TW202241901A - Purinone derivative, preparation method therefor and application thereof in medicine - Google Patents

Abstract

The present application provides a purinone derivative, a preparation method therefor and an application thereof in medicine. Specifically, the present application provides a purinone derivative as represented by formula (IG), a preparation method therefor, a pharmaceutical composition comprising the derivative, and an application of the derivative as a therapeutic agent, particularly a use as a DNA-PK inhibitor and the use of same in the preparation of a drug for treating or preventing cancer, wherein substituents in the formula (IG) have the same definitions as those in the description.

Description

嘌呤酮衍生物、其製備方法及其在醫藥上的應用 Purinone derivative, its preparation method and its application in medicine

本揭露屬於醫藥領域，關於一種嘌呤酮衍生物、其製備方法及其在醫藥上的應用。特別地，本揭露關於通式(IG)所示的嘌呤酮衍生物、其製備方法及含有該衍生物的醫藥組成物，以及其作為DNA-PK抑制劑在製備治療和/或預防癌症的藥物中的用途。 The disclosure belongs to the field of medicine, and relates to a purinone derivative, its preparation method and its application in medicine. In particular, the disclosure relates to purinone derivatives represented by general formula (IG), their preparation methods and pharmaceutical compositions containing the derivatives, and their use as DNA-PK inhibitors in the preparation of drugs for treating and/or preventing cancer use in .

DNA依賴性蛋白激酶(DNA-PK)是由催化亞基DNA-PKcs和Ku蛋白(Ku70/Ku80)的異二聚體組成的絲胺酸/羥丁胺酸蛋白激酶複合物，是DNA損傷修復過程中的一個重要蛋白(Cancer Discovery,2014,4,1126-1139)；在維持端粒酶的穩定性、參與天然免疫及V(D)J重組、以及轉錄調節等方面也發揮著重要作用(Curr Opin Allergy Clin Immunol,2009,9,503-509)。 DNA-dependent protein kinase (DNA-PK) is a serine/hydroxybutyrate protein kinase complex composed of a heterodimer of the catalytic subunit DNA-PKcs and Ku protein (Ku70/Ku80), and is a DNA damage repair An important protein in the process (Cancer Discovery, 2014, 4, 1126-1139); it also plays an important role in maintaining the stability of telomerase, participating in innate immunity and V(D)J recombination, and transcription regulation ( Curr Opin Allergy Clin Immunol, 2009, 9, 503-509).

真核生物的DNA修復主要有4種類型：核苷酸切除修復(NER)、鹼基切除修復(BER)、錯配修復(MMR)和雙鏈斷裂修復(DSBR)。NER可切除大片段的DNA損傷，BER可修復個別鹼基的損傷，MMR用於修復鹼基的錯配，而DSBR又包括兩種機制：非同源末端連接(NHEJ)和同源重組(HR)。NHEJ直接 連接斷端而不需要範本，HR需要使用完整的姐妹染色單體作為修復範本。NHEJ是最主要的修復途徑，在細胞週期的所有期中均能發生。而HR主要發生在細胞週期的G2/M期(ChemMedChem,2017,12,895-900)。在DNA損傷修復中起主導作用的是三個PI3K相關激酶(PIKK)家族的激酶：DNA依賴性蛋白激酶(DNA-PK)、毛細血管擴張性共濟失調症突變激酶(ATM)，以及ATM和Rad3相關激酶(ATR)。DNA-PK主要參與NHEJ途徑，ATM主要參與HR途徑，而ATR主要修復單鏈DNA損傷(Nat Rev Clin Oncol.,2019,81-104)。 There are four main types of DNA repair in eukaryotes: nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR) and double-strand break repair (DSBR). NER can excise large fragments of DNA damage, BER can repair individual base damage, MMR is used to repair base mismatches, and DSBR includes two mechanisms: non-homologous end joining (NHEJ) and homologous recombination (HR ). NHEJ Direct To join the broken ends without a template, HR needs to use the intact sister chromatid as a template for repair. NHEJ is the most important repair pathway and can occur in all phases of the cell cycle. HR mainly occurs in the G2/M phase of the cell cycle (ChemMedChem, 2017, 12, 895-900). Three kinases from the PI3K-related kinase (PIKK) family play a dominant role in DNA damage repair: DNA-dependent protein kinase (DNA-PK), ataxia telangiectasia mutated kinase (ATM), and ATM and Rad3-related kinase (ATR). DNA-PK is mainly involved in the NHEJ pathway, ATM is mainly involved in the HR pathway, and ATR is mainly involved in the repair of single-strand DNA damage (Nat Rev Clin Oncol., 2019, 81-104).

當DNA雙鏈斷裂時，環狀Ku70/Ku80異源二聚體識別和結合斷裂的DNA末端，招募DNA-PKcs。DNA-PKcs的募集促進了Ku異源二聚體向DNA雙鏈體中的移動，使得DNA-PKcs可用作斷裂DNA末端的系鏈並防止外切核酸酶的降解。同時，與DNA的結合促進了DNA-PKcs催化活性的啟動，主要的自磷酸化位點是Ser2056和Thr2609。DNA-PKcs還導致一系列下游蛋白的磷酸化，包括Artemis、DNA連接酶4、組蛋白H2A變體(H2AX)等，共同完成DNA雙鏈修復(Nat Rev Clin Oncol.,2019,81-104)。 When DNA double-strand breaks, the circular Ku70/Ku80 heterodimer recognizes and binds to the broken DNA end, recruiting DNA-PKcs. Recruitment of DNA-PKcs promotes the movement of Ku heterodimers into the DNA duplex, allowing DNA-PKcs to serve as tethers for breaking DNA ends and preventing degradation by exonucleases. At the same time, the combination with DNA promotes the initiation of DNA-PKcs catalytic activity, and the main autophosphorylation sites are Ser2056 and Thr2609. DNA-PKcs also leads to the phosphorylation of a series of downstream proteins, including Artemis, DNA ligase 4, histone H2A variant (H2AX), etc., to complete DNA double-strand repair (Nat Rev Clin Oncol., 2019, 81-104) .

DNA-PK在多種類型的腫瘤組織中均有高表達，可以藉由刺激血管再生及腫瘤細胞遷移導致腫瘤轉移(Clin Cancer Res,2019,25,5623-5637)。而且DNA-PK活性的增加與化療藥的耐藥及較差的預後密切相關。研究表明，DNA-PK抑制劑能明顯增加腫瘤細胞對x射線輻照(IR)及化療藥的敏感性，並增加PAPR抑制劑olaparib的抑瘤作用(Nat Commun.,2019,10,5065-5079；Mol Cancer Res.,2019,17,2457-2468)。 DNA-PK is highly expressed in various types of tumor tissues and can lead to tumor metastasis by stimulating angiogenesis and tumor cell migration (Clin Cancer Res, 2019, 25, 5623-5637). Moreover, the increase of DNA-PK activity is closely related to the resistance of chemotherapy drugs and poor prognosis. Studies have shown that DNA-PK inhibitors can significantly increase the sensitivity of tumor cells to x-ray irradiation (IR) and chemotherapy drugs, and increase the antitumor effect of the PAPR inhibitor olaparib (Nat Commun., 2019, 10, 5065-5079 ; Mol Cancer Res., 2019, 17, 2457-2468).

目前以AstraZeneca和Merck為代表的公司發表了若干DNA-PK抑制劑的專利(WO2019238929A1、WO2018114999A1和WO2014183850A1等)， 這些結構類型的化合物無論是體外活性還是選擇性都還有提高的空間。其中AstraZeneca的小分子DNA-PK抑制劑於2019年10月進入臨床一期。目前還沒有DNA-PK抑制劑藥物被批准上市，因此相關病患人群中存在重大未滿足的醫學需求。 At present, companies represented by AstraZeneca and Merck have published several patents on DNA-PK inhibitors (WO2019238929A1, WO2018114999A1 and WO2014183850A1, etc.), There is room for improvement in both in vitro activity and selectivity of these structural types of compounds. Among them, AstraZeneca's small molecule DNA-PK inhibitor entered the clinical phase I in October 2019. There are currently no DNA-PK inhibitor drugs approved for marketing, so there is a significant unmet medical need in the relevant patient population.

本揭露的目的在於提供一種通式(IG)所示的化合物或其可藥用的鹽： The purpose of this disclosure is to provide a compound represented by general formula (IG) or a pharmaceutically acceptable salt thereof:

其中， in,

G¹、G²和G³相同或不同，且各自獨立為CR²或氮原子； G ¹ , G ² and G ³ are the same or different, and are each independently CR ² or a nitrogen atom;

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

環B為環烷基或雜環基； Ring B is cycloalkyl or heterocyclyl;

R¹相同或不同，且各自獨立地選自氫原子、鹵素、烷基、烯基、炔基、烷氧基、鹵烷基、鹵烷氧基、側氧、氰基、胺基、硝基、羥基和羥烷基； R ^are the same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, side oxygen, cyano, amino, nitro , hydroxyl and hydroxyalkyl;

R²相同或不同，且各自獨立地選自氫原子、鹵素、烷基、烯基、炔基、烷氧基、鹵烷基、鹵烷氧基、氰基、胺基、硝基、羥基和羥烷基； R ² are the same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxyl and Hydroxyalkyl;

R³選自氫原子、烷基、鹵烷基、環烷基和雜環基，其中該烷基、鹵烷基、環烷基和雜環基各自獨立地視需要被選自鹵素、烷基、烯基、炔基、烷氧基、鹵烷基、鹵烷氧基、側氧、氰基、胺基、硝基、羥基、羥烷基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； ^R is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group and a heterocyclyl group, wherein each of the alkyl group, haloalkyl group, cycloalkyl group and heterocyclyl group is independently selected from halogen, alkyl , alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, pendant oxygen, cyano, amine, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and hetero One or more substituents in the aryl group are substituted;

R⁴相同或不同，且各自獨立地選自氫原子、鹵素、烷基、烯基、炔基、烷氧基、鹵烷基、鹵烷氧基、側氧、氰基、胺基、硝基、羥基和羥烷基； R ^are the same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, side oxygen, cyano, amino, nitro , hydroxyl and hydroxyalkyl;

p為0、1、2、3、4或5；且 p is 0, 1, 2, 3, 4 or 5; and

q為0、1、2、3、4或5。 q is 0, 1, 2, 3, 4 or 5.

在本揭露一些較佳的實施方案中，該通式(IG)所示的化合物或其可藥用的鹽，其中G¹為CR²或氮原子；G²和G³相同或不同，且各自獨立為CR²；R²如通式(IG)中所定義。 In some preferred embodiments of the present disclosure, the compound represented by the general formula (IG) or a pharmaceutically acceptable salt thereof, wherein G ¹ is CR ² or a nitrogen atom; G ² and G ³ are the same or different, and each independently is CR ² ; R ² is as defined in general formula (IG).

在本揭露一些較佳的實施方案中，該通式(IG)所示的化合物或其可藥用的鹽，其中G¹為氮原子；G²和G³相同或不同，且各自獨立為CR²；R²如通式(IG)中所定義。 In some preferred embodiments of the present disclosure, the compound represented by the general formula (IG) or a pharmaceutically acceptable salt thereof, wherein G ¹ is a nitrogen atom; G ² and G ³ are the same or different, and each independently represents CR ² ; R ² is as defined in general formula (IG).

本揭露一些較佳的實施方案中，提供一種通式(I)所示的化合物或其可藥用的鹽： In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is provided:

其中， in,

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

環B為環烷基或雜環基； Ring B is cycloalkyl or heterocyclyl;

R¹相同或不同，且各自獨立地選自氫原子、鹵素、烷基、烯基、炔基、烷氧基、鹵烷基、鹵烷氧基、側氧、氰基、胺基、硝基、羥基和羥烷基； R ^are the same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, side oxygen, cyano, amino, nitro , hydroxyl and hydroxyalkyl;

R²相同或不同，且各自獨立地選自氫原子、鹵素、烷基、烯基、炔基、烷氧基、鹵烷基、鹵烷氧基、氰基、胺基、硝基、羥基和羥烷基； R ² are the same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxyl and Hydroxyalkyl;

R³選自氫原子、烷基、鹵烷基、環烷基和雜環基，其中該烷基、鹵烷基、環烷基和雜環基各自獨立地視需要被選自鹵素、烷基、烯基、炔基、烷氧基、鹵烷基、鹵烷氧基、側氧、氰基、胺基、硝基、羥基、羥烷基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； ^R is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group and a heterocyclyl group, wherein each of the alkyl group, haloalkyl group, cycloalkyl group and heterocyclyl group is independently selected from halogen, alkyl , alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, pendant oxygen, cyano, amine, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and hetero One or more substituents in the aryl group are substituted;

R⁴相同或不同，且各自獨立地選自氫原子、鹵素、烷基、烯基、炔基、烷氧基、鹵烷基、鹵烷氧基、側氧、氰基、胺基、硝基、羥基和羥烷基； R ^are the same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, side oxygen, cyano, amino, nitro , hydroxyl and hydroxyalkyl;

n為0、1、2或3； n is 0, 1, 2 or 3;

p為0、1、2、3、4或5；且 p is 0, 1, 2, 3, 4 or 5; and

q為0、1、2、3、4或5。 q is 0, 1, 2, 3, 4 or 5.

本揭露一些較佳的實施方案中，提供一種通式(II)所示的化合物或其可藥用的鹽： In some preferred embodiments of the present disclosure, a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof is provided:

其中， in,

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

環B為環烷基或雜環基； Ring B is cycloalkyl or heterocyclyl;

R¹相同或不同，且各自獨立地選自氫原子、鹵素、烷基、烯基、炔基、烷氧基、鹵烷基、鹵烷氧基、側氧、氰基、胺基、硝基、羥基和羥烷基； R ^are the same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, side oxygen, cyano, amino, nitro , hydroxyl and hydroxyalkyl;

R²相同或不同，且各自獨立地選自氫原子、鹵素、烷基、烯基、炔基、烷氧基、鹵烷基、鹵烷氧基、氰基、胺基、硝基、羥基和羥烷基； R ² are the same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxyl and Hydroxyalkyl;

R³選自氫原子、烷基、鹵烷基、環烷基和雜環基，其中該烷基、鹵烷基、環烷基和雜環基各自獨立地視需要被選自鹵素、烷基、烯基、炔基、烷氧基、鹵烷基、鹵烷氧基、側氧、氰基、胺基、硝基、羥基、羥烷基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； ^R is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group and a heterocyclyl group, wherein each of the alkyl group, haloalkyl group, cycloalkyl group and heterocyclyl group is independently selected from halogen, alkyl , alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, pendant oxygen, cyano, amine, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and hetero One or more substituents in the aryl group are substituted;

R⁴相同或不同，且各自獨立地選自氫原子、鹵素、烷基、烯基、炔基、烷氧基、鹵烷基、鹵烷氧基、側氧、氰基、胺基、硝基、羥基和羥烷基； R ^are the same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, side oxygen, cyano, amino, nitro , hydroxyl and hydroxyalkyl;

n為0、1或2； n is 0, 1 or 2;

p為0、1、2、3、4或5；且 p is 0, 1, 2, 3, 4 or 5; and

q為0、1、2、3、4或5。 q is 0, 1, 2, 3, 4 or 5.

在本揭露一些較佳的實施方案中，該通式(IG)、通式(I)或通式(II)所示的化合物或其可藥用的鹽，其中環A為5至6員雜芳基或3至6員雜環基；較佳為5員雜芳基或5至6員雜環基；更佳選自咪唑基、吡唑基、***基、1,2,4-噁二唑-5(2H)-酮、噻唑基、吡咯基、噻吩基和呋喃基。 In some preferred embodiments of the present disclosure, the compound represented by general formula (IG), general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-6 membered hetero Aryl or 3 to 6 membered heterocyclic group; preferably 5 membered heteroaryl or 5 to 6 membered heterocyclic group; more preferably selected from imidazolyl, pyrazolyl, triazolyl, 1,2,4-oxo Oxadiazol-5( 2H )-one, thiazolyl, pyrrolyl, thienyl and furyl.

在本揭露一些較佳的實施方案中，該通式(IG)、通式(I)或通式(II)所示的化合物或其可藥用的鹽，其中環A為5員雜芳基，較佳選自咪唑基、吡唑基、***基、噻唑基、吡咯基、噻吩基和呋喃基。 In some preferred embodiments of the present disclosure, the compound represented by general formula (IG), general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heteroaryl , preferably selected from imidazolyl, pyrazolyl, triazolyl, thiazolyl, pyrrolyl, thienyl and furyl.

在本揭露一些較佳的實施方案中，該通式(IG)、通式(I)或通式(II)所示的化合物或其可藥用的鹽，其中環B為3至14員雜環基；較佳為3至 6員雜環基；更佳為6員雜環基；甚至更佳為四氫吡喃基；最佳為

。 In some preferred embodiments of the present disclosure, the compound represented by general formula (IG), general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein ring B is a 3- to 14-membered hetero Cyclic group; preferably 3 to 6-membered heterocyclic group; more preferably 6-membered heterocyclic group; even more preferably tetrahydropyranyl; most preferably

.

在本揭露一些較佳的實施方案中，該通式(IG)、通式(I)或通式(II)所示的化合物或其可藥用的鹽，其中環A為5員雜芳基或5至6員雜環基；且環B為3至6員雜環基。 In some preferred embodiments of the present disclosure, the compound represented by general formula (IG), general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heteroaryl or a 5 to 6 membered heterocyclyl; and Ring B is a 3 to 6 membered heterocyclyl.

在本揭露一些較佳的實施方案中，該通式(IG)、通式(I)或通式(II)所示的化合物，或其可藥用的鹽，其中R³為C_1-6烷基或3至6員環烷基；較佳地，R³為甲基或環丙基；更佳地，R³為甲基。 In some preferred embodiments of the present disclosure, the compound represented by general formula (IG), general formula (I) or general formula (II), or a pharmaceutically acceptable salt thereof, wherein R ³ is C _1-6 Alkyl or 3 to 6-membered cycloalkyl; preferably, R ³ is methyl or cyclopropyl; more preferably, R ³ is methyl.

在本揭露一些較佳的實施方案中，該通式(IG)、通式(I)或通式(II)所示的化合物或其可藥用的鹽，其中R¹相同或不同，且各自獨立地選自氫原子、鹵素、C_1-6烷基和側氧；較佳地，R¹相同或不同，且各自獨立地選自氫原子、C_1-6烷基和側氧；進一步佳地，R¹相同或不同，且各自獨立地選自氫原子、甲基和側氧；更佳地，R¹相同或不同，且各自獨立地為氫原子或側氧。 In some preferred embodiments of the present disclosure, the compound represented by general formula (IG), general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein R ¹ are the same or different, and each independently selected from hydrogen atom, halogen, C _1-6 alkyl and side oxygen; preferably, R ¹ is the same or different, and each independently selected from hydrogen atom, C _1-6 alkyl and side oxygen; further preferred Preferably, R ¹ are the same or different, and are each independently selected from a hydrogen atom, a methyl group, and a side oxygen; more preferably, R ¹ are the same or different, and are each independently a hydrogen atom or a side oxygen.

在本揭露一些較佳的實施方案中，該通式(IG)、通式(I)或通式(II)所示的化合物或其可藥用的鹽，其中R¹相同或不同，且各自獨立地選自氫原子、C_1-6烷基和側氧；較佳地，R¹相同或不同，且各自獨立地為氫原子或C_1-6烷基；更佳地，R¹為C_1-6烷基；最佳地，R¹為甲基。 In some preferred embodiments of the present disclosure, the compound represented by general formula (IG), general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein R ¹ are the same or different, and each independently selected from hydrogen atom, C _1-6 alkyl and side oxygen; preferably, R ¹ is the same or different, and each independently is a hydrogen atom or C _1-6 alkyl; more preferably, R ¹ is C _1-6 alkyl; most preferably, R ¹ is methyl.

在本揭露一些較佳的實施方案中，該通式(IG)、通式(I)或通式(II)所示的化合物或其可藥用的鹽，其中R²相同或不同，且各自獨立地選自氫原子、鹵素、氰基和C_1-6烷基；較佳地，R²相同或不同，且各自獨立地選自氫原子、氰基和C_1-6烷基；進一步佳地，R²相同或不同，且各自獨立地為氫原子或氰基；更佳地，R²為氫原子。 In some preferred embodiments of the present disclosure, the compound represented by general formula (IG), general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein R ² are the same or different, and each independently selected from hydrogen atom, halogen, cyano and C _1-6 alkyl; preferably, R ² is the same or different, and each independently selected from hydrogen atom, cyano and C _1-6 alkyl; further preferred Preferably, R ² is the same or different, and each independently is a hydrogen atom or a cyano group; more preferably, R ² is a hydrogen atom.

在本揭露一些較佳的實施方案中，該通式(IG)、通式(I)或通式(II)所示的化合物或其可藥用的鹽，其中R⁴相同或不同，且各自獨立地為氫原子或C_1-6烷基；較佳地，R⁴為氫原子。 In some preferred embodiments of the present disclosure, the compound represented by general formula (IG), general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein R ⁴ are the same or different, and each are independently a hydrogen atom or a C _1-6 alkyl group; preferably, R ⁴ is a hydrogen atom.

在本揭露一些較佳的實施方案中，該通式(IG)、通式(I)或通式(II)所示的化合物或其可藥用的鹽，其中p為0、1、2或3，較佳為0或1。 In some preferred embodiments of the present disclosure, the compound represented by general formula (IG), general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2 or 3, preferably 0 or 1.

在本揭露一些較佳的實施方案中，該通式(I)或通式(II)所示的化合物或其可藥用的鹽，其中n為0或1。 In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

在本揭露一些較佳的實施方案中，該通式(IG)、通式(I)或通式(II)所示的化合物或其可藥用的鹽，其中q為0或1。 In some preferred embodiments of the present disclosure, the compound represented by general formula (IG), general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof, wherein q is 0 or 1.

在本揭露一些較佳的實施方案中，該通式(IG)所示的化合物或其可藥用的鹽，其中G¹為CR²或氮原子；G²和G³相同或不同，且各自獨立為CR²； 環A為5員雜芳基或5至6員雜環基；環B為

；R³為甲基或環丙基；R¹ 相同或不同，且各自獨立地選自氫原子、C_1-6烷基和側氧；R²相同或不同，且各自獨立地選自氫原子、氰基和C_1-6烷基；R⁴為氫原子；p為0、1、2或3；且q為0或1。 In some preferred embodiments of the present disclosure, the compound represented by the general formula (IG) or a pharmaceutically acceptable salt thereof, wherein G ¹ is CR ² or a nitrogen atom; G ² and G ³ are the same or different, and each is independently CR ² ; ring A is 5-membered heteroaryl or 5-6 membered heterocyclyl; ring B is

; R ³ is methyl or cyclopropyl; R ¹ is the same or different, and each independently selected from a hydrogen atom, C _1-6 alkyl and side oxygen; R ² is the same or different, and each independently selected from a hydrogen atom , cyano and C _1-6 alkyl; R ⁴ is a hydrogen atom; p is 0, 1, 2 or 3; and q is 0 or 1.

在本揭露一些較佳的實施方案中，該通式(IG)所示的化合物或其可藥用的鹽，其中G¹為氮原子；G²和G³相同或不同，且各自獨立為CR²；環A 為5員雜芳基；環B為

；R³為甲基；R¹為C_1-6烷基；p為0或1；R²為氫 原子；R⁴為氫原子；且q為0或1。 In some preferred embodiments of the present disclosure, the compound represented by the general formula (IG) or a pharmaceutically acceptable salt thereof, wherein G ¹ is a nitrogen atom; G ² and G ³ are the same or different, and each independently represents CR ² ; Ring A is a 5-membered heteroaryl; Ring B is

R ³ is a methyl group; R ¹ is a C _1-6 alkyl group; p is 0 or 1; R ² is a hydrogen atom; R ⁴ is a hydrogen atom; and q is 0 or 1.

在本揭露一些較佳的實施方案中，該通式(I)所示的化合物或其 可藥用的鹽，其中環A為5員雜芳基或5至6員雜環基；環B為

；R³為 甲基或環丙基；R¹相同或不同，且各自獨立地選自氫原子、C_1-6烷基和側氧；R²相同或不同，且各自獨立地選自氫原子、氰基和C_1-6烷基；R⁴為氫原子；n為0或1；p為0、1、2或3；且q為0或1。 In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heteroaryl or a 5-6 membered heterocyclic group; ring B is

; R ³ is methyl or cyclopropyl; R ¹ is the same or different, and each independently selected from a hydrogen atom, C _1-6 alkyl and side oxygen; R ² is the same or different, and each independently selected from a hydrogen atom , cyano and C _1-6 alkyl; R ⁴ is a hydrogen atom; n is 0 or 1; p is 0, 1, 2 or 3; and q is 0 or 1.

在本揭露一些較佳的實施方案中，該通式(II)所示的化合物或其 可藥用的鹽，其中環A為5員雜芳基或5至6員雜環基；環B為

；R³為 甲基或環丙基；R¹相同或不同，且各自獨立地選自氫原子、C_1-6烷基和側氧；p為0、1、2或3；R²相同或不同，且各自獨立地選自氫原子、氰基和C_1-6烷基；n為0或1；R⁴為氫原子；且q為0或1。 In some preferred embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heteroaryl or a 5-6 membered heterocyclic group; ring B is

; R ³ is methyl or cyclopropyl; R ¹ is the same or different, and each independently selected from a hydrogen atom, C _1-6 alkyl and side oxygen; p is 0, 1, 2 or 3; R ² is the same or different, and each independently selected from a hydrogen atom, a cyano group, and a C _1-6 alkyl group; n is 0 or 1; R ⁴ is a hydrogen atom; and q is 0 or 1.

在本揭露一些較佳的實施方案中，該通式(II)所示的化合物或其 可藥用的鹽，其中環A為5員雜芳基；環B為

；R³為甲基；R¹為C_1-6烷 基；p為0或1；R²為氫原子；n為0或1；R⁴為氫原子；且q為0或1。 In some preferred embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-membered heteroaryl; ring B is

R ³ is a methyl group; R ¹ is a C _1-6 alkyl group; p is 0 or 1; R ² is a hydrogen atom; n is 0 or 1; R ⁴ is a hydrogen atom; and q is 0 or 1.

表A 本揭露的典型化合物包括但不限於：

Table A Typical compounds of the present disclosure include, but are not limited to:

本揭露的另一方面關於一種製備通式(IG)所示的化合物，或其可藥用的鹽的方法，該方法包括： Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IG), or a pharmaceutically acceptable salt thereof, the method comprising:

通式(IA)所示的化合物或其鹽與通式(IGB)所示的化合物或其鹽發生偶聯反應，得到通式(IG)所示的化合物或其可藥用的鹽， Compounds represented by general formula (IA) or salts thereof are coupled with compounds represented by general formula (IGB) or salts thereof to obtain compounds represented by general formula (IG) or pharmaceutically acceptable salts thereof,

其中， in,

X為鹵素；較佳為氯原子； X is a halogen; preferably a chlorine atom;

環A、環B、G¹、G²、G³、R¹、R³、R⁴、p和q如通式(IG)中所定義。 Ring A, Ring B, G ¹ , G ² , G ³ , R ¹ , R ³ , R ⁴ , p and q are as defined in the general formula (IG).

本揭露的另一方面關於一種製備通式(I)所示的化合物，或其可藥用的鹽的方法，該方法包括： Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I), or a pharmaceutically acceptable salt thereof, the method comprising:

通式(IA)所示的化合物或其鹽與通式(IB)所示的化合物或其鹽發生偶聯反應，得到通式(I)所示的化合物或其可藥用的鹽， The compound represented by the general formula (IA) or its salt is coupled with the compound represented by the general formula (IB) or its salt to obtain the compound represented by the general formula (I) or its pharmaceutically acceptable salt,

其中， in,

X為鹵素；較佳為氯原子； X is a halogen; preferably a chlorine atom;

環A、環B、R¹至R⁴、n、p和q如通式(I)中所定義。 Ring A, ring B, R ¹ to R ⁴ , n, p and q are as defined in the general formula (I).

本揭露的另一方面關於一種製備通式(II)所示的化合物，或其可藥用的鹽的方法，該方法包括： Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II), or a pharmaceutically acceptable salt thereof, the method comprising:

通式(IA)所示的化合物或其鹽與通式(IIB)所示的化合物或其鹽發生偶聯反應，得到通式(II)所示的化合物或其可藥用的鹽， Compounds represented by general formula (IA) or salts thereof are coupled with compounds represented by general formula (IIB) or salts thereof to obtain compounds represented by general formula (II) or pharmaceutically acceptable salts thereof,

其中， in,

X為鹵素；較佳為氯原子； X is a halogen; preferably a chlorine atom;

環A、環B、R¹至R⁴、n、p和q如通式(II)中所定義。 Ring A, ring B, R ¹ to R ⁴ , n, p and q are as defined in the general formula (II).

本揭露的另一方面關於一種醫藥組成物，該醫藥組成物含有本揭露通式(IG)、通式(I)、通式(II)和表A所示的化合物或其可藥用的鹽，以及一種或多種藥學上可接受的載體、稀釋劑或賦形劑。 Another aspect of the present disclosure relates to a pharmaceutical composition, which contains the compound shown in the general formula (IG), general formula (I), general formula (II) and Table A of the present disclosure or a pharmaceutically acceptable salt thereof , and one or more pharmaceutically acceptable carriers, diluents or excipients.

本揭露進一步關於通式(IG)、通式(I)、通式(II)和表A所示的化合物或其可藥用的鹽、或包括其的醫藥組成物在製備用於抑制DNA-PK的藥物中的用途。 This disclosure is further related to the compound shown in general formula (IG), general formula (I), general formula (II) and Table A or its pharmaceutically acceptable salt, or the pharmaceutical composition comprising it in the preparation for inhibiting DNA- PK use in medicine.

本揭露進一步關於通式(IG)、通式(I)、通式(II)和表A所示的化合物或其可藥用的鹽、或包括其的醫藥組成物在製備用於治療和/或預防癌症的藥物中的用途，較佳為在製備用於治療和/或預防DNA-PK介導的癌症的藥物 中的用途。其中該癌症較佳選自白血病、多發性骨髓瘤、淋巴瘤、骨髓增生異常綜合征、乳腺癌、肺癌、子宮內膜癌、中樞神經系統腫瘤、胚胎發育不良性神經上皮腫瘤、多形性成膠質細胞瘤、混合性膠質瘤、成神經管細胞瘤、成視網膜細胞瘤、成神經細胞瘤、生殖細胞瘤、畸胎瘤、胃癌、食道癌、肝癌、膽管細胞癌、結直腸癌、小腸癌、胰腺癌、皮膚癌、黑色素瘤、甲狀腺癌、頭頸癌、唾液腺癌、***癌、睾丸癌、卵巢癌、宮頸癌、外陰癌、膀胱癌、腎癌、鱗狀細胞癌、肉瘤、胃腸道間質瘤(GIST)和兒科癌症。其中該淋巴瘤選自霍奇金氏疾病和非霍奇金淋巴瘤(包括套細胞淋巴瘤)；其中該肺癌為非小細胞肺癌(NSCLC)(包括鱗狀細胞癌、腺癌和大細胞癌等)或小細胞肺癌(SCLC)，更佳為非小細胞肺癌(NSCLC)；腎癌較佳選自腎細胞癌、透明細胞和腎嗜酸細胞瘤；其中該肉瘤較佳選自軟骨肉瘤、平滑肌肉瘤、軟組織肉瘤、尤文氏肉瘤和卡波氏肉瘤。 The present disclosure further relates to the compound shown in general formula (IG), general formula (I), general formula (II) and Table A or its pharmaceutically acceptable salt, or the pharmaceutical composition comprising it in the preparation for treatment and/or Or use in medicines for preventing cancer, preferably in the preparation of medicines for treating and/or preventing DNA-PK-mediated cancers use in . Wherein the cancer is preferably selected from leukemia, multiple myeloma, lymphoma, myelodysplastic syndrome, breast cancer, lung cancer, endometrial cancer, central nervous system tumor, dysembryoplastic neuroepithelial tumor, pleomorphic Glioblastoma, mixed glioma, medulloblastoma, retinoblastoma, neuroblastoma, germ cell tumor, teratoma, gastric cancer, esophageal cancer, liver cancer, cholangiocarcinoma, colorectal cancer, small bowel cancer , pancreatic cancer, skin cancer, melanoma, thyroid cancer, head and neck cancer, salivary gland cancer, prostate cancer, testicular cancer, ovarian cancer, cervical cancer, vulvar cancer, bladder cancer, kidney cancer, squamous cell carcinoma, sarcoma, gastrointestinal tract GIST and pediatric cancers. wherein the lymphoma is selected from Hodgkin's disease and non-Hodgkin's lymphoma (including mantle cell lymphoma); wherein the lung cancer is non-small cell lung cancer (NSCLC) (including squamous cell carcinoma, adenocarcinoma and large cell carcinoma etc.) or small cell lung cancer (SCLC), more preferably non-small cell lung cancer (NSCLC); kidney cancer is preferably selected from renal cell carcinoma, clear cell and renal oncocytoma; wherein the sarcoma is preferably selected from chondrosarcoma, Leiomyosarcoma, soft tissue sarcoma, Ewing's sarcoma, and Kaposi's sarcoma.

本揭露進一步關於一種抑制DNA-PK的方法，其包括給予所需患者治療有效量的通式(IG)、通式(I)、通式(II)和表A所示的化合物或其可藥用的鹽、或包括其的醫藥組成物。 The present disclosure further relates to a method of inhibiting DNA-PK, which comprises administering a therapeutically effective amount of a compound shown in general formula (IG), general formula (I), general formula (II) and Table A or its druggable amount to a patient in need. Salts for use, or pharmaceutical compositions comprising them.

本揭露進一步關於一種治療和/或預防癌症的方法，較佳為治療和/或預防DNA-PK介導的癌症的方法，其包括給予所需患者治療有效量的通式(IG)、通式(I)、通式(II)和表A所示的化合物或其可藥用的鹽、或包括其的醫藥組成物。其中該癌症較佳選自白血病、多發性骨髓瘤、淋巴瘤、骨髓增生異常綜合征、乳腺癌、肺癌、子宮內膜癌、中樞神經系統腫瘤、胚胎發育不良性神經上皮腫瘤、多形性成膠質細胞瘤、混合性膠質瘤、成神經管細胞瘤、成視網膜細胞瘤、成神經細胞瘤、生殖細胞瘤、畸胎瘤、胃癌、食道癌、肝癌、膽管細胞癌、結直腸癌、小腸癌、胰腺癌、皮膚癌、黑色素瘤、甲狀腺癌、頭頸癌、唾液腺癌、 ***癌、睾丸癌、卵巢癌、宮頸癌、外陰癌、膀胱癌、腎癌、鱗狀細胞癌、肉瘤、胃腸道間質瘤(GIST)和兒科癌症。其中該淋巴瘤選自霍奇金氏疾病和非霍奇金淋巴瘤(包括套細胞淋巴瘤)；其中該肺癌為非小細胞肺癌(NSCLC)(包括鱗狀細胞癌、腺癌和大細胞癌等)或小細胞肺癌(SCLC)，更佳為非小細胞肺癌(NSCLC)；腎癌較佳選自腎細胞癌、透明細胞和腎嗜酸細胞瘤；其中該肉瘤較佳選自軟骨肉瘤、平滑肌肉瘤、軟組織肉瘤、尤文氏肉瘤和卡波氏肉瘤。 This disclosure further relates to a method for treating and/or preventing cancer, preferably a method for treating and/or preventing DNA-PK-mediated cancer, which comprises administering a therapeutically effective amount of general formula (IG), general formula (I), a compound represented by general formula (II) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. Wherein the cancer is preferably selected from leukemia, multiple myeloma, lymphoma, myelodysplastic syndrome, breast cancer, lung cancer, endometrial cancer, central nervous system tumor, dysembryoplastic neuroepithelial tumor, pleomorphic Glioblastoma, mixed glioma, medulloblastoma, retinoblastoma, neuroblastoma, germ cell tumor, teratoma, gastric cancer, esophageal cancer, liver cancer, cholangiocarcinoma, colorectal cancer, small bowel cancer , pancreatic cancer, skin cancer, melanoma, thyroid cancer, head and neck cancer, salivary gland cancer, Prostate, testicular, ovarian, cervical, vulvar, bladder, kidney, squamous cell, sarcoma, gastrointestinal stromal tumor (GIST), and pediatric cancers. wherein the lymphoma is selected from Hodgkin's disease and non-Hodgkin's lymphoma (including mantle cell lymphoma); wherein the lung cancer is non-small cell lung cancer (NSCLC) (including squamous cell carcinoma, adenocarcinoma and large cell carcinoma etc.) or small cell lung cancer (SCLC), more preferably non-small cell lung cancer (NSCLC); kidney cancer is preferably selected from renal cell carcinoma, clear cell and renal oncocytoma; wherein the sarcoma is preferably selected from chondrosarcoma, Leiomyosarcoma, soft tissue sarcoma, Ewing's sarcoma, and Kaposi's sarcoma.

本揭露進一步關於一種通式(IG)、通式(I)、通式(II)和表A所示的化合物或其可藥用的鹽、或包括其的醫藥組成物，其用作藥物。 The present disclosure further relates to a compound represented by general formula (IG), general formula (I), general formula (II) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, which is used as a medicine.

本揭露進一步關於一種通式(IG)、通式(I)、通式(II)和表A所示的化合物或其可藥用的鹽、或包括其的醫藥組成物，其用作抑制DNA-PK的藥物。 The present disclosure further relates to a compound represented by general formula (IG), general formula (I), general formula (II) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, which is used for inhibiting DNA -PK drugs.

本揭露進一步關於一種通式(IG)、通式(I)、通式(II)和表A所示的化合物或其可藥用的鹽、或包括其的醫藥組成物，其用作治療和/或預防癌症的藥物，較佳用作治療和/或預防DNA-PK介導的癌症的藥物。其中該癌症較佳選自白血病、多發性骨髓瘤、淋巴瘤、骨髓增生異常綜合征、乳腺癌、肺癌、子宮內膜癌、中樞神經系統腫瘤、胚胎發育不良性神經上皮腫瘤、多形性成膠質細胞瘤、混合性膠質瘤、成神經管細胞瘤、成視網膜細胞瘤、成神經細胞瘤、生殖細胞瘤、畸胎瘤、胃癌、食道癌、肝癌、膽管細胞癌、結直腸癌、小腸癌、胰腺癌、皮膚癌、黑色素瘤、甲狀腺癌、頭頸癌、唾液腺癌、***癌、睾丸癌、卵巢癌、宮頸癌、、外陰癌、膀胱癌、腎癌、鱗狀細胞癌、肉瘤、胃腸道間質瘤(GIST)和兒科癌症。其中該淋巴瘤選自霍奇金氏疾病和非霍奇金淋巴瘤(包括套細胞淋巴瘤)；其中該肺癌為非小細胞肺癌(NSCLC)(包括鱗狀細胞癌、腺癌和大 細胞癌等)或小細胞肺癌(SCLC)，較佳為非小細胞肺癌(NSCLC)；腎癌較佳選自腎細胞癌、透明細胞和腎嗜酸細胞瘤；其中該肉瘤較佳選自軟骨肉瘤、平滑肌肉瘤、軟組織肉瘤、尤文氏肉瘤和卡波氏肉瘤。 The disclosure further relates to a compound represented by general formula (IG), general formula (I), general formula (II) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, which is used for treating and And/or a drug for preventing cancer, preferably used as a drug for treating and/or preventing DNA-PK-mediated cancer. Wherein the cancer is preferably selected from leukemia, multiple myeloma, lymphoma, myelodysplastic syndrome, breast cancer, lung cancer, endometrial cancer, central nervous system tumor, dysembryoplastic neuroepithelial tumor, pleomorphic Glioblastoma, mixed glioma, medulloblastoma, retinoblastoma, neuroblastoma, germ cell tumor, teratoma, gastric cancer, esophageal cancer, liver cancer, cholangiocarcinoma, colorectal cancer, small bowel cancer , pancreatic cancer, skin cancer, melanoma, thyroid cancer, head and neck cancer, salivary gland cancer, prostate cancer, testicular cancer, ovarian cancer, cervical cancer, vulvar cancer, bladder cancer, kidney cancer, squamous cell carcinoma, sarcoma, gastrointestinal tract Stromal tumor (GIST) and pediatric cancers. wherein the lymphoma is selected from Hodgkin's disease and non-Hodgkin's lymphoma (including mantle cell lymphoma); wherein the lung cancer is non-small cell lung cancer (NSCLC) (including squamous cell carcinoma, adenocarcinoma and large cell carcinoma, etc.) or small cell lung cancer (SCLC), preferably non-small cell lung cancer (NSCLC); kidney cancer is preferably selected from renal cell carcinoma, clear cell and renal oncocytoma; wherein the sarcoma is preferably selected from cartilage Sarcoma, Leiomyosarcoma, Soft Tissue Sarcoma, Ewing's Sarcoma, and Kaposi's Sarcoma.

上述癌症定義中出現的腫瘤為惡性腫瘤。 A tumor that appears in the above definition of cancer is a malignant tumor.

可將活性化合物製成適合於藉由任何適當途徑給藥的形式，藉由常規方法使用一種或多種藥學上可接受的載體來配製本揭露的組成物。因此，本揭露的活性化合物可以配製成用於口服給藥、注射(例如靜脈內、肌肉內或皮下)給藥，吸入或吹入給藥的各種劑型。本揭露的化合物也可以配製成持續釋放劑型，例如片劑、硬或軟膠囊、水性或油性混懸液、乳劑、注射液、可分散性粉末或顆粒、栓劑、錠劑或糖漿。 The active compounds may be prepared in a form suitable for administration by any suitable route, and the compositions of the present disclosure may be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure may be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular or subcutaneous), administration by inhalation or insufflation. The disclosed compounds can also be formulated into sustained release dosage forms, such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges or syrups.

作為一般性指導，活性化合物較佳是以單位劑量的方式，或者是以患者可以以單劑自我給藥的方式。本揭露化合物或組成物的單位劑量的表達方式可以是片劑、膠囊、扁囊劑、瓶裝藥水、藥粉、顆粒劑、錠劑、栓劑、再生藥粉或液體製劑。合適的單位劑量可以是0.1至1000mg。 As a general guide, the active compound is preferably presented in unit dosage form, or in such a form that the patient can self-administer as a single dose. The unit dose of the disclosed compounds or compositions may be expressed in the form of tablets, capsules, cachets, bottled liquids, powders, granules, lozenges, suppositories, reconstitution powders or liquid preparations. A suitable unit dosage may be from 0.1 to 1000 mg.

本揭露的醫藥組成物除活性化合物外，可含有一種或多種輔料，該輔料選自以下成分：填充劑(稀釋劑)、黏合劑、潤濕劑、崩解劑或賦形劑等。根據給藥方法的不同，組成物可含有0.1至99重量%的活性化合物。 In addition to the active compound, the pharmaceutical composition of the present disclosure may contain one or more excipients selected from the following components: fillers (diluents), binders, wetting agents, disintegrants or excipients. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of active compound.

片劑含有活性成分和用於混合的適宜製備片劑的無毒的可藥用的賦形劑。這些賦形劑可以是惰性賦形劑、造粒劑、崩解劑、黏合劑和潤滑劑。這些片劑可以不包衣或可藉由掩蓋藥物的味道或在胃腸道中延遲崩解和吸收，因而在較長時間內提供緩釋作用的已知技術將其包衣。 Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrants, binders and lubricants. These tablets may be uncoated or coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over a longer period of time.

也可用其中活性成分與惰性固體稀釋劑或其中活性成分與水溶性載體或油溶媒混合的軟明膠膠囊提供口服製劑。 Oral formulations can also be provided in soft gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, or where the active ingredient is mixed with a water-soluble carrier or an oil vehicle.

水混懸液含有活性物質和用於混合的適宜製備水懸浮液的賦形劑。此類賦形劑是懸浮劑、分散劑或濕潤劑。水混懸液也可以含有一種或多種防腐劑、一種或多種著色劑、一種或多種矯味劑和一種或多種甜味劑。 Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.

油混懸液可藉由使活性成分懸浮於植物油，或礦物油配製而成。油懸浮液可含有增稠劑。可加入上述的甜味劑和矯味劑，以提供可口的製劑。可藉由加入抗氧化劑保存這些組成物。 Oily suspensions can be formulated by suspending the active ingredient in a vegetable or mineral oil. The oily suspensions may contain a thickening agent. Sweetening and flavoring agents as mentioned above may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.

本揭露的醫藥組成物也可以是水包油乳劑的形式。油相可以是植物油，或礦物油或其混合物。適宜的乳化劑可以是天然產生的磷脂，乳劑也可以含有甜味劑、矯味劑、防腐劑和抗氧劑。此類製劑也可含有緩和劑、防腐劑、著色劑和抗氧劑。 The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase may be vegetable oil, or mineral oil or mixtures thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening agents, flavoring agents, preservatives and antioxidants. Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.

本揭露的醫藥組成物可以是無菌注射水溶液形式。可以使用的可接受的溶媒或溶劑有水、林格氏液和等滲氯化鈉溶液。無菌注射製劑可以是其中活性成分溶於油相的無菌注射水包油微乳可藉由局部大量注射，將注射液或微乳注入患者的血流中。或者，最好按可保持本揭露化合物恆定迴圈濃度的方式給予溶液和微乳。為保持這種恆定濃度，可使用連續靜脈內遞藥裝置。這種裝置的實例是Deltec CADD-PLUS.TM.5400型靜脈注射泵。 The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Among the acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase. The injection or microemulsion can be injected into the patient's bloodstream by local bolus injection. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain this constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM. Model 5400 IV pump.

本揭露的醫藥組成物可以是用於肌內和皮下給藥的無菌注射水或油混懸液的形式。可按已知技術，用上述那些適宜的分散劑或濕潤劑和懸浮劑配製該混懸液。無菌注射製劑也可以是在腸胃外可接受的無毒稀釋劑或溶劑中 製備的無菌注射溶液或混懸液。此外，可方便地用無菌固定油作為溶劑或懸浮介質。為此目的，可使用任何調和固定油。此外，脂肪酸也可以製備注射劑。 The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation can also be in a parenterally acceptable nontoxic diluent or solvent Prepared sterile injectable solutions or suspensions. In addition, sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blended and fixed oil may be used. In addition, fatty acids are also used in the preparation of injectables.

可按用於直腸給藥的栓劑形式給予本揭露化合物。可藉由將藥物與在普通溫度下為固體但在直腸中為液體，因而在直腸中會溶化而釋放藥物的適宜的無刺激性賦形劑混合來製備這些醫藥組成物。 Compounds of the disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

可藉由加入水來製備水混懸的可分散粉末和顆粒給予本揭露化合物。可藉由將活性成分與分散劑或濕潤劑、懸浮劑或一種或多種防腐劑混合來製備這些醫藥組成物。 Aqueous suspensions of dispersible powders and granules can be prepared by the addition of water to administer the disclosed compounds. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.

如所屬技術領域具有通常知識者所熟知的，藥物的給藥劑量依賴於多種因素，包括但並非限定於以下因素：所用具體化合物的活性、患者的年齡、患者的體重、患者的健康狀況、患者的行為、患者的飲食、給藥時間、給藥方式、***的速率、藥物的組合、疾病的嚴重性等；另外，最佳的治療方式如治療的模式、化合物的日用量或可藥用的鹽的種類可以根據傳統的治療方案來驗證。 As is well known to those of ordinary skill in the art, the dosage of a drug to be administered depends on a variety of factors including, but not limited to, the activity of the particular compound used, the age of the patient, the weight of the patient, the state of the patient's health, the patient's behavior, patient’s diet, administration time, administration method, excretion rate, drug combination, disease severity, etc.; in addition, the optimal treatment method such as the mode of treatment, the daily dosage of the compound or the pharmaceutically acceptable The type of salt can be verified according to the traditional treatment plan.

術語說明 Glossary

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

術語“烷基”指飽和脂肪族烴基團，其為包含1至20個碳原子的直鏈或支鏈基團，較佳含有1至12個(例如1、2、3、4、5、6、7、8、9、10、11和12個)碳原子的烷基(即C_1-12烷基)，更佳為含有1至6個碳原子的烷基(即C_1-6烷基)。非限制性實例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、第二丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、 2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各種支鏈異構體等。更佳的是含有1至6個碳原子的低級烷基，非限制性實施例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、第二丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，當被取代時，其可以在任何可使用的連接點上被取代，該取代基較佳選自D原子、鹵素、烷基、烷氧基、鹵烷基、鹵烷氧基、環烷基氧基、雜環基氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基、雜芳基中的一個或多個。 The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 12 (such as 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 11 and 12) carbon atoms (i.e. C _1-12 alkyl), more preferably an alkyl group containing 1 to 6 carbon atoms (i.e. C _1-6 alkyl ). Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, second-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, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 ,3-Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl , 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-di Methylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl , 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4 -Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3 -Ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, Dibutyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl Base, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2- Dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methyl Amylpentyl, 2,3-dimethylbutyl, etc. Alkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituent is preferably selected from D atom, halogen, alkyl, alkoxy, haloalkane In group, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl one or more.

術語“亞(伸)烷基”指飽和的直鏈或支鏈脂肪族烴基，其為從母體烷的相同碳原子或兩個不同的碳原子上除去兩個氫原子所衍生的殘基，其為包含1至20個碳原子的直鏈或支鏈基團(即C_1-20亞(伸)烷基)，較佳含有1至12個(例如1、2、3、4、5、6、7、8、9、10、11和12個)碳原子(即C_1-12亞(伸)烷基)，更佳含有1至6個碳原子的亞(伸)烷基(即C_1-6亞(伸)烷基)。亞(伸)烷基的非限制性實例包括但不限於亞甲基(-CH₂-)、1,1-亞乙基(-CH(CH₃)-)、1,2-伸乙基(- CH₂CH₂)-、1,1-亞丙基(-CH(CH₂CH₃)-)、1,2-伸丙基(-CH₂CH(CH₃)-)、1,3-伸丙基(-CH₂CH₂CH₂-)、1,4-伸丁基(-CH₂CH₂CH₂CH₂-)等。亞(伸)烷基可以是取代的或非取代的，當被取代時，其可以在任何可使用的連接點上被取代，取代基較佳選自烯基、炔基、烷氧基、鹵烷氧基、環烷基氧基、雜環基氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基和側氧中的一個或多個。 The term "(alkylene)" refers to a saturated linear or branched aliphatic hydrocarbon group, which is a residue derived from the same carbon atom or two different carbon atoms of a parent alkane by removing two hydrogen atoms, which It is a linear or branched group (i.e. C _1-20 (alkylene)) containing 1 to 20 carbon atoms, preferably containing 1 to 12 (such as 1, 2, 3, 4, 5, 6 , 7, 8, 9, 10, 11 and 12) carbon atoms (ie C _1-12 (alkylene)), more preferably containing 1 to 6 carbon atoms (ie C _{1 -6} (alkylene) alkylene). Non-limiting examples of alkylene include, but are not limited to, methylene ( _-CH2- ), 1,1-ethylene (-CH( _CH3 )-), 1,2-ethylene ( - CH ₂ CH ₂ )-, 1,1-propylene (-CH(CH ₂ CH ₃ )-), 1,2-propylidene (-CH ₂ CH(CH ₃ )-), 1,3- Propylene (-CH ₂ CH ₂ CH ₂ -), 1,4-butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -), etc. Alkylene may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably the substituent is selected from alkenyl, alkynyl, alkoxy, halo Alkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl One or more of group, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and pendant oxygen.

術語“烯基”指分子中含有至少一個碳碳雙鍵的烷基化合物，其中烷基的定義如上所述。較佳含有2至12個(例如2、3、4、5、6、7、8、9、10、11和12個)碳原子的烯基(即C_2-12烯基)，更佳含有2至6個碳原子的烯基(即C_2-6烯基)。烯基可以是取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自烷氧基、鹵素、鹵烷基、鹵烷氧基、環烷基氧基、雜環基氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基中的一個或多個。 The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl groups preferably containing 2 to 12 (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e. C _2-12 alkenyl), more preferably containing Alkenyl of 2 to 6 carbon atoms (ie C _2-6 alkenyl). Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, ring One or more of alkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

術語“炔基”指分子中含有至少一個碳碳三鍵的烷基化合物，其中烷基的定義如上所述。較佳含有2至12個(例如2、3、4、5、6、7、8、9、10、11和12個)碳原子的炔基(即C_2-12炔基)，更佳含有2至6個碳原子的炔基(即C_2-6炔基)。炔基可以是取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自烷氧基、鹵素、鹵烷基、鹵烷氧基、環烷基氧基、雜環基氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基中的一個或多個。 The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl groups preferably containing 2 to 12 (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e. C _2-12 alkynyl), more preferably containing Alkynyl of 2 to 6 carbon atoms (ie C _2-6 alkynyl). Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, ring One or more of alkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

術語“環烷基”指飽和或部分不飽和單環或多環環狀烴取代基，環烷基環包含3至20個碳原子(即3至20員環烷基)，較佳包含3至14個(例如 3、4、5、6、7、8、9、10、11、12、13和14個)碳原子(即3至14員環烷基)，較佳包含3至8個碳原子(即3至8員環烷基)，更佳包含3至6個碳原子(即3至6員環烷基)。單環環烷基的非限制性實例包括環丙基、環丁基、環戊基、環戊烯基、環己基、環己烯基、環己二烯基、環庚基、環庚三烯基、環辛基等；多環環烷基包括螺環烷基、稠環烷基和橋環烷基。 The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The cycloalkyl ring contains 3 to 20 carbon atoms (ie, 3 to 20 membered cycloalkyl), preferably 3 to 20 members. 14 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14) carbon atoms (ie 3 to 14 membered cycloalkyl), preferably containing 3 to 8 carbon atoms (ie 3 to 8-membered cycloalkyl), more preferably containing 3 to 6 carbon atoms (ie 3 to 6-membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Base, cyclooctyl, etc.; polycyclic cycloalkyl includes spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl.

術語“螺環烷基”指5至20員(即5至20員螺環烷基)，單環之間共用一個碳原子(稱螺原子)的多環基團，其可以含有一個或多個雙鍵。較佳為6至14員(即6至14員螺環烷基)，更佳為7至10員(例如7、8、9或10員)(即7至10員螺環烷基)。根據環與環之間共用螺原子的數目將螺環烷基分為單螺環烷基、雙螺環烷基或多螺環烷基，較佳為單螺環烷基和雙螺環烷基。更佳為3員/5員、3員/6員、4員/4員、4員/5員、4員/6員、5員/5員、5員/6員或6員/6員單螺環烷基。螺環烷基的非限制性實例包括： The term "spirocycloalkyl" refers to a polycyclic group with 5 to 20 members (that is, a 5 to 20 membered spirocycloalkyl group) that shares one carbon atom (called a spiro atom) between monocyclic rings, which may contain one or more double bond. It is preferably 6 to 14 members (ie 6 to 14 membered spirocycloalkyl), more preferably 7 to 10 members (eg 7, 8, 9 or 10 members) (ie 7 to 10 membered spirocycloalkyl). According to the number of spiro atoms shared between the ring and the ring, the spirocycloalkyl group is divided into single spirocycloalkyl, double spirocycloalkyl or multi-spirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl . More preferably 3/5 members, 3/6 members, 4/4 members, 4/5 members, 4/6 members, 5/5 members, 5/6 members or 6/6 members Single spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

術語“稠環烷基”指5至20員(即5至20員稠環烷基)，系統中的每個環與體系中的其他環共用毗鄰的一對碳原子的全碳多環基團，其中一個或多個環可以含有一個或多個雙鍵。較佳為6至14員(即6至14員稠環烷基)，更佳為7至10員(例如7、8、9或10員)(即7至10員稠環烷基)。根據組成環的數目可以分為雙環、三環、四環和多環稠環烷基，較佳為雙環或三環，更佳為3員/4員、3員/5員、3員/6員、4員/4員、4員/5員、4員/6員、5員/4員、5員/5 員、5員/6員、6員/3員、6員/4員、6員/5員和6員/6員雙環稠環烷基。稠環烷基的非限制性實例包括： The term "fused cycloalkyl" refers to a 5 to 20 membered (i.e. 5 to 20 membered fused cycloalkyl) all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system , where one or more rings may contain one or more double bonds. It is preferably 6 to 14 members (ie 6 to 14 membered fused cycloalkyl), more preferably 7 to 10 members (eg 7, 8, 9 or 10 members) (ie 7 to 10 membered fused cycloalkyl). According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic and polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered members, 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/4 members, 5 members/5 members member, 5 member/6 member, 6 member/3 member, 6 member/4 member, 6 member/5 member and 6 member/6 member bicyclic fused cycloalkyl. Non-limiting examples of fused cycloalkyl groups include:

術語“橋環烷基”指5至20員(即5至20員橋環烷基)，任意兩個環共用兩個不直接連接的碳原子的全碳多環基團，其可以含有一個或多個雙鍵。較佳為6至14員(即6至14員橋環烷基)，更佳為7至10員(例如7、8、9或10員)(即7至10員橋環烷基)。根據組成環的數目可以分為雙環、三環、四環和多環橋環烷基，較佳為雙環、三環或四環，更佳為雙環或三環。橋環烷基的非限制性實例包括： The term "bridged cycloalkyl" refers to 5 to 20 members (i.e. 5 to 20 member bridged cycloalkyl), any two rings share two carbon atoms not directly connected to the full carbon polycyclic group, which may contain one or multiple double bonds. It is preferably 6 to 14 members (ie 6 to 14 membered bridged cycloalkyl), more preferably 7 to 10 members (eg 7, 8, 9 or 10 members) (ie 7 to 10 membered bridged cycloalkyl). According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic and polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

該環烷基環包括如上所述的環烷基(包括單環、螺環、稠環和橋環)稠合於芳基、雜芳基或雜環烷基環上，其中與母體結構連接在一起的環為環烷 基，非限制性實例包括

、

、

；較佳為

或

The cycloalkyl ring includes a cycloalkyl group as described above (including monocyclic, spiro, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring wherein the bond to the parent structure is at The rings together are cycloalkyl, non-limiting examples include

,

,

; preferably

or

環烷基可以是取代的或非取代的，當被取代時，其可以在任何可使用的連接點上被取代，取代基較佳選自鹵素、烷基、烷氧基、鹵烷基、鹵烷氧 基、環烷基氧基、雜環基氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基、雜芳基中的一個或多個。 Cycloalkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, halo Alkoxy One or more of radical, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

術語“烷氧基”指-O-(烷基)，其中烷基的定義如上所述。烷氧基的非限制性實例包括：甲氧基、乙氧基、丙氧基和丁氧基。烷氧基可以是視需要取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自D原子、鹵素、烷氧基、鹵烷基、鹵烷氧基、環烷基氧基、雜環基氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基。 The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy and butoxy. Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from D atoms, halogen, alkoxy, haloalkyl, Haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

術語“雜環基”指飽和或部分不飽和單環或多環環狀取代基，其包含3至20個環原子(即3至20員雜環基)，其中一個或多個環原子為選自氮、氧和硫的雜原子，該硫可視需要被氧化(即形成亞碸或碸)，但不包括-O-O-、-O-S-或-S-S-的環部分，其餘環原子為碳。較佳包含3至14個(例如3、4、5、6、7、8、9、10、11、12、13和14個)環原子(即3至14員雜環基)，其中1~4個(例如1、2、3和4個)是雜原子；進一步佳包含6至14個環原子(例如6、7、8、9、10、11、12、13和14個)(即6至14員雜環基)，其中1-3是雜原子(例如1、2和3個)；更佳包含3至8個環原子(即3至8員雜環基)，其中1-3個(例如1、2和3個)是雜原子；甚至更佳包含3至6個環原子(即3至6員雜環基)，其中1-3個(例如1、2和3個)是雜原子；最佳包含5或6個環原子(即5至6員雜環基)，其中1-3個是雜原子；最最佳包含6個環原子(即6員雜環基)，其中1-3個是雜原子。單環雜環基的非限制性實例包括吡咯烷基、1,2,4-噁二唑-5(2H)-酮、四氫吡喃基、1,2,3,6-四氫吡啶基、哌啶基、哌嗪基、嗎啉基、硫代嗎啉基、高哌嗪基等。多環雜環基包括螺雜環基、稠雜環基和橋雜環基。 The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent comprising 3 to 20 ring atoms (i.e. 3 to 20 membered heterocyclyl), wherein one or more ring atoms are optionally Heteroatoms from nitrogen, oxygen, and sulfur, which can be optionally oxidized (ie, to form oxon or thion), excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. Preferably comprising 3 to 14 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14) ring atoms (ie 3 to 14 membered heterocyclyl), wherein 1 to 4 (e.g. 1, 2, 3 and 4) are heteroatoms; further preferably comprising 6 to 14 ring atoms (e.g. 6, 7, 8, 9, 10, 11, 12, 13 and 14) (i.e. 6 to 14-membered heterocyclyl), wherein 1-3 are heteroatoms (for example, 1, 2 and 3); more preferably contain 3 to 8 ring atoms (ie, 3-8 membered heterocyclyl), of which 1-3 (e.g. 1, 2 and 3) are heteroatoms; even more preferably contain 3 to 6 ring atoms (i.e. 3 to 6 membered heterocyclyl), of which 1-3 (e.g. 1, 2 and 3) are heteroatoms Atoms; optimally contain 5 or 6 ring atoms (i.e. 5 to 6 membered heterocyclic groups), of which 1-3 are heteroatoms; most optimally contain 6 ring atoms (i.e. 6 membered heterocyclic groups), of which 1 -3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, 1,2,4-oxadiazol-5( 2H )-one, tetrahydropyranyl, 1,2,3,6-tetrahydropyridine Base, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclyls include spiroheterocyclyls, fused heterocyclyls and bridged heterocyclyls.

術語“螺雜環基”指5至20員(即5至20員螺雜環基)，單環之間共用一個原子(稱螺原子)的多環雜環基團，其中一個或多個環原子為選自氮、氧和硫的雜原子，該硫可視需要被氧化(即形成亞碸或碸)，其餘環原子為碳。其可以含有一個或多個雙鍵。較佳為6至14員(例如6、7、8、9、10、11、12、13和14員)(即6至14員螺雜環基)，更佳為7至10員(例如7、8、9或10員)(即7至10員螺雜環基)。根據環與環之間共用螺原子的數目將螺雜環基分為單螺雜環基、雙螺雜環基或多螺雜環基，較佳為單螺雜環基和雙螺雜環基。更佳為3員/5員、3員/6員、4員/4員、4員/5員、4員/6員、5員/5員、5員/6員或6員/6員單螺雜環基。螺雜環基的非限制性實例包括： The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group with 5 to 20 members (that is, a 5 to 20 membered spiroheterocyclyl) that shares one atom (called a spiro atom) between monocyclic rings, wherein one or more rings The atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur optionally being oxidized (ie to form argon or thionium), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably 6 to 14 members (eg 6, 7, 8, 9, 10, 11, 12, 13 and 14 members) (ie 6 to 14 membered spiroheterocyclyl), more preferably 7 to 10 members (eg 7 , 8, 9 or 10 members) (ie 7 to 10 membered spiroheterocyclyl). According to the number of shared spiro atoms between rings, spiroheterocyclyls are divided into single spiroheterocyclyls, double spiroheterocyclyls or polyspiroheterocyclyls, preferably single spiroheterocyclyls and double spiroheterocyclyls . More preferably 3/5 members, 3/6 members, 4/4 members, 4/5 members, 4/6 members, 5/5 members, 5/6 members or 6/6 members Monospiroheterocyclyl. Non-limiting examples of spiroheterocyclyls include:

術語“稠雜環基”指5至20員(即5至20員稠雜環基)，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，其中一個或多個環原子為選自氮、氧和硫的雜原子，該硫可視需要被側氧(即形成亞碸或碸)，其餘環原子為碳。較佳為6至14員(例如6、7、8、9、10、11、12、13和14員)(即6至14員稠雜環基)，更佳為7至10員(例如7、8、9或10員)(即7至10員稠雜環基)。根據組成環的數目可以分為雙環、三環、四環和多環稠雜環基，較佳為雙環或三環，更佳為3員/4員、3員/5員、3員/6員、4員/4員、4員/5員、4員/6員、5員/4員、5員/5員、5員/6員、6員/3員、6員/4員、6員/5員和6員/6員雙環稠雜環基。稠雜環基的非限制性實例包括： The term "fused heterocyclic group" refers to a polycyclic heterocyclic group with 5 to 20 members (ie, 5 to 20 membered fused heterocyclic group), 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 double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, the sulfur optionally being pendant by oxygen (i.e., forming argon or sulfur), and the rest The ring atoms are carbon. Preferably 6 to 14 members (such as 6, 7, 8, 9, 10, 11, 12, 13 and 14 members) (ie, 6 to 14 membered fused heterocyclyl), more preferably 7 to 10 members (such as 7 , 8, 9 or 10 members) (ie 7 to 10 membered fused heterocyclyl). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic and polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered members, 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/4 members, 5 members/5 members, 5 members/6 members, 6 members/3 members, 6 members/4 members, 6-membered/5-membered and 6-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

術語“橋雜環基”指5至20員(即5至20員橋雜環基)，任意兩個環共用兩個不直接連接的原子的多環雜環基團，其可以含有一個或多個雙鍵，其中一個或多個環原子為選自氮、氧和硫的雜原子，該硫可視需要被氧化(即形成亞碸或碸)，其餘環原子為碳。較佳為6至14員(例如6、7、8、9、10、11、12、13和14員)(即6至14員橋雜環基)，更佳為7至10員(例如7、8、9或10員)(即7至10員橋雜環基)。根據組成環的數目可以分為雙環、三環、四環和多環橋雜環基，較佳為雙環、三環或四環，更佳為雙環或三環。橋雜環基的非限制性實例包括： The term "bridged heterocyclic group" refers to a 5 to 20-membered (ie, 5 to 20-membered bridged heterocyclic group), a polycyclic heterocyclic group that any two rings share two atoms that are not directly connected, which may contain one or more One or more ring atoms are heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, the sulfur being optionally oxidized (ie to form argon or sulfur), and the remaining ring atoms are carbon. Preferably it is 6 to 14 members (such as 6, 7, 8, 9, 10, 11, 12, 13 and 14 members) (ie 6 to 14 membered bridged heterocyclyl), more preferably 7 to 10 members (such as 7 , 8, 9 or 10 members) (ie 7 to 10 member bridged heterocyclyl). According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic and polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

該雜環基環包括如上所述的雜環基(包括單環、螺雜環、稠雜環和橋雜環)稠合於芳基、雜芳基或環烷基環上，其中與母體結構連接在一起的環為雜環基，其非限制性實例包括： The heterocyclyl ring includes a heterocyclyl as described above (including monocyclic, spiroheterocycle, fused heterocycle and bridged heterocycle) fused to an aryl, heteroaryl or cycloalkyl ring wherein the parent structure The rings joined together are heterocyclyl, non-limiting examples of which include:

和

等。

with

Wait.

雜環基可以是取代的或非取代的，當被取代時，其可以在任何可使用的連接點上被取代，取代基較佳選自鹵素、烷基、烷氧基、鹵烷基、鹵烷氧基、環烷基氧基、雜環基氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基、雜芳基中的一個或多個。 The heterocyclyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, halo One or more of alkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl indivual.

術語“芳基”指具有共軛的π電子體系的6至14員全碳單環或稠合多環(稠合多環是共用毗鄰碳原子對的環)基團(即6至14員芳基)，較佳為6至10員(即6至10員芳基)，例如苯基和萘基。該芳基環包括如上所述的芳基環稠合於雜芳基、雜環基或環烷基環上，其中與母體結構連接在一起的環為芳基環，其非限制性實例包括： The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (a fused polycyclic ring is a ring that shares adjacent pairs of carbon atoms) group (i.e., a 6 to 14 membered aryl group) having a conjugated π-electron system. group), preferably 6 to 10 membered (ie 6 to 10 membered aryl), such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring wherein the ring bonded to the parent structure is an aryl ring, non-limiting examples of which include:

芳基可以是取代的或非取代的，當被取代時，其可以在任何可使用的連接點上被取代，取代基較佳選自鹵素、烷基、烷氧基、鹵烷基、鹵烷氧基、環烷基氧基、雜環基氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基、雜芳基中的一個或多個。 Aryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkane One or more of oxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl .

術語“雜芳基”指包含1至4個雜原子(例如1、2、3和4個)、5至14個環原子的雜芳族體系(即5至14員雜芳基)，其中雜原子選自氧、硫和氮。雜芳基較佳為5至10員(例如5、6、7、8、9或10員)(即5至10員雜芳基)， 更佳為5員或6員(即5至6員雜芳基)，最佳為5員(即5員雜芳基)，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、噠嗪基、咪唑基、吡唑基、***基、噻唑基和四唑基等。該雜芳基環包括如上述的雜芳基稠合於芳基、雜環基或環烷基環上，其中與母體結構連接在一起的環為雜芳基環，其非限制性實例包括： The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms (e.g. 1, 2, 3 and 4), 5 to 14 ring atoms (i.e. 5 to 14 membered heteroaryl), wherein hetero The atoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered (eg 5, 6, 7, 8, 9 or 10 membered) (ie 5 to 10 membered heteroaryl), More preferably 5-membered or 6-membered (ie 5 to 6-membered heteroaryl), most preferably 5-membered (ie 5-membered heteroaryl), such as furyl, thienyl, pyridyl, pyrrolyl, N-alkyl Pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl and tetrazolyl, etc. The heteroaryl ring includes a heteroaryl as described above fused to an aryl, heterocyclyl or cycloalkyl ring wherein the ring bonded to the parent structure is a heteroaryl ring, non-limiting examples of which include:

雜芳基可以是取代的或非取代的，當被取代時，其可以在任何可使用的連接點上被取代，取代基選自鹵素、烷基、烷氧基、鹵烷基、鹵烷氧基、環烷基氧基、雜環基氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基、雜芳基中的一個或多個。 Heteroaryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy One or more of radical, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

上述環烷基、雜環基、芳基和雜芳基包括從母體環原子上除去一個氫原子所衍生的殘基，或從母體的相同環原子或兩個不同的環原子上除去兩個氫原子所衍生的殘基即“二價環烷基”、“二價雜環基”、“亞(伸)芳基”、“亞(伸)雜芳基”。 The above cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived by removing one hydrogen atom from a parent ring atom, or by removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent The residue derived from the atom is "divalent cycloalkyl", "divalent heterocyclic group", "(extended) arylene", "(extended) heteroaryl".

術語“胺基保護基”是為了使分子其它部位進行反應時胺基保持不變，用易於脫去的基團對胺基進行保護。非限制性實施例包含(三甲基矽)乙氧基甲基、四氫吡喃基、第三丁氧羰基、乙醯基、苄基、烯丙基和對甲氧苄基等。這些基團可視需要地被選自鹵素、烷氧基或硝基中的1-3個取代基所取代。 The term "amino group protecting group" is used to protect the amine group with a group that is easy to remove in order to keep the amine group unchanged when other parts of the molecule react. Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy or nitro.

術語“羥基保護基”是指通常用於阻斷或保護羥基而反應在化合物的其它官能團上進行的羥基衍生物。作為示例，較佳地，該羥基保護基可以是(C_1-10烷基或芳基)₃矽烷基，例如：三乙基矽基、三異丙基矽基、第三丁基二甲基矽烷基(TBS)、第三丁基二苯基矽基等；可以是C_1-10烷基或取代烷基，較佳烷氧基或芳基取代的烷基，更佳C_1-6烷氧基取代的C_1-6烷基或苯基取代的C_1-6烷基，最佳C_1-4烷氧基取代的C_1-4烷基，例如：甲基、第三丁基、烯丙基、苄基、甲氧基甲基(MOM)、乙氧基乙基、2-四氫吡喃基(THP)等；可以是(C_1-10烷基或芳香基)醯基，例如：甲醯基、乙醯基、苯甲醯基、對硝基苯甲醯基等；可以是(C_1-6烷基或6至10員芳基)磺醯基；也可以是(C_1-6烷氧基或6至10員芳基氧基)羰基。 The term "hydroxyl protecting group" refers to a hydroxy derivative that is usually used to block or protect a hydroxy group to react on other functional groups of the compound. As an example, preferably, the hydroxyl protecting group can be (C _1-10 alkyl or aryl) ₃ silyl group, for example: triethylsilyl, triisopropylsilyl, tertiary butyldimethyl Silyl (TBS), tertiary butyldiphenylsilyl, etc.; can be C _1-10 alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C _1-6 alkane Oxygen substituted C _1-6 alkyl or phenyl substituted C _1-6 alkyl, the best C _1-4 alkoxy substituted C _1-4 alkyl, for example: methyl, tertiary butyl, Allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), etc.; can be (C _1-10 alkyl or aryl) acyl, For example: formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.; can be (C _1-6 alkyl or 6 to 10 member aryl) sulfonyl; can also be (C _1-6 alkoxy or 6 to 10 membered aryloxy)carbonyl.

術語“環烷基氧基”指環烷基-O-，其中環烷基如上所定義。 The term "cycloalkyloxy" refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.

術語“雜環基氧基”指雜環基-O-，其中雜環基如上所定義。 The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

術語“芳基氧基”指芳基-O-，其中芳基如上所定義。 The term "aryloxy" refers to aryl-O-, wherein aryl is as defined above.

術語“雜芳基氧基”指雜芳基-O-，其中雜芳基如上所定義。 The term "heteroaryloxy" refers to heteroaryl-O-, wherein heteroaryl is as defined above.

術語“烷硫基”指烷基-S-，其中烷基如上所定義。 The term "alkylthio" refers to alkyl-S-, wherein alkyl is as defined above.

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

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

術語“氘代烷基”指烷基被一個或多個氘原子取代，其中烷基如上所定義。 The term "deuteroalkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

術語“羥烷基”指烷基被一個或多個羥基取代，其中烷基如上所定義。 The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

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

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

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

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

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

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

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

術語“羰基”指C=O。 The term "carbonyl" refers to C=O.

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

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

本揭露所述化合物的化學結構中，鍵“

”表示未指定構型，即如果化學結構中存在手性異構體，鍵“

”可以為“

”或“

”，或者同時包含“

”和“

”兩種構型。 In the chemical structures of the compounds described in this disclosure, the bond "

"indicates that no configuration is specified, i.e. if chiral isomers exist in the chemical structure, the bond"

"can be"

"or"

, or both "

"with"

"Two configurations.

本揭露所述化合物的化學結構中，鍵“

”並未指定構型，即可以為Z構型或E構型，或者同時包含兩種構型。 In the chemical structures of the compounds described in this disclosure, the bond "

" does not specify the configuration, it can be the Z configuration or the E configuration, or both configurations.

本揭露的化合物包括其同位素衍生物。術語“同位素衍生物”指結構不同僅在於存在一種或多種同位素富集原子的化合物。例如，具有本揭露的結 構，用“氘”或“氚”代替氫，或者用¹⁸F-氟標記(¹⁸F同位素)代替氟，或者用¹¹C-，¹³C-，或者¹⁴C-富集的碳(¹¹C-，¹³C-，或者¹⁴C-碳標記；¹¹C-，¹³C-，或者¹⁴C-同位素)代替碳原子的化合物處於本揭露的範圍內。這樣的化合物可用作例如生物學測定中的分析工具或探針，或者可以用作疾病的體內診斷成像示蹤劑，或者作為藥效學、藥動學或受體研究的示蹤劑。其中氘化形式的化合物為與碳原子連接的各個可用的氫原子可獨立地被氘原子替換。所屬技術領域具有通常知識者能夠參考相關文獻合成氘化形式的式(I)化合物。在製備氘代形式的化合物時可使用市售的氘代起始物質，或它們可使用常規技術採用氘代試劑合成，氘代試劑包括但不限於氘代硼烷、三氘代硼烷四氫呋喃溶液、氘代氫化鋰鋁、氘代碘乙烷和氘代碘甲烷等。氘代物通常可以保留與未氘代的化合物相當的活性，並且當氘代在某些特定位點時可以取得更好的代謝穩定性，從而獲得某些治療優勢。 Compounds of the present disclosure include isotopic derivatives thereof. The term "isotopically derivative" refers to compounds that differ in structure only by the presence of one or more isotopically enriched atoms. For example, with the structure of the present disclosure, hydrogen is replaced by "deuterium" or "tritium", or fluorine is replaced by ¹⁸ F-fluorine label ( ¹⁸ F isotope), or ¹¹ C-, ¹³ C-, or ¹⁴ C-enriched Compounds in which carbon atoms are replaced by carbon ( ¹¹ C-, ¹³ C-, or ¹⁴ C-carbon labels; ¹¹ C-, ¹³ C-, or ¹⁴ C-isotopes) are within the scope of the present disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies. A deuterated form of a compound is one in which each available hydrogen atom attached to a carbon atom is independently replaced by a deuterium atom. Those skilled in the art can refer to the relevant literature to synthesize the deuterated form of the compound of formula (I). Commercially available deuterated starting materials can be used in the preparation of deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including but not limited to deuterated borane, trideuterioborane in tetrahydrofuran , deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc. Deuterated compounds generally retain comparable activity to non-deuterated compounds, and can achieve better metabolic stability when deuterated at certain sites, thereby gaining certain therapeutic advantages.

“視需要地”或“視需要”是指意味著隨後所描述的事件或環境可以但不必然發生，該說明包括該事件或環境發生或不發生的場合。例如“視需要的被鹵素或者氰基取代的C_1-6烷基”是指鹵素或者氰基可以但不必然存在，該說明包括烷基被鹵素或者氰基取代的情形和烷基不被鹵素或氰基取代的情形。 "Optionally" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example, "C _1-6 alkyl optionally substituted by halogen or cyano" means that halogen or cyano may but not necessarily exist, and this description includes the case where the alkyl is substituted by halogen or cyano and the alkyl is not substituted by halogen. Or the case of cyano substitution.

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

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

“可藥用的鹽”是指本揭露化合物的鹽，可選自無機鹽或有機鹽。這類鹽用於哺乳動物體內時具有安全性和有效性，且具有應有的生物活性。可以在化合物的最終分離和純化過程中，或藉由使合適的基團與合適的鹼或酸反應來單獨製備。通常用於形成藥學上可接受的鹽的鹼包括無機鹼，例如氫氧化鈉和氫氧化鉀，以及有機鹼，例如胺。通常用於形成藥學上可接受的鹽的酸包括無機酸以及有機酸。 "Pharmaceutically acceptable salt" refers to a salt of a compound of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals, and have proper biological activity. They can be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate group with an appropriate base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as amines. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

針對藥物或藥理學活性劑而言，術語“治療有效量”是指無毒的但能達到預期效果的藥物或藥劑的足夠用量。有效量的確定因人而異，取決於受體的年齡和一般情況，也取決於具體的活性物質，個案中合適的有效量可以由所屬技術領域具有通常知識者根據常規試驗確定。 For a drug or a pharmacologically active agent, the term "therapeutically effective amount" refers to a non-toxic but sufficient amount of the drug or agent to achieve the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the subject, and also depends on the specific active substance. The appropriate effective amount in a case can be determined by a person with ordinary knowledge in the art according to routine experiments.

本文所用的術語“藥學上可接受的”是指這些化合物、材料、組成物和/或劑型，在合理的醫學判斷範圍內，適用於與患者組織接觸而沒有過度毒性、刺激性、過敏反應或其他問題或併發症，具有合理的獲益/風險比，並且對預期的用途是有效。 As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with patient tissues without undue toxicity, irritation, allergic reaction or Other problems or complications that have a reasonable benefit/risk ratio and are valid for the intended use.

本文所使用的，單數形式的“一個”、“一種”和“該”包括複數引用，反之亦然，除非上下文另外明確指出。 As used herein, the singular forms "a", "an" and "the" include plural references and vice versa unless the context clearly dictates otherwise.

當將術語“約”應用於諸如pH、濃度、溫度等的參數時，表明該參數可以變化±10%，並且有時更佳地在±5%之內。如所屬技術領域具有通常知識者將理解的，當參數不是關鍵時，通常僅出於說明目的給出數位，而不是限制。 When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it means that the parameter may vary by ±10%, and sometimes preferably within ±5%. As will be understood by those of ordinary skill in the art, when a parameter is not critical, the digits are generally given for illustrative purposes only, and not for limitation.

本揭露化合物的合成方法 The synthetic method of the disclosed compound

為了完成本揭露的目的，本揭露採用如下技術方案： In order to accomplish the purpose of this disclosure, this disclosure adopts the following technical solutions:

方案一 Option One

本揭露通式(IG)所示的化合物，或其可藥用的鹽的製備方法，該方法包括： The present disclosure discloses a compound represented by general formula (IG), or a preparation method of a pharmaceutically acceptable salt thereof, the method comprising:

通式(IA)所示的化合物或其鹽與通式(IGB)所示的化合物或其鹽，在鹼性條件下，在催化劑存在下，發生偶聯反應，得到通式(IG)所示的化合物或其可藥用的鹽， The compound represented by the general formula (IA) or its salt and the compound represented by the general formula (IGB) or its salt, under alkaline conditions, in the presence of a catalyst, a coupling reaction occurs to obtain the compound represented by the general formula (IG) or a pharmaceutically acceptable salt thereof,

其中， in,

X為鹵素；較佳為氯原子； X is a halogen; preferably a chlorine atom;

環A、環B、G¹、G²、G³、R¹、R³、R⁴、p和q如通式(IG)中所定義。 Ring A, Ring B, G ¹ , G ² , G ³ , R ¹ , R ³ , R ⁴ , p and q are as defined in the general formula (IG).

方案二 Option II

本揭露通式(I)所示的化合物，或其可藥用的鹽的製備方法，該方法包括： The present disclosure discloses a compound represented by general formula (I), or a preparation method of a pharmaceutically acceptable salt thereof, the method comprising:

通式(IA)所示的化合物或其鹽與通式(IB)所示的化合物或其鹽，在鹼性條件下，在催化劑存在下，發生偶聯反應，得到通式(I)所示的化合物或其可藥用的鹽， The compound represented by the general formula (IA) or its salt and the compound represented by the general formula (IB) or its salt, under alkaline conditions, in the presence of a catalyst, a coupling reaction occurs to obtain the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof,

其中， in,

X為鹵素；較佳為氯原子； X is a halogen; preferably a chlorine atom;

環A、環B、R¹至R⁴、n、p和q如通式(I)中所定義。 Ring A, ring B, R ¹ to R ⁴ , n, p and q are as defined in the general formula (I).

方案三 third solution

本揭露通式(II)所示的化合物，或其可藥用的鹽的製備方法，該方法包括： The present disclosure discloses a compound represented by general formula (II), or a preparation method of a pharmaceutically acceptable salt thereof, the method comprising:

通式(IA)所示的化合物或其鹽與通式(IIB)所示的化合物或其鹽，在鹼性條件下，在催化劑存在下，發生偶聯反應，得到通式(II)所示的化合物或其可藥用的鹽， The compound represented by the general formula (IA) or its salt and the compound represented by the general formula (IIB) or its salt, under alkaline conditions, in the presence of a catalyst, a coupling reaction occurs to obtain the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof,

其中， in,

X為鹵素；較佳為氯原子； X is a halogen; preferably a chlorine atom;

環A、環B、R¹至R⁴、n、p和q如通式(II)中所定義。 Ring A, ring B, R ¹ to R ⁴ , n, p and q are as defined in the general formula (II).

以上合成方案中提供鹼性條件的試劑包括有機鹼類和無機鹼類，該有機鹼類包括但不限於三乙胺、N,N-二異丙基乙胺、正丁基鋰、二異丙基胺基鋰、醋酸鈉、醋酸鉀、第三丁醇鈉、第三丁醇鉀或1,8-二氮雜二環十一碳-7-烯，該無機鹼類包括但不限於氫化鈉、磷酸鉀、碳酸鈉、碳酸鉀、碳酸銫、氫氧化鈉、氫氧化鋰和氫氧化鉀；較佳為碳酸銫。 The reagents that provide basic conditions in the above synthesis scheme include organic bases and inorganic bases, the organic bases include but not limited to triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropyl Lithium amide, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide or 1,8-diazabicycloundec-7-ene, the inorganic bases include but not limited to sodium hydride , potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide and potassium hydroxide; preferably cesium carbonate.

以上合成方案中所用的催化劑包括但不限於四(三苯基膦)鈀、二氯化鈀、醋酸鈀、甲烷磺酸(2-二環己基膦)-3,6-二甲氧基-2',4',6'-三異丙基-1,1'-聯 苯)(2'-胺基-1,1'-聯苯-2-基)鈀(II)、1,1’-雙(二苄基磷)二氯二戊鐵鈀、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀二氯甲烷絡合物、三(二亞苄基丙酮)二鈀等，較佳為甲烷磺酸(2-二環己基膦)-3,6-二甲氧基-2',4',6'-三異丙基-1,1'-聯苯)(2'-胺基-1,1'-聯苯-2-基)鈀(II)。 The catalysts used in the above synthesis scheme include but are not limited to tetrakis(triphenylphosphine) palladium, palladium dichloride, palladium acetate, methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2 ',4',6'-triisopropyl-1,1'-linked Benzene)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), 1,1'-bis(dibenzylphosphine)dichlorodipentyliron palladium, [1,1' -bis(diphenylphosphino)ferrocene]palladium dichloride, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, tris(di Benzylideneacetone) dipalladium, etc., preferably methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1 '-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II).

上述步驟的反應較佳在溶劑中進行，所用的溶劑包括但不限於：乙二醇二甲醚、醋酸、甲醇、乙醇、乙腈、正丁醇、甲苯、四氫呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亞碸、1,4-二噁烷、水、N,N-二甲基甲醯胺、N,N-二甲基乙醯胺、1,2-二溴乙烷及其混合物。 The reaction of the above steps is preferably carried out in a solvent, and the solvent used includes but is not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, acetic acid Ethyl ester, n-hexane, dimethylsulfide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromo Ethane and its mixtures.

以下結合實施例用於進一步描述本揭露，但這些實施例並非限制著本揭露的範圍。 The following examples are used to further describe the present disclosure, but these examples do not limit the scope of the present disclosure.

[實施例] [Example]

化合物的結構是藉由核磁共振(NMR)或/和質譜(MS)來確定的。NMR位移(δ)以10^-6(ppm)的單位給出。NMR的測定是用Bruker AVANCE NEO 500M核磁儀，測定溶劑為氘代二甲基亞碸(DMSO-d ₆ )、氘代氯仿(CDCl₃)、氘代甲醇(CD₃OD)，內標為四甲基矽烷(TMS)。 Compound structures were determined by nuclear magnetic resonance (NMR) or/and mass spectroscopy (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). The determination of NMR is carried out with a Bruker AVANCE NEO 500M nuclear magnetic instrument, and the determination solvent is deuterated dimethyl sulfide (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard is four Methylsilane (TMS).

MS的測定用Agilent 1200/1290 DAD-6110/6120 Quadrupole MS液質聯用儀(生產商：Agilent，MS型號：6110/6120 Quadrupole MS)、waters ACQuity UPLC-QD/SQD(生產商：waters，MS型號：waters ACQuity Qda Detector/waters SQ Detector)、THERMO Ultimate 3000-Q Exactive(生產商：THERMO，MS型號：THERMO Q Exactive)。 The determination of MS uses Agilent 1200/1290 DAD-6110/6120 Quadrupole MS liquid mass spectrometer (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS Model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

高效液相色譜法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489高效液相色譜儀。 High-performance liquid chromatography (HPLC) was analyzed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high-performance liquid chromatography.

手性HPLC分析測定使用Agilent 1260 DAD高效液相色譜儀。 Chiral HPLC analysis and determination using Agilent 1260 DAD high performance liquid chromatography.

高效液相製備使用Waters 2545-2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson GX-281製備型色譜儀。 Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs were used for HPLC preparation.

手性製備使用Shimadzu LC-20AP製備型色譜儀。 Chiral preparation A Shimadzu LC-20AP preparative chromatograph was used.

CombiFlash快速製備儀使用Combiflash Rf200(TELEDYNE ISCO)。 The CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).

薄層層析矽膠板使用煙臺黃海HSGF254或青島GF254矽膠板，薄層色譜法(TLC)使用的矽膠板採用的規格是0.15mm~0.2mm，薄層層析分離純化產品採用的規格是0.4mm~0.5mm。 The thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm~0.2mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm. ~0.5mm.

矽膠管柱色譜法一般使用煙臺黃海矽膠200至300目矽膠為載體。 Silica gel column chromatography generally uses Yantai Huanghai silica gel 200 to 300 mesh silica gel as the carrier.

激酶平均抑制率及IC₅₀值的測定用NovoStar酶標儀(德國BMG公司)。 Kinase average inhibition rate and IC ₅₀ value were measured with NovoStar microplate reader (BMG Company, Germany).

本揭露的已知的起始原料可以採用或按照本領域已知的方法來合成，或可購買自ABCR GmbH & Co.KG，Acros Organics，Aldrich Chemical Company，韶遠化學科技(Accela ChemBio Inc)、達瑞化學品等公司。 The known starting materials of the present disclosure can be used or synthesized according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darui Chemicals and other companies.

實施例中無特殊說明，反應均能夠在氬氣氛或氮氣氛下進行。 Unless otherwise specified in the examples, the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.

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

氫氣氛是指反應瓶連接一個約1L容積的氫氣氣球。 The hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

加壓氫化反應使用Parr 3916EKX型氫化儀和清藍QL-500型氫氣發生器或HC2-SS型氫化儀。 The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenator.

氫化反應通常抽真空，充入氫氣，重複操作3次。 The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.

微波反應使用CEM Discover-S 908860型微波反應器。 For the microwave reaction, a CEM Discover-S 908860 microwave reactor was used.

實施例中無特殊說明，溶液是指水溶液。 Unless otherwise specified in the examples, the solution refers to an aqueous solution.

實施例中無特殊說明，反應的溫度為室溫，為20℃~30℃。 Unless otherwise specified in the examples, the temperature of the reaction is room temperature, which is 20° C. to 30° C.

實施例中的反應進程的監測採用薄層色譜法(TLC)，反應所使用的展開劑，純化化合物採用的管柱層析的沖提劑的體系和薄層色譜法的展開劑體系包括：A：二氯甲烷/甲醇體系，溶劑的體積比根據化合物的極性不同而進行調節，也可以加入少量的三乙胺和醋酸等鹼性或酸性試劑進行調節。 The monitoring of the reaction process in the embodiment adopts thin-layer chromatography (TLC), the developing agent used in the reaction, the system of the eluting agent of the column chromatography adopted by the purified compound and the developing agent system of the thin-layer chromatography include: A : Dichloromethane/methanol system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.

實施例1 Example 1

4-甲基-5-((7-甲基-8-側氧-9-(四氫-2H-吡喃-4-基)-8,9-二氫-7H-嘌呤-2-基)胺基)-2-(1H-吡唑-1-基)苯甲腈1 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2 H -pyran-4-yl)-8,9-dihydro-7 H -purine-2- Base) amino)-2-( 1H -pyrazol-1-yl)benzonitrile 1

第一步 first step

4-甲基-5-硝基-2-(1H-吡唑-1-基)苯甲腈1b 4-Methyl-5-nitro-2-( 1H -pyrazol-1-yl)benzonitrile 1b

將2-氟-4-甲基-5-硝基苯甲腈1a(1.00g，5.55mmol，採用專利申請“WO2017125530A1,P256”公開的方法製備而得)、吡唑(908mg，13.34mmol，畢得)和碳酸鉀(921mg，6.66mmol，滬試)混合懸浮於25mL N,N-二甲基甲醯胺中，攪拌2小時。反應液中加入50mL水，用乙酸乙酯(30mL×3)萃取，所得有機相減壓濃縮，殘餘物用CombiFlash快速製備儀以沖提劑體系A純化，得到標題產物1b(522mg)，產率：41.2%。 2-Fluoro-4-methyl-5-nitrobenzonitrile 1a (1.00g, 5.55mmol, prepared by the method disclosed in the patent application "WO2017125530A1, P256"), pyrazole (908mg, 13.34mmol, Bi ) and potassium carbonate (921mg, 6.66mmol, Shanghai test) were mixed and suspended in 25mL N , N -dimethylformamide, and stirred for 2 hours. 50 mL of water was added to the reaction solution, extracted with ethyl acetate (30 mL×3), the obtained organic phase was concentrated under reduced pressure, and the residue was purified with a CombiFlash rapid preparation apparatus with eluent system A to obtain the title product 1b (522 mg). : 41.2%.

MS m/z(ESI)：228.9[M+1]。 MS m/z (ESI): 228.9 [M+1].

第二步 second step

5-胺基-4-甲基-2-(1H-吡唑-1-基)苯甲腈1c 5-Amino-4-methyl-2-( 1H -pyrazol-1-yl)benzonitrile 1c

將化合物1b(522mg，2.29mmol)和鈀碳(濕)(49mg，0.46mmol，伊諾凱)混合懸浮於50mL乙醇中，氫氣置換6次，攪拌反應17小時。反應液過濾，濾液減壓濃縮得到標題產物1c(450mg)，產率：99.2%。 Compound 1b (522mg, 2.29mmol) and palladium on carbon (wet) (49mg, 0.46mmol, Enoke) were mixed and suspended in 50mL of ethanol, hydrogen was replaced 6 times, and the reaction was stirred for 17 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 1c (450mg), yield: 99.2%.

MS m/z(ESI)：198.9[M+1]。 MS m/z (ESI): 198.9 [M+1].

第三步 third step

4-甲基-5-((7-甲基-8-側氧-9-(四氫-2H-吡喃-4-基)-8,9-二氫-7H-嘌呤-2-基)胺基)-2-(1H-吡唑-1-基)苯甲腈1 4-methyl-5-((7-methyl-8-oxo-9-(tetrahydro-2 H -pyran-4-yl)-8,9-dihydro-7 H -purine-2- Base) amino)-2-( 1H -pyrazol-1-yl)benzonitrile 1

在氬氣氛下，將化合物1c(74mg，0.37mmol)、2-氯-7-甲基-9-(四氫-2H-吡喃-4-基)-7,9-二氫-8H-嘌呤-8-酮1d(100mg，0.37mmol，採用專利申請“CN110177791A,P43”公開的方法製備而得)、甲烷磺酸(2-二環己基膦)-3,6-二甲氧基-2',4',6'-三異丙基-1,1'-聯苯)(2'-胺基-1,1'-聯苯-2-基)鈀(II)(34mg，0.037mmol，艾康)和碳酸銫 (243mg，0.75mmol，韶遠)溶解於20mL 1,4-二噁烷中，加熱至100℃，攪拌17小時。反應液減壓濃縮，殘餘物用CombiFlash快速製備儀以沖提劑體系A純化，得到標題產物1(70mg)，產率：43.7%。 Under argon atmosphere, compound 1c (74mg, 0.37mmol), 2-chloro-7-methyl-9-(tetrahydro- 2H -pyran-4-yl)-7,9-dihydro- 8H -Purin-8-one 1d (100mg, 0.37mmol, prepared by the method disclosed in the patent application "CN110177791A, P43"), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy- 2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (34mg, 0.037mmol , Aikon) and cesium carbonate (243 mg, 0.75 mmol, Shaoyuan) were dissolved in 20 mL of 1,4-dioxane, heated to 100 ° C, and stirred for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified with the eluent system A by CombiFlash to obtain the title product 1 (70 mg), yield: 43.7%.

MS m/z(ESI)：431.1[M+1]。 MS m/z (ESI): 431.1 [M+1].

¹H NMR(500MHz,DMSO-d ₆ )：δ 8.81(s,1H),8.35-8.29(m,2H),8.18(s,1H),7.85-7.80(m,1H),7.66(s,1H),6.65-6.55(m,1H),4.45-4.40(m,1H),4.00-3.97(m,2H),3.50-3.40(m,5H),2.56-2.53(m,2H),2.43(s,3H),1.71-1.69(m,2H)。 ¹ H NMR (500MHz, DMSO- d ₆ ): δ 8.81(s,1H),8.35-8.29(m,2H),8.18(s,1H),7.85-7.80(m,1H),7.66(s,1H ),6.65-6.55(m,1H),4.45-4.40(m,1H),4.00-3.97(m,2H),3.50-3.40(m,5H),2.56-2.53(m,2H),2.43(s ,3H), 1.71-1.69(m,2H).

實施例2 Example 2

7-甲基-2-((2-甲基-4-(1H-1,2,3-***-1-基)苯基)胺基)-9-(四氫-2H-吡喃-4-基)-7,9-二氫-8H-嘌呤-8-酮2 7-methyl-2-((2-methyl-4-(1 H -1,2,3-triazol-1-yl)phenyl)amino)-9-(tetrahydro-2 H -pyridine pyran-4-yl)-7,9-dihydro- 8H -purin-8-one 2

第一步 first step

1-(3-甲基-4-硝基苯基)-1H-1,2,3-***2c 1-(3-Methyl-4-nitrophenyl)-1 H -1,2,3-triazole 2c

將4-氟-2-甲基-1-硝基苯2a(3.0g，19.34mmol，採用專利申請“US20100324043A1,P26”公開的方法製備而得)溶於20mL N,N-二甲基甲醯胺中，依次加入1,2,3-***(1.74g，25.2mmol)和碳酸鉀(4.01g，29.05mmol)，80℃攪拌3小時。加入水，乙酸乙酯萃取(30mL×3)，合併有機相，飽和氯化鈉溶液洗滌，無水硫酸鈉乾燥，過濾，減壓濃縮，殘餘物用CombiFlash快速製備儀以沖提劑體系A純化，得到化合物2b(1.5g，產率：38.0%)和化合物2c(1.8g，產率：45.4%)。 Dissolve 4-fluoro-2-methyl-1-nitrobenzene 2a (3.0 g, 19.34 mmol, prepared by the method disclosed in the patent application "US20100324043A1, P26") in 20 mL of N , N -dimethylformamide To the amine, 1,2,3-triazole (1.74 g, 25.2 mmol) and potassium carbonate (4.01 g, 29.05 mmol) were sequentially added, and stirred at 80° C. for 3 hours. Add water, extract with ethyl acetate (30mL×3), combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Compound 2b (1.5 g, yield: 38.0%) and compound 2c (1.8 g, yield: 45.4%) were obtained.

MS m/z(ESI)：205.1[M+1]。 MS m/z (ESI): 205.1 [M+1].

第二步 second step

2-甲基-4-(1H-1,2,3-***-1-基)苯胺2d 2-Methyl-4-( 1H -1,2,3-triazol-1-yl)aniline 2d

氫氣氛下，將化合物2c(100mg，0.49mmol)溶於15mL甲醇中，加入10% Pd/C(80mg)，室溫攪拌1小時。矽藻土過濾，甲醇洗滌一次，濾液旋乾，得到化合物2d(80mg)，產率：93.8%。 Under a hydrogen atmosphere, compound 2c (100 mg, 0.49 mmol) was dissolved in 15 mL of methanol, 10% Pd/C (80 mg) was added, and stirred at room temperature for 1 hour. Celite was filtered, methanol was washed once, and the filtrate was spin-dried to obtain compound 2d (80 mg), yield: 93.8%.

MS m/z(ESI)：175.0[M+1]。 MS m/z (ESI): 175.0 [M+1].

第三步 third step

7-甲基-2-((2-甲基-4-(1H-1,2,3-***-1-基)苯基)胺基)-9-(四氫-2H-吡喃-4-基)-7,9-二氫-8H-嘌呤-8-酮2 7-methyl-2-((2-methyl-4-(1 H -1,2,3-triazol-1-yl)phenyl)amino)-9-(tetrahydro-2 H -pyridine pyran-4-yl)-7,9-dihydro- 8H -purin-8-one 2

將化合物2d(80mg，0.46mmol)和化合物1d(120mg，0.45mmol)分別懸浮於1,4-二噁烷(10mL)中，依次加入甲烷磺酸(2-二環己基膦)-3,6-二甲氧基-2',4',6'-三異丙基-1,1'-聯苯)(2'-胺基-1,1'-聯苯-2-基)鈀(II)(30mg，0.033mmol)和碳酸銫(292mg，0.90mmol)，加熱至100℃，攪拌17小時。反應液減壓濃縮，殘餘物用CombiFlash快速製備儀以沖提劑體系A純化，得到標題產物2(108mg)，產率：59.5%。 Compound 2d (80mg, 0.46mmol) and compound 1d (120mg, 0.45mmol) were suspended in 1,4-dioxane (10mL), and methanesulfonic acid (2-dicyclohexylphosphine)-3,6 -Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II ) (30mg, 0.033mmol) and cesium carbonate (292mg, 0.90mmol), heated to 100°C and stirred for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified with the eluent system A by CombiFlash to obtain the title product 2 (108 mg), yield: 59.5%.

MS m/z(ESI)：407.1[M+1]。 MS m/z (ESI): 407.1 [M+1].

¹H NMR(500MHz,DMSO-d ₆ )：δ 8.75(s,1H),8.60(s,1H),8.10(s,1H),7.96(s,1H),7.86(d,1H),7.75(s,1H),7.67(d,1H),4.45(brs,1H),4.02(d,2H),3.43(t,2H),3.25(s,3H),2.56(brs,2H),2.36(s,3H),1.64(d,2H)。 ¹ H NMR (500MHz, DMSO- d ₆ ): δ 8.75(s,1H),8.60(s,1H),8.10(s,1H),7.96(s,1H),7.86(d,1H),7.75( s,1H),7.67(d,1H),4.45(brs,1H),4.02(d,2H),3.43(t,2H),3.25(s,3H),2.56(brs,2H),2.36(s ,3H), 1.64(d,2H).

實施例3 Example 3

7-甲基-2-((2-甲基-4-(2H-1,2,3-***-2-基)苯基)胺基)-9-(四氫-2H-吡喃-4-基)-7,9-二氫-8H-嘌呤-8-酮3 7-methyl-2-((2-methyl-4-( 2H -1,2,3-triazol-2-yl)phenyl)amino)-9-(tetrahydro- 2H -pyridine pyran-4-yl)-7,9-dihydro- 8H -purin-8-one 3

第一步 first step

2-甲基-4-(2H-1,2,3-***-2-基)苯胺3 ^a 2-Methyl-4-( 2H -1,2,3-triazol-2-yl)aniline 3 ^a

將化合物2b(120mg，0.60mmol)溶於15mL甲醇中，加入10% Pd/C(80mg)，氫氣置換三次，室溫攪拌1小時。矽藻土過濾，甲醇洗滌一次，濾液旋乾，得到化合物3a(100mg)，產率：94.8%。 Compound 2b (120 mg, 0.60 mmol) was dissolved in 15 mL of methanol, 10% Pd/C (80 mg) was added, hydrogen was replaced three times, and stirred at room temperature for 1 hour. Celite was filtered, methanol was washed once, and the filtrate was spin-dried to obtain compound 3a (100 mg), yield: 94.8%.

MS m/z(ESI)：175.0[M+1]。 MS m/z (ESI): 175.0 [M+1].

第二步 second step

7-甲基-2-((2-甲基-4-(2H-1,2,3-***-2-基)苯基)胺基)-9-(四氫-2H-吡喃-4-基)-7,9-二氫-8H-嘌呤-8-酮3 7-methyl-2-((2-methyl-4-( 2H -1,2,3-triazol-2-yl)phenyl)amino)-9-(tetrahydro- 2H -pyridine pyran-4-yl)-7,9-dihydro- 8H -purin-8-one 3

將化合物3a(100mg，0.57mmol)和化合物1d(139mg，0.52mmol)懸浮於1,4-二噁烷(10mL)中，依次加入甲烷磺酸(2-二環己基膦)-3,6-二甲氧基-2',4',6'-三異丙基-1,1'-聯苯)(2'-胺基-1,1'-聯苯-2-基)鈀(II)(30mg，0.033mmol)和碳酸銫(375mg，1.15mmol)，加熱至100℃，攪拌17小時。反應液減壓濃縮，殘餘物用CombiFlash快速製備儀以沖提劑體系A純化，得到標題產物3(110mg)，產率：48.5%。 Compound 3a (100mg, 0.57mmol) and compound 1d (139mg, 0.52mmol) were suspended in 1,4-dioxane (10mL), and methanesulfonic acid (2-dicyclohexylphosphine)-3,6- Dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (30mg, 0.033mmol) and cesium carbonate (375mg, 1.15mmol), heated to 100°C and stirred for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified with the eluent system A by CombiFlash to obtain the title product 3 (110 mg), yield: 48.5%.

MS m/z(ESI)：407.1[M+1]。 MS m/z (ESI): 407.1 [M+1].

¹H NMR(500MHz,DMSO-d ₆ )：δ 8.56(s,1H),8.10(s,1H),8.09(s,1H),7.90(s,1H),7.82(d,1H),7.80(s,1H),7.78(d,1H),4.39-4.45(m,1H),3.4.00(d,2H),3.42(t,2H),3.31(s,3H),2.54-2.57(m,2H),2.36(s,3H),1.67(d,2H)。 ¹ H NMR (500MHz, DMSO- d ₆ ): δ 8.56(s,1H),8.10(s,1H),8.09(s,1H),7.90(s,1H),7.82(d,1H),7.80( s,1H),7.78(d,1H),4.39-4.45(m,1H),3.4.00(d,2H),3.42(t,2H),3.31(s,3H),2.54-2.57(m, 2H), 2.36(s, 3H), 1.67(d, 2H).

實施例4 Example 4

7-甲基-2-((2-甲基-4-(1H-吡唑-1-基)苯基)胺基)-9-(四氫-2H-吡喃-4-基)-7,9-二氫-8H-嘌呤-8-酮4 7-methyl-2-((2-methyl-4-(1 H -pyrazol-1-yl)phenyl)amino)-9-(tetrahydro-2 H -pyran-4-yl) -7,9-Dihydro-8 H -purin-8-one 4

在氬氣氛下，將化合物1d(100mg，0.37mmol)、2-甲基-4-(1H-吡唑-1-基)苯胺4a(65mg，0.37mmol，採用專利申請“WO2004062665A1,P39”公開的方法製備而得)、甲烷磺酸(2-二環己基膦)-3,6-二甲氧基-2',4',6'-三異丙基-1,1'-聯苯)(2'-胺 基-1,1'-聯苯-2-基)鈀(II)(34mg，0.037mmol，艾康)和碳酸銫(243mg，0.75mmol，韶遠)溶解於10mL 1,4-二噁烷中，加熱至100℃，攪拌17小時。反應液減壓濃縮，殘餘物用CombiFlash快速製備儀以沖提劑體系A純化，得到標題產物4(64.2mg)，產率：42.5%。 Under argon atmosphere, compound 1d (100mg, 0.37mmol), 2-methyl-4-( 1H -pyrazol-1-yl) aniline 4a (65mg, 0.37mmol, disclosed in patent application "WO2004062665A1, P39" prepared by the method), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-Amino-1,1'-biphenyl-2-yl)palladium(II) (34mg, 0.037mmol, Aikon) and cesium carbonate (243mg, 0.75mmol, Shaoyuan) were dissolved in 10mL 1,4 -in dioxane, heated to 100°C and stirred for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified with the eluent system A by CombiFlash to obtain the title product 4 (64.2 mg), yield: 42.5%.

MS m/z(ESI)：406.1[M+1]。 MS m/z (ESI): 406.1 [M+1].

¹H NMR(500MHz,DMSO-d ₆ )：δ 8.49(s,1H),8.42-8.41(m,1H),8.05(s,1H),7.71-7.68(m,3H),7.60-7.58(m,1H),6.52-6.51(m,1H),4.44-4.37(m,1H),3.99-3.95(m,2H),3.44-3.39(m,2H),3.30(s,3H),2.57-2.52(m,2H),2.32(s,3H),1.68-1.64(m,2H)。 ¹ H NMR (500MHz, DMSO- d ₆ ): δ 8.49(s,1H),8.42-8.41(m,1H),8.05(s,1H),7.71-7.68(m,3H),7.60-7.58(m ,1H),6.52-6.51(m,1H),4.44-4.37(m,1H),3.99-3.95(m,2H),3.44-3.39(m,2H),3.30(s,3H),2.57-2.52 (m,2H), 2.32(s,3H), 1.68-1.64(m,2H).

實施例5 Example 5

3-(3-甲基-4-((7-甲基-8-側氧-9-(四氫-2H-吡喃-4-基)-8,9-二氫-7H-嘌呤-2-基)胺基)苯基)-1,2,4-噁二唑-5(2H)-酮5 3-(3-methyl-4-((7-methyl-8-oxo-9-(tetrahydro-2 H -pyran-4-yl)-8,9-dihydro-7 H -purine -2-yl)amino)phenyl)-1,2,4-oxadiazol-5(2 H )-one 5

第一步 first step

3-甲基-4-((7-甲基-8-側氧-9-(四氫-2H-吡喃-4-基-8,9-二氫-7H-嘌呤-2-基)胺基)苯甲腈5b 3-methyl-4-((7-methyl-8-oxo-9-(tetrahydro-2 H -pyran-4-yl-8,9-dihydro-7 H -purin-2-yl )amino)benzonitrile 5b

在氬氣氛下，將化合物1d(280mg，1.04mmol)、4-胺基3-甲基苯甲腈5a(160mg，1.21mmol，採用專利申請“WO2011086377A1,P26-27”公開的方法製備而得)、甲烷磺酸(2-二環己基膦)-3,6-二甲氧基-2',4',6'-三異丙基-1,1'-聯苯)(2'-胺基-1,1'-聯苯-2-基)鈀(II)(60mg，0.066mmol)和碳酸銫(790mg，2.42mmol)溶解於20mL 1,4-二噁烷中，加熱至100℃，攪拌17小時。反應液減壓濃縮，殘餘物用CombiFlash快速製備儀以沖提劑體系A純化，得到化合物5b(320mg)，產率：72.5%。 Under an argon atmosphere, compound 1d (280mg, 1.04mmol), 4-amino 3-methylbenzonitrile 5a (160mg, 1.21mmol, prepared by the method disclosed in the patent application "WO2011086377A1, P26-27") , Methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino -1,1'-biphenyl-2-yl)palladium(II) (60mg, 0.066mmol) and cesium carbonate (790mg, 2.42mmol) were dissolved in 20mL of 1,4-dioxane, heated to 100°C and stirred 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by a CombiFlash rapid preparation apparatus with eluent system A to obtain compound 5b (320 mg), yield: 72.5%.

MS m/z(ESI)：365.1[M+1]。 MS m/z (ESI): 365.1 [M+1].

第二步 second step

N'-羥基-3-甲基-4-((7-甲基-8-側氧-9-(四氫-2H-吡喃-4-基)-8,9-二氫-7H-嘌呤-2-基)胺基)苯甲脒5c N' -Hydroxy-3-methyl-4-((7-methyl-8-oxo-9-(tetrahydro-2 H -pyran-4-yl)-8,9-dihydro-7 H -Purin-2-yl)amino)benzamidine 5c

將化合物5b(320mg，0.88mmol)溶於15mL乙醇中，依次加入碳酸氫鈉(222mg，2.64mmol)和氯化羥胺(184mg，2.64mmol)，70℃攪拌17小時。濃縮，加入水，過濾，水洗，得到化合物5c(220mg)，產率：63.0%。 Compound 5b (320mg, 0.88mmol) was dissolved in 15mL of ethanol, sodium bicarbonate (222mg, 2.64mmol) and hydroxylamine chloride (184mg, 2.64mmol) were added sequentially, and stirred at 70°C for 17 hours. Concentrate, add water, filter, and wash with water to obtain compound 5c (220mg), yield: 63.0%.

MS m/z(ESI)：398.1[M+1]。 MS m/z (ESI): 398.1 [M+1].

第三步 third step

3-(3-甲基-4-((7-甲基-8-側氧-9-(四氫-2H-吡喃-4-基)-8,9-二氫-7H-嘌呤-2-基)胺基)苯基)-1,2,4-噁二唑-5(2H)-酮5 3-(3-methyl-4-((7-methyl-8-oxo-9-(tetrahydro-2 H -pyran-4-yl)-8,9-dihydro-7 H -purine -2-yl)amino)phenyl)-1,2,4-oxadiazol-5(2 H )-one 5

將化合物5c(220mg，0.55mmol)懸浮於10mL 1,4-二噁烷中，依次加入1,8-二氮雜二環[5.4.0]十一碳-7-烯(93mg，0.61mmol)和二咪唑甲酮(99mg，0.61 mmol)，90℃攪拌3小時。濃縮，加入水，稀鹽酸中和，過濾，水洗，甲醇重結晶，過濾得到標題產物5(95mg)，產率：40.5%。 Compound 5c (220mg, 0.55mmol) was suspended in 10mL 1,4-dioxane, and 1,8-diazabicyclo[5.4.0]undec-7-ene (93mg, 0.61mmol) was added successively and diimidazolone (99 mg, 0.61 mmol), stirred at 90° C. for 3 hours. Concentrate, add water, neutralize with dilute hydrochloric acid, filter, wash with water, recrystallize from methanol, filter to obtain the title product 5 (95mg), yield: 40.5%.

MS m/z(ESI)：424.1[M+1]。 MS m/z (ESI): 424.1 [M+1].

¹H NMR(500MHz,DMSO-d ₆ )：δ 12.7(s,1H),8.62(s,1H),8.15(s,1H),8.03(d,1H),7.65(s,1H),7.60(d,1H),4.40-4.45(m,1H),3.99(d,2H),3.43(t,2H),3.30(s,3H),2.54-2.57(m,2H),2.35(s,3H),1.69(d,2H)。 ¹ H NMR (500MHz, DMSO- d ₆ ): δ 12.7(s,1H),8.62(s,1H),8.15(s,1H),8.03(d,1H),7.65(s,1H),7.60( d,1H),4.40-4.45(m,1H),3.99(d,2H),3.43(t,2H),3.30(s,3H),2.54-2.57(m,2H),2.35(s,3H) ,1.69(d,2H).

實施例6 Example 6

4-甲基-2-(1-甲基-1H-吡唑-4-基)-5-((7-甲基-8-側氧-9-(四氫-2H-吡喃-4-基)-8,9-二氫-7H-嘌呤-2-基)胺基)苯甲腈6 4-methyl-2-(1-methyl-1 H -pyrazol-4-yl)-5-((7-methyl-8-oxo-9-(tetrahydro-2 H -pyran- 4-yl) -8,9 -dihydro-7H-purin-2-yl)amino)benzonitrile 6

在氬氣氛下，將化合物1d(100mg，0.37mmol)、5-胺基-4-甲基-2-(1-甲基-1H-吡唑-4-基)苯甲腈6a(90mg，0.42mmol，採用專利申請“WO2017125530A1,P317-318”公開的方法製備而得)、甲烷磺酸(2-二環己基膦)-3,6-二甲氧基-2',4',6'-三異丙基-1,1'-聯苯)(2'-胺基-1,1'-聯苯-2-基)鈀(II)(34mg，0.037mmol，艾康)和碳酸銫(364mg，1.12mmol，韶遠)溶解於15mL 1,4-二噁烷中，加熱至100℃，攪拌17小時。反應液減壓濃縮，殘餘物用CombiFlash快速製備儀以沖提劑體系A純化，得到標題產物6(57.2mg)，產率：34.6%。 Under argon atmosphere, compound 1d (100 mg, 0.37 mmol), 5-amino-4-methyl-2-(1-methyl-1 H -pyrazol-4-yl)benzonitrile 6a (90 mg, 0.42mmol, prepared by the method disclosed in the patent application "WO2017125530A1, P317-318"), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (34mg, 0.037mmol, Icon) and cesium carbonate ( 364mg, 1.12mmol, Shaoyuan) was dissolved in 15mL 1,4-dioxane, heated to 100°C, and stirred for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified with the eluent system A by CombiFlash to obtain the title product 6 (57.2 mg), yield: 34.6%.

MS m/z(ESI)：445.0[M+1]。 MS m/z (ESI): 445.0 [M+1].

¹H NMR(500MHz,DMSO-d ₆ )：δ 8.65(s,1H),8.19(s,1H),8.16(s,1H),8.13(s,1H),7.91(s,1H),7.56(s,1H),4.44-4.38(m,1H),4.00-3.96(m,2H),3.92(s,3H),3.47-3.44(m,2H),3.31(s,3H),2.52-2.49(m,2H),2.36(s,3H),1.70-1.67(m,2H)。 ¹ H NMR (500MHz, DMSO- d ₆ ): δ 8.65(s,1H),8.19(s,1H),8.16(s,1H),8.13(s,1H),7.91(s,1H),7.56( s,1H),4.44-4.38(m,1H),4.00-3.96(m,2H),3.92(s,3H),3.47-3.44(m,2H),3.31(s,3H),2.52-2.49( m,2H), 2.36(s,3H), 1.70-1.67(m,2H).

實施例7 Example 7

4-甲基-2-(1-甲基-1H-吡唑-5-基)-5-((7-甲基-8-側氧-9-(四氫-2H-吡喃-4-基)-8,9-二氫-7H-嘌呤-2-基)胺基)苯甲腈7 4-methyl-2-(1-methyl-1 H -pyrazol-5-yl)-5-((7-methyl-8-oxo-9-(tetrahydro-2 H -pyran- 4-yl)-8,9-dihydro- 7H -purin-2-yl)amino)benzonitrile 7

第一步 first step

4-甲基-2-(1-甲基-1H-吡唑-5-基)-5-硝基苯甲腈7b 4-Methyl-2-(1-methyl- 1H -pyrazol-5-yl)-5-nitrobenzonitrile 7b

氬氣氛下，將2-溴-4-甲基-5-硝基苯甲腈7a(300mg，1.24mmol，採用專利申請“WO2017125530A1,P311”公開的方法製備而得)、(1-甲基-1H-吡唑-5-基)硼酸(220mg，1.75mmol，韶遠)、[1,1-雙(二苯基磷)二茂鐵]二氯化鈀(92mg，0.13mmol，艾康)和碳酸鉀(517mg，3.74mmol，滬試)混合懸浮於18mL 1,4-二噁烷和水(V/V=5：1)的混合溶劑中，升溫至100℃，攪拌7小時。反應液減壓濃縮，殘 餘物用CombiFlash快速製備儀以沖提劑體系A純化，得到標題產物7b(94mg)，產率：31.2%。 Under an argon atmosphere, 2-bromo-4-methyl-5-nitrobenzonitrile 7a (300 mg, 1.24 mmol, prepared by the method disclosed in the patent application "WO2017125530A1, P311"), (1-methyl- 1 H -pyrazol-5-yl)boronic acid (220mg, 1.75mmol, Shaoyuan), [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (92mg, 0.13mmol, Aikon) Mix with potassium carbonate (517mg, 3.74mmol, Shanghai test) and suspend in 18mL of a mixed solvent of 1,4-dioxane and water (V/V=5:1), heat up to 100°C, and stir for 7 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by CombiFlash with eluent system A to obtain the title product 7b (94 mg), yield: 31.2%.

MS m/z(ESI)：242.9[M+1]。 MS m/z (ESI): 242.9 [M+1].

第二步 second step

5-胺基-4-甲基-2-(1-甲基-1H-吡唑-5-基)苯甲腈7c 5-Amino-4-methyl-2-(1-methyl-1 H -pyrazol-5-yl)benzonitrile 7c

將化合物7b(94mg，0.39mmol)和鈀碳(濕)(42mg，0.39mmol，伊諾凱)混合懸浮於20mL乙醇中，氫氣置換6次，攪拌反應17小時。反應液過濾，濾液減壓濃縮得到標題產物7c(75mg)，產率：91.1%。 Compound 7b (94mg, 0.39mmol) and palladium on carbon (wet) (42mg, 0.39mmol, Enoke) were mixed and suspended in 20mL of ethanol, hydrogen was replaced 6 times, and the reaction was stirred for 17 hours. The reaction liquid was filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 7c (75 mg), yield: 91.1%.

MS m/z(ESI)：213.0[M+1]。 MS m/z (ESI): 213.0 [M+1].

第三步 third step

4-甲基-2-(1-甲基-1H-吡唑-5-基)-5-((7-甲基-8-側氧-9-(四氫-2H-吡喃-4-基)-8,9-二氫-7H-嘌呤-2-基)胺基)苯甲腈7 4-methyl-2-(1-methyl-1 H -pyrazol-5-yl)-5-((7-methyl-8-oxo-9-(tetrahydro-2 H -pyran- 4-yl)-8,9-dihydro- 7H -purin-2-yl)amino)benzonitrile 7

在氬氣氛下，將化合物7c(75mg，0.35mmol)、化合物1d(100mg，0.37mmol)、甲烷磺酸(2-二環己基膦)-3,6-二甲氧基-2',4',6'-三異丙基-1,1'-聯苯)(2'-胺基-1,1'-聯苯-2-基)鈀(II)(33mg，0.036mmol，艾康)和碳酸銫(346mg，1.06mmol，韶遠)溶解於15mL 1,4-二噁烷中，加熱至100℃，攪拌17小時。反應液減壓濃縮，殘餘物用CombiFlash快速製備儀以沖提劑體系A純化，得到標題產物7(75.4mg)，產率：48.0%。 Under argon atmosphere, compound 7c (75mg, 0.35mmol), compound 1d (100mg, 0.37mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (33mg, 0.036mmol, Icon) and Cesium carbonate (346mg, 1.06mmol, Shaoyuan) was dissolved in 15mL of 1,4-dioxane, heated to 100°C, and stirred for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified with the eluent system A by CombiFlash to obtain the title product 7 (75.4 mg), yield: 48.0%.

MS m/z(ESI)：445.1[M+1]。 MS m/z (ESI): 445.1 [M+1].

¹H NMR(500MHz,DMSO-d ₆ )：δ 8.82(s,1H),8.39(s,1H),8.19(s,1H),7.55-7.54(m,1H),7.51(s,1H),6.48-6.47(m,1H),4.47-4.40(m,1H),4.00-3.96(m,2H),3.79 (s,3H),3.45-3.40(m,2H),3.33(s,3H),2.56-2.47(m,2H),2.42(s,3H),1.72-1.68(m,2H)。 ¹ H NMR (500MHz, DMSO- d ₆ ): δ 8.82(s,1H),8.39(s,1H),8.19(s,1H),7.55-7.54(m,1H),7.51(s,1H), 6.48-6.47(m,1H),4.47-4.40(m,1H),4.00-3.96(m,2H),3.79(s,3H),3.45-3.40(m,2H),3.33(s,3H), 2.56-2.47 (m, 2H), 2.42 (s, 3H), 1.72-1.68 (m, 2H).

實施例8 Example 8

4-甲基-2-(1-甲基-1H-吡唑-3-基)-5-((7-甲基-8-側氧-9-(四氫-2H-吡喃-4-基)-8,9-二氫-7H-嘌呤-2-基)胺基)苯甲腈8 4-methyl-2-(1-methyl-1 H -pyrazol-3-yl)-5-((7-methyl-8-oxo-9-(tetrahydro-2 H -pyran- 4-yl) -8,9 -dihydro-7H-purin-2-yl)amino)benzonitrile 8

第一步 first step

4-甲基-2-(1-甲基-1H-吡唑-3-基)-5-硝基苯甲腈8 ^a 4-methyl-2-(1-methyl- 1H -pyrazol-3-yl)-5-nitrobenzonitrile 8 ^a

氬氣氛下，將化合物7a(300mg，1.24mmol)、(1-甲基-1H-吡唑-3-基)硼酸(187mg，1.49mmol，採用專利申請“US20190106427A1,P446-447”公開的方法製備而得)、[1,1-雙(二苯基磷)二茂鐵]二氯化鈀(92mg，0.13mmol，艾康)和碳酸鉀(517mg，3.74mmol，滬試)混合懸浮於25mL 1,4-二噁烷和水(V/V=5：1)的混合溶劑中，升溫至100℃，攪拌7小時。反應液減壓濃縮，殘餘物用CombiFlash快速製備儀以沖提劑體系A純化，得到標題產物8a(96mg)，產率：31.8%。 Under argon atmosphere, compound 7a (300mg, 1.24mmol), (1-methyl- 1H -pyrazol-3-yl) boronic acid (187mg, 1.49mmol, using the method disclosed in the patent application "US20190106427A1, P446-447" prepared), [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (92mg, 0.13mmol, Ai Kang) and potassium carbonate (517mg, 3.74mmol, Shanghai test) were mixed and suspended in 25mL In a mixed solvent of 1,4-dioxane and water (V/V=5:1), heat up to 100°C and stir for 7 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified with the eluent system A by CombiFlash to obtain the title product 8a (96 mg), yield: 31.8%.

MS m/z(ESI)：242.9[M+1]。 MS m/z (ESI): 242.9 [M+1].

第二步 second step

5-胺基-4-甲基-2-(1-甲基-1H-吡唑-3-基)苯甲腈8b 5-Amino-4-methyl-2-(1-methyl-1 H -pyrazol-3-yl)benzonitrile 8b

將化合物8a(96mg，0.40mmol)和鈀碳(濕)(43mg，0.40mmol，伊諾凱)混合懸浮於20mL乙醇中，氫氣置換6次，攪拌反應17小時。反應液過濾，濾液減壓濃縮得到標題產物8b(71mg)，產率：84.4%。 Compound 8a (96mg, 0.40mmol) and palladium on carbon (wet) (43mg, 0.40mmol, Enoke) were mixed and suspended in 20mL of ethanol, hydrogen was replaced 6 times, and the reaction was stirred for 17 hours. The reaction liquid was filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 8b (71 mg), yield: 84.4%.

MS m/z(ESI)：213.0[M+1]。 MS m/z (ESI): 213.0 [M+1].

第三步 third step

4-甲基-2-(1-甲基-1H-吡唑-3-基)-5-((7-甲基-8-側氧-9-(四氫-2H-吡喃-4-基)-8,9-二氫-7H-嘌呤-2-基)胺基)苯甲腈8 4-methyl-2-(1-methyl-1 H -pyrazol-3-yl)-5-((7-methyl-8-oxo-9-(tetrahydro-2 H -pyran- 4-yl) -8,9 -dihydro-7H-purin-2-yl)amino)benzonitrile 8

在氬氣氛下，將化合物8b(71mg，0.334mmol)、化合物1d(100mg，0.37mmol)、甲烷磺酸(2-二環己基膦)-3,6-二甲氧基-2',4',6'-三異丙基-1,1'-聯苯)(2'-胺基-1,1'-聯苯-2-基)鈀(II)(31mg，0.034mmol，艾康)和碳酸銫(327mg，1.00mmol，韶遠)溶解於15mL 1,4-二噁烷中，加熱至100℃，攪拌17小時。反應液減壓濃縮，殘餘物用CombiFlash快速製備儀以沖提劑體系A純化，得到標題化合物8(81.1mg)，產率：54.5%。 Under argon atmosphere, compound 8b (71mg, 0.334mmol), compound 1d (100mg, 0.37mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (31mg, 0.034mmol, Icon) and Cesium carbonate (327mg, 1.00mmol, Shaoyuan) was dissolved in 15mL of 1,4-dioxane, heated to 100°C, and stirred for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified with the eluent system A by CombiFlash to obtain the title compound 8 (81.1 mg), yield: 54.5%.

MS m/z(ESI)：445.0[M+1]。 MS m/z (ESI): 445.0 [M+1].

¹H NMR(500MHz,DMSO-d ₆ )：δ 8.69(s,1H),8.24(s,1H),8.16(s,1H),7.83-7.82(m,1H),7.76(s,1H),6.80-6.79(m,1H),4.46-4.39(m,1H),4.00-3.97(m,2H),3.93(s,3H),3.45-3.40(m,2H),3.32(s,3H),2.56-2.47(m,2H),2.40(s,3H),1.71-1.68(m,2H)。 ¹ H NMR (500MHz, DMSO- d ₆ ): δ 8.69(s,1H),8.24(s,1H),8.16(s,1H),7.83-7.82(m,1H),7.76(s,1H), 6.80-6.79(m,1H),4.46-4.39(m,1H),4.00-3.97(m,2H),3.93(s,3H),3.45-3.40(m,2H),3.32(s,3H), 2.56-2.47 (m, 2H), 2.40 (s, 3H), 1.71-1.68 (m, 2H).

實施例9 Example 9

7-甲基-2-((4-甲基-6-(1-甲基-1H-吡唑-4-基)吡啶-3-基)胺基)-9-(四氫-2H-吡喃-4-基)-7,9-二氫-8H-嘌呤-8-酮9 7-methyl-2-((4-methyl-6-(1-methyl-1 H -pyrazol-4-yl)pyridin-3-yl)amino)-9-(tetrahydro-2 H -pyran-4-yl)-7,9-dihydro-8 H -purin-8-one 9

第一步 first step

4-甲基-2-(1-甲基-1H-吡唑-4-基)-5-硝基吡啶9b 4-methyl-2-(1-methyl-1 H -pyrazol-4-yl)-5-nitropyridine 9b

氬氣氛下，將2-溴-4-甲基-5-硝基吡啶9a(300mg，1.38mmol，畢得醫藥)、(1-甲基-1H-吡唑-4-基)硼酸(192mg，1.52mmol，韶遠)、[1,1-雙(二苯基磷)二茂鐵]二氯化鈀(102mg，0.139mmol，艾康)和碳酸鉀(574mg，4.15mmol，滬試)混合懸浮於18mL 1,4-二噁烷和水(V/V=5：1)的混合溶劑中，升溫至100℃，攪拌17小時。將反應液減壓濃縮，殘餘物用CombiFlash快速製備儀以沖提劑體系A純化，得到標題產物9b(200mg)，產率：66.3%。 Under argon atmosphere, 2-bromo-4-methyl-5-nitropyridine 9a (300mg, 1.38mmol, Biide Pharmaceuticals), (1-methyl- 1H -pyrazol-4-yl)boronic acid (192mg , 1.52mmol, Shaoyuan), [1,1-bis(diphenylphosphino)ferrocene] palladium dichloride (102mg, 0.139mmol, Ai Kang) and potassium carbonate (574mg, 4.15mmol, Shanghai test) mixed Suspend in 18 mL of a mixed solvent of 1,4-dioxane and water (V/V=5:1), heat up to 100°C, and stir for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified with the eluent system A by CombiFlash to obtain the title product 9b (200 mg), yield: 66.3%.

MS m/z(ESI)：218.9[M+1]。 MS m/z (ESI): 218.9 [M+1].

第二步 second step

4-甲基-6-(1-甲基-1H-吡唑-4-基)吡啶-3-胺9c 4-methyl-6-(1-methyl- 1H -pyrazol-4-yl)pyridin-3-amine 9c

將化合物9b(200mg，0.916mmol)和鈀碳(濕)(98mg，0.39mmol，伊諾凱)混合懸浮於25mL乙醇中，氫氣置換6次，攪拌反應17小時。反應液過濾，濾液減壓濃縮得到標題產物9c(172mg)，產率：99.7%。 Compound 9b (200mg, 0.916mmol) and palladium on carbon (wet) (98mg, 0.39mmol, Enoke) were mixed and suspended in 25mL of ethanol, hydrogen was replaced 6 times, and the reaction was stirred for 17 hours. The reaction liquid was filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 9c (172 mg), yield: 99.7%.

MS m/z(ESI)：188.9[M+1]。 MS m/z (ESI): 188.9 [M+1].

第三步 third step

7-甲基-2-((4-甲基-6-(1-甲基-1H-吡唑-4-基)吡啶-3-基)胺基)-9-(四氫-2H-吡喃-4-基)-7,9-二氫-8H-嘌呤-8-酮9 7-methyl-2-((4-methyl-6-(1-methyl-1 H -pyrazol-4-yl)pyridin-3-yl)amino)-9-(tetrahydro-2 H -pyran-4-yl)-7,9-dihydro-8 H -purin-8-one 9

在氬氣氛下，將化合物9c(183mg，0.972mmol)、化合物1d(200mg，0.744mmol)、甲烷磺酸(2-二環己基膦)-3,6-二甲氧基-2',4',6'-三異丙基-1,1'-聯苯)(2'-胺基-1,1'-聯苯-2-基)鈀(II)(68mg，0.075mmol，艾康)和碳酸銫(728mg，2.23mmol，韶遠)加入到30mL 1,4-二噁烷中，加熱至100℃，攪拌17小時。反應液減壓濃縮，殘餘物用CombiFlash快速製備儀以沖提劑體系A純化，得到標題產物9(145.7mg)，產率：46.5%。 Under argon atmosphere, compound 9c (183mg, 0.972mmol), compound 1d (200mg, 0.744mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4' , 6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (68 mg, 0.075 mmol, Icon) and Cesium carbonate (728mg, 2.23mmol, Shaoyuan) was added into 30mL of 1,4-dioxane, heated to 100°C, and stirred for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified with the eluent system A by CombiFlash to obtain the title product 9 (145.7 mg), yield: 46.5%.

MS m/z(ESI)：421.0[M+1]。 MS m/z (ESI): 421.0 [M+1].

¹H NMR(500MHz,DMSO-d ₆ )：δ 8.64(s,1H),8.54(s,1H),8.19(s,1H),8.02(s,1H),7.93(s,1H),7.51(s,1H),4.43-4.37(m,1H),3.98-3.95(m,2H),3.89(s,3H),3.44-3.39(m,2H),3.34(s,3H),2.56-2.48(m,2H),2.25(s,3H),1.68-1.65(m,2H)。 ¹ H NMR (500MHz, DMSO- d ₆ ): δ 8.64(s,1H),8.54(s,1H),8.19(s,1H),8.02(s,1H),7.93(s,1H),7.51( s,1H),4.43-4.37(m,1H),3.98-3.95(m,2H),3.89(s,3H),3.44-3.39(m,2H),3.34(s,3H),2.56-2.48( m,2H), 2.25(s,3H), 1.68-1.65(m,2H).

生物學評價 biological evaluation

以下結合測試例進一步描述解釋本揭露，但這些測試例並非意味著限制本揭露的範圍。 The following further describes and explains the present disclosure in combination with test examples, but these test examples are not meant to limit the scope of the present disclosure.

測試例1 test case 1

DNA-PK酶學實驗方法 DNA-PK enzymatic experiment method

1.實驗目的 1. Purpose of the experiment

採用HTRF方法檢測磷酸化P53的水準，反應化合物對DNA-PK酶活性的抑制作用，根據抑制效應的IC₅₀評價化合物的體外活性。 The HTRF method was used to detect the level of phosphorylated P53 to reflect the inhibitory effect of the compound on the DNA-PK enzyme activity, and the in vitro activity of the compound was evaluated according to the IC ₅₀ of the inhibitory effect.

2.實驗方法 2. Experimental method

用反應緩衝液[25mM HEPES(Gibco，貨號：15630-080)，pH8.0,0.01% Brij-35(Thermo，貨號：20150)，1%甘油(生工，貨號：A100854-0100)]稀釋受質P53(Eurofins，貨號：14-952-M)至500nM；用稀釋緩衝液[25mM HEPES pH8.0,0.01% Brij-35，1%甘油，5mM DTT(生工，貨號：B645939)，1mg/mL BSA(碧雲天，貨號：ST023)]稀釋DNA-PK酶(Eurofins，貨號：14-950M)至0.16nM；用稀釋緩衝液稀釋醋酸鎂(Sigma，貨號：63052)至40mM後稀釋ATP(Thermo，貨號：PV3227)至29.2μM。用液體工作站(PV3227，貨號：SP2-096-0125-03)在384孔板(Thermo，貨號：267462)中依次加入配製好的化合物10μL、DNA-PK酶2.5μL、500nM P53受質2.5μL、ATP 5μL。混勻後25℃孵育1小時。 Dilute the subject with reaction buffer [25mM HEPES (Gibco, catalog number: 15630-080), pH8.0, 0.01% Brij-35 (Thermo, catalog number: 20150), 1% glycerol (Shenggong, catalog number: A100854-0100)] Substance P53 (Eurofins, Cat. No.: 14-952-M) to 500 nM; with dilution buffer [25mM HEPES pH8.0, 0.01% Brij-35, 1% glycerol, 5mM DTT (Shenggong, Cat. No.: B645939), 1mg/ mL BSA (Beyond, Cat. No.: ST023)] dilute DNA-PK enzyme (Eurofins, Cat. No.: 14-950M) to 0.16nM; dilute magnesium acetate (Sigma, Cat. , Cat. No.: PV3227) to 29.2 μM. Add 10 μL of the prepared compound, 2.5 μL of DNA-PK enzyme, 2.5 μL of 500 nM P53 substrate, ATP 5 μL. After mixing, incubate at 25°C for 1 hour.

用液體工作站在384孔板中依次加入終止液[12.5mM HEPES pH8.0、0.005% Brij-35、0.5%甘油、250mM EDTA(Thermo，貨號：AM9260G)]和檢測混合物[50mM HEPES pH7.0,150mM NaCl(生工，貨號：B548121)、267mM KF(國藥，7789-23-3)、0.1%膽酸鈉(Sigma，貨號：C6445)、0.01%吐溫20(Sigma，貨號：P7949)、0.0125%疊氮化鈉(Sigma，貨號：S8032)、抗磷酸化-p53 Eu(Cisbio，貨號：61P08KAE)0.42ng/孔和抗-GST-d2(Cisbio，61GSTDLF)25ng/孔]各5μL， 25℃孵育過夜。使用酶標儀(BMG，PHERAstar FS)讀取665nm和620nm吸收光的數值。使用Graphpad Prism 6對資料進行分析處理見表1。 Add stop solution [12.5mM HEPES pH8.0, 0.005% Brij-35, 0.5% glycerol, 250mM EDTA (Thermo, catalog number: AM9260G)] and detection mixture [50mM HEPES pH7.0, 150mM NaCl (Sanko, product number: B548121), 267mM KF (Sinopharm, 7789-23-3), 0.1% sodium cholate (Sigma, product number: C6445), 0.01% Tween 20 (Sigma, product number: P7949), 0.0125% Sodium azide (Sigma, catalog number: S8032), anti-phosphorylated-p53 Eu (Cisbio, catalog number: 61P08KAE) 0.42ng/well and anti-GST-d2 (Cisbio, 61GSTDLF) 25ng/well] 5 μL each, Incubate overnight at 25°C. A microplate reader (BMG, PHERAstar FS) was used to read the values of light absorbed at 665 nm and 620 nm. The data were analyzed and processed using Graphpad Prism 6, as shown in Table 1.

表1本揭露化合物對DNA-PK酶的抑制活性的IC₅₀值

Table 1 The disclosed compounds are to the IC ₅₀ value of the inhibitory activity of DNA-PK enzyme

結論：本揭露化合物對DNA-PK酶具有很好的抑制作用。 Conclusion: The disclosed compound has good inhibitory effect on DNA-PK enzyme.

測試例2 test case 2

DNA-PK細胞增殖抑制實驗 DNA-PK cell proliferation inhibition assay

1.實驗目的 1. Purpose of the experiment

藉由檢測細胞內ATP水準反應細胞活性，研究化合物對非小細胞肺癌細胞系A549的殺傷作用，根據殺傷效應的IC₅₀大小評價化合物的體外活性。 The killing effect of the compound on the non-small cell lung cancer cell line A549 was studied by detecting the ATP level in the cell to reflect the cell activity, and the in vitro activity of the compound was evaluated according to the IC ₅₀ of the killing effect.

2.實驗方法 2. Experimental method

A549細胞(ATCC，CCL-185)使用胰酶(Gibico，25200-072)37℃消化3分鐘，用完全培養基[F-12K培養基(Gibico，21127030)，10% FBS(ThermoFisher Scientific，10099-141)]重新懸浮計數，在96孔板(Corning，3903)中每孔加入 1000個細胞，放入CO₂恆溫培養箱(Thermo Fisher，HERAcell 240i)37℃培養過夜。 A549 cells (ATCC, CCL-185) were digested with trypsin (Gibico, 25200-072) at 37°C for 3 minutes, and then filled with complete medium [F-12K medium (Gibico, 21127030), 10% FBS (ThermoFisher Scientific, 10099-141) ] resuspended for counting, 1000 cells were added to each well of a 96-well plate (Corning, 3903), and cultured overnight at 37° C. in a CO ₂ incubator (Thermo Fisher, HERAcell 240i).

使用Bravo液體工作站(Agilent Technologies，SGS120TH34702)配製化合物，配製好的化合物用完全培養基稀釋備用。取出細胞培養板，吸出培液10μL，加入稀釋好的化合物5μL，放回CO₂恆溫培養箱培養1小時；博來黴素(selleck，S1214)使用完全培養基稀釋至20μM，在培養板中每孔加入5μL(終濃度為500nM)。將培養板放回CO₂恆溫培養箱繼續培養。6天後取出培養板，每孔加入50μL CellTiter-Glo(Promega，G7573)，25℃避光孵育5分鐘。使用酶標儀(PerkinElmer，Vector3)檢測發光的數值，使用Graphpad Prism 6對資料進行分析處理，結果見表2。 Bravo Liquid Workstation (Agilent Technologies, SGS120TH34702) was used to prepare compounds, and the prepared compounds were diluted with complete medium for use. Take out the cell culture plate, suck out 10 μL of the culture medium, add 5 μL of the diluted compound, and put it back in the CO ₂ incubator for 1 hour; bleomycin (selleck, S1214) is diluted to 20 μM with complete medium, and in each well of the culture plate Add 5 μL (500 nM final concentration). Put the culture plate back into the _CO2 incubator to continue the culture. After 6 days, the culture plate was taken out, 50 μL CellTiter-Glo (Promega, G7573) was added to each well, and incubated at 25° C. in the dark for 5 minutes. A microplate reader (PerkinElmer, Vector3) was used to detect the value of luminescence, and Graphpad Prism 6 was used to analyze and process the data. The results are shown in Table 2.

表2本揭露化合物對DNA-PK細胞增殖的抑制活性的IC₅₀值

Table 2 IC ₅₀ value of the inhibitory activity of the disclosed compounds on DNA-PK cell proliferation

結論：本揭露化合物對DNA-PK細胞增殖具有很好的抑制作用。 Conclusion: The disclosed compound has a good inhibitory effect on the proliferation of DNA-PK cells.

測試例3 Test case 3

TTK酶學實驗 TTK Enzyme Experiment

1.實驗目的 1. Purpose of the experiment

採用Lantha Screen方法檢測ATP水準變化，反應化合物對TTK酶活性的抑制作用，根據抑制效應的IC₅₀評價化合物的選擇性。 The Lantha Screen method was used to detect the change of ATP level, to reflect the inhibitory effect of the compound on the TTK enzyme activity, and to evaluate the selectivity of the compound according to the IC ₅₀ of the inhibitory effect.

2.實驗方法 2. Experimental method

用反應緩衝液[50mM HEPES(Gibco，#11344-041)pH7.5、10mM MgCl₂(Sigma，#M2670)、2mM DTT(Sigma，# D0632)、0.01%Triton X-100(Sigma，# T9284)]分別稀釋TTK酶(Invitrogen，# PR7264B)、受質螢光素-Poly GAT(Invitrogen，# PV3611)及ATP(ADP-Glo Kinase Assay Kit,Promega,#V9102)。在96孔板(Corning，#3365)中依次加入配製好的化合物100nL及TTK酶、受質、ATP各5μL。混勻後28℃孵育30分鐘。每孔加入10μL檢測緩衝液(LanthaScreen® Tb-PY20抗體試劑盒，Invitrogen，# PV3552)，混勻後28℃孵育1小時。使用Envision(PE)讀取發光的數值。使用Graphpad Prism對資料進行分析處理，結果見表3。 With reaction buffer [50mM HEPES (Gibco, #11344-041) pH7.5, 10mM _MgCl2 (Sigma, #M2670), 2mM DTT (Sigma, #D0632), 0.01%Triton X-100 (Sigma, #T9284) ] Dilute TTK enzyme (Invitrogen, # PR7264B), substrate luciferin-Poly GAT (Invitrogen, #PV3611) and ATP (ADP-Glo Kinase Assay Kit, Promega, #V9102). In a 96-well plate (Corning, #3365), 100 nL of the prepared compound and 5 μL each of TTK enzyme, substrate and ATP were sequentially added. After mixing, incubate at 28°C for 30 minutes. Add 10 μL detection buffer (LanthaScreen® Tb-PY20 Antibody Kit, Invitrogen, # PV3552) to each well, mix well and incubate at 28°C for 1 hour. Luminescence values were read using Envision (PE). The data were analyzed and processed using Graphpad Prism, and the results are shown in Table 3.

表3本揭露化合物對TTK酶的抑制活性的IC₅₀值

結論：本揭露化合物對TTK酶抑制作用較弱，對DNA-PK酶有較好的選擇抑制作用。 Table 3 IC ₅₀ value of the inhibitory activity of the compounds disclosed in this disclosure to TTK enzymes

Conclusion: The disclosed compound has a weak inhibitory effect on TTK enzyme, but has a better selective inhibitory effect on DNA-PK enzyme.

測試例4 Test case 4

藥物代謝動力學評價 Pharmacokinetic Evaluation

一、C57小鼠試驗 1. C57 mouse experiment

1、摘要 1. Summary

以C57小鼠為受試動物，應用LC/MS/MS法測定了C57小鼠灌胃(i.g.)/靜脈注射(i.v.)給予實施例9化合物和陽性對照例1後不同時刻血漿中的藥物濃度。研究本揭露化合物在C57小鼠體內的藥物代謝動力學行為，評價其藥動學特徵。 Taking C57 mice as the experimental animals, the application of LC/MS/MS method has determined the drug concentration in the blood plasma of C57 mice at different times after intragastric (i.g.)/intravenous injection (i.v.) administration of the compound of Example 9 and positive control example 1 . To study the pharmacokinetic behavior of the disclosed compound in C57 mice, and to evaluate its pharmacokinetic characteristics.

2、試驗方案 2. Test plan

2.1試驗藥品 2.1 Test drugs

實施例9化合物和陽性對照例1。陽性對照例1(見WO2018114999A1實施例3化合物)，結構如下： Example 9 compound and positive control example 1. Positive control example 1 (see WO2018114999A1 Example 3 compound), the structure is as follows:

2.2試驗動物 2.2 Test animals

C57小鼠36隻，雌性，平均分成4組，購自維通利華實驗動物有限公司。 Thirty-six C57 mice, female, were equally divided into 4 groups and purchased from Weitong Lihua Experimental Animal Co., Ltd.

2.3藥物配製 2.3 Drug preparation

稱取一定量的實施例9化合物和陽性對照例1，加5%體積DMSO+5%體積吐溫80+90%體積生理鹽水，使其溶解，配製成0.1mg/mL澄明溶液。 Weigh a certain amount of the compound of Example 9 and positive control example 1, add 5% volume DMSO + 5% volume Tween 80 + 90% volume saline, dissolve them, and prepare a 0.1 mg/mL clear solution.

2.4給藥 2.4 Administration

灌胃給藥組：給藥劑量為2.0mg/kg，給藥體積為0.2mL/10g。 Oral administration group: the dosage is 2.0 mg/kg, and the volume of administration is 0.2 mL/10 g.

靜脈注射給藥組：給藥劑量為1.0mg/kg，給藥體積為0.1mL/10g。 Intravenous injection administration group: the administration dose is 1.0mg/kg, and the administration volume is 0.1mL/10g.

3.操作 3. Operation

灌胃給藥組：於給藥後0.25、0.5、1.0、2.0、4.0、6.0、8.0、11.0、24.0小時採血0.1mL，置EDTA-K2抗凝試管中，10000rpm離心5分鐘(4℃)，1小時內分離血漿，-80℃保存待測。採血至離心過程在冰浴條件下操作。 Intragastric administration group: 0.1 mL of blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration, placed in an EDTA-K2 anticoagulant test tube, centrifuged at 10,000 rpm for 5 minutes (4°C), The plasma was separated within 1 hour and stored at -80°C until testing. The process from blood collection to centrifugation was operated under ice bath conditions.

靜脈注射給藥組：於給藥後5分鐘，0.25、0.5、1.0、2.0、4.0、8.0、11.0、24小時採血0.1mL，處理同灌胃組。 Intravenous injection group: 5 minutes after administration, 0.1 mL of blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 11.0, and 24 hours, and the treatment was the same as that of the intragastric administration group.

測定不同濃度的藥物給藥後小鼠血漿中的待測化合物含量：取給藥後各時刻的小鼠血漿樣品25μL，加入200μL乙腈和50μL內標溶液喜樹鹼(100ng/mL)，渦旋混合5分鐘，離心10分鐘(4000rpm)，血漿樣品取上清液0.1μL進行LC/MS/MS分析。 Determination of the content of the compound to be tested in mouse plasma after administration of different concentrations of drugs: Take 25 μL of mouse plasma samples at various times after administration, add 200 μL of acetonitrile and 50 μL of internal standard solution camptothecin (100 ng/mL), vortex Mix for 5 minutes, centrifuge for 10 minutes (4000 rpm), and take 0.1 μL of the supernatant from the plasma sample for LC/MS/MS analysis.

4、藥物代謝動力學參數結果 4. Results of pharmacokinetic parameters

表4本揭露化合物的藥物代謝動力學參數如下：

結論：本揭露化合物在C57小鼠體內具有很好的藥物代謝吸收活性，口服生物利用度高，具有藥物代謝動力學優勢。 Table 4 The pharmacokinetic parameters of the disclosed compounds are as follows:

Conclusion: The disclosed compound has good drug metabolism and absorption activity in C57 mice, high oral bioavailability, and pharmacokinetic advantages.

二、比格(Beagle)犬試驗 2. Beagle dog test

1、摘要 1. Summary

以比格犬為受試動物，應用LC/MS/MS法測定了比格犬灌胃(i.g.)/靜脈注射(i.v.)給予實施例9化合物和陽性對照例1後不同時刻血漿中的藥物濃度。研究本揭露化合物在比格犬體內的藥物代謝動力學行為，評價其藥動學特徵。 Taking Beagle dogs as test animals, the LC/MS/MS method was used to measure the concentration of drugs in the blood plasma of Beagle dogs at different times after intragastric (i.g.)/intravenous injection (i.v.) administration of the compound of Example 9 and positive control example 1 . To study the pharmacokinetic behavior of the compound disclosed in Beagle dogs, and to evaluate its pharmacokinetic characteristics.

2、試驗方案 2. Test plan

2.1試驗藥品 2.1 Test drugs

實施例9化合物和陽性對照例1。 Example 9 compound and positive control example 1.

2.2試驗動物 2.2 Test animals

比格犬16隻，雌雄各半，平均分成4組，禁食一夜後分別灌胃及靜脈注射給藥。 Sixteen Beagle dogs, half male and half male, were equally divided into 4 groups, and administered by intragastric administration and intravenous injection after overnight fasting.

2.3藥物配製 2.3 Drug preparation

稱取一定量的實施例9化合物和陽性對照例1，加5%體積DMSO+20%體積PG+20%體積PEG400+55%體積生理鹽水，配製成0.4mg/mL澄明溶液(灌胃給藥組)和0.25mg/mL澄明溶液(靜脈注射給藥組)。 Weigh a certain amount of the compound of Example 9 and positive control example 1, add 5% volume DMSO+20% volume PG+20% volume PEG400+55% volume normal saline, and prepare 0.4mg/mL clear solution (gastric administration drug group) and 0.25mg/mL clear solution (intravenous injection group).

2.4給藥 2.4 Administration

灌胃給藥組：給藥劑量為2.0mg/kg，給藥體積為5.0mL/kg。 Oral administration group: the dosage is 2.0 mg/kg, and the volume of administration is 5.0 mL/kg.

靜脈注射給藥組：給藥劑量為0.5mg/kg，給藥體積為2.0mL/kg。 Intravenous injection administration group: the administration dose is 0.5mg/kg, and the administration volume is 2.0mL/kg.

3.操作 3. Operation

灌胃給藥組：於給藥前及給藥後0.25、0.5、1.0、2.0、4.0、6.0、8.0、12.0、24.0小時，由頸靜脈或前肢靜脈採血1.0mL，置EDTA-K2抗凝試管中，10000rpm離心5分鐘(4℃)，1小時內分離血漿，-80℃保存待測。採血至離心過程在冰浴條件下操作。給藥後3小時進食。 Oral administration group: 1.0 mL of blood was collected from the jugular vein or forelimb vein before and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, and 24.0 hours after the administration, and placed in an EDTA-K2 anticoagulant test tube In the process, centrifuge at 10,000 rpm for 5 minutes (4°C), separate the plasma within 1 hour, and store it at -80°C for testing. The process from blood collection to centrifugation was operated under ice bath conditions. Eat 3 hours after dosing.

靜脈注射給藥組：於給藥前及給藥後5分鐘，0.25、0.5、1.0、2.0、4.0、8.0、12.0、24小時採血，處理同灌胃給藥組。 Intravenous injection group: blood was collected before administration and 5 minutes after administration, at 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, and 24 hours, and the treatment was the same as that of the intragastric administration group.

測定不同濃度的藥物給藥後比格犬血漿中的待測化合物含量：取給藥後各時刻的比格犬血漿樣品20μL，加入400μL甲醇(其中含有100ng/mL內標溶液)進行蛋白質沉澱，渦旋混合1分鐘，以18000g離心7分鐘，血漿樣品取上清液1μL進行LC/MS/MS分析。 Determination of the content of the compound to be tested in the Beagle dog plasma after the administration of different concentrations of drugs: take 20 μL of the Beagle dog plasma samples at various moments after the administration, add 400 μL of methanol (which contains 100ng/mL internal standard solution) for protein precipitation, Vortex for 1 minute, centrifuge at 18,000 g for 7 minutes, and take 1 μL of the supernatant from the plasma sample for LC/MS/MS analysis.

4、藥物代謝動力學參數結果 4. Results of pharmacokinetic parameters

表5本揭露化合物的藥物代謝動力學參數如下：

結論：本揭露化合物在比格犬體內具有很好的藥物代謝吸收活性，口服生物利用度高，具有藥物代謝動力學優勢。 Table 5 The pharmacokinetic parameters of the disclosed compounds are as follows:

Conclusion: The disclosed compound has good drug metabolism and absorption activity in Beagle dogs, high oral bioavailability, and pharmacokinetic advantages.

Claims (16)

一種通式(IG)所示的化合物或其可藥用的鹽， A compound represented by general formula (IG) or a pharmaceutically acceptable salt thereof,

其中， in, G¹、G²和G³相同或不同，且各自獨立為CR²或氮原子； G ¹ , G ² and G ³ are the same or different, and are each independently CR ² or a nitrogen atom; 環A選自環烷基、雜環基、芳基和雜芳基； Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; 環B為環烷基或雜環基； Ring B is cycloalkyl or heterocyclyl; R¹相同或不同，且各自獨立地選自氫原子、鹵素、烷基、烯基、炔基、烷氧基、鹵烷基、鹵烷氧基、側氧、氰基、胺基、硝基、羥基和羥烷基； R ^are the same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, side oxygen, cyano, amino, nitro , hydroxyl and hydroxyalkyl; R²相同或不同，且各自獨立地選自氫原子、鹵素、烷基、烯基、炔基、烷氧基、鹵烷基、鹵烷氧基、氰基、胺基、硝基、羥基和羥烷基； R ² are the same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxyl and Hydroxyalkyl; R³選自氫原子、烷基、鹵烷基、環烷基和雜環基，其中該烷基、鹵烷基、環烷基和雜環基各自獨立地視需要被選自鹵素、烷基、烯基、炔基、烷氧基、鹵烷基、鹵烷氧基、側氧、氰基、胺基、硝基、羥基、羥烷基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； ^R is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group and a heterocyclyl group, wherein each of the alkyl group, haloalkyl group, cycloalkyl group and heterocyclyl group is independently selected from halogen, alkyl , alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, pendant oxygen, cyano, amine, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and hetero One or more substituents in the aryl group are substituted; R⁴相同或不同，且各自獨立地選自氫原子、鹵素、烷基、烯基、炔基、烷氧基、鹵烷基、鹵烷氧基、側氧、氰基、胺基、硝基、羥基和羥烷基； R ^are the same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, side oxygen, cyano, amino, nitro , hydroxyl and hydroxyalkyl; p為0、1、2、3、4或5；且 p is 0, 1, 2, 3, 4 or 5; and q為0、1、2、3、4或5。 q is 0, 1, 2, 3, 4 or 5. 如請求項1所述的通式(IG)所示的化合物或其可藥用的鹽，其中G¹為CR²或氮原子；G²和G³相同或不同，且各自獨立為CR²；R²如請求項1中所定義。 The compound represented by the general formula (IG) or a pharmaceutically acceptable salt thereof as claimed in item 1, wherein G ¹ is CR ² or a nitrogen atom; G ² and G ³ are the same or different, and each independently is CR ² ; R ² is as defined in Claim 1. 如請求項1或2所述的通式(IG)所示的化合物或其可藥用的鹽，其為通式(I)所示的化合物或其可藥用的鹽： The compound represented by the general formula (IG) or its pharmaceutically acceptable salt as described in Claim 1 or 2, which is the compound represented by the general formula (I) or its pharmaceutically acceptable salt:

其中， in, n為0、1、2或3； n is 0, 1, 2 or 3; 環A、環B、R¹至R⁴、p和q如請求項1中所定義。 Ring A, Ring B, R ¹ to R ⁴ , p and q are as defined in Claim 1. 如請求項1至3中任一項所述的通式(IG)所示的化合物或其可藥用的鹽，其中環A為5至6員雜芳基或3至6員雜環基；較佳為5員雜芳基或5至6員雜環基。 A compound represented by general formula (IG) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 3, wherein ring A is a 5 to 6 membered heteroaryl group or a 3 to 6 membered heterocyclic group; Preferably it is a 5-membered heteroaryl group or a 5- to 6-membered heterocyclic group. 如請求項1至4中任一項所述的通式(IG)所示的化合物或其可藥用的鹽，其中環B為3至14員雜環基；較佳為3至6員雜環基；更佳為6員雜環基；甚至更佳為四氫吡喃基。 A compound represented by general formula (IG) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 4, wherein ring B is a 3 to 14 membered heterocyclic group; preferably a 3 to 6 membered heterocyclic group; Cyclic; more preferably 6-membered heterocyclyl; even more preferably tetrahydropyranyl. 如請求項1至5中任一項所述的通式(IG)所示的化合物或其可藥用的鹽，其中R³為C_1-6烷基或3至6員環烷基；較佳地，R³為甲基或環丙基。 A compound represented by general formula (IG) or a pharmaceutically acceptable salt thereof as described in any one of claim items 1 to 5, wherein R ³ is C _1-6 alkyl or 3 to 6 membered cycloalkyl; Preferably, R ³ is methyl or cyclopropyl. 如請求項1至6中任一項所述的通式(IG)所示的化合物或其可藥用的鹽，其中R¹相同或不同，且各自獨立地選自氫原子、鹵素、C_1-6烷基和側氧。 The compound represented by general formula (IG) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 6, wherein R ¹ are the same or different, and are each independently selected from hydrogen atom, halogen, C _{1 -6} alkyl and pendant oxygen. 如請求項1至7中任一項所述的通式(IG)所示的化合物或其可藥用的鹽，其中R²相同或不同，且各自獨立地選自氫原子、鹵素、氰基和C_1-6烷基；較佳地，R²為氫原子。 The compound represented by the general formula (IG) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 7, wherein R ² are the same or different, and each independently selected from a hydrogen atom, a halogen, a cyano group And C _1-6 alkyl; preferably, R ² is a hydrogen atom. 如請求項1至8中任一項所述的通式(IG)所示的化合物或其可藥用的鹽，其中R⁴相同或不同，且各自獨立地為氫原子或C_1-6烷基。 A compound represented by general formula (IG) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 8, wherein R ⁴ are the same or different, and each independently represents a hydrogen atom or a C _1-6 alkane base. 如請求項1至9中任一項所述的通式(IG)所示的化合物或其可藥用的鹽，其中p為0、1、2或3。 The compound represented by general formula (IG) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 9, wherein p is 0, 1, 2 or 3. 如請求項1所述的通式(IG)所示的化合物或其可藥用的鹽，其選自以下化合物： The compound represented by the general formula (IG) or a pharmaceutically acceptable salt thereof as claimed in item 1, which is selected from the following compounds:

一種製備如請求項1所述的通式(IG)所示的化合物或其可藥用的鹽的方法，該方法包括： A method for preparing a compound represented by general formula (IG) or a pharmaceutically acceptable salt thereof as claimed in claim 1, the method comprising:

通式(IA)的化合物或其鹽與通式(IGB)的化合物或其鹽發生偶聯反應，得到通式(IG)的化合物或其可藥用的鹽， A compound of general formula (IA) or a salt thereof is coupled with a compound of general formula (IGB) or a salt thereof to obtain a compound of general formula (IG) or a pharmaceutically acceptable salt thereof, 其中， in, X為鹵素；較佳為氯原子； X is a halogen; preferably a chlorine atom; 環A、環B、G¹、G²、G³、R¹、R³、R⁴、p和q如請求項1中所定義。 Ring A, Ring B, G ¹ , G ² , G ³ , R ¹ , R ³ , R ⁴ , p and q are as defined in Claim 1. 一種製備如請求項3所述的通式(I)所示的化合物或其可藥用的鹽的方法，該方法包括： A method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 3, the method comprising:

通式(IA)的化合物或其鹽與通式(IB)的化合物或其鹽發生偶聯反應，得到通式(I)的化合物或其可藥用的鹽， A compound of general formula (IA) or a salt thereof is coupled with a compound of general formula (IB) or a salt thereof to obtain a compound of general formula (I) or a pharmaceutically acceptable salt thereof, 其中， in, X為鹵素；較佳為氯原子； X is a halogen; preferably a chlorine atom; 環A、環B、R¹至R⁴、n、p和q如請求項3中所定義。 Ring A, Ring B, R ¹ to R ⁴ , n, p and q are as defined in claim 3. 一種醫藥組成物，該醫藥組成物含有如請求項1至11中任一項所述的通式(IG)所示的化合物或其可藥用的鹽，以及一種或多種藥學上可接受的載體、稀釋劑或賦形劑。 A pharmaceutical composition, which contains a compound represented by the general formula (IG) or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 11, and one or more pharmaceutically acceptable carriers , diluent or excipient. 一種如請求項1至11中任一項所述的通式(IG)所示的化合物或其可藥用的鹽或如請求項14所述的醫藥組成物在製備用於抑制DNA-PK的藥物中的用途。 A compound represented by the general formula (IG) as described in any one of claim items 1 to 11 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in claim item 14 is used in the preparation of a drug for inhibiting DNA-PK Uses in medicine. 一種如請求項1至11中任一項所述的通式(IG)所示的化合物或其可藥用的鹽或如請求項14所述的醫藥組成物在製備用於治療和/或預防癌症的藥物中的用途；其中該癌症較佳選自白血病、多發性骨髓瘤、淋巴瘤、骨髓增生異常綜合征、乳腺癌、肺癌、子宮內膜癌、中樞神經系統腫瘤、胚胎發育不良性神經上皮腫瘤、多形性成膠質細胞瘤、混合性膠質瘤、成神經管細胞瘤、成視網膜細胞瘤、成神經細胞瘤、生殖細胞瘤、畸胎瘤、胃癌、食道癌、肝癌、膽管細胞癌、結直腸癌、小腸癌、胰腺癌、皮膚癌、黑色素瘤、甲狀腺癌、頭頸癌、唾液腺癌、***癌、睾丸癌、卵巢癌、宮頸癌、外陰癌、膀胱癌、腎癌、鱗狀細胞癌、肉瘤、胃腸道間質瘤(GIST)和兒科癌症；其中該肉瘤較佳選自軟骨肉瘤、平滑肌肉瘤、軟組織肉瘤、尤文氏肉瘤和卡波氏肉瘤；其中該肺癌較佳為非小細胞肺癌。 A compound represented by general formula (IG) as described in any one of claim items 1 to 11 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in claim item 14 is used for treatment and/or prevention Use in medicine for cancer; wherein the cancer is preferably selected from the group consisting of leukemia, multiple myeloma, lymphoma, myelodysplastic syndrome, breast cancer, lung cancer, endometrial cancer, central nervous system tumors, embryonic dysplasia Epithelial tumors, glioblastoma multiforme, mixed glioma, medulloblastoma, retinoblastoma, neuroblastoma, germ cell tumor, teratoma, gastric cancer, esophageal cancer, liver cancer, cholangiocarcinoma , colorectal cancer, small bowel cancer, pancreatic cancer, skin cancer, melanoma, thyroid cancer, head and neck cancer, salivary gland cancer, prostate cancer, testicular cancer, ovarian cancer, cervical cancer, vulvar cancer, bladder cancer, kidney cancer, squamous cell cancer Carcinoma, sarcoma, gastrointestinal stromal tumor (GIST) and pediatric cancer; wherein the sarcoma is preferably selected from chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, Ewing's sarcoma and Kaposi's sarcoma; wherein the lung cancer is preferably non-small cell lung cancer.