WO2022143533A1

WO2022143533A1 - Quinazoline derivative and use thereof in medicine

Info

Publication number: WO2022143533A1
Application number: PCT/CN2021/141677
Authority: WO
Inventors: 周锡兵; 魏用刚; 张靖; 楚洪柱; 孙毅
Original assignee: 成都百裕制药股份有限公司
Priority date: 2020-12-30
Filing date: 2021-12-27
Publication date: 2022-07-07
Also published as: CN116249529A

Abstract

Disclosed are a quinazoline derivative of formula (I), a pharmaceutical composition containing the derivative and the use thereof in medicine, in particular the use as an SOS1 inhibitor and the use in the preparation of a medicament for the treatment or prevention of diseases associated with SOS1.

Description

喹唑啉衍生物及其在医药上的应用Quinazoline derivatives and their applications in medicine

技术领域technical field

本发明属于药物化学领域，具体地涉及喹唑啉衍生物及其在医药上的应用。The invention belongs to the field of medicinal chemistry, and particularly relates to quinazoline derivatives and their application in medicine.

背景技术Background technique

SOS1是鸟嘌呤核苷酸交换因子(GEF)，可与RAS蛋白相互作用将GDP转化为GTP，或从非活性状态转变为活性状态以发出细胞增殖信号。RAS基因(包括KRAS、NRAS和HRAS)是最常出现突变的致癌基因，大约30％的癌症中存在RAS基因突变。RAS超蛋白家族属于小GTP酶(small GTPase)蛋白家族，可作为水解酶结合并水解GTP形成GDP。当RAS蛋白与GDP结合时无活性，但结合后分离缓慢；SOS1可催化GDP的解离，使得RAS蛋白能够与GTP结合而被激活，并通过MAPK、PI3K和Ral-GEFs等多条下游信号通路促进细胞生存、增殖和细胞因子释放等(Liu et al.,2019)。已发表的数据表明SOS1对KRAS突变引发癌症至关重要(Jeng et al.,2012)。抑制SOS1水平降低了KRAS突变的肿瘤细胞的增殖速率和存活率。SOS1 is a guanine nucleotide exchange factor (GEF) that interacts with RAS proteins to convert GDP to GTP, or from an inactive state to an active state to signal cell proliferation. The RAS gene (including KRAS, NRAS, and HRAS) is the most frequently mutated oncogene and is present in approximately 30% of cancers. The RAS superprotein family belongs to the small GTPase protein family, which acts as a hydrolase to bind and hydrolyze GTP to form GDP. When RAS protein binds to GDP, it is inactive, but it separates slowly after binding; SOS1 can catalyze the dissociation of GDP, so that RAS protein can be activated by binding to GTP, and through multiple downstream signaling pathways such as MAPK, PI3K and Ral-GEFs Promote cell survival, proliferation and cytokine release, etc. (Liu et al., 2019). Published data suggest that SOS1 is critical for KRAS mutations to initiate cancer (Jeng et al., 2012). Inhibition of SOS1 levels reduced the proliferation rate and survival of KRAS-mutated tumor cells.

此外，SOS1通过RAS突变以外的机制参与了癌症中RAS家族蛋白信号的激活。SOS1与衔接蛋白Grb2相互作用，产生的SOS1/Grb2复合物与活化/磷酸化的受体酪氨酸激酶结合。SOS1定位于细胞膜上，靠近RAS家族蛋白，使SOS1能够促进RAS家族蛋白激活。Furthermore, SOS1 is involved in the activation of RAS family protein signaling in cancer through mechanisms other than RAS mutations. SOS1 interacts with the adaptor protein Grb2, and the resulting SOS1/Grb2 complex binds to activated/phosphorylated receptor tyrosine kinases. SOS1 is localized on the cell membrane, close to RAS family proteins, enabling SOS1 to promote RAS family protein activation.

SOS1异常也与癌症相关。在胚胎横纹肌肉瘤、睾丸支持细胞肿瘤、皮肤颗粒细胞瘤和肺腺癌中发现SOS1突变。同时，在膀胱癌和***癌中也有SOS1过表达的报道。Abnormal SOS1 is also associated with cancer. SOS1 mutations are found in embryonal rhabdomyosarcoma, Sertoli cell tumor, granulosa cell tumor of the skin, and lung adenocarcinoma. Meanwhile, SOS1 overexpression has also been reported in bladder cancer and prostate cancer.

目前尚无针对SOS1抑制剂的疗法获批，在肿瘤领域仍属于未被满足的临床需求。因此，仍然需要开发安全有效的SOS1抑制剂，以更好满足患者的临床需求。There is currently no approved therapy for SOS1 inhibitors, which is still an unmet clinical need in the field of oncology. Therefore, there is still a need to develop safe and effective SOS1 inhibitors to better meet the clinical needs of patients.

发明内容SUMMARY OF THE INVENTION

本申请的一个或多个实施方式的目的之一在于提供新型喹唑啉衍生物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，或者包含以上的药物组合物，其可用于抑制SOS1。One of the objectives of one or more embodiments of the present application is to provide novel quinazoline derivatives or their stereoisomers, tautomers, mesomers, racemates, enantiomers, Diastereomers, or mixtures thereof, or solvates, metabolites, co-crystals, prodrugs, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the above, are useful for inhibiting SOS1.

本申请的一个或多个实施方式提供了通式(I)的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐：One or more embodiments of the present application provide compounds of general formula (I) or stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers thereof Isomers, or mixtures thereof, or solvates, metabolites, co-crystals, prodrugs, or pharmaceutically acceptable salts thereof:

X为-(OCR ²R ³CR ⁴R ⁵) _x-，其中O端与Z相连，C端与O相连；x为0、1或2； X is -(OCR ² R ³ CR ⁴ R ⁵ ) _x -, wherein the O end is connected to Z, and the C end is connected to O; x is 0, 1 or 2;

Y为-(OCR ⁶R ⁷CR ⁸R ⁹) _y-，其中O端与Z相连，C端与O相连；y为0、1或2； Y is -(OCR ⁶ R ⁷ CR ⁸ R ⁹ ) _y -, wherein the O end is connected to Z, and the C end is connected to O; y is 0, 1 or 2;

Z为-(CR ¹⁰R ¹¹) _z-；z为0、1、2、3、4或5； Z is -(CR ¹⁰ R ¹¹ ) _z -; z is 0, 1, 2, 3, 4 or 5;

所述R ²、R ³、R ⁴、R ⁵、R ⁶、R ⁷、R ⁸、R ⁹、R ¹⁰、R ¹¹各自独立为H、C _1-6烷基、C _1-6卤代烷基、C _1-6烷氧基、C _1-6环烷基或C _1-6杂环烷基； The R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ are each independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 cycloalkyl or C _1-6 heterocycloalkyl;

任选地，各个R ²与R ³、各个R ⁴与R ⁵、各个R ⁶与R ⁷、各个R ⁸与R ⁹、各个R ¹⁰与R ¹¹的任意一组与其相连的碳原子形成C _1-6环烷基或C _1-6杂环烷基，所述C _1-6杂环烷基含有1 或2个氧原子； Optionally, any set of carbon atoms to which each R ² and R ³ , each R ⁴ and R ⁵ , each R ⁶ and R ⁷ , each R ⁸ and R ⁹ , each R ¹⁰ and R ¹¹ is attached to form C _{1 -6} cycloalkyl or C _1-6 heterocycloalkyl, said C _1-6 heterocycloalkyl containing 1 or 2 oxygen atoms;

任选地，所述R ²或R ³和R ⁴或R ⁵与其相连的两个碳原子或者R ⁶或R ⁷和R ⁸或R ⁹与其相连的两个碳原子形成C _1-6环烷基或C _1-6杂环烷基，所述C _1-6杂环烷基含有1或2个氧原子； Optionally, the two carbon atoms to which the R ² or R ³ and R ⁴ or R ⁵ are attached or the two carbon atoms to which R ⁶ or R ⁷ and R ⁸ or R ⁹ are attached form a C _1-6 cycloalkane or C _1-6 heterocycloalkyl, the C _1-6 heterocycloalkyl contains 1 or 2 oxygen atoms;

各个R ¹相同或不同，各自独立地为卤素、氨基、C _1-6烷基、C _1-6环烷基，其中所述的C _1-6烷基和C _1-6环烷基任选地被选自羟基和卤素中的一个或多个取代基所取代； Each R ¹ is the same or different, and each independently is halogen, amino, C _1-6 alkyl, C _1-6 cycloalkyl, wherein said C _1-6 alkyl and C _1-6 cycloalkyl are optional is substituted with one or more substituents selected from hydroxy and halogen;

n为1、2或3。n is 1, 2 or 3.

在一个或多个实施方式中，x为0、1或2；y为0、1或2；和z为2、3、4或5。In one or more embodiments, x is 0, 1, or 2; y is 0, 1, or 2; and z is 2, 3, 4, or 5.

在一个或多个实施方式中，x为0、y为0、z为2，x为0、y为0、z为3，x为0、y为0、z为4，x为0、y为0、z为5，x为1、y为1、z为2，x为0、y为1、z为2，x为1、y为0、z为2，x为1、y为2、z为2，或x为2、y为1、z为2。In one or more embodiments, x is 0, y is 0, z is 2, x is 0, y is 0, z is 3, x is 0, y is 0, z is 4, x is 0, y is 0, z is 5, x is 1, y is 1, z is 2, x is 0, y is 1, z is 2, x is 1, y is 0, z is 2, x is 1, y is 2 , z is 2, or x is 2, y is 1, and z is 2.

在一个或多个实施方式中，所述R ²、R ³、R ⁴、R ⁵、R ⁶、R ⁷、R ⁸、R ⁹、R ¹⁰、R ¹¹各自独立为H或C _1-6烷基。 In one or more embodiments, each of said R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ is independently H or C _1-6 alkane base.

本申请的一个或多个实施方式提供了化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐：One or more embodiments of the present application provide compounds or stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, or the same thereof A mixture, or a solvate, metabolite, co-crystal, prodrug or pharmaceutically acceptable salt thereof:

本申请的一个或多个实施方式提供了药物组合物，其包含：One or more embodiments of the present application provide pharmaceutical compositions comprising:

(1)本申请所述的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐；(1) The compound described in this application or its stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or solvates, metabolites, co-crystals, prodrugs or pharmaceutically acceptable salts thereof;

(2)任选的一种或者多种其他活性成分；以及(2) optionally one or more other active ingredients; and

(3)药学上可接受的载体和/或赋形剂。(3) A pharmaceutically acceptable carrier and/or excipient.

本申请的一个或多个实施方式提供了本申请的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，或者本申请的组合物在制备用于治疗或预防癌症或肿瘤的药物中的用途。One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer thereof , or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug or pharmaceutically acceptable salt thereof, or use of a composition of the present application in the manufacture of a medicament for the treatment or prevention of cancer or tumor.

在一个或多个实施方式中，所述癌症或肿瘤为胚胎横纹肌肉瘤、睾丸支持细胞肿瘤、皮肤颗粒细胞瘤、肺腺癌、膀胱癌或***癌。In one or more embodiments, the cancer or tumor is embryonal rhabdomyosarcoma, Sertoli cell tumor, granulosa cell tumor of the skin, lung adenocarcinoma, bladder cancer, or prostate cancer.

本申请的一个或多个实施方式提供了本申请所述的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，或者本申请所述的组合物在制备SOS1抑制剂中的用途。One or more embodiments of the present application provide compounds described herein or stereoisomers, tautomers, meso, racemates, enantiomers, diastereomers thereof Conforms, or mixtures thereof, or solvates, metabolites, co-crystals, prodrugs, or pharmaceutically acceptable salts thereof, or the use of the compositions described herein in the preparation of SOS1 inhibitors.

本申请的一个或多个实施方式提供了本申请的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，或者本申请所述的组合物在制备用于治疗或预防与SOS1相关的疾病中的用途。One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer thereof , or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or use of a composition described herein in the manufacture of a composition for the treatment or prevention of a disease associated with SOS1.

本申请的一个或多个实施方式提供了本申请的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，或者本申请的组合物，其作为药物。One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer thereof , or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or a composition of the present application, as a medicament.

本申请的一个或多个实施方式提供了本申请的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，或者本申请的组合物，其用于治疗或预防癌症或肿瘤。One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer thereof , or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or a composition of the present application, for use in the treatment or prevention of cancer or tumor.

本申请的一个或多个实施方式提供了本申请的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，或者本申请的组合物，其作为SOS1抑制剂。One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer thereof , or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or a composition of the present application, as a SOS1 inhibitor.

本申请的一个或多个实施方式提供了本申请的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，或者本申请的组合物，其用于治疗或预防与SOS1相关的疾病。One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer thereof , or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or a composition of the present application, for use in the treatment or prevention of a disease associated with SOS1.

本申请的一个或多个实施方式提供了治疗或预防癌症或肿瘤的方法，其包括向有此需要的对象给予本申请的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，或者本申请的组合物。One or more embodiments of the present application provide a method of treating or preventing cancer or tumor comprising administering to a subject in need thereof a compound of the present application or a stereoisomer, tautomer, mesomer thereof , racemates, enantiomers, diastereomers, or mixtures thereof, or solvates, metabolites, co-crystals, prodrugs, or pharmaceutically acceptable salts thereof, or compositions of the present application .

本申请的一个或多个实施方式提供了治疗或预防与SOS1相关的疾病的方法，其包括向有此需要的对象给予本申请的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，或者本申请的组合物。One or more embodiments of the present application provide a method of treating or preventing a disease associated with SOS1, comprising administering to a subject in need thereof a compound of the present application, or a stereoisomer, tautomer, endogenous isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or solvates, metabolites, co-crystals, prodrugs, or pharmaceutically acceptable salts thereof, or the combination.

本申请的一个或多个实施方式提供了抑制SOS1的方法，其包括向有此需要的对象给予本申请的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，或者本申请的组合物。One or more embodiments of the present application provide methods of inhibiting SOS1, comprising administering to a subject in need thereof a compound of the present application or a stereoisomer, tautomer, meso, racemic isomers, enantiomers, diastereomers, or mixtures thereof, or solvates, metabolites, co-crystals, prodrugs, or pharmaceutically acceptable salts thereof, or compositions of the present application.

在一个或多个实施方式中，所述与SOS1相关的疾病为癌症或肿瘤。In one or more embodiments, the disease associated with SOS1 is cancer or tumor.

在一个或多个实施方式中，所述与SOS1相关的疾病为胚胎横纹肌肉瘤、睾丸支持细胞肿瘤、皮肤颗粒细胞瘤、肺腺癌、膀胱癌或***癌。In one or more embodiments, the disease associated with SOS1 is embryonal rhabdomyosarcoma, Sertoli cell tumor, granulosa cell tumor of the skin, lung adenocarcinoma, bladder cancer, or prostate cancer.

发明详述Detailed description of the invention

除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, terms used in the specification and claims have the following meanings.

本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括 ¹²C、 ¹³C和 ¹⁴C，氢的同位素包括氕(H)、氘(D，又叫重氢)、氚(T，又叫超重氢)，氧的同位素包括 ¹⁶O、 ¹⁷O和 ¹⁸O，硫的同位素包括 ³²S、 ³³S、 ³⁴S和 ³⁶S，氮的同位素包括 ¹⁴N和 ¹⁵N，氟的同位素包括 ¹⁷F和 ¹⁹F，氯的同位素包括 ³⁵Cl和 ³⁷Cl，溴的同位素包括 ⁷⁹Br和 ⁸¹Br。 The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention all include their isotopic conditions, and the carbons involved in the groups and compounds of the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, wherein isotopes of carbon include ¹² C, ¹³ C and ¹⁴ C, and isotopes of hydrogen include protium (H), deuterium (D, Also known as heavy hydrogen), tritium (T, also known as super-heavy hydrogen), the isotopes of oxygen include ¹⁶ O, ¹⁷ O and ¹⁸ O, the isotopes of sulfur include ³² S, ³³ S, ³⁴ S and ³⁶ S, and the isotopes of nitrogen include ¹⁴ N and ¹⁵ N, fluorine isotopes include ¹⁷ F and ¹⁹ F, chlorine isotopes include ³⁵ Cl and ³⁷ Cl, and bromine isotopes include ⁷⁹ Br and ⁸¹ Br.

“烷基”是指1至20个碳原子的直链或支链饱和脂肪族烃基，优选为1至8个(例如1、2、3、4、5、6、7、8个)碳原子的烷基，更优选为1至6个碳原子的烷基，进一步优选为 1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体；当烷基被取代基时，可以任选进一步被1个或者多个取代基所取代。"Alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably 1 to 8 (eg 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms , more preferably an alkyl group of 1 to 6 carbon atoms, further preferably an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched chain isomers thereof; when the alkyl group is substituted, it can be optionally further substituted by one or more substituents.

“烷氧基”是指烷基中至少1个碳原子被氧原子取代所形成的基团。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。所述的烷基定义与上文所述的“烷基”定义相同。"Alkoxy" refers to a group formed by substituting at least one carbon atom in an alkyl group with an oxygen atom. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyl oxy and cyclobutoxy. The definition of alkyl is the same as the definition of "alkyl" described above.

“烯基”是指含有1至10个(例如1、2、3、4、5、6、7、8、9、10个)碳-碳双键，由2至20个碳原子组成的直链或者支链不饱和脂肪族烃基，优选2至12个(例如2、3、4、5、6、7、8、9、10、11、12个)碳原子的烯基，更优选2至8个碳原子的烯基，进一步优选2至6个碳原子的烯基。非限制性实施例包括乙烯基、丙烯-2-基、丁烯-2-基、丁烯-2-基、戊烯-2-基、戊烯-4-基、己烯-2-基、己烯-3基、庚烯-2-基、庚烯-3-基、庚烯-4-基、辛烯-3-基、壬烯-3-基、癸烯-4-基和十一烯-3-基。所述的烯基可以任选进一步被1个或者多个取代基所取代。"Alkenyl" means a straight chain consisting of 2 to 20 carbon atoms containing 1 to 10 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon-carbon double bonds Chain or branched unsaturated aliphatic hydrocarbon groups, preferably alkenyl groups of 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 2 to 12 An alkenyl group of 8 carbon atoms, more preferably an alkenyl group of 2 to 6 carbon atoms. Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, Hexen-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl and undecen-yl Alken-3-yl. The alkenyl group may be optionally further substituted with one or more substituents.

“炔基”是指含有1至10个(例如1、2、3、4、5、6、7、8、9、或10个)碳-碳叁键，由2至20个碳原子组成的直链或者支链不饱和脂肪族烃基，优选2至12个(例如2、3、4、5、6、7、8、9、10、11或12个)碳原子的炔基，更优选2至8个碳原子的炔基，进一步优选2至6个碳原子的炔基。非限制性实施例包括乙炔基、丙炔-1-基、丙炔-2-基、丁炔-1-基、丁炔-2-基、丁炔-3-基、3,3-二甲基丁炔-2-基、戊炔-1-基、戊炔-2-基、己炔-1-基、1-庚炔-1-基、庚炔-3-基、庚炔-4-基、辛炔-3-基、壬炔-3-基、癸炔-4-基、十一炔-3-基、十二炔-4-基。所述的炔基可以任选进一步被一至多个取代基所取代。"Alkynyl" means a carbon-carbon triple bond containing 1 to 10 (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon-carbon triple bonds, consisting of 2 to 20 carbon atoms Linear or branched unsaturated aliphatic hydrocarbon groups, preferably alkynyl groups of 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms, more preferably 2 An alkynyl group of to 8 carbon atoms, more preferably an alkynyl group of 2 to 6 carbon atoms. Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethyl butyn-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyn-4- yl, octyn-3-yl, nonyn-3-yl, decyn-4-yl, undecyn-3-yl, dodecyn-4-yl. The alkynyl group may optionally be further substituted with one or more substituents.

“芳基”是指是指取代的或未取代的芳香环，其可以是5至8元(例如5、6、7、8元)的单环、5至12元(例如5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，其可以是桥环或者螺环，非限制性实施例包括苯基、萘基。所述的芳基可以任选进一步被1个或者多个取代基所取代。"Aryl" means a substituted or unsubstituted aromatic ring, which may be a 5- to 8-membered (eg, 5, 6, 7, 8) , 8, 9, 10, 11, 12 membered) bicyclic ring or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, which may be a bridged ring or a spiro ring, non-limiting implementation Examples include phenyl, naphthyl. The aryl group may optionally be further substituted with one or more substituents.

“杂芳基”是指取代的或未取代的芳香环，其可以是3至8元(例如3、4、5、6、7、8元)的单环、5至12元(例如5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，且包含1至6个(例如1、2、3、4、5、6个)选自N、O或S的杂原子，优选5至8元杂芳基，杂芳基的环中选择性取代的1至4个(例如1、2、3、4个)N、S可被氧化成各种氧化态。杂芳基可以连接在杂原子或者碳原子上，杂芳基可以是桥环或者螺环，非限制性实施例包括环吡啶基、呋喃基、噻吩基、吡喃基、吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基苯并咪唑基、苯并吡啶基、吡咯并吡啶基。杂芳基任选进一步被1个或多个取代基所取代。"Heteroaryl" refers to a substituted or unsubstituted aromatic ring, which may be a 3 to 8 membered (eg 3, 4, 5, 6, 7, 8 membered) monocyclic, 5 to 12 membered (eg 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 6 (eg 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S, preferably 5- to 8-membered heteroaryl, 1 to 4 (eg 1, 2) optionally substituted in the ring of heteroaryl , 3, 4) N, S can be oxidized into various oxidation states. Heteroaryl groups can be attached to heteroatoms or carbon atoms, and heteroaryl groups can be bridged or spirocyclic, non-limiting examples include cyclopyridyl, furyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, Pyrazinyl, pyridazinyl, imidazolyl, piperidinylbenzimidazolyl, benzopyridyl, pyrrolopyridyl. Heteroaryl groups are optionally further substituted with one or more substituents.

“碳环基”或“碳环”是指饱和或者不饱和的芳香环或者非芳香环。当为芳香环时，其定义与上文“芳基”的定义相同；当为非芳香环时，其可以是3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，可以是桥环或者螺环，非限制性实施例包括环丙基、环丁基、环戊基、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-2-烯基、1-环己基-3-烯基、环己烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基、环十二烷基、

所述的“碳环基”或“碳环”任选进一步被1个或者多个取代基所取代。 "Carbocyclyl" or "carbocycle" refers to a saturated or unsaturated aromatic or non-aromatic ring. When aromatic, it is as defined above for "aryl"; when non-aromatic, it may be 3 to 10 membered (eg 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic ring, 4 to 12 membered (eg 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) (membered) tricyclic ring system, which can be bridged or spiro, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2 -Alkenyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, cyclohexadienyl, cyclohexyl Heptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl,

Said "carbocyclyl" or "carbocycle" is optionally further substituted with one or more substituents.

“杂环基”或“杂环”是指饱和或不饱和的芳香性杂环或者非芳香性杂环，当为芳香性杂环时，其定义与上文“杂芳基”定义相同；当为非芳香性杂环时，其可以是3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，且包含1至4个(例如1、2、3、4个)选自N、O或S的杂原子，优选3至8元杂环基。“杂环基”或“杂环”的环中选择性取代的1至4个(例如1、2、3、4个)N、S可被氧化成各种氧化态；“杂环基”或“杂环”可以连接在杂原子或者碳原子上；“杂环基”或“杂环”可以为桥环或者螺环。“杂环基”或“杂环”的非限制性实施例包括环氧乙基、环氧丙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、硫杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、氧杂环庚基、硫杂环庚基、氧氮杂卓基、二氮杂卓基、硫氮杂卓基、吡啶基、哌啶基、高哌啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、哌嗪基、高哌嗪基、咪唑基、哌啶基、吗啉基、硫代吗啉基、噻噁烷基、1,3-二噻烷基、二氢呋喃基、二噻戊环基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、2-吡咯啉基、3-吡咯啉基、二氢吲哚基、2H-吡喃基、4H-吡喃基、二氧杂环己基、1,3-二氧戊基、吡唑啉基、二噻烷基、二噻茂烷基、二氢噻吩基、吡唑烷基、咪唑啉基、咪唑烷基、1,2,3,4-四氢异喹啉基、3-氮杂双环[3.1.0]己基、3-氮杂双环[4.1.0]庚基、氮杂双环[2.2.2]己基、3H-吲哚基喹嗪基、N-吡啶基尿素、1,1-二氧硫代吗啉基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。所述的“杂环基”或“杂环”可以任选进一步被1个或者多个取代基所取代。"Heterocyclyl" or "heterocycle" refers to a saturated or unsaturated aromatic heterocycle or a non-aromatic heterocycle, and when it is an aromatic heterocycle, its definition is the same as the definition of "heteroaryl" above; when When it is a non-aromatic heterocycle, it can be a 3- to 10-membered (eg 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic, 4- to 12-membered (eg 7, 8, 9, 10, 11, 12 membered) bicyclic ring or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 4 (eg 1, 2, 3, 4) heteroatoms selected from N, O or S, preferably a 3- to 8-membered heterocyclic group. Optionally substituted 1 to 4 (eg 1, 2, 3, 4) N, S in the ring of "heterocyclyl" or "heterocycle" can be oxidized to various oxidation states; "heterocyclyl" or A "heterocycle" can be attached to a heteroatom or a carbon atom; a "heterocyclyl" or "heterocycle" can be a bridged ring or a spirocyclic ring. Non-limiting examples of "heterocyclyl" or "heterocycle" include oxiranyl, glycidyl, azetidinyl, oxetanyl, azetidinyl, thietanyl , 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, oxepanyl, thiepanyl, oxygen Azazelyl, diazepine, thiazepinyl, pyridyl, piperidinyl, homopiperidinyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyridyl Azinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, 1,3-dithianyl, dihydrofuran base, dithiopenyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzene Imidazolyl, benzopyridyl, pyrrolopyridyl, chromanyl, 2-pyrrolinyl, 3-pyrrolinyl, indoline, 2H-pyranyl, 4H-pyranyl , Dioxanyl, 1,3-dioxopentyl, pyrazolinyl, dithianyl, dithiazolinyl, dihydrothienyl, pyrazolidine, imidazolinyl, imidazolidinyl, 1,2,3,4-Tetrahydroisoquinolinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-Indolylquinazinyl, N-pyridylurea, 1,1-dioxothiomorpholinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl Alkyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl. Said "heterocyclyl" or "heterocycle" may be optionally further substituted with one or more substituents.

“环烷基”是指饱和的环烃基，其环可以为3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至20元(例如10、11、12、13、14、15、16、17、18、19、20元)多环体系，环碳原子优选3至10个碳原子，进一步优选3至8个碳原子。“环烷基”非限制性实施例包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、1,5-环辛二烯基、1,4-环己二烯基和环庚三烯基等。当环烷基被取代时，可以任选进一步被1个或者多个取代基所取代。"Cycloalkyl" refers to a saturated cyclic hydrocarbon group, the ring of which may be 3 to 10 membered (eg 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic, 4 to 12 membered (eg 4 , 5, 6, 7, 8, 9, 10, 11, 12 yuan) double ring or 10 to 20 yuan (such as 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 yuan) and more In the ring system, the ring carbon atoms are preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms. Non-limiting examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexyl Alkenyl, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl and cycloheptatrienyl and the like. When cycloalkyl is substituted, it may be optionally further substituted with one or more substituents.

“杂环烷基”是指取代的或未取代的饱和非芳香环基，其可以是3至8元(例如3、4、5、6、7、8元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系，且包含1、2或3个选自N、O或S的杂原子，优选3至8元杂环基。“杂环烷基”的环中选择性取代的1、2或3个N、S可被氧化成各种氧化态；“杂环烷基”可以连接在杂原子或者碳原子上；“杂环烷基”可以为桥环或者螺环。“杂环烷基”非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、哌啶基、哌叮基、吗啉基、硫代吗啉基、1,3-二噻烷基、四氢呋喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。"Heterocycloalkyl" refers to a substituted or unsubstituted saturated non-aromatic ring group, which may be a (eg 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring systems, including 1, 2 or 3 heteroatoms selected from N, O or S, preferably a 3- to 8-membered heterocyclic group. Optionally substituted 1, 2 or 3 N, S in the ring of "heterocycloalkyl" can be oxidized to various oxidation states; "heterocycloalkyl" can be attached to a heteroatom or carbon atom; "heterocycloalkyl" Alkyl" can be bridged or spiro. Non-limiting examples of "heterocycloalkyl" include oxiranyl, azetidinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxetanyl Oxolanyl, 1,3-dioxanyl, azepanyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, tetrahydrofuranyl , tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxa Tricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl.

当上文所述的“烷基”、“烷氧基”、“烯基”、“炔基”、“芳基”、“杂芳基”、“碳环基”、“碳环”、“杂环基”、“杂环”、“环烷基”、“杂环烷基”或者“杂环基”被取代时，可以选进一步被0、1、2、3、4、5、6、7、8、9或者10个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、C _1-6烷基氨基、＝O、C _1-6烷基、C _1-6烷氧基、C _2-6烯基、C _2-6炔基、-NR _q4R _q5、＝NR _q6、-C(＝O)OC _1-6烷基、-OC(＝O)C _1-6烷基、-C(＝O)NR _q4R _q5、C _3-8环烷基、C _3-8杂环烷基、C _6-10芳基、C _5-10杂芳基、-C(＝O)OC _6-10芳基、-OC(＝O)C _6-10芳基、-OC(＝O)C _5-10杂芳基、-C(＝O)OC _5-10杂芳基、-OC(＝O)C _3-8杂环烷基、-C(＝O)OC _3-8杂环烷基、-OC(＝O)C _3-8环烷基、 -C(＝O)OC _3-8环烷基、-NHC(＝O)C _3-8杂环烷基、-NHC(＝O)C _6-10芳基、-NHC(＝O)C _5-10杂芳基、-NHC(＝O)C _3-8环烷基、-NHC(＝O)C _3-8杂环烷基、-NHC(＝O)C _2-6烯基或者-NHC(＝O)C _2-6炔基的取代基所取代，且其中所述的取代基C _1-6烷基、C _1-6烷氧基、C _2-6烯基、C _2-6炔基、C _3-8环烷基、C _3-8杂环烷基、C _6-10芳基、C _5-10杂芳基、-NHC(＝O)C _6-10芳基、-NHC(＝O)C _5-10杂芳基、-NHC(＝O)C _3-8杂环烷基或者-NHC(＝O)C _3-8环烷基任选进一步被1至3个选自OH、F、Cl、Br、I、C _1-6烷基、C _1-6烷氧基、-NR _q4R _q5或者＝O的取代基所取代；R _q1选自C _1-6烷基、C _1-6烷氧基或者C _6-10芳基；R _q2、R _q3选自H或者C _1-6烷基；其中，R _q4、R _q5选自H、C _1-6烷基、-NH(C＝NR _q1)NR _q2R _q3、-S(＝O) ₂NR _q2R _q3、-C(＝O)R _q1或者-C(＝O)NR _q2R _q3，其中所述的C _1-6烷基任选进一步被1个或者多个选自OH、F、Cl、Br、I、C _1-6烷基、C _1-6烷氧基、C _6-10芳基、C _5-10杂芳基、C _3-8环烷基或者C _3-8杂环烷基的取代基所取代；或者R _q4与R _q5及N原子形成一个3至8元杂环，所述杂环可以含有1个或者多个选自N、O或者S的杂原子。 When the above-mentioned "alkyl", "alkoxy", "alkenyl", "alkynyl", "aryl", "heteroaryl", "carbocyclyl", "carbocycle", " When "heterocyclyl", "heterocycle", "cycloalkyl", "heterocycloalkyl" or "heterocyclyl" is substituted, it may be further selected by 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 selected from F, Cl, Br, I, hydroxyl, mercapto, nitro, cyano, amino, C _1-6 alkylamino, =O, C _1-6 alkyl, C _{1 -6} alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, -NR _q4 R _q5 , =NR _q6 , -C(=O)OC _1-6 alkyl, -OC(=O)C _1-6 alkyl, -C(=O)NR _q4 R _q5 , C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, C _6-10 aryl, C _5-10 heteroaryl, - C(=O)OC _6-10 aryl, -OC(=O)C _6-10 aryl, -OC(=O)C _5-10 heteroaryl, -C(=O)OC _5-10 heteroaryl Aryl, -OC(=O)C _3-8 heterocycloalkyl, -C(=O)OC _3-8 heterocycloalkyl, -OC(=O)C _3-8 cycloalkyl, -C( =O)OC _3-8 cycloalkyl, -NHC(=O)C _3-8 heterocycloalkyl, -NHC(=O)C _6-10 aryl, -NHC(=O)C _5-10 hetero Aryl, -NHC(=O)C _3-8 cycloalkyl, -NHC(=O)C _3-8 heterocycloalkyl, -NHC(=O)C _2-6 alkenyl or -NHC(=O ) C _2-6 alkynyl substituents, and wherein the substituents C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, C _3-8 heterocycloalkyl, C _6-10 aryl, C _5-10 heteroaryl, -NHC(=O)C _6-10 aryl, -NHC(=O) C _5-10 heteroaryl, -NHC(=O)C _3-8 heterocycloalkyl or -NHC(=O) C _3-8 cycloalkyl is optionally further selected from 1 to 3 groups selected from OH, F, Cl, Br, I, C _1-6 alkyl, C _1-6 alkoxy, -NR _q4 R _q5 or a substituent of =O; R _q1 is selected from C _1-6 alkyl, C _1-6 Alkoxy or C _6-10 aryl; R _q2 and R _q3 are selected from H or C _1-6 alkyl; wherein, R _q4 and R _q5 are selected from H, C _1-6 alkyl, -NH (C= NR _q1 ) NR _q2 R _q3 , -S(=O) ₂ NR _q2 R _q3 , -C(=O)R _q1 or -C(=O)NR _q2 R _q3 , wherein said C _1-6 alkyl Optionally further selected by one or more selected from OH, F, Cl, Br, I, C _1-6 alkyl, C _1-6 alkoxy, C _6-10 aryl, C _5-10 hetero substituted by substituents of aryl, C _3-8 cycloalkyl or C _3-8 heterocycloalkyl; or R _q4 , R _q5 and N atom form a 3- to 8-membered heterocycle, which may contain 1 one or more heteroatoms selected from N, O or S.

卤素包括F、Cl、Br和I。Halogens include F, Cl, Br and I.

“药学上可接受的盐”或者“其药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性，且所述的游离酸通过与无毒的无机碱或者有机碱，所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。"Pharmaceutically acceptable salt" or "a pharmaceutically acceptable salt thereof" means that a compound of the present invention retains the biological effectiveness and properties of a free acid or free base that is treated with a non-toxic inorganic base or Organic bases, said free bases are salts obtained by reacting with non-toxic inorganic or organic acids.

“药物组合物”是指一种或多种本发明所述化合物、其药学上可接受的盐或前药和其它化学组分形成的混合物，其中，“其它化学组分”是指药学上可接受的载体、赋形剂和/或一种或多种其它治疗剂。"Pharmaceutical composition" refers to a mixture of one or more of the compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable Accepted carriers, excipients and/or one or more other therapeutic agents.

“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。"Carrier" refers to a material that is not appreciably irritating to the organism and that does not abrogate the biological activity and properties of the administered compound.

“赋形剂”是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实施例包括碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。"Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binding agents agent and disintegrant.

“前药”是指可经体内代谢转化为具有生物活性的本发明化合物。本发明的前药通过修饰本发明化合物中的氨基或者羧基来制备，该修饰可以通过常规的操作或者在体内被除去，而得到母体化合物。当本发明的前药被施予哺乳动物个体时，前药被割裂形成游离的氨基或者羧基。A "prodrug" refers to a compound of the present invention that can be metabolized in vivo into a biologically active compound. The prodrugs of the present invention are prepared by modifying the amino or carboxyl groups in the compounds of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.

“共晶”是指活性药物成分(API)和共晶形成物(CCF)在氢键或其他非共价键的作用下结合而成的晶体，其中API和CCF的纯态在室温下均为固体，并且各组分间存在固定的化学计量比。共晶是一种多组分晶体，既包含两种中性固体之间形成的二元共晶，也包含中性固体与盐或溶剂化物形成的多元共晶。"Co-crystal" refers to a crystal formed by the combination of an active pharmaceutical ingredient (API) and a co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, wherein the pure states of API and CCF are both at room temperature solid, and there is a fixed stoichiometric ratio between the components. A co-crystal is a multicomponent crystal that includes both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between neutral solids and salts or solvates.

“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和构象异构体。"Stereoisomers" refer to isomers resulting from different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.

“任选”或“任选地”或“选择性的”或“选择性地”是指随后所述的事件或状况可以但未必发生，该描述包括其中发生该事件或状况的情况及其中未发生的情况。例如，“任选地被烷基取代的杂环基”是指该烷基可以但未必存在，该描述包括其中杂环基被烷基取代的情况，及其中杂环基未被烷基取代的情况。"Optional" or "optionally" or "selective" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not occur what happened. For example, "heterocyclyl optionally substituted with an alkyl group" means that the alkyl group may, but need not, be present, and the description includes instances where the heterocyclyl group is substituted with an alkyl group, as well as where the heterocyclyl group is not substituted with an alkyl group Happening.

具体实施方式Detailed ways

以下实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited thereto.

化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以 10 ^-6(ppm)的单位给出。NMR的测定是用Bruker Avance III 400和Bruker Avance 300核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d ₆)，氘代氯仿(CDCl ₃)，氘代甲醇(CD ₃OD)，内标为四甲基硅烷(TMS)； The structures of the compounds were determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10<" ⁶ > (ppm). NMR was measured by Bruker Avance III 400 and Bruker Avance 300 nuclear magnetic instruments, and the solvents were deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), The internal standard is tetramethylsilane (TMS);

MS的测定用Agilent 6120B(ESI)和Agilent 6120B(APCI)；Agilent 6120B (ESI) and Agilent 6120B (APCI) were used for MS determination;

薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm；The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm-0.20mm, and the specification used for TLC separation and purification products is 0.4mm -0.5mm;

柱层析一般使用烟台黄海硅胶200-300目硅胶为载体。Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

实施例2Example 2

(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-2-甲基-7,8,10,11-四氢-[1,4,7]三酮基[2,3-g]喹唑啉-4-胺(化合物2)(R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-7,8,10,11-tetrahydro-[1,4, 7] Triketo[2,3-g]quinazolin-4-amine (Compound 2)

(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3 -g]quinazolin-4-amine

第一步：first step:

2-甲基-7,8,10,11-四氢-[1,4,7]三酮[2,3-g]喹唑啉-4(3H)-酮(2A)2-Methyl-7,8,10,11-tetrahydro-[1,4,7]triketo[2,3-g]quinazolin-4(3H)-one (2A)

2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4(3H)-one2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4(3H)-one

向500mL反应瓶中加入化合物1C(572mg，3mmol，1equiv)，250mL N,N-二甲基甲酰胺以及碳酸钾(1.24g，9mmol，3equiv)，80℃下搅拌反应1小时后，缓慢滴加二乙二醇双对甲苯磺酸酯(12.4g，3mmol，1equiv)的50mL N,N-二甲基甲酰胺溶液，滴加完成后继续搅拌1小时。反应完成后，减压蒸馏除去溶剂，加入20mL水，3×30mL二氯甲烷萃取，合并有机相，硫酸钠干燥，旋蒸除去溶剂，柱层析分离得到化合物2A(白色固体，477mg，产率60％)。Compound 1C (572 mg, 3 mmol, 1 equiv), 250 mL of N,N-dimethylformamide and potassium carbonate (1.24 g, 9 mmol, 3 equiv) were added to a 500 mL reaction flask, and the reaction was stirred at 80°C for 1 hour, and then slowly added dropwise. Diethylene glycol bis-p-toluenesulfonate (12.4 g, 3 mmol, 1 equiv) in 50 mL of N,N-dimethylformamide solution was added dropwise and continued to stir for 1 hour. After the reaction was completed, the solvent was distilled off under reduced pressure, 20 mL of water was added, extracted with 3×30 mL of dichloromethane, the organic phases were combined, dried over sodium sulfate, the solvent was removed by rotary evaporation, and the compound 2A (white solid, 477 mg, yield) was obtained by column chromatography. 60%).

¹H NMR(400MHz,DMSO-d ₆):δ(ppm)12.06(s,1H),7.96(s,1H),7.64(s,1H),7.18(s,1H),4.57-4.55(m,2H),4.32-4.30(m,2H),3.84-3.83(m,4H),2.30(s,3H)。 ¹ H NMR (400MHz, DMSO-d ₆ ): δ(ppm) 12.06(s,1H), 7.96(s,1H), 7.64(s,1H), 7.18(s,1H), 4.57-4.55(m, 2H), 4.32-4.30 (m, 2H), 3.84-3.83 (m, 4H), 2.30 (s, 3H).

LC-MS m/z(ESI)＝263.1[M+1]。LC-MS m/z (ESI) = 263.1 [M+1].

第二步：Step 2:

2-甲基-7,8,10,11-四氢-[1,4,7]三酮基[2,3-g]喹唑啉-4-基2,4,6-三异丙基苯磺酸酯(2B)2-Methyl-7,8,10,11-tetrahydro-[1,4,7]triketo[2,3-g]quinazolin-4-yl 2,4,6-triisopropyl Benzenesulfonate (2B)

2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-yl 2,4,6-triisopropylbenzenesulfonate2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-yl 2,4,6-triisopropylbenzenesulfonate

向25mL反应管中加入化合物2A(477mg，1.82mmol，1equiv)，2,4,6-三异丙基苯磺酰氯(1.1g，3.64mmol，2equiv)，抽换氮气三次，加入三乙胺(756μL，5.64mmol，3equiv)，4-二甲氨基吡啶(48mg，0.4mmol)和二氯甲烷(15mL)，室温过夜搅拌反应。反应结束后，饱和碳酸氢钠溶液洗涤，硫酸钠干燥，旋蒸除去溶剂，柱层析分离得到化合物2B(白色固体，600mg，产率62％)。Compound 2A (477 mg, 1.82 mmol, 1 equiv), 2,4,6-triisopropylbenzenesulfonyl chloride (1.1 g, 3.64 mmol, 2 equiv) were added to a 25 mL reaction tube, nitrogen was purged three times, and triethylamine ( 756 μL, 5.64 mmol, 3 equiv), 4-dimethylaminopyridine (48 mg, 0.4 mmol) and dichloromethane (15 mL), and the reaction was stirred at room temperature overnight. After the reaction, the mixture was washed with saturated sodium bicarbonate solution, dried over sodium sulfate, evaporated to remove the solvent, and separated by column chromatography to obtain compound 2B (white solid, 600 mg, yield 62%).

¹H NMR(400MHz,DMSO-d ₆):δ(ppm)7.51(s,1H),7.43(s,1H),7.35(s,2H),4.57-4.55(m,2H),4.32-4.30(m,2H),4.25-4.17(m,2H),3.84-3.83(m,4H),2.96(p,1H),2.42(s,3H),1.20(t,18H)。 ¹ H NMR (400MHz, DMSO-d ₆ ): δ(ppm) 7.51(s, 1H), 7.43(s, 1H), 7.35(s, 2H), 4.57-4.55(m, 2H), 4.32-4.30( m, 2H), 4.25-4.17 (m, 2H), 3.84-3.83 (m, 4H), 2.96 (p, 1H), 2.42 (s, 3H), 1.20 (t, 18H).

LC-MS m/z(ESI)＝529.2[M+1]。LC-MS m/z (ESI) = 529.2 [M+1].

第三步：third step:

向25mL反应管中加入化合物2B(50mg)，(R)-3-(1-氨基乙基)-5-(三氟甲基)苯胺(23mg，1.2equiv)，三乙胺(0.1mL)，二甲基亚砜(2mL)，90℃搅拌反应。反应结束后，减压蒸馏除去溶剂，柱层析分离得到化合物2(白色固体，35mg，产率82％)。To a 25mL reaction tube was added compound 2B (50mg), (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline (23mg, 1.2equiv), triethylamine (0.1mL), In dimethyl sulfoxide (2 mL), the reaction was stirred at 90°C. After the reaction, the solvent was distilled off under reduced pressure, and the compound 2 (white solid, 35 mg, yield 82%) was obtained by column chromatography.

¹H NMR(400MHz,CDCl ₃):δ(ppm)7.40-7.34(m,2H),7.06(s,1H),6.92(s,1H),6.79(s,1H),5.90(br,1H),5.61-5.56(m,1H),4.47(t,2H),4.38(d,2H),3.91-3.90(m,6H),2.57(s,3H),1.66(d,3H)。 ¹ H NMR (400MHz, CDCl ₃ ): δ(ppm) 7.40-7.34(m, 2H), 7.06(s, 1H), 6.92(s, 1H), 6.79(s, 1H), 5.90(br, 1H) , 5.61-5.56(m, 1H), 4.47(t, 2H), 4.38(d, 2H), 3.91-3.90(m, 6H), 2.57(s, 3H), 1.66(d, 3H).

LC-MS m/z(ESI)＝449.2[M+1]。LC-MS m/z (ESI) = 449.2 [M+1].

实施例3Example 3

(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-2'-甲基-7'H，9'H-螺环[环丙烷-1,8'-[1,4]二氧西平[2,3-g]喹唑啉]-4'-胺(化合物3)(R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-2'-methyl-7'H,9'H-spiro[cyclopropane-1 ,8'-[1,4]Dioxazepine[2,3-g]quinazoline]-4'-amine (Compound 3)

(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2'-methyl-7'H,9'H-spiro[cyclopropane- 1,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'-amine(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2'-methyl-7'H,9'H-spiro[cyclopropane- 1,8'-[1,4 ]dioxepino[2,3-g]quinazolin]-4'-amine

第一步：first step:

2'-甲基-7'H，9'H-螺环[环丙烷-1,8'-[1,4]二氧西平[2,3-g]喹唑啉]-4'(3'H)-酮(3A)2'-Methyl-7'H,9'H-spiro[cyclopropane-1,8'-[1,4]dioxazepine[2,3-g]quinazoline]-4'(3' H)-keto (3A)

2'-methyl-7'H,9'H-spiro[cyclopropane-1,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'(3'H)-one2'-methyl-7'H,9'H-spiro[cyclopropane-1,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'(3'H)-one

向500mL反应瓶中加入化合物1C(572mg，3mmol，1equiv)，250mL二甲基甲酰胺以及碳酸钾(1.24g，9mmol，3equiv)，80℃下搅拌反应1小时后，缓慢滴加环丙烷-1,1-二基双(亚甲基)双(4-甲苯磺酸酯)(1.23g,3mmol,1equiv)的50mL二甲基甲酰胺溶液，滴加完成后继续搅拌1小时。反应完成后，减压蒸馏除去溶剂，加入20mL水，3×30mL二氯甲烷萃取，合并有机相，硫酸钠干燥，旋蒸除去溶剂得到化合物3A并直接用于下一步(黄色固体，550mg，产率71％)。Compound 1C (572 mg, 3 mmol, 1 equiv), 250 mL of dimethylformamide and potassium carbonate (1.24 g, 9 mmol, 3 equiv) were added to a 500 mL reaction flask, and the reaction was stirred at 80°C for 1 hour, and then cyclopropane-1 was slowly added dropwise. , 1-diylbis(methylene)bis(4-toluenesulfonate) (1.23g, 3mmol, 1equiv) in 50mL of dimethylformamide solution was added dropwise and continued to stir for 1 hour. After the reaction was completed, the solvent was distilled off under reduced pressure, 20 mL of water was added, extracted with 3×30 mL of dichloromethane, the organic phases were combined, dried over sodium sulfate, and the solvent was removed by rotary evaporation to obtain compound 3A, which was directly used in the next step (yellow solid, 550 mg, yielded). rate 71%).

¹H NMR(400MHz,DMSO-d ₆):δ(ppm)12.07(s,1H),8.00(s,1H),7.58(s,1H),7.20(s,1H),4.14-4.06(m,2H),2.35(s,3H),0.65-0.63(m,4H)。LC-MS m/z(ESI)＝307.2[M+1]。 ¹ H NMR (400MHz, DMSO-d ₆ ): δ(ppm) 12.07(s, 1H), 8.00(s, 1H), 7.58(s, 1H), 7.20(s, 1H), 4.14-4.06(m, 2H), 2.35(s, 3H), 0.65-0.63(m, 4H). LC-MS m/z (ESI) = 307.2 [M+1].

LC-MS m/z(ESI)＝259.1[M+1]。LC-MS m/z (ESI) = 259.1 [M+1].

第二步：Step 2:

2'-甲基-7'H，9'H-螺环[环丙烷-1,8'-[1,4]二氧肾上腺素[2,3-g]喹唑啉]-4'-基2,4,6-三异丙苯磺酸酯(3B)2'-Methyl-7'H,9'H-spiro[cyclopropane-1,8'-[1,4]dioxin[2,3-g]quinazolin]-4'-yl 2,4,6-Triisopropylbenzenesulfonate (3B)

2'-methyl-7'H,9'H-spiro[cyclopropane-1,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'-yl 2,4,6-triisopropylbenzenesulfonate2'-methyl-7'H,9'H-spiro[cyclopropane-1,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'-yl 2,4,6-triisopropylbenzenesulfonate

向25mL反应管中加入化合物3A(550mg，2.13mmol，1equiv)，2,4,6-三异丙基苯磺酰氯(1.28g，4.26mmol，2equiv)，抽换氮气三次，加入三乙胺(856μL，6.39mmol，3equiv)， 4-二甲氨基吡啶(48mg，0.4mmol)和二氯甲烷(15mL)，室温过夜搅拌反应。反应结束后，饱和碳酸氢钠溶液洗涤，硫酸钠干燥，旋蒸除去溶剂，柱层析分离得到化合物3B(白色固体，656mg，产率59％)。Compound 3A (550 mg, 2.13 mmol, 1 equiv), 2,4,6-triisopropylbenzenesulfonyl chloride (1.28 g, 4.26 mmol, 2 equiv) were added to a 25 mL reaction tube, nitrogen was purged three times, and triethylamine ( 856 μL, 6.39 mmol, 3 equiv), 4-dimethylaminopyridine (48 mg, 0.4 mmol) and dichloromethane (15 mL), the reaction was stirred at room temperature overnight. After the reaction, the mixture was washed with saturated sodium bicarbonate solution, dried over sodium sulfate, evaporated to remove the solvent, and isolated by column chromatography to obtain compound 3B (white solid, 656 mg, yield 59%).

¹H NMR(400MHz,DMSO-d ₆):δ(ppm)7.65(s,1H),7.23(s,1H),6.96(s,2H),4.60-4.53(m,2H),4.04-4.00(m,4H),2.84-2.77(m,1H),2.56(s,3H),1.10-1.17(m,18H),0.64-0.63(m,4H)。 ¹ H NMR (400MHz, DMSO-d ₆ ): δ(ppm) 7.65(s, 1H), 7.23(s, 1H), 6.96(s, 2H), 4.60-4.53(m, 2H), 4.04-4.00( m, 4H), 2.84-2.77 (m, 1H), 2.56 (s, 3H), 1.10-1.17 (m, 18H), 0.64-0.63 (m, 4H).

LC-MS m/z(ESI)＝525.3[M+1]。LC-MS m/z (ESI) = 525.3 [M+1].

第三步：third step:

(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2'-methyl-7'H,9'H-spiro[cyclopropane-1,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'-amine(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2'-methyl-7'H,9'H-spiro[cyclopropane-1,8'-[1,4 ]dioxepino[2,3-g]quinazolin]-4'-amine

向25mL反应管中加入化合物3B(50mg)，(R)-3-(1-氨基乙基)-5-(三氟甲基)苯胺(23mg，1.2equiv)，三乙胺(0.1mL)，二甲基亚砜(2mL)，90℃搅拌反应。反应结束后，减压蒸馏除去溶剂，柱层析分离得到化合物3(白色固体，30mg，产率70％)。To a 25mL reaction tube was added compound 3B (50mg), (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline (23mg, 1.2equiv), triethylamine (0.1mL), In dimethyl sulfoxide (2 mL), the reaction was stirred at 90°C. After the reaction, the solvent was distilled off under reduced pressure, and the compound 3 (white solid, 30 mg, yield 70%) was obtained by column chromatography.

¹H NMR(400MHz,CDCl ₃)δ(ppm)7.35(s,1H),7.30(s,1H),7.06(s,1H),6.89(s,1H),6.79(s,1H),5.62-5.55(m,2H),4.02-3.94(m,4H),3.88(br,2H),2.56(s,3H)1.63(d,3H),0.73-0.66(m,4H)。 ¹ H NMR (400MHz, CDCl ₃ )δ(ppm) 7.35(s, 1H), 7.30(s, 1H), 7.06(s, 1H), 6.89(s, 1H), 6.79(s, 1H), 5.62- 5.55(m, 2H), 4.02-3.94(m, 4H), 3.88(br, 2H), 2.56(s, 3H) 1.63(d, 3H), 0.73-0.66(m, 4H).

LC-MS m/z(ESI)＝445.2[M+1]。LC-MS m/z (ESI) = 445.2 [M+1].

实施例4Example 4

N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-2,7-二甲基-7,8,10,11-四氢-[1,4,7]三酮基[2,3-g]喹唑啉-4-胺(化合物4)N-((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrahydro-[1 ,4,7]Triketo[2,3-g]quinazolin-4-amine (Compound 4)

N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amineN-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2 ,3-g]quinazolin-4-amine

第一步：first step:

1-(2-(苄氧基)乙氧基)丙-2-醇(4B)1-(2-(Benzyloxy)ethoxy)propan-2-ol (4B)

1-(2-(benzyloxy)ethoxy)propan-2-ol1-(2-(benzyloxy)ethoxy)propan-2-ol

向100mL反应瓶中加入苄基乙二醇(4.5g，30mmol，3equiv)，25mL二氯甲烷以及三氟化硼***(42mg，0,3mmol，0.01equiv)，冷却至0℃，缓慢滴加环氧丙烷(580mg,10mmol,1equiv)，滴加完成后继续搅拌1小时。反应完成后，旋蒸除去溶剂，柱层析分离得到化合物4B(无色液体，1.42g，产率68％)。Add benzyl ethylene glycol (4.5 g, 30 mmol, 3 equiv), 25 mL of dichloromethane and boron trifluoride ether (42 mg, 0,3 mmol, 0.01 equiv) to a 100 mL reaction flask, cool to 0 °C, and slowly add ring Oxypropane (580 mg, 10 mmol, 1 equiv) was added dropwise and stirring was continued for 1 hour. After the reaction was completed, the solvent was removed by rotary evaporation, and the compound 4B was obtained by column chromatography (colorless liquid, 1.42 g, yield 68%).

¹H NMR(400MHz,DMSO-d ₆):δ(ppm)7.35-7.30(m,5H),5.55(br,1H),4.62(s,1H),3.67-4.02(m,7H),1.21(d,3H)。 ¹ H NMR (400MHz, DMSO-d ₆ ): δ(ppm) 7.35-7.30(m, 5H), 5.55(br, 1H), 4.62(s, 1H), 3.67-4.02(m, 7H), 1.21( d, 3H).

LC-MS m/z(ESI)＝211.2[M+1]。LC-MS m/z (ESI) = 211.2 [M+1].

第二步：Step 2:

1-(2-羟基乙氧基)丙-2-醇(4C)1-(2-Hydroxyethoxy)propan-2-ol (4C)

1-(2-hydroxyethoxy)propan-2-ol1-(2-hydroxyethoxy)propan-2-ol

向100mL反应瓶中加入化合物4B(1.4g，6.7mmol，1equiv)，对甲苯磺酸吡啶盐(33mg，0.13mmol，0.02equiv)，乙烯基乙基醚(2.4g，33.5mmol，5equiv)，和二氯甲烷(25mL)，室温搅拌反应1小时。反应结束后，加入1mL三乙胺，旋蒸除去溶剂，得粗产物1.9g直接用于下一步。To a 100 mL reaction flask was added compound 4B (1.4 g, 6.7 mmol, 1 equiv), pyridinium p-toluenesulfonate (33 mg, 0.13 mmol, 0.02 equiv), vinyl ethyl ether (2.4 g, 33.5 mmol, 5 equiv), and Dichloromethane (25 mL) was stirred at room temperature for 1 hour. After the reaction, 1 mL of triethylamine was added, and the solvent was removed by rotary evaporation to obtain 1.9 g of a crude product, which was directly used in the next step.

于上一步反应瓶中加入氢氧化钯/碳(380mg,20wt％),在氢气氛围下50℃搅拌反应，反应结束后通过硅藻土过滤，旋蒸除去溶剂。然后加入20mL氯化氢乙酸乙酯溶液和1mL水，室温搅拌5分钟，旋蒸除去溶剂得粗产物4C 780mg(无色液体，两步总产率97％)，直接用于下一步。Palladium hydroxide/carbon (380 mg, 20 wt %) was added to the reaction flask in the previous step, and the reaction was stirred at 50° C. under a hydrogen atmosphere. After the reaction, it was filtered through celite, and the solvent was removed by rotary evaporation. Then add 20 mL of hydrogen chloride ethyl acetate solution and 1 mL of water, stir at room temperature for 5 minutes, and remove the solvent by rotary evaporation to obtain 780 mg of crude product 4C (colorless liquid, two-step total yield 97%), which is directly used in the next step.

¹H NMR(400MHz,DMSO-d ₆):δ(ppm)5.01(br,2H),3.61-4.89(m,7H),1.12(d,3H)。 ¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm) 5.01 (br, 2H), 3.61-4.89 (m, 7H), 1.12 (d, 3H).

LC-MS m/z(ESI)＝121.1[M+1]。LC-MS m/z(ESI)=121.1 [M+1].

第三步：third step:

1-(2-(对甲苯氧基)乙氧基)丙-2-基4-甲苯磺酸酯(4D)1-(2-(p-Tolyloxy)ethoxy)propan-2-yl 4-toluenesulfonate (4D)

1-(2-(tosyloxy)ethoxy)propan-2-yl 4-methylbenzenesulfonate1-(2-(tosyloxy)ethoxy)propan-2-yl 4-methylbenzenesulfonate

向100mL反应瓶中加入化合物4C(600mg，5mmol，1equiv)，对甲苯磺酰氯(2.85g，15mmol，3equiv)，DMAP(1.83g,15mmol,3equiv)以及二氯甲烷(20mL)，室温过夜搅拌反应。反应结束后，分别用20mL 2M盐酸溶液和20mL水洗涤，硫酸钠干燥，旋蒸除去溶剂，柱层析分离得到4D(白色固体，1.75g，产率82％)。Compound 4C (600 mg, 5 mmol, 1 equiv), p-toluenesulfonyl chloride (2.85 g, 15 mmol, 3 equiv), DMAP (1.83 g, 15 mmol, 3 equiv) and dichloromethane (20 mL) were added to a 100 mL reaction flask, and the reaction was stirred overnight at room temperature. . After the reaction, washed with 20 mL of 2M hydrochloric acid solution and 20 mL of water, respectively, dried over sodium sulfate, evaporated to remove the solvent, and separated by column chromatography to obtain 4D (white solid, 1.75 g, yield 82%).

¹H NMR(600MHz,DMSO-d6):δ(ppm)7.80-7.74(m,4H),7.50-7.42(m,4H),4.62-3.41(m,7H),2.42(s,6H),1.02(d,3H)。 ¹ H NMR (600MHz, DMSO-d6): δ (ppm) 7.80-7.74 (m, 4H), 7.50-7.42 (m, 4H), 4.62-3.41 (m, 7H), 2.42 (s, 6H), 1.02 (d, 3H).

LC-MS m/z(ESI)＝429.1[M+1]。LC-MS m/z (ESI) = 429.1 [M+1].

第四步：the fourth step:

2,11-二甲基-7,8,10,11-四氢-[1,4,7]三酮[2,3-g]喹唑啉-4(3H)-酮(4E)2,11-Dimethyl-7,8,10,11-tetrahydro-[1,4,7]triketo[2,3-g]quinazolin-4(3H)-one (4E)

2,11-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4(3H)-one2,11-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4(3H)-one

向500mL反应瓶中加入化合物1C(572mg，3mmol，1equiv)，250mL二甲基甲酰胺以及碳酸钾(1.24g，9mmol，3equiv)，100℃下搅拌反应1小时后，缓慢滴加化合物4D(1.28g,3mmol,1equiv)的50mL二甲基甲酰胺溶液，滴加完成后于120℃继续搅拌2小时。反应完成后，减压蒸馏除去溶剂，加入20mL水，3×30mL二氯甲烷萃取，合并有机相，硫酸钠干燥，旋蒸除去溶剂得到化合物4E并直接用于下一步(淡棕色固体，391mg，产率47％)。Compound 1C (572 mg, 3 mmol, 1 equiv), 250 mL of dimethylformamide and potassium carbonate (1.24 g, 9 mmol, 3 equiv) were added to a 500 mL reaction flask, and the reaction was stirred at 100 °C for 1 hour, and then compound 4D (1.28 g) was slowly added dropwise. g, 3 mmol, 1 equiv) in 50 mL of dimethylformamide solution, after the dropwise addition was completed, stirring was continued at 120° C. for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, 20 mL of water was added, extracted with 3×30 mL of dichloromethane, the organic phases were combined, dried over sodium sulfate, and the solvent was removed by rotary evaporation to obtain compound 4E, which was directly used in the next step (light brown solid, 391 mg, yield 47%).

¹H NMR(600MHz,DMSO-d ₆)δ12.07(s,1H),8.00(s,1H),7.58(s,1H),7.20(s,1H),4.51-3.46(m,7H),2.35(s,3H),1.03(d,3H)。 ¹ H NMR (600MHz, DMSO-d ₆ )δ12.07(s,1H), 8.00(s,1H), 7.58(s,1H), 7.20(s,1H), 4.51-3.46(m,7H), 2.35(s, 3H), 1.03(d, 3H).

LC-MS m/z(ESI)＝277.1[M+1]。LC-MS m/z (ESI) = 277.1 [M+1].

第五步：the fifth step:

2,7-二甲基-7,8,10,11-四氢-[1,4,7]三酮基[2,3-g]喹唑啉-4-基2,4,6-三异丙基苯磺酸酯(4F)2,7-Dimethyl-7,8,10,11-tetrahydro-[1,4,7]triketo[2,3-g]quinazolin-4-yl 2,4,6-triketo Cumene Sulfonate (4F)

2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-yl 2,4,6-triisopropylbenzenesulfonate2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-yl 2,4,6-triisopropylbenzenesulfonate

向25mL反应管中加入化合物4E(391mg，1.41mmol，1equiv)，2,4,6-三异丙基苯磺酰氯(850mg，2.82mmol，2equiv)，抽换氮气三次，加入三乙胺(567μL，4.23mmol，3equiv)，4-二甲氨基吡啶(24mg，0.2mmol)和二氯甲烷15mL)，室温过夜搅拌反应。反应结束后，饱和碳酸氢钠溶液洗涤，硫酸钠干燥，旋蒸除去溶剂，柱层析分离得到化合物4F(白色固体，540mg，产率71％)。Compound 4E (391 mg, 1.41 mmol, 1 equiv), 2,4,6-triisopropylbenzenesulfonyl chloride (850 mg, 2.82 mmol, 2 equiv) were added to a 25 mL reaction tube, nitrogen was purged three times, and triethylamine (567 μL) was added. , 4.23 mmol, 3 equiv), 4-dimethylaminopyridine (24 mg, 0.2 mmol) and dichloromethane 15 mL), and the reaction was stirred at room temperature overnight. After the reaction, the mixture was washed with saturated sodium bicarbonate solution, dried over sodium sulfate, evaporated to remove the solvent, and separated by column chromatography to obtain compound 4F (white solid, 540 mg, yield 71%).

¹H NMR(600MHz,DMSO-d ₆)δ.69(s,1H),7.10(s,1H),6.96(s,2H),4.60-3.46(m,9H),2.80(p,1H),2.52(s,3H),1.13(m,18H),1.05(d,3H)。 ¹ H NMR (600MHz, DMSO-d ₆ )δ.69(s,1H), 7.10(s,1H), 6.96(s,2H), 4.60-3.46(m,9H), 2.80(p,1H), 2.52(s, 3H), 1.13(m, 18H), 1.05(d, 3H).

LC-MS m/z(ESI)＝543.3[M+1]。LC-MS m/z (ESI) = 543.3 [M+1].

第六步：Step 6:

(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-2,7-二甲基-7,8,10,11-四氢-[1,4,7]三酮基[2,3-g]喹唑啉-4-胺(化合物4)(R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrahydro-[1 ,4,7]Triketo[2,3-g]quinazolin-4-amine (Compound 4)

向25mL反应管中加入化合物4F(50mg)，(R)-3-(1-氨基乙基)-5-(三氟甲基)苯胺(22mg，1.2equiv)，三乙胺(0.1mL)，二甲基亚砜(2mL)，90℃搅拌反应。反应结束后，减压蒸馏除去溶剂，柱层析分离得到化合物4(白色固体，30mg，产率65％)。To a 25mL reaction tube was added compound 4F (50mg), (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline (22mg, 1.2equiv), triethylamine (0.1mL), In dimethyl sulfoxide (2 mL), the reaction was stirred at 90°C. After the reaction, the solvent was distilled off under reduced pressure, and the compound 4 (white solid, 30 mg, yield 65%) was obtained by column chromatography.

¹H NMR(400MHz,DMSO-d ₆)δ(ppm)8.07-8.06(m,2H),7.05(s,1H),6.89(s,1H),6.84(s,1H),6.69(s,1H),5.55-5.49(m,3H),4.56-4.53(m,1H),4.15-3.62(m,6H),2.34(s,3H),1.53(d,3H),1.03-1.01(m,3H)。 ¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm) 8.07-8.06(m, 2H), 7.05(s, 1H), 6.89(s, 1H), 6.84(s, 1H), 6.69(s, 1H) ), 5.55-5.49(m, 3H), 4.56-4.53(m, 1H), 4.15-3.62(m, 6H), 2.34(s, 3H), 1.53(d, 3H), 1.03-1.01(m, 3H) ).

LC-MS m/z(ESI)＝463.2[M+1]。LC-MS m/z (ESI) = 463.2 [M+1].

实施例5Example 5

(R)-N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-2,7-二甲基-7,8,10,11-四氢-[1,4,7]三酮基[2,3-g]喹唑啉-4-胺(化合物5)(R)-N-((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrakis Hydro-[1,4,7]triketo[2,3-g]quinazolin-4-amine (Compound 5)

(R)-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine(R)-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7 ]trioxonino[2,3-g]quinazolin-4-amine

第一步：first step:

(S)-1-(2-((6-羟基-2-甲基-4-氧代-3,4-二氢喹唑啉-7-基)氧基)乙氧基)丙烷-2-基4-甲基苯磺酸酯(5B)(S)-1-(2-((6-Hydroxy-2-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)ethoxy)propane-2- 4-Methylbenzenesulfonate (5B)

(S)-1-(2-((6-hydroxy-2-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)ethoxy)propan-2-yl 4-methylbenzenesulfonate(S)-1-(2-((6-hydroxy-2-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)ethoxy)propan-2-yl 4-methylbenzenesulfonate

向250mL反应瓶中加入化合物1C(572mg，3mmol，1equiv)，50mL DMF以及K ₂CO ₃(1.24g，9mmol，3equiv)，50℃下搅拌反应1小时后，在8小时内缓慢滴加5A(以合成化合物4D相同的方法使用(S)-环氧丙烷为起始原料得到化合物5A，1.28g,3mmol,1 equiv)的20mL DMF溶液，加入200mL水，EA/MeOH＝95：5的混合溶剂萃取多次，合并有机相，Na ₂SO ₄干燥，旋蒸除去溶剂，DCM/PE打浆得到5B(淡黄固体，510mg，产率38％)。 Compound 1C (572 mg, 3 mmol, 1 equiv), 50 mL of DMF and K ₂ CO ₃ (1.24 g, 9 mmol, 3 equiv) were added to a 250 mL reaction flask, and the reaction was stirred at 50 ° C for 1 hour, and then slowly added dropwise 5A ( Using (S)-propylene oxide as the starting material to obtain compound 5A, 1.28 g, 3 mmol, 1 equiv) in 20 mL of DMF solution in the same manner as compound 4D was added, 200 mL of water was added, and a mixed solvent of EA/MeOH=95:5 was added. After multiple extractions, the organic phases were combined, dried over Na ₂ SO ₄ , evaporated to remove the solvent, and slurried with DCM/PE to obtain 5B (pale yellow solid, 510 mg, yield 38%).

LC-MS m/z(ESI)＝449.1[M+1]。LC-MS m/z (ESI) = 449.1 [M+1].

第二步：Step 2:

(R)-2,7-二甲基-7,8,10,11-四氢-[1,4,7]三酮[2,3-g]喹唑啉-4(3H)-酮(5C)(R)-2,7-Dimethyl-7,8,10,11-tetrahydro-[1,4,7]triketo[2,3-g]quinazolin-4(3H)-one ( 5C)

(R)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4(3H)-one(R)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4(3H)-one

向250mL反应瓶中加入化合物5B(510mg，1.14mmol，1equiv)，120mL DMF以及K ₂CO ₃(628mg g，4.55mmol，4equiv)，100℃下搅拌反应，4小时加入200mL水，DCM萃取多次，合并有机相，Na ₂SO ₄干燥，旋蒸除去溶剂，柱层析分离得到化合物5C(白色固体，113mg，产率36％)。 Compound 5B (510 mg, 1.14 mmol, 1 equiv), 120 mL DMF and K ₂ CO ₃ (628 mg g, 4.55 mmol, 4 equiv) were added to a 250 mL reaction flask, the reaction was stirred at 100° C., 200 mL of water was added for 4 hours, and DCM was extracted several times. , the organic phases were combined, dried over Na ₂ SO ₄ , the solvent was removed by rotary evaporation, and the compound 5C was obtained by column chromatography (white solid, 113 mg, yield 36%).

¹H NMR(400MHz,DMSO-d6)δ11.99(s,1H),7.60(s,1H),7.02(s,1H),5.11(ddd,J＝13.1,8.9,1.9Hz,1H),4.30–3.45(m,8H),2.29(s,3H),1.32(d,J＝6.4Hz,3H)。 ¹ H NMR (400MHz, DMSO-d6) δ 11.99 (s, 1H), 7.60 (s, 1H), 7.02 (s, 1H), 5.11 (ddd, J=13.1, 8.9, 1.9Hz, 1H), 4.30 -3.45(m, 8H), 2.29(s, 3H), 1.32(d, J=6.4Hz, 3H).

LC-MS m/z(ESI)＝277.1[M+1]。LC-MS m/z (ESI) = 277.1 [M+1].

第三步：third step:

向25mL反应管中加入化合物5C(50mg)，卡特缩合剂(1.5equiv)，1,8-二偶氮杂双螺环[5.4.0]十一-7-烯(2equiv)，DMF(2mL)，室温搅拌反应30分钟后，加入(R)-3-(1-氨基乙基)-5-(三氟甲基)苯胺(22mg，1.2equiv)，室温搅拌反应。反应结束后，减压蒸馏除去溶剂，制备HPLC分离分别得到化合物5(白色固体，51mg，产率62％)。To a 25mL reaction tube was added compound 5C (50mg), Carter condensing agent (1.5equiv), 1,8-disazobispiro[5.4.0]undec-7-ene (2equiv), DMF (2mL) , After stirring the reaction at room temperature for 30 minutes, (R)-3-(1-aminoethyl)-5-(trifluoromethyl)aniline (22 mg, 1.2 equiv) was added, and the reaction was stirred at room temperature. After the reaction, the solvent was distilled off under reduced pressure, and compound 5 (white solid, 51 mg, yield 62%) was obtained by preparative HPLC separation.

¹H NMR(400MHz,DMSO-d6)δ8.03(d,J＝6.5Hz,2H),7.04(s,1H),6.85(d,J＝10.7Hz,2H),6.69(d,J＝2.1Hz,1H),5.55(s,3H),4.99(ddd,J＝12.9,8.5,2.0Hz,1H),4.38(ddd,J＝9.3,6.4,2.8Hz,1H),4.08(dt,J＝13.1,3.2Hz,1H),4.00–3.47(m,5H),2.34(s,3H),1.54(d,J＝7.3Hz,3H),1.37(d,J＝6.4Hz,3H)。 ¹ H NMR(400MHz,DMSO-d6)δ8.03(d,J=6.5Hz,2H),7.04(s,1H),6.85(d,J=10.7Hz,2H),6.69(d,J=2.1 Hz,1H),5.55(s,3H),4.99(ddd,J＝12.9,8.5,2.0Hz,1H),4.38(ddd,J＝9.3,6.4,2.8Hz,1H),4.08(dt,J＝ 13.1, 3.2Hz, 1H), 4.00–3.47 (m, 5H), 2.34 (s, 3H), 1.54 (d, J=7.3Hz, 3H), 1.37 (d, J=6.4Hz, 3H).

LC-MS m/z(ESI)＝463.2[M+1]LC-MS m/z(ESI)=463.2[M+1]

实施例6Example 6

(S)-N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-2,7-二甲基-7,8,10,11-四氢-[1,4,7]三酮基[2,3-g]喹唑啉-4-胺(化合物6)(S)-N-((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrakis Hydro-[1,4,7]triketo[2,3-g]quinazolin-4-amine (Compound 6)

(S)-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine(S)-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7 ]trioxonino[2,3-g]quinazolin-4-amine

以实施例5相同方法合成。Synthesized in the same way as Example 5.

¹H NMR(400MHz,DMSO-d6)δ8.00(d,J＝6.5Hz,2H),7.05(s,1H),6.88(d,J＝10.7Hz,2H),6.73(d,J＝2.1Hz,1H),5.52(s,3H),4.99-4.90(m,1H),4.45-4.38(m,1H),4.03–3.47(m,6H),2.34(s,3H),1.54(d,J＝7.3Hz,3H),1.35(d,J＝6.4Hz,3H)。 ¹ H NMR(400MHz,DMSO-d6)δ8.00(d,J=6.5Hz,2H),7.05(s,1H),6.88(d,J=10.7Hz,2H),6.73(d,J=2.1 Hz, 1H), 5.52(s, 3H), 4.99-4.90(m, 1H), 4.45-4.38(m, 1H), 4.03-3.47(m, 6H), 2.34(s, 3H), 1.54(d, J=7.3Hz, 3H), 1.35 (d, J=6.4Hz, 3H).

LC-MS m/z(ESI)＝463.2[M+1]。LC-MS m/z (ESI) = 463.2 [M+1].

实施例7Example 7

(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-2'-甲基-7'H，9'H-螺环[oxetane-3,8'-[1,4]二氧西平[2,3-g]喹唑啉]-4'-胺(化合物7)(R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-2'-methyl-7'H,9'H-spiro[oxetane-3, 8'-[1,4]Dioxazepine[2,3-g]quinazoline]-4'-amine (Compound 7)

(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2'-methyl-7'H,9'H-spiro[oxetane-3,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'-amine(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2'-methyl-7'H,9'H-spiro[oxetane-3,8'-[1,4 ]dioxepino[2,3-g]quinazolin]-4'-amine

以实施例3相同方法合成。Synthesized in the same way as Example 3.

¹H NMR(400MHz,DMSO-d6)δ8.32(s,1H),7.22(s,1H),6.87(d,1H),6.75(s,2H),5.2(s,1H),5.15–5.03(m,1H),4.63(s,4H),4.55(s,4H),2.57(s,3H),1.59(d,3H)。 ¹ H NMR (400MHz, DMSO-d6) δ8.32(s,1H), 7.22(s,1H), 6.87(d,1H), 6.75(s,2H), 5.2(s,1H), 5.15–5.03 (m, 1H), 4.63 (s, 4H), 4.55 (s, 4H), 2.57 (s, 3H), 1.59 (d, 3H).

LC-MS m/z(ESI)＝461.2[M+1]。LC-MS m/z (ESI) = 461.2 [M+1].

实施例8Example 8

N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-2,7,9-三甲基-8,9-二氢-7H-[1,4]二氧肾上腺素[2,3-g]喹唑啉-4-胺(化合物8)N-((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-2,7,9-trimethyl-8,9-dihydro-7H-[1 ,4]Dioxynephrine [2,3-g]quinazolin-4-amine (Compound 8)

N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7,9-trimethyl-8,9-dihydro-7H-[1,4]dioxepino[2,3-g]quinazolin-4-amineN-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7,9-trimethyl-8,9-dihydro-7H-[1,4]dioxepino[2,3 -g]quinazolin-4-amine

以实施例3相同方法合成。Synthesized in the same way as Example 3.

¹H NMR(400MHz,DMSO-d6)δ7.71(s,1H),7.58(s,1H),7.00(dt,1H),6.92(dq,2H),5.20(s,1H),5.15–5.03(m,1H),3.71(qd,2H),3.52(s,2H),2.54(s,3H),2.00(dt,1H),1.84(dt,1H),1.48(d,3H),1.33(dd,6H)。 ¹ H NMR (400MHz, DMSO-d6)δ7.71(s,1H), 7.58(s,1H), 7.00(dt,1H), 6.92(dq,2H), 5.20(s,1H), 5.15–5.03 (m,1H),3.71(qd,2H),3.52(s,2H),2.54(s,3H),2.00(dt,1H),1.84(dt,1H),1.48(d,3H),1.33( dd, 6H).

实施例9Example 9

N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-2,7,11-三甲基-7,8,10,11-四氢-[1,4,7]三酮基[2,3-g]喹唑啉-4-胺(化合物9)N-((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-2,7,11-trimethyl-7,8,10,11-tetrahydro- [1,4,7]Triketo[2,3-g]quinazolin-4-amine (Compound 9)

N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7,11-trimethyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amineN-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7,11-trimethyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino [2,3-g]quinazolin-4-amine

以实施例3相同方法合成。Synthesized in the same way as Example 3.

¹H NMR(400MHz,DMSO-d6)δ8.03(d,J＝6.5Hz,2H),7.04(s,1H),6.85(d,J＝10.7Hz,2H),6.69(d,J＝2.1Hz,1H),5.55(s,3H),4.99(ddd,J＝12.9,8.5,2.0Hz,1H),4.38(ddd,J＝9.3,6.4,2.8Hz,1H),4.08(dt,J＝13.1,3.2Hz,1H),4.00–3.47(m,5H),2.34(s,3H),1.54(d,J＝7.3Hz,3H),1.42-1.35(m,6H)。 ¹ H NMR(400MHz,DMSO-d6)δ8.03(d,J=6.5Hz,2H),7.04(s,1H),6.85(d,J=10.7Hz,2H),6.69(d,J=2.1 Hz,1H),5.55(s,3H),4.99(ddd,J＝12.9,8.5,2.0Hz,1H),4.38(ddd,J＝9.3,6.4,2.8Hz,1H),4.08(dt,J＝ 13.1, 3.2Hz, 1H), 4.00–3.47 (m, 5H), 2.34 (s, 3H), 1.54 (d, J=7.3Hz, 3H), 1.42–1.35 (m, 6H).

LC-MS m/z(ESI)＝477.2[M+1]。LC-MS m/z (ESI) = 477.2 [M+1].

实施例10Example 10

N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-2-甲基-7-(三氟甲基)-7,8,10,11-四氢-[1,4,7]三酮基[2,3-g]喹唑啉-4-胺(化合物10)N-((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-7-(trifluoromethyl)-7,8,10,11 -Tetrahydro-[1,4,7]triketo[2,3-g]quinazolin-4-amine (Compound 10)

N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-7-(trifluoromethyl)-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amineN-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-7-(trifluoromethyl)-7,8,10,11-tetrahydro-[1,4,7 ]trioxonino[2,3-g]quinazolin-4-amine

以实施例5相同方法合成。Synthesized in the same way as Example 5.

¹H NMR(400MHz,DMSO-d6)δ7.84(s,1H),7.60(s,1H),7.22–6.95(m,2H),6.87(dt,1H),5.06(qt,1H),4.99–4.81(m,3H),4.73(dt,1H),3.87–3.59(m,3H),3.52(dq,2H),3.18(s,1H),2.51(s,3H),1.48(d,3H)。 ¹ H NMR (400MHz, DMSO-d6)δ7.84(s,1H),7.60(s,1H),7.22-6.95(m,2H),6.87(dt,1H),5.06(qt,1H),4.99 –4.81(m,3H),4.73(dt,1H),3.87–3.59(m,3H),3.52(dq,2H),3.18(s,1H),2.51(s,3H),1.48(d,3H) ).

LC-MS m/z(ESI)＝517.2[M+1]。LC-MS m/z (ESI) = 517.2 [M+1].

实施例11Example 11

N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-11-乙基-2-甲基-7,8,10,11-四氢-[1,4,7]三酮基[2,3-g]喹唑啉-4-胺(化合物11)N-((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-11-ethyl-2-methyl-7,8,10,11-tetrahydro- [1,4,7]Triketo[2,3-g]quinazolin-4-amine (Compound 11)

N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-11-ethyl-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amineN-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-11-ethyl-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino [2,3-g]quinazolin-4-amine

以实施例4相同方法合成。Synthesized in the same way as Example 4.

¹H NMR(400MHz,DMSO-d6)δ7.66(s,1H),7.54(t,1H),7.27(s,1H),7.23–7.11(m,1H),6.09(s,2H),6.04–5.94(m,1H),5.01–4.76(m,1H),4.11(dt,1H),3.91(dt,1H),3.75(p,1H),3.70–3.59(m,2H),3.53(dt,1H),3.34(dd,1H),3.15(s,1H),2.51(s,3H),1.72–1.47(m,2H),1.47(d,3H),0.88(t,3H)。 ¹ H NMR (400MHz, DMSO-d6) δ7.66(s,1H), 7.54(t,1H), 7.27(s,1H), 7.23–7.11(m,1H), 6.09(s,2H), 6.04 –5.94(m,1H),5.01–4.76(m,1H),4.11(dt,1H),3.91(dt,1H),3.75(p,1H),3.70–3.59(m,2H),3.53(dt , 1H), 3.34(dd, 1H), 3.15(s, 1H), 2.51(s, 3H), 1.72–1.47(m, 2H), 1.47(d, 3H), 0.88(t, 3H).

LC-MS m/z(ESI)＝477.2[M+1]。LC-MS m/z (ESI) = 477.2 [M+1].

实施例12Example 12

N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-2,7,10-三甲基-7,8,9,10-四氢-[1,4]二氧环己烷[2,3-g]喹唑啉-4-胺(化合物12)N-((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-2,7,10-trimethyl-7,8,9,10-tetrahydro- [1,4]Dioxane[2,3-g]quinazolin-4-amine (Compound 12)

N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7,10-trimethyl-7,8,9,10-tetrahydro-[1,4]dioxocino[2,3-g]quinazolin-4-amineN-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7,10-trimethyl-7,8,9,10-tetrahydro-[1,4]dioxocino[2 ,3-g]quinazolin-4-amine

以实施例3相同方法合成，采用Prep-HPLC分离得到化合物12-1、化合物12-2、化合物12-3、化合物12-4。It was synthesized in the same way as Example 3, and separated by Prep-HPLC to obtain compound 12-1, compound 12-2, compound 12-3 and compound 12-4.

化合物12-1： ¹H NMR(400MHz,DMSO-d6)δ7.56(q,1H),7.19(d,2H),6.09(s,2H),5.99(dt,1H),5.02–4.80(m,1H),3.97(dp,2H),3.14(s,1H),2.51(s,3H),1.90–1.57(m,2H),1.56–1.34(m,5H),1.23(t,6H)。 Compound 12-1: ¹ H NMR (400 MHz, DMSO-d6) δ 7.56(q, 1H), 7.19(d, 2H), 6.09(s, 2H), 5.99(dt, 1H), 5.02-4.80(m , 1H), 3.97 (dp, 2H), 3.14 (s, 1H), 2.51 (s, 3H), 1.90–1.57 (m, 2H), 1.56–1.34 (m, 5H), 1.23 (t, 6H).

LC-MS m/z(ESI)＝461.2[M+1]。LC-MS m/z (ESI) = 461.2 [M+1].

化合物12-2： ¹H NMR(400MHz,DMSO-d6)δ7.55(s,1H),7.50–7.38(m,1H),7.32–7.15(m,2H),6.20–5.96(m,3H),4.94–4.73(m,1H),3.99(dh,2H),3.08(s,1H),2.51(s,3H),1.89–1.61(m,2H),1.56–1.35(m,5H),1.24(dd,6H)。 Compound 12-2: ¹ H NMR (400MHz, DMSO-d6) δ7.55(s,1H), 7.50-7.38(m,1H), 7.32-7.15(m,2H), 6.20-5.96(m,3H) ,4.94–4.73(m,1H),3.99(dh,2H),3.08(s,1H),2.51(s,3H),1.89–1.61(m,2H),1.56–1.35(m,5H),1.24 (dd, 6H).

LC-MS m/z(ESI)＝461.2[M+1]。LC-MS m/z (ESI) = 461.2 [M+1].

化合物12-3： ¹H NMR(400MHz,DMSO-d ₆)δ7.55(s,1H),7.43(dd,1H),7.36–7.19(m,2H),6.19–5.96(m,3H),4.97–4.80(m,1H),3.99(dh,2H),3.08(s,1H),2.51(s,3H),1.75(tdd,2H),1.61–1.30(m,5H),1.24(dd,6H)。 Compound 12-3: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.55 (s, 1H), 7.43 (dd, 1H), 7.36-7.19 (m, 2H), 6.19-5.96 (m, 3H), 4.97–4.80 (m, 1H), 3.99 (dh, 2H), 3.08 (s, 1H), 2.51 (s, 3H), 1.75 (tdd, 2H), 1.61–1.30 (m, 5H), 1.24 (dd, 6H).

LC-MS m/z(ESI)＝461.2[M+1]。LC-MS m/z (ESI) = 461.2 [M+1].

化合物12-4： ¹H NMR(400MHz,DMSO-d6)δ7.55(s,1H),7.52–7.40(m,1H),7.26(q,1H),7.20(s,1H),6.18–5.98(m,3H),5.01–4.72(m,1H),3.99(dh,2H),3.08(s,1H),2.51(s,3H),1.87–1.63(m,2H),1.51–1.35(m,5H),1.24(dd,6H)。 Compound 12-4: ¹ H NMR (400 MHz, DMSO-d6) δ 7.55(s, 1H), 7.52-7.40(m, 1H), 7.26(q, 1H), 7.20(s, 1H), 6.18-5.98 (m, 3H), 5.01–4.72 (m, 1H), 3.99 (dh, 2H), 3.08 (s, 1H), 2.51 (s, 3H), 1.87–1.63 (m, 2H), 1.51–1.35 (m , 5H), 1.24 (dd, 6H).

LC-MS m/z(ESI)＝461.2[M+1]。LC-MS m/z (ESI) = 461.2 [M+1].

实施例13Example 13

N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-2,7,8-三甲基-7,8-二氢-[1,4]二氧基[2,3-g]喹唑啉-4-胺(化合物13)N-((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-2,7,8-trimethyl-7,8-dihydro-[1,4 ]Dioxy[2,3-g]quinazolin-4-amine (Compound 13)

N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7,8-trimethyl-7,8-dihydro-[1,4]dioxino[2,3-g]quinazolin-4-amineN-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,7,8-trimethyl-7,8-dihydro-[1,4]dioxino[2,3-g ]quinazolin-4-amine

以实施例3相同方法合成。Synthesized in the same way as Example 3.

¹H NMR(400MHz,DMSO-d6)δ7.46(d,2H),7.41–7.38(m,1H),7.29(q,1H),6.08(s,2H),6.08–6.01(m,1H),4.97–4.82(m,1H),3.97(qd,2H),3.07(s,1H),2.51(s,3H),1.41(d,3H),1.37–1.26(m,6H)。 ¹ H NMR (400MHz, DMSO-d6)δ7.46(d,2H), 7.41-7.38(m,1H), 7.29(q,1H), 6.08(s,2H), 6.08-6.01(m,1H) , 4.97–4.82 (m, 1H), 3.97 (qd, 2H), 3.07 (s, 1H), 2.51 (s, 3H), 1.41 (d, 3H), 1.37–1.26 (m, 6H).

LC-MS m/z(ESI)＝433.2[M+1]。LC-MS m/z (ESI) = 433.2 [M+1].

实施例14Example 14

顺式-N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-10-甲基-1,3,3a，5,6,14a-六氢呋喃[3'，4'：8,9][1,4,7]三酮基[2,3-g]喹唑啉-12-胺(化合物14)cis-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-10-methyl-1,3,3a,5,6,14a-hexa Hydrofuran[3',4':8,9][1,4,7]triketo[2,3-g]quinazolin-12-amine (Compound 14)

cis-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-10-methyl-1,3,3a,5,6,14a-hexahydrofuro[3',4':8,9][1,4,7]trioxonino[2,3-g]quinazolin-12-aminecis-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-10-methyl-1,3,3a,5,6,14a-hexahydrofuro[3',4': 8,9][1,4,7]trioxonino[2,3-g]quinazolin-12-amine

以实施例5相同方法合成，采用Prep-HPLC分离得到化合物14-1、化合物14-2。It was synthesized in the same way as in Example 5, and separated by Prep-HPLC to obtain compound 14-1 and compound 14-2.

化合物14-1： ¹H NMR(400MHz,DMSO-d6)δ7.53(s,1H),7.27(s,1H),7.14(d,1H), 6.97(q,1H),6.96–6.77(m,1H),5.03–4.79(m,3H),4.41(q,1H),4.13(dt,1H),4.00(dt,1H),3.96–3.82(m,2H),3.82–3.62(m,3H),3.50(td,2H),3.10(s,1H),2.51(s,3H),1.37(d,3H)。 Compound 14-1: ¹ H NMR (400 MHz, DMSO-d6) δ 7.53(s, 1H), 7.27(s, 1H), 7.14(d, 1H), 6.97(q, 1H), 6.96–6.77(m ,1H),5.03–4.79(m,3H),4.41(q,1H),4.13(dt,1H),4.00(dt,1H),3.96–3.82(m,2H),3.82–3.62(m,3H ), 3.50(td, 2H), 3.10(s, 1H), 2.51(s, 3H), 1.37(d, 3H).

LC-MS m/z(ESI)＝491.2[M+1]。LC-MS m/z (ESI) = 491.2 [M+1].

化合物14-2：1H NMR(400MHz,DMSO-d6)δ7.72(s,1H),7.33(s,1H),7.22–7.08(m,1H),6.97(q,1H),6.88(q,1H),5.03–4.75(m,3H),4.34–3.31(m,10H),3.13(s,1H),2.51(s,3H),1.37(d,3H)。Compound 14-2: 1H NMR (400MHz, DMSO-d6)δ7.72(s,1H), 7.33(s,1H), 7.22–7.08(m,1H), 6.97(q,1H), 6.88(q, 1H), 5.03–4.75 (m, 3H), 4.34–3.31 (m, 10H), 3.13 (s, 1H), 2.51 (s, 3H), 1.37 (d, 3H).

LC-MS m/z(ESI)＝491.2[M+1]。LC-MS m/z (ESI) = 491.2 [M+1].

实施例15Example 15

(S)-N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-乙基-2-甲基-7,8,10,11-四氢-[1,4,7]三酮基[2,3-g]喹唑啉-4-胺(化合物15)(S)-N-((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-7-ethyl-2-methyl-7,8,10,11 -Tetrahydro-[1,4,7]triketo[2,3-g]quinazolin-4-amine (Compound 15)

(S)-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-ethyl-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine(S)-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-ethyl-2-methyl-7,8,10,11-tetrahydro-[1,4 ,7]trioxonino[2,3-g]quinazolin-4-amine

以实施例5相同方法合成。Synthesized in the same way as Example 5.

化合物15： ¹H NMR(400MHz,DMSO-d ₆)δ7.67(s,1H),7.51–7.37(m,1H),7.37–7.23(m,2H),6.11(s,2H),6.03(dt,1H),4.97–4.71(m,1H),4.07(ddd,1H),4.01–3.79(m,2H),3.74–3.49(m,3H),3.34(dd,1H),3.08(s,1H),2.51(s,3H),1.85–1.68(m,1H),1.68–1.49(m,1H),1.38(d,3H),0.92(t,3H)。 Compound 15: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.67 (s, 1H), 7.51-7.37 (m, 1H), 7.37-7.23 (m, 2H), 6.11 (s, 2H), 6.03 ( dt, 1H), 4.97–4.71 (m, 1H), 4.07 (ddd, 1H), 4.01–3.79 (m, 2H), 3.74–3.49 (m, 3H), 3.34 (dd, 1H), 3.08 (s, 1H), 2.51 (s, 3H), 1.85–1.68 (m, 1H), 1.68–1.49 (m, 1H), 1.38 (d, 3H), 0.92 (t, 3H).

LC-MS m/z(ESI)＝477.2[M+1]。LC-MS m/z (ESI) = 477.2 [M+1].

实施例16Example 16

(R)-N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-乙基-2-甲基-7,8,10,11-四氢-[1,4,7]三酮基[2,3-g]喹唑啉-4-胺(化合物16)(R)-N-((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-7-ethyl-2-methyl-7,8,10,11 -Tetrahydro-[1,4,7]triketo[2,3-g]quinazolin-4-amine (Compound 16)

(R)-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-ethyl-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine(R)-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-ethyl-2-methyl-7,8,10,11-tetrahydro-[1,4 ,7]trioxonino[2,3-g]quinazolin-4-amine

以实施例5相同方法合成。Synthesized in the same way as Example 5.

¹H NMR(400MHz,DMSO-d6)δ7.67(s,1H),7.43(q,1H),7.30(q,1H),7.20(s,1H),6.08(s,2H),6.04–5.98(m,1H),5.01–4.73(m,1H),4.53(ddd,1H),3.96–3.26(m,6H),3.13 (s,1H),2.51(s,3H),1.84–1.47(m,2H),1.37(d,3H),0.88(t,3H)。 ¹ H NMR (400MHz, DMSO-d6) δ7.67(s,1H), 7.43(q,1H), 7.30(q,1H), 7.20(s,1H), 6.08(s,2H), 6.04–5.98 (m, 1H), 5.01–4.73 (m, 1H), 4.53 (ddd, 1H), 3.96–3.26 (m, 6H), 3.13 (s, 1H), 2.51 (s, 3H), 1.84–1.47 (m , 2H), 1.37(d, 3H), 0.88(t, 3H).

LC-MS m/z(ESI)＝477.2[M+1]。LC-MS m/z (ESI) = 477.2 [M+1].

实施例17Example 17

顺式-N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-11-甲基-1,2,3,4,4a，6,7,15a-八氢苯并[8,9][1,4,7]三酮基[2,3-g]喹唑啉-13-胺(化合物17)cis-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-11-methyl-1,2,3,4,4a,6,7 ,15a-Octahydrobenzo[8,9][1,4,7]triketo[2,3-g]quinazolin-13-amine (Compound 17)

cis-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-11-methyl-1,2,3,4,4a,6,7,15a-octahydrobenzo[8,9][1,4,7]trioxonino[2,3-g]quinazolin-13-aminecis-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-11-methyl-1,2,3,4,4a,6,7,15a-octahydrobenzo[8, 9][1,4,7]trioxonino[2,3-g]quinazolin-13-amine

以实施例5相同方法合成，采用Prep-HPLC分离得到化合物17-1和化合物17-2。It was synthesized in the same way as in Example 5, and compound 17-1 and compound 17-2 were obtained by Prep-HPLC separation.

化合物17-1： ¹H NMR(400MHz,DMSO-d6)δ7.55(d,1H),7.50(s,1H),7.24(s,1H),7.19(q,1H),6.09(s,2H),5.99(td,1H),5.05–4.89(m,1H),4.46(q,1H),4.16(dt,1H),4.01(s,0H),3.61–3.39(m,3H),3.16(s,1H),2.51(s,3H),2.00–1.86(m,1H),1.79–1.19(m,10H)。 Compound 17-1: ¹ H NMR (400MHz, DMSO-d6)δ7.55(d,1H), 7.50(s,1H), 7.24(s,1H), 7.19(q,1H), 6.09(s,2H) ), 5.99(td, 1H), 5.05–4.89(m, 1H), 4.46(q, 1H), 4.16(dt, 1H), 4.01(s, 0H), 3.61–3.39(m, 3H), 3.16( s, 1H), 2.51 (s, 3H), 2.00–1.86 (m, 1H), 1.79–1.19 (m, 10H).

LC-MS m/z(ESI)＝503.2[M+1]。LC-MS m/z (ESI) = 503.2 [M+1].

化合物17-2： ¹H NMR(400MHz,DMSO-d6)δ7.67(s,1H),7.51(dd,1H),7.31(s,1H),7.28–7.20(m,1H),6.09(s,2H),6.00(q,1H),5.01–4.80(m,1H),4.14(dt,1H),3.92(dt,1H),3.62(dt,1H),3.55–3.34(m,3H),3.23(s,1H),2.51(s,3H),2.00–1.16(m,11H)。 Compound 17-2: ¹ H NMR (400 MHz, DMSO-d6) δ 7.67(s, 1H), 7.51(dd, 1H), 7.31(s, 1H), 7.28-7.20(m, 1H), 6.09(s ,2H),6.00(q,1H),5.01–4.80(m,1H),4.14(dt,1H),3.92(dt,1H),3.62(dt,1H),3.55–3.34(m,3H), 3.23(s, 1H), 2.51(s, 3H), 2.00–1.16(m, 11H).

LC-MS m/z(ESI)＝503.2[M+1]。LC-MS m/z (ESI) = 503.2 [M+1].

实施例18Example 18

N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-异丙基-2-甲基-7,8,10,11-四氢-[1,4,7]三酮基[2,3-g]喹唑啉-4-胺(化合物18)N-((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-7-isopropyl-2-methyl-7,8,10,11-tetrahydro -[1,4,7]Triketo[2,3-g]quinazolin-4-amine (Compound 18)

N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-isopropyl-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amineN-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-isopropyl-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino [2,3-g]quinazolin-4-amine

以实施例5相同方法合成。Synthesized in the same way as Example 5.

¹H NMR(400MHz,DMSO-d6)δ7.62(s,1H),7.40(dq,1H),7.29(d,2H),6.12(s,2H),6.03(dt,1H),4.97–4.82(m,1H),4.14(dt,1H),4.03–3.75(m,2H),3.75–3.40(m,4H),3.14(s,1H),2.51(s,3H),2.02(h,1H),1.38(d,3H),0.84(dd,6H)。 ¹ H NMR (400MHz, DMSO-d6)δ7.62(s,1H), 7.40(dq,1H), 7.29(d,2H), 6.12(s,2H), 6.03(dt,1H), 4.97–4.82 (m, 1H), 4.14 (dt, 1H), 4.03–3.75 (m, 2H), 3.75–3.40 (m, 4H), 3.14 (s, 1H), 2.51 (s, 3H), 2.02 (h, 1H) ), 1.38(d, 3H), 0.84(dd, 6H).

LC-MS m/z(ESI)＝491.2[M+1]。LC-MS m/z (ESI) = 491.2 [M+1].

实施例19Example 19

(R)-N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-(乙氧基甲基)-2-甲基-7,8,10,11-四氢-[1,4,7]三酮基[2,3-g]喹唑啉-4-胺(化合物19)(R)-N-((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-7-(ethoxymethyl)-2-methyl-7, 8,10,11-Tetrahydro-[1,4,7]triketo[2,3-g]quinazolin-4-amine (Compound 19)

(R)-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-(ethoxymethyl)-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine(R)-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-(ethoxymethyl)-2-methyl-7,8,10,11-tetrahydro-[1 ,4,7]trioxonino[2,3-g]quinazolin-4-amine

以实施例5相同方法合成。Synthesized in the same way as Example 5.

¹H NMR(400MHz,DMSO-d6)δ7.72(d,2H),7.32(dt,2H),6.10(s,2H),6.05–5.93(m,1H),4.83–4.58(m,1H),4.05–3.78(m,3H),3.72–3.13(m,9H),2.51(s,3H),1.41(d,3H),1.08(t,3H)。 ¹ H NMR (400MHz, DMSO-d6)δ7.72(d,2H), 7.32(dt,2H), 6.10(s,2H), 6.05–5.93(m,1H), 4.83–4.58(m,1H) , 4.05–3.78 (m, 3H), 3.72–3.13 (m, 9H), 2.51 (s, 3H), 1.41 (d, 3H), 1.08 (t, 3H).

LC-MS m/z(ESI)＝507.2[M+1]。LC-MS m/z (ESI) = 507.2 [M+1].

实施例20Example 20

(S)-N-((R)-1-(3-氨基-5-(三氟甲基)苯基)乙基)-7-(乙氧基甲基)-2-甲基-7,8,10,11-四氢-[1,4,7]三酮基[2,3-g]喹唑啉-4-胺(化合物20)(S)-N-((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-7-(ethoxymethyl)-2-methyl-7, 8,10,11-Tetrahydro-[1,4,7]triketo[2,3-g]quinazolin-4-amine (Compound 20)

(S)-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-(ethoxymethyl)-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine(S)-N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-(ethoxymethyl)-2-methyl-7,8,10,11-tetrahydro-[1 ,4,7]trioxonino[2,3-g]quinazolin-4-amine

以实施例5相同方法合成。Synthesized in the same way as Example 5.

¹H NMR(400MHz,DMSO-d6)δ7.79(s,1H),7.62(s,1H),7.50–7.34(m,1H),7.34–7.24(m,1H),6.11(s,2H),6.03(dd,1H),4.95–4.76(m,1H),4.52(ddd,1H),3.95–3.19(m,10H),3.12(s,1H),2.51(s,3H),1.38(d,3H),1.08(t,3H)。 ¹ H NMR (400MHz, DMSO-d6) δ7.79(s,1H), 7.62(s,1H), 7.50–7.34(m,1H), 7.34–7.24(m,1H), 6.11(s,2H) ,6.03(dd,1H),4.95–4.76(m,1H),4.52(ddd,1H),3.95–3.19(m,10H),3.12(s,1H),2.51(s,3H),1.38(d , 3H), 1.08(t, 3H).

LC-MS m/z(ESI)＝507.2[M+1]。LC-MS m/z (ESI) = 507.2 [M+1].

实施例21Example 21

N-((1R)-1-(3-(2,2-二氟环丙基)-2-氟苯基)乙基)-2-甲基-7,8,10,11-四氢-[1,4,7]三酮基[2,3-g]喹唑啉-4-胺(化合物21)N-((1R)-1-(3-(2,2-difluorocyclopropyl)-2-fluorophenyl)ethyl)-2-methyl-7,8,10,11-tetrahydro- [1,4,7]Triketo[2,3-g]quinazolin-4-amine (Compound 21)

N-((1R)-1-(3-(2,2-difluorocyclopropyl)-2-fluorophenyl)ethyl)-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amineN-((1R)-1-(3-(2,2-difluorocyclopropyl)-2-fluorophenyl)ethyl)-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[ 2,3-g]quinazolin-4-amine

向25mL反应管中加入化合物2A，卡特缩合剂(1.5equiv)，1,8-二偶氮杂双螺环[5.4.0]十一-7-烯，DMF，室温搅拌反应30分钟后，加入化合物21A(以Advanced Synthesis and Catalysis,2018,vol.360,#21,p.4104–4114中所报道的方法合成，然后以WO2018115380A1中所报道方法得到化合物21A)，室温搅拌反应。反应结束后，减压蒸馏除去溶剂，制备HPLC分离分别得到化合物21(白色固体)。Compound 2A, Carter condensing agent (1.5equiv), 1,8-diazabispiro[5.4.0]undec-7-ene, DMF were added to a 25mL reaction tube, and the reaction was stirred at room temperature for 30 minutes, then added Compound 21A (synthesized by the method reported in Advanced Synthesis and Catalysis, 2018, vol.360, #21, p.4104-4114, then compound 21A was obtained by the method reported in WO2018115380A1), and the reaction was stirred at room temperature. After the reaction, the solvent was distilled off under reduced pressure, and compound 21 (white solid) was obtained by preparative HPLC separation.

¹H NMR(400MHz,DMSO-d6)δ7.69(d,2H),7.43–7.28(m,1H),7.25–7.02(m,2H),4.82(dd,1H),4.65(qd,1H),4.15(ddd,1H),3.86–3.12(m,7H),2.51(s,3H),2.37–2.16(m,1H),1.57–1.07(m,5H)。 ¹ H NMR (400MHz, DMSO-d6)δ7.69(d,2H), 7.43-7.28(m,1H), 7.25-7.02(m,2H), 4.82(dd,1H), 4.65(qd,1H) , 4.15 (ddd, 1H), 3.86–3.12 (m, 7H), 2.51 (s, 3H), 2.37–2.16 (m, 1H), 1.57–1.07 (m, 5H).

LC-MS m/z(ESI)＝460.2[M+1]。LC-MS m/z (ESI) = 460.2 [M+1].

实施例22Example 22

(R)-2,2-二氟-2-(3-(1-((2-甲基-7,8,10,11-四氢-[1,4,7]三酮基[2,3-g]喹唑啉-4-基)氨基)乙基)苯基)乙烷-1-醇(化合物22)(R)-2,2-Difluoro-2-(3-(1-((2-methyl-7,8,10,11-tetrahydro-[1,4,7]triketo[2, 3-g]Quinazolin-4-yl)amino)ethyl)phenyl)ethane-1-ol (Compound 22)

(R)-2,2-difluoro-2-(3-(1-((2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-yl)amino)ethyl)phenyl)ethan-1-ol(R)-2,2-difluoro-2-(3-(1-((2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin -4-yl)amino)ethyl)phenyl)ethan-1-ol

向25mL反应管中加入化合物2A，卡特缩合剂(1.5equiv)，1,8-二偶氮杂双螺环[5.4.0]十一-7-烯，DMF，室温搅拌反应30分钟后，加入化合物22A(以WO2018115380A1中所报道方法得到化合物22A)，室温搅拌反应。反应结束后，减压蒸馏除去溶剂，制备HPLC分离分别得到化合物22(白色固体)。Compound 2A, Carter condensing agent (1.5equiv), 1,8-diazabispiro[5.4.0]undec-7-ene, DMF were added to a 25mL reaction tube, and the reaction was stirred at room temperature for 30 minutes, then added Compound 22A (compound 22A was obtained by the method reported in WO2018115380A1), and the reaction was stirred at room temperature. After the reaction, the solvent was distilled off under reduced pressure, and compound 22 (white solid) was obtained by preparative HPLC separation.

¹H NMR(400MHz,DMSO-d6)δ7.66–7.22(m,6H),4.95–4.81(m,1H),4.62(d,1H),4.50–4.41(m,1H),4.20–3.98(m,2H),3.98–3.72(m,3H),3.65–3.44(m,2H),3.34–3.12(m,3H),2.51(s,3H),1.36(d,3H)。 ¹ H NMR (400MHz, DMSO-d6)δ7.66-7.22(m,6H), 4.95-4.81(m,1H), 4.62(d,1H), 4.50-4.41(m,1H), 4.20-3.98( m, 2H), 3.98–3.72 (m, 3H), 3.65–3.44 (m, 2H), 3.34–3.12 (m, 3H), 2.51 (s, 3H), 1.36 (d, 3H).

LC-MS m/z(ESI)＝446.1[M+1]。LC-MS m/z (ESI) = 446.1 [M+1].

实施例24Example 24

N-((1R)-1-(3-(2,2-二氟环丙基)苯基)乙基)-2-甲基-7,8,10,11-四氢-[1,4,7]三酮基[2,3-g]喹唑啉-4-胺(化合物24)N-((1R)-1-(3-(2,2-difluorocyclopropyl)phenyl)ethyl)-2-methyl-7,8,10,11-tetrahydro-[1,4 ,7]Triketo[2,3-g]quinazolin-4-amine (Compound 24)

N-((1R)-1-(3-(2,2-difluorocyclopropyl)phenyl)ethyl)-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amineN-((1R)-1-(3-(2,2-difluorocyclopropyl)phenyl)ethyl)-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3 -g]quinazolin-4-amine

以实施例21相同方法合成。Synthesized in the same manner as Example 21.

¹H NMR(400MHz,DMSO-d6)δ7.67(d,2H),7.56–7.08(m,4H),5.06–4.79(m,1H),4.63–4.25(m,2H),4.00–3.04(m,7H),2.68–2.25(m,4H),1.67–0.89(m,5H)。 ¹ H NMR(400MHz,DMSO-d6)δ7.67(d,2H),7.56-7.08(m,4H),5.06-4.79(m,1H),4.63-4.25(m,2H),4.00-3.04( m, 7H), 2.68–2.25 (m, 4H), 1.67–0.89 (m, 5H).

LC-MS m/z(ESI)＝442.2[M+1]。LC-MS m/z (ESI) = 442.2 [M+1].

实施例25Example 25

(R)-N-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-2-甲基-8,9,10,11-四氢-7H-[1,4]二氧杂环[2,3-g]喹唑啉-4-胺(化合物25)(R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-8,9,10,11-tetrahydro-7H-[1, 4] Dioxo[2,3-g]quinazolin-4-amine (Compound 25)

(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-8,9,10,11-tetrahydro-7H-[1,4]dioxonino[2,3-g]quinazolin-4-amine(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-8,9,10,11-tetrahydro-7H-[1,4]dioxonino[2,3 -g]quinazolin-4-amine

以实施例5相同方法合成。Synthesized in the same way as Example 5.

¹H NMR(400MHz,DMSO-d6)δ7.78(s,1H),7.66(s,1H),7.15(t,1H),7.06–6.93(m,1H),6.87(dt,1H),5.02–4.72(m,3H),4.39(ddt,1H),4.18–3.81(m,3H),3.15(s,1H),2.51(s,3H),1.98(dddd,1H),1.81–1.30(m,8H)。 ¹ H NMR (400MHz, DMSO-d6) δ 7.78(s, 1H), 7.66(s, 1H), 7.15(t, 1H), 7.06–6.93(m, 1H), 6.87(dt, 1H), 5.02 –4.72(m,3H),4.39(ddt,1H),4.18–3.81(m,3H),3.15(s,1H),2.51(s,3H),1.98(dddd,1H),1.81–1.30(m , 8H).

LC-MS m/z(ESI)＝447.2[M+1]。LC-MS m/z (ESI) = 447.2 [M+1].

实施例27Example 27

(R)-N-(1-(2-氟-3-(1-氟乙烯基)苯基)乙基)-2-甲基-7,8,10,11-四氢-[1,4,7]三酮基[2,3-g]喹唑啉-4-胺(化合物27)(R)-N-(1-(2-Fluoro-3-(1-fluorovinyl)phenyl)ethyl)-2-methyl-7,8,10,11-tetrahydro-[1,4 ,7]Triketo[2,3-g]quinazolin-4-amine (Compound 27)

(R)-N-(1-(2-fluoro-3-(1-fluorovinyl)phenyl)ethyl)-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine(R)-N-(1-(2-fluoro-3-(1-fluorovinyl)phenyl)ethyl)-2-methyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2 ,3-g]quinazolin-4-amine

向25mL反应管中加入化合物A2，卡特缩合剂(1.5equiv)，1,8-二偶氮杂双螺环[5.4.0]十一-7-烯，DMF，室温搅拌反应30分钟后，加入化合物27A(以WO2018115380A1中所报道方法得到化合物27A)，室温搅拌反应。反应结束后，减压蒸馏除去溶剂，制备HPLC分离分别得到化合物27(白色固体)。Compound A2, Carter condensing agent (1.5equiv), 1,8-diazabispiro[5.4.0]undec-7-ene, DMF were added to a 25mL reaction tube, and the reaction was stirred at room temperature for 30 minutes, then added Compound 27A (compound 27A was obtained by the method reported in WO2018115380A1), and the reaction was stirred at room temperature. After the reaction, the solvent was distilled off under reduced pressure, and compound 27 (white solid) was obtained by preparative HPLC separation.

¹H NMR(400MHz,DMSO-d6)δ7.64(d,2H),7.35(td,1H),7.16–7.02(m,2H),4.97–4.72(m,2H),4.60(d,1H),4.47(d,1H),4.18–3.21(m,9H),2.51(s,3H),1.33(d,3H)。 ¹ H NMR (400MHz, DMSO-d6) δ7.64(d,2H), 7.35(td,1H), 7.16-7.02(m,2H), 4.97-4.72(m,2H), 4.60(d,1H) , 4.47(d, 1H), 4.18–3.21(m, 9H), 2.51(s, 3H), 1.33(d, 3H).

LC-MS m/z(ESI)＝428.1[M+1]。LC-MS m/z (ESI) = 428.1 [M+1].

实施例28Example 28

(S)-N-((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)-2,7-二甲基-7,8,10,11-四氢-[1,4,7]三酮基[2,3-g]喹唑啉-4-胺(化合物28)(S)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrakis Hydro-[1,4,7]triketo[2,3-g]quinazolin-4-amine (Compound 28)

(S)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine(S)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7] trioxonino[2,3-g]quinazolin-4-amine

以实施例5相同方法合成。Synthesized in the same way as Example 5.

¹H NMR(400MHz,DMSO-d6)δ7.80(s,1H),7.59(s,1H),7.52–7.43(m,1H),7.30–7.15(m,2H),4.91–4.81(m,1H),4.58(ddd,1H),3.91(h,1H),3.78(ddd,1H),3.71–3.59(m,2H),3.48(ddd,1H),3.34–3.24(m,2H),2.51(s,3H),1.30(dd,6H)。 ¹ H NMR(400MHz, DMSO-d6)δ7.80(s,1H),7.59(s,1H),7.52-7.43(m,1H),7.30-7.15(m,2H),4.91-4.81(m, 1H), 4.58 (ddd, 1H), 3.91 (h, 1H), 3.78 (ddd, 1H), 3.71–3.59 (m, 2H), 3.48 (ddd, 1H), 3.34–3.24 (m, 2H), 2.51 (s, 3H), 1.30 (dd, 6H).

LC-MS m/z(ESI)＝448.2[M+1]。LC-MS m/z (ESI) = 448.2 [M+1].

实施例29Example 29

(S)-N-((R)-1-(2-氟-3-(三氟甲基)苯基)乙基)-2,7-二甲基-7,8,10,11-四氢-[1,4,7]三酮基 [2,3-g]喹唑啉-4-胺(化合物29)(S)-N-((R)-1-(2-Fluoro-3-(trifluoromethyl)phenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrakis Hydro-[1,4,7]triketo[2,3-g]quinazolin-4-amine (Compound 29)

(S)-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine(S)-N-((R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7 ]trioxonino[2,3-g]quinazolin-4-amine

以实施例5相同方法合成。Synthesized in the same way as Example 5.

¹H NMR(400MHz,DMSO-d6)δ7.81(s,1H),7.59–7.45(m,3H),7.23(t,1H),4.67–4.54(m,2H),3.92(h,1H),3.78(ddd,1H),3.70–3.60(m,2H),3.58(s,1H),3.48(ddd,1H),3.29(dd,1H),2.51(s,3H),1.41(d,3H),1.28(d,3H)。 ¹ H NMR (400MHz, DMSO-d6)δ7.81(s,1H), 7.59–7.45(m,3H), 7.23(t,1H), 4.67–4.54(m,2H), 3.92(h,1H) ,3.78(ddd,1H),3.70–3.60(m,2H),3.58(s,1H),3.48(ddd,1H),3.29(dd,1H),2.51(s,3H),1.41(d,3H) ), 1.28(d, 3H).

LC-MS m/z(ESI)＝466.2[M+1]。LC-MS m/z (ESI) = 466.2 [M+1].

实施例30Example 30

(S)-N-((R)-1-(3-环丙基-2-氟苯基)乙基)-2,7-二甲基-7,8,10,11-四氢-[1,4,7]三酮基[2,3-g]喹唑啉-4-胺(化合物30)(S)-N-((R)-1-(3-Cyclopropyl-2-fluorophenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrahydro-[ 1,4,7]Triketo[2,3-g]quinazolin-4-amine (Compound 30)

(S)-N-((R)-1-(3-cyclopropyl-2-fluorophenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine(S)-N-((R)-1-(3-cyclopropyl-2-fluorophenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[ 2,3-g]quinazolin-4-amine

以实施例5相同方法合成。Synthesized in the same way as Example 5.

¹H NMR(400MHz,DMSO-d6)δ7.81(s,1H),7.59(s,1H),7.44–7.25(m,1H),7.25–7.03(m,2H),4.73–4.51(m,2H),4.00–3.21(m,7H),2.51(s,3H),2.29–2.15(m,1H),1.40(d,3H),1.28(d,3H),1.22–1.04(m,2H),1.01–0.77(m,2H)。 ¹ H NMR(400MHz, DMSO-d6)δ7.81(s,1H),7.59(s,1H),7.44-7.25(m,1H),7.25-7.03(m,2H),4.73-4.51(m, 2H), 4.00–3.21 (m, 7H), 2.51 (s, 3H), 2.29–2.15 (m, 1H), 1.40 (d, 3H), 1.28 (d, 3H), 1.22–1.04 (m, 2H) , 1.01–0.77 (m, 2H).

LC-MS m/z(ESI)＝438.2[M+1]。LC-MS m/z (ESI) = 438.2 [M+1].

实施例31Example 31

2-(3-((R)-1-((S)-2,7-二甲基-7,8,10,11-四氢-[1,4,7]三酮基[2,3-g]喹唑啉-4-基)氨基)乙基)苯基)-2,2-二氟乙烷-1-醇(化合物31)2-(3-((R)-1-((S)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]triketo[2,3 -g]quinazolin-4-yl)amino)ethyl)phenyl)-2,2-difluoroethane-1-ol (compound 31)

2-(3-((R)-1-(((S)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-yl)amino)ethyl)phenyl)-2,2-difluoroethan-1-ol2-(3-((R)-1-(((S)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin -4-yl)amino)ethyl)phenyl)-2,2-difluoroethan-1-ol

以实施例5相同方法合成。Synthesized in the same way as Example 5.

¹H NMR(400MHz,DMSO-d6)δ7.81(s,1H),7.61(s,1H),7.52–7.43(m,3H),7.34(ddd,1H),4.84(q,1H),4.66–4.54(m,2H),4.19–3.01(m,9H),2.51(s,3H),1.37(d,3H),1.27(d,3H)。 ¹ H NMR (400MHz, DMSO-d6) δ 7.81(s,1H), 7.61(s,1H), 7.52–7.43(m,3H), 7.34(ddd,1H), 4.84(q,1H), 4.66 – 4.54 (m, 2H), 4.19 – 3.01 (m, 9H), 2.51 (s, 3H), 1.37 (d, 3H), 1.27 (d, 3H).

LC-MS m/z(ESI)＝460.2[M+1]。LC-MS m/z (ESI) = 460.2 [M+1].

实施例32Example 32

(S)-2,7-二甲基-N-((R)-1-(萘-2-基)乙基)-7,8,10,11-四氢-[1,4,7]三酮基[2,3-g]喹唑啉-4-胺(化合物32)(S)-2,7-Dimethyl-N-((R)-1-(naphthalen-2-yl)ethyl)-7,8,10,11-tetrahydro-[1,4,7] Triketo[2,3-g]quinazolin-4-amine (Compound 32)

(S)-2,7-dimethyl-N-((R)-1-(naphthalen-2-yl)ethyl)-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine(S)-2,7-dimethyl-N-((R)-1-(naphthalen-2-yl)ethyl)-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2, 3-g]quinazolin-4-amine

以实施例5相同方法合成。Synthesized in the same way as Example 5.

¹H NMR(400MHz,DMSO-d6)δ8.03–7.83(m,3H),7.80(d,2H),7.73(s,1H),7.69(d,1H),7.55(dtd,2H),4.92(q,1H),4.13–3.89(m,2H),3.85(ddd,1H),3.77–3.49(m,3H),3.44–3.19(m,2H),2.51(s,3H),1.44(d,3H),1.29(d,3H)。 ¹ H NMR (400MHz, DMSO-d6) δ8.03-7.83(m,3H), 7.80(d,2H), 7.73(s,1H), 7.69(d,1H), 7.55(dtd,2H), 4.92 (q, 1H), 4.13–3.89 (m, 2H), 3.85 (ddd, 1H), 3.77–3.49 (m, 3H), 3.44–3.19 (m, 2H), 2.51 (s, 3H), 1.44 (d , 3H), 1.29(d, 3H).

LC-MS m/z(ESI)＝430.2[M+1]。LC-MS m/z (ESI) = 430.2 [M+1].

实施例33Example 33

(7S)-N-((1R)-1-(3-(2,2-二氟环丙基)-2-氟苯基)乙基)-2,7-二甲基-7,8,10,11-四氢-[1,4,7]三酮基[2,3-g]喹唑啉-4-胺(化合物33)(7S)-N-((1R)-1-(3-(2,2-difluorocyclopropyl)-2-fluorophenyl)ethyl)-2,7-dimethyl-7,8, 10,11-Tetrahydro-[1,4,7]triketo[2,3-g]quinazolin-4-amine (Compound 33)

(7S)-N-((1R)-1-(3-(2,2-difluorocyclopropyl)-2-fluorophenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine(7S)-N-((1R)-1-(3-(2,2-difluorocyclopropyl)-2-fluorophenyl)ethyl)-2,7-dimethyl-7,8,10,11-tetrahydro-[1, 4,7]trioxonino[2,3-g]quinazolin-4-amine

以实施例5相同方法合成。Synthesized in the same way as Example 5.

¹H NMR(400MHz,DMSO-d6)δ7.79(s,1H),7.57(s,1H),7.40–7.31(m,1H),7.25–7.07(m,2H),4.82–4.40(m,2H),3.94(h,1H),3.77(ddd,1H),3.74–3.59(m,3H),3.47(ddd,1H),3.30(d,1H),2.61–2.19(m,4H),1.54–1.00(m,8H)。 ¹ H NMR (400MHz, DMSO-d6)δ7.79(s,1H), 7.57(s,1H), 7.40–7.31(m,1H), 7.25–7.07(m,2H), 4.82–4.40(m, 2H), 3.94 (h, 1H), 3.77 (ddd, 1H), 3.74–3.59 (m, 3H), 3.47 (ddd, 1H), 3.30 (d, 1H), 2.61–2.19 (m, 4H), 1.54 -1.00 (m, 8H).

LC-MS m/z(ESI)＝474.2[M+1]。LC-MS m/z (ESI) = 474.2 [M+1].

实施例34Example 34

(S)-2,7-二甲基-N-((R)-1-(2-甲基-3-(三氟甲基)苯基)乙基)-7,8,10,11-四氢-[1,4,7]三酮基[2,3-g]喹唑啉-4-胺(化合物34)(S)-2,7-Dimethyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7,8,10,11- Tetrahydro-[1,4,7]triketo[2,3-g]quinazolin-4-amine (Compound 34)

(S)-2,7-dimethyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine(S)-2,7-dimethyl-N-((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7,8,10,11-tetrahydro-[1,4,7 ]trioxonino[2,3-g]quinazolin-4-amine

以实施例5相同方法合成。Synthesized in the same way as Example 5.

¹H NMR(400MHz,DMSO-d6)δ7.60(s,1H),7.49–7.28(m,3H),4.71(qd,1H),4.58(ddd,1H),4.03–3.52(m,4H),3.48(ddd,1H),3.28(dd,1H),3.13(s,1H),2.51(s,3H),2.33(s,3H),1.39(d,3H),1.27(d,3H)。 ¹ H NMR (400MHz, DMSO-d6)δ7.60(s,1H), 7.49-7.28(m,3H), 4.71(qd,1H), 4.58(ddd,1H), 4.03-3.52(m,4H) , 3.48(ddd, 1H), 3.28(dd, 1H), 3.13(s, 1H), 2.51(s, 3H), 2.33(s, 3H), 1.39(d, 3H), 1.27(d, 3H).

LC-MS m/z(ESI)＝462.2[M+1]。LC-MS m/z (ESI) = 462.2 [M+1].

实施例35Example 35

(S)-2,7-二甲基-N-((R)-1-(3-(三氟甲基)苯基)乙基)-7,8,10,11-四氢-[1,4,7]三酮基[2,3-g]喹唑啉-4-胺(化合物35)(S)-2,7-Dimethyl-N-((R)-1-(3-(trifluoromethyl)phenyl)ethyl)-7,8,10,11-tetrahydro-[1 ,4,7]Triketo[2,3-g]quinazolin-4-amine (Compound 35)

(S)-2,7-dimethyl-N-((R)-1-(3-(trifluoromethyl)phenyl)ethyl)-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2,3-g]quinazolin-4-amine(S)-2,7-dimethyl-N-((R)-1-(3-(trifluoromethyl)phenyl)ethyl)-7,8,10,11-tetrahydro-[1,4,7]trioxonino[2 ,3-g]quinazolin-4-amine

以实施例5相同方法合成。Synthesized in the same way as Example 5.

¹H NMR(400MHz,DMSO-d6)δ7.78(d,2H),7.60(s,1H),7.57–7.32(m,3H),4.89(q,1H),4.56(ddd,1H),3.90(h,1H),3.77(ddd,1H),3.72–3.57(m,2H),3.48(ddd,1H),3.34–3.18(m,2H),2.51(s,3H),1.37(d,3H),1.27(d,3H)。 ¹ H NMR (400MHz, DMSO-d6) δ 7.78 (d, 2H), 7.60 (s, 1H), 7.57–7.32 (m, 3H), 4.89 (q, 1H), 4.56 (ddd, 1H), 3.90 (h, 1H), 3.77 (ddd, 1H), 3.72–3.57 (m, 2H), 3.48 (ddd, 1H), 3.34–3.18 (m, 2H), 2.51 (s, 3H), 1.37 (d, 3H) ), 1.27(d, 3H).

LC-MS m/z(ESI)＝448.2[M+1]。LC-MS m/z (ESI) = 448.2 [M+1].

实施例36Example 36

(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2'-甲基-7'H,9'H-螺[环丙烷-1,8'-[1,4]二恶英[2,3-g]喹唑啉]-4'-胺(化合物36)(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2'-methyl-7'H,9'H-spiro[cyclopropane-1, 8'-[1,4]dioxin[2,3-g]quinazoline]-4'-amine (Compound 36)

(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2'-methyl-7'H,9'H-spiro[cyclopropane-1,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'-amine(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2'-methyl-7'H,9'H-spiro[cyclopropane-1,8'-[1,4] dioxepino[2,3-g]quinazolin]-4'-amine

以实施例3相同方法合成化合物3A，向25mL反应管中加入化合物3A(50mg)，卡特缩合剂(1.5equiv)，1,8-二偶氮杂双螺环[5.4.0]十一-7-烯(2equiv)，DMF(2mL)，室温搅拌反应30分钟后，加入(R)-1-(3-(二氟甲基)-2-氟苯基)乙-1-胺(44mg，1.2equiv)，室温搅拌反应。反应结束后，减压蒸馏除去溶剂，制备HPLC分离分别得到化合物36(白色固体，45mg，产率54％)。Compound 3A was synthesized in the same manner as Example 3, and compound 3A (50 mg), Carter condensing agent (1.5 equiv), 1,8-disazobisspiro[5.4.0]undec-7 were added to a 25 mL reaction tube -ene (2equiv), DMF (2 mL), after stirring the reaction at room temperature for 30 minutes, add (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine (44 mg, 1.2 equiv), and the reaction was stirred at room temperature. After the reaction, the solvent was distilled off under reduced pressure, and compound 36 (white solid, 45 mg, yield 54%) was obtained by preparative HPLC separation.

¹H NMR(400MHz,DMSO-d6)δ8.23(d,1H),8.11(s,1H),7.67(t,1H),7.48(t,1H),7.37–7.23(m,2H),7.10(d,1H),5.79–5.76(m,1H),4.03–3.93(m,4H),2.30(s,3H),1.56(d,3H),0.67–0.66(m,4H)。 ¹ H NMR (400MHz, DMSO-d6) δ8.23(d,1H), 8.11(s,1H), 7.67(t,1H), 7.48(t,1H), 7.37–7.23(m,2H), 7.10 (d, 1H), 5.79–5.76 (m, 1H), 4.03–3.93 (m, 4H), 2.30 (s, 3H), 1.56 (d, 3H), 0.67–0.66 (m, 4H).

LC-MS m/z(ESI)＝430.17[M+1]。LC-MS m/z (ESI) = 430.17 [M+1].

实施例37Example 37

(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2'-甲基-7'H,9'H-螺[环丁烷-1,8'-[1,4]二恶英[2,3-g]喹唑啉]-4'-胺(化合物37)(R)-N-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-2'-methyl-7'H,9'H-spiro[cyclobutane-1 ,8'-[1,4]dioxin[2,3-g]quinazoline]-4'-amine (Compound 37)

(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2'-methyl-7'H,9'H-spiro[cyclobutane-1,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'-amine(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2'-methyl-7'H,9'H-spiro[cyclobutane-1,8'-[1,4] dioxepino[2,3-g]quinazolin]-4'-amine

以实施例36相同方法合成。Synthesized in the same manner as in Example 36.

¹H NMR(400MHz,DMSO-d6)δ8.23(d,1H),8.08(s,1H),7.68(s,1H),7.48(t,1H),7.26(dd,2H),7.08(d,1H),5.76(p,1H),4.17–4.08(m,4H),2.29(s,3H),1.91(dq,6H),1.56(d,3H)。 ¹ H NMR(400MHz,DMSO-d6)δ8.23(d,1H),8.08(s,1H),7.68(s,1H),7.48(t,1H),7.26(dd,2H),7.08(d , 1H), 5.76 (p, 1H), 4.17–4.08 (m, 4H), 2.29 (s, 3H), 1.91 (dq, 6H), 1.56 (d, 3H).

LC-MS m/z(ESI)＝444.18[M+1]。LC-MS m/z (ESI) = 444.18 [M+1].

实施例38Example 38

(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2'-甲基-7'H,9'H-螺[氧杂环丁烷-3,8'-[1,4]二恶英[2,3-g]喹唑啉]-4'-胺(化合物38)(R)-N-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-2'-methyl-7'H,9'H-spiro[oxetane -3,8'-[1,4]dioxin[2,3-g]quinazoline]-4'-amine (compound 38)

(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2'-methyl-7'H,9'H-spiro[oxetane-3,8'-[1 ,4]dioxepino[2,3-g]quinazolin]-4'-amine(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2'-methyl-7'H,9'H-spiro[oxetane-3,8'-[1 ,4] dioxepino[2,3-g]quinazolin]-4'-amine

¹H NMR(400MHz,DMSO-d6)δ8.30(d,1H),8.13(s,1H),7.66(t,1H),7.48(t,1H),7.36–7.23(dd,2H),7.10(d,1H),5.77(p,1H),4.51–4.41(m,8H),2.30(s,3H),1.57(d,3H)。 ¹ H NMR (400MHz, DMSO-d6) δ8.30(d,1H), 8.13(s,1H), 7.66(t,1H), 7.48(t,1H), 7.36–7.23(dd,2H), 7.10 (d, 1H), 5.77 (p, 1H), 4.51–4.41 (m, 8H), 2.30 (s, 3H), 1.57 (d, 3H).

LC-MS m/z(ESI)＝446.16[M+1]。LC-MS m/z (ESI) = 446.16 [M+1].

实施例39Example 39

(R)-2'-甲基-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7'H,9'H-螺[环丙烷-1,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'-胺(化合物39)(R)-2'-Methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7'H,9'H-spiro[cyclopropane-1 ,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'-amine (Compound 39)

(R)-2'-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7'H,9'H-spiro[cyclopropane-1,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'-amine(R)-2'-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7'H,9'H-spiro[cyclopropane-1,8'-[1,4 ]dioxepino[2,3-g]quinazolin]-4'-amine

¹H NMR(400MHz,DMSO-d6)δ8.58(d,1H),7.92(d,1H),7.58(d,1H),7.48-7.23(m,3H),5.86(t,1H),4.19–4.01(m,4H),2.59(s,3H),2.53(s,3H),1.63(d,3H),0.70-0.66(m,4H)。 ¹ H NMR (400MHz, DMSO-d6)δ8.58(d,1H), 7.92(d,1H), 7.58(d,1H), 7.48-7.23(m,3H), 5.86(t,1H), 4.19 -4.01(m, 4H), 2.59(s, 3H), 2.53(s, 3H), 1.63(d, 3H), 0.70-0.66(m, 4H).

LC-MS m/z(ESI)＝444.18[M+1]。LC-MS m/z (ESI) = 444.18 [M+1].

实施例40Example 40

(R)-2'-甲基-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7'H，9'H-螺[环丁烷-1,8'-[1,4]二氧西平[2,3-g]喹唑啉]-4'-胺(化合物40)(R)-2'-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7'H,9'H-spiro[cyclobutane- 1,8'-[1,4]Dioxazepine[2,3-g]quinazoline]-4'-amine (Compound 40)

(R)-2'-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7'H,9'H-spiro[cyclobutane-1,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'-amine(R)-2'-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7'H,9'H-spiro[cyclobutane-1,8'-[1,4 ]dioxepino[2,3-g]quinazolin]-4'-amine

¹H NMR(400MHz,DMSO-d6)δ8.30(d,1H),8.06(d,1H),7.77(d,1H),7.51(dd,1H),7.33(t,1H),7.06(s,1H),5.68(p,1H),4.17-4.09(m,4H),2.62(d,3H),2.28(s,3H),1.97-1.86(m,3H),1.51(d,3H)。 ¹ H NMR (400MHz, DMSO-d6)δ8.30(d,1H), 8.06(d,1H), 7.77(d,1H), 7.51(dd,1H), 7.33(t,1H), 7.06(s , 1H), 5.68(p, 1H), 4.17-4.09(m, 4H), 2.62(d, 3H), 2.28(s, 3H), 1.97-1.86(m, 3H), 1.51(d, 3H).

LC-MS m/z(ESI)＝458.20[M+1]。LC-MS m/z (ESI) = 458.20 [M+1].

实施例41Example 41

(R)-2'-甲基-N-(1-(2-甲基-3-(三氟甲基)苯基)乙基)-7'H，9'H-螺[氧杂环丁烷-3,8'-[1,4]二氧西平[2,3-g]喹唑啉]-4'-胺(化合物41)(R)-2'-Methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7'H,9'H-spiro[oxetine Alkyl-3,8'-[1,4]dioxazepine[2,3-g]quinazoline]-4'-amine (Compound 41)

(R)-2'-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7'H,9'H-spiro[oxetane-3,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'-amine(R)-2'-methyl-N-(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)-7'H,9'H-spiro[oxetane-3,8'-[1,4 ]dioxepino[2,3-g]quinazolin]-4'-amine

¹H NMR(400MHz,DMSO-d6)δ8.32(d,1H),8.10(S,1H),7.76(d,1H),7.51(d,1H),7.51(dd,1H),7.33(t,1H),7.09(s,1H),5.68(p,4H),4.97-4.40(m,8H),2.61(d,3H),2.28(s,3H),1.97-1.86(m,3H),1.52(d,3H)。 ¹ H NMR (400MHz, DMSO-d6)δ8.32(d,1H), 8.10(S,1H), 7.76(d,1H), 7.51(d,1H), 7.51(dd,1H), 7.33(t ,1H),7.09(s,1H),5.68(p,4H),4.97-4.40(m,8H),2.61(d,3H),2.28(s,3H),1.97-1.86(m,3H), 1.52(d, 3H).

LC-MS m/z(ESI)＝460.18[M+1]。LC-MS m/z (ESI) = 460.18 [M+1].

实施例42Example 42

(R)-2,2-二氟-2-(3-(1-((2'-甲基-7'H，9'H-螺[氧杂环丁烷-3,8'-[1,4]二氧西平[2,3-g]喹唑啉]-4'-基)氨基)乙基)苯基)乙烷-1-醇(化合物42)(R)-2,2-Difluoro-2-(3-(1-((2'-methyl-7'H,9'H-spiro[oxetane-3,8'-[1 ,4]Dioxazepine[2,3-g]quinazolin]-4'-yl)amino)ethyl)phenyl)ethane-1-ol (Compound 42)

(R)-2,2-difluoro-2-(3-(1-((2'-methyl-7'H,9'H-spiro[oxetane-3,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'-yl)amino)ethyl)phenyl)ethan-1-ol(R)-2,2-difluoro-2-(3-(1-((2'-methyl-7'H,9'H-spiro[oxetane-3,8'-[1,4]dioxepino[2 ,3-g]quinazolin]-4'-yl)amino)ethyl)phenyl)ethan-1-ol

¹H NMR(400MHz,DMSO-d6)δ8.16(d,1H),8.03(s,1H),7.63(d,1H),7.56(dt,1H),7.43-7.34(m,2H),7.02(s,1H),5.60(dt,2H),4.55–4.31(m,8H),3.68(td,2H),2.30(d,3H),1.52(dd,3H)。 ¹ H NMR (400MHz, DMSO-d6)δ8.16(d,1H), 8.03(s,1H), 7.63(d,1H), 7.56(dt,1H), 7.43-7.34(m,2H), 7.02 (s, 1H), 5.60 (dt, 2H), 4.55–4.31 (m, 8H), 3.68 (td, 2H), 2.30 (d, 3H), 1.52 (dd, 3H).

LC-MS m/z(ESI)＝458.19[M+1]。LC-MS m/z (ESI) = 458.19 [M+1].

实施例43Example 43

(R)-2,2-二氟-2-(3-(1-((2'-甲基-7'H，9'H-螺[环丁烷-1,8'-[1,4]二氧西平[2,3-g]喹唑啉]-4'-基)氨基)乙基)苯基)乙烷-1-醇(化合物43)(R)-2,2-Difluoro-2-(3-(1-((2'-methyl-7'H,9'H-spiro[cyclobutane-1,8'-[1,4 ]Dioxazepine[2,3-g]quinazolin]-4'-yl)amino)ethyl)phenyl)ethane-1-ol (Compound 43)

(R)-2,2-difluoro-2-(3-(1-((2'-methyl-7'H,9'H-spiro[cyclobutane-1,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'-yl)amino)ethyl)phenl)ethan-1-ol(R)-2,2-difluoro-2-(3-(1-((2'-methyl-7'H,9'H-spiro[cyclobutane-1,8'-[1,4]dioxepino[2 ,3-g]quinazolin]-4'-yl)amino)ethyl)phen)ethan-1-ol

¹H NMR(400MHz,DMSO-d6)δ8.16(d,1H),8.03(s,1H),7.63(d,1H),7.56(dt,1H),7.43-7.34(m,2H),7.07(s,1H),5.73(s,4H),5.62(dt,2H),3.83(td,2H),2.34(s,3H),1.97-1.85(m,6H),1.56(d,3H)。 ¹ H NMR (400MHz, DMSO-d6)δ8.16(d,1H), 8.03(s,1H), 7.63(d,1H), 7.56(dt,1H), 7.43-7.34(m,2H), 7.07 (s, 1H), 5.73 (s, 4H), 5.62 (dt, 2H), 3.83 (td, 2H), 2.34 (s, 3H), 1.97-1.85 (m, 6H), 1.56 (d, 3H).

LC-MS m/z(ESI)＝456.20[M+1]。LC-MS m/z (ESI) = 456.20 [M+1].

实施例44Example 44

(R)-2,2-二氟-2-(3-(1-((2'-甲基-7'H，9'H-螺环[环丙烷-1,8'-[1,4]二氧肾上腺素[2,3-g]喹唑啉]-4'-基)氨基)乙基)苯基)乙烷-1-醇(化合物44)(R)-2,2-Difluoro-2-(3-(1-((2'-methyl-7'H,9'H-spiro[cyclopropane-1,8'-[1,4 ]Dioxynephrine[2,3-g]quinazolin]-4'-yl)amino)ethyl)phenyl)ethan-1-ol (Compound 44)

(R)-2,2-difluoro-2-(3-(1-((2'-methyl-7'H,9'H-spiro[cyclopropane-1,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'-yl)amino)ethyl)phenyl)ethan-1-ol(R)-2,2-difluoro-2-(3-(1-((2'-methyl-7'H,9'H-spiro[cyclopropane-1,8'-[1,4]dioxepino[2 ,3-g]quinazolin]-4'-yl)amino)ethyl)phenyl)ethan-1-ol

¹H NMR(400MHz,DMSO-d ₆)δ8.19(d,1H),8.07(s,1H),7.64(d,1H),7.57(d,1H),7.42(t,1H),7.36(dt,1H),7.10(s,1H),5.63(dt,2H),4.08–3.90(m,4H),3.83(td,2H),2.35(s,3H),1.57(d,3H),0.66(d,4H)。 ¹ H NMR (400MHz, DMSO-d ₆ )δ8.19(d,1H), 8.07(s,1H), 7.64(d,1H), 7.57(d,1H), 7.42(t,1H), 7.36( dt,1H),7.10(s,1H),5.63(dt,2H),4.08–3.90(m,4H),3.83(td,2H),2.35(s,3H),1.57(d,3H),0.66 (d, 4H).

LC-MS m/z(ESI)＝443.19[M+1]。LC-MS m/z (ESI) = 443.19 [M+1].

实施例45Example 45

N-((1R)-1-(3-(2,2-二氟环丙基)-2-氟苯基)乙基)-2'-甲基-7'H，9'H-螺[氧杂环丁烷-3,8'-[1,4]二氧西平[2,3-g]喹唑啉]-4'-胺(化合物45)N-((1R)-1-(3-(2,2-Difluorocyclopropyl)-2-fluorophenyl)ethyl)-2'-methyl-7'H,9'H-spiro[ Oxetane-3,8'-[1,4]dioxazepine[2,3-g]quinazoline]-4'-amine (Compound 45)

N-((1R)-1-(3-(2,2-difluorocyclopropyl)-2-fluorophenyl)ethyl)-2'-methyl-7'H,9'H-spiro[oxetane-3,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'-amineN-((1R)-1-(3-(2,2-difluorocyclopropyl)-2-fluorophenyl)ethyl)-2'-methyl-7'H,9'H-spiro[oxetane-3,8'-[ 1,4]dioxepino[2,3-g]quinazolin]-4'-amine

¹H NMR(400MHz,DMSO-d6)δ8.19(d,1H),8.13(d,1H),7.41(td,1H),7.18–7.04(m,3H),5.88–5.57(m,1H),4.65–4.38(m,8H),3.03(ddd,1H),2.30(d,3H),2.11–1.86(m,2H),1.54(dd,3H)。 ¹ H NMR (400MHz, DMSO-d6)δ8.19(d,1H), 8.13(d,1H), 7.41(td,1H), 7.18–7.04(m,3H), 5.88–5.57(m,1H) , 4.65–4.38 (m, 8H), 3.03 (ddd, 1H), 2.30 (d, 3H), 2.11–1.86 (m, 2H), 1.54 (dd, 3H).

LC-MS m/z(ESI)＝472.18[M+1]。LC-MS m/z (ESI) = 472.18 [M+1].

实施例46Example 46

N-((1R)-1-(3-(2,2-二氟环丙基)-2-氟苯基)乙基)-2'-甲基-7'H，9'H-螺[环丁烷-1,8'-[1,4]二氧西平[2,3-g]喹唑啉]-4'-胺(化合物46)N-((1R)-1-(3-(2,2-Difluorocyclopropyl)-2-fluorophenyl)ethyl)-2'-methyl-7'H,9'H-spiro[ Cyclobutane-1,8'-[1,4]dioxazepine[2,3-g]quinazoline]-4'-amine (Compound 46)

N-((1R)-1-(3-(2,2-difluorocyclopropyl)-2-fluorophenyl)ethyl)-2'-methyl-7'H,9'H-spiro[cyclobutane-1,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'-amineN-((1R)-1-(3-(2,2-difluorocyclopropyl)-2-fluorophenyl)ethyl)-2'-methyl-7'H,9'H-spiro[cyclobutane-1,8'-[ 1,4]dioxepino[2,3-g]quinazolin]-4'-amine

¹H NMR(400MHz,DMSO-d6)δ8.16(d,1H),8.08(d,1H),7.40(ddd,1H),7.21–7.01(m,3H),6.00–5.57(m,1H),4.24–3.99(m,4H),3.03(ddd,1H),2.29(d,3H),2.09–1.81(m,8H),1.54(dd,3H)。 ¹ H NMR (400MHz, DMSO-d6)δ8.16(d,1H), 8.08(d,1H), 7.40(ddd,1H), 7.21–7.01(m,3H), 6.00–5.57(m,1H) , 4.24–3.99 (m, 4H), 3.03 (ddd, 1H), 2.29 (d, 3H), 2.09–1.81 (m, 8H), 1.54 (dd, 3H).

LC-MS m/z(ESI)＝470.20[M+1]。LC-MS m/z (ESI) = 470.20 [M+1].

实施例47Example 47

N-((1R)-1-(3-(2,2-二氟环丙基)-2-氟苯基)乙基)-2'-甲基-7'H，9'H-螺环[1,8'-[1,4]二氧西平[2,3-g]喹唑啉]-4'-胺(化合物47)N-((1R)-1-(3-(2,2-Difluorocyclopropyl)-2-fluorophenyl)ethyl)-2'-methyl-7'H,9'H-spiro [1,8'-[1,4]Dioxazepine[2,3-g]quinazoline]-4'-amine (Compound 47)

N-((1R)-1-(3-(2,2-difluorocyclopropyl)-2-fluorophenyl)ethyl)-2'-methyl-7'H,9'H-spiro[cyclopropane-1,8'-[1,4]dioxepino[2,3-g]quinazolin]-4'-amineN-((1R)-1-(3-(2,2-difluorocyclopropyl)-2-fluorophenyl)ethyl)-2'-methyl-7'H,9'H-spiro[cyclopropane-1,8'-[ 1,4]dioxepino[2,3-g]quinazolin]-4'-amine

¹H NMR(400MHz,DMSO-d6)δ8.20(d,1H),8.12(d,1H),7.42(ddt,1H),7.12(dt,3H),5.79(dt,1H),4.08–3.83(m,4H),3.02(td,1H),2.31(d,3H),2.11–1.86(m,2H),1.54(d,3H),0.66(d,4H)。 ¹ H NMR (400MHz, DMSO-d6)δ8.20(d,1H), 8.12(d,1H), 7.42(ddt,1H), 7.12(dt,3H), 5.79(dt,1H), 4.08–3.83 (m, 4H), 3.02 (td, 1H), 2.31 (d, 3H), 2.11–1.86 (m, 2H), 1.54 (d, 3H), 0.66 (d, 4H).

LC-MS m/z(ESI)＝456.18[M+1]。LC-MS m/z (ESI) = 456.18 [M+1].

生物学试验biological test

一、H358细胞的增殖实验1. Proliferation experiment of H358 cells

利用纳升移液***(Labcyte，Echo 550)将梯度稀释好的待测化合物加入384孔细胞培养板(Corning，CLS3830-50EA)中，设置复孔。阳性对照组加入等体积的培养基，阴性对照组加入等体积的DMSO，1000rpm室温离心1分钟。将NCI-H358细胞(ATCC，CRL-5807) 接种到含有化合物的384培养板中，阴性对照组加入等量等体积细胞，阳性对照组仅加入等体积的培养基。1000rpm室温离心1分钟，最终化合物的DMSO终浓度为0.5％，放置于37℃，5％CO ₂恒温培养箱孵育72小时。加入20μL/well的

3D(Promega，G9683)至384孔细胞培养板中，避光320rpm震荡20分钟，避光室温孵育2小时。 Using a nanoliter pipetting system (Labcyte, Echo 550), the serially diluted test compounds were added to a 384-well cell culture plate (Corning, CLS3830-50EA), and duplicate wells were set up. An equal volume of culture medium was added to the positive control group, and an equal volume of DMSO was added to the negative control group, and centrifuged at 1000 rpm for 1 minute at room temperature. NCI-H358 cells (ATCC, CRL-5807) were inoculated into 384 culture plates containing compounds, an equal volume of cells was added to the negative control group, and an equal volume of culture medium was added to the positive control group. Centrifuge at 1000 rpm for 1 min at room temperature, the final compound has a final concentration of 0.5% DMSO, and place it in a 37°C, 5% CO ₂ constant temperature incubator for 72 hours. Add 20 μL/well

3D (Promega, G9683) was placed in a 384-well cell culture plate, shaken at 320 rpm in the dark for 20 minutes, and incubated at room temperature in the dark for 2 hours.

用Envision多功能酶标(Perkin Elmer，Envision 2104)仪读取发光值。使用XLFIT软件用以下非线性拟合公式来得到化合物的IC ₅₀(半数抑制浓度)： The luminescence value was read with an Envision multifunctional enzyme labeler (Perkin Elmer, Envision 2104). The IC50 ( _50% inhibitory concentration) of the compound was obtained using the XLFIT software with the following nonlinear fit equation:

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

X:化合物浓度log值X: compound concentration log value

Y:抑制率(％)Y: Inhibition rate (%)

抑制率(％)＝100×(阴性对照平均值-化合物读值)/(阴性对照平均值-阳性对照平均值)Inhibition rate (%)=100×(mean value of negative control-compound reading)/(mean value of negative control-mean value of positive control)

对于本申请的化合物抑制NCI-H358细胞增殖能力，测得的IC ₅₀见表1(A表示测得的IC ₅₀≤0.5μM；B表示测得的IC ₅₀在0.5μM到1μM之间；C表示测得的IC ₅₀在1μM到10μM之间。 For the ability of the compounds of the present application to inhibit the proliferation of NCI-H358 cells, the measured IC ₅₀ is shown in Table 1 (A means the measured IC ₅₀ ≤ 0.5 μM; B means the measured IC ₅₀ is between 0.5 μM and 1 μM; C means _IC50s were measured between 1 μM and 10 μM.

表1 NCI-H358 3D细胞增殖实验结果Table 1 Results of NCI-H358 3D cell proliferation experiments

化合物编号Compound number	NCI-H358 IC ₅₀ NCI-H358 IC ₅₀	化合物编号Compound number	NCI-H358 IC ₅₀ NCI-H358 IC ₅₀
化合物2Compound 2	AA	化合物17-1Compound 17-1	CC
化合物3Compound 3	AA	化合物19Compound 19	CC
化合物4Compound 4	AA	化合物20Compound 20	CC
化合物5Compound 5	AA	化合物21Compound 21	CC
化合物5Compound 5	AA	化合物22Compound 22	AA
化合物6Compound 6	AA	化合物24Compound 24	CC
化合物7Compound 7	AA	化合物25Compound 25	AA
化合物8Compound 8	AA	化合物27Compound 27	BB
化合物9Compound 9	AA	化合物28Compound 28	AA
化合物10Compound 10	AA	化合物29Compound 29	AA
化合物11Compound 11	BB	化合物30Compound 30	BB
化合物12-1Compound 12-1	CC	化合物31Compound 31	AA
化合物12-2Compound 12-2	CC	化合物32Compound 32	BB
化合物12-3Compound 12-3	BB	化合物33Compound 33	AA
化合物12-4Compound 12-4	BB	化合物34Compound 34	AA
化合物13-Compound 13-	BB	化合物35Compound 35	AA
化合物14Compound 14	AA
化合物15Compound 15	CC
化合物16Compound 16	CC

结果表明，本申请的化合物能够很好的抑制NCI-H358细胞的增殖。The results show that the compounds of the present application can well inhibit the proliferation of NCI-H358 cells.

二、测试抑制KRAS-G12C蛋白与SOS1蛋白间的相互作用实验2. Test to inhibit the interaction between KRAS-G12C protein and SOS1 protein

1)1X缓冲液配制(现配现用)：Hepes:5mM；NaCl:150mM；EDTA:10mM；Igepal:0.0025％；KF:100mM；DTT:1mM；BSA:0.05％。1) 1X buffer preparation (prepared and used now): Hepes: 5 mM; NaCl: 150 mM; EDTA: 10 mM; Igepal: 0.0025%; KF: 100 mM; DTT: 1 mM; BSA: 0.05%.

2)用1X缓冲液将化合物稀释成2％的工作液，5uL/孔加到对应孔中，1000转，离心1分钟。2) Dilute the compound into 2% working solution with 1X buffer, add 5uL/well to the corresponding well, 1000 rpm, and centrifuge for 1 minute.

3)His-SOS1 cat 4X工作液配制：用1X缓冲液将SOS1(5uM)稀释成终浓度为24nM的工作液，取2.5uL/孔加到对应孔中，Blank孔不含SOS1蛋白，室温孵育30min。3) Preparation of His-SOS1 cat 4X working solution: Dilute SOS1 (5uM) with 1X buffer to a working solution with a final concentration of 24nM, add 2.5uL/well to the corresponding well, Blank well does not contain SOS1 protein, incubate at room temperature 30min.

4)KRAS(G12C)+MAb Anti GST-Eu cryptate+MAb Anti 6HIS-XL665 4X工作液配制：将KRAS(G12C),MAb Anti GST-Eu cryptate和MAb Anti 6HIS-XL665(400ng/uL)用1X缓冲液进行稀释，其中KRAS(G12C)蛋白终浓度为80nM,MAb Anti GST-Eu cryptate的终浓度为1ng/uL，MAb Anti 6HIS-XL665(400ng/uL)的终浓度为8ng/uL.4) KRAS(G12C)+MAb Anti GST-Eu cryptate+MAb Anti 6HIS-XL665 4X working solution preparation: KRAS(G12C), MAb Anti GST-Eu cryptate and MAb Anti 6HIS-XL665 (400ng/uL) were prepared with 1X buffer The final concentration of KRAS(G12C) protein was 80nM, the final concentration of MAb Anti GST-Eu cryptate was 1ng/uL, and the final concentration of MAb Anti 6HIS-XL665 (400ng/uL) was 8ng/uL.

5)孵育结束后，取2.5uL/孔上述混合液加到对应孔中，1000转，离心1分钟，此时体系中各成分终浓度如下：5) After the incubation, add 2.5uL/well of the above mixture to the corresponding well, centrifuge at 1000 rpm for 1 minute, and the final concentrations of the components in the system are as follows:

DMSODMSO	0.010.01
His-SOS1 catHis-SOS1 cat	6nM6nM
KRAS(G12C)KRAS(G12C)	20nM20nM
MAb Anti 6HIS-XL665MAb Anti 6HIS-XL665	2ng/uL2ng/uL
MAb Anti GST-Eu cryptateMAb Anti GST-Eu cryptate	0.25ng/uL0.25ng/uL

6)封膜后置于25℃孵育1小时。6) Incubate at 25°C for 1 hour after sealing.

7)读数：激发(excitation)为320nm，发光(emission)为615nm，665nm。7) Reading: excitation at 320 nm, emission at 615 nm, 665 nm.

8)用Graphpad Prism计算得到化合物的IC ₅₀。 8) Calculate the _IC50 of the compound using Graphpad Prism.

本发明化合物抑制KRAS-G12C蛋白与SOS1蛋白间的相互作用能力，测得的IC ₅₀见表2(A表示测得的IC ₅₀≤0.2μM；B表示测得的IC ₅₀在0.2μM到0.5μM之间；C表示测得的IC ₅₀在0.5μM到1μM之间。 The ability of the compounds of the present invention to inhibit the interaction between KRAS-G12C protein and SOS1 protein, the measured IC ₅₀ is shown in Table 2 (A means the measured IC ₅₀ ≤ 0.2 μM; B means the measured IC ₅₀ is between 0.2 μM and 0.5 μM between; C indicates the measured _IC50 between 0.5 μM and 1 μM.

表2 抑制KRAS-G12C蛋白与SOS1蛋白间的相互作用能力的IC ₅₀ Table 2 _IC50 of the ability to inhibit the interaction between KRAS-G12C protein and SOS1 protein

化合物编号Compound number	SOS1:KRAS-G12C IC ₅₀ SOS1: KRAS-G12C IC ₅₀	化合物编号Compound number	SOS1:KRAS-G12C IC ₅₀ SOS1: KRAS-G12C IC ₅₀
化合物3Compound 3	AA	化合物42Compound 42	AA
化合物5Compound 5	AA	化合物43Compound 43	AA
化合物6Compound 6	AA	化合物44Compound 44	AA
化合物36Compound 36	BB	化合物45Compound 45	CC
化合物37Compound 37	CC
化合物38Compound 38	AA
化合物41Compound 41	CC

结果表明，本申请的化合物抑制KRAS-G12C蛋白与SOS1蛋白间的相互作用能力的IC ₅₀＜1μM。 The results show that the compound of the present application has an IC ₅₀ <1 μM for the ability to inhibit the interaction between KRAS-G12C protein and SOS1 protein.

本发明说明书对具体实施方案进行了详细描述，本领域技术人员应认识到，上述实施方案是示例性的，不能理解为对本发明的限制，对于本领域技术人员来说，在不脱离本发明原理的前提下，通过对本发明进行若干改进和修饰，这些改进和修饰获得技术方案也落在本发明的权利要求书的保护范围内。The specification of the present invention describes the specific embodiments in detail. Those skilled in the art should realize that the above-mentioned embodiments are exemplary and should not be construed as limiting the present invention. For those skilled in the art, without departing from the principles of the present invention Under the premise, by carrying out several improvements and modifications to the present invention, the technical solutions obtained by these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

通式(I)的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐：A compound of general formula (I) or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a solvent thereof Compounds, metabolites, co-crystals, prodrugs or pharmaceutically acceptable salts:

X为-(OCR ²R ³CR ⁴R ⁵) _x-，其中O端与Z相连，C端与O相连；x为0、1或2； X is -(OCR ² R ³ CR ⁴ R ⁵ ) _x -, wherein the O end is connected to Z, and the C end is connected to O; x is 0, 1 or 2;

Y为-(OCR ⁶R ⁷CR ⁸R ⁹) _y-，其中O端与Z相连，C端与O相连；y为0、1或2； Y is -(OCR ⁶ R ⁷ CR ⁸ R ⁹ ) _y -, wherein the O end is connected to Z, and the C end is connected to O; y is 0, 1 or 2;

Z为-(CR ¹⁰R ¹¹) _z-；z为0、1、2、3、4或5； Z is -(CR ¹⁰ R ¹¹ ) _z -; z is 0, 1, 2, 3, 4 or 5;

所述R ²、R ³、R ⁴、R ⁵、R ⁶、R ⁷、R ⁸、R ⁹、R ¹⁰、R ¹¹各自独立为H、C _1-6烷基、C _1-6卤代烷基、C _1-6烷氧基、C _1-6环烷基或C _1-6杂环烷基； The R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ are each independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 cycloalkyl or C _1-6 heterocycloalkyl;

任选地，各个R ²与R ³、各个R ⁴与R ⁵、各个R ⁶与R ⁷、各个R ⁸与R ⁹、各个R ¹⁰与R ¹¹的任意一组与其相连的碳原子形成C _1-6环烷基或C _1-6杂环烷基，所述C _1-6杂环烷基含有1或2个氧原子； Optionally, any set of carbon atoms to which each R ² and R ³ , each R ⁴ and R ⁵ , each R ⁶ and R ⁷ , each R ⁸ and R ⁹ , each R ¹⁰ and R ¹¹ is attached to form C _{1 -6} cycloalkyl or C _1-6 heterocycloalkyl, said C _1-6 heterocycloalkyl containing 1 or 2 oxygen atoms;

各个R ¹相同或不同，各自独立地为卤素、氨基、C _1-6烷基、C _1-6环烷基，其中所述的C _1-6烷基和C _1-6环烷基任选地被选自羟基和卤素中的一个或多个取代基所取代； Each R ¹ is the same or different, and each independently is halogen, amino, C _1-6 alkyl, C _1-6 cycloalkyl, wherein said C _1-6 alkyl and C _1-6 cycloalkyl are optional is substituted with one or more substituents selected from hydroxy and halogen;

n为1、2或3。n is 1, 2 or 3.
如权利要求1所述的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，其中The compound of claim 1 or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a mixture thereof Solvates, metabolites, co-crystals, prodrugs or pharmaceutically acceptable salts, wherein

x为0、1或2；x is 0, 1 or 2;

y为0、1或2；和y is 0, 1, or 2; and

z为2、3、4或5。z is 2, 3, 4 or 5.
如权利要求1所述的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，其中The compound of claim 1 or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a mixture thereof Solvates, metabolites, co-crystals, prodrugs or pharmaceutically acceptable salts, wherein

x为0、y为0、z为2，x is 0, y is 0, z is 2,

x为0、y为0、z为3，x is 0, y is 0, z is 3,

x为0、y为0、z为4，x is 0, y is 0, z is 4,

x为0、y为0、z为5，x is 0, y is 0, z is 5,

x为1、y为1、z为2，x is 1, y is 1, z is 2,

x为0、y为1、z为2，x is 0, y is 1, z is 2,

x为1、y为0、z为2，x is 1, y is 0, z is 2,

x为1、y为2、z为2，或x is 1, y is 2, z is 2, or

x为2、y为1、z为2。x is 2, y is 1, and z is 2.
如权利要求1所述的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，其中所述R ²、R ³、R ⁴、R ⁵、R ⁶、R ⁷、R ⁸、R ⁹、R ¹⁰、R ¹¹各自独立为H或C _1-6烷基。 The compound of claim 1 or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a mixture thereof Solvate, metabolite, co-crystal, prodrug or pharmaceutically acceptable salt, wherein said R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ is each independently H or C _1-6 alkyl.
化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐：Compounds or their stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or solvates, metabolites, co- Crystals, prodrugs or pharmaceutically acceptable salts:
化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐：Compounds or their stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or solvates, metabolites, co- Crystals, prodrugs or pharmaceutically acceptable salts:
药物组合物，其包含：A pharmaceutical composition comprising:

(1)权利要求1-6中任一项所述的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐；(1) The compound according to any one of claims 1 to 6, or a stereoisomer, tautomer, meso, racemate, enantiomer, or diastereomer thereof body, or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug or pharmaceutically acceptable salt thereof;

(2)任选的一种或者多种其他活性成分；以及(2) optionally one or more other active ingredients; and

(3)药学上可接受的载体和/或赋形剂。(3) A pharmaceutically acceptable carrier and/or excipient.
权利要求1-6中任一项所述的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，或者权利要求7所述的组合物在制备用于治疗或预防癌症或肿瘤的药物中的用途；优选地，所述癌症为胚胎横纹肌肉瘤、睾丸支持细胞肿瘤、皮肤颗粒细胞瘤、肺腺癌、膀胱癌或***癌。The compound of any one of claims 1-6, or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or A mixture thereof, or a solvate, metabolite, co-crystal, prodrug or pharmaceutically acceptable salt thereof, or the use of the composition of claim 7 in the preparation of a medicament for the treatment or prevention of cancer or tumor; preferably Typically, the cancer is embryonal rhabdomyosarcoma, Sertoli cell tumor, granulosa cell tumor of the skin, lung adenocarcinoma, bladder cancer or prostate cancer.
权利要求1-6中任一项所述的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，或者权利要求7所述的组合物在制备SOS1抑制剂中的用途。The compound of any one of claims 1-6, or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or A mixture thereof, or a solvate, metabolite, co-crystal, prodrug or pharmaceutically acceptable salt thereof, or the use of the composition of claim 7 in the preparation of an SOS1 inhibitor.
权利要求1-6中任一项所述的化合物或者其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物，或者其溶剂化物、代谢产物、共晶、前药或药学上可接受的盐，或者权利要求7所述的组合物在制备用于治疗或预防与SOS1相关的疾病中的用途。The compound of any one of claims 1-6, or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer, or A mixture thereof, or a solvate, metabolite, co-crystal, prodrug or pharmaceutically acceptable salt thereof, or use of the composition of claim 7 for the preparation of a disease for the treatment or prophylaxis of SOS1.