts. The individual salts are obtained by conventional methods known to those skilled in the art, for example by contacting these with organic or inorganic acids or bases in solvents or dispersants or by anion or cation exchange with other salts.

因此，在本申請中當提及“化合物”、“本發明化合物”或“本發明所化合物”時，包括所有所述化合物形式、例如其前藥、穩定同位素衍生物、可藥用的鹽、異構體、內消旋體、外消旋體、對映異構體、非對映異體及其混合物。Therefore, in this application, when referring to "compound", "compound of the invention" or "compound of the invention", it includes all said compound forms, such as its prodrugs, stable isotope derivatives, pharmaceutically acceptable salts, Isomers, meso, racemates, enantiomers, diastereomers and mixtures thereof.

在本文中、術語“腫瘤”包括良性腫瘤和惡性腫瘤(例如癌症)。As used herein, the term "tumor" includes benign tumors and malignant tumors (eg, cancer).

在本文中，術語“癌症”包括WEE-l蛋白激酶參與其發生的各種惡性腫瘤、包括但不限於非小細胞肺癌、食管癌、黑色素瘤、橫紋肌肉榴、細胞癌、多發性骨髓瘤、乳腺癌卵巢癌、子宮膜癌、宮頸癌、胃癌、結癌、膀胱癌、胰腺癌、肺癌、乳腺癌、***癌和肝癌(例如肝細胞癌)，更具體為肝癌、胃癌和膀胱癌。As used herein, the term "cancer" includes various malignancies in which WEE-1 protein kinase is involved, including but not limited to non-small cell lung cancer, esophageal cancer, melanoma, rhabdomyosarcoma, cell carcinoma, multiple myeloma, breast Cancer ovarian cancer, uterine cancer, cervical cancer, gastric cancer, node cancer, bladder cancer, pancreatic cancer, lung cancer, breast cancer, prostate cancer and liver cancer (eg hepatocellular carcinoma), more specifically liver cancer, stomach cancer and bladder cancer.

本文所使用術語“有效量”、“治療有效量”或“藥學有效量”是指服用後足以在某種程度上緩解所治療的疾病或病症的一個或多個症狀的至少一種藥劑或化合物的量。其結果可以為跡象、症狀或病因的消減和/或緩解或生物系統的任何其他所需變化。例如，用於治療的“有效量”是在臨床上提供顯著的病症緩解效果所需的包含本文公開化合物的組合物的量。可使用諸如劑量遞增試驗的技術測定適合於任意個體病例中的有效量。As used herein, the terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" refer to an amount of at least one agent or compound that, when administered, is sufficient to alleviate, to some extent, one or more symptoms of the disease or condition being treated. quantity. The result may be a reduction and/or alleviation of signs, symptoms or causes or any other desired change in the biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide clinically significant relief of a condition. The effective amount appropriate in any individual case can be determined using techniques such as dose escalation testing.

本發明使用的術語“多晶型物”或“多晶型(現象)”是指本發明的化合物具有多種晶型格形態，本發明的一些化合物可能有一個以上的晶體形式，本發明涵蓋所有的多品型態或其混合物。The term "polymorph" or "polymorph (phenomenon)" used in the present invention means that the compound of the present invention has multiple crystal lattice forms. Some compounds of the present invention may have more than one crystal form. The present invention covers all Multiple forms or mixtures thereof.

本發明化合物的中間體化合物及其多品形物也在本發明的範圍內。Intermediate compounds of the compounds of the present invention and polymorphs thereof are also within the scope of the present invention.

結晶經常產生本發明化合物的溶劑化物，本文所用術語“溶劑化物”是指由一個或多個本發明化合物分子和一個或多個溶劑分子組合成的合體。Crystallization often results in solvates of the compounds of the invention. As used herein, the term "solvate" refers to a combination of one or more molecules of the compound of the invention and one or more solvent molecules.

溶劑可以是水，這種情況下，溶劑化物是水合物。另外還可以是有機溶劑。因此，本發明化合物可作為水合物存在，包括一水合物、二水合物、半水合物、三水合物、四水合物等，以及相應的溶劑化形態。本發明化合物可以是真溶劑化物，但在其他一些情況下，本發明化合物也可能只是偶然保留了水或水跟一些其他溶劑的混合物本發明化合物可在一種溶劑中反應或在一種溶劑中沉澱或結晶。本發明化合物的溶劑化物也包括在本發明的範圍內。The solvent may be water, in which case the solvate is a hydrate. In addition, it can also be an organic solvent. Accordingly, the compounds of the present invention may exist as hydrates, including monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, etc., as well as corresponding solvated forms. The compounds of the present invention may be true solvates, but in other cases the compounds of the present invention may only accidentally retain water or a mixture of water and some other solvent. The compounds of the present invention may react in a solvent or precipitate in a solvent or crystallize. Solvates of the compounds of this invention are also included within the scope of this invention.

本文所用的跟製劑、組合物或成分相關的術語“可接受的”是指對治療主體的總體健康沒有持續的有害影響。The term "acceptable" as used herein in connection with a formulation, composition or ingredient means no sustained deleterious effect on the general health of the subject treated.

本文所用術語“藥學上可接受的”是指不影響本發明化合物的生物活性或性質的物質(如載體或稀釋劑)，並且相對無毒，即該物質可施用於個體而不造成不良的生物反應或以不良方式與組合物中包含的任意組分相互作用。As used herein, the term "pharmaceutically acceptable" refers to substances (such as carriers or diluents) that do not affect the biological activity or properties of the compounds of the invention and are relatively non-toxic, i.e., the substances can be administered to an individual without causing adverse biological reactions. or interact in an undesirable manner with any component contained in the composition.

“藥學上可接受的載體”包括但不限於已經被相關政府行政部門批准的可以被用於人類和馴養動物的佐劑、載體、賦形劑、助劑、脫臭劑、稀釋劑、保鮮劑、染料/著色劑、風味增強劑、表面活性劑和潤濕劑、分散劑、懸浮劑、穩定劑等滲劑、溶劑、或乳化劑。"Pharmaceutically acceptable carriers" include, but are not limited to, adjuvants, carriers, excipients, auxiliaries, deodorants, diluents, and preservatives that have been approved by relevant government administrative departments and can be used for humans and domestic animals. , dyes/colorants, flavor enhancers, surfactants and wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers.

文所用術語“主體”、“患者”、“對象”或“個體”是指患有疾病、紊亂或病症等的個體，包括哺乳動物和非哺乳動物，哺乳動物的實例包括但不限於哺乳動物綱的任何成員：人，非人的靈長類動物(例如黑猩猩和其他猿類和猴)；家畜，例如牛，馬、綿羊，山羊，豬；家養動物，例如兔，狗和貓；實驗室動物，包括齧齒類動物，如大鼠、小鼠和豚鼠等。非人哺乳動物的實例包括但不限於鳥類和魚類等。在本文提供的一個有關方法和組合物的實施方案中，所述哺乳動物為人。As used herein, the terms "subject", "patient", "subject" or "individual" refer to an individual suffering from a disease, disorder or condition, including mammals and non-mammals. Examples of mammals include, but are not limited to, the class Mammalia. Any member of: humans, nonhuman primates (such as chimpanzees and other apes and monkeys); domestic animals, such as cattle, horses, sheep, goats, pigs; domestic animals, such as rabbits, dogs, and cats; laboratory animals , including rodents such as rats, mice and guinea pigs. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.

本文所用術語“治療”是指對哺乳動物特別是人類的相關疾病病症的治療，包括 (i)預防哺乳動物，特別是之前已經暴露在某個疾病或病症下但尚未被診斷患有該疾病或病症的哺乳動物，產生相應的疾病或病症； (ii)抑制疾病或病症，即，控制其發展； (iii)緩解疾病或病症，即，使疾病或病症消退緩； (iv)緩解疾病或病症引起的症狀。 The term "treatment" as used herein refers to the treatment of related diseases and conditions in mammals, especially humans, including (i) Preventing the development of a corresponding disease or condition in mammals, especially mammals that have been previously exposed to a disease or condition but have not yet been diagnosed with the disease or condition; (ii) inhibit a disease or condition, that is, control its progression; (iii) alleviate a disease or condition, that is, cause the disease or condition to subside; (iv) Relieve symptoms caused by a disease or condition.

本文所用術語“疾病”和“病症”可以互相替代，也可以是不同意思，因為某些特定疾病或病症還沒有已知的致病因數(所以發病原因尚不清楚)，所以還不能被認作疾病而只能被看做不想要的狀況或綜合症，所述綜合症或多或少有一些具體症狀已經被臨床研究人員證實。The terms "disease" and "disorder" are used herein interchangeably and may have different meanings. Because some specific diseases or disorders have no known causative agent (so the cause of the disease is not yet known), they cannot yet be recognized as such. Diseases can only be seen as unwanted conditions or syndromes with more or less specific symptoms that have been confirmed by clinical researchers.

本文所用術語“服用”、“施用”、“給藥”等是指能夠將化合物或組合物遞送到進行生物作用的所需位點的方法這些方法。包括但不限於口服途徑、經十二指腸途徑、胃腸外注射(包括靜脈內、皮下、腹膜內、肌內、動脈內注射或輸注)、局部給藥和經直腸給藥。在優選的實施方案中，本文討論的化合物和組合物通過口服施用。As used herein, the terms "administering," "administering," "administering," and the like refer to methods capable of delivering a compound or composition to a desired site where a biological effect occurs. Including but not limited to oral route, transduodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration and rectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

下面具體地描述本發明式(I)或式(II)化合物的製備方法，但這些具體方法不對本發明構成任何限制。The preparation method of the compound of formula (I) or formula (II) of the present invention is described in detail below, but these specific methods do not constitute any limitation on the present invention.

以上說明的式(I)或式(II)化合物可使用標準的合成技術或公知的技術與文中結合的方法來合成。此外，在此提到的溶劑，溫度和其他反應條件可以改變。用於式(I)或式(II)化合物的合成的起始物料可以由合成或從商業來源上獲得。本文所述的化合物和其他具有不同取代基的有關化合物可使用公知的技術和原料來合成，包括發現於March，ADVANCED ORGANIC CHEMISTRY 4th Ed.，(Wiley 1992)；Carey和Sundberg，ADVANCED ORGANIC CHEMISTRY 4th Ed.，Vols.A和B(Plenum 2000，2001)，Green和Wuts，PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3＜rd＞ Ed.，(Wiley 1999)中的方法。化合物製備的一般方法可通過使用適當的試劑和在此提供的分子式中引入不同基團的條件來改變。The compounds of formula (I) or formula (II) described above can be synthesized using standard synthesis techniques or known techniques combined with methods herein. In addition, the solvents, temperatures and other reaction conditions mentioned herein may be varied. Starting materials for the synthesis of compounds of formula (I) or formula (II) can be obtained synthetically or from commercial sources. The compounds described herein and other related compounds having various substituents can be synthesized using well-known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4th Ed. ., Vols. A and B (Plenum 2000, 2001), Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3<rd> Ed., (Wiley 1999). General methods of compound preparation may be modified by the use of appropriate reagents and conditions for the introduction of different groups in the formulas provided herein.

一方面，本文所述的化合物根據工藝中公知的方法。然而方法的條件，例如反應物、溶劑、鹼、所用化合物的量、反應溫度、反應所需時間等不限於下面的解釋。本發明化合物還可以任選將在本說明書中描述的或本領域已知的各種合成方法組合起來而方便的製得，這樣的組合可由本發明所屬領域的技術人員容易的進行。一方面，本發明還提供了一種所述的式(II)或式(II)化合物的製備方法，其採用下列方法製備：In one aspect, the compounds described herein are according to methods well known in the art. However, the conditions of the method, such as reactants, solvents, bases, amounts of compounds used, reaction temperature, time required for reaction, etc. are not limited to the following explanations. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art. Such combinations can be easily performed by those skilled in the art to which the present invention belongs. On the one hand, the present invention also provides a method for preparing the compound of formula (II) or formula (II), which is prepared by the following method:

方法A Method A

方法B Method B

方法C Method C

方法D Method D

具體實施方法Specific implementation methods

本發明還提供製備所述化合物的方法。本發明通式(I)所述化合物的製備，可通過以下示例性方法和實施例完成，但這些方法和實施例不應以任何方式被認為是對本發明範圍的限制。也可地本領域技術人員所知的合成技術合成本發明所述的化合物，或者綜合使用本領域已知方法和本發明所述的方法。每步應所得的產物用本領域已知的分離技術得到，包括但不限於萃取、過濾、蒸餾、結晶、色譜分離等。合成所需要的起始原料和化學試劑可以根據文獻(reaxys)常規合成或購買。The invention also provides methods of preparing said compounds. The preparation of the compound described in general formula (I) of the present invention can be accomplished by the following exemplary methods and examples, but these methods and examples should not be considered to limit the scope of the present invention in any way. The compounds described in the present invention can also be synthesized using synthetic techniques known to those skilled in the art, or a combination of methods known in the art and methods described in the present invention can be used. The product obtained in each step should be obtained using separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatographic separation, etc. The starting materials and chemical reagents required for synthesis can be routinely synthesized or purchased according to the literature (reaxys).

除非另有說明，溫度是攝氏溫度。試劑購自Chem blocks Inc、Astatech Inc或麥克林等商業供應商，並且這些試劑可直接使用無需進一步純化，除非另有說明。Temperatures are in degrees Celsius unless otherwise stated. Reagents were purchased from commercial suppliers such as Chem blocks Inc, Astatech Inc, or McLean, and these reagents were used directly without further purification unless otherwise stated.

除非另有說明，下列反應在室溫、無水溶劑中、氮氣或氣的正壓下或使用乾燥管進行；玻璃器皿烘乾和/或加熱乾燥。Unless otherwise stated, the following reactions were performed at room temperature, in anhydrous solvents, under positive pressure of nitrogen or gas, or using drying tubes; glassware oven drying and/or heat drying.

除非另有說明，柱色譜純化使用青島海洋化工廠的200-300目矽膠；製備薄層色譜使用煙臺市化學工業研究所生產的薄層色譜矽膠預製板(HSGF254)；MS的測定用 Therno LCD Fleet型(ESI)液相色譜-質譜聯用儀。Unless otherwise stated, 200-300 mesh silica from Qingdao Ocean Chemical Plant was used for column chromatography purification; thin layer chromatography silica prefabricated plate (HSGF254) produced by Yantai Institute of Chemical Industry was used for preparative thin layer chromatography; Therno LCD Fleet was used for MS determination. Type (ESI) liquid chromatography-mass spectrometer.

核磁數據(1H NMR)使用 Bruker Avance-400MHz或Varian Oxford-400Hz核磁儀，核磁數據使用的溶劑有CDCl 3、CD 3OD、D 2O、DMS-d6等，以四甲基矽烷(0.000ppm)為基準或以殘留溶劑為基準(CDCl 3:7.26ppm；CD 3OD: 3.31ppm；D 2O: 4.79ppm；d6-DMSO: 2.50ppm)當標明峰形多樣性時，以下簡寫表示不同峰形：s(單峰)、d(雙重峰)、t(三重峰)、q(四重峰)、m(多重峰)、br(寬峰)、dd(雙雙重峰)、dt(雙三重峰)。如果給出了耦合常數，則以 Hertz(Hz)為單位。 Nuclear magnetic data (1H NMR) uses a Bruker Avance-400MHz or Varian Oxford-400Hz nuclear magnetic instrument. The solvents used for nuclear magnetic data include CDCl 3 , CD 3 OD, D 2 O, DMS-d6, etc., with tetramethylsilane (0.000ppm) As the basis or based on the residual solvent (CDCl 3: 7.26ppm; CD 3 OD: 3.31ppm; D 2 O: 4.79ppm; d6-DMSO: 2.50ppm) when peak shape diversity is indicated, the following abbreviations represent different peak shapes : s (single peak), d (double peak), t (triplet), q (quartet), m (multiple peak), br (broad peak), dd (double doublet), dt (double triplet) ). If coupling constants are given, they are in Hertz (Hz).

實施例Example 11

3-(2,6- 二氯苯基 )-7-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 )-2-(( 六氫 -1H- 吡咯啉 -7a- 基 ) 甲氧基 ) 嘧啶並 [4,5-d] 嘧啶 -4(3H)- 酮 ( 化合物 1) 的製備 3-(2,6- dichlorophenyl )-7-((4-(4- methylpyrazin -1- yl ) phenyl ) amino )-2-(( hexahydro -1H- pyrroline -7a Preparation of -yl ) methoxy ) pyrimido [4,5-d] pyrimidin -4(3H) -one ( compound 1 )

第一步 :3-(2,6- 二氯苯基 )-7- 甲硫基嘧啶 [4,5-d] 嘧啶 -2,4(1H,3H)- 二酮的製備將10g 4-氨基-2-（甲硫基）嘧啶-5-羧酸乙酯溶於150ML DMF中，然後加入3.15gNaH，並在室溫下攪拌5分鐘。向反應液中添加9.70 g 2,6-二氯苯基異氰酸酯，並在室溫下攪拌1小時。向反應溶液中加入乙酸乙酯和1 N鹽酸水溶液，並分離有機層。用飽和鹽水沖洗，用無水硫酸鈉乾燥，然後蒸發掉溶劑。沉澱的固體用甲醇固化，並通過過濾取出固體，以獲得13.7 g作為白色固體化合物3-(2,6-二氯苯基)-7-(甲硫基)嘧啶[4,5-d]嘧啶-2,4(1H,3H)-二酮。 LC/MS(ESI): m/z =355[M+H] +。 Step 1 : Preparation of 3-(2,6- dichlorophenyl )-7- methylthiopyrimidine [4,5-d] pyrimidine -2,4(1H,3H) -dione. Add 10g of 4-amino -2-(Methylthio)pyrimidine-5-carboxylic acid ethyl ester was dissolved in 150 ML DMF, then 3.15 g NaH was added and stirred at room temperature for 5 minutes. 9.70 g of 2,6-dichlorophenyl isocyanate was added to the reaction solution, and stirred at room temperature for 1 hour. Ethyl acetate and 1 N aqueous hydrochloric acid solution were added to the reaction solution, and the organic layer was separated. Rinse with saturated brine, dry over anhydrous sodium sulfate, and then evaporate the solvent. The precipitated solid was solidified with methanol, and the solid was taken out by filtration to obtain 13.7 g of compound 3-(2,6-dichlorophenyl)-7-(methylthio)pyrimidine[4,5-d]pyrimidine as a white solid -2,4(1H,3H)-dione. LC/MS(ESI): m/z =355[M+H] + .

第二步 :2-氯-3-(2,6- 二氯苯基 )-7- 甲硫基嘧啶 [4,5-d] 嘧啶 -4(3H)- 酮的製備將3-(2,6-二氯苯基)-7-(甲硫基)嘧啶[4,5-d]嘧啶-2,4(1H,3H)-二酮(5.31g 15 mmol)溶於POCl 3(80 mL)中，加入少量N,N-二甲苯胺，加熱回流攪拌反應4h。然後倒入冰水中淬滅，過濾得到固體產品，水洗，乾燥得到粗品黃色固體2-氯-3-(2,6-二氯苯基)-7-(甲硫基)嘧啶[4,5-d]嘧啶-4(3H)-酮(4.86 g，78%)，無需再純化進行下一反應。 LC/MS(ESI): m/z =374[M+H] +。 Step 2 : Preparation of 2-chloro-3-(2,6- dichlorophenyl )-7- methylthiopyrimidine [4,5-d] pyrimidin -4(3H) -one. 3-(2, 6-Dichlorophenyl)-7-(methylthio)pyrimidine[4,5-d]pyrimidine-2,4(1H,3H)-dione (5.31g 15 mmol) was dissolved in POCl 3 (80 mL) , add a small amount of N,N-dimethylaniline, heat to reflux and stir for 4 hours. Then pour into ice water to quench, filter to obtain a solid product, wash with water, and dry to obtain crude yellow solid 2-chloro-3-(2,6-dichlorophenyl)-7-(methylthio)pyrimidine [4,5- d]pyrimidin-4(3H)-one (4.86 g, 78%), proceed to the next reaction without further purification. LC/MS(ESI): m/z =374[M+H] + .

第三步 :2-( 四氫 -1H- 吡呤環 -7a(5H)- 基 ) 甲氧基 )-3-(2,6- 二氯苯基 )-7- 甲硫基嘧啶 [4,5-d] 嘧啶 -4(3H)- 酮的製備將2-氯-3-(2,6-二氯苯基)-7-(甲硫基)嘧啶[4,5-d]嘧啶-4(3H)-酮(373 mg，1 mmol)、六氫吡呤環-7a-甲醇(53 mg，0.33 mmol)、碳酸鉀(62 mg，0.45 mmol)催化量碘化鉀和DMF(10 mL)混合，加熱到120℃，攪拌反應4小時。冷卻至室溫，減壓蒸溶，柱層析得到類白色固體2-(四氫-1H-吡呤環-7a(5H)-基)甲氧基)-7-(甲硫基)嘧啶[4,5-d]嘧啶-4(3H)-酮(416 mg，87%)。LC/MS(ESI): m/z =479[M+H] +。 The third step : 2-( tetrahydro -1H- pyridine ring -7a(5H)-yl ) methoxy ) -3-(2,6- dichlorophenyl )-7- methylthiopyrimidine [4, Preparation of 5-d] pyrimidin -4(3H) -one from 2-chloro-3-(2,6-dichlorophenyl)-7-(methylthio)pyrimidine[4,5-d]pyrimidine-4 (3H)-one (373 mg, 1 mmol), hexahydropyridine ring-7a-methanol (53 mg, 0.33 mmol), potassium carbonate (62 mg, 0.45 mmol), catalytic amounts of potassium iodide and DMF (10 mL) were mixed, Heat to 120°C and stir for 4 hours. Cool to room temperature, evaporate under reduced pressure, and obtain off-white solid 2-(tetrahydro-1H-pyridine ring-7a(5H)-yl)methoxy)-7-(methylthio)pyrimidine[ 4,5-d]pyrimidin-4(3H)-one (416 mg, 87%). LC/MS(ESI): m/z =479[M+H] + .

第四步 :2-( 四氫 -1H- 吡呤環 -7a(5H)- 基 ) 甲氧基 )-3-(2,6- 二氯苯基 )-7- 甲碸基嘧啶 [4,5-d] 嘧啶 -4(3H)- 酮的製備將2-(四氫-1H-吡呤環-7a(5H)-基)甲氧基)-7-(甲硫基)嘧啶[4,5-d]嘧啶-4(3H)-酮(382 mg，0.8 mmol)溶於10 mLCH 2Cl 2中，加入間氯過氧苯甲酸(522 mg，3mmol)，並在室溫下攪拌2小時。反應溶液用CH 2Cl 2稀釋，並用飽和NaHCO 3和Na 2S 2O 3清洗。有機層用MgSO 4乾燥，減壓蒸溶，柱層析得到黃色固體2-(四氫-1H-吡呤環-7a(5H)-基)甲氧基)-7-甲碸基嘧啶[4,5-d]嘧啶-4(3H)-酮(392 mg，96%)。LC/MS(ESI): m/z =511[M+H] +。 Step 4 : 2-( Tetrahydro -1H- pyridinyl -7a(5H)-yl ) methoxy ) -3-(2,6- dichlorophenyl )-7- methylpropylpyrimidine [4, Preparation of 5-d] pyrimidin -4(3H) -one: 2-(tetrahydro-1H-pyridinyl ring-7a(5H)-yl)methoxy)-7-(methylthio)pyrimidine[4, 5-d]pyrimidin-4(3H)-one (382 mg, 0.8 mmol) was dissolved in 10 mL CH 2 Cl 2 , m-chloroperoxybenzoic acid (522 mg, 3 mmol) was added, and stirred at room temperature for 2 hours. . The reaction solution was diluted with CH2Cl2 and washed with saturated NaHCO3 and Na2S2O3 . The organic layer was dried with MgSO 4 , evaporated under reduced pressure, and column chromatography obtained a yellow solid 2-(tetrahydro-1H-pyridine ring-7a(5H)-yl)methoxy)-7-methylpyrimidine [4 ,5-d]pyrimidin-4(3H)-one (392 mg, 96%). LC/MS(ESI): m/z =511[M+H] + .

第五步 :2-( 四氫 -1H- 吡呤環 -7a(5H)- 基 ) 甲氧基 )-3-(2,6- 二氯苯基 )-7-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 ) 嘧啶 [4,5-d] 嘧啶 -4(3H)- 酮的製備將2-(四氫-1H-吡呤環-7a(5H)-基)甲氧基)-7-甲碸基嘧啶[4,5-d]嘧啶-4(3H)-酮(51 mg，0.1 mmol)溶於10ml DMF中，加入DIPEA(65mg，0.5 mmol)和4-(4-甲基呱嗪-1-基)苯胺(23 mg，0.12 mmol)，並在室溫下攪拌24小時。倒入冰水，過濾得到粗品，然後經快速柱分離得到黃色固體2-(四氫-1H-吡呤環-7a(5H)-基)甲氧基)-7-((4-(4-甲基呱嗪-1-基)苯基)氨基)嘧啶[4,5-d]嘧啶-4(3H)-酮(50 mg，83%)。 1H NMR (300 MHz, DMSO-d 6) δ 10.77(s, 1H), 9.12(s, 1H), 7.42-7.99(m, 4H), 6.88-7.29(m, 3H), 4.41(s, 2H), 3.46-3.61(m, 4H), 3.01-3.15(m, 4H), 2.48–2.58(m, 4H), 2.01-2.27(m, 5H), 1.87-1.96(m, 4H), 1.78-1.80(m, 2H), 1.69-1.76(m, 2H)；LC/MS(ESI): m/z =622.2[M+H] +。 Step 5 : 2-( tetrahydro -1H- pyridine ring -7a(5H)-yl ) methoxy ) -3-(2,6- dichlorophenyl )-7-((4-(4- Preparation of methylpyridazin -1- yl ) phenyl ) amino ) pyrimidine [4,5-d] pyrimidin -4(3H) -one by converting 2-(tetrahydro-1H-pyridine ring-7a(5H)- (Methoxy)-7-methylpropylpyrimidin[4,5-d]pyrimidin-4(3H)-one (51 mg, 0.1 mmol) was dissolved in 10 ml DMF, and DIPEA (65 mg, 0.5 mmol) and 4-(4-Methylpyrazin-1-yl)aniline (23 mg, 0.12 mmol) and stirred at room temperature for 24 hours. Pour into ice water, filter to obtain the crude product, and then perform flash column separation to obtain a yellow solid 2-(tetrahydro-1H-pyridine ring-7a(5H)-yl)methoxy)-7-((4-(4- Methylpyridazin-1-yl)phenyl)amino)pyrimidin[4,5-d]pyrimidin-4(3H)-one (50 mg, 83%). 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.77(s, 1H), 9.12(s, 1H), 7.42-7.99(m, 4H), 6.88-7.29(m, 3H), 4.41(s, 2H ), 3.46-3.61(m, 4H), 3.01-3.15(m, 4H), 2.48–2.58(m, 4H), 2.01-2.27(m, 5H), 1.87-1.96(m, 4H), 1.78-1.80 (m, 2H), 1.69-1.76(m, 2H); LC/MS(ESI): m/z =622.2[M+H] + .

實施例Example 22

3-(2,6- 二氟苯基 )-7-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 )-2-(( 六氫 -1H- 吡咯啉 -7a- 基 ) 甲氧基 ) 嘧啶並 [4,5-d] 嘧啶 -4(3H)- 酮 ( 化合物 2) 的製備 用與 實施例 1相似的方法得到化合物 2(51 mg，產率86％)。LC/MS(ESI): m/z =589.3[M+H] +。 3-(2,6- difluorophenyl )-7-((4-(4- methylpyrazin -1- yl ) phenyl ) amino )-2-(( hexahydro -1H- pyrroline -7a Preparation of -yl ) methoxy ) pyrimido [4,5-d] pyrimidin -4(3H) -one ( compound 2 ) Compound 2 (51 mg, yield 86%) was obtained using a method similar to Example 1 . LC/MS(ESI): m/z =589.3[M+H] + .

實施例Example 33

3-(2,6- 二甲基苯基 )-7-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 )-2-(( 六氫 -1H- 吡咯啉 -7a- 基 ) 甲氧基 ) 嘧啶並 [4,5-d] 嘧啶 -4(3H)- 酮 ( 化合物 3) 的製備 用與 實施例 1相似的方法得到化合物 3(45 mg，產率78％)。 1H NMR (300 MHz, CDCl 3) δ 9.22(s, 1H), 7.06-7.78 (m, 7H), 4.19 (s, 2H), 3.31(m, 4H), 2.60-2.68(m, 6H), 2.40(s, 3H), 2.15(s, 6H), 2.07-2.19(m, 2H), 1.87-1.98(m, 4H), 1.66-1.80 (m, 2H)；LC/MS(ESI): m/z =581.3[M+H] +。 3-(2,6- dimethylphenyl )-7-((4-(4- methylpyrazin -1- yl ) phenyl ) amino )-2-(( hexahydro -1H - pyrroline- Preparation of 7a- yl ) methoxy ) pyrimido [4,5-d] pyrimidin -4(3H) -one ( compound 3) Compound 3 (45 mg, yield 78%) was obtained using a method similar to Example 1 . 1 H NMR (300 MHz, CDCl 3 ) δ 9.22(s, 1H), 7.06-7.78 (m, 7H), 4.19 (s, 2H), 3.31(m, 4H), 2.60-2.68(m, 6H), 2.40(s, 3H), 2.15(s, 6H), 2.07-2.19(m, 2H), 1.87-1.98(m, 4H), 1.66-1.80 (m, 2H); LC/MS(ESI): m/ z =581.3[M+H] + .

實施例Example 44

(2,6- 二氯苯基 )-7-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 )-2-(( 金剛烷 -1- 基 ) 甲氧基 ) 嘧啶並 [4,5-d] 嘧啶 -4(3H)- 酮 ( 化合物 4) 的製備 用與 實施例 1相似的方法得到化合物 4(53 mg，產率82％)。 1H NMR (300 MHz, DMSO-d 6) δ 10.78(s, 1H), 9.12(s, 1H), 7.42-7.80(m, 4H), 6.88-7.28(m, 3H), 4.04(s, 2H), 3.46-3.61(m, 4H), 3.01-3.15(m, 4H), 2.01(m, 3H), 1.69-1.72(m, 12H)；LC/MS(ESI): m/z =647.2[M+H] +。 (2,6- Dichlorophenyl )-7-((4-(4- methylpyrazin -1- yl ) phenyl ) amino )-2-(( adamantan- 1- yl ) methoxy ) Preparation of pyrimido [4,5-d] pyrimidin -4(3H) -one ( compound 4) Compound 4 (53 mg, yield 82%) was obtained using a method similar to Example 1 . 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.78(s, 1H), 9.12(s, 1H), 7.42-7.80(m, 4H), 6.88-7.28(m, 3H), 4.04(s, 2H ), 3.46-3.61(m, 4H), 3.01-3.15(m, 4H), 2.01(m, 3H), 1.69-1.72(m, 12H); LC/MS(ESI): m/z =647.2[M +H] + .

實施例Example 55

(2,6- 二氟苯基 )-7-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 )-2-(( 金剛烷 -1- 基 ) 甲氧基 ) 嘧啶 [4,5-d] 嘧啶 -4(3H)- 酮 ( 化合物 5) 的製備 用與 實施例 1相似的方法得到化合物 5(56 mg，產率91％)。LC/MS(ESI): m/z =614[M+H] +。 (2,6- Difluorophenyl )-7-((4-(4- methylprazin- 1- yl ) phenyl ) amino )-2-(( adamantan -1- yl ) methoxy ) Preparation of pyrimidine [4,5-d] pyrimidine -4(3H) -one ( compound 5) Compound 5 (56 mg, yield 91%) was obtained using a method similar to Example 1 . LC/MS(ESI): m/z =614[M+H] + .

實施例Example 66

3-(2,6- 二甲基苯基 )-7-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 )-2-(( 金剛烷 -1- 基 ) 甲氧基 ) 嘧啶 [4,5-d] 嘧啶 -4(3H)- 酮 ( 化合物 6) 的製備 用與 實施例 1相似的方法得到化合物 6(50 mg，產率83％)。 1H NMR (300 MHz, CDCl 3) δ 9.22(s, 1H), 7.06-7.78 (m, 7H), 3.93 (s, 2H), 2.01 (m, 3H), 1.70-1.76 (m, 12H)；LC/MS(ESI): m/z =606.3[M+H] +。 3-(2,6- Dimethylphenyl )-7-((4-(4- methylpyridazin -1- yl ) phenyl ) amino )-2-(( adamantan- 1- yl ) methyl Preparation of oxy ) pyrimidine [4,5-d] pyrimidin -4(3H) -one ( compound 6) Compound 6 (50 mg, yield 83%) was obtained using a method similar to Example 1 . 1 H NMR (300 MHz, CDCl 3 ) δ 9.22 (s, 1H), 7.06-7.78 (m, 7H), 3.93 (s, 2H), 2.01 (m, 3H), 1.70-1.76 (m, 12H); LC/MS(ESI): m/z =606.3[M+H] + .

實施例Example 77

2-( 金剛烷 -1- 基甲氧 基 )-3-(2,6- 二氯苯基 )-7-((3- 甲基 -1,2,3,4,4a,5- 六氫苯並 [b] 吡嗪並 [1,2-d][1,4] 惡嗪 -8- 基 ) 氨基 ) 嘧啶 [4,5-d] 嘧啶 -4(3H)- 酮 ( 化合物 7) 的製備 用與 實施例 6相似的方法得到化合物 7(53 mg，產率78％)。LC/MS(ESI): m/z =675.3[M+H] +。 2-( adamant -1- ylmethoxy )-3-(2,6- dichlorophenyl )-7-((3- methyl - 1,2,3,4,4a,5- hexahydro Benzo [b] pyrazino [1,2-d][1,4] oxazin -8- yl ) amino ) pyrimidine [4,5-d] pyrimidin - 4(3H) -one ( compound 7) Preparation Compound 7 (53 mg, yield 78%) was obtained using a method similar to Example 6 . LC/MS(ESI): m/z =675.3[M+H] + .

實施例Example 88

2-( 金剛烷 -1- 基甲氧 基 )-3-(2,6- 二氯苯基 )-7-((4-(1- 甲基呱啶 -4- 基 ) 苯基 ) 氨基 ) 嘧啶 [4,5-d] 嘧啶 -4(3H)- 酮 ( 化合物 8) 的製備 用與 實施例 6相似的方法得到化合物 8(49 mg，產率76％)。LC/MS(ESI): m/z =646[M+H] +。 2-( adamant -1- ylmethoxy )-3-(2,6- dichlorophenyl )-7-((4-(1- methylpyridin- 4 - yl ) phenyl ) amino ) Preparation of pyrimidine [4,5-d] pyrimidine -4(3H) -one ( compound 8) Compound 8 (49 mg, yield 76%) was obtained using a method similar to Example 6 . LC/MS(ESI): m/z =646[M+H] + .

實施例Example 99

2-( 金剛烷 -1- 基甲氧 基 )-3-(2,6- 二氯苯基 )-7-((2,4,4- 三甲基 -1,2,3,4- 四氫異喹啉 -7- 基 ) 氨基 ) 嘧啶 [4,5-d] 嘧啶 -4(3H)- 酮 ( 化合物 9) 的製備 用與 實施例 6相似的方法得到化合物 9(56 mg，產率87％)。LC/MS(ESI): m/z =646.3[M+H] +。 2-( adamant -1- ylmethoxy )-3-(2,6- dichlorophenyl )-7-((2,4,4- trimethyl - 1,2,3,4- tetramethyl Preparation of hydroisoquinolin- 7- yl ) amino ) pyrimidine [4,5-d] pyrimidin -4(3H) -one ( compound 9) Compound 9 (56 mg, yield 87%) was obtained using a method similar to Example 6 . LC/MS(ESI): m/z =646.3[M+H] + .

實施例Example 1010

2-( 金剛烷 -1- 基甲氧 基 )-3-(2,6- 二氯苯基 )-7-((2'- 甲基 -2',3'- 二氫 -1'H- 螺 [ 環丙烷 -1,4'- 異異喹啉 ]-7’- 基 ) 氨基 ) 嘧啶 [4,5-d] 嘧啶 -4(3H)- 酮 ( 化合物 10) 的製備 用與 實施例 6相似的方法得到化合物 10(46 mg，產率72％)。LC/MS(ESI): m/z =644.2[M+H] +。 2-( adamant -1- ylmethoxy )-3-(2,6- dichlorophenyl )-7-((2'- methyl - 2',3'- dihydro -1'H- Preparation of spiro [ cyclopropane -1,4'- isoisoquinolin ]-7'- yl ) amino ) pyrimidine [4,5-d] pyrimidin -4(3H) -one ( compound 10) Compound 10 (46 mg, yield 72%) was obtained using a method similar to Example 6 . LC/MS(ESI): m/z =644.2[M+H] + .

實施例Example 1111

2-( 金剛烷 -1- 基甲氧 基 )-3-(2,6- 二甲基苯基 )-7-((2'- 甲基 -2',3'- 二氫 -1'H- 螺 [ 環丙烷 -1,4'- 異異喹啉 ]-7’- 基 ) 氨基 ) 嘧啶 [4,5-d] 嘧啶 -4(3H)- 酮 ( 化合物 11) 的製備 用與 實施例 1相似的方法得到化合物 11(41 mg，產率69％)。LC/MS(ESI): m/z =603.3[M+H] +。 2-( adamant -1- ylmethoxy )-3-(2,6- dimethylphenyl )-7-((2'- methyl - 2',3'- dihydro -1'H - Preparation of spiro [ cyclopropane -1,4'- isoisoquinolin ]-7'- yl ) amino ) pyrimidine [4,5-d] pyrimidin -4(3H) -one ( compound 11) Compound 11 (41 mg, yield 69%) was obtained using a method similar to Example 1 . LC/MS(ESI): m/z =603.3[M+H] + .

實施例Example 1212

2-( 金剛烷 -1- 基甲氧 基 )-3-(2,6- 二甲基苯基 )-7-((2,4,4- 三甲基 -1,2,3,4- 四氫異喹啉 -7- 基 ) 氨基 ) 嘧啶 [4,5-d] 嘧啶 -4(3H)- 酮 ( 化合物 12) 的製備 用與 實施例 1相似的方法得到化合物 12(51 mg，產率84％)。LC/MS(ESI): m/z =605.3[M+H] +。 2-( adamant -1- ylmethoxy )-3-(2,6- dimethylphenyl ) -7-((2,4,4- trimethyl -1,2,3,4- Preparation of tetrahydroisoquinolin -7- yl ) amino ) pyrimidine [4,5-d] pyrimidin -4(3H) -one ( compound 12) Compound 12 (51 mg, yield 84%) was obtained using a method similar to Example 1 . LC/MS(ESI): m/z =605.3[M+H] + .

實施例13 Example 13

3-(2,6- 二氯苯基 )-7-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 )-2-((1- 甲基吡咯烷 -2- 基 ) 甲氧基 ) 嘧啶 [4,5-d] 嘧啶 -4(3H)- 酮 ( 化合物 13) 的製備 3-(2,6- Dichlorophenyl )-7-((4-(4- methylpyrazin -1- yl ) phenyl ) amino )-2-((1- methylpyrrolidine -2- Preparation of methyl ) methoxy ) pyrimidine [4,5-d] pyrimidin -4(3H) -one ( compound 13)

第一步 :3-(2,6- 二氯苯基 )-7- 甲碸基嘧啶 [4,5-d] 嘧啶 -2,4(1H,3H)- 二酮的製備將3-(2,6-二氯苯基)-7-甲硫基嘧啶[4,5-d]嘧啶-2,4(1H,3H)-二酮(3.82 g，8 mmol)溶於50 mLCH 2Cl 2中，加入間氯過氧苯甲酸(5.22 g，30mmol)，並在室溫下攪拌2小時。反應溶液用CH 2Cl 2稀釋，並用飽和NaHCO 3和Na 2S 2O 3清洗。有機層用MgSO 4乾燥，減壓蒸溶，柱層析得到黃色固體3-(2,6-二氯苯基)-7-甲碸基嘧啶[4,5-d]嘧啶-2,4(1H,3H)-二酮(2.84 g，92%)。LC/MS(ESI): m/z =388[M+H] +。 Step 1 : Preparation of 3-(2,6- dichlorophenyl )-7- methyltenylpyrimidine [4,5-d] pyrimidine -2,4(1H,3H) -dione. ,6-Dichlorophenyl)-7-methylthiopyrimidine[4,5-d]pyrimidine-2,4(1H,3H)-dione (3.82 g, 8 mmol) was dissolved in 50 mLCH 2 Cl 2 , add m-chloroperoxybenzoic acid (5.22 g, 30 mmol), and stir at room temperature for 2 hours. The reaction solution was diluted with CH2Cl2 and washed with saturated NaHCO3 and Na2S2O3 . The organic layer was dried with MgSO4 , evaporated under reduced pressure, and column chromatography obtained yellow solid 3-(2,6-dichlorophenyl)-7-methylpropylpyrimidine[4,5-d]pyrimidine-2,4( 1H,3H)-diketone (2.84 g, 92%). LC/MS(ESI): m/z =388[M+H] + .

第二步 :3-(2,6- 二氯苯基 )-7-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 ) 嘧啶 [4,5-d] 嘧啶 -2,4(1H,3H)- 二酮的製備將3-(2,6-二氯苯基)-7-甲碸基嘧啶[4,5-d]嘧啶-2,4(1H,3H)-二酮(1.16 g，3 mmol)溶於25ml DMF中，加入DIPEA(1.94 g，15 mmol)和4-(4-甲基呱嗪-1-基)苯胺( 0.48 g，0.12 mmol)，並在室溫下攪拌24小時。倒入冰水，過濾得到粗品，然後經快速柱分離得到黃色固體3-(2,6-二氯苯基)-7-((4-(4-甲基呱嗪-1-基)苯基)氨基)嘧啶[4,5-d]嘧啶-2,4(1H,3H)-二酮(1.33 g，89%)。 LC/MS(ESI): m/z =499[M+H] +。 Step 2 : 3-(2,6- dichlorophenyl )-7-((4-(4- methylpyridazin -1- yl ) phenyl ) amino ) pyrimidine [4,5-d ] pyrimidine- Preparation of 2,4(1H,3H) -dione from 3-(2,6-dichlorophenyl)-7-methylpyrimidine[4,5-d]pyrimidine-2,4(1H,3H) -Diketone (1.16 g, 3 mmol) was dissolved in 25 ml DMF, DIPEA (1.94 g, 15 mmol) and 4-(4-methylpyrazin-1-yl)aniline (0.48 g, 0.12 mmol) were added, and Stir at room temperature for 24 hours. Pour into ice water, filter to obtain crude product, and then perform flash column separation to obtain yellow solid 3-(2,6-dichlorophenyl)-7-((4-(4-methylpyrazin-1-yl)phenyl) )Amino)pyrimidine[4,5-d]pyrimidine-2,4(1H,3H)-dione (1.33 g, 89%). LC/MS(ESI): m/z =499[M+H] + .

第三步 :2-氯-3-(2,6- 二氯苯基 )-7-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 ) 嘧啶 [4,5-d] 嘧啶 -4(3H)- 酮的製備將3-(2,6-二氯苯基)-7-((4-(4-甲基呱嗪-1-基)苯基)氨基)嘧啶[4,5-d]嘧啶-2,4(1H,3H)-二酮(1.25g 2.5 mmol)溶於POCl 3(20 mL)中，加入少量N,N-二甲苯胺，加熱回流攪拌反應4h。然後倒入冰水中淬滅，過濾得到固體產品，水洗，乾燥得到粗品黃色固體2-氯-3-(2,6-二氯苯基)-7-((4-(4-甲基呱嗪-1-基)苯基)氨基)嘧啶[4,5-d]嘧啶-4(3H)-酮(0.93 g，72%)，無需再純化進行下一反應。LC/MS(ESI): m/z =517[M+H] +。 Step 3 : 2-Chloro-3-(2,6- dichlorophenyl )-7-((4-(4- methylpyrazin - 1-yl ) phenyl ) amino ) pyrimidine [4,5- d] Preparation of pyrimidine -4(3H) -one using 3-(2,6-dichlorophenyl)-7-((4-(4-methylpyrazin-1-yl)phenyl)amino)pyrimidine [4,5-d]pyrimidine-2,4(1H,3H)-dione (1.25g 2.5 mmol) was dissolved in POCl 3 (20 mL), add a small amount of N,N-xylidine, heat to reflux and stir the reaction 4h. Then pour into ice water to quench, filter to obtain a solid product, wash with water, and dry to obtain a crude yellow solid 2-chloro-3-(2,6-dichlorophenyl)-7-((4-(4-methylchlorophenyl)) -1-yl)phenyl)amino)pyrimidine[4,5-d]pyrimidin-4(3H)-one (0.93 g, 72%) was carried out to the next reaction without further purification. LC/MS(ESI): m/z =517[M+H] + .

第四步 :3-(2,6- 二氯苯基 )-7-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 )-2-((1- 甲基吡咯烷 -2- 基 ) 甲氧基 ) 嘧啶 [4,5-d] 嘧啶 -4(3H)- 酮的製備將2-氯-3-(2,6-二氯苯基)-7-((4-(4-甲基呱嗪-1-基)苯基)氨基)嘧啶[4,5-d]嘧啶-4(3H)-酮(52 mg，0.1 mmol)、N-甲基吡咯烷-2-甲醇(23 mg，0.2 mmol)、碳酸鉀(62 mg，0.45 mmol)催化量碘化鉀和DMF(10 mL)混合，加熱到120℃，攪拌反應4小時。冷卻至室溫，倒入水中，過濾得到粗品經柱層析得到類白色固體3-(2,6-二氯苯基)-7-((4-(4-甲基呱嗪-1-基)苯基)氨基)-2-((1-甲基吡咯烷-2-基)甲氧基)嘧啶[4,5-d]嘧啶-4(3H)-酮(53 mg，92%)。LC/MS(ESI): m/z =576[M+H] +。 Step 4 : 3-(2,6- dichlorophenyl )-7-((4-(4- methylpyrazin -1- yl ) phenyl ) amino )-2-((1- methylpyrrole) Preparation of alk -2- yl ) methoxy ) pyrimidine [4,5-d] pyrimidin -4(3H) -one by 2-chloro-3-(2,6-dichlorophenyl)-7-(( 4-(4-methylpyridazin-1-yl)phenyl)amino)pyrimidin[4,5-d]pyrimidin-4(3H)-one (52 mg, 0.1 mmol), N-methylpyrrolidine- 2-Methanol (23 mg, 0.2 mmol), potassium carbonate (62 mg, 0.45 mmol), catalytic amount of potassium iodide and DMF (10 mL) were mixed, heated to 120°C, and stirred for 4 hours. Cool to room temperature, pour into water, filter to obtain the crude product, and then undergo column chromatography to obtain an off-white solid 3-(2,6-dichlorophenyl)-7-((4-(4-methylpyrazin-1-yl) )phenyl)amino)-2-((1-methylpyrrolidin-2-yl)methoxy)pyrimidin[4,5-d]pyrimidin-4(3H)-one (53 mg, 92%). LC/MS(ESI): m/z =576[M+H] + .

實施例Example 1414

3-(2,6- 二氯苯基 )-7-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 )-2-((1-( 二甲基氨基甲基 ) 環丙烷 ) 甲氧基 ) 嘧啶 [4,5-d] 嘧啶 -4(3H)- 酮 ( 化合物 14) 的製備 用與 實施例 13相似的方法得到化合物 14(51 mg，產率84％)。LC/MS(ESI): m/z =610.2[M+H] +。 3-(2,6- Dichlorophenyl )-7-((4-(4- methylchlorozin- 1- yl ) phenyl ) amino )-2-((1-( dimethylaminomethyl Preparation of ) cyclopropane ) methoxy ) pyrimidine [4,5-d] pyrimidin -4(3H) -one ( compound 14) Compound 14 (51 mg, yield 84%) was obtained using a method similar to Example 13 . LC/MS(ESI): m/z =610.2[M+H] + .

實施例Example 1515

3-(2,6- 二氯苯基 )-7-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 )-2-((1-( 吡咯烷 -1- 甲基 ) 環丙烷 ) 甲氧基 ) 嘧啶 [4,5-d] 嘧啶 -4(3H)- 酮 ( 化合物 15) 的製備 用與 實施例 13相似的方法得到化合物 15(58 mg，產率91％)。LC/MS(ESI): m/z =636.2[M+H] +。 3-(2,6- Dichlorophenyl )-7-((4-(4- methylpyrazin -1- yl ) phenyl ) amino )-2-((1-( pyrrolidine- 1- methyl) Preparation of cyclopropane)methoxy) pyrimidine [ 4,5 - d ] pyrimidin - 4(3H) -one ( compound 15) Compound 15 (58 mg, yield 91%) was obtained using a method similar to Example 13 . LC/MS(ESI): m/z =636.2[M+H] + .

實施例Example 1616

3-(2,6- 二氯苯基 )-7-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 )-2-((1- 甲基呱啶 -3- 基 ) 甲氧基 ) 嘧啶 [4,5-d] 嘧啶 -4(3H)- 酮 ( 化合物 16) 的製備 用與 實施例 13相似的方法得到化合物 16(47 mg，產率88％)。LC/MS(ESI): m/z =610[M+H] +。 3-(2,6- Dichlorophenyl )-7-((4-(4- methylpyridin- 1- yl ) phenyl ) amino )-2-((1- methylpiridin- 3- Preparation of methyl ) methoxy ) pyrimidine [4,5-d] pyrimidin -4(3H) -one ( compound 16) Compound 16 (47 mg, yield 88%) was obtained using a method similar to Example 13 . LC/MS(ESI): m/z =610[M+H] + .

實施例Example 1717

3-(2,6- 二氯苯基 )-7-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 )-2-((1,4- 二甲基呱嗪 -2- 基 ) 甲氧基 ) 嘧啶 [4,5-d] 嘧啶 -4(3H)- 酮 ( 化合物 17) 的製備 用與 實施例 13相似的方法得到化合物 17(49 mg，產率79％)。LC/MS(ESI): m/z =625[M+H] +。 3-(2,6- Dichlorophenyl )-7-((4-(4- methylchlorophenyl) phenyl ) amino ) -2 - ((1,4- dimethylchlorophenyl) Preparation of -2- yl ) methoxy ) pyrimidine [4,5-d] pyrimidin -4(3H) -one ( compound 17) Compound 17 (49 mg, yield 79%) was obtained using a method similar to Example 13 . LC/MS(ESI): m/z =625[M+H] + .

實施例Example 1818

3-(2,6- 二氯苯基 )-7-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 )-2-(3-( 二甲氨基 ) 丙氧基 ) 嘧啶 [4,5-d] 嘧啶 -4(3H)- 酮 ( 化合物 18) 的製備 用與 實施例 13相似的方法得到化合物 18(49 mg，產率84％)。LC/MS(ESI): m/z =584[M+H] +。 3-(2,6- Dichlorophenyl )-7-((4-(4- methylchlorozin- 1- yl ) phenyl ) amino )-2-(3-( dimethylamino ) propoxy ) Preparation of pyrimidine [4,5-d] pyrimidine -4(3H) -one ( compound 18) Compound 18 (49 mg, yield 84%) was obtained using a method similar to Example 13 . LC/MS(ESI): m/z =584[M+H] + .

實施例Example 1919

2-(( 六氫 -1H- 吡咯啉 -7a- 基 ) 甲氧基 )-3-(2,6- 二氯苯基 )-6-((3- 甲基 -1,2,3,4,4a,5- 六氫苯並 [b] 吡嗪並 [1,2-d][1,4] 惡嗪 -8- 基 ) 氨基 ) 嘧啶 [4,5-d] 嘧啶 -4(3H)- 酮 ( 化合物 19) 的製備 用與 實施例 1相似的方法得到化合物 19(60 mg，產率92％)。LC/MS(ESI): m/z =650.2[M+H] +。 2-(( Hexahydro -1H- pyrrolin -7a-yl ) methoxy ) -3-(2,6- dichlorophenyl )-6-((3- methyl -1,2,3,4 ,4a,5- hexahydrobenzo [b] pyrazino [1,2-d][1,4] oxazin -8- yl ) amino ) pyrimidine [4,5-d] pyrimidine -4(3H) - Preparation of ketone ( compound 19) Compound 19 (60 mg, yield 92%) was obtained using a method similar to Example 1 . LC/MS(ESI): m/z =650.2[M+H] + .

實施例Example 2020

2-(( 六氫 -1H- 吡咯啉 -7a- 基 ) 甲氧基 )-3-(2,6- 二氯苯基 )-7-((4-(1- 甲基呱啶 -4- 基 ) 苯基 ) 氨基 ) 嘧啶 [4,5-d] 嘧啶 -4(3H)- 酮 ( 化合物 20) 的製備 用與 實施例 1相似的方法得到化合物 20(50 mg，產率81％)。LC/MS(ESI): m/z =621.2[M+H] +。 2-(( Hexahydro -1H- pyrrolin- 7a-yl ) methoxy ) -3-(2,6- dichlorophenyl )-7-((4-(1- methylpiridin -4- Preparation of base ) phenyl ) amino ) pyrimidine [4,5-d] pyrimidin -4(3H) -one ( compound 20) Compound 20 (50 mg, yield 81%) was obtained using a method similar to Example 1 . LC/MS(ESI): m/z =621.2[M+H] + .

實施例Example 21twenty one

2-(( 六氫 -1H- 吡咯啉 -7a- 基 ) 甲氧基 )-3-(2,6- 二氯苯基 )-7-((2,4,4- 三甲基 -1,2,3,4- 四氫異喹啉 -7- 基 ) 氨基 ) 嘧啶 [4,5-d] 嘧啶 -4(3H)- 酮 ( 化合物 21) 的製備 用與 實施例 1相似的方法得到化合物21(53 mg，產率86％)。LC/MS(ESI): m/z =621.2[M+H] +。 2-(( Hexahydro -1H- pyrrolin -7a-yl ) methoxy ) -3-(2,6- dichlorophenyl )-7-((2,4,4- trimethyl -1, Preparation of 2,3,4- tetrahydroisoquinolin -7- yl ) amino ) pyrimidine [4,5-d] pyrimidin -4(3H) -one ( compound 21) Compound 21 (53 mg, yield 86%) was obtained using a method similar to Example 1 . LC/MS(ESI): m/z =621.2[M+H] + .

實施例Example 22twenty two

2-(( 六氫 -1H- 吡咯啉 -7a- 基 ) 甲氧基 )-3-(2,6- 二氯基苯基 )-7-((2'- 甲基 -2',3'- 二氫 -1'H- 螺 [ 環丙烷 -1,4'- 異異喹啉 ]-7’- 基 ) 氨基 ) 嘧啶 [4,5-d] 嘧啶 -4(3H)- 酮 ( 化合物 22) 的製備 用與 實施例 1相似的方法得到化合物 22(46 mg，產率74％)。LC/MS(ESI): m/z =619.2[M+H] +。 2-(( Hexahydro -1H- pyrrolin -7a- yl ) methoxy )-3-(2,6- dichlorophenyl )-7-((2'- methyl - 2',3' -Dihydro - 1'H- spiro [ cyclopropane -1,4'- isoquinolin ]-7'- yl ) amino ) pyrimidin [4,5-d] pyrimidin -4(3H) -one ( compound 22 ) preparation Compound 22 (46 mg, yield 74%) was obtained using a method similar to Example 1 . LC/MS(ESI): m/z =619.2[M+H] + .

實施例Example 23twenty three

2-(( 六氫 -1H- 吡咯啉 -7a- 基 ) 甲氧基 )-3-(2,6- 二甲基苯基 )-7-((2'- 甲基 -2',3'- 二氫 -1'H- 螺 [ 環丙烷 -1,4'- 異異喹啉 ]-7’- 基 ) 氨基 ) 嘧啶 [4,5-d] 嘧啶 -4(3H)- 酮 ( 化合物 23) 的製備 用與 實施例 3相似的方法得到化合物 23(50 mg，產率86％)。LC/MS(ESI): m/z =578.3[M+H] +。 2-(( Hexahydro -1H- pyrrolin - 7a- yl ) methoxy )-3-(2,6 -dimethylphenyl )-7-((2'- methyl - 2',3' -Dihydro - 1'H- spiro [ cyclopropane -1,4'- isoquinolin ]-7'- yl ) amino ) pyrimidin [4,5-d] pyrimidin -4(3H) -one ( compound 23 ) preparation Compound 23 (50 mg, yield 86%) was obtained using a method similar to Example 3 . LC/MS(ESI): m/z =578.3[M+H] + .

實施例Example 24twenty four

2-(( 六氫 -1H- 吡咯啉 -7a- 基 ) 甲氧基 )-3-(2,6- 二甲基苯基 )-7-((3- 甲基 -1,2,3,4,4a,5- 六氫苯並 [b] 吡嗪並 [1,2-d][1,4] 惡嗪 -8- 基 ) 氨基 ) 嘧啶 [4,5-d] 嘧啶 -4(3H)- 酮 ( 化合物 24) 的製備 用與 實施例 3相似的方法得到化合物 24(55 mg，產率91％)。LC/MS(ESI): m/z =609.3[M+H] +。 2-(( Hexahydro -1H- pyrrolin- 7a- yl ) methoxy )-3-(2,6 -dimethylphenyl )-7-((3- methyl - 1,2,3, 4,4a,5- hexahydrobenzo [b] pyrazino [1,2-d][1,4] oxazin -8- yl ) amino ) pyrimidine [4,5-d] pyrimidine -4(3H ) -Ketone ( Compound 24) Preparation Compound 24 (55 mg, yield 91%) was obtained using a method similar to Example 3 . LC/MS(ESI): m/z =609.3[M+H] + .

實施例Example 2525

2-(( 六氫 -1H- 吡咯啉 -7a- 基 ) 甲氧基 )-3-(2,6- 二甲基苯基 )-7-((4-(1- 甲基呱啶 -4- 基 ) 苯基 ) 氨基 ) 嘧啶 [4,5-d] 嘧啶 -4(3H)- 酮 ( 化合物 25) 的製備 用與 實施例 3相似的方法得到化合物 25(50 mg，產率89％)。LC/MS(ESI): m/z =580[M+H] +。 2-(( Hexahydro -1H- pyrrolin- 7a- yl ) methoxy )-3- ( 2,6 -dimethylphenyl )-7-((4-(1- methylpyridin -4) Preparation of -yl ) phenyl ) amino ) pyrimidine [4,5-d] pyrimidine - 4(3H) -one ( compound 25) Compound 25 (50 mg, yield 89%) was obtained using a method similar to Example 3 . LC/MS(ESI): m/z =580[M+H] + .

實施例Example 2626

2-(( 六氫 -1H- 吡咯啉 -7a- 基 ) 甲氧基 )-3-(2,6- 二甲基苯基 )-7-((2,4,4- 三甲基 -1,2,3,4- 四氫異喹啉 -7- 基 ) 氨基 ) 嘧啶 [4,5-d] 嘧啶 -4(3H)- 酮 ( 化合物 26) 的製備 用與 實施例 3相似的方法得到化合物 26(45 mg，產率77％)。LC/MS(ESI): m/z =580[M+H] +。 2-(( Hexahydro -1H- pyrrolin -7a- yl ) methoxy )-3-(2,6 -dimethylphenyl )-7-((2,4,4- trimethyl -1 , Preparation of 2,3,4- tetrahydroisoquinolin- 7- yl ) amino ) pyrimidine [4,5-d] pyrimidin -4(3H) -one ( compound 26) Compound 26 (45 mg, yield 77%) was obtained using a method similar to Example 3 . LC/MS(ESI): m/z =580[M+H] + .

實施例Example 2727

3-(2,6- 二氯苯基 )-7-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 )-2- 苄氧基嘧啶 [4,5-d] 嘧啶 -4(3H)- 酮 ( 化合物 27) 的製備用與 實施例 13相似的方法得到化合物 27(52 mg，產率88％)。LC/MS(ESI): m/z =589[M+H] +。 3-(2,6- Dichlorophenyl )-7-((4-(4- methylpyrazin -1- yl ) phenyl ) amino )-2- benzyloxypyrimidine [4,5-d] Preparation of pyrimidine -4(3H) -one ( compound 27) Compound 27 (52 mg, yield 88%) was obtained using a method similar to Example 13 . LC/MS(ESI): m/z =589[M+H] + .

實施例Example 2828

3-(2,6- 二氯苯基 )-7-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 )-2-(( 吡啶 -3- 基 ) 甲氧基 ) 嘧啶 [4,5-d] 嘧啶 -4(3H)- 酮 ( 化合物 28) 的製備用與 實施例 13相似的方法得到化合物 28(49 mg，產率83％)。LC/MS(ESI): m/z =590[M+H] +。 3-(2,6- Dichlorophenyl )-7-((4-(4- methylpyridin- 1- yl ) phenyl ) amino )-2-(( pyridin -3- yl ) methoxy ) Preparation of pyrimidine [4,5-d] pyrimidin -4(3H) -one ( compound 28) Compound 28 (49 mg, yield 83%) was obtained using a method similar to Example 13 . LC/MS(ESI): m/z =590[M+H] + .

實施例Example 2929

N-(3-(2,6- 二氯苯基 )-7-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 )-4- 氧代 -3,4- 二氫嘧啶 [4,5-d] 嘧啶 -2- 基 ) 煙醯胺 ( 化合物 29) 的製備用與 實施例 3相似的方法 得到化合物 29(48 mg，產率79％)。LC/MS(ESI): m/z =603[M+H] +。 N-(3-(2,6- dichlorophenyl )-7-((4-(4- methylprazin- 1- yl ) phenyl ) amino )-4- oxo - 3,4- di Preparation of Hydropyrimidine [4,5-d] pyrimidin -2- yl ) nicotinamide ( Compound 29) Compound 29 (48 mg, yield 79%) was obtained using a method similar to Example 3 . LC/MS(ESI): m/z =603[M+H] + .

實施例Example 3030

N-(3-(2,6- 二氯苯基 )-7-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 )-4- 氧代 -3,4- 二氫嘧啶 [4,5-d] 嘧啶 -2- 基 ) 呋喃 -2- 甲醯胺 ( 化合物 30) 的製備用與 實施例 3相似的方法得到化合物 30(50 mg，產率84％)。LC/MS(ESI): m/z =592[M+H] +。 N-(3-(2,6- dichlorophenyl )-7-((4-(4- methylprazin- 1- yl ) phenyl ) amino )-4- oxo - 3,4- di Preparation of Hydropyrimidine [4,5-d] pyrimidin -2- yl ) furan -2- methamide ( Compound 30) Compound 30 (50 mg, yield 84%) was obtained using a method similar to Example 3 . LC/MS(ESI): m/z =592[M+H] + .

實施例Example 3131

N-(3-(2,6- 二氯苯基 )-7-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 )-4- 氧代 -3,4- 二氫嘧啶 [4,5-d] 嘧啶 -2- 基 ) 惡唑 -2- 甲醯胺 ( 化合物 31) 的製備用與 實施例 3相似的方法得到化合物 31(53mg，產率89％)。LC/MS(ESI): m/z =593[M+H] +。 N-(3-(2,6- dichlorophenyl )-7-((4-(4- methylprazin- 1- yl ) phenyl ) amino )-4- oxo - 3,4- di Preparation of Hydropyrimidine [4,5-d] pyrimidin -2- yl ) oxazole -2- methamide ( Compound 31) Compound 31 (53 mg, yield 89%) was obtained using a method similar to Example 3 . LC/MS(ESI): m/z =593[M+H] + .

實施例Example 3232

N-(3-(2,6- 二氯苯基 )-7-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 )-4- 氧代 -3,4- 二氫嘧啶 [4,5-d] 嘧啶 -2- 基 )-1- 甲基 -1H- 吡唑 -5- 甲醯胺 ( 化合物 32) 的製備用與 實施例 3相似的方法得到化合物 32(51 mg，產率85％)。LC/MS(ESI): m/z =606[M+H] +。 N-(3-(2,6- dichlorophenyl )-7-((4-(4- methylprazin- 1- yl ) phenyl ) amino )-4- oxo - 3,4- di Preparation of Hydropyrimidine [4,5-d] pyrimidin -2- yl )-1- methyl -1H- pyrazole -5- carboxamide ( compound 32 ) Compound 32 (51 mg, yield 85%). LC/MS(ESI): m/z =606[M+H] + .

實施例Example 3333

1- 苄基 -3-(2,6- 二氯苯基 )-7-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 ) 嘧啶 [4,5-d] 嘧啶 -2,4(1H,3H)- 二酮 ( 化合物 33) 的製備 1- benzyl - 3-(2,6- dichlorophenyl )-7-((4-(4- methylpyrazin- 1-yl ) phenyl ) amino ) pyrimidine [4,5-d] pyrimidine Preparation of -2,4(1H,3H) -dione ( compound 33)

第一步 :1- 苄基 -3-(2,6- 二氯苯基 )-7-( 甲硫基 ) 嘧啶 [4,5-d] 嘧啶 -2,4(1H,3H)- 二酮的製備將3-(2,6-二氯苯基)-7-(甲硫基)嘧啶[4,5-d]嘧啶-2,4(1H,3H)-二酮(354 mg，1 mmol)、苄氯(151 mg，1.2 mmol)、碳酸鉀(620 mg，4.5 mmol)催化量碘化鉀和DMF(25 mL)混合，加熱到120℃，攪拌反應4小時。冷卻至室溫，倒入水中，過濾得到類白色固體3-(2,6-二氯苯基)-7-((4-(4-甲基呱嗪-1-基)苯基)氨基)-2-((1-甲基吡咯烷-2-基)甲氧基)嘧啶[4,5-d]嘧啶-4(3H)-酮(347 mg，78%)。LC/MS(ESI): m/z =446[M+H] +。 Step 1 : 1- benzyl -3-(2,6- dichlorophenyl )-7-( methylthio ) pyrimidine [4,5-d] pyrimidine -2,4(1H,3H) -dione Preparation of 3-(2,6-dichlorophenyl)-7-(methylthio)pyrimidine[4,5-d]pyrimidine-2,4(1H,3H)-dione (354 mg, 1 mmol ), benzyl chloride (151 mg, 1.2 mmol), potassium carbonate (620 mg, 4.5 mmol), catalytic amount of potassium iodide and DMF (25 mL) were mixed, heated to 120°C, and stirred for 4 hours. Cool to room temperature, pour into water, and filter to obtain an off-white solid 3-(2,6-dichlorophenyl)-7-((4-(4-methylpyrazin-1-yl)phenyl)amino) -2-((1-methylpyrrolidin-2-yl)methoxy)pyrimidin[4,5-d]pyrimidin-4(3H)-one (347 mg, 78%). LC/MS(ESI): m/z =446[M+H] + .

第二步 :1- 苄基 -3-(2,6- 二氯苯基 )-7- 甲碸基嘧啶 [4,5-d] 嘧啶 -2,4(1H,3H)- 二酮的製備將3-(2,6-二氯苯基)-7-甲硫基嘧啶[4,5-d]嘧啶-2,4(1H,3H)-二酮(311 mg，0.7 mmol)溶於10 mLCH 2Cl 2中，加入間氯過氧苯甲酸(359 mg，2.1mmol)，並在室溫下攪拌2小時。反應溶液用CH 2Cl 2稀釋，並用飽和NaHCO 3和Na 2S 2O 3清洗。有機層用MgSO 4乾燥，減壓蒸溶，柱層析得到黃色固體1-苄基-3-(2,6-二氯苯基)-7-甲碸基嘧啶[4,5-d]嘧啶-2,4(1H,3H)-二酮(290 mg，87%)。LC/MS(ESI): m/z =478[M+H] +。 Step 2 : Preparation of 1- benzyl -3-(2,6- dichlorophenyl )-7- methylpropylpyrimidine [4,5-d] pyrimidine -2,4(1H,3H) -dione Dissolve 3-(2,6-dichlorophenyl)-7-methylthiopyrimidine[4,5-d]pyrimidine-2,4(1H,3H)-dione (311 mg, 0.7 mmol) in 10 To mLCH2Cl2 , add m-chloroperoxybenzoic acid (359 mg, 2.1 mmol) and stir at room temperature for 2 hours. The reaction solution was diluted with CH2Cl2 and washed with saturated NaHCO3 and Na2S2O3 . The organic layer was dried with MgSO4 , evaporated under reduced pressure, and column chromatography obtained a yellow solid 1-benzyl-3-(2,6-dichlorophenyl)-7-methylpropylpyrimidine[4,5-d]pyrimidine. -2,4(1H,3H)-dione (290 mg, 87%). LC/MS(ESI): m/z =478[M+H] + .

第三步 :1- 苄基 -3-(2,6- 二氯苯基 )-7-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 ) 嘧啶 [4,5-d] 嘧啶 -2,4(1H,3H)- 二酮的製備將1-苄基-3-(2,6-二氯苯基)-7-甲碸基嘧啶[4,5-d]嘧啶-2,4(1H,3H)-二酮(95 mg，0.2 mmol)溶於10 ml DMF中，加入DIPEA(78 mg，0.6 mmol)和4-(4-甲基呱嗪-1-基)苯胺( 46 mg，0.24 mmol)，並在室溫下攪拌24小時。倒入冰水，過濾得到粗品，然後經快速柱分離得到類白色固體1-苄基-3-(2,6-二氯苯基)-7-((4-(4-甲基呱嗪-1-基)苯基)氨基)嘧啶[4,5-d]嘧啶-2,4(1H,3H)-二酮(104 mg，89%)。 LC/MS(ESI): m/z =589[M+H] +。 Step 3 : 1- benzyl -3-(2,6- dichlorophenyl )-7-((4-(4- methylpyrazin -1- yl ) phenyl ) amino ) pyrimidine [4,5 Preparation of -d] pyrimidine -2,4(1H,3H) -dione from 1-benzyl-3-(2,6-dichlorophenyl)-7-methylpropylpyrimidine[4,5-d] Pyrimidine-2,4(1H,3H)-dione (95 mg, 0.2 mmol) was dissolved in 10 ml DMF, and DIPEA (78 mg, 0.6 mmol) and 4-(4-methylpyridazin-1-yl) were added ) aniline (46 mg, 0.24 mmol) and stirred at room temperature for 24 hours. Pour into ice water, filter to obtain the crude product, and then perform flash column separation to obtain an off-white solid 1-benzyl-3-(2,6-dichlorophenyl)-7-((4-(4-methylpyrazine- 1-yl)phenyl)amino)pyrimidine[4,5-d]pyrimidine-2,4(1H,3H)-dione (104 mg, 89%). LC/MS(ESI): m/z =589[M+H] + .

實施例Example 3434

3-(2,6- 二氯苯基 )-7-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 )-1-( 吡啶 -4- 基甲基 ) 嘧啶 [4,5-d] 嘧啶 -2,4(1H,3H)- 二酮 ( 化合物 34) 的製備 用與 實施例 33相似的方法得到化合物 96(88 mg，產率74％)。LC/MS(ESI): m/z =590[M+H] +。 3-(2,6- Dichlorophenyl )-7-((4-(4- methylpyridin- 1- yl ) phenyl ) amino )-1-( pyridin -4- ylmethyl ) pyrimidine [ Preparation of 4,5-d] pyrimidine -2,4(1H,3H) -dione ( compound 34) Compound 96 (88 mg, yield 74%) was obtained using a method similar to Example 33 . LC/MS(ESI): m/z =590[M+H] + .

實施例Example 3535

3-(2,6- 二氯苯基 )-7-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 )-1-(( 六氫 -1H- 吡咯啉 -7a- 基 ) 甲基 ) 嘧啶 [4,5-d] 嘧啶 -2,4(1H,3H)- 二酮 ( 化合物 36) 的製備 用與 實施例 33相似的方法得到化合物 36(97 mg，產率78％)。LC/MS(ESI): m/z =622[M+H] +。 3-(2,6- dichlorophenyl )-7-((4-(4- methylpyrazin -1- yl ) phenyl ) amino )-1-(( hexahydro -1H- pyrroline -7a Preparation of -yl ) methyl ) pyrimidine [4,5-d] pyrimidine -2,4(1H,3H) -dione ( compound 36 ) Compound 36 (97 mg, yield 78%) was obtained using a method similar to Example 33 . LC/MS(ESI): m/z =622[M+H] + .

實施例Example 3636

1- 苄基 -3-(2,6- 二甲基苯基 )-7-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 ) 嘧啶 [4,5-d] 嘧啶 -2,4(1H,3H)- 二酮 ( 化合物 36) 的製備 用與 實施例 33相似的方法得到化合物 36(95 mg，產率87％)。LC/MS(ESI): m/z =548[M+H] +。 1- Benzyl - 3-(2,6- dimethylphenyl )-7-((4-(4- methylpyrazin- 1- yl ) phenyl ) amino ) pyrimidine [4,5-d] Preparation of pyrimidine -2,4(1H,3H) -dione ( compound 36) Compound 36 (95 mg, yield 87%) was obtained using a method similar to Example 33 . LC/MS(ESI): m/z =548[M+H] + .

實施例Example 3737

3-(2,6- 二甲基苯基 )-7-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 )-1-( 吡啶 -4- 基甲基 ) 嘧啶 [4,5-d] 嘧啶 -2,4(1H,3H)- 二酮 ( 化合物 37) 的製備 用與 實施例 33相似的方法得到化合物 37(83 mg，產率76％)。LC/MS(ESI): m/z =549.3[M+H] +。 3-(2,6- Dimethylphenyl )-7-((4-(4- methylpyridin- 1- yl ) phenyl ) amino )-1-( pyridin -4- ylmethyl ) pyrimidine Preparation of [4,5-d] pyrimidine -2,4(1H,3H) -dione ( compound 37) Compound 37 (83 mg, yield 76%) was obtained using a method similar to Example 33 . LC/MS(ESI): m/z =549.3[M+H] + .

實施例Example 3838

3-(2,6- 二甲基苯基 )-7-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 )-1-(( 六氫 -1H- 吡咯啉 -7a- 基 ) 甲基 ) 嘧啶 [4,5-d] 嘧啶 -2,4(1H,3H)- 二酮 ( 化合物 38) 的製備 用與 實施例 33相似的方法得到化合物 38(72 mg，產率62％)。LC/MS(ESI): m/z =581[M+H] +。 3-(2,6- dimethylphenyl )-7-((4-(4- methylpyrazin -1- yl ) phenyl ) amino )-1-(( hexahydro -1H - pyrroline- Preparation of 7a- yl ) methyl ) pyrimidine [4,5-d] pyrimidine -2,4(1H,3H) -dione ( compound 38) Compound 38 (72 mg, yield 62%) was obtained using a method similar to Example 33 . LC/MS(ESI): m/z =581[M+H] + .

實施例Example 3939

3-(2,6- 二氯苯基 )-7-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 )-1-((1-(( 二甲氨基 ) 甲基 ) 環丙基 ) 甲基 ) 嘧啶 [4,5-d] 嘧啶 -2,4(1H,3H)- 二酮 ( 化合物 39) 的製備用與 實施例 33相似的方法得到化合物 39(84 mg，產率69％)。LC/MS(ESI): m/z =610[M+H] +。 3-(2,6- Dichlorophenyl )-7-((4-(4- methylchlorozin- 1- yl ) phenyl ) amino )-1-((1-(( dimethylamino ) methyl Preparation of cyclopropyl ) methyl ) pyrimidine [4,5-d] pyrimidine-2,4(1H,3H)-dione (compound 39 ) Compound 39 ( 84 mg) was obtained using a method similar to Example 33 , yield 69%). LC/MS(ESI): m/z =610[M+H] + .

實施例Example 4040

3-(2,6- 二氯苯基 )-7-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 )-1-((1-( 吡咯烷 -1- 基甲基 ) 環丙基 ) 甲基 ) 嘧啶 [4,5-d] 嘧啶 -2,4(1H,3H)- 二酮 ( 化合物 40) 的製備用與 實施例 33相似的方法得到化合物 40(91 mg，產率72％)。LC/MS(ESI): m/z =636[M+H] +。 3-(2,6- Dichlorophenyl )-7-((4-(4- methylpyrazin -1- yl ) phenyl ) amino )-1-((1-( pyrrolidin- 1- yl) Preparation of methyl ) cyclopropyl ) methyl ) pyrimidine [4,5-d] pyrimidine -2,4(1H,3H) -dione ( compound 40) Compound 40 (91) was obtained using a method similar to Example 33 mg, yield 72%). LC/MS(ESI): m/z =636[M+H] + .

實施例Example 4141

3-(2,6- 二氯苯基 )-7-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 )-1-( 金剛烷 -1- 基甲基 ) 嘧啶 [4,5-d] 嘧啶 -2,4(1H,3H)- 二酮 ( 化合物 41) 的製備用與 實施例 33相似的方法得到化合物 41(87 mg，產率67％)。LC/MS(ESI): m/z =647[M+H] +。 3-(2,6- Dichlorophenyl )-7-((4-(4- methylpyrazin -1- yl ) phenyl ) amino )-1-( adamant - 1-ylmethyl ) pyrimidine Preparation of [4,5-d] pyrimidine -2,4(1H,3H) -dione ( compound 41) Compound 41 (87 mg, yield 67%) was obtained using a method similar to Example 33 . LC/MS(ESI): m/z =647[M+H] + .

類似實施例 1-41 的合成，可以得到如下化合物： Similar to the synthesis in Example 1-41 , the following compounds can be obtained:

實施例Example 4242

2- 丙烯基 -1-(6-(2- 羥基丙基 -2- 基 ) 吡啶 -2- 基 )-6-((5-(4- 甲基呱嗪 -1- 基 ) 吡啶 -2- 基 ) 氨基 )-1,2- 二氫 -3H- 吡唑 [4,3-c] 噠嗪 -3- 酮 ( 化合物 42) 的製備 2- propenyl -1-(6-(2- hydroxypropyl- 2- yl ) pyridin -2- yl )-6-((5-(4- methylpyrazin -1- yl ) pyridin -2- Preparation of ( hydroxy ) amino )-1,2- dihydro -3H- pyrazole [4,3-c] pyridazin -3- one ( compound 42)

第一步 :2- 丙烯基 -6-氯-1,2- 二氫 -3H- 吡唑 [4,3-c] 噠嗪 -3- 酮的製備向4,6-二氯噠嗪-3-羧酸甲酯（9.89 g，47.8 mmol）溶於150mL的 THF溶液中加入DIPEA（20.8 ml，120 mmol）和1-烯丙基肼甲酸叔丁酯（8.22 g，47.8 mmol），反應物回流72小時，然後在真空中濃縮。向殘渣中添加Et 2O（50 ml），過濾，濾液減蒸縮溶，殘渣在冰浴中冷卻，然後添加TFA（40 ml）。在室溫下攪拌所得溶液1 h，然後在70 ℃下攪拌1 h。減蒸縮溶，將殘餘物溶解在THF（50ml）中，並在冰浴中冷卻，然後添加 NaH（75ml）。在RT下攪拌所得溶液15分鐘，然後通過加醋酸調至pH=3。減蒸縮溶，然後加入100 ml氯仿和100 ml水，並用50 ml飽和食鹽水洗滌有機相，無水Mg 2SO 4乾燥，在真空中濃縮，並用正己烷打漿。用乙醇和Et 2O洗滌固體沉澱物，然後在真空下乾燥，得到黃色固體化合物2-丙烯基-6-氯-1,2-二氫-3H-吡唑[4,3-c]噠嗪-3-酮(4.41 g，44%)。LC/MS(ESI): m/z =211[M+H] +。 Step 1 : Preparation of 2- propenyl -6-chloro-1,2- dihydro -3H- pyrazole [4,3-c] pyridazin -3- one to 4,6-dichloropyridazine-3 -Methyl carboxylate (9.89 g, 47.8 mmol) was dissolved in 150 mL of THF solution, DIPEA (20.8 ml, 120 mmol) and 1-allylcarbazinecarboxylic acid tert-butyl ester (8.22 g, 47.8 mmol) were added, and the reactant was refluxed 72 hours and then concentrated in vacuo. Et 2 O (50 ml) was added to the residue, filtered, the filtrate was evaporated and dissolved, the residue was cooled in an ice bath, and then TFA (40 ml) was added. The resulting solution was stirred at room temperature for 1 h and then at 70 °C for 1 h. After evaporation, the residue was dissolved in THF (50 ml) and cooled in an ice bath, then NaH (75 ml) was added. The resulting solution was stirred at RT for 15 minutes and then adjusted to pH=3 by adding acetic acid. Dissolve under reduced evaporation, then add 100 ml chloroform and 100 ml water, and wash the organic phase with 50 ml saturated brine, dry over anhydrous Mg 2 SO 4 , concentrate in vacuum, and beat with n-hexane. The solid precipitate was washed with ethanol and Et 2 O and then dried under vacuum to obtain a yellow solid compound 2-propenyl-6-chloro-1,2-dihydro-3H-pyrazole[4,3-c]pyridazine -3-one (4.41 g, 44%). LC/MS(ESI): m/z =211[M+H] + .

第二步 :2- 丙烯基 -6-((5-(4- 甲基呱嗪 -1- 基 ) 吡啶 -2- 基 ) 氨基 )-1,2- 二氫 -3H- 吡唑 [4,3-c] 噠嗪 -3- 酮的製備將2-丙烯基-6-氯-1,2-二氫-3H-吡唑[4,3-c]噠嗪-3-酮(2.1 g，10 mmol)、5-(4-甲基呱嗪-1-基)-2-氨基吡啶(1.92 g，10 mmol)、碳酸鉀(6.21 g，45 mmol)催化量碘化鉀和DMF(80 mL)混合，加熱到120℃，攪拌反應4小時。冷卻至室溫，倒入水中，過濾得到粗品經柱層析得到類白色固體2-丙烯基-6-((5-(4-甲基呱嗪-1-基)吡啶-2-基)氨基)-1,2-二氫-3H-吡唑[4,3-c]噠嗪-3-酮(2.89 g，79%)。LC/MS(ESI): m/z =367[M+H] +。 Second step : 2- propenyl -6-((5-(4- methylpyridin- 1- yl ) pyridin -2- yl ) amino )-1,2- dihydro -3H- pyrazole [4, Preparation of 3-c] pyridazin - 3-one 2-propenyl-6-chloro-1,2-dihydro-3H-pyrazole[4,3-c]pyridazin-3-one (2.1 g, 10 mmol), 5-(4-methylpyridazin-1-yl)-2-aminopyridine (1.92 g, 10 mmol), potassium carbonate (6.21 g, 45 mmol), catalytic amount of potassium iodide and DMF (80 mL) were mixed , heated to 120°C, stirred and reacted for 4 hours. Cool to room temperature, pour into water, filter to obtain crude product, and obtain off-white solid 2-propenyl-6-((5-(4-methylpyrazin-1-yl)pyridin-2-yl)amino through column chromatography )-1,2-dihydro-3H-pyrazole[4,3-c]pyridazin-3-one (2.89 g, 79%). LC/MS(ESI): m/z =367[M+H] + .

第三步 :2- 丙烯基 -1-(6-(2- 羥基丙基 -2- 基 ) 吡啶 -2- 基 )-6-((5-(4- 甲基呱嗪 -1- 基 ) 吡啶 -2- 基 ) 氨基 )-1,2- 二氫 -3H- 吡唑 [4,3-c] 噠嗪 -3- 酮的製備向2-丙烯基-6-((5-(4-甲基呱嗪-1-基)吡啶-2-基)氨基)-1,2-二氫-3H-吡唑[4,3-c]噠嗪-3-酮（73 mg，0.2 mmol）和2-（6-溴-2-吡啶基）丙烷-2-醇（52 mg，0.24 mmol）在10 mL二氧六環中的攪拌溶液中添加碘化銅（38 mg，0.20 mmol）、碳酸鉀（42 mg，0.3 mmol）和N，N’-二甲基乙二胺（20 mg，0.22 mmol），並在80°C下攪拌過夜。反應完成後，減壓除去溶劑；用水稀釋殘渣，並用乙酸乙酯（15 mL*3）萃取。用鹽水溶液洗滌合併的有機層，在無水硫酸鈉上乾燥，並在減壓下濃縮以獲得粗產物，通過快速色譜法純化以獲得2-丙烯基-1-(6-(2-羥基丙基-2-基)吡啶-2-基)-6-((5-(4-甲基呱嗪-1-基)吡啶-2-基)氨基)-1,2-二氫-3H-吡唑[4,3-c]噠嗪-3-酮(48 mg，產率48％)。 LC/MS(ESI): m/z =502[M+H] +。 Step 3 : 2- propenyl -1-(6-(2- hydroxypropyl- 2- yl ) pyridin -2- yl )-6-((5-(4- methylpyrazin -1- yl ) Preparation of pyridin -2- yl ) amino )-1,2- dihydro -3H- pyrazole [4,3-c] pyridazin - 3-one Methylpyridazin-1-yl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazole[4,3-c]pyridazin-3-one (73 mg, 0.2 mmol) and To a stirred solution of 2-(6-bromo-2-pyridyl)propan-2-ol (52 mg, 0.24 mmol) in 10 mL dioxane was added copper iodide (38 mg, 0.20 mmol), potassium carbonate (42 mg, 0.3 mmol) and N,N'-dimethylethylenediamine (20 mg, 0.22 mmol) and stir at 80°C overnight. After the reaction is completed, remove the solvent under reduced pressure; dilute the residue with water and extract with ethyl acetate (15 mL*3). The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product, which was purified by flash chromatography to obtain 2-propenyl-1-(6-(2-hydroxypropyl -2-yl)pyridin-2-yl)-6-((5-(4-methylpyridin-1-yl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazole [4,3-c]pyridazin-3-one (48 mg, 48% yield). LC/MS(ESI): m/z =502[M+H] + .

實施例Example 4343

2- 丙烯基 -1-(6-(2- 羥基丙基 -2- 基 ) 苯基 )-6-((5-(4- 甲基呱嗪 -1- 基 ) 吡啶 -2- 基 ) 氨基 )-1,2- 二氫 -3H- 吡唑 [4,3-c] 噠嗪 -3- 酮 ( 化合物 43) 的製備 用與 實施例 42相似的方法得到化合物 43(62 mg，產率62％)。LC/MS(ESI): m/z =501[M+H] +。 2- propenyl- 1-(6-(2- hydroxypropyl- 2- yl ) phenyl )-6-((5-(4- methylpyrazin -1- yl ) pyridin -2- yl ) amino Preparation of )-1,2- dihydro -3H- pyrazole [4,3-c] pyridazin -3- one ( compound 43) Compound 43 (62 mg, yield 62%) was obtained using a method similar to Example 42 . LC/MS(ESI): m/z =501[M+H] + .

實施例Example 4444

(R)-2- 丙烯基 -1-(7- 乙基 -7- 羥基 -6,7- 二氫 -5H- 環戊 [b] 吡啶 -2- 基 )-6-((5-(4- 甲基呱嗪 -1- 基 ) 吡啶 -2- 基 ) 氨基 )-1,2- 二氫 -3H- 吡唑 [4,3-c] 噠嗪 -3- 酮 ( 化合物 44) 的製備 用與 實施例 42相似的方法得到化合物 44(54 mg，產率51％)。LC/MS(ESI): m/z =528[M+H] +。 (R)-2- propenyl -1-(7- ethyl -7- hydroxy -6,7- dihydro -5H- cyclopenta [b] pyridin -2- yl )-6-((5-(4 Preparation of -methylpyridin -1- yl ) pyridin -2- yl ) amino )-1,2- dihydro -3H- pyrazole [4,3-c] pyridazin -3- one ( compound 44) Compound 44 (54 mg, yield 51%) was obtained using a method similar to Example 42 . LC/MS(ESI): m/z =528[M+H] + .

實施例Example 4545

(R)-2- 丙烯基 -1-(7- 乙基 -7- 羥基 -6,7- 二氫 -5H- 環戊 [b] 吡啶 -2- 基 )-6-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 )-1,2- 二氫 -3H- 吡唑 [4,3-c] 噠嗪 -3- 酮 ( 化合物 45) 的製備 用與 實施例 44相似的方法得到化合物 45(60 mg，產率57％)。LC/MS(ESI): m/z =527[M+H] +。 (R)-2- propenyl -1-(7- ethyl -7- hydroxy -6,7- dihydro -5H- cyclopenta [b] pyridin -2- yl )-6-((4-(4 Preparation of -methylpyridazin -1- yl ) phenyl )-1,2- dihydro -3H- pyrazole [4,3-c] pyridazin -3- one ( compound 45) Compound 45 (60 mg, yield 57%) was obtained using a method similar to Example 44 . LC/MS(ESI): m/z =527[M+H] + .

實施例Example 4646

2- 丙烯基 -1-(6-(2- 羥基丙基 -2- 基 ) 吡啶 -2- 基 )-6-((3- 甲基 -1,2,3,4,4a,5- 六氫苯並 [b] 吡嗪並 [1,2-d][1,4] 惡嗪 -8- 基 ) 氨基 )-1,2- 二氫 -3H- 吡唑 [4,3-c] 噠嗪 -3- 酮 ( 化合物 46) 的製備 用與 實施例 45相似的方法得到化合物 46(48 mg，產率45％)。LC/MS(ESI): m/z =529[M+H] +。 2- propenyl -1-(6-(2- hydroxypropyl- 2- yl ) pyridin -2- yl )-6-((3- methyl- 1,2,3,4,4a,5- hexa Hydrobenzo [b] pyrazino [1,2-d][1,4] oxazin -8- yl ) amino )-1,2- dihydro -3H- pyrazole [4,3-c] da Preparation of oxazin -3- one ( compound 46) Compound 46 (48 mg, yield 45%) was obtained using a method similar to Example 45 . LC/MS(ESI): m/z =529[M+H] + .

實施例Example 4747

(R)-2- 丙烯基 -1-(7- 乙基 -7- 羥基 -6,7- 二氫 -5H- 環戊 [b] 吡啶 -2- 基 )-6-((3- 甲基 -1,2,3,4,4a,5- 六氫苯並 [b] 吡嗪並 [1,2-d][1,4] 惡嗪 -8- 基 ) 氨基 )-1,2- 二氫 -3H- 吡唑 [4,3-c] 噠嗪 -3- 酮 ( 化合物 47) 的製備 用與 實施例 45相似的方法得到化合物 47(53 mg，產率48％)。LC/MS(ESI): m/z =555[M+H] +。 (R)-2- propenyl -1-(7- ethyl -7- hydroxy -6,7- dihydro -5H- cyclopenta [b] pyridin -2- yl )-6-((3- methyl -1,2,3,4,4a,5 -hexahydrobenzo [b] pyrazino [1,2-d][1,4] oxazin -8- yl ) amino )-1,2- di Preparation of hydrogen -3H- pyrazole [4,3-c] pyridazin -3- one ( compound 47) Compound 47 (53 mg, yield 48%) was obtained using a method similar to Example 45 . LC/MS(ESI): m/z =555[M+H] + .

實施例Example 4848

(R)-2- 丙烯基 -1-(6-(2- 羥基丙基 -2- 基 ) 吡啶 -2- 基 )-6-((2,4,4- 三甲基 -1,2,3,4- 四氫異喹啉 -7- 基 ) 氨基 )-1,2- 二氫 -3H- 吡唑 [4,3-c] 噠嗪 -3- 酮 ( 化合物 48) 的製備 用與 實施例 43相似的方法得到化合物 48(57 mg，產率58％)。LC/MS(ESI): m/z =500[M+H] +。 (R)-2- propenyl -1-(6-(2- hydroxypropyl- 2- yl ) pyridin -2- yl )-6-((2,4,4- trimethyl -1,2, Preparation of 3,4- tetrahydroisoquinolin -7- yl ) amino )-1,2- dihydro -3H- pyrazole [4,3-c] pyridazin -3- one ( compound 48) Compound 48 (57 mg, yield 58%) was obtained using a method similar to Example 43 . LC/MS(ESI): m/z =500[M+H] + .

實施例Example 4949

(R)-2- 丙烯基 -1-(7- 乙基 -7- 羥基 -6,7- 二氫 -5H- 環戊 [b] 吡啶 -2- 基 )-6-(2'- 甲基 -2',3'- 二氫 -1'H- 螺 [ 環丙烷 -1,4'- 異異喹啉 ]-7’- 基 )-1,2- 二氫 -3H- 吡唑 [4,3-c] 噠嗪 -3- 酮 ( 化合物 49) 的製備 用與 實施例 45相似的方法得到化合物 49(56 mg，產率54％)。LC/MS(ESI): m/z =524[M+H] +。 (R)-2- propenyl -1-(7- ethyl -7- hydroxy -6,7- dihydro -5H- cyclopenta [b] pyridin -2- yl )-6-(2'- methyl -2',3'- dihydro -1'H- spiro [ cyclopropane -1,4'- isoisoquinolin ]-7'- yl )-1,2- dihydro -3H- pyrazole [4, Preparation of 3-c] pyridazin -3- one ( compound 49) Compound 49 (56 mg, yield 54%) was obtained using a method similar to Example 45 . LC/MS(ESI): m/z =524[M+H] + .

實施例Example 5050

(R)-2- 丙烯基 -1-(7- 乙基 -7- 羥基 -6,7- 二氫 -5H- 環戊 [b] 吡啶 -2- 基 )-6-((2,4,4- 三甲基 -1,2,3,4- 四氫異喹啉 -7- 基 ) 氨基 )-1,2- 二氫 -3H- 吡唑 [4,3-c] 噠嗪 -3- 酮 ( 化合物 51) 的製備 用與 實施例 45相似的方法得到化合物 50(50 mg，產率48％)。LC/MS(ESI): m/z =526[M+H] +。 (R)-2- propenyl -1-(7- ethyl -7- hydroxy -6,7- dihydro -5H- cyclopenta [b] pyridin -2- yl )-6-((2,4, 4- Trimethyl -1,2,3,4- tetrahydroisoquinolin -7- yl ) amino )-1,2- dihydro -3H- pyrazole [4,3-c] pyridazine -3- Preparation of Ketone ( Compound 51) Compound 50 (50 mg, yield 48%) was obtained using a method similar to Example 45 . LC/MS(ESI): m/z =526[M+H] + .

實施例Example 5151

2-(2,6- 二氯苯基 )-1-(6-(2- 羥基丙基 -2- 基 ) 吡啶 -2- 基 )-6-((5-(4- 甲基呱嗪 -1- 基 ) 吡啶 -2- 基 ) 氨基 )-1,2- 二氫 -3H- 吡唑 [4,3-c] 噠嗪 -3- 酮 ( 化合物 94) 的製備 2-(2,6- Dichlorophenyl )-1-(6-(2- hydroxypropyl- 2- yl ) pyridin -2- yl )-6-((5-(4 - methylpyrazine- Preparation of 1- yl ) pyridin -2- yl ) amino )-1,2- dihydro -3H- pyrazole [4,3-c] pyridazin -3- one ( compound 94)

第一步 :2-(2,6- 二氯苯基 )-6-氯-1,2- 二氫 -3H- 吡唑 [4,3-c] 噠嗪 -3- 酮的製備向4,6-二氯噠嗪-3-羧酸甲酯（9.89 g，47.8 mmol）溶於150mL的 THF溶液中加入DIPEA（20.8 ml，120 mmol）和2,6-二氯苯肼鹽酸鹽（10.18 g，47.8 mmol），反應物回流72小時，然後在真空中濃縮。向殘渣中添加Et 2O（50 ml），過濾，濾液減蒸縮溶，殘渣在冰浴中冷卻，然後添加TFA（40 ml）。在室溫下攪拌所得溶液1 h，然後在70 ℃下攪拌1 h。減蒸縮溶，將殘餘物溶解在THF（50ml）中，並在冰浴中冷卻，然後添加 NaH（75ml）。在RT下攪拌所得溶液15分鐘，然後通過加醋酸調至pH=3。減蒸縮溶，然後加入100 ml氯仿和100 ml水，並用50 ml飽和食鹽水洗滌有機相，無水Mg 2SO 4乾燥，在真空中濃縮，並用正己烷打漿。用乙醇和Et 2O洗滌固體沉澱物，然後在真空下乾燥，得到黃色固體化合物2-(2,6-二氯苯基)-6-氯-1,2-二氫-3H-吡唑[4,3-c]噠嗪-3-酮(8.13 g，54%)。 LC/MS(ESI): m/z =316[M+H] +。 Step 1 : Preparation of 2-(2,6- dichlorophenyl )-6-chloro-1,2- dihydro -3H- pyrazole [4,3-c] pyridazin -3- one toward 4, 6-Dichloropyridazine-3-carboxylic acid methyl ester (9.89 g, 47.8 mmol) was dissolved in 150 mL of THF solution, and DIPEA (20.8 ml, 120 mmol) and 2,6-dichlorophenylhydrazine hydrochloride (10.18 g, 47.8 mmol), the reaction was refluxed for 72 h and then concentrated in vacuo. Et 2 O (50 ml) was added to the residue, filtered, the filtrate was evaporated and dissolved, the residue was cooled in an ice bath, and then TFA (40 ml) was added. The resulting solution was stirred at room temperature for 1 h and then at 70 °C for 1 h. After evaporation, the residue was dissolved in THF (50 ml) and cooled in an ice bath, then NaH (75 ml) was added. The resulting solution was stirred at RT for 15 minutes and then adjusted to pH=3 by adding acetic acid. Dissolve under reduced evaporation, then add 100 ml chloroform and 100 ml water, and wash the organic phase with 50 ml saturated brine, dry over anhydrous Mg 2 SO 4 , concentrate in vacuum, and beat with n-hexane. The solid precipitate was washed with ethanol and Et 2 O, and then dried under vacuum to obtain a yellow solid compound 2-(2,6-dichlorophenyl)-6-chloro-1,2-dihydro-3H-pyrazole [ 4,3-c]pyridazin-3-one (8.13 g, 54%). LC/MS(ESI): m/z =316[M+H] + .

第二步 :2-(2,6- 二氯苯基 )-6-((5-(4- 甲基呱嗪 -1- 基 ) 吡啶 -2- 基 ) 氨基 )-1,2- 二氫 -3H- 吡唑 [4,3-c] 噠嗪 -3- 酮的製備將2-(2,6-二氯苯基)-6-氯-1,2-二氫-3H-吡唑[4,3-c]噠嗪-3-酮(1.58 g，5 mmol)、5-(4-甲基呱嗪-1-基)-2-氨基吡啶(0.96 g，5 mmol)、碳酸鉀(3.45g，25 mmol)催化量碘化鉀和DMF(50 mL)混合，加熱到120℃，攪拌反應4小時。冷卻至室溫，倒入水中，過濾得到粗品經柱層析得到類白色固體2-(2,6-二氯苯基)-6-((5-(4-甲基呱嗪-1-基)吡啶-2-基)氨基)-1,2-二氫-3H-吡唑[4,3-c]噠嗪-3-酮(1.86 g，79%)。 LC/MS(ESI): m/z =471[M+H] +。 Step 2 : 2-(2,6- dichlorophenyl )-6-((5-(4- methylpyridin- 1- yl ) pyridin -2- yl ) amino )-1,2- dihydro Preparation of -3H- pyrazole [4,3-c] pyridazin - 3-one 2-(2,6-dichlorophenyl)-6-chloro-1,2-dihydro-3H-pyrazole[ 4,3-c]pyridazin-3-one (1.58 g, 5 mmol), 5-(4-methylpyridazin-1-yl)-2-aminopyridine (0.96 g, 5 mmol), potassium carbonate ( Mix 3.45g, 25 mmol) catalytic amount of potassium iodide and DMF (50 mL), heat to 120°C, and stir for 4 hours. Cool to room temperature, pour into water, filter to obtain the crude product, and then undergo column chromatography to obtain an off-white solid 2-(2,6-dichlorophenyl)-6-((5-(4-methylpyrazin-1-yl) )pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazole[4,3-c]pyridazin-3-one (1.86 g, 79%). LC/MS(ESI): m/z =471[M+H] + .

第三步 :2-(2,6- 二氯苯基 )-1-(6-(2- 羥基丙基 -2- 基 ) 吡啶 -2- 基 )-6-((5-(4- 甲基呱嗪 -1- 基 ) 吡啶 -2- 基 ) 氨基 )-1,2- 二氫 -3H- 吡唑 [4,3-c] 噠嗪 -3- 酮的製備向2-(2,6-二氯苯基)-6-((5-(4-甲基呱嗪-1-基)吡啶-2-基)氨基)-1,2-二氫-3H-吡唑[4,3-c]噠嗪-3-酮（94 mg，0.2 mmol）和2-(6-溴-2-吡啶基)丙烷-2-醇（52 mg，0.24 mmol）在10 mL二氧六環中的攪拌溶液中添加CuI(38 mg，0.2 mmol)、K 2CO 3(42 mg，0.3 mmol)和N,N’-二甲基乙二胺(20 mg，0.22 mmol)，並在80°C下攪拌過夜。反應完成後，減壓除去溶劑；用水稀釋殘渣，並用乙酸乙酯(15 mL*3)萃取。用鹽水溶液洗滌合併的有機層，在無水硫酸鈉上乾燥，並在減壓下濃縮以獲得粗產物，通過快速色譜法純化以獲得2-(2,6-二氯苯基)-1-(6-(2-羥基丙基-2-基)吡啶-2-基)-6-((5-(4-甲基呱嗪-1-基)吡啶-2-基)氨基)-1,2-二氫-3H-吡唑[4,3-c]噠嗪-3-酮(52 mg，產率43％)。 LC/MS(ESI): m/z =607[M+H] +。 Step 3 : 2-(2,6- dichlorophenyl )-1-(6-(2- hydroxypropyl- 2- yl ) pyridin -2- yl )-6-((5-(4- methyl Preparation of pyrazin -1- yl ) pyridin -2- yl ) amino )-1,2- dihydro -3H- pyrazole [4,3-c] pyridazin -3- one toward 2-(2,6 -Dichlorophenyl)-6-((5-(4-methylpyridin-1-yl)pyridin-2-yl)amino)-1,2-dihydro-3H-pyrazole[4,3- c] Pyridazin-3-one (94 mg, 0.2 mmol) and 2-(6-bromo-2-pyridyl)propan-2-ol (52 mg, 0.24 mmol) stirred in 10 mL of dioxane CuI (38 mg, 0.2 mmol), K 2 CO 3 (42 mg, 0.3 mmol) and N,N'-dimethylethylenediamine (20 mg, 0.22 mmol) were added to the solution and stirred at 80°C. Stay overnight. After the reaction was completed, the solvent was removed under reduced pressure; the residue was diluted with water and extracted with ethyl acetate (15 mL*3). The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product, which was purified by flash chromatography to obtain 2-(2,6-dichlorophenyl)-1-( 6-(2-hydroxypropyl-2-yl)pyridin-2-yl)-6-((5-(4-methylpyridin-1-yl)pyridin-2-yl)amino)-1,2 -Dihydro-3H-pyrazole[4,3-c]pyridazin-3-one (52 mg, yield 43%). LC/MS(ESI): m/z =607[M+H] + .

實施例 52 6- 丙烯基 -5-(6-(2- 羥基丙基 -2- 基 ) 吡啶 -2- 基 )-3-((5-(4- 甲基呱嗪 -1- 基 ) 吡啶 -2- 基 ) 氨基 )-5,6- 二氫 -3H- 吡唑 [3,4-e][1,2,4] 三嗪 -7- 酮 ( 化合物 101) 的製備 Example 52 6- propenyl- 5-(6-(2- hydroxypropyl- 2- yl ) pyridin -2- yl )-3-((5-(4- methylpyrazin -1- yl ) pyridine Preparation of -2- yl ) amino )-5,6- dihydro -3H- pyrazole [3,4-e][1,2,4] triazin -7- one ( compound 101)

第一步 :6- 丙烯基 -3-( 甲硫基 )-5,6- 二氫 -3H- 吡唑 [3,4-e][1,2,4] 三嗪 -7- 酮的製備向3-甲硫基-5-氯-[1,2,4]三嗪-6-甲酸乙酯（11.1 g，47.8 mmol）溶於150mL的 THF溶液中加入DIPEA（20.8 ml，120 mmol）和1-烯丙基肼甲酸叔丁酯（8.23 g，47.8 mmol），反應物回流72小時，然後在真空中濃縮。向殘渣中添加Et 2O（50 ml），過濾，濾液減蒸縮溶，殘渣在冰浴中冷卻，然後添加TFA（40 ml）。在室溫下攪拌所得溶液1 h，然後在70 ℃下攪拌1 h。減蒸縮溶，將殘餘物溶解在THF（50ml）中，並在冰浴中冷卻，然後添加 NaOH（75ml）。在RT下攪拌所得溶液15分鐘，然後通過加醋酸調至pH=3。減蒸縮溶，然後加入100 ml氯仿和100 ml水，並用50 ml飽和食鹽水洗滌有機相，無水Mg 2SO 4乾燥，在真空中濃縮，並用正己烷打漿。用乙醇和Et 2O洗滌固體沉澱物，然後在真空下乾燥，得到黃色固體化合物6-丙烯基-3-(甲硫基)-5,6-二氫-3H-吡唑[3,4-e][1,2,4]三嗪-7-酮(5.0 g，47%)。 LC/MS(ESI): m/z =224[M+H] +。 Step 1 : Preparation of 6- propenyl -3-( methylthio )-5,6- dihydro -3H- pyrazole [3,4-e][1,2,4] triazin -7- one To a solution of ethyl 3-methylthio-5-chloro-[1,2,4]triazine-6-carboxylate (11.1 g, 47.8 mmol) in 150 mL of THF was added DIPEA (20.8 ml, 120 mmol) and tert-Butyl 1-allylcarbazinecarboxylate (8.23 g, 47.8 mmol). The reaction was refluxed for 72 hours and concentrated in vacuo. Et 2 O (50 ml) was added to the residue, filtered, the filtrate was evaporated and dissolved, the residue was cooled in an ice bath, and then TFA (40 ml) was added. The resulting solution was stirred at room temperature for 1 h and then at 70 °C for 1 h. After evaporation, the residue was dissolved in THF (50 ml) and cooled in an ice bath, then NaOH (75 ml) was added. The resulting solution was stirred at RT for 15 minutes and then adjusted to pH=3 by adding acetic acid. Dissolve under reduced evaporation, then add 100 ml chloroform and 100 ml water, and wash the organic phase with 50 ml saturated brine, dry over anhydrous Mg 2 SO 4 , concentrate in vacuum, and beat with n-hexane. The solid precipitate was washed with ethanol and Et 2 O and then dried under vacuum to obtain a yellow solid compound 6-propenyl-3-(methylthio)-5,6-dihydro-3H-pyrazole [3,4- e][1,2,4]triazin-7-one (5.0 g, 47%). LC/MS(ESI): m/z =224[M+H] + .

第二步 :6- 丙烯基 -5-(6-(2- 羥基丙基 -2- 基 ) 吡啶 -2- 基 )-3-( 甲硫基 )-5,6- 二氫 -3H- 吡唑 [3,4-e][1,2,4] 三嗪 -7- 酮的製備向6-丙烯基-3-(甲硫基)-5,6-二氫-3H-吡唑[3,4-e][1,2,4]三嗪-7-酮（224 mg，1 mmol）和2-(6-溴-2-吡啶基)丙烷-2-醇（260 mg，1.2 mmol）溶於20 mL二氧六環中的溶液中，攪拌加入CuI(190 mg，1 mmol)、K 2CO 3(210 mg，1.5 mmol)和N,N’-二甲基乙二胺(100 mg，1.1 mmol)，並在80°C下攪拌過夜。反應完成後，減壓除去溶劑；用水稀釋殘渣，並用乙酸乙酯(10 mL*3)萃取。用鹽水溶液洗滌合併的有機層，在無水硫酸鈉上乾燥，並在減壓下濃縮以獲得粗產物，通過快速色譜法純化以獲得6-丙烯基-5-(6-(2-羥基丙基-2-基)吡啶-2-基)-3-(甲硫基)-5,6-二氫-3H-吡唑[3,4-e][1,2,4]三嗪-7-酮(258 mg，產率72％)。 LC/MS(ESI): m/z =359[M+H] +。 Step 2 : 6- propenyl -5-(6-(2- hydroxypropyl- 2- yl ) pyridin -2- yl )-3-( methylthio )-5,6- dihydro -3H- pyridin Preparation of Azole [3,4-e][1,2,4] triazin -7- one toward 6-propenyl-3-(methylthio)-5,6-dihydro-3H-pyrazole[3 ,4-e][1,2,4]triazin-7-one (224 mg, 1 mmol) and 2-(6-bromo-2-pyridyl)propan-2-ol (260 mg, 1.2 mmol) Dissolve in 20 mL of dioxane, add CuI (190 mg, 1 mmol), K 2 CO 3 (210 mg, 1.5 mmol) and N,N'-dimethylethylenediamine (100 mg) with stirring. , 1.1 mmol) and stirred at 80°C overnight. After the reaction was completed, the solvent was removed under reduced pressure; the residue was diluted with water and extracted with ethyl acetate (10 mL*3). The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product, which was purified by flash chromatography to obtain 6-propenyl-5-(6-(2-hydroxypropyl -2-yl)pyridin-2-yl)-3-(methylthio)-5,6-dihydro-3H-pyrazole[3,4-e][1,2,4]triazine-7- ketone (258 mg, 72% yield). LC/MS(ESI): m/z =359[M+H] + .

第三步 :6- 丙烯基 -3-((5-(4- 甲基呱嗪 -1- 基 ) 吡啶 -2- 基 ) 氨基 )-5,6- 二氫 -3H- 吡唑 [3,4-e][1,2,4] 三嗪 -7- 酮的製備將6-丙烯基-5-(6-(2-羥基丙基-2-基)吡啶-2-基)-3-(甲硫基)-5,6-二氫-3H-吡唑[3,4-e][1,2,4]三嗪-7-酮(180 mg，0.5 mmol)溶於10 mLCH 2Cl 2中，加入間氯過氧苯甲酸(522 mg，6 mmol)，並在室溫下攪拌2小時。反應溶液用CH 2Cl 2稀釋，並用飽和NaHCO 3和Na 2S 2O 3清洗。有機層用MgSO 4乾燥，減壓蒸溶，柱層析得到黃色固體6-丙烯基-3-(甲碸基)-5,6-二氫-3H-吡唑[3,4-e][1,2,4]三嗪-7-酮(183 mg，94%)。LC/MS(ESI): m/z =391[M+H] +。 The third step : 6- propenyl -3-((5-(4- methylpyridin -1- yl ) pyridin -2- yl ) amino )-5,6- dihydro -3H- pyrazole [3, Preparation of 4-e][1,2,4] triazin -7- one from 6-propenyl-5-(6-(2-hydroxypropyl-2-yl)pyridin-2-yl)-3- (Methylthio)-5,6-dihydro-3H-pyrazole[3,4-e][1,2,4]triazin-7-one (180 mg, 0.5 mmol) was dissolved in 10 mL CH 2 Cl 2 , add m-chloroperoxybenzoic acid (522 mg, 6 mmol) and stir at room temperature for 2 hours. The reaction solution was diluted with CH2Cl2 and washed with saturated NaHCO3 and Na2S2O3 . The organic layer was dried with MgSO 4 , evaporated under reduced pressure, and subjected to column chromatography to obtain a yellow solid 6-propenyl-3-(methylpropyl)-5,6-dihydro-3H-pyrazole [3,4-e][ 1,2,4]triazin-7-one (183 mg, 94%). LC/MS(ESI): m/z =391[M+H] + .

第四步 :6- 丙烯基 -5-(6-(2- 羥基丙基 -2- 基 ) 吡啶 -2- 基 )-3-((5-(4- 甲基呱嗪 -1- 基 ) 吡啶 -2- 基 ) 氨基 )-5,6- 二氫 -3H- 吡唑 [3,4-e][1,2,4] 三嗪 -7- 酮的製備將6-丙烯基-3-(甲碸基)-5,6-二氫-3H-吡唑[3,4-e][1,2,4]三嗪-7-酮(117 mg，0.3 mmol)溶於25ml DMF中，加入DIPEA(194 mg，1.5 mmol)和4-(4-甲基呱嗪-1-基)苯胺( 70 mg，0.36 mmol)，並在室溫下攪拌24小時。倒入冰水，過濾得到粗品，然後經快速柱分離得到黃色固體6-丙烯基-3-((5-(4-甲基呱嗪-1-基)吡啶-2-基)氨基)-5,6-二氫-3H-吡唑[3,4-e][1,2,4]三嗪-7-酮(133 mg，89%)。1 H NMR (400 MHz, DMSO-d6) 10.13 (m, 1H), 7.56-8.10 (m, 6H), 5.67 (dd, 1H), 5.31 (br, 1H), 5.01 (dd, 1H), 4.69-4.84 (m, 3H), 3.51-3.88 (m, 4H), 3.11-3.23 (m, 4H), 2.43 (s, 3H), 1.47(s, 6H)；LC/MS(ESI): m/z =502[M+H] +。 Step 4 : 6- propenyl -5-(6-(2- hydroxypropyl- 2- yl ) pyridin -2- yl )-3-((5-(4- methylpyrazin -1- yl ) Preparation of pyridin -2- yl ) amino )-5,6- dihydro -3H- pyrazole [3,4-e][1,2,4] triazin -7- one from 6-propenyl-3- (Methyl)-5,6-dihydro-3H-pyrazole[3,4-e][1,2,4]triazin-7-one (117 mg, 0.3 mmol) was dissolved in 25 ml DMF, DIPEA (194 mg, 1.5 mmol) and 4-(4-methylprazin-1-yl)aniline (70 mg, 0.36 mmol) were added and stirred at room temperature for 24 hours. Pour into ice water, filter to obtain the crude product, and then perform flash column separation to obtain a yellow solid 6-propenyl-3-((5-(4-methylpyrazin-1-yl)pyridin-2-yl)amino)-5 ,6-dihydro-3H-pyrazole[3,4-e][1,2,4]triazin-7-one (133 mg, 89%). 1 H NMR (400 MHz, DMSO-d6) 10.13 (m, 1H), 7.56-8.10 (m, 6H), 5.67 (dd, 1H), 5.31 (br, 1H), 5.01 (dd, 1H), 4.69- 4.84 (m, 3H), 3.51-3.88 (m, 4H), 3.11-3.23 (m, 4H), 2.43 (s, 3H), 1.47 (s, 6H); LC/MS(ESI): m/z = 502[M+H] + .

實施例Example 5353

2-(2,6- 二氯苯基 )-1-(6-(2- 羥基丙基 -2- 基 ) 吡啶 -2- 基 )-6-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 )-1,2- 二氫 -3H- 吡唑 [4,3-c] 噠嗪 -3- 酮 ( 化合物 95) 的製備 用與 實施例 51相似的方法得到化合物 95(58 mg，產率48％)。LC/MS(ESI): m/z =606[M+H] +。 2-(2,6- Dichlorophenyl )-1-(6-(2- hydroxypropyl- 2- yl ) pyridin -2- yl )-6-((4-(4 - methylpyrazine- Preparation of 1- yl ) phenyl ) amino )-1,2- dihydro -3H- pyrazole [4,3-c] pyridazin -3- one ( compound 95) Compound 95 (58 mg, yield 48%) was obtained using a method similar to Example 51 . LC/MS(ESI): m/z =606[M+H] + .

實施例Example 5454

(R)-2-(2,6- 二氯苯基 )-1-(7- 乙基 -7- 羥基 -6,7- 二氫 -5H- 環戊 [b] 吡啶 -2- 基 )-6-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 )-1,2- 二氫 -3H- 吡唑 [4,3-c] 噠嗪 -3- 酮 ( 化合物 96) 的製備 用與 實施例 51相似的方法得到化合物 96(53 mg，產率42％)。LC/MS(ESI): m/z =632[M+H] +。 (R)-2-(2,6- dichlorophenyl )-1-(7- ethyl -7- hydroxy - 6,7- dihydro -5H- cyclopenta [b] pyridin -2- yl )- 6-((4-(4- methylpyridazin- 1- yl) phenyl ) amino ) -1,2- dihydro - 3H- pyrazole [4,3-c] pyridazin -3- one ( compound 96) Preparation Compound 96 (53 mg, yield 42%) was obtained using a method similar to Example 51 . LC/MS(ESI): m/z =632[M+H] + .

實施例Example 5555

2- 丙烯基 -1-(6-(2- 羥基丙基 -2- 基 ) 吡啶 -2- 基 )-6-((3- 甲基 -1,2,3,4,4a,5- 六氫呱嗪並 [1,2-d] 吡啶 [2,3-b][1,4] 惡嗪 -8- 基 ) 氨基 )-1,2- 二氫 -3H- 吡唑 [4,3-c] 噠嗪 -3- 酮 ( 化合物 97) 的製備 用與 實施例 51相似的方法得到化合物 97(40 mg，產率38％)。LC/MS(ESI): m/z =530[M+H] +。 2- propenyl -1-(6-(2- hydroxypropyl- 2- yl ) pyridin -2- yl )-6-((3- methyl- 1,2,3,4,4a,5- hexa Hydropiazino [1,2-d] pyridine [2,3-b][1,4] oxazin -8- yl ) amino )-1,2- dihydro -3H- pyrazole [4,3- c] Preparation of pyridazin -3- one ( compound 97) Compound 97 (40 mg, yield 38%) was obtained using a method similar to Example 51 . LC/MS(ESI): m/z =530[M+H] + .

實施例Example 5656

2- 丙烯基 -1-(6-(2- 羥基丙基 -2- 基 ) 吡啶 -2- 基 )-6-((8- 甲基 -6,6a,7,8,9,10- 六氫呱嗪並 [1,2-d] 吡啶 [3,2-b][1,4] 惡嗪 -8- 基 ) 氨基 )-1,2- 二氫 -3H- 吡唑 [4,3-c] 噠嗪 -3- 酮 ( 化合物 98) 的製備 用與 實施例 45相似的方法得到化合物 98(48mg，產率45％)。LC/MS(ESI): m/z =530[M+H] +。 2- propenyl -1-(6-(2- hydroxypropyl- 2- yl ) pyridin -2- yl )-6-((8- methyl -6,6a,7,8,9,10- hexa Hydropiazino [1,2-d] pyridine [3,2-b][1,4] oxazin -8- yl ) amino )-1,2- dihydro -3H- pyrazole [4,3- c] Preparation of pyridazin -3- one ( compound 98) Compound 98 (48 mg, yield 45%) was obtained using a method similar to Example 45 . LC/MS(ESI): m/z =530[M+H] + .

實施例Example 5757

(R)-2- 丙烯基 -1-(7- 乙基 -7- 羥基 -6,7- 二氫 -5H- 環戊 [b] 吡啶 -2- 基 )-6-((3- 甲基 -1,2,3,4,4a,5- 六氫苯並 [b] 吡嗪 [1,2-d][1,4] 惡嗪 -9- 基 ) 氨基 )-1,2- 二氫 -3H- 吡唑 [4,3-c] 噠嗪 -3- 酮 ( 化合物 99) 的製備 用與 實施例 45相似的方法得到化合物 99(58 mg，產率52％)。LC/MS(ESI): m/z =555[M+H] +。 (R)-2- propenyl -1-(7- ethyl -7- hydroxy -6,7- dihydro -5H- cyclopenta [b] pyridin -2- yl )-6-((3- methyl -1,2,3,4,4a,5 -hexahydrobenzo [b] pyrazine [1,2-d][1,4] oxazin -9- yl ) amino )-1,2- dihydro Preparation of -3H- pyrazole [4,3-c] pyridazin -3- one ( compound 99) Compound 99 (58 mg, yield 52%) was obtained using a method similar to Example 45 . LC/MS(ESI): m/z =555[M+H] + .

實施例Example 5858

(R)-2- 丙烯基 -1-(7- 乙基 -7- 羥基 -6,7- 二氫 -5H- 環戊 [b] 吡啶 -2- 基 )-6-((8- 甲基 -6,6a,7,8,9,10- 六氫呱嗪並 [1,2-d] 吡啶 [3,2-b][1,4] 惡嗪 -2- 基 ) 氨基 )-1,2- 二氫 -3H- 吡唑 [4,3-c] 噠嗪 -3- 酮 ( 化合物 100) 的製備 用與 實施例 45相似的方法得到化合物 100(51 mg，產率46％)。LC/MS(ESI): m/z =556[M+H] +。 (R)-2- propenyl -1-(7- ethyl -7- hydroxy -6,7- dihydro -5H- cyclopenta [b] pyridin -2- yl )-6-((8- methyl -6,6a,7,8,9,10 -hexahydropyrazino [1,2-d] pyridine [3,2-b][1,4] oxazin -2- yl ) amino )-1, Preparation of 2- dihydro -3H- pyrazole [4,3-c] pyridazin -3- one ( compound 100) Compound 100 (51 mg, yield 46%) was obtained using a method similar to Example 45 . LC/MS(ESI): m/z =556[M+H] + .

實施例Example 5959

2- 丙烯基 -1-(6-(2- 羥基丙基 -2- 基 ) 吡啶 -2- 基 )-6-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 )-1,2- 二氫 -3H- 吡唑 [4,3-c] 噠嗪 -3- 酮 ( 化合物 102) 的製備 用與 實施例 51相似的方法得到化合物 102(124 mg，產率82％)。LC/MS(ESI): m/z =502[M+H] +。 2- propenyl- 1-(6-(2- hydroxypropyl- 2- yl ) pyridin -2- yl )-6-((4-(4- methylpyrazin -1- yl ) phenyl ) amino Preparation of )-1,2- dihydro -3H- pyrazole [4,3-c] pyridazin -3- one ( compound 102) Compound 102 (124 mg, yield 82%) was obtained using a method similar to Example 51 . LC/MS(ESI): m/z =502[M+H] + .

實施例Example 6060

2- 丙烯基 -1-(6-(2- 羥基丙基 -2- 基 ) 吡啶 -2- 基 )-6-((8- 甲基 -6,6a,7,8,9,10- 六氫呱嗪並 [1,2-d] 吡啶 [3,2-b][1,4] 惡嗪 -2- 基 ) 氨基 )-1,2- 二氫 -3H- 吡唑 [4,3-c] 噠嗪 -3- 酮 ( 化合物 103) 的製備 用與 實施例 52相似的方法得到化合物 103(108 mg，產率68％)。LC/MS(ESI): m/z =531[M+H] +。 2- propenyl -1-(6-(2- hydroxypropyl- 2- yl ) pyridin -2- yl )-6-((8- methyl -6,6a,7,8,9,10- hexa Hydropiazino [1,2-d] pyridine [3,2-b][1,4] oxazin -2- yl ) amino )-1,2- dihydro -3H- pyrazole [4,3- c] Preparation of pyridazin -3- one ( compound 103) Compound 103 (108 mg, yield 68%) was obtained using a method similar to Example 52 . LC/MS(ESI): m/z =531[M+H] + .

實施例Example 6161

(R)-2- 丙烯基 -1-(7- 乙基 -7- 羥基 -6,7- 二氫 -5H- 環戊 [b] 吡啶 -2- 基 )-6-((3- 甲基 -1,2,3,4,4a,5- 六氫苯並 [b] 呱嗪 [1,2-d][1,4] 惡嗪 -9- 基 ) 氨基 )-1,2- 二氫 -3H- 吡唑 [4,3-c] 噠嗪 -3- 酮 ( 化合物 104) 的製備 用與 實施例 52相似的方法得到化合物 104(130 mg，產率78％)。LC/MS(ESI): m/z =556[M+H] +。 (R)-2- propenyl -1-(7- ethyl -7- hydroxy -6,7- dihydro -5H- cyclopenta [b] pyridin -2- yl )-6-((3- methyl -1,2,3,4,4a,5 -hexahydrobenzo [b] pyrazine [1,2-d][1,4] oxazin -9- yl ) amino )-1,2- dihydro Preparation of -3H- pyrazole [4,3-c] pyridazin -3- one ( compound 104) Compound 104 (130 mg, yield 78%) was obtained using a method similar to Example 52 . LC/MS(ESI): m/z =556[M+H] + .

實施例Example 6262

(R)-2- 丙烯基 -1-(7- 乙基 -7- 羥基 -6,7- 二氫 -5H- 環戊 [b] 吡啶 -2- 基 )-6-((8- 甲基 -6,6a,7,8,9,10- 六氫呱嗪並 [1,2-d] 吡啶 [3,2-b][1,4] 惡嗪 -2- 基 ) 氨基 )-1,2- 二氫 -3H- 吡唑 [4,3-c] 噠嗪 -3- 酮 ( 化合物 105) 的製備 用與 實施例 52相似的方法得到化合物 105(126 mg，產率76％)。LC/MS(ESI): m/z =557[M+H] +。 (R)-2- propenyl -1-(7- ethyl -7- hydroxy -6,7- dihydro -5H- cyclopenta [b] pyridin -2- yl )-6-((8- methyl -6,6a,7,8,9,10 -hexahydropyrazino [1,2-d] pyridine [3,2-b][1,4] oxazin -2- yl ) amino )-1, Preparation of 2- dihydro -3H- pyrazole [4,3-c] pyridazin -3- one ( compound 105) Compound 105 (126 mg, yield 76%) was obtained using a method similar to Example 52 . LC/MS(ESI): m/z =557[M+H] + .

實施例Example 6363

(R)-2- 丙烯基 -1-(7- 乙基 -7- 羥基 -6,7- 二氫 -5H- 環戊 [b] 吡啶 -2- 基 )-6-((4-(4- 甲基呱嗪 -1- 基 ) 苯基 ) 氨基 )-1,2- 二氫 -3H- 吡唑 [4,3-c] 噠嗪 -3- 酮 ( 化合物 106) 的製備 用與 實施例 52相似的方法得到化合物 106(131 mg，產率83％)。LC/MS(ESI): m/z =528[M+H] +。 (R)-2- propenyl -1-(7- ethyl -7- hydroxy -6,7- dihydro -5H- cyclopenta [b] pyridin -2- yl )-6-((4-(4 Preparation of -methylpyridazin -1- yl ) phenyl ) amino )-1,2- dihydro -3H- pyrazole [4,3-c] pyridazin -3- one ( compound 106) Compound 106 (131 mg, yield 83%) was obtained using a method similar to Example 52 . LC/MS(ESI): m/z =528[M+H] + .

實施例Example 6464

(R)-2- 丙烯基 -1-(7- 乙基 -7- 羥基 -6,7- 二氫 -5H- 環戊 [b] 吡啶 -2- 基 )-6-((5-(4- 甲基呱嗪 -1- 基 ) 吡啶 -2- 基 ) 氨基 )-1,2- 二氫 -3H- 吡唑 [4,3-c] 噠嗪 -3- 酮 ( 化合物 107) 的製備 用與 實施例 52相似的方法得到化合物 107(129 mg，產率82％)。LC/MS(ESI): m/z =529[M+H] +。 (R)-2- propenyl -1-(7- ethyl -7- hydroxy -6,7- dihydro -5H- cyclopenta [b] pyridin -2- yl )-6-((5-(4 Preparation of -methylpyridin -1- yl ) pyridin -2- yl ) amino )-1,2- dihydro -3H- pyrazole [4,3-c] pyridazin -3- one ( compound 107) Compound 107 (129 mg, yield 82%) was obtained using a method similar to Example 52 . LC/MS(ESI): m/z =529[M+H] + .

實施例Example 6565

(R)-2- 丙烯基 -1-(7- 乙基 -7- 羥基 -6,7- 二氫 -5H- 環戊 [b] 吡啶 -2- 基 )-6-((3- 甲基 -1,2,3,4,4a,5- 六氫苯並 [b] 呱嗪 [1,2-d][1,4] 惡嗪 -8- 基 ) 氨基 )-1,2- 二氫 -3H- 吡唑 [4,3-c] 噠嗪 -3- 酮 ( 化合物 108) 的製備 用與 實施例 52相似的方法得到化合物 108(130 mg，產率78％)。LC/MS(ESI): m/z =556[M+H] +。 (R)-2- propenyl -1-(7- ethyl -7- hydroxy -6,7- dihydro -5H- cyclopenta [b] pyridin -2- yl )-6-((3- methyl -1,2,3,4,4a,5 -hexahydrobenzo [b] pyrazine [1,2-d][1,4] oxazin -8- yl ) amino )-1,2- dihydro Preparation of -3H- pyrazole [4,3-c] pyridazin -3- one ( compound 108) Compound 108 (130 mg, yield 78%) was obtained using a method similar to Example 52 . LC/MS(ESI): m/z =556[M+H] + .

實施例 66 ： 生物活性測試以下結合測試例進一步描述解釋本發明，但這些實施並非意味著限制本發明的範圍。 Example 66 : Biological Activity Test The present invention is further described and explained below in conjunction with test examples, but these implementations are not meant to limit the scope of the present invention.

測試例test case 11 、化合物抑制, compounds inhibit Wee-1Wee-1 酶活性測定Enzyme activity assay

運用Lanthra Screen Wee-1激酶試劑盒(invitrogen)，測定化合物抑制Wee-1激酶活性。在DMSO中從0.2 mM的工作濃度進行4倍梯度稀釋，稀釋10個濃度，5μL Wee-1激酶(終濃度5nM)，5μL Eu-Anti-GST Antibody(終濃度2nM)混合物和5μL kinase Tracer 178(終濃度50nM)充分混合後，在室溫孵育一小時後，讀板。從單獨的培養基(細胞數為零)得到最小信號值，抑制率%=(最大信號值化合物信號值)/(最大信號值一最小信號值×100%，使用 Graphpadprism5軟體處理數據。通過S形劑量反應曲線擬合計算IC 50值。其中“A”表示IC 50≤10 nM；“B”表示10nM＜IC 50≤500 nM；“C”表示500nM＜IC 50≤2000 nM；“D”表示2000nM＜IC 50。 Lanthra Screen Wee-1 Kinase Kit (invitrogen) was used to determine the inhibition of Wee-1 kinase activity by compounds. Make a 4-fold gradient dilution of 10 in DMSO from a working concentration of 0.2 mM, 5 μL of Wee-1 Kinase (5 nM final concentration), 5 μL of Eu-Anti-GST Antibody (2 nM final concentration) mix and 5 μL of kinase Tracer 178 ( After mixing thoroughly (final concentration 50 nM), incubate at room temperature for one hour and read the plate. The minimum signal value was obtained from the culture medium alone (the number of cells was zero). The inhibition rate % = (maximum signal value compound signal value) / (maximum signal value - minimum signal value × 100%. Use Graphpadprism5 software to process the data. Through S-shaped dose Calculate the IC 50 value by fitting the reaction curve. “A” means IC 50 ≤10 nM; “B” means 10nM＜IC 50 ≤500 nM; “C” means 500nM＜IC 50 ≤2000 nM; “D” means 2000nM＜ IC 50 .

表1.本發明化合物抑制Wee1激酶活性的IC 50 化合物 IC 50 化合物 IC 50 化合物 IC 50 1 A 8 A 15 A 2 A 9 A 16 A 3 A 10 A 17 A 4 A 12 A 18 A 5 A 13 A 101 A 6 A 14 A 103 A Table 1. IC 50 of compounds of the present invention inhibiting Wee1 kinase activity compound IC 50 compound IC 50 compound IC 50 1 A 8 A 15 A 2 A 9 A 16 A 3 A 10 A 17 A 4 A 12 A 18 A 5 A 13 A 101 A 6 A 14 A 103 A

測試例test case 22 、化合物的細胞增殖活性測定, Determination of cell proliferation activity of compounds

採用CellTiter-Glo＜TM＞活細胞檢測試劑盒，測定受試化合物對人非小細胞肺癌細胞NCI-H23增殖的抑制作用。其中，培養基為添加終濃度為10％的胎牛血清、McCoy's 5A培養基。CellTiter-Glo＜TM＞ live cell detection kit was used to determine the inhibitory effect of the test compound on the proliferation of human non-small cell lung cancer cell NCI-H23. Among them, the culture medium is fetal bovine serum and McCoy's 5A medium with a final concentration of 10%.

試驗步驟：用胰酶消化已達到80％細胞融合的NCI-H23細胞，離心重懸計數，用培養基分別製成6000個細胞/mL的NCI-H23細胞懸液，加入96孔細胞培養板(90μL/孔)，置於含5％CO 2的細胞培養箱中於37°C培養。細胞培養24小時後，參考化合物表及受試化合物用DMSO溶解成濃度為30mM的母液。用NCI-H23的培養基將稀釋好的化合物母液進行進一步稀釋，並將稀釋好的混合液分別轉移至相應的細胞板中，受試化合物終濃度為1μM (作為IC 50測試的起始濃度)，四倍遞減稀釋9個濃度，9個濃度分別為：10μM、2.5μM、0.625μM、0.156μM、0.039μM、0.0098μM、0.0024μM、0.0006μM和0.000015μM，混勻離心，置於含5％CO 2的細胞培養箱中於37°C培養3天。取出96孔細胞培養板，加入CellTiterGlo(CTG，化學發光細胞活性檢測試劑盒)試劑(100μL/孔)，混勻離心，於室溫孵育10分鐘。輕輕震盪後在SpectraMax M5  Reader 上測定450nm波長處的吸光度，以650 nm 處吸光度作為參比(即450nm吸光度-650nm吸光度），計算抑制率。運用軟體Graphpad Prism 6 並採用計算公式 XY-analysis/Nonlinear regression(curve fit)/Dose response-Inhibition/log(inhibitor)vs. response-Variable slope(four parameters) 進行IC 50曲線擬合併計算出IC 50值。其中“A”表示IC 50≤10 nM；“B”表示10nM＜IC 50≤500 nM；“C”表示500nM＜IC 50≤2000 nM；“D”表示2000nM＜IC 50。 Test steps: Use trypsin to digest NCI-H23 cells that have reached 80% cell confluence, centrifuge and resuspend for counting. Use culture medium to prepare NCI-H23 cell suspension of 6000 cells/mL, and add it to a 96-well cell culture plate (90 μL /well) and cultured at 37°C in a cell culture incubator containing 5% CO2 . After the cells were cultured for 24 hours, the reference compound table and the test compound were dissolved in DMSO to a stock solution with a concentration of 30mM. Further dilute the diluted compound stock solution with NCI-H23 culture medium, and transfer the diluted mixture to the corresponding cell plate. The final concentration of the test compound is 1 μM (as the starting concentration for the IC 50 test). Four-fold descending dilution to 9 concentrations, the 9 concentrations are: 10μM, 2.5μM, 0.625μM, 0.156μM, 0.039μM, 0.0098μM, 0.0024μM, 0.0006μM and 0.000015μM, mix and centrifuge, place in 5% CO 2 cells were cultured at 37°C for 3 days. Take out the 96-well cell culture plate, add CellTiterGlo (CTG, chemiluminescence cell activity detection kit) reagent (100 μL/well), mix and centrifuge, and incubate at room temperature for 10 minutes. After gentle shaking, measure the absorbance at a wavelength of 450nm on the SpectraMax M5 Reader. Use the absorbance at 650 nm as a reference (ie, 450nm absorbance - 650nm absorbance) to calculate the inhibition rate. Use the software Graphpad Prism 6 and use the calculation formula XY-analysis/Nonlinear regression(curve fit)/Dose response-Inhibition/log(inhibitor) vs. response-Variable slope(four parameters) to fit the IC 50 curve and calculate the IC 50 value . Among them, “A” means IC 50 ≤10 nM; “B” means 10nM＜IC 50 ≤500 nM; “C” means 500nM＜IC 50 ≤2000 nM; “D” means 2000nM＜IC 50 .

表2.本發明化合物抑制NCI-H23細胞生長的IC 50 化合物 IC 50 化合物 IC 50 化合物 IC 50 1 B 4 B 34 C 3 B 33 C 101 B Table 2. IC 50 of compounds of the present invention inhibiting the growth of NCI-H23 cells compound IC 50 compound IC 50 compound IC 50 1 B 4 B 34 C 3 B 33 C 101 B

儘管以上已經對本發明作了詳細描述，但是本領域技術人員理解，在不偏離本發明的精神和範圍的前提下可以對本發明進行各種修改和改變。本發明的權利範圍並不限於上文所作的詳細描述，而應歸屬於專利申請範圍。Although the present invention has been described in detail above, those skilled in the art will understand that various modifications and changes can be made to the present invention without departing from the spirit and scope of the invention. The scope of rights of the present invention is not limited to the detailed description above, but belongs to the scope of the patent application.

無。without.

無。without.

無。without.

Claims (4)

一種化合物、其藥學上可接受的鹽或其立體異構體，所述的化合物選自以下任一種： 或其藥學上可接受的鹽、溶劑化物、多晶型物或異構體。 A compound, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, the compound being selected from any of the following: or a pharmaceutically acceptable salt, solvate, polymorph or isomer thereof. 一種藥物組合物，其包含如請求項1所述的化合物、其藥學上可接受的鹽或其立體異構體，以及藥學上可接受的載體。A pharmaceutical composition comprising the compound described in claim 1, its pharmaceutically acceptable salt or its stereoisomer, and a pharmaceutically acceptable carrier. 一種如請求項1中任一項所述的化合物、其藥學上可接受的鹽或其立體異構體、以及如請求項2所述的藥物組合物在製備用來治療跟WEE1活性相關的疾病的藥物中的用途。A compound as described in any one of claim 1, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and a pharmaceutical composition as described in claim 2 for use in the treatment of diseases related to WEE1 activity uses in medicines. 如請求項3所述的用途，其中所述跟WEE1活性相關的疾病為肝癌、乳腺癌、惡性膠質瘤、黑色素瘤、成人腦瘤、兒童腦瘤、卵巢癌、結腸癌、宮頸癌、骨肉瘤、肺癌、胃癌、頭頸癌或白血病。The use as described in claim 3, wherein the diseases related to WEE1 activity are liver cancer, breast cancer, malignant glioma, melanoma, adult brain tumors, children's brain tumors, ovarian cancer, colon cancer, cervical cancer, and osteosarcoma , lung cancer, stomach cancer, head and neck cancer or leukemia.
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