TW202214608A

TW202214608A - Fused pyridazine derivatives, preparation method and medical use thereof

Info

Publication number: TW202214608A
Application number: TW110126621A
Authority: TW
Inventors: 李心; 陳陽; 王斌; 賀峰; 陶維康
Original assignee: 大陸商江蘇恆瑞醫藥股份有限公司; 大陸商上海恆瑞醫藥有限公司
Priority date: 2020-07-20
Filing date: 2021-07-20
Publication date: 2022-04-16
Also published as: WO2022017339A1

Abstract

The present disclosure relates to fused pyridazine derivatives, preparation method and medical use thereof. Specifically, the present disclosure relates to a fused pyridazine derivative represented by the general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially as a SOS1 inhibitor, as well as its use in the preparation of medicaments for the treatment of conditions or disorders ameliorated by the inhibition of SOS1.

Description

稠合噠嗪類衍生物、其製備方法及其在醫藥上的應用 Condensed pyridazine derivative, its preparation method and its application in medicine

本公開屬於醫藥領域，涉及一種通式(I)所示的稠合噠嗪類衍生物、其製備方法、含有該衍生物的醫藥組成物以及其作為治療劑的用途，特別是作為SOS1抑制劑的用途和在製備用於治療藉由對SOS1的抑制而改善的病況或病症的藥物中的用途。 The present disclosure belongs to the field of medicine, and relates to a fused pyridazine derivative represented by general formula (I), its preparation method, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially as a SOS1 inhibitor and in the manufacture of a medicament for the treatment of a condition or disorder ameliorated by inhibition of SOS1.

RAS是在腫瘤中突變率最高的致癌基因之一，約30%的人類惡性腫瘤與RAS基因的突變有關。RAS家族包括KRAS、NRAS和HRAS，其中KRAS突變最為常見，約占85%。KRAS被激活以後，藉由以RAF-MEK-ERK、PI3K-AKT-mTOR及TIAM1-RAc為代表的眾多下游信號通路，調控細胞增殖、存活、遷移及代謝等多個方面的功能。KRAS基因突變後，蛋白持續處於活化狀態，導致下游信號通路持續激活而促進腫瘤發生。 RAS is one of the oncogenes with the highest mutation rate in tumors, and about 30% of human malignancies are associated with mutations in the RAS gene. The RAS family includes KRAS, NRAS and HRAS, of which KRAS mutations are the most common, accounting for about 85%. After KRAS is activated, it regulates the functions of cell proliferation, survival, migration and metabolism through numerous downstream signaling pathways represented by RAF-MEK-ERK, PI3K-AKT-mTOR and TIAM1-RAc. After KRAS gene mutation, the protein is continuously activated, which leads to the continuous activation of downstream signaling pathways and promotes tumorigenesis.

由於KRAS蛋白表面缺乏傳統意義上的小分子結合位點，並與鳥苷酸有著超高親和力而極難被抑制，長久以來被認為是不可成藥的藥物靶點。但基於KRAS異常激活在癌症進展中的重要性和普遍性，KRAS一直並仍然是藥物開發非常關注的靶點。目前針對抑制KRAS通路的藥物開發思路主要有以下幾個方面： Due to the lack of traditional small molecule binding sites on the surface of KRAS protein, and its high affinity for guanylate, which is extremely difficult to inhibit, it has long been considered as an undruggable drug. object target. However, based on the importance and prevalence of aberrant KRAS activation in cancer progression, KRAS has been and remains a target of great interest in drug development. The current drug development ideas for inhibiting the KRAS pathway mainly include the following aspects:

1)針對KRAS G12C開發的小分子共價抑制劑，可以將G12C突變體不可逆地鎖定在失活狀態，目前安進和mirati公司的臨床I期數據都顯示了不俗的效果。但KRAS G12C的突變只是其諸多突變的一種，其他重要突變體諸如G12V、G12D、G12S、G12A、G13V/D等依然缺乏有效藥物。 1) The small-molecule covalent inhibitor developed for KRAS G12C can irreversibly lock the G12C mutant in an inactive state. Currently, the clinical phase I data of Amgen and mirati have shown good results. However, the mutation of KRAS G12C is only one of its many mutations, and other important mutants such as G12V, G12D, G12S, G12A, G13V/D still lack effective drugs.

2)在KRAS上尋找其他可以靶向更多突變體的位點：主要針對結合下游效應分子的位點/與蛋白分子激活相關的位點，目前都處於臨床前階段，對活性抑制的IC₅₀普遍在微莫耳級別。 2) Look for other sites on KRAS that can target more mutants: mainly targeting sites that bind downstream effector molecules/sites related to protein molecule activation, which are currently in the preclinical stage, IC ₅₀ for activity inhibition Usually at the micromolar level.

3)針對KRAS下游信號蛋白的抑制：例如針對RAF、MEK、ERK等抑制劑的開發，目前臨床上單用多效果不佳。 3) Inhibition of KRAS downstream signaling proteins: For example, the development of inhibitors such as RAF, MEK, ERK, etc., is currently clinically ineffective.

4)針對KRAS上游通路的抑制：如SHP2的抑制劑等。 4) Inhibition of the upstream pathway of KRAS: such as inhibitors of SHP2, etc.

5)針對KRAS的修飾及定位：如法尼基轉移酶等阻斷KRAS的膜定位從而達到抑制其作用的效果。 5) Modification and localization of KRAS: such as farnesyl transferase, block the membrane localization of KRAS to achieve the effect of inhibiting its effect.

6)藉由RNAi的方法敲低KRAS的表達。 6) KRAS expression was knocked down by RNAi.

總體而言，除了KRAS G12C抑制劑以外，目前仍缺乏對多種突變有效的廣譜KRAS抑制劑。而阻斷KRAS的激活分子與KRAS的結合，比如選擇性抑制SOS1-即鳥嘌呤核苷酸交換因子(GEF)的小分子抑制劑，能藉由干擾RAS-SOS1相互作用而阻斷KRAS的激活，能達到廣譜抑制KRAS活性的目的。 Overall, with the exception of KRAS G12C inhibitors, there is still a lack of broad-spectrum KRAS inhibitors that are effective against multiple mutations. Blocking KRAS activating molecules from binding to KRAS, such as selective inhibition of SOS1, a small molecule inhibitor of guanine nucleotide exchange factor (GEF), can block KRAS activation by interfering with the RAS-SOS1 interaction , can achieve the purpose of broad-spectrum inhibition of KRAS activity.

KARS蛋白是一種小GTP酶(small GTPase)，在細胞內，KRAS蛋白在失活狀態(與鳥苷二磷酸(GDP)結合)和激活狀態(與鳥苷三磷酸(GTP)結合)之間轉換。這種轉變受到鳥嘌呤核苷酸交換因子(GEF)和GTP酶激活蛋白(GAP)的調控。KRAS的GEF主要有三類，分別是SOS(sevenless son)1&2、Ras-GRF和Ras-GRP，其中後兩類只在神經元及白細胞中表達，只有SOS在多種組織中廣泛表達，被認為在RAS的激活中起到主導作用。由於SOS1的表達量較SOS2更高，且較SOS2的活性更強，目前針對SOS的研究主要集中在SOS1。SOS1對於KRAS蛋白的具體激活途徑如下：上游信號(如生長因子)激活膜表面受體後，藉由SHP2-Grb2激活SOS1，SOS1與KRAS結合，藉由引起一系列構象變化，催化KRAS與GDP的解離，進而與GTP結合，形成具有活性的KRAS-GTP。 KARS protein is a small GTPase (small GTPase), in cells, KRAS protein is in an inactive state (binding to guanosine diphosphate (GDP)) and an activated state (binding to guanosine diphosphate (GDP)) glycoside triphosphate (GTP) binding). This transition is regulated by guanine nucleotide exchange factor (GEF) and GTPases activating protein (GAP). There are three main types of GEFs in KRAS, namely SOS (sevenless son) 1&2, Ras-GRF and Ras-GRP. The latter two types are only expressed in neurons and leukocytes. Only SOS is widely expressed in various tissues and is considered to be in RAS. play a leading role in the activation. Since the expression level of SOS1 is higher than that of SOS2, and its activity is stronger than that of SOS2, the current research on SOS mainly focuses on SOS1. The specific activation pathway of SOS1 for KRAS protein is as follows: After upstream signals (such as growth factors) activate membrane surface receptors, SOS1 is activated by SHP2-Grb2, SOS1 binds to KRAS, and catalyzes the interaction between KRAS and GDP by causing a series of conformational changes. It dissociates and then combines with GTP to form active KRAS-GTP.

已經公開的作為SOS1抑制劑的化合物的專利申請包括WO2018115380A1、WO2019122129A1、WO2018172250A1和WO2016077793A1等。 Patent applications that have disclosed compounds as SOS1 inhibitors include WO2018115380A1, WO2019122129A1, WO2018172250A1, and WO2016077793A1, among others.

本公開的目的在於提供一種通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽： The purpose of the present disclosure is to provide a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof , or a pharmaceutically acceptable salt thereof:

其中， in,

環A為芳基或雜芳基； Ring A is aryl or heteroaryl;

G為CR⁵或N原子； G is CR ⁵ or N atom;

R⁰選自鹵素、烷基、烷氧基、鹵烷基、鹵烷氧基、羥烷基、烯基、炔基、羥基、胺基、-(CH₂)_pNR⁶R⁷、環烷基氧基、雜環基氧基、環烷基、雜環基、芳基和雜芳基，其中該烷基、環烷基氧基、雜環基氧基、環烷基、雜環基、芳基和雜芳基各自獨立地任選地被選自鹵素、烷基、鹵烷基、羥基、羥烷基、烷氧基、鹵烷氧基、側氧、=NH、胺基、硝基、氰基、-S(O)₂R⁹、-C(O)R¹⁰、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基取代； R ⁰ is selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, hydroxy, amino, -(CH ₂ ) _p NR ⁶ R ⁷ , cycloalkane oxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, Aryl and heteroaryl are each independently optionally selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, pendant oxygen, =NH, amine, nitro , cyano, -S(O) ₂ R ⁹ , -C(O)R ¹⁰ , cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted with one or more substituents;

R¹選自氫原子、鹵素、烷基、鹵烷基、烷氧基、鹵烷氧基、羥烷基、氰基和環烷基； R ¹ is selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano and cycloalkyl;

R²選自鹵素、烷基、鹵烷基、羥烷基、羥基、氰基、環烷基和雜環基，其中該烷基、環烷基和雜環基各自獨立地任選地被選自鹵素、烷基、鹵烷基、羥基、羥烷基、烷氧基、鹵烷氧基、胺基、硝基和氰基中的一個或多個取代基取代； R ^is selected from halogen, alkyl, haloalkyl, hydroxyalkyl, hydroxy, cyano, cycloalkyl and heterocyclyl, wherein each of the alkyl, cycloalkyl and heterocyclyl is independently optionally selected Substituted from one or more substituents of halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amine, nitro and cyano;

R³選自氫原子、烷基、鹵烷基、羥烷基、環烷基、雜環基、芳基和雜芳基，其中該烷基、鹵烷基、羥烷基、環烷基、雜環基、芳基和雜芳基各自獨立地任選地被選自鹵素、烷基、烯基、炔基、烷氧基、鹵烷基、鹵烷氧基、氰基、胺基、硝基、羥基、羥烷基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； ^R is selected from hydrogen atom, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, Heterocyclyl, aryl, and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro substituted with one or more substituents of radicals, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R⁴選自氫原子、鹵素、烷基、鹵烷基、烷氧基、鹵烷氧基、羥基、羥烷基和-(CH₂)_pNR⁶R⁷； R ⁴ is selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl and -(CH ₂ ) _p NR ⁶ R ⁷ ;

R和R⁵相同或不同，各自獨立地選自氫原子、鹵素、烷基、烷氧基、鹵烷基、鹵烷氧基、烯基、炔基、環烷基、雜環基、芳基、雜芳基、環烷基氧基、雜環基氧基、芳基氧基、雜芳基氧基、-(CH₂)_pNR⁶R⁷、氰基和硝基，其中該烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基各自獨立地任選地被選自烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、氰基、硝基和-(CH₂)_qNR¹¹R¹²中的一個或多個取代基所取代； R and R ⁵ are the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl , heteroaryl, cycloalkyloxy, heterocyclyloxy, aryloxy, heteroaryloxy, -(CH ₂ ) _p NR ⁶ R ⁷ , cyano and nitro, wherein the alkyl, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, cyano, substituted with one or more substituents in nitro and -(CH ₂ ) _q NR ¹¹ R ¹² ;

R⁸相同或不同，各自獨立地選自鹵素、烷基、烯基、炔基、鹵烷基、烷氧基、鹵烷氧基、氰基、胺基、-(CH₂)_pNR⁶R⁷、硝基、羥基、羥烷基、-S(O)₂烷基、環烷基、雜環基、芳基和雜芳基，其中該烷基、鹵烷基、羥烷基、環烷基、雜環基、芳基和雜芳基各自獨立地任選地被選自羥基、鹵素、鹵烷基、烷氧基、鹵烷氧基、氰基、硝基、羥烷基、-(CH₂)_qNR¹¹R¹²、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基取代； R ⁸ are the same or different, each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, -(CH ₂ ) _p NR ⁶ R ⁷ , nitro, hydroxyl, hydroxyalkyl, -S(O) ₂ alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, cycloalkane group, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from hydroxy, halo, haloalkyl, alkoxy, haloalkoxy, cyano, nitro, hydroxyalkyl, -( CH ₂ ) _q NR ¹¹ R ¹² , substituted with one or more substituents in cycloalkyl, heterocyclyl, aryl and heteroaryl;

R⁹和R¹⁰相同或不同，各自獨立地選自氫原子、烷基、鹵烷基、羥烷基、-(CH₂)_qNR¹¹R¹²、環烷基和雜環基，其中該烷基、環烷基和雜環基各自獨立地任選地被選自羥基、鹵素、烷基、鹵烷基、羥烷基、烷氧基、鹵烷氧基、氰基、胺基和硝基中的一個或多個取代基取代； R ⁹ and R ¹⁰ are the same or different, each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, -(CH ₂ ) _q NR ¹¹ R ¹² , a cycloalkyl group and a heterocyclyl group, wherein the alkane , cycloalkyl, and heterocyclyl are each independently optionally selected from hydroxy, halo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cyano, amine, and nitro one or more of the substituents in the substituted;

R⁶、R⁷、R¹¹和R¹²相同或不同，各自獨立地選自氫原子、烷基、鹵烷基、羥烷基、環烷基、雜環基、芳基和雜芳基； R ⁶ , R ⁷ , R ¹¹ and R ¹² are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

p和q相同或不同，各自獨立地選自0、1和2； p and q are the same or different, each independently selected from 0, 1 and 2;

n選自0、1、2、3、4和5。 n is selected from 0, 1, 2, 3, 4 and 5.

其中， in,

環A為芳基或雜芳基； Ring A is aryl or heteroaryl;

G為CR⁵或N原子； G is CR ⁵ or N atom;

R⁰選自鹵素、烷基、烷氧基、鹵烷基、鹵烷氧基、羥烷基、烯基、炔基、羥基、胺基、-(CH₂)_pNR⁶R⁷、環烷基氧基、雜環基氧基、環烷基、雜環基、芳基和雜芳基，其中該烷基、環烷基氧基、雜環基氧基、環烷基、雜環基、芳基和雜芳基各自獨立地任選地被選自鹵素、烷基、鹵烷基、羥基、羥烷基、烷氧基、鹵烷氧基、胺基、硝基、氰基、-S(O)₂R⁹、-C(O)R¹⁰、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基取代； R ⁰ is selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, hydroxy, amino, -(CH ₂ ) _p NR ⁶ R ⁷ , cycloalkane oxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, Aryl and heteroaryl are each independently optionally selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amine, nitro, cyano, -S (O) ₂ R ⁹ , -C(O)R ¹⁰ , one or more substituents in cycloalkyl, heterocyclyl, aryl and heteroaryl;

R⁹和R¹⁰相同或不同，各自獨立地選自氫原子、烷基、鹵烷基、羥烷基、-(CH₂)_qNR¹¹R¹²、環烷基和雜環基； R ⁹ and R ¹⁰ are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, -(CH ₂ ) _q NR ¹¹ R ¹² , a cycloalkyl group and a heterocyclic group;

n選自0、1、2、3、4和5。 n is selected from 0, 1, 2, 3, 4 and 5.

在本公開的一些較佳的實施方案中，一種通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中G為CR⁵，R⁵如通式(I)中所定義；較佳地，G為CH。 In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein G is CR ⁵ , and R ⁵ is as defined in general formula (I); preferably, G is CH.

在本公開的一些較佳的實施方案中，一種通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其為通式(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽： In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is the compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, non- Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

其中，環A、R、R⁰、R¹、R³、R⁴、R⁵、R⁸和n如通式(I)中所定義。 wherein Rings A, R, R ⁰ , R ¹ , R ³ , R ⁴ , R ⁵ , R ⁸ and n are as defined in general formula (I).

在本公開的一些較佳的實施方案中，一種通式(I)或(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R⁰選自烷氧基、羥烷基、環烷基氧基、雜環基氧基、環烷基、雜環基、芳基和雜芳基，其中該環烷基氧基、雜環基氧基、環烷基、雜環基、芳基和雜芳基各自獨立地任選地被選自鹵素、烷基、鹵烷基、羥基、羥烷基、烷氧基、鹵烷氧基、胺基、硝基、氰基、-S(O)₂R⁹和-C(O)R¹⁰中的一個或多個取代基取代；其中，R⁹和R¹⁰相同或不同，各自獨立地選自氫原子、烷基、鹵烷基、胺基和羥烷基； In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, non- An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁰ is selected from alkoxy, hydroxyalkyl, cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocycle aryl, aryl, and heteroaryl, wherein the cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from halogen, alkyl , one or more of haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amine, nitro, cyano, -S(O) ₂ R ⁹ and -C(O)R ¹⁰ wherein, R ⁹ and R ¹⁰ are the same or different, and each is independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, an amino group and a hydroxyalkyl group;

較佳地，R⁰選自環烷基氧基、雜環基氧基、環烷基、雜環基、芳基和雜芳基，其中該環烷基氧基、雜環基氧基、環烷基、雜環基、芳基和雜芳基各自獨立地任選地被選自羥基和-C(O)R¹⁰中的一個或多個取代基取代；R¹⁰為烷基； Preferably, R ⁰ is selected from cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the cycloalkyloxy, heterocyclyloxy, ring Alkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from hydroxy and -C(O)R ¹⁰ ; R ¹⁰ is alkyl;

進一步較佳地，R⁰選自C_1-6烷氧基、五員雜環基氧基和六員雜環基，該五員雜環基氧基和六員雜環基各自獨立地任選地被-C(O)R¹⁰和/或羥基取代，其中R¹⁰為C_1-6烷基； Further preferably, R ⁰ is selected from C _1-6 alkoxy, five-membered heterocyclyloxy and six-membered heterocyclyl, the five-membered heterocyclyloxy and six-membered heterocyclyl are each independently optional is substituted by -C(O)R ¹⁰ and/or hydroxy, wherein R ¹⁰ is C _1-6 alkyl;

更佳地，R⁰選自四氫呋喃基氧基和哌啶基，該四氫呋喃基氧基和哌啶基各自獨立地任選地被-C(O)R¹⁰和/或羥基取代，其中R¹⁰為C_1-6烷基。 More preferably, R ⁰ is selected from tetrahydrofuranyloxy and piperidinyl, each of which is independently optionally substituted by -C(O)R ¹⁰ and/or hydroxy, wherein R ¹⁰ is C _1-6 alkyl.

在本公開的一些較佳的實施方案中，一種通式(I)或(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R⁰為

或

；環B選自環烷基、雜環基、芳基和雜芳基； In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, non- An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁰ is

or

; Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

較佳地，R⁰選自

、

、

和

；W選自氧原子、硫原子、

、

、NR^13a和CR^13bR^13c； Preferably, R ⁰ is selected from

,

and

; W is selected from oxygen atom, sulfur atom,

,

, NR ^13a and CR ^13b R ^13c ;

R¹³相同或不同，各自獨立地選自鹵素、烷基、鹵烷基、羥基、羥烷基、烷氧基、鹵烷氧基、側氧、=NH、胺基、硝基、氰基、-S(O)₂R⁹、-C(O)R¹⁰、環烷基、雜環基、芳基和雜芳基； R ¹³ are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, pendant oxygen, =NH, amine, nitro, cyano, -S(O) ^2R9 , _-C (O) ^R10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

R^13a、R^13b和R^13c相同或不同，各自獨立地選自鹵素、烷基、鹵烷基、羥基、羥烷基、烷氧基、鹵烷氧基、胺基、硝基、氰基、-S(O)₂R⁹、-C(O)R¹⁰、環烷基、雜環基、芳基和雜芳基； R ^13a , R ^13b and R ^13c are the same or different, each independently selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amine, nitro, cyano, -S(O) ^2R9 , _-C (O) ^R10 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

j為0、1或2； j is 0, 1 or 2;

k為1或2； k is 1 or 2;

u為0、1、2、3、4或5； u is 0, 1, 2, 3, 4, or 5;

v為0、1、2或3； v is 0, 1, 2, or 3;

R⁹~R¹⁰如通式(I)中所定義。 R ⁹ to R ¹⁰ are as defined in the general formula (I).

在本公開的一些較佳的實施方案中，一種通式(I)或(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式或其可藥用的鹽，其中R⁰選自

、

、

In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, non- enantiomer, or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein R ^is selected from

,

v為0、1、2或3； v is 0, 1, 2, or 3;

在本公開的一些較佳的實施方案中，一種通式(I)或(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R^13a為-C(O)R¹⁰；R¹⁰為C_1-6烷基或C_1-6羥烷基，該C_1-6烷基任選可被C_1-6烷氧基和氰基取代。 In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, non- Enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^13a is -C(O)R ¹⁰ ; R ¹⁰ is C _1-6 alkyl or C _1-6 hydroxyalkyl, the C _1-6 alkyl may optionally be substituted with C _1-6 alkoxy and cyano.

在本公開的一些較佳的實施方案中，一種通式(I)或(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R¹³和R^13b較佳為氫原子。 In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, non- An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹³ and R ^13b are preferably hydrogen atoms.

在本公開的一些較佳的實施方案中，一種通式(I)或(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R^13c為-C(O)R¹⁰；R¹⁰為二C_1-6烷基胺基或3-6員雜環基；較佳地，R^13c為-C(O)-二C_1-6烷基胺基或-C(O)-5至6員雜環基；更佳地，R^13c為-C(O)N(CH₃)₂或-C(O)嗎啉基。 In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, non- Enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^13c is -C(O)R ¹⁰ ; R ¹⁰ is _{diC 1-6} alkylamino or 3-6 membered heterocycle Preferably, R ^13c is -C(O)-di-C _1-6 alkylamino group or -C(O)-5- to 6-membered heterocyclic group; more preferably, R ^13c is -C(O )N( _CH3 ) ₂ or -C(O)morpholinyl.

在本公開的一些較佳的實施方案中，一種通式(I)或(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中u為0或1。 In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, non- An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein u is 0 or 1.

在本公開的一些較佳的實施方案中，一種通式(I)或(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中j為1。 In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, non- An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein j is 1.

在本公開的一些較佳的實施方案中，一種通式(I)或(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中v為0。 In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, non- An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein v is 0.

在本公開的一些較佳的實施方案中，一種通式(I)或(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其為通式(III)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽： In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, non- Enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (III) or its tautomer, meso, racemate, enantiomer A isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

其中，R、R⁰、R¹、R⁴、R⁵、R⁸和n如通式(I)中所定義。 wherein R, R ⁰ , R ¹ , R ⁴ , R ⁵ , R ⁸ and n are as defined in general formula (I).

在本公開的一些較佳的實施方案中，一種通式(I)、(II)或(III)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R⁸相同或不同，各自獨立地選自鹵素、烷基、烯基、炔基、鹵烷基、烷氧基、鹵烷氧基、氰基、胺基、-(CH₂)_pNR⁶R⁷、硝基、羥基、羥烷基和-S(O)₂烷基，其中該烷基、鹵烷基和羥烷基各自獨立地任選地被選自羥基、鹵素、鹵烷基、烷氧基、鹵烷氧基、氰基、硝基、羥烷基和-(CH₂)_qNR¹¹R¹²中的一個或多個取代基取代；p和q各自獨立地選自0、1或2；R⁶、R⁷、R¹¹和R¹²相同或不同，各自獨立地選自氫原子、烷基、鹵烷基和羥烷基； In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ⁸ are the same or different, each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, Alkoxy, haloalkoxy, cyano, amine, -(CH ₂ ) _p NR ⁶ R ⁷ , nitro, hydroxy, hydroxyalkyl and -S(O) ₂ alkyl, wherein the alkyl, halogen Alkyl and hydroxyalkyl are each independently optionally selected from hydroxy, halo, haloalkyl, alkoxy, haloalkoxy, cyano, nitro, hydroxyalkyl and -(CH ₂ ) _q NR ¹¹ One or more substituents in R ¹² are substituted; p and q are each independently selected from 0, 1 or 2; R ⁶ , R ⁷ , R ¹¹ and R ¹² are the same or different, each independently selected from hydrogen atom, alkane group, haloalkyl and hydroxyalkyl;

較佳地，R⁸相同或不同，各自獨立地選自鹵素、C_1-6烷基、C_1-6鹵烷基、胺基、-(CH₂)_pNR⁶R⁷和C_1-6羥烷基，其中該C_1-6鹵烷基任選地被一個或多個羥基取代；R⁶和R⁷為氫原子或C_1-6烷基，p為0、1或2。 Preferably, R ⁸ is the same or different, each independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, amino, -(CH ₂ ) _p NR ⁶ R ⁷ and C _1-6 Hydroxyalkyl, wherein the C _1-6 haloalkyl is optionally substituted with one or more hydroxyl groups; R ⁶ and R ⁷ are hydrogen atoms or C _1-6 alkyl, and p is 0, 1, or 2.

在本公開的一些較佳的實施方案中，一種通式(I)、(II)或(III)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R¹選自氫原子、鹵素、烷基、鹵烷基、烷氧基、鹵烷氧基和羥烷基； In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ¹ is selected from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy and hydroxy alkyl;

較佳地，R¹選自氫原子、C_1-6烷基和鹵素。 Preferably, R ¹ is selected from hydrogen atom, C _1-6 alkyl group and halogen.

進一步較佳地，R¹為C_1-6烷基。 Further preferably, R ¹ is C _1-6 alkyl.

更佳地，R¹為甲基。 More preferably, R ¹ is methyl.

在本公開的一些較佳的實施方案中，一種通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R²選自鹵素、烷基、鹵烷基、羥烷基和環烷基，其中該烷基和環烷基各自獨立地任選地被選自烷氧基、鹵烷氧基和胺基中的一個或多個取代基取代； In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^is selected from halogen, alkyl, haloalkyl, hydroxyalkyl, and cycloalkyl, wherein each of the alkyl and cycloalkyl is independently optional is substituted with one or more substituents selected from alkoxy, haloalkoxy and amine;

較佳地，R²選自鹵素、烷基、鹵烷基和羥烷基； Preferably, R ² is selected from halogen, alkyl, haloalkyl and hydroxyalkyl;

進一步較佳地，R²為氫原子或C_1-6烷基。 Further preferably, R ² is a hydrogen atom or a C _1-6 alkyl group.

更佳地，R²為甲基。 More preferably, R ² is methyl.

在本公開的一些較佳的實施方案中，一種通式(I)或(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R³選自氫原子、烷基、鹵烷基、羥烷基和環烷基，其中該烷基、鹵烷基、羥烷基和環烷基各自獨立地任選地被選自鹵素、烷基、烷氧基、鹵烷基、鹵烷氧基、胺基和羥烷基中的一個或多個取代基所取代； In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or (II) or its tautomer, meso, racemate, enantiomer, non- An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ^R is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, and a cycloalkyl group, wherein the alkyl group, haloalkyl group , hydroxyalkyl and cycloalkyl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, amino and hydroxyalkyl replace;

較佳地，R³選自氫原子、烷基、鹵烷基和羥烷基。 Preferably, R ³ is selected from hydrogen atoms, alkyl groups, haloalkyl groups and hydroxyalkyl groups.

進一步較佳地，R³為氫原子或C_1-6烷基。 Further preferably, R ³ is a hydrogen atom or a C _1-6 alkyl group.

再進一步較佳地，R²為C_1-6烷基。 Still further preferably, R ² is C _1-6 alkyl.

更佳地，R³為氫原子。 More preferably, R ³ is a hydrogen atom.

在本公開的一些較佳的實施方案中，一種通式(I)、(II)或(III)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R⁴選自氫原子、鹵素、烷基、鹵烷基和羥烷基；較佳地，R⁴選自氫原子、鹵素、C_1-6烷基、C_1-6鹵烷基和C_1-6羥烷基； In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is selected from hydrogen atom, halogen, alkyl, haloalkyl and hydroxyalkyl; preferably, R ⁴ selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 hydroxyalkyl;

更佳地，R⁴為氫原子。 More preferably, R ⁴ is a hydrogen atom.

在本公開的一些較佳的實施方案中，一種通式(I)、(II)或(III)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R選自氫原子、鹵素、烷基、烷氧基、鹵烷基、鹵烷氧基、-(CH₂)_pNR⁶R⁷、氰基和硝基；R⁶和R⁷相同或不同，各自獨立地選自氫原子、烷基、鹵烷基和羥烷基；p為0、1或2； In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -( CH ₂ ) _p NR ⁶ R ⁷ , cyano and nitro; R ⁶ and R ⁷ are the same or different, each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group and a hydroxyalkyl group; p is 0, 1 or 2 ;

較佳地，R為C_1-6烷氧基； Preferably, R is C _1-6 alkoxy;

更佳地，R為甲氧基。 More preferably, R is methoxy.

在本公開的一些較佳的實施方案中，一種通式(I)、(II)或(III)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R⁵選自氫原子、鹵素、烷基、烷氧基、鹵烷基、鹵烷氧基、-(CH₂)_pNR⁶R⁷和氰基；R⁶和R⁷相同或不同，各自獨立地選自氫原子、烷基、鹵烷基和羥烷基；p為0、1或2； In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer A isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, - (CH ₂ ) _p NR ⁶ R ⁷ and cyano; R ⁶ and R ⁷ are the same or different, each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group and a hydroxyalkyl group; p is 0, 1 or 2;

較佳地，R⁵選自氫原子、鹵素、C_1-6烷基和C_1-6鹵烷基；更佳地，R⁵為氫原子。 Preferably, R ⁵ is selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; more preferably, R ⁵ is hydrogen atom.

在本公開的一些較佳的實施方案中，一種通式(I)、(II)或(III)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R⁶和R⁷相同或不同，各自獨立地選自氫原子、烷基、鹵烷基和羥烷基； In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ⁶ and R ⁷ are the same or different, each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, and a hydroxyalkane base;

較佳地，R⁶和R⁷相同或不同，各自獨立地為氫原子或C_1-6烷基。 Preferably, R ⁶ and R ⁷ are the same or different, and are each independently a hydrogen atom or a C _1-6 alkyl group.

在本公開的一些較佳的實施方案中，一種通式(I)、(II)或(III)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R¹¹和R¹²相同或不同，各自獨立地選自氫原子、烷基、鹵烷基和羥烷基； In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ¹¹ and R ¹² are the same or different, each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, and a hydroxyalkane base;

較佳地，R¹¹和R¹²相同或不同，各自獨立地為氫原子或C_1-6烷基。 Preferably, R ¹¹ and R ¹² are the same or different, and are each independently a hydrogen atom or a C _1-6 alkyl group.

在本公開的一些較佳的實施方案中，一種通式(I)、(II)或(III)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R⁹和R¹⁰相同或不同，各自獨立地選自氫原子、烷基、鹵烷基和羥烷基； In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ⁹ and R ¹⁰ are the same or different, each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, and a hydroxyalkane base;

較佳地，R⁹和R¹⁰相同或不同，各自獨立地為氫原子或C_1-6烷基。 Preferably, R ⁹ and R ¹⁰ are the same or different, and are each independently a hydrogen atom or a C _1-6 alkyl group.

在本公開的一些較佳的實施方案中，一種通式(I)、(II)或(III)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中p為0或1，較佳為0。 In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer A isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein p is 0 or 1, preferably 0.

在本公開的一些較佳的實施方案中，一種通式(I)、(II)或(III)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中q為0或1，較佳為0。 In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer Construct, non-pair An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein q is 0 or 1, preferably 0.

在本公開的一些較佳的實施方案中，一種通式(I)、(II)或(III)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中n為1、2或3，較佳為2。 In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (III) or its tautomer, meso, racemate, enantiomer A isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 1, 2 or 3, preferably 2.

在本公開的一些較佳的實施方案中，一種通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其為通式(IV)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽： In some preferred embodiments of the present disclosure, a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is the compound represented by the general formula (IV) or its tautomer, meso, racemate, enantiomer, non- Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

其中，環A、G、R、R⁰、R¹、R²、R³、R⁴、R⁸和n如通式(I)中所定義。 wherein rings A, G, R, R ⁰ , R ¹ , R ² , R ³ , R ⁴ , R ⁸ and n are as defined in general formula (I).

在本公開的一些較佳的實施方案中，一種通式(I)、(II)或(IV)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中環A為苯基或5至6員雜芳基。 In some preferred embodiments of the present disclosure, a compound represented by general formula (I), (II) or (IV) or its tautomer, meso, racemate, enantiomer A isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl or 5- to 6-membered heteroaryl.

在本公開的一些較佳的實施方案中，一種通式(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中環A為苯基或5至6員雜芳基； R⁰選自

、

、

、

、

、

、

、

和

；v為0；R^13a為-C(O)R¹⁰；R¹⁰為C_1-6烷基或C_1- ₆羥烷基，該C_1-6烷基任選可被C_1-6烷氧基和氰基取代；R¹³和R^13b為氫原子；R^13c為-C(O)-二C_1-6烷基胺基或-C(O)-5至6員雜環基；R⁸相同或不同，各自獨立地選自鹵素、C_1-6烷基、C_1-6鹵烷基、胺基、-(CH₂)_pNR⁶R⁷和C_1-6羥烷基，其中該C_1-6鹵烷基任選地被一個或多個羥基取代；R⁶和R⁷為氫原子或C_1-6烷基，p為0、1或2；R¹選自氫原子、C_1-6烷基和鹵素；R³為氫原子或C_1-6烷基；R⁴選自氫原子、鹵素、C_1-6烷基、C_1-6鹵烷基和C_1-6羥烷基；R為C_1-6烷氧基；R⁵選自氫原子、鹵素、C_1-6烷基和C_1-6鹵烷基；n為1、2或3。 In some preferred embodiments of the present disclosure, a compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is a phenyl group or a 5- to 6-membered heteroaryl group; R ⁰ is selected from

,

and

; v is 0; R ^13a is -C(O)R ¹⁰ ; R ¹⁰ is C _1-6 alkyl or C _1-6 hydroxyalkyl, the C _1-6 _{alkyl optionally can be replaced by C 1-6} _alkane Oxygen and cyano group substitution; R ¹³ and R ^13b are hydrogen atoms; R ^13c is -C(O) _{-diC 1-6} alkylamino group or -C(O)-5- to 6-membered heterocyclic group; R ⁸ are the same or different, each independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, amino, -(CH ₂ ) _p NR ⁶ R ⁷ and C _1-6 hydroxyalkyl, wherein The C _1-6 haloalkyl is optionally substituted by one or more hydroxyl groups; R ⁶ and R ⁷ are hydrogen atoms or C _1-6 alkyl groups, p is 0, 1 or 2; R ¹ is selected from hydrogen atoms, C _1-6 alkyl and halogen; R ³ is hydrogen atom or C _1-6 alkyl; R ⁴ is selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 hydroxyalkyl; R is C _1-6 alkoxy; R ⁵ is selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; n is 1, 2 or 3.

表A 本公開的典型化合物包括但不限於： Table A Typical compounds of the present disclosure include, but are not limited to:

本公開的另一方面涉及通式(IA)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽： Another aspect of the present disclosure pertains to compounds of formula (IA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof , or a pharmaceutically acceptable salt thereof:

其中，X為鹵素，較佳為氯； Wherein, X is halogen, preferably chlorine;

R⁰選自溴、碘、烷基、烷氧基、鹵烷基、鹵烷氧基、羥烷基、烯基、炔基、羥基、胺基、-(CH₂)_pNR⁶R⁷、雜環基氧基、環烷基、雜環基、芳基和雜芳基，其中該烷基、環烷基氧基、雜環基氧基、環烷基、雜環基、芳基和雜芳基各自獨立地任選地被選自鹵素、烷基、鹵烷基、羥基、羥烷基、烷氧基、鹵烷氧基、胺基、硝基、氰基、-S(O)₂R⁹、-C(O)R¹⁰、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基取代； R ⁰ is selected from bromine, iodine, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, hydroxyl, amino, -(CH ₂ ) _p NR ⁶ R ⁷ , Heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heterocyclyl The aryl groups are each independently optionally selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amine, nitro, cyano, -S(O) ₂ Substituted with one or more substituents in R ⁹ , -C(O)R ¹⁰ , cycloalkyl, heterocyclyl, aryl and heteroaryl;

R¹選自溴、碘、烷基、鹵烷基、烷氧基、鹵烷氧基、羥烷基、氰基和環烷基； R ¹ is selected from bromine, iodine, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano and cycloalkyl;

R選自鹵素、烷基、烷氧基、鹵烷基、鹵烷氧基、烯基、炔基、環烷基、雜環基、芳基、雜芳基、環烷基氧基、雜環基氧基、芳基氧基、雜芳基氧基、-(CH₂)_pNR⁶R⁷、氰基和硝基，其中該烷基、烯基、炔基、環烷基、雜環基、芳基和雜芳基各自獨立地任選地被選自烷基、鹵烷基、烷氧基、鹵烷氧基、鹵素、氰基、硝基和-(CH₂)_qNR¹¹R¹²中的一個或多個取代基所取代； R is selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycle aryloxy, aryloxy, heteroaryloxy, -(CH ₂ ) _p NR ⁶ R ⁷ , cyano and nitro, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl , aryl, and heteroaryl are each independently optionally selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, cyano, nitro, and -(CH ₂ ) _q NR ¹¹ R ¹² substituted by one or more of the substituents in;

G、R⁶、R⁷、R⁹、R¹⁰、R¹¹、R¹²、p、q和R⁴如通式(I)中所定義。 G, R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , p, q and R ⁴ are as defined in general formula (I).

本公開的另一方面涉及通式(IIA)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽： Another aspect of the present disclosure pertains to compounds of formula (IIA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof , or a pharmaceutically acceptable salt thereof:

R、R⁰、R¹、R⁴和R⁵如通式(II)中所定義。 R, R ⁰ , R ¹ , R ⁴ and R ⁵ are as defined in general formula (II).

本公開的另一方面涉及通式(IVA)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽： Another aspect of the present disclosure pertains to compounds of general formula (IVA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof , or a pharmaceutically acceptable salt thereof:

其中，環A、G、R、R⁰、R¹-R⁴、R⁸和n如通式(I)中所定義。 wherein Rings A, G, R, R ⁰ , R ¹ -R ⁴ , R ⁸ and n are as defined in general formula (I).

本公開的另一方面涉及通式(IAA)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽： Another aspect of the present disclosure pertains to compounds of general formula (IAA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof , or a pharmaceutically acceptable salt thereof:

其中，W選自氧原子、硫原子、

、

、NR^13a和CR^13bR^13c； Wherein, W is selected from oxygen atom, sulfur atom,

,

, NR ^13a and CR ^13b R ^13c ;

j為0、1或2； j is 0, 1 or 2;

k為1或2； k is 1 or 2;

v為0、1、2或3； v is 0, 1, 2, or 3;

環A、G、R、R^1-R⁴、R^8-R¹⁰和n如通式(I)中所定義。 Rings ^A , G, R, R1 ^- R4, R8 ^- ^R10 and n are as defined in general formula (I).

本公開的另一方面涉及通式(IIAA)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽： Another aspect of the present disclosure pertains to compounds of general formula (IIAA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof , or a pharmaceutically acceptable salt thereof:

其中，W選自氧原子、硫原子、

、

,

, NR ^13a and CR ^13b R ^13c ;

j為0、1或2； j is 0, 1 or 2;

k為1或2； k is 1 or 2;

v為0、1、2或3； v is 0, 1, 2, or 3;

環A、R、R¹、R^3-R⁵、R^8-R¹⁰和n如通式(II)中所定義。 Rings ^A , R, R1, R3 ^- R5, ^R8 ^- ^R10 and n are as defined in general formula (II).

本公開的另一方面涉及通式(IIIAA)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽： Another aspect of the present disclosure pertains to compounds of general formula (IIIAA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof , or a pharmaceutically acceptable salt thereof:

其中W選自氧原子、硫原子、

、

、NR^13a和CR^13bR^13c； wherein W is selected from oxygen atoms, sulfur atoms,

,

, NR ^13a and CR ^13b R ^13c ;

j為0、1或2； j is 0, 1 or 2;

k為1或2； k is 1 or 2;

v為0、1、2或3； v is 0, 1, 2, or 3;

R、R¹、R^4-R⁵、R^8-R¹⁰和n如通式(III)中所定義。 R, R ¹ , R ^4- R ⁵ , R ^8- R ¹⁰ and n are as defined in general formula (III).

本公開的典型化合物包括但不限於： Typical compounds of the present disclosure include, but are not limited to:

本公開的另一方面涉及一種製備通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽的方法，該方法包括以下步驟： Another aspect of the present disclosure relates to a method for preparing the compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or its A method in the form of a mixture, or a pharmaceutically acceptable salt thereof, comprising the steps of:

通式(IA)的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽與通式(IB)或其鹽反應，得到通式(I)的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，該反應為取代反應； The compound of general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof and The general formula (IB) or its salt is reacted to obtain the compound of the general formula (I) or its tautomer, meso, racemate, Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, the reaction is a substitution reaction;

其中，X為鹵素； Wherein, X is halogen;

環A、G、R、R⁰、R¹、R²、R³、R⁴、R⁸和n如通式(I)中所定義。 Rings A, G, R, R ⁰ , R ¹ , R ² , R ³ , R ⁴ , R ⁸ and n are as defined in general formula (I).

通式(IAA)經氧化反應得到通式(I)； The general formula (IAA) is oxidized to obtain the general formula (I);

其中，R⁰為

； where ^R0 is

;

W選自氧原子、硫原子、

、

、NR^13a和CR^13bR^13c； W is selected from oxygen atom, sulfur atom,

,

, NR ^13a and CR ^13b R ^13c ;

j為0、1或2； j is 0, 1 or 2;

k為1或2； k is 1 or 2;

v為0、1、2或3； v is 0, 1, 2, or 3;

環A、G、R、R¹、R²、R³、R⁴、R⁸和n如通式(I)中所定義。 Rings A, G, R, R ¹ , R ² , R ³ , R ⁴ , R ⁸ and n are as defined in general formula (I).

本公開的另一方面涉及一種製備通式(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽的方法，該方法包括以下步驟： Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, or its A method in the form of a mixture, or a pharmaceutically acceptable salt thereof, comprising the steps of:

通式(IIA)的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽與通式(IIB)或其鹽反應，得到通式(II)的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，該反應為取代反應； The compound of general formula (IIA) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof and The general formula (IIB) or its salt is reacted to obtain the compound of the general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, or its In the form of a mixture, or a pharmaceutically acceptable salt thereof, the reaction is a substitution reaction;

其中，X為鹵素； Wherein, X is halogen;

環A、R、R⁰、R¹、R³、R⁴、R⁵、R⁸和n如通式(II)中所定義。 Rings A, R, R ⁰ , R ¹ , R ³ , R ⁴ , R ⁵ , R ⁸ and n are as defined in general formula (II).

通式(IIAA)經氧化反應得到通式(II)； The general formula (IIAA) is oxidized to obtain the general formula (II);

其中，R⁰為

； where ^R0 is

;

W選自氧原子、硫原子、

、

、NR^13a和CR^13bR^13c； W is selected from oxygen atom, sulfur atom,

,

, NR ^13a and CR ^13b R ^13c ;

j為0、1或2； j is 0, 1 or 2;

k為1或2； k is 1 or 2;

v為0、1、2或3； v is 0, 1, 2, or 3;

環A、R、R¹、R³、R⁴、R⁵、R⁸和n如通式(II)中所定義。 Rings A, R, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁸ and n are as defined in general formula (II).

本公開的另一方面涉及一種製備通式(III)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽的方法，該方法包括以下步驟： Another aspect of the present disclosure relates to the preparation of the compound represented by the general formula (III) or its tautomer, meso, racemate, enantiomer, diastereomer, or its A method in the form of a mixture, or a pharmaceutically acceptable salt thereof, comprising the steps of:

通式(IIA)的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽與通式(IIIB)或其鹽反應，得到通式(III)的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，該反應為取代反應； The compound of general formula (IIA) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof and The general formula (IIIB) or its salt is reacted to obtain the compound of the general formula (III) or its tautomer, meso, racemate, enantiomer, diastereomer, or its In the form of a mixture, or a pharmaceutically acceptable salt thereof, the reaction is a substitution reaction;

其中，X為鹵素； Wherein, X is halogen;

R、R⁰、R¹、R⁴、R⁵、R⁸和n如通式(III)中所定義。 R, R ⁰ , R ¹ , R ⁴ , R ⁵ , R ⁸ and n are as defined in general formula (III).

通式(IIIAA)經氧化反應得到通式(III)； The general formula (IIIAA) is oxidized to obtain the general formula (III);

其中，R⁰為

； where ^R0 is

;

W選自氧原子、硫原子、

、

、NR^13a和CR^13bR^13c； W is selected from oxygen atom, sulfur atom,

,

, NR ^13a and CR ^13b R ^13c ;

j為0、1或2； j is 0, 1 or 2;

k為1或2； k is 1 or 2;

v為0、1、2或3； v is 0, 1, 2, or 3;

R、R¹、R⁴、R⁵、R⁸和n如通式(III)中所定義。 R, R ¹ , R ⁴ , R ⁵ , R ⁸ and n are as defined in general formula (III).

本公開的另一方面涉及一種製備通式(IV)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽的方法，該方法包括以下步驟： Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (IV) or its tautomer, meso, racemate, enantiomer, diastereomer, or its A method in the form of a mixture, or a pharmaceutically acceptable salt thereof, comprising the steps of:

通式(IVA)的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽經還原反應，得到通式(IV)的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽， Compounds of general formula (IVA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof Reduction reaction to obtain the compound of general formula (IV) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or its pharmaceutically acceptable salt used,

其中，環A、G、R、R⁰、R¹-R⁴、R⁸和n如通式(IV)中所定義。 wherein Rings A, G, R, R ⁰ , R ¹ -R ⁴ , R ⁸ and n are as defined in general formula (IV).

本公開的另一方面涉及一種醫藥組成物，該醫藥組成物含有治療有效量的本公開通式(I)、(II)、(III)、(IV)或表A所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，以及一種或多種藥學上可接受的載體、稀釋劑或賦形劑。 Another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by the general formula (I), (II), (III), (IV) or Table A of the present disclosure or their interaction Variant, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers , diluent or excipient.

本公開進一步涉及通式(I)、(II)、(III)、(IV)或表A所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽或者包含其的醫藥組成物在製備用於抑制SOS1的藥物中的用途。 The present disclosure further relates to compounds of general formula (I), (II), (III), (IV) or Table A or tautomers, mesomers, racemates, enantiomers thereof Use of , diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting SOS1.

本公開進一步涉及通式(I)、(II)、(III)、(IV)或表A所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽或者包含其的醫藥組成物在製備用於治療和/或預防癌症、炎症、RAS病、努南綜合症(NS)、伴有多斑的努南綜合症(NSML)、毛細血管畸形-動靜脈畸形綜合症(CM-AVM)、科斯特洛綜合症(CS)、心-面-皮膚綜合症(CFC)、萊格斯綜合症、遺傳性牙齦纖維瘤病、或其它增殖性疾病的藥物中的用途，較佳為癌症；該癌症較佳自黑色素瘤、皮膚癌、肝癌、腎癌、肺癌、鼻咽癌、胃癌、食道癌、結腸直腸癌、膽囊癌、膽管癌、絨毛膜上皮癌、胰腺癌、真性紅細胞增多症、兒科腫瘤、宮頸癌、卵巢癌、乳腺癌、膀胱癌、尿路上皮癌、輸尿管腫瘤、***癌、精原細胞瘤、睾丸腫瘤、白血病、頭頸瘤、子宮內膜癌、甲狀腺癌、淋巴瘤、肉瘤、骨瘤、成神經細胞瘤、神經母細胞瘤、腦瘤、骨髓瘤、星形細胞瘤、膠質母細胞瘤和膠質瘤；該RAS病較佳為1型神經纖維瘤病(NF1)；該肺癌較佳為非小細胞肺癌，進一步較佳為轉移性非小細胞肺癌；該白血病較佳為慢性淋巴細胞白血病或急性髓性白血病；該淋巴瘤較佳為瀰漫性大B細胞淋巴瘤；該骨髓瘤較佳為多發性骨髓瘤；該骨瘤較佳為骨軟骨瘤；該肝癌較佳為肝細胞癌；該結腸直腸癌較佳為結腸癌或直腸癌；該頭頸癌較佳為頭頸鱗狀細胞癌；該肉瘤較佳為骨肉瘤。 The present disclosure further relates to compounds of general formula (I), (II), (III), (IV) or Table A or tautomers, mesomers, racemates, enantiomers thereof , diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation for the treatment and/or prevention of cancer, inflammation, RAS disease, Noonan syndrome (NS) , Noonan syndrome with multiple spots (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardio-facial-cutaneous syndrome (CFC), Lay Use in the medicament of Guts syndrome, hereditary gingival fibromatosis, or other proliferative diseases, preferably cancer; the cancer is preferably black melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, colorectal cancer, gallbladder cancer, bile duct cancer, chorioepithelial cancer, pancreatic cancer, polycythemia vera, pediatric oncology, cervical cancer , ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral tumor, prostate cancer, seminoma, testicular tumor, leukemia, head and neck tumor, endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma, Neuroblastoma, neuroblastoma, brain tumor, myeloma, astrocytoma, glioblastoma and glioma; the RAS disease is preferably neurofibromatosis type 1 (NF1); the lung cancer is preferably Non-small cell lung cancer, more preferably metastatic non-small cell lung cancer; the leukemia is preferably chronic lymphocytic leukemia or acute myeloid leukemia; the lymphoma is preferably diffuse large B-cell lymphoma; the myeloma is preferably is multiple myeloma; the osteoma is preferably osteochondroma; the liver cancer is preferably hepatocellular carcinoma; the colorectal cancer is preferably colon cancer or rectal cancer; the head and neck cancer is preferably head and neck squamous cell carcinoma; The sarcoma is preferably osteosarcoma.

本公開還涉及一種抑制SOS1的方法，其包括給予所需患者治療有效量的通式(I)、(II)、(III)、(IV)或表A或所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，或包含其的醫藥組成物。 The present disclosure also relates to a method of inhibiting SOS1 comprising administering to a patient in need thereof a therapeutically effective amount of a compound of general formula (I), (II), (III), (IV) or Table A or shown, or a tautomer thereof body, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

本公開還涉及一種治療和/或預防SOS1介導的疾病的方法，其包括給予所需患者治療有效量的通式(I)、(II)、(III)、(IV)或表A所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，或包含其的醫藥組成物。 The present disclosure also relates to a method of treating and/or preventing SOS1-mediated diseases, comprising administering to a patient in need thereof a therapeutically effective amount of formula (I), (II), (III), (IV) or shown in Table A the compound or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical containing the same composition.

本公開還涉及一種治療和/或預防癌症、炎症、RAS病、努南綜合症(NS)、伴有多斑的努南綜合症(NSML)、毛細血管畸形-動靜脈畸形綜合症(CM-AVM)、科斯特洛綜合症(CS)、心-面-皮膚綜合症(CFC)、萊格斯綜合症、遺傳性牙齦纖維瘤病、或其它增殖性疾病的方法，較佳為治療癌症的方法，其包括給予所需患者治療有效量的通式(I)、(II)、(III)、(IV) 或表A所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，或包含其的醫藥組成物；其中該癌症較佳選自黑色素瘤、皮膚癌、肝癌、腎癌、肺癌、鼻咽癌、胃癌、食道癌、結腸直腸癌、膽囊癌、膽管癌、絨毛膜上皮癌、胰腺癌、真性紅細胞增多症、兒科腫瘤、宮頸癌、卵巢癌、乳腺癌、膀胱癌、尿路上皮癌、輸尿管腫瘤、***癌、精原細胞瘤、睾丸腫瘤、白血病、頭頸瘤、子宮內膜癌、甲狀腺癌、淋巴瘤、肉瘤、骨瘤、成神經細胞瘤、神經母細胞瘤、腦瘤、骨髓瘤、星形細胞瘤、膠質母細胞瘤和膠質瘤；該RAS病較佳為1型神經纖維瘤病(NF1)；該肺癌較佳為非小細胞肺癌，進一步較佳為轉移性非小細胞肺癌；該白血病較佳為慢性淋巴細胞白血病或急性髓性白血病；該淋巴瘤較佳為瀰漫性大B細胞淋巴瘤；該骨髓瘤較佳為多發性骨髓瘤；該骨瘤較佳為骨軟骨瘤；該肝癌較佳為肝細胞癌；該結腸直腸癌較佳為結腸癌或直腸癌；該頭頸癌較佳為頭頸鱗狀細胞癌；該肉瘤較佳為骨肉瘤。 The present disclosure also relates to a treatment and/or prophylaxis of cancer, inflammation, RAS disease, Noonan syndrome (NS), Noonan syndrome with multiple spots (NSML), capillary malformation-arteriovenous malformation syndrome (CM- AVM), Costello Syndrome (CS), Cardio-Facial-Skin Syndrome (CFC), Leggers Syndrome, Hereditary Gingival Fibromatosis, or other proliferative diseases, preferably for the treatment of cancer A method comprising administering to a patient in need thereof a therapeutically effective amount of formula (I), (II), (III), (IV) Or a compound shown in Table A or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; wherein the cancer is preferably selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric cancer, esophagus cancer, colorectal cancer, gallbladder cancer, bile duct cancer, chorioepithelium Cancer, Pancreatic Cancer, Polycythemia Vera, Pediatric Oncology, Cervical Cancer, Ovarian Cancer, Breast Cancer, Bladder Cancer, Urothelial Cancer, Ureteral Tumor, Prostate Cancer, Seminoma, Testicular Tumor, Leukemia, Head and Neck Tumor, Uterus Endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma, neuroblastoma, neuroblastoma, brain tumor, myeloma, astrocytoma, glioblastoma and glioma; the RAS disease is preferably Neurofibromatosis type 1 (NF1); the lung cancer is preferably non-small cell lung cancer, more preferably metastatic non-small cell lung cancer; the leukemia is preferably chronic lymphocytic leukemia or acute myeloid leukemia; the lymphoma is preferably Preferably diffuse large B cell lymphoma; the myeloma is preferably multiple myeloma; the osteoma is preferably osteochondroma; the liver cancer is preferably hepatocellular carcinoma; the colorectal cancer is preferably colon cancer or Rectal cancer; the head and neck cancer is preferably head and neck squamous cell carcinoma; the sarcoma is preferably osteosarcoma.

本公開進一步涉及一種通式(I)、(II)、(III)、(IV)或表A示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，或包含其的醫藥組成物，其用作藥物。 The present disclosure further relates to a compound represented by the general formula (I), (II), (III), (IV) or Table A or its tautomer, meso, racemate, enantiomer , a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

本公開還涉及通式(I)、(II)、(III)、(IV)或表A所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，或包含其的醫藥組成物，其用作SOS1抑制劑。 The present disclosure also relates to compounds of general formula (I), (II), (III), (IV) or Table A or tautomers, mesomers, racemates, enantiomers thereof , a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a SOS1 inhibitor.

本公開還涉及通式(I)、(II)、(III)、(IV)或表A所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，或包含其的醫藥組成物，其用於治療和/或預防SOS1介導的疾病。 The present disclosure also relates to compounds of general formula (I), (II), (III), (IV) or Table A or tautomers, mesomers, racemates, enantiomers thereof , diastereomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the treatment and/or prevention of SOS1-mediated diseases.

本公開還涉及通式(I)、(II)、(III)、(IV)或表A所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，或包含其的醫藥組成物，其用於治療和/或預防癌症、炎症、RAS病、努南綜合症(NS)、伴有多斑的努南綜合症(NSML)、毛細血管畸形-動靜脈畸形綜合症(CM-AVM)、科斯特洛綜合症(CS)、心-面-皮膚綜合症(CFC)、萊格斯綜合症、遺傳性牙齦纖維瘤病、或其它增殖性疾病，較佳為用於治療和/或預防癌症；其中該癌症較佳自黑色素瘤、皮膚癌、肝癌、腎癌、肺癌、鼻咽癌、胃癌、食道癌、結腸直腸癌、膽囊癌、膽管癌、絨毛膜上皮癌、胰腺癌、真性紅細胞增多症、兒科腫瘤、宮頸癌、卵巢癌、乳腺癌、膀胱癌、尿路上皮癌、輸尿管腫瘤、***癌、精原細胞瘤、睾丸腫瘤、白血病、頭頸瘤、子宮內膜癌、甲狀腺癌、淋巴瘤、肉瘤、骨瘤、成神經細胞瘤、神經母細胞瘤、腦瘤、骨髓瘤、星形細胞瘤、膠質母細胞瘤和膠質瘤；該RAS病較佳為1型神經纖維瘤病(NF1)；該肺癌較佳為非小細胞肺癌，進一步較佳為轉移性非小細胞肺癌；該白血病較佳為慢性淋巴細胞白血病或急性髓性白血病；該淋巴瘤較佳為瀰漫性大B細胞淋巴瘤；該骨髓瘤較佳為多發性骨髓瘤；該骨瘤較佳為骨軟骨瘤；該肝癌較佳為肝細胞癌；該結腸直腸癌較佳為結腸癌或直腸癌；該頭頸癌較佳為頭頸鱗狀細胞癌；該肉瘤較佳為骨肉瘤。 The present disclosure also relates to compounds of general formula (I), (II), (III), (IV) or Table A or tautomers, mesomers, racemates, enantiomers thereof , diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the treatment and/or prevention of cancer, inflammation, RAS disease, Noonan syndrome (NS ), Noonan syndrome with multiple spots (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardio-facial-cutaneous syndrome (CFC), Leggers syndrome, hereditary gingival fibromatosis, or other proliferative diseases, preferably for the treatment and/or prevention of cancer; wherein the cancer is preferably selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, Nasopharyngeal cancer, gastric cancer, esophagus cancer, colorectal cancer, gallbladder cancer, bile duct cancer, chorioepithelial cancer, pancreatic cancer, polycythemia vera, pediatric cancer, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer cancer, ureteral tumor, prostate cancer, seminoma, testicular tumor, leukemia, head and neck tumor, endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma, neuroblastoma, neuroblastoma, brain tumor, Myeloma, astrocytoma, glioblastoma and glioma; the RAS disease is preferably neurofibromatosis type 1 (NF1); the lung cancer is preferably non-small cell lung cancer, more preferably metastatic non-small cell lung cancer cell lung cancer; the leukemia is preferably chronic lymphocytic leukemia or acute myeloid leukemia; the lymphoma is preferably diffuse large B-cell lymphoma; the myeloma is preferably multiple myeloma; the osteoma is preferably bone chondroma; the liver cancer is preferably hepatocellular carcinoma; the colorectal cancer is preferably colon cancer or rectal cancer; the head and neck cancer is preferably head and neck squamous cell carcinoma; the sarcoma is preferably osteosarcoma.

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

作為一般性指導，本公開的活性化合物較佳是以單位劑量的方式，或者是以患者可以以單劑自我給藥的方式。本公開化合物或組成物的單位劑量的表達方式可以是片劑、膠囊、扁囊劑、瓶裝藥水、藥粉、顆粒劑、錠劑、栓劑、再生藥粉或液體製劑。合適的單位劑量可以是0.1~1000mg。 As a general guide, the active compounds of the present disclosure are preferably presented in unit dosage form or in a form that the patient can self-administer in a single dose. A unit dose of a compound or composition of the present disclosure may be expressed as a tablet, capsule, cachet, vial, powder, granule, lozenge, suppository, reconstituted powder, or liquid. A suitable unit dose may be 0.1 to 1000 mg.

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

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

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

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

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

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

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

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

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

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

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

術語說明 Glossary

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

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

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

術語“烯基”指分子中含有至少一個碳碳雙鍵的烷基化合物，其中烷基的定義如上所述。烯基可以是取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自氫原子、烷基、烷氧基、鹵素、鹵烷基、鹵烷氧基、環烷基氧基、雜環基氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基。 The term "alkenyl" refers to an alkyl compound having at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, haloalkyls, one of haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, or multiple substituents.

術語“炔基”指分子中含有至少一個碳碳三鍵的烷基化合物，其中烷基的定義如上所述。炔基可以是取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自氫原子、烷基、烷氧基、鹵素、鹵烷基、鹵烷氧基、環烷基氧基、雜環基氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基。 The term "alkynyl" refers to an alkyl compound having at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, haloalkyls, one of haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, or multiple substituents.

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

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

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

術語“橋環烷基”指5至20員，任意兩個環共用兩個不直接連接的碳原子的全碳多環基團，其可以含有一個或多個雙鍵。較佳為6至14員，更佳為7至10員(例如7、8、9或10員)。根據組成環的數目可以分為雙環、三環、四環或多環橋環烷基，較佳為雙環、三環或四環，更佳為雙環或三環。橋環烷基的非限制性實例包括： The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly attached carbon atoms, which may contain one or more double bonds. Preferably it is 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

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

、

、

等；較佳為

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

,

etc.; preferably

環烷基可以是取代的或非取代的，當被取代時，其可以在任何可使用的連接點上被取代，該取代基較佳獨立地任選選自氫原子、鹵素、烷基、烷氧基、鹵烷基、鹵烷氧基、環烷基氧基、雜環基氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基、雜芳基中的一個或多個取代基。 Cycloalkyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, preferably independently optionally selected from hydrogen atoms, halogens, Alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl , aryl, and one or more substituents in heteroaryl.

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

術語“雜環基”指飽和或部分不飽和單環或多環環狀取代基，其包含3至20個環原子，其中一個或多個環原子為選自氮、氧和硫的雜原子，該硫可任選被氧化(即形成亞碸或碸)，但不包括-O-O-、-O-S-或-S-S-的環部分，其餘環原子為碳。較佳包含3至12個(例如3、4、5、6、7、8、9、10、11和12個)環原子，其中1~4個(例如1、2、3和4個)是雜原子；更佳包含3至8個環原子(例如3、4、5、6、7和8個)，其中1-3是雜原子(例如1、2和3個)；更佳包含3至6個環原子，其中1-3個是雜原子；最較佳包含5或6個環原子，其中1-3個是雜原子。單環雜環基的非限制性實例包括吡咯烷基、四氫吡喃基、1,2.3.6-四氫吡啶基、哌啶基、哌嗪基、嗎啉基、硫嗎啉基、高哌嗪基等。多環雜環基包括螺環、稠環和橋環的雜環基。 The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing from 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, The sulfur can be optionally oxidized (ie, to form arsenite or arsenic), but does not include ring moieties of -O-O-, -O-S-, or -S-S-, the remaining ring atoms being carbon. It preferably contains 3 to 12 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1 to 4 (eg 1, 2, 3 and 4) are Heteroatoms; more preferably 3 to 8 ring atoms (eg 3, 4, 5, 6, 7 and 8), of which 1-3 are heteroatoms (eg 1, 2 and 3); more preferably 3 to 6 ring atoms, of which 1-3 are heteroatoms; preferably 5 or 6 ring atoms, of which 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homo Piperazinyl etc. Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.

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

術語“稠雜環基”指5至20員，系統中的每個環與體系中的其他環共享毗鄰的一對原子的多環雜環基團，一個或多個環可以含有一個或多個雙鍵，其中一個或多個環原子為選自氮、氧和硫的雜原子，該硫可任選被氧化(即形成亞碸或碸)，其餘環原子為碳。較佳為6至14員，更佳為7至10員(例如7、8、9或10員)。根據組成環的數目可以分為雙環、三環、四環或多環稠雜環基，較佳為雙環或三環，更佳為3員/4員、3員/5員、3員/6員、4員/4員、4員/5員、4員/6員、5員/4員、5員/5員、5員/6員、6員/3員、6員/4員、6員/5員和6員/6員雙環稠雜環基。稠雜環基的非限制性實例包括： The term "fused heterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more A double bond in which one or more ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which may be optionally oxidized (ie, to form thionite or thionite), and the remaining ring atoms are carbon. Preferably it is 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3/4, 3/5, 3/6 Member, 4 Member/4 Member, 4 Member/5 Member, 4 Member/6 Member, 5 Member/4 Member, 5 Member/5 Member, 5 Member/6 Member, 6 Member/3 Member, 6 Member/4 Member, 6-membered/5-membered and 6-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclyl groups include:

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

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

和

等。

and

Wait.

雜環基可以是取代的或非取代的，當被取代時，其可以在任何可使用的連接點上被取代，該取代基較佳獨立地任選選自氫原子、鹵素、烷基、烷氧基、鹵烷基、鹵烷氧基、環烷基氧基、雜環基氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基、雜芳基中的一個或多個取代基。 Heterocyclyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably independently optionally selected from hydrogen atoms, halogens, alkyls, alkanes Oxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl, One or more substituents in a heteroaryl group.

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

芳基可以是取代的或非取代的，當被取代時，其可以在任何可使用的連接點上被取代，該取代基較佳獨立地任選選自氫原子、鹵素、烷基、烷氧基、鹵烷基、鹵烷氧基、環烷基氧基、雜環基氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基、雜芳基中的一個或多個取代基。 Aryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably independently optionally selected from hydrogen, halogen, alkyl, alkoxy alkyl, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl, heterocyclyl One or more substituents in an aryl group.

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

雜芳基可以是取代的或非取代的，當被取代時，其可以在任何可使用的連接點上被取代，該取代基較佳獨立地任選選自氫原子、鹵素、烷基、烷氧基、鹵烷基、鹵烷氧基、環烷基氧基、雜環基氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基、雜芳基中的一個或多個取代基。 Heteroaryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, alkanes Oxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl, One or more substituents in a heteroaryl group.

上述環烷基、雜環基、芳基和雜芳基具有1個從母體環原子上除去一個氫原子所衍生的殘基，或2個從母體的相同或兩個不同的環原子上除去兩個氫原子所衍生的殘基，即“二價環烷基”、“二價雜環基”、“伸芳基”、“伸雜芳基”。 The cycloalkyl, heterocyclyl, aryl and heteroaryl groups described above have one residue derived by removing one hydrogen atom from the parent ring atom, or two residues by removing two from the same or two different ring atoms of the parent. Residues derived from a hydrogen atom, namely "divalent cycloalkyl", "divalent heterocyclic group", "aryl extended", "heteroaryl extended".

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

術語“羥基保護基”是本領域已知的適當的用於羥基保護的基團，參見文獻(“Protective Groups in Organic Synthesis”，5^Th Ed.T.W.Greene & P.G.M.Wuts)中的羥基保護基團。作為示例，較佳地，該羥基保護基可以是(C_1-10烷基或芳基)₃矽烷基，例如：三乙基矽基，三異丙基矽基，第三丁基二甲基矽基，第三丁基二苯基矽基等；可以是C_1-10烷基或取代烷基，較佳烷氧基取代的烷基或芳基取代的烷基，更佳C_1-6烷氧基取代的C_1-6烷基或苯基取代的C_1-6烷基，最佳C_1-4烷氧基取代的C_1-4烷基，例如：甲基、第三丁基、苄基、甲氧基甲基(MOM)、乙氧基乙基、等；可以是(C_1-10烷基或芳香基)醯基，例如：甲醯基、乙醯基、苯甲醯基、對硝基苯甲醯基等；可以是(C_1-6烷基或C_6-10芳基)磺醯基；也可以是(C_1-6烷氧基或C_6-10芳基氧基)羰基。 The term "hydroxyl protecting group" is a suitable group for hydroxyl protection known in the art, see the literature ("Protective Groups in Organic Synthesis", 5 ^Th Ed. TW Greene & PGMWuts) for hydroxyl protecting groups. As an example, preferably, the hydroxyl protecting group can be a (C _1-10 alkyl or aryl) ₃ silyl group, such as: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl Silicon, tert-butyldiphenylsilyl, etc.; can be C _1-10 alkyl or substituted alkyl, preferably alkoxy substituted alkyl or aryl substituted alkyl, more preferably C _1-6 Alkoxy substituted C _1-6 alkyl or phenyl substituted C _1-6 alkyl, the best C _1-4 alkoxy substituted C _1-4 alkyl, for example: methyl, tert-butyl , benzyl, methoxymethyl (MOM), ethoxyethyl, etc.; can be (C _1-10 alkyl or aryl) aryl, such as: methyl, acetyl, benzyl can be (C _1-6 alkyl or C _6-10 aryl) sulfonyl; also can be (C _1-6 alkoxy or C _6-10 aryl) oxy) carbonyl.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

本公開所述化合物的化學結構中，鍵“

”表示未指定構型，即如果化學結構中存在手性異構體，鍵“

”可以為“

”或“

”，或者同時包含“

”和“

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

"Indicates an unspecified configuration, i.e. if a chiral isomer exists in the chemical structure, the bond"

"can be"

"or"

", or both "

"and"

"Two configurations.

本公開的化合物還可包含其同位素衍生物。術語“同位素衍生物”指結構不同僅在於存在一種或多種同位素富集原子的化合物。例如，具有本公開的結構，除了用“氘”或“氚”代替氫，或者用¹⁸F-氟標記(¹⁸F同位素)代替氟，或者用¹¹C-、¹³C-、或者¹⁴C-富集的碳(¹¹C-、¹³C-、或者¹⁴C-碳標記；¹¹C-、¹³C-、或者¹⁴C-同位素)代替碳原子的化合物處於本公開的範圍內。這樣的化合物可用作例如生物學測定中的分析工具或探針，或者可以用作疾病的體內診斷成像示蹤劑，或者作為藥效學、藥動學或受體研究的示蹤劑。本公開還包括各種氘化形式的化合物。與碳原子連接的各個可用的氫原子可獨立地被氘原子替換。所屬技術領域具有通常知識者能夠參考相關文獻合成氘化形式的化合物。在製備氘代形式的化合物時可使用市售的氘代起始物質，或它們可使用常規技術採用氘代試劑合成，氘代試劑包括但不限於氘代硼烷、三氘代硼烷四氫呋喃溶液、氘代氫化鋰鋁、氘代碘乙烷和氘代碘甲烷等。氘代物通常可以保留與未氘代的化合物相當的活性，並且當氘代在某些特定位點時可以取得更好的代謝穩定性，從而獲得某些治療優勢。 The compounds of the present disclosure may also include isotopic derivatives thereof. The term "isotopic derivatives" refers to compounds that differ in structure only by the presence of one or more isotopically enriched atoms. For example, having the structures of the present disclosure, except replacing hydrogen with "deuterium" or "tritium", or replacing fluorine with ^an18F -fluorine label ( ^18F isotope), or ^using11C- , ^13C- , ^or14C -rich Compounds in which a set of carbon ( ¹¹ C-, ¹³ C-, or ¹⁴ C-carbon labels; ¹¹ C-, ¹³ C-, or ¹⁴ C-isotopes) in place of carbon atoms are within the scope of this disclosure. Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies. The present disclosure also includes compounds in various deuterated forms. Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. One of ordinary skill in the art can refer to the relevant literature to synthesize the deuterated form of the compound. Commercially available deuterated starting materials can be used in preparing deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated borane in tetrahydrofuran , Deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc. Deuterated compounds generally retain comparable activity to undeuterated compounds, and when deuterated at certain specific sites can achieve better metabolic stability, resulting in certain therapeutic advantages.

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

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

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

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

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

本文所用的術語“溶劑化物”是指本公開的化合物與一種或多種，較佳地為1-3種，無論是有機的還是無機的溶劑分子的物理結合。該物理結合包括氫鍵。在某些情況下，例如，當在結晶固體的晶格中摻入一種或多種，較佳1-3種溶劑分子時，溶劑化物將被分離。示例性的溶劑化物包括但不限於水合物、乙醇化物、甲醇化物和異丙醇化物。溶劑化方法是本領域公知的。 The term "solvate" as used herein refers to a physical association of a compound of the present disclosure with one or more, preferably 1-3, solvent molecules, whether organic or inorganic. This physical bond includes hydrogen bonding. In some cases, for example, when incorporated in the crystal lattice of a crystalline solid One or more, preferably 1-3 solvent molecules, the solvate will be isolated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

“前藥”是指可以在生理條件下，例如藉由在血液中水解，在體內轉化以產生活性原藥化合物。 "Prodrug" means a compound that can be transformed in vivo under physiological conditions, such as by hydrolysis in blood, to yield the active prodrug compound.

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

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

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

本公開化合物的合成方法 Synthetic methods of compounds of the present disclosure

為了完成本公開的目的，本公開採用如下技術方案： In order to accomplish the purpose of the present disclosure, the present disclosure adopts the following technical solutions:

方案一 Option One

本公開通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽的製備方法，該方法包括以下步驟： The compound represented by the general formula (I) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable The preparation method of the salt used, the method comprises the following steps:

通式(IA)的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽與通式(IB)或其鹽(較佳為鹽酸鹽)在酸性或鹼性條件下(可選在微波條件下)反應，得到通式(I)的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，該反應為取代反應； The compound of general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof and The general formula (IB) or its salt (preferably hydrochloride) is reacted under acidic or basic conditions (optionally under microwave conditions) to obtain the compound of general formula (I) or its tautomer, internal elimination A isomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the reaction is a substitution reaction;

其中，X為鹵素； Wherein, X is halogen;

方案二 Option II

其中，R⁰為

； where ^R0 is

;

W選自氧原子、硫原子、

、

、NR^13a和CR^13bR^13c； W is selected from oxygen atom, sulfur atom,

,

, NR ^13a and CR ^13b R ^13c ;

j為0、1或2； j is 0, 1 or 2;

k為1或2； k is 1 or 2;

v為0、1、2或3； v is 0, 1, 2, or 3;

方案三 third solution

本公開通式(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽的製備方法，該方法包括以下步驟： The compound represented by the general formula (II) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable The preparation method of the salt used, the method comprises the following steps:

通式(IIA)的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽與通式(IIB)或其鹽(較佳為鹽酸鹽)在酸性或鹼性條件下(可選在微波條件下)反應，得到通式(II)的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，該反應為取代反應； The compound of general formula (IIA) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof and The general formula (IIB) or its salt (preferably hydrochloride) is reacted under acidic or basic conditions (optionally under microwave conditions) to obtain the compound of general formula (II) or its tautomer, internal elimination A isomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the reaction is a substitution reaction;

其中，X為鹵素； Wherein, X is halogen;

方案四 Option 4

其中R⁰為

； where ^R0 is

;

W選自氧原子、硫原子、

、

、NR^13a和CR^13bR^13c； W is selected from oxygen atom, sulfur atom,

,

, NR ^13a and CR ^13b R ^13c ;

j為0、1或2； j is 0, 1 or 2;

k為1或2； k is 1 or 2;

v為0、1、2或3； v is 0, 1, 2, or 3;

方案五 Option five

本公開通式(III)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽的製備方法，該方法包括以下步驟： The compound represented by the general formula (III) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable The preparation method of the salt used, the method comprises the following steps:

通式(IIA)的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽與通式(IIIB)或其鹽(較佳為鹽酸鹽)在酸性或鹼性條件下(可選在微波條件下)反應，得到通式(III)的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，該反應為取代反應； The compound of general formula (IIA) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof and The general formula (IIIB) or its salt (preferably hydrochloride) is reacted under acidic or basic conditions (optionally under microwave conditions) to obtain the compound of general formula (III) or its tautomer, internal elimination A isomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the reaction is a substitution reaction;

其中，X為鹵素； Wherein, X is halogen;

方案六 Option 6

其中，R⁰為

； where ^R0 is

;

W選自氧原子、硫原子、

、

、NR^13a和CR^13bR^13c； W is selected from oxygen atom, sulfur atom,

,

, NR ^13a and CR ^13b R ^13c ;

j為0、1或2； j is 0, 1 or 2;

k為1或2； k is 1 or 2;

v為0、1、2或3； v is 0, 1, 2, or 3;

方案七 Option 7

本公開通式(IV)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽的製備方法，該方法包括以下步驟： The compound represented by the general formula (IV) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable The preparation method of the salt used, the method comprises the following steps:

通式(IVA)的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽在催化劑作用下經還原反應，得到通式(IV)的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽， The compound of general formula (IVA) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof in Through reduction reaction under the action of catalyst, the compound of general formula (IV) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof is obtained, or a pharmaceutically acceptable salt thereof,

提供上述反應中該酸性條件的試劑包括但不限於：氯化銨、三氟乙酸、鹽酸、氯化氫的1,4-二噁烷溶液、三氟乙酸、甲酸、乙酸、鹽酸、硫酸、甲磺酸、硝酸、磷酸和對苯甲磺酸；較佳為氯化銨。 The reagents that provide the acidic conditions in the above reaction include but are not limited to: ammonium chloride, trifluoroacetic acid, hydrochloric acid, hydrogen chloride in 1,4-dioxane, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid , nitric acid, phosphoric acid and p-toluenesulfonic acid; preferably ammonium chloride.

提供上述反應中該鹼性條件的試劑包括有機鹼和無機鹼類，該有機鹼類包括但不限於：三乙胺、N,N-二異丙基乙胺、正丁基鋰、二異丙基胺基鋰、醋酸鉀、第三丁醇鈉、第三丁醇鉀或1,8-二氮雜環[5,4,0]十一碳-7-烯，該無機鹼類包括但不限於：氫化鈉、磷酸鉀、碳酸鈉、醋酸鈉、醋酸鉀、碳酸鉀或碳酸銫、氫氧化鈉、氫氧化鋰和氫氧化鉀；較佳為N,N-二異丙基乙胺。 The reagents that provide the alkaline conditions in the above reaction include organic bases and inorganic bases, and the organic bases include but are not limited to: triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylamine Lithium propylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide or 1,8-diazacyclo[5,4,0]undec-7-ene, the inorganic bases including but Not limited to: sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate or cesium carbonate, sodium hydroxide, lithium hydroxide and potassium hydroxide; preferably N,N-diisopropylethylamine.

上述氧化反應中所用的催化劑體系包括但不限於：PhSiH/Mn(dpm)₂(或Mn(dpm)₃或Mn(acac)₂或Co(sdmg)₃)、四苯基卟啉錳(III)配合物/NaBH₄(或Pt-H₂)、四苯基卟啉鈷(II)配合物/NaBH₄(或EtNBH₄)、(二(水楊基-γ-亞胺基丙基)甲胺)鈷(II)/一級醇、Co(acac)₂、Co(salen)、Co(acacen)、BH₃等。所用的氧化劑包括但不限於氧氣、空氣、過氧化氫等，其中Mn(dpm)₂為二(2,2,6,6-四甲基-3,5-庚二酮)錳，Mn(dpm)₃為三(2,2,6,6-四甲基-3,5-庚二酮)錳(CAS登記號為14324-99-3，又名：三(2,2,6,6-四甲基-3,5-庚烯酸)錳)，Mn(acac)₂為二(乙醯丙酮)錳(II)(CAS登記號14024-58-9)，Co(acac)₂為二(乙醯丙酮)鈷(II)(CAS登記號193620-63-2)、Co(salen)為N,N'-二(水楊基)乙二胺鈷(II)(CAS登記號14167-18-1)、Co(acacen)為N,N'-二(乙醯丙酮)乙二胺鈷(II)、Co(sdmg)₃為二(N-水楊亞基-2-胺基異丁酮)鈷酸鈉(CAS登記號704900-51-6)；較佳催化劑體系為PhSiH/Mn(dpm)₃或PhSiH/Mn(acac)₂，較佳氧化劑為氧氣。 The catalyst system used in the above-mentioned oxidation reaction includes but is not limited to: PhSiH/Mn(dpm) ₂ (or Mn(dpm) ₃ or Mn(acac) ₂ or Co(sdmg) ₃ ), tetraphenylporphyrin manganese (III) Complex/NaBH ₄ (or Pt-H ₂ ), Tetraphenylporphyrin cobalt(II) complex/NaBH ₄ (or EtNBH ₄ ), (bis(salicyl-γ-iminopropyl)methylamine ) Cobalt(II)/primary alcohol, Co(acac) ₂ , Co(salen), Co( _acacen ), BH3, etc. The oxidant used includes but is not limited to oxygen, air, hydrogen peroxide, etc., wherein Mn(dpm) ₂ is bis(2,2,6,6-tetramethyl-3,5-heptanedione) manganese, Mn(dpm) ) ₃ is three (2,2,6,6-tetramethyl-3,5-heptanedione) manganese (CAS registration number is 14324-99-3, also known as: three (2,2,6,6- Tetramethyl-3,5-heptenoic acid) manganese), Mn(acac) ₂ is bis(acetylacetone)manganese(II) (CAS Reg. No. 14024-58-9), Co(acac) ₂ is bis(acac) Acetylacetone) cobalt(II) (CAS Reg. No. 193620-63-2), Co(salen) is N,N'-bis(salicyl)ethylenediamine cobalt(II) (CAS Reg. No. 14167-18- 1), Co(acacen) is N,N'-bis(acetylacetone) ethylenediamine cobalt(II), Co(sdmg) ₃ is bis(N-salicylidene-2-aminoisobutanone)cobalt acid Sodium (CAS Reg. No. 704900-51-6); the preferred catalyst system is PhSiH/Mn(dpm) ₃ or PhSiH/Mn(acac) ₂ , and the preferred oxidant is oxygen.

上述還原反應中所用的催化劑包括但不限於：鈀碳、鐵粉、雷尼鎳、鋅粉、四-三苯基膦鈀、二氯化鈀、醋酸鈀、1,1’-雙(二苄基磷)二氯二戊鐵鈀、三(二亞苄基丙酮)二鈀等，較佳為鈀碳。所用的還原劑包括但不限於氫氣、稀鹽酸、醋酸或稀硫酸，較佳為氫氣。 The catalyst used in the above-mentioned reduction reaction includes but is not limited to: palladium carbon, iron powder, Raney nickel, zinc powder, tetrakis-triphenylphosphine palladium, palladium dichloride, palladium acetate, 1,1'-bis(dibenzyl) (phosphorus) dipentyl iron palladium dichloro, tris(dibenzylideneacetone) dipalladium, etc., preferably palladium carbon. The reducing agent used includes but is not limited to hydrogen, dilute hydrochloric acid, acetic acid or dilute sulfuric acid, preferably hydrogen.

上述反應較佳在溶劑中進行，所用溶劑包括但不限於：醋酸、甲醇、乙醇、乙腈、正丁醇、甲苯、四氫呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亞碸、1,4-二噁烷、乙二醇二甲醚、水、N,N-二甲基乙醯胺或N,N-二甲基甲醯胺及其混合物。 The above reaction is preferably carried out in a solvent, and the solvent used includes but is not limited to: acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate Ester, n-hexane, dimethylsulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water, N,N-dimethylacetamide or N,N-dimethylformamide and its mixture.

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

實施例 Example

化合物的結構是藉由核磁共振(NMR)或/和質譜(MS)來確定的。NMR位移(δ)以10^-6(ppm)的單位給出。NMR的測定是用Bruker AVANCE-400核磁儀或Bruker AVANCE NEO 500M，測定溶劑為氘代二甲基亞碸(DMSO-d ₆)、氘代氯仿(CDCl₃)、氘代甲醇(CD₃OD)，內標為四甲基矽烷(TMS)。 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-400 nuclear magnetic instrument or Bruker AVANCE NEO 500M, and the solvent was deuterated dimethyl sulfoxide (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD) , the internal standard is tetramethylsilane (TMS).

MS的測定用Agilent 1200/1290 DAD-6110/6120 Quadrupole MS液質聯用儀(生產商：Agilent，MS型號：6110/6120 Quadrupole MS)、waters ACQuity UPLC-QD/SQD(生產商：waters，MS型號：waters ACQuity Qda Detector/waters SQ Detector)THERMO Ultimate 3000-Q Exactive(生產商：THERMO，MS型號：THERMO Q Exactive) For MS measurement, Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC/MS (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS Model: waters ACQuity Qda Detector/waters SQ Detector) THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS Model: THERMO Q Exactive)

高效液相色譜法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489高效液相色譜儀。 High Performance Liquid Chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD and a Waters HPLC e2695-2489 high performance liquid chromatograph.

手性HPLC分析測定使用Agilent 1260 DAD高效液相色譜儀。 Chiral HPLC analysis was determined using an Agilent 1260 DAD high performance liquid chromatograph.

高效液相製備色譜法使用Waters 2545-2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson GX-281製備型色譜儀。 High performance liquid preparative chromatography used Waters 2545-2767, Waters 2767-SQ Detector2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

手性製備使用Shimadzu LC-20AP製備型色譜儀。 Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

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

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

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

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

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

實施例中無特殊說明，反應能夠均在氬氣氛或氮氣氛下進行。 There is no special description in the examples, and the reactions can all be carried out in an argon atmosphere or a nitrogen atmosphere.

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

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

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

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

微波反應使用CEM Discover-S 908860型微波反應器。 The microwave reaction used a CEM Discover-S 908860 microwave reactor.

實施例中無特殊說明，溶液是指水溶液。 There is no special description in the examples, and the solution refers to an aqueous solution.

實施例中無特殊說明，反應的溫度為室溫，為20℃~30℃。 There is no special description in the examples, and the temperature of the reaction is room temperature, which is 20°C to 30°C.

實施例中的反應進程的監測採用薄層色譜法(TLC)，反應所使用的展開劑，純化化合物採用的管柱層析色譜法的沖提劑的體系和薄層色譜法的展開劑體系包括：A：二氯甲烷/甲醇體系，B：正己烷/乙酸乙酯體系，C：石油醚/乙酸乙酯體系，溶劑的體積比根據化合物的極性不同而進行調節，也可以加入少量的三乙胺和醋酸等鹼性或酸性試劑進行調節。 The monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of the column chromatography method and the developing solvent system of the thin layer chromatography method used for purifying the compound include: : A: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethyl ether can also be added Basic or acidic reagents such as amines and acetic acid are used for adjustment.

實施例1 Example 1

N-((R)-1-(3-胺基-5-(三氟甲基)苯基)乙基)-6-甲氧基-4-甲基-7-(((S)-四氫呋喃-3-基)氧基)酞嗪-1-胺1 N -(( R )-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-methoxy-4-methyl-7-((( S )-tetrahydrofuran -3-yl)oxy)phthalazin-1-amine 1

第一步 first step

(S)-4-甲氧基-3-((四氫呋喃-3-基)氧基)苯甲酸甲酯1b ( S )-4-Methoxy-3-((tetrahydrofuran-3-yl)oxy)benzoic acid methyl ester 1b

將3-羥基-4-甲氧基苯甲酸甲酯1a(5.00g，27.45mmol，上海畢得)、(3R)-四氫呋喃-3-醇(2.42g，27.45mmol，上海畢得)和三苯基膦(8.64g，32.94mmol，泰坦)溶於四氫呋喃(50mL)中，氬氣置換三次，0℃並且氬氣氛下緩慢滴加偶氮二甲酸二異丙酯(6.66g，32.94mmol，上海韶遠)。反應液升至室溫並且氬氣氛下攪拌16小時。將反應液倒入水(100mL)中，用乙酸乙酯(50mL×3)萃取。合併有機相，飽和氯化鈉溶液洗滌(100mL)，無水硫酸鈉乾燥並過濾。濾液減壓濃縮，所得殘餘物用管柱層析色譜法以沖提劑體系B純化得到標題化合物1b(4.5g)，產率：64%。 Methyl 3-hydroxy-4-methoxybenzoate 1a (5.00 g, 27.45 mmol, Shanghai Bide), ( 3R )-tetrahydrofuran-3-ol (2.42 g, 27.45 mmol, Shanghai Bide) and tris Phenylphosphine (8.64 g, 32.94 mmol, Titan) was dissolved in tetrahydrofuran (50 mL), replaced with argon three times, and diisopropyl azodicarboxylate (6.66 g, 32.94 mmol, Shanghai) was slowly added dropwise at 0°C under argon atmosphere. Shaoyuan). The reaction was warmed to room temperature and stirred under an argon atmosphere for 16 hours. The reaction solution was poured into water (100 mL), and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography with eluent system B to give the title compound 1b (4.5 g), yield: 64%.

MS m/z(ESI)：253.1[M+1]。 MS m/z (ESI): 253.1 [M+1].

第二步 second step

(S)-2-溴-4-甲氧基-5-((四氫呋喃-3-基)氧基)苯甲酸甲酯1c ( S )-Methyl 2-bromo-4-methoxy-5-((tetrahydrofuran-3-yl)oxy)benzoate 1c

將化合物1b(3.30g，13.08mmol)溶解於二氯甲烷(30mL)中，0℃分三批加入N-溴代琥珀醯亞胺(3.03g，17.01mmol，上海韶遠)，加完後加入氫溴酸(1mL，50%水溶液)，反應液緩慢升至室溫攪拌16小時。反應液減壓濃縮，所得殘餘物用管柱層析色譜法以沖提劑體系B純化得到標題化合物1c(1.6g)，產率：29%。 Compound 1b (3.30 g, 13.08 mmol) was dissolved in dichloromethane (30 mL), and N -bromosuccinimide (3.03 g, 17.01 mmol, Shanghai Shaoyuan) was added in three batches at 0° C. Hydrobromic acid (1 mL, 50% aqueous solution), the reaction solution was slowly warmed to room temperature and stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by column chromatography with eluent system B to obtain the title compound 1c (1.6 g), yield: 29%.

MS m/z(ESI)：331.0[M+1]。 MS m/z (ESI): 331.0 [M+1].

第三步 third step

(S)-2-(1-乙氧基乙烯基)-4-甲氧基-5-((四氫呋喃-3-基)氧基)苯甲酸甲酯1d ( S )-Methyl 2-(1-ethoxyvinyl)-4-methoxy-5-((tetrahydrofuran-3-yl)oxy)benzoate 1d

將化合物1c(1.6g，4.83mmol)、雙三苯基膦二氯化鈀(339mg，0.48mmol，百靈威)溶於1,4-二噁烷(20mL)，氬氣置換3次後緩慢滴加三丁基(1-乙氧基乙烯)錫(1.92g，5.31mmol，上海畢得)。反應液升至100℃攪拌16小時。反應液冷卻後倒入到飽和氟化鉀水溶液(50mL)中淬滅，乙酸乙酯(25mL×3)萃取。合併有機相，飽和氯化鈉溶液洗滌(100mL)，無水硫酸鈉乾燥並過濾。濾液減壓濃縮，所得殘餘物用管柱層析色譜法以沖提劑體系B純化得到標題化合物1d(1.3g)，產率：83%。 Compound 1c (1.6 g, 4.83 mmol) and bistriphenylphosphine palladium dichloride (339 mg, 0.48 mmol, Bailingwei) were dissolved in 1,4-dioxane (20 mL), replaced with argon for 3 times and slowly added dropwise Tributyl(1-ethoxyethylene)tin (1.92 g, 5.31 mmol, Shanghai Bide). The reaction solution was raised to 100°C and stirred for 16 hours. The reaction solution was cooled, poured into saturated potassium fluoride aqueous solution (50 mL) to quench, and extracted with ethyl acetate (25 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography with eluent system B to give the title compound 1d (1.3 g), yield: 83%.

MS m/z(ESI)：323.0[M+1]。 MS m/z (ESI): 323.0 [M+1].

第四步 the fourth step

(S)-2-乙醯基-4-甲氧基-5-((四氫呋喃-3-基)氧基)苯甲酸甲酯1e ( S )-2-Acetyl-4-methoxy-5-((tetrahydrofuran-3-yl)oxy)benzoic acid methyl ester 1e

將化合物1d(1.3g，4.0mmol)溶於四氫呋喃(8mL)，加入濃鹽酸(8mL)，攪拌反應2小時。反應液減壓濃縮，得到標題產物1e(1.1g)，產品不經純化直接用於下一步反應。 Compound 1d (1.3 g, 4.0 mmol) was dissolved in tetrahydrofuran (8 mL), concentrated hydrochloric acid (8 mL) was added, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the title product 1e (1.1 g), which was used in the next reaction without purification.

MS m/z(ESI)：295.1[M+1]。 MS m/z (ESI): 295.1 [M+1].

第五步 the fifth step

(S)-6-甲氧基-4-甲基-7-((四氫呋喃-3-基)氧基)酞嗪-1-酚1f ( S )-6-Methoxy-4-methyl-7-((tetrahydrofuran-3-yl)oxy)phthalazin-1-ol 1f

將化合物1e(1.1g，4.0mmol)、甲醇(6mL)和水合肼(3mL，80%水溶液)混合，升至80℃攪拌16小時。反應液冷卻後減壓濃縮，所得殘餘物用管柱層析色譜法以沖提劑體系B純化得到標題化合物1f(620mg)，產率：55.9%。 Compound 1e (1.1 g, 4.0 mmol), methanol (6 mL) and hydrazine hydrate (3 mL, 80% aqueous solution) were mixed, raised to 80°C and stirred for 16 hours. The reaction solution was cooled and concentrated under reduced pressure, and the obtained residue was purified by column chromatography using eluent system B to obtain the title compound 1f (620 mg), yield: 55.9%.

MS m/z(ESI)：277.1[M+1]。 MS m/z (ESI): 277.1 [M+1].

第六步 Step 6

(S)-1-氯-6-甲氧基-4-甲基-7-((四氫呋喃-3-基)氧基)酞嗪1g ( S )-1-Chloro-6-methoxy-4-methyl-7-((tetrahydrofuran-3-yl)oxy)phthalazine 1g

將化合物1f(200mg，0.724mmol)溶解於三氯氧磷(2mL)中，加熱至80℃攪拌16小時。反應液冷卻後減壓濃縮，所得殘餘物用管柱層析色譜法以沖提劑體系B純化得到標題化合物1g(170mg)，產率：79%。 Compound 1f (200 mg, 0.724 mmol) was dissolved in phosphorus oxychloride (2 mL), heated to 80°C and stirred for 16 hours. The reaction solution was cooled and concentrated under reduced pressure, and the obtained residue was purified by column chromatography using eluent system B to obtain 1 g (170 mg) of the title compound, yield: 79%.

MS m/z(ESI)：295.0[M+1]。 MS m/z (ESI): 295.0 [M+1].

第七步 Step 7

6-甲氧基-4-甲基-N-((R)-1-(3-硝基-5-(三氟甲基)苯基)乙基)-7-(((S)-四氫呋喃-3-基)氧基)酞嗪-1-胺1h 6-Methoxy-4-methyl- N -(( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-7-((( S )-tetrahydrofuran -3-yl)oxy)phthalazin-1-amine 1h

將化合物1g(170mg，0.577mmol)、化合物(R)-1-(3-硝基-5-(三氟甲基)苯基)乙胺鹽酸鹽(162mg，0.692mmol，採用專利申請“CN110167928A”中說明書第89頁的實施例B-6a公開的方法製備而得)、氯化銨(62mg，1.15mmol)和正丁醇(2mL)混合。反應液升溫至110℃攪拌16小時。反應液冷卻後減壓濃縮，所得殘餘物用管柱層析色譜法以沖提劑體系B純化得到標題化合物1h(190mg)，產率：66%。 Compound 1g (170mg, 0.577mmol), compound ( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethanamine hydrochloride (162mg, 0.692mmol) were prepared using patent application "CN110167928A""prepared by the method disclosed in Example B-6a on page 89 of the manual), ammonium chloride (62 mg, 1.15 mmol) and n-butanol (2 mL). The reaction solution was heated to 110°C and stirred for 16 hours. The reaction solution was cooled and concentrated under reduced pressure, and the obtained residue was purified by column chromatography using eluent system B to obtain the title compound 1h (190 mg), yield: 66%.

MS m/z(ESI)：493.1[M+1]。 MS m/z (ESI): 493.1 [M+1].

第八步 Step 8

將化合物1h(130mg，0.26mmol)溶於甲醇(2mL)，加入10%鈀碳(32mg，0.03mmol)，氫氣置換三次後攪拌16小時。將反應液用矽藻土過濾，濾液減壓濃縮後用高效液相製備色譜法純化得到標題化合物1(20.6mg，白色固體)，產率：13%。 Compound 1h (130 mg, 0.26 mmol) was dissolved in methanol (2 mL), 10% palladium on carbon (32 mg, 0.03 mmol) was added, hydrogen was replaced three times, and the mixture was stirred for 16 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure and purified by preparative high performance liquid chromatography to obtain the title compound 1 (20.6 mg, white solid), yield: 13%.

MS m/z(ESI)：463.1[M+1]。 MS m/z (ESI): 463.1 [M+1].

¹H NMR(400MHz,DMSO-d ₆)：δ 7.77(s,1H),7.25(s,1H),7.19(d,1H),6.84(d,2H),6.66(s,1H),5.49(s,2H),5.43-5.39(m,1H),5.36-5.32(m,1H),4.04-4.01(m,1H),3.96(s,3H),3.92-3.81(m,3H),2.60(s,3H),2.43-2.32(m,1H),2.09-2.01(m,1H),1.55(d,3H)。 ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.77(s,1H), 7.25(s,1H), 7.19(d,1H), 6.84(d,2H), 6.66(s,1H), 5.49( s,2H),5.43-5.39(m,1H),5.36-5.32(m,1H),4.04-4.01(m,1H),3.96(s,3H),3.92-3.81(m,3H),2.60( s, 3H), 2.43-2.32 (m, 1H), 2.09-2.01 (m, 1H), 1.55 (d, 3H).

實施例2 Example 2

2,2-二氟-2-(2-氟-3-((R)-1-((6-甲氧基-4-甲基-7-(((S)-四氫呋喃-3-基)氧基)酞嗪-1-基)胺基)乙基)苯基)乙醇2 2,2-Difluoro-2-(2-fluoro-3-(( R )-1-((6-methoxy-4-methyl-7-((( S )-tetrahydrofuran-3-yl) Oxy)phthalazin-1-yl)amino)ethyl)phenyl)ethanol 2

將化合物1g(45mg，0.15mmol)、化合物(R)-2-(3-(1-胺基乙基)-2-氟苯基)-2,2-二氟乙醇鹽酸鹽2a(47mg，0.18mmol，採用專利申請“US2019194192”中說明書第105頁的實施例B-5公開的方法製備而得)、N,N-二異丙基乙胺(60mg，0.46mmol)溶於2mL 1,4-二噁烷，微波120℃反應2小時。反應液冷卻後減壓濃縮，用高效液相製備色譜法純化所得標題化合物2(36mg)，產率：49.3%。 Compound 1g (45mg, 0.15mmol), compound ( R )-2-(3-(1-aminoethyl)-2-fluorophenyl)-2,2-difluoroethanol hydrochloride 2a (47mg, 0.18mmol, prepared by the method disclosed in Example B-5 on page 105 of the patent application "US2019194192"), N , N -diisopropylethylamine (60mg, 0.46mmol) was dissolved in 2mL 1,4 -Dioxane, microwave reaction at 120°C for 2 hours. The reaction solution was cooled, concentrated under reduced pressure, and the obtained title compound 2 (36 mg) was purified by preparative high performance liquid chromatography. Yield: 49.3%.

MS m/z(ESI)：478.1[M+1]。 MS m/z (ESI): 478.1 [M+1].

¹H NMR(500MHz,CD₃OD)：δ 7.80(s,1H),7.57-7.54(m,1H),7.44-7.41(m,1H),7.35(s,1H),7.16-7.13(m,1H),5.76-5.72(m,1H),5.40-5.38(m,1H),4.13-3.95(m,9H),2.67(s,3H),2.45-2.37(m,1H),2.29-2.23(m,1H),1.71-1.70(d,3H)。 ¹ H NMR (500 MHz, CD ₃ OD): δ 7.80 (s, 1H), 7.57-7.54 (m, 1H), 7.44-7.41 (m, 1H), 7.35 (s, 1H), 7.16-7.13 (m, 1H), 5.76-5.72(m, 1H), 5.40-5.38(m, 1H), 4.13-3.95(m, 9H), 2.67(s, 3H), 2.45-2.37(m, 1H), 2.29-2.23( m, 1H), 1.71-1.70(d, 3H).

實施例3 Example 3

1-((S)-3-((4-(((R)-1-(3-(1,1-二氟-2-羥乙基)-2-氟苯基)乙基)胺基)-7-甲氧基-1-甲基酞嗪-6-基)氧基)吡咯烷-1-基)乙酮3 1-(( S )-3-((4-((( R )-1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino )-7-methoxy-1-methylphthalazin-6-yl)oxy)pyrrolidin-1-yl)ethanone 3

第一步 first step

(R)-3-(甲苯磺醯氧基)吡咯烷-1-甲酸第三丁酯3b ( R )-3-(Tosyloxy)pyrrolidine-1-carboxylic acid tert-butyl ester 3b

將化合物(R)-1-第三丁氧羰基-3-羥基吡咯烷3a(1.5g，8mmol，上海畢得)、對甲苯磺醯氯(1.83g，9.6mmol，上海畢得)和三乙胺(1.62g，16mmol)溶於二氯甲烷(50mL)中，加入4-二甲胺基吡啶(0.1g，0.8mmol)，反應液攪拌2小時。將反應液倒入水(100mL)中，用乙酸乙酯(50mL×3)萃取。合併有機相，飽和氯化鈉溶液洗滌(100mL)，無水硫酸鈉乾燥並過濾。濾液減壓濃縮，所得殘餘物用管柱層析色譜法以沖提劑體系B純化得到標題化合物3b(1.1g)，產率：40.2%。 Compound ( R )-1-tert-butoxycarbonyl-3-hydroxypyrrolidine 3a (1.5 g, 8 mmol, Shanghai Bide), p-toluenesulfonyl chloride (1.83 g, 9.6 mmol, Shanghai Bide) and triethyl The amine (1.62 g, 16 mmol) was dissolved in dichloromethane (50 mL), 4-dimethylaminopyridine (0.1 g, 0.8 mmol) was added, and the reaction solution was stirred for 2 hours. The reaction solution was poured into water (100 mL), and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography with eluent system B to give the title compound 3b (1.1 g), yield: 40.2%.

MS m/z(ESI)：342.4[M+1]。 MS m/z (ESI): 342.4 [M+1].

第二步 second step

2-溴-5-羥基-4-甲氧基苯甲酸甲酯3d Methyl 2-bromo-5-hydroxy-4-methoxybenzoate 3d

將化合物2-溴-5-羥基-4-甲氧基苯甲酸3c(5g，20.2mmol)溶於30mL甲醇中，冰浴下滴加濃硫酸(1.98g，20.2mmol)，回流攪拌反應14小時，反應液冷卻後減壓濃縮，殘餘物倒入冰水中，析出固體，過濾，乾燥後得到標題化合物3d(5g)，產率：94.6%。 The compound 2-bromo-5-hydroxy-4-methoxybenzoic acid 3c (5 g, 20.2 mmol) was dissolved in 30 mL of methanol, concentrated sulfuric acid (1.98 g, 20.2 mmol) was added dropwise under an ice bath, and the reaction was stirred under reflux for 14 hours , the reaction solution was cooled and concentrated under reduced pressure, the residue was poured into ice water, the solid was precipitated, filtered and dried to obtain the title compound 3d (5 g), yield: 94.6%.

MS m/z(ESI)：261.1[M+1]。 MS m/z (ESI): 261.1 [M+1].

第三步 third step

5-乙醯氧基-2-溴-4-甲氧基苯甲酸甲酯3e Methyl 5-acetoxy-2-bromo-4-methoxybenzoate 3e

將化合物3d(2g，7.66mmol)溶於20mL二氯甲烷中，加入N,N-二異丙基乙基胺(2.97g，22.98mmol)，冰浴下滴加乙酸酐(0.937g，9.19mmol)，自然升至室溫反應14小時，反應液減壓濃縮，所得殘餘物用管柱層析色譜法以沖提劑體系B純化得到標題化合物3e(2g)，產率：86%。 Compound 3d (2 g, 7.66 mmol) was dissolved in 20 mL of dichloromethane, N , N -diisopropylethylamine (2.97 g, 22.98 mmol) was added, and acetic anhydride (0.937 g, 9.19 mmol) was added dropwise under an ice bath ), the reaction was naturally raised to room temperature for 14 hours, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by column chromatography with eluent system B to obtain the title compound 3e (2 g), yield: 86%.

MS m/z(ESI)：303.1[M+1]。 MS m/z (ESI): 303.1 [M+1].

第四步 the fourth step

5-乙醯氧基-2-(1-乙氧基乙烯基)-4-甲氧基苯甲酸甲酯3f 5-Acetyloxy-2-(1-ethoxyvinyl)-4-methoxybenzoic acid methyl ester 3f

將化合物3e(2.3g，7.59mmol)、雙三苯基膦二氯化鈀(532mg，0.76mmol，百靈威)溶於1,4-二噁烷(20mL)，氬氣置換3次後緩慢滴加三丁基(1-乙氧基乙烯)錫(3g，8.35mmol，上海畢得)。反應液升至100℃攪拌16小時。反應液冷卻後減壓濃縮，得到標題化合物3f(2.3g)，產品不經純化直接用於下一步反應。 Compound 3e (2.3 g, 7.59 mmol) and bistriphenylphosphine palladium dichloride (532 mg, 0.76 mmol, Bailingwei) were dissolved in 1,4-dioxane (20 mL), replaced with argon three times and then slowly added dropwise Tributyl(1-ethoxyethylene)tin (3 g, 8.35 mmol, Shanghai Bide). The reaction solution was raised to 100°C and stirred for 16 hours. The reaction solution was cooled and concentrated under reduced pressure to obtain the title compound 3f (2.3 g), which was used in the next reaction without purification.

MS m/z(ESI)：295.1[M+1]。 MS m/z (ESI): 295.1 [M+1].

第五步 the fifth step

5-乙醯氧基-2-乙醯基-4-甲氧基苯甲酸甲酯3g 5-Acetyloxy-2-acetyl-4-methoxybenzoic acid methyl ester 3g

將化合物3f(2.2g，7.45mmol)溶於四氫呋喃(8mL)中，加入濃鹽酸(10mL)，攪拌反應2小時。反應液減壓濃縮，所得殘餘物用管柱層析色譜法以沖提劑體系B純化得到標題化合物3g(2g)，產率：98%。 Compound 3f (2.2 g, 7.45 mmol) was dissolved in tetrahydrofuran (8 mL), concentrated hydrochloric acid (10 mL) was added, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by column chromatography using eluent system B to obtain the title compound 3 g (2 g), yield: 98%.

MS m/z(ESI)：267.1[M+1]。 MS m/z (ESI): 267.1 [M+1].

第六步 Step 6

6-甲氧基-4-甲基酞嗪-1,7-二酚3h 6-Methoxy-4-methylphthalazine-1,7-diol 3h

將化合物3g(2g，7.51mmol)，甲醇(10mL)和水合肼(521mg，10.2mmol)混合，升至80℃攪拌16小時。反應液冷卻，減壓濃縮後過濾，固體用冰乙醇洗滌後乾燥得到標題化合物3h(1.4g)，產率90.7%。 Compound 3 g (2 g, 7.51 mmol), methanol (10 mL) and hydrazine hydrate (521 mg, 10.2 mmol) were mixed, and the mixture was heated to 80°C and stirred for 16 hours. The reaction solution was cooled, concentrated under reduced pressure, filtered, and the solid was washed with ice ethanol and dried to obtain the title compound 3h (1.4 g) in a yield of 90.7%.

MS m/z(ESI)：207.1[M+1]。 MS m/z (ESI): 207.1 [M+1].

第七步 Step 7

(S)-3-((4-羥基-7-甲氧基-1-甲基酞嗪-6基)氧基)吡咯烷-1-甲酸第三丁酯3i ( S )-3-((4-Hydroxy-7-methoxy-1-methylphthalazin-6yl)oxy)pyrrolidine-1-carboxylic acid tert-butyl ester 3i

將化合物3b(120mg，0.38mmol)、3h(90mg，0.41mmol)、N,N-二甲基甲醯胺(3mL)加入反應瓶中，升至70℃攪拌5小時。反應液冷卻後減壓濃縮，將反應液倒入水(20mL)中，用乙酸乙酯(15mL×3)萃取。合併有機相，飽和氯化鈉溶液洗滌(20mL)，無水硫酸鈉乾燥並過濾。濾液減壓濃縮得到粗品標題化合物3i(80mg)，產率：51%。 Compound 3b (120 mg, 0.38 mmol), 3h (90 mg, 0.41 mmol), and N , N -dimethylformamide (3 mL) were added to the reaction flask, and the mixture was heated to 70° C. and stirred for 5 hours. The reaction solution was cooled, concentrated under reduced pressure, poured into water (20 mL), and extracted with ethyl acetate (15 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the crude title compound 3i (80 mg), yield: 51%.

MS m/z(ESI)：376.4[M+1]。 MS m/z (ESI): 376.4 [M+1].

第八步 Step 8

(S)-1-氯-6-甲氧基-4-甲基-7-(吡咯烷-3-基氧基)酞嗪鹽酸鹽3j ( S )-1-Chloro-6-methoxy-4-methyl-7-(pyrrolidin-3-yloxy)phthalazine hydrochloride 3j

將化合物3i(40mg，0.106mmol)溶於三氯氧磷(2mL)，升至70℃攪拌3小時。反應液冷卻後減壓濃縮得到標題化合物3j(50mg)，產品不經純化直接用於下一步反應。 Compound 3i (40 mg, 0.106 mmol) was dissolved in phosphorus oxychloride (2 mL), raised to 70°C and stirred for 3 hours. The reaction solution was cooled and concentrated under reduced pressure to obtain the title compound 3j (50 mg). The product was used in the next reaction without purification.

MS m/z(ESI)：294.1[M+1]。 MS m/z (ESI): 294.1 [M+1].

第九步 Step 9

(S)-1-(3-((4-氯-7-甲氧基-1-甲基酞嗪-6-基)氧基)吡咯烷-1-基)乙酮3k ( S )-1-(3-((4-Chloro-7-methoxy-1-methylphthalazin-6-yl)oxy)pyrrolidin-1-yl)ethanone 3k

將化合物3j(50mg，0.17mmol)溶於二氯甲烷(5mL)，加入N,N-二異丙基乙胺(70mg，0.51mmol)、乙醯氯(20mg，0.25mmol)攪拌反應2小時。所得殘餘物用管柱層析色譜法以沖提劑體系B純化得到標題化合物3k(50mg)，產率：87.4%。 Compound 3j (50 mg, 0.17 mmol) was dissolved in dichloromethane (5 mL), N , N -diisopropylethylamine (70 mg, 0.51 mmol) and acetyl chloride (20 mg, 0.25 mmol) were added and the reaction was stirred for 2 hours. The resulting residue was purified by column chromatography with eluent system B to give the title compound 3k (50 mg), yield: 87.4%.

MS m/z(ESI)：336.3[M+1]。 MS m/z (ESI): 336.3 [M+1].

第十步 Step 10

將化合物3k(30mg，0.089mmol)、(R)-2-(3-(1-胺基乙基)-2-氟苯基)-2,2-二氟乙醇鹽酸鹽(2a)(40mg，0.178mmol)、氯化銨(10mg，0.178mmol)和正丁醇(1mL)混合。微波升溫至110℃攪拌1小時。將反應液用矽藻土過濾，濾液減壓濃縮後用高效液相製備色譜法純化得到標題化合物3(3mg)，產率：6.5%。 Compound 3k (30 mg, 0.089 mmol), ( R )-2-(3-(1-aminoethyl)-2-fluorophenyl)-2,2-difluoroethanol hydrochloride ( 2a ) (40 mg , 0.178 mmol), ammonium chloride (10 mg, 0.178 mmol) and n-butanol (1 mL) were mixed. The microwave was heated to 110°C and stirred for 1 hour. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure and purified by preparative high performance liquid chromatography to obtain the title compound 3 (3 mg), yield: 6.5%.

MS m/z(ESI)：519.2[M+1]。 MS m/z (ESI): 519.2 [M+1].

¹H NMR(500MHz,CD3OD)：δ 7.73(s,1H),7.61-7.58(m,1H),7.50-7.47(m,2H),7.27-7.25(m,1H),5.75-5.71(m,1H),4.15-4.10(m,3H),3.82-3.79(m,2H),3.62-3.59(m,2H),2.81-2.77(m,1H),2.31-2.28(m,2H),2.25-2.22(m,3H),2.15-2.12(m,2H),1.72-1.69(m,3H),1.56-1.54(d,3H)。 ¹ H NMR (500MHz, CD3OD): δ 7.73(s,1H), 7.61-7.58(m,1H), 7.50-7.47(m,2H), 7.27-7.25(m,1H), 5.75-5.71(m, 1H), 4.15-4.10(m, 3H), 3.82-3.79(m, 2H), 3.62-3.59(m, 2H), 2.81-2.77(m, 1H), 2.31-2.28(m, 2H), 2.25- 2.22 (m, 3H), 2.15-2.12 (m, 2H), 1.72-1.69 (m, 3H), 1.56-1.54 (d, 3H).

實施例4 Example 4

(R)-1-(4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)胺基)-7-甲氧基-1-甲基酞嗪-6-基)-4-羥基哌啶-1-基)乙酮4 ( R )-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalein oxazin-6-yl)-4-hydroxypiperidin-1-yl)ethanone 4

第一步 first step

1,7-二氯-6-甲氧基-4-甲基酞嗪4a 1,7-Dichloro-6-methoxy-4-methylphthalazine 4a

將化合物3h(2g，9.7mmol)與三氯氧磷(15mL)混合，緩慢加入N,N-二異丙基乙胺(3.8g，29.1mmol)，升溫至90℃反應14小時。反應液減壓濃縮，倒入冰水，用飽和碳酸氫鈉水溶液調節pH至7-8左右，二氯甲烷萃取(30mL×2)，無水硫酸鈉乾燥，過濾，減壓濃縮，殘餘物用管柱層析色譜法以沖提劑體系B純化得到標題化合物4a(1.4g)，產率：59.4%。 Compound 3h (2 g, 9.7 mmol) was mixed with phosphorus oxychloride (15 mL), N , N -diisopropylethylamine (3.8 g, 29.1 mmol) was slowly added, and the temperature was raised to 90° C. to react for 14 hours. The reaction solution was concentrated under reduced pressure, poured into ice water, adjusted to pH 7-8 with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography with eluent system B afforded the title compound 4a (1.4 g), yield: 59.4%.

MS m/z(ESI)：243.1[M+1]。 MS m/z (ESI): 243.1 [M+1].

第二步 second step

(R)-7-氯-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-6-甲氧基-4-甲基酞嗪-1-胺4b ( R )-7-Chloro- N- (1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-methoxy-4-methylphthalazin-1-amine 4b

將化合物4a(150mg，0.62mmol)、化合物(R)-1-(3-(二氟甲基)-2-氟苯基)乙胺鹽酸鹽(139mg，0.62mmol，採用專利申請“EP2018086197”中說明書第141頁的實施例B-5公開的方法製備而得)、氯化銨(16.5mg，0.31mmol)和正丁醇(2mL)混合。微波120℃反應1小時。反應液冷卻後減壓濃縮，所得殘餘物用高效液相製備色譜法純化得到標題化合物4b(15mg)，產率：6.15%。 Compound 4a (150mg, 0.62mmol), compound ( R )-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine hydrochloride (139mg, 0.62mmol) were prepared using patent application "EP2018086197" prepared by the method disclosed in Example B-5 on page 141 of the specification), ammonium chloride (16.5 mg, 0.31 mmol) and n-butanol (2 mL). Microwave at 120°C for 1 hour. The reaction solution was cooled and concentrated under reduced pressure, and the obtained residue was purified by high performance liquid preparative chromatography to obtain the title compound 4b (15 mg), yield: 6.15%.

MS m/z(ESI)：396.1[M+1]。 MS m/z (ESI): 396.1 [M+1].

第三步 third step

(R)-1-(4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)胺基)-7-甲氧基-1-甲基酞嗪-6-基)-5,6-二氫吡啶-1(2H)-基)乙酮4c ( R )-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalein oxazin-6-yl)-5,6-dihydropyridin-1( 2H )-yl)ethanone 4c

將化合物4b(15mg，0.038mmol)、化合物1-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,6-二氫吡啶-1(2H)-基)乙酮(11mg，0.042mmol，上海畢得)、三(二亞苄基丙酮)二鈀(10.4mg，0.011mmol，百靈威)、2-雙環己基膦-2'-甲基聯苯(4.4mg，0.011mmol，上海韶遠)、無水碳酸鉀(16mg，0.011mmol)溶於1,4-二噁烷(2mL)和水(0.5mL)，微波100℃反應1小時，反應液減壓濃縮，採用薄層色譜法以沖提劑體系A純化得到標題化合物4c(10mg)，產率：54.5%。 Compound 4b (15 mg, 0.038 mmol), compound 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3 ,6-dihydropyridin-1( 2H )-yl)ethanone (11mg, 0.042mmol, Shanghai Bide), tris(dibenzylideneacetone)dipalladium (10.4mg, 0.011mmol, Bailingwei), 2- Dicyclohexylphosphine-2'-methylbiphenyl (4.4 mg, 0.011 mmol, Shanghai Shaoyuan), anhydrous potassium carbonate (16 mg, 0.011 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.5 mL) , microwave reaction at 100 °C for 1 hour, the reaction solution was concentrated under reduced pressure, and purified by thin layer chromatography with eluent system A to obtain the title compound 4c (10 mg), yield: 54.5%.

MS m/z(ESI)：485.2[M+1]。 MS m/z (ESI): 485.2 [M+1].

第四步 the fourth step

將化合物4c(10mg，20.6μmol)、三(2,2,6,6-四甲基-3,5-庚烯酸)錳(3mg，5μmol，上海畢得)、苯矽烷(4.5mg，41.2μmol，泰坦)溶於異丙醇(2mL)和二氯甲烷(0.2mL)，氧氣置換，攪拌反應14小時。反應液減壓濃縮，殘餘物用高效液相製備色譜法純化得到標題化合物4(1.2mg)，產率：11.5%。 Compound 4c (10 mg, 20.6 μmol), tris(2,2,6,6-tetramethyl-3,5-heptenoic acid) manganese (3 mg, 5 μmol, Shanghai Bide), phenylsilane (4.5 mg, 41.2 μmol, Titan) was dissolved in isopropanol (2 mL) and dichloromethane (0.2 mL), oxygen was replaced, and the reaction was stirred for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography to obtain the title compound 4 (1.2 mg), yield: 11.5%.

MS m/z(ESI)：503.2[M+1]。 MS m/z (ESI): 503.2 [M+1].

¹H NMR(500MHz,CD₃OD)：δ 8.53(s,1H),7.61-7.58(m,1H),7.46-7.44(m,1H),7.43(s,1H),7.30-7.24(m,1H),7.19-6.90(q,1H),5.76-5.55(m,1H),4.66-4.49(m,1H),4.11(s,3H),3.91-3.90(m,1H),3.88-3.87(m,1H),3.21-3.20(m,1H),2.64(s,3H),2.62-2.52(m,2H),2.20(s,3H),1.86-1.76(m,2H),1.70(d,3H)。 ¹ H NMR (500 MHz, CD ₃ OD): δ 8.53 (s, 1H), 7.61-7.58 (m, 1H), 7.46-7.44 (m, 1H), 7.43 (s, 1H), 7.30-7.24 (m, 1H), 7.19-6.90(q, 1H), 5.76-5.55(m, 1H), 4.66-4.49(m, 1H), 4.11(s, 3H), 3.91-3.90(m, 1H), 3.88-3.87( m, 1H), 3.21-3.20(m, 1H), 2.64(s, 3H), 2.62-2.52(m, 2H), 2.20(s, 3H), 1.86-1.76(m, 2H), 1.70(d, 3H).

實施例5 Example 5

(R)-1-(4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)胺基)-7-甲氧基-1-甲基酞嗪-6-基)-4-羥基哌啶-1-基)-2-甲氧基乙-1-酮5 ( R )-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalein oxazin-6-yl)-4-hydroxypiperidin-1-yl)-2-methoxyethan-1-one 5

第一步 first step

4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,2,3,6-四氫吡啶鹽酸鹽5b 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborol-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride 5b

將化合物4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-5,6-二氫吡啶-1(2H)-羧酸第三丁酯5a(1g，3.23mmol，上海畢得)溶於4N鹽酸1,4-二噁烷溶液中，攪拌反應3小時。反應液減壓濃縮得到粗產物5b(790mg)，產率：99.4%，產物不經純化，直接用於下一步反應。 Compound 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-5,6-dihydropyridine-1( 2H ) - 3-butyl carboxylate 5a (1 g, 3.23 mmol, Shanghai Bide) was dissolved in a 4N hydrochloric acid solution in 1,4-dioxane, and the reaction was stirred for 3 hours. The reaction solution was concentrated under reduced pressure to obtain crude product 5b (790 mg), yield: 99.4%, and the product was directly used in the next reaction without purification.

MS m/z(ESI)：210.1[M+1]。 MS m/z (ESI): 210.1 [M+1].

第二步 second step

2-甲氧基-1-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,6-二氫吡啶-1(2H)-基)乙-1-酮5c 2-Methoxy-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3,6-dihydro Pyridin-1( 2H )-yl)ethan-1-one 5c

將化合物5b(1.7g，6.92mmol)、甲氧基乙酸(805mg，8.93mmol，上海韶遠)溶解於四氫呋喃(5mL)中，依次加入2-(7-偶氮苯并***)-N,N,N,N-四甲基脲六氟磷酸鹽(4.63g，12.17mmol)與N,N-二異丙基乙胺(2.63g，20.35mmol)，攪拌反應14小時。反應液減壓濃縮，殘餘物管柱層析色譜法以沖提劑體系A純化，得到標題化合物5c(1.2g)，產率：52.5%。 Compound 5b (1.7 g, 6.92 mmol), methoxyacetic acid (805 mg, 8.93 mmol, Shanghai Shaoyuan) were dissolved in tetrahydrofuran (5 mL), followed by adding 2-(7-azobenzotriazole) -N , N , N , N -tetramethylurea hexafluorophosphate (4.63 g, 12.17 mmol) and N , N -diisopropylethylamine (2.63 g, 20.35 mmol) were reacted with stirring for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system A to obtain the title compound 5c (1.2 g), yield: 52.5%.

MS m/z(ESI)：282.0[M+1]。 MS m/z (ESI): 282.0 [M+1].

第三步 third step

採用實施例4中的合成路線第三至第四步，將第三步原料化合物1-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,6-二氫吡啶-1(2H)-基)乙酮替換為化合物5c，製得化合物5(15mg)，產率：22%。 Using the third to fourth steps of the synthetic route in Example 4 , the third step raw material compound 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane Cyclopentan-2-yl)-3,6-dihydropyridin-1( 2H )-yl)ethanone was replaced with compound 5c to obtain compound 5 (15 mg), yield: 22%.

MS m/z(ESI)：533.1[M+1]。 MS m/z (ESI): 533.1 [M+1].

¹H NMR(500MHz，甲醇-d ₄)：δ 8.51(s,1H),7.59(t,1H),7.43(t,1H),7.34(s,1H),7.17(t,1H),7.00(t,1H),5.72(d,1H),4.47(s,1H),4.31(d,1H),4.20(s,1H),4.05(s,3H),3.83(dd,1H),3.63(t,1H),3.47(s,3H),3.23(t,1H),2.67(s,3H),2.64-2.50(m,2H),1.80(t,2H),1.69(d,3H)。 ¹ H NMR (500 MHz, methanol- d ₄ ): δ 8.51(s,1H), 7.59(t,1H), 7.43(t,1H), 7.34(s,1H), 7.17(t,1H), 7.00( t, 1H), 5.72(d, 1H), 4.47(s, 1H), 4.31(d, 1H), 4.20(s, 1H), 4.05(s, 3H), 3.83(dd, 1H), 3.63(t , 1H), 3.47(s, 3H), 3.23(t, 1H), 2.67(s, 3H), 2.64-2.50(m, 2H), 1.80(t, 2H), 1.69(d, 3H).

實施例6 Example 6

(R)-4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)胺基)-7-甲氧基-1-甲基酞嗪-6-基)-4-羥基-N,N-二甲基環己烷-1-甲醯胺6 ( R )-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine-6 -yl)-4-hydroxy- N , N -dimethylcyclohexane-1-carboxamide 6

第一步 first step

4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)環己-3-烯羧酸6b 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl)cyclohex-3-enecarboxylic acid 6b

將化合物4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)環己-3-烯羧酸甲酯6a(1g，3.76mmol)、一水合氫氧化鋰(631mg，15mmol)溶於10mL四氫呋喃、2mL水和5mL甲醇的混合溶劑中，攪拌反應16小時，滴加2N鹽酸，調節pH至5-6，減壓濃縮至乾，得到標題化合物6b(1.8g)，不經純化直接下一步。 The compound 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)cyclohex-3-enecarboxylic acid methyl ester 6a (1 g, 3.76 mmol), lithium hydroxide monohydrate (631 mg, 15 mmol) were dissolved in a mixed solvent of 10 mL of tetrahydrofuran, 2 mL of water and 5 mL of methanol, stirred for 16 hours, added dropwise with 2N hydrochloric acid, adjusted to pH 5-6, and concentrated under reduced pressure to Drying gave the title compound 6b (1.8 g), which was taken to the next step without purification.

MS m/z(ESI)：251.1[M-1]。 MS m/z (ESI): 251.1 [M-1].

第二步 second step

N,N-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)環己-3-烯甲醯胺6c N , N -Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)cyclohex-3-enecarboxamide Amine 6c

將化合物6b(150mg，595μmol)和2M的N,N-二甲基胺(595μL，1.2mmol)溶解於N,N-二甲基甲醯胺(2mL)中，依次加入N,N-二異丙基乙胺(154mg，1.2mmol)和2-(7-偶氮苯并***)-N,N,N,N-四甲基脲六氟磷酸鹽(280mg，1.2mmol)，氮氣氛下反應14小時。反應液濃縮，殘餘物用管柱層析色譜法以沖提劑體系A純化，得到標題化合物6c(150mg)，產率：90%。 Compound 6b (150 mg, 595 μmol) and 2M N , N -dimethylamine (595 μL, 1.2 mmol) were dissolved in N , N -dimethylformamide (2 mL), followed by N , N -diiso Propylethylamine (154 mg, 1.2 mmol) and 2-(7-azobenzotriazole) -N , N , N , N -tetramethylurea hexafluorophosphate (280 mg, 1.2 mmol) under nitrogen atmosphere React for 14 hours. The reaction solution was concentrated, and the residue was purified by column chromatography with eluent system A to obtain the title compound 6c (150 mg), yield: 90%.

MS m/z(ESI)：280.1[M+1]。 MS m/z (ESI): 280.1 [M+1].

第三步 third step

採用實施例4中的合成路線，將第三步原料化合物1-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3,6-二氫吡啶-1(2H)-基)乙酮替換為化合物6c，製得化合物6(3mg)，產率：14.4%。 Using the synthetic route in Example 4 , the raw material compound 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- yl)-3,6-dihydropyridin-1( 2H) -yl)ethanone was replaced with compound 6c to obtain compound 6 (3 mg), yield: 14.4%.

MS m/z(ESI)：531.1[M+1]。 MS m/z (ESI): 531.1 [M+1].

¹H NMR(400MHz,CD₃OD)：δ 8.41(s,1H),7.60(t,1H),7.46-7.43(m,2H),7.20-7.14(m,1H),7.02-6.92(m,1H),5.74(q,1H),4.08(s,3H),3.16(s,3H),3.02-2.91(m,6H),2.69(s,3H),2.13-2.07(m,3H),1.82-1.70(m,6H)。 ¹ H NMR (400 MHz, CD ₃ OD): δ 8.41 (s, 1H), 7.60 (t, 1H), 7.46-7.43 (m, 2H), 7.20-7.14 (m, 1H), 7.02-6.92 (m, 1H), 5.74(q, 1H), 4.08(s, 3H), 3.16(s, 3H), 3.02-2.91(m, 6H), 2.69(s, 3H), 2.13-2.07(m, 3H), 1.82 -1.70(m, 6H).

實施例7 Example 7

(S)-1-(4-(4-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)胺基)-7-甲氧基-1-甲基酞嗪-6-基)哌啶-1-基)-2-羥基丙-1-酮7 ( S )-1-(4-(4-((( R )-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1 -Methylphthalazin-6-yl)piperidin-1-yl)-2-hydroxypropan-1-one 7

第一步 first step

(R)-4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)胺基)-7-甲氧基-1-甲基酞嗪-6-基)-5,6-二氫吡啶-1(2H)-羧酸第三丁酯7a ( R )-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine-6 -yl)-5,6-dihydropyridine-1( 2H )-carboxylate tert-butyl ester 7a

將化合物4b(35mg，0.088mmol)、化合物4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊戊烷-2-基)-3,6-二氫-2H-吡啶-1-羧酸第三丁酯 (42mg，0.132mmol，上海畢得)、[1,1'-雙(二異丙基膦)二茂鐵]二氯鈀(10mg，0.017mmol)、無水碳酸鉀(37mg，0.265mmol)溶於1,4-二噁烷(2mL)和水(0.5mL)，110℃反應4小時，反應液減壓濃縮，採用薄層色譜法以沖提劑體系A純化得到標題化合物7a(45mg)，產率：93.7%。 Compound 4b (35 mg, 0.088 mmol), compound 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3,6 - Dihydro- 2H -pyridine-1-carboxylate tert-butyl ester (42 mg, 0.132 mmol, Shanghai Bide), [1,1'-bis(diisopropylphosphine)ferrocene]dichloropalladium ( 10 mg, 0.017 mmol), anhydrous potassium carbonate (37 mg, 0.265 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.5 mL), reacted at 110 °C for 4 hours, the reaction solution was concentrated under reduced pressure, and thin layer chromatography was used Purification with eluent system A gave the title compound 7a (45 mg), yield: 93.7%.

MS m/z(ESI)：543.2[M+1]。 MS m/z (ESI): 543.2 [M+1].

第二步 second step

(R)-4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)胺基)-7-甲氧基-1-甲基酞嗪-6-基)哌啶-1-羧酸第三丁酯7b ( R )-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine-6 -yl)piperidine-1-carboxylic acid tert-butyl ester 7b

將化合物7a(45mg，82μmol)溶於甲醇(3mL)，加入鈀碳(10%)(13mg)，氫氣置換，攪拌反應14小時。反應液減壓濃縮得到標題化合物7b(40mg)，產率：88.6%。 Compound 7a (45 mg, 82 μmol) was dissolved in methanol (3 mL), palladium carbon (10%) (13 mg) was added, hydrogen was replaced, and the reaction was stirred for 14 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound 7b (40 mg), yield: 88.6%.

MS m/z(ESI)：545.3[M+1]。 MS m/z (ESI): 545.3 [M+1].

第三步 third step

(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)胺基)-6-甲氧基-4-甲基-7-(哌啶-4-基)酞嗪-1-胺鹽酸鹽7c ( R )-N-(1-(3-(difluoromethyl)-2 - fluorophenyl)ethyl)amino)-6-methoxy-4-methyl-7-(piperidine-4 -yl)phthalazin-1-amine hydrochloride 7c

將化合物7b(40mg，0.073mmol)溶於4N鹽酸1,4-二噁烷溶液中，攪拌反應2小時。反應液減壓濃縮得到粗產物7c(35mg)，產率：99.1%，產物不經純化，直接用於下一步反應。 Compound 7b (40 mg, 0.073 mmol) was dissolved in a 4N hydrochloric acid solution in 1,4-dioxane, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain crude product 7c (35 mg), yield: 99.1%, and the product was directly used in the next reaction without purification.

MS m/z(ESI)：445.2[M+1]。 MS m/z (ESI): 445.2 [M+1].

第四步 the fourth step

將化合物7c(35mg，0.072mmol)、L-乳酸(13mg，0.145mmol，上海韶遠試劑有限公司)溶解於N,N-二甲基甲醯胺(2mL)中，依次加入2-(7-偶氮苯并***)-N,N,N,N-四甲基脲六氟磷酸鹽(25mg，0.109mmol)與N,N-二異丙基乙胺(46mg，0.364mmol)，攪拌反應3小時。反應液減壓濃縮，殘餘物高效液相製備色法純化得到標題化合物7(12mg)，產率：31.9%。 Compound 7c (35mg, 0.072mmol), L -lactic acid (13mg, 0.145mmol, Shanghai Shaoyuan Reagent Co., Ltd.) were dissolved in N , N -dimethylformamide (2mL), followed by adding 2-(7- Azobenzotriazole) -N , N , N , N -tetramethylurea hexafluorophosphate (25mg, 0.109mmol) and N , N -diisopropylethylamine (46mg, 0.364mmol), stirred for reaction 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography to obtain the title compound 7 (12 mg), yield: 31.9%.

MS m/z(ESI)：517.2[M+1]。 MS m/z (ESI): 517.2 [M+1].

¹H NMR(500MHz,CD₃OD)：δ 8.27(t,1H),7.56(t,1H),7.44(t,1H),7.32(d,1H),7.20-7.10(m,1H),5.74(q,1H),4.77(d,1H),4.07(d,2H),3.52(d,2H),3.29(d,4H),2.91-2.83(m,1H),2.68(s,2H),2.00(d,3H),1.88(s,2H),1.69(d,3H),1.37(d,3H)。 ¹ H NMR (500 MHz, CD ₃ OD): δ 8.27 (t, 1H), 7.56 (t, 1H), 7.44 (t, 1H), 7.32 (d, 1H), 7.20-7.10 (m, 1H), 5.74 (q, 1H), 4.77(d, 1H), 4.07(d, 2H), 3.52(d, 2H), 3.29(d, 4H), 2.91-2.83(m, 1H), 2.68(s, 2H), 2.00(d,3H), 1.88(s,2H), 1.69(d,3H), 1.37(d,3H).

實施例8 Example 8

1-((S)-3-((4-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)胺基)-7-甲氧基-1-甲基酞嗪-6-基)氧基)吡咯烷-1-基)乙酮8 1-(( S )-3-((4-((( R )-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy- 1-Methylphthalazin-6-yl)oxy)pyrrolidin-1-yl)ethanone 8

採用實施例3中的合成路線，將第十步原料化合物(R)-2-(3-(1-胺基乙基)-2-氟苯基)-2,2-二氟乙醇鹽酸鹽替換為化合物(R)-1-(3-(二氟甲基)-2-氟苯基)乙胺鹽酸鹽，製得標題化合物8(5mg)，產率：4.3%。 Using the synthetic route in Example 3 , the tenth step raw material compound ( R )-2-(3-(1-aminoethyl)-2-fluorophenyl)-2,2-difluoroethanol hydrochloride Substituted with compound ( R )-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine hydrochloride, the title compound 8 (5 mg) was obtained, yield: 4.3%.

MS m/z(ESI)：489.2[M+1]。 MS m/z (ESI): 489.2 [M+1].

¹H NMR(500MHz,CD₃OD)：δ 7.93(d,1H),7.58(t,1H),7.48-7.40(m,2H),7.18(t,1H),5.71-5.66(m,1H),4.04-4.04(m,2H),3.89-3.82(m,2H),3.63-3.52(m,2H),2.70(s,1H),2.47-2.29(m,2H),2.24-2.15(m,3H),2.13-2.21(m,2H),1.71(d,3H),1.61(d,3H)。 ¹ H NMR (500 MHz, CD ₃ OD): δ 7.93 (d, 1H), 7.58 (t, 1H), 7.48-7.40 (m, 2H), 7.18 (t, 1H), 5.71-5.66 (m, 1H) ,4.04-4.04(m,2H),3.89-3.82(m,2H),3.63-3.52(m,2H),2.70(s,1H),2.47-2.29(m,2H),2.24-2.15(m, 3H), 2.13-2.21 (m, 2H), 1.71 (d, 3H), 1.61 (d, 3H).

實施例9 Example 9

(R)-(4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)胺基)-7-甲氧基-1-甲基酞嗪-6-基)-4-羥基環己基)(嗎啉基)甲酮9 ( R )-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine- 6-yl)-4-hydroxycyclohexyl)(morpholinyl)methanone 9

採用實施例6中的合成路線，將第二步原料化合物N,N-二甲基胺替換為化合物嗎啡啉，製得化合物9(10mg)，產率：48.4%。 Using the synthetic route in Example 6 , the second-step raw material compound N , N -dimethylamine was replaced with the compound morpholine to obtain compound 9 (10 mg), yield: 48.4%.

MS m/z(ESI)：573.1[M+1]。 MS m/z (ESI): 573.1 [M+1].

¹H NMR(500MHz，甲醇-d ₄)：δ 8.40(s,1H),7.60(t,1H),7.44(t,1H),7.36(s,1H),7.17(t,1H),7.01(t,1H),5.77(q,1H),4.09(s,3H),3.69-3.61(m,8H),3.02-2.98(m,1H),2.90-2.81(m,2H),2.70(s,3H),2.58-2.53(m,2H),2.23-2.17(m,2H),1.76-1.70(m,2H),1.68(d,3H)。 ¹ H NMR (500 MHz, methanol- d ₄ ): δ 8.40 (s, 1H), 7.60 (t, 1H), 7.44 (t, 1H), 7.36 (s, 1H), 7.17 (t, 1H), 7.01 ( t, 1H), 5.77(q, 1H), 4.09(s, 3H), 3.69-3.61(m, 8H), 3.02-2.98(m, 1H), 2.90-2.81(m, 2H), 2.70(s, 3H), 2.58-2.53 (m, 2H), 2.23-2.17 (m, 2H), 1.76-1.70 (m, 2H), 1.68 (d, 3H).

實施例10 Example 10

(R)-3-(4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)胺基)-7-甲氧基-1-甲基酞嗪-6-基)-4-羥基哌啶-1-基)-3-側氧丙烷腈10 ( R )-3-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalein Azin-6-yl)-4-hydroxypiperidin-1-yl)-3-oxopropanenitrile 10

採用實施例5中的合成路線，將第二步原料化合物甲氧基乙酸替換為化合物氰基乙酸，製得化合物10(7mg)，產率：48.2%。 Using the synthetic route in Example 5 , the second step starting material compound methoxyacetic acid was replaced with compound cyanoacetic acid to obtain compound 10 (7 mg), yield: 48.2%.

MS m/z(ESI)：528.2[M+1]。 MS m/z (ESI): 528.2 [M+1].

¹H NMR(500MHz，甲醇-d ₄)：δ 8.55(s,1H),7.62(t,1H),7.47(t,1H),7.39(s,1H),7.20(t,1H),7.02(t,1H),5.76(q,1H),4.65(s,3H), 4.47-4.40(m,2H),4.36(s,2H),3.76-3.73(m,2H),2.69(s,3H),2.29-2.24(m,2H),1.84-1.80(m,2H),1.71(d,3H)。 ¹ H NMR (500 MHz, methanol- d ₄ ): δ 8.55(s,1H), 7.62(t,1H), 7.47(t,1H), 7.39(s,1H), 7.20(t,1H), 7.02( t, 1H), 5.76(q, 1H), 4.65(s, 3H), 4.47-4.40(m, 2H), 4.36(s, 2H), 3.76-3.73(m, 2H), 2.69(s, 3H) , 2.29-2.24 (m, 2H), 1.84-1.80 (m, 2H), 1.71 (d, 3H).

實施例11 Example 11

(R)-4-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)胺基)-7-甲氧基-1-甲基酞嗪-6-基)氧基)四氫-2H-硫代吡喃1,1-二氧化物11 ( R )-4-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine- 6-yl)oxy)tetrahydro- 2H -thiopyran 1,1-dioxide 11

採用實施例1中第一至第七步的合成路線，將第一步原料化合物(3R)-四氫呋喃-3-醇替換為化合物4-羥基四氫-2H-硫代吡喃1,1-二氧化物，將第七步原料化合物(R)-1-(3-硝基-5-(三氟甲基)苯基)乙胺鹽酸鹽替換為化合物(R)-1-(3-(二氟甲基)-2-氟苯基)乙胺鹽酸鹽，製得化合物11(10mg)，產率：5.8%。 Using the synthetic route of the first to seventh steps in Example 1 , the first step raw material compound ( 3R )-tetrahydrofuran-3-ol was replaced with the compound 4-hydroxytetrahydro- 2H -thiopyran 1,1 - Dioxide, the seventh step starting compound ( R )-1-(3-nitro-5-(trifluoromethyl)phenyl)ethanamine hydrochloride is replaced by compound ( R )-1-(3 -(difluoromethyl)-2-fluorophenyl)ethanamine hydrochloride to obtain compound 11 (10 mg), yield: 5.8%.

MS m/z(ESI)：510.2[M+1]。 MS m/z (ESI): 510.2 [M+1].

¹H NMR(500MHz，甲醇-d ₄)：δ 8.01(s,1H),7.57(t,1H),7.44(t,1H),7.39(s,1H),7.17(t,1H),7.01(t,1H),5.72(q,1H),5.06(tt,1H),4.08(s,3H),3.48(ddd,2H),3.14-3.05(m,2H),2.68(s,3H),2.62-2.52(m,2H),2.48-2.38(m,2H),1.70(d,3H)。 ¹ H NMR (500 MHz, methanol- d ₄ ): δ 8.01 (s, 1H), 7.57 (t, 1H), 7.44 (t, 1H), 7.39 (s, 1H), 7.17 (t, 1H), 7.01 ( t,1H),5.72(q,1H),5.06(tt,1H),4.08(s,3H),3.48(ddd,2H),3.14-3.05(m,2H),2.68(s,3H),2.62 -2.52(m, 2H), 2.48-2.38(m, 2H), 1.70(d, 3H).

實施例12 Example 12

(R)-4-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)胺基)-7-甲氧基-1-甲基酞嗪-6-基)-4-羥基-1-亞胺基四氫-2H-硫代吡喃1-氧化物12 ( R )-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine-6 -yl)-4-hydroxy-1-iminotetrahydro- 2H -thiopyran 1-oxide 12

第一步 first step

(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-7-(3,6-二氫-2H-硫代吡喃-4-基)-6-甲氧基-4-甲基酞嗪-1-胺12b ( R )-N-(1-(3-(difluoromethyl)-2 - fluorophenyl)ethyl)-7-(3,6-dihydro- 2H -thiopyran-4-yl )-6-methoxy-4-methylphthalazine-1-amine 12b

將化合物4b(82mg，124.3μmol)、化合物2-(3,6-二氫-2H-硫代吡喃-4-基)-4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷12a(42.2mg，186.4μmol，上海畢得)、三(二亞苄基丙酮)二鈀(29.6mg，49.7μmol)、無水碳酸鉀(68.7mg，497.2μmol)溶於1,4-二噁烷(2mL)和水(0.5mL)中，加熱至110℃反應8小時，反應液減壓濃縮，用管柱層析色譜法以沖提劑體系A純化得到標題化合物12b(50mg)，產率：87.5%。 Compound 4b (82 mg, 124.3 μmol), compound 2-(3,6-dihydro- 2H -thiopyran-4-yl)-4,4,5,5-tetramethyl-1,3, 2-Dioxaborolane 12a (42.2mg, 186.4μmol, Shanghai Bide), Tris(dibenzylideneacetone)dipalladium (29.6mg, 49.7μmol), Anhydrous potassium carbonate (68.7mg, 497.2μmol) ) was dissolved in 1,4-dioxane (2mL) and water (0.5mL), heated to 110°C for 8 hours, the reaction solution was concentrated under reduced pressure, and purified by column chromatography with eluent system A to obtain The title compound 12b (50 mg), yield: 87.5%.

MS m/z(ESI)：460.2[M+1]。 MS m/z (ESI): 460.2 [M+1].

第二步 second step

4-(4-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)胺基)-7-甲氧基-1-甲基酞嗪-6-基)-1-亞胺基-1,2,3,6-四氫-1λ⁶-硫代吡喃1-氧化物12c 4-(4-((( R )-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine-6 -yl)-1-imino-1,2,3,6-tetrahydro-1λ ⁶ -thiopyran 1-oxide 12c

將化合物12b(100mg，217.6μmol)溶於5mL乙醇中，加入醋酸碘苯(222mg，652.8μmol)和乙酸銨(67.1mg，870.4μmol)，攪拌反應3小時，反應液減壓濃縮，用管柱層析色譜法以沖提劑體系A純化得到標題化合物12c(37mg)，產率：34.6%。 Compound 12b (100 mg, 217.6 μmol) was dissolved in 5 mL of ethanol, iodobenzene acetate (222 mg, 652.8 μmol) and ammonium acetate (67.1 mg, 870.4 μmol) were added, and the reaction was stirred for 3 hours. Purification by chromatography with eluent system A afforded the title compound 12c (37 mg), yield: 34.6%.

MS m/z(ESI)：491.1[M+1]。 MS m/z (ESI): 491.1 [M+1].

第三步 third step

將化合物12c(37mg，75.4μmol)、三(2,2,6,6-四甲基-3,5-庚烯酸)錳(22.8mg，37.7μmol)、苯矽烷(16.3mg，150.8μmol)溶於異丙醇(2mL)和二氯甲烷(0.2mL)，氧氣置換，攪拌反應14小時。反應液減壓濃縮，殘餘物用高效液相製備色譜法純化得到標題化合物12(6mg)，產率：15.6%。 Compound 12c (37 mg, 75.4 μmol), tris(2,2,6,6-tetramethyl-3,5-heptenoic acid) manganese (22.8 mg, 37.7 μmol), phenylsilane (16.3 mg, 150.8 μmol) Dissolve in isopropanol (2 mL) and dichloromethane (0.2 mL), replace with oxygen, and stir the reaction for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography to obtain the title compound 12 (6 mg), yield: 15.6%.

MS m/z(ESI)：509.2[M+1]。 MS m/z (ESI): 509.2 [M+1].

¹H NMR(500MHz，甲醇-d ₄)：δ 8.59(d,1H),7.61(t,1H),7.45(t,1H),7.38(d,1H),7.18(t,1H),7.01(t,1H),5.75(q,1H),4.10(d,3H),3.74-3.61(m,2H),3.31-3.25(m,2H),3.19-3.08(m,2H),2.70(d,3H),2.05(dt,2H),1.70(d,3H)。 ¹ H NMR (500 MHz, methanol- d ₄ ): δ 8.59(d,1H), 7.61(t,1H), 7.45(t,1H), 7.38(d,1H), 7.18(t,1H), 7.01( t, 1H), 5.75(q, 1H), 4.10(d, 3H), 3.74-3.61(m, 2H), 3.31-3.25(m, 2H), 3.19-3.08(m, 2H), 2.70(d, 3H), 2.05 (dt, 2H), 1.70 (d, 3H).

實施例13 Example 13

(R)-1-(3-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)胺基)-7-甲氧基-1-甲基酞嗪-6-基)氧基)氮雜環丁烷-1-基)乙-1-酮13 ( R )-1-(3-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methyl Phthazin-6-yl)oxy)azetidin-1-yl)ethan-1-one 13

第一步 first step

1-乙醯氮雜環丁烷-3-基4-甲基苯磺酸酯13b 1-Acetylazetidine-3-yl 4-methylbenzenesulfonate 13b

將化合物1-(3-羥基氮雜環丁烷-1-基)乙酮13a(10g，86.8mmol，上海畢得)、4-二甲胺基吡啶(534mg，4.3mmol，上海韶遠)、三乙胺(17.5g，173mmol)溶於200mL二氯甲烷中，加入4-甲苯磺醯氯(24.8g，130.3mmol)，攪拌反應14小時，反應液減壓濃縮後，殘餘物用管柱層析色譜法以沖提劑體系C純化得到標題化合物13b(15g)，產率64.1%。 Compound 1-(3-hydroxyazetidin-1-yl)ethanone 13a (10 g, 86.8 mmol, Shanghai Bide), 4-dimethylaminopyridine (534 mg, 4.3 mmol, Shanghai Shaoyuan), Triethylamine (17.5 g, 173 mmol) was dissolved in 200 mL of dichloromethane, 4-toluenesulfonyl chloride (24.8 g, 130.3 mmol) was added, and the reaction was stirred for 14 hours. After the reaction solution was concentrated under reduced pressure, the residue was subjected to a column layer. Purification by analytical chromatography with eluent system C afforded the title compound 13b (15 g) in 64.1% yield.

MS m/z(ESI)：270.1[M+1]。 MS m/z (ESI): 270.1 [M+1].

第二步 second step

(R)-7-(苄氧基)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-6-甲氧基-4-甲基酞嗪-1-胺13c ( R )-7-(benzyloxy)-N-(1-(3-(difluoromethyl)-2 - fluorophenyl)ethyl)-6-methoxy-4-methylphthalazine- 1-amine 13c

採用實施例3中的合成路線第七步和第十步，將第七步原料化合物3b替換為化合物苄溴，將第十步原料化合物(R)-2-(3-(1-胺基乙基)-2-氟苯基)-2,2-二氟乙醇鹽酸鹽替換為化合物(R)-1-(3-(二氟甲基)-2-氟苯基)乙胺鹽酸鹽，製得標題化合物13c(120mg)，產率：40.4%。 Adopt the seventh step and tenth step of the synthetic route in the embodiment 3 , replace the seventh step raw material compound 3b with compound benzyl bromide, and the tenth step raw material compound ( R )-2-(3-(1-aminoethyl) ( R )-1-(3-(difluoromethyl)-2-fluorophenyl)ethanamine hydrochloride , the title compound 13c (120 mg) was obtained, yield: 40.4%.

MS m/z(ESI)：468.2[M+1]。 MS m/z (ESI): 468.2 [M+1].

第三步 third step

(R)-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)胺基)-7-甲氧基-1-甲基酞嗪-6-酚13d ( R )-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazin-6-ol 13d

將化合物13c(120mg，256.7μmol)溶於用甲醇(10mL)，加入10%鈀碳催化劑(濕)(30mg)，氫氣置換，攪拌反應14小時。反應液用矽藻土過濾，減壓得到粗品化合物13d(80mg)，產率：82.5%，不經純化直接下一步。 Compound 13c (120 mg, 256.7 μmol) was dissolved in methanol (10 mL), 10% palladium-carbon catalyst (wet) (30 mg) was added, hydrogen was replaced, and the reaction was stirred for 14 hours. The reaction solution was filtered through celite, and the crude compound 13d (80 mg) was obtained under reduced pressure. The yield was 82.5%, which was directly used in the next step without purification.

MS m/z(ESI)：378.2[M+1]。 MS m/z (ESI): 378.2 [M+1].

第四步 the fourth step

將化合物13b(14.3mg，53μmol)、化合物13d(20mg，53μmol)、碳酸銫(34.5mg，106μmol)、N,N-二甲基甲醯胺(3mL)加入反應瓶中，升至70℃攪拌5小時。反應液冷卻後減壓濃縮，殘餘物用高效液相製備色譜法純化得到標題化合物13(6mg)，產率：23.8%。 Compound 13b (14.3 mg, 53 μmol), compound 13d (20 mg, 53 μmol), cesium carbonate (34.5 mg, 106 μmol), N , N -dimethylformamide (3 mL) were added to the reaction flask, and the temperature was raised to 70 °C and stirred 5 hours. The reaction solution was cooled, concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography to obtain the title compound 13 (6 mg), yield: 23.8%.

MS m/z(ESI)：475.2[M+1]。 MS m/z (ESI): 475.2 [M+1].

¹H NMR(500MHz，甲醇-d ₄)：δ 7.58(d,2H),7.44(t,1H),7.38(s,1H),7.18(t,1H),7.01(t,1H),5.73(q,1H),5.37-5.31(m,1H),4.77-4.61(m,1 H),4.55(dd,1H),4.38(ddd,1H),4.16-4.08(m,1H),4.07(s,3H),2.68(s,3H),1.97(s,3H),1.71(d,3H)。 ¹ H NMR (500 MHz, methanol- d ₄ ): δ 7.58(d,2H), 7.44(t,1H), 7.38(s,1H), 7.18(t,1H), 7.01(t,1H), 5.73( q,1H),5.37-5.31(m,1H),4.77-4.61(m,1H),4.55(dd,1H),4.38(ddd,1H),4.16-4.08(m,1H),4.07(s , 3H), 2.68 (s, 3H), 1.97 (s, 3H), 1.71 (d, 3H).

實施例14 Example 14

(S)-1-(4-(4-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)胺基)-7-甲氧基-1-甲基酞嗪-6-基)-4-羥基哌啶-1-基)-2-羥基丙-1-酮14 ( S )-1-(4-(4-((( R )-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1 -Methylphthalazin-6-yl)-4-hydroxypiperidin-1-yl)-2-hydroxypropan-1-one 14

採用實施例5中的合成路線，將第二步原料化合物甲氧基乙酸替換為化合物L-乳酸，製得化合物14(12mg)，產率：9.6%。 Using the synthetic route in Example 5 , the second-step raw material compound methoxyacetic acid was replaced with compound L -lactic acid to obtain compound 14 (12 mg), yield: 9.6%.

MS m/z(ESI)：533.2[M+1]。 MS m/z (ESI): 533.2 [M+1].

¹H NMR(500MHz，甲醇-d ₄)：δ 8.52(d,1H),7.60(t,1H),7.44(t,1H),7.36(s,1H),7.19(t,1H),7.06(d,1H),5.73(q,1H),4.06(d,3H),3.99(s,1H),3.67(d,1H),3.26(t,2H),2.69(s,3H),2.66-2.43(m,2H),1.82(q,2H),1.70(d,3H),1.41(dd,3H),1.32(d,1H)。 ¹ H NMR (500 MHz, methanol- d ₄ ): δ 8.52(d,1H), 7.60(t,1H), 7.44(t,1H), 7.36(s,1H), 7.19(t,1H), 7.06( d, 1H), 5.73(q, 1H), 4.06(d, 3H), 3.99(s, 1H), 3.67(d, 1H), 3.26(t, 2H), 2.69(s, 3H), 2.66-2.43 (m, 2H), 1.82 (q, 2H), 1.70 (d, 3H), 1.41 (dd, 3H), 1.32 (d, 1H).

實施例15 Example 15

(R)-4-((4-((1-(3-(1,1-二氟-2-羥乙基)-2-氟苯基)乙基)胺基)-7-甲氧基-1-甲基酞嗪-6-基)氧基)四氫-2H-硫代吡喃1,1-二氧化物15 ( R )-4-((4-((1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy -1-Methylphthalazin-6-yl)oxy)tetrahydro- 2H -thiopyran 1,1-dioxide 15

採用實施例3中的合成路線，將第一步原料化合物3a替換為化合物4-羥基四氫-2H-硫代吡喃1,1-二氧化物，製得標題化合物15(15mg)，產率：19.3%。 Using the synthetic route in Example 3 , the first step starting compound 3a was replaced with the compound 4-hydroxytetrahydro- 2H -thiopyran 1,1-dioxide to obtain the title compound 15 (15 mg), yielding Rate: 19.3%.

MS m/z(ESI)：540.2[M+1]。 MS m/z (ESI): 540.2 [M+1].

¹H NMR(400MHz,CD₃OD)：δ 8.02(s,1H),7.54(t,1H),7.43-7.40(m,1H),7.14(t,1H)5.73(q,1H),5.07-5.06(m,1H),4.08-4.03(m,5H),3.52-3.47(m,3H),3.12-3.08(m,2H),2.69(s,3H),2.59-2.56(m,2H),2.44-2.42(m,2H),1.70(d,3H)。 ¹ H NMR (400 MHz, CD ₃ OD): δ 8.02 (s, 1H), 7.54 (t, 1H), 7.43-7.40 (m, 1H), 7.14 (t, 1H) 5.73 (q, 1H), 5.07- 5.06(m, 1H), 4.08-4.03(m, 5H), 3.52-3.47(m, 3H), 3.12-3.08(m, 2H), 2.69(s, 3H), 2.59-2.56(m, 2H), 2.44-2.42 (m, 2H), 1.70 (d, 3H).

實施例16 Example 16

(R)-2,2-二氟-2-(2-氟-3-(1-((15-甲基-2,3,5,6,8,9-六氫-[1,4,7,10]四氧雜環十二并[2,3-g]酞嗪-12-基)胺基)乙基)苯基)乙烷-1-醇16 ( R )-2,2-difluoro-2-(2-fluoro-3-(1-((15-methyl-2,3,5,6,8,9-hexahydro-[1,4, 7,10] Tetraoxanedodeco[2,3- g ]phthalazin-12-yl)amino)ethyl)phenyl)ethan-1-ol 16

第一步 first step

4-甲基酞嗪-1,6,7-三醇氫溴酸鹽16a 4-Methylphthalazine-1,6,7-triol hydrobromide 16a

將化合物3h(1g，4.84mmol)用30mL氫溴酸溶液溶解，加熱至120℃反應16小時。冷卻至室溫後過濾，濾液減壓濃縮真空乾燥得到粗品標題化合物16a(1.1g)，產率：83%。 Compound 3h (1 g, 4.84 mmol) was dissolved in 30 mL of hydrobromic acid solution, heated to 120° C. and reacted for 16 hours. After cooling to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure and dried in vacuo to obtain the crude title compound 16a (1.1 g). Yield: 83%.

MS m/z(ESI)：274.0[M+1]。 MS m/z (ESI): 274.0 [M+1].

第二步 second step

15-甲基-2,3,5,6,8,9-六氫-[1,4,7,10]四氧雜環十二并[2,3-g]酞嗪-12-酚16b 15-Methyl-2,3,5,6,8,9-hexahydro-[1,4,7,10]tetraoxanedodecodo[2,3- g ]phthalazin-12-ol 16b

將化合物16a(130mg，476μmol)、化合物三乙二醇二(對甲苯磺酸酯)(261.9mg，571.2μmol，上海畢得醫藥科技有限公司)、無水碳酸鉀(329mg，2.38mmol)溶於10mL N,N-二甲基甲醯胺中，90℃攪拌2小時，反應液減壓濃縮，用薄層層析色譜法以展開劑體系A純化所得殘餘物，得到標題化合物16b(100mg)，產率：68.5%。 Compound 16a (130 mg, 476 μmol), compound triethylene glycol bis(p-toluenesulfonate) (261.9 mg, 571.2 μmol, Shanghai Bide Pharmaceutical Technology Co., Ltd.), and anhydrous potassium carbonate (329 mg, 2.38 mmol) were dissolved in 10 mL N , N -dimethylformamide, stirred at 90°C for 2 hours, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography with developing solvent system A to obtain the title compound 16b (100 mg) as the product Rate: 68.5%.

MS m/z(ESI)：307.1[M+1]。 MS m/z (ESI): 307.1 [M+1].

第三步 third step

12-氯-15-甲基-2,3,5,6,8,9-六氫-[1,4,7,10]四氧雜環十二并[2,3-g]酞嗪16c 12-Chloro-15-methyl-2,3,5,6,8,9-hexahydro-[1,4,7,10]tetraoxanedodecano[2,3- g ]phthalazine 16c

將化合物16b(100mg，326.4μmol)溶解於10mL三氯氧磷中，120℃攪拌反應3小時。反應液減壓濃縮，倒入冰水，飽和碳酸氫鈉調節pH至中性，乙酸乙酯萃取(10mL×2)後，合併有機相，無水硫酸鈉乾燥，減壓濃縮即得標題化合物16c(60mg)，收率：56.5%。 Compound 16b (100 mg, 326.4 μmol) was dissolved in 10 mL of phosphorus oxychloride, and the reaction was stirred at 120° C. for 3 hours. The reaction solution was concentrated under reduced pressure, poured into ice water, adjusted to neutral pH with saturated sodium bicarbonate, extracted with ethyl acetate (10 mL×2), combined with the organic phases, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound 16c ( 60 mg), yield: 56.5%.

MS m/z(ESI)：325.1[M+1]。 MS m/z (ESI): 325.1 [M+1].

第四步 the fourth step

將化合物16c(30mg，92.3μmol)、化合物2a(24.3mg，110.8μmol)、氯化銨(2.47mg，46.2μmol)和正丁醇(1mL)混合。微波升溫至110℃攪拌1小時。將反應液用矽藻土過濾，濾液減壓濃縮後用高效液相製備色譜法純化得到標題化合物16(5mg)，產率：10.6%。 Compound 16c (30 mg, 92.3 μmol), compound 2a (24.3 mg, 110.8 μmol), ammonium chloride (2.47 mg, 46.2 μmol) and n-butanol (1 mL) were mixed. The microwave was heated to 110°C and stirred for 1 hour. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure and purified by preparative high performance liquid chromatography to obtain the title compound 16 (5 mg), yield: 10.6%.

MS m/z(ESI)：508.2[M+1]。 MS m/z (ESI): 508.2 [M+1].

¹H NMR(500MHz，甲醇-d ₄)：δ 8.02(s,1H),7.56-7.53(m,2H),7.44(t,1H),7.16(t,1H),5.74(q,1H),4.43-4.42(m,2H),4.38-4.37(m,2H),4.17-4.07(m,2H),3.95-3.90(m,4H),3.80(s,4H),2.65(s,3H),1.70(d,3H)。 ¹ H NMR (500 MHz, methanol- d ₄ ): δ 8.02 (s, 1H), 7.56-7.53 (m, 2H), 7.44 (t, 1H), 7.16 (t, 1H), 5.74 (q, 1H), 4.43-4.42(m, 2H), 4.38-4.37(m, 2H), 4.17-4.07(m, 2H), 3.95-3.90(m, 4H), 3.80(s, 4H), 2.65(s, 3H), 1.70(d, 3H).

實施例17 Example 17

(R)-4-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)胺基)-7-甲氧基-1-甲基酞嗪-6-基)氧基)-1-亞胺基四氫-2H-硫代吡喃1-氧化物17 ( R )-4-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-1-methylphthalazine- 6-yl)oxy)-1-iminotetrahydro- 2H -thiopyran 1-oxide 17

第一步 first step

(R)-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-6-甲氧基-4-甲基-7-((四氫-2H-硫代吡喃-4-基)氧基)酞嗪-1-胺17b ( R )-N-(1-(3-(difluoromethyl)-2 - fluorophenyl)ethyl)-6-methoxy-4-methyl-7-((tetrahydro- 2H- Thiopyran-4-yl)oxy)phthalazin-1-amine 17b

採用實施例3中的合成路線，將第一步原料化合物3a替換為化合物四氫-2H-硫代吡喃-4-醇17a，將第十步原料化合物(R)-2-(3-(1-胺基乙基)-2-氟苯基)-2,2-二氟乙醇鹽酸鹽替換為化合物(R)-1-(3-(二氟甲基)-2-氟苯基)乙胺鹽酸鹽，製得標題化合物17b(100mg)，產率：34%。 Using the synthetic route in Example 3 , the first step raw material compound 3a was replaced with compound tetrahydro- 2H -thiopyran-4-ol 17a , and the tenth step raw material compound ( R )-2-(3- (1-aminoethyl)-2-fluorophenyl)-2,2-difluoroethanol hydrochloride was replaced with compound ( R )-1-(3-(difluoromethyl)-2-fluorophenyl ) ethylamine hydrochloride to obtain the title compound 17b (100 mg), yield: 34%.

MS m/z(ESI)：478.2[M+1]。 MS m/z (ESI): 478.2 [M+1].

第二步 second step

將化合物17b(100mg，209.4μmol)溶於5mL乙醇中，加入醋酸碘苯(214mg，629.2μmol)和乙酸銨(65mg，843.2μmol)，室溫反應3小時，反應液減壓濃縮，用高效液相製備色譜法純化所得標題化合物17(8mg)，產率：7.5%。 Compound 17b (100 mg, 209.4 μmol) was dissolved in 5 mL of ethanol, iodobenzene acetate (214 mg, 629.2 μmol) and ammonium acetate (65 mg, 843.2 μmol) were added, and the reaction was carried out at room temperature for 3 hours. The obtained title compound 17 (8 mg) was purified by phase preparative chromatography, yield: 7.5%.

MS m/z(ESI)：509.1[M+1]。 MS m/z (ESI): 509.1 [M+1].

¹H NMR(500MHz，甲醇-d ₄)：δ 8.02-8.01(d,1H),7.59-7.56(q,1H),7.46-7.43(q,1H),7.39(d,1H),7.19-7.16(q,1H),7.12-6.90(q,1H),5.74-5.70(t,1H),5.08-5.06(m,1H),4.08-4.07(d,3H),3.57-3.47(m,2H),3.20-3.17(m,2H),2.68(s,3H),2.55-2.50(m,2H),2.45-2.39(m,2H),1.71-1.70(d,3H)。 ¹ H NMR (500 MHz, methanol- d ₄ ): δ 8.02-8.01(d,1H), 7.59-7.56(q,1H), 7.46-7.43(q,1H), 7.39(d,1H), 7.19-7.16 (q,1H), 7.12-6.90(q,1H), 5.74-5.70(t,1H), 5.08-5.06(m,1H), 4.08-4.07(d,3H), 3.57-3.47(m,2H) , 3.20-3.17(m, 2H), 2.68(s, 3H), 2.55-2.50(m, 2H), 2.45-2.39(m, 2H), 1.71-1.70(d, 3H).

生物學評價 Biological evaluation

測試例1 本公開化合物抑制KRAS蛋白各亞型G12D或G12V與SOS1蛋白間的相互作用能力 Test Example 1 The compound of the present disclosure inhibits the interaction between each subtype G12D or G12V of KRAS protein and SOS1 protein

以下方法用來測定化合物抑制KRAS蛋白各亞型G12D或G12V與SOS1蛋白間的相互作用能力。實驗方法簡述如下： The following methods were used to determine the ability of compounds to inhibit the interaction between the KRAS protein isoforms G12D or G12V and the SOS1 protein. The experimental method is briefly described as follows:

1、實驗材料及儀器 1. Experimental materials and instruments

1)生物素標記試劑盒(Dojindo，LK03) 1) Biotin labeling kit (Dojindo, LK03)

2)GDP(SIGMA，G7127) 2) GDP (SIGMA, G7127)

3)AlphaLISA谷胱甘肽受體珠(Glutathione Acceptor Beads)(PerkinElmer，AL109C) 3) AlphaLISA Glutathione Acceptor Beads (PerkinElmer, AL109C)

4)AlphaScreen鏈黴親和素供體珠(Streptavidin Donor Beads)(PerkinElmer，6760002S) 4) AlphaScreen Streptavidin Donor Beads (PerkinElmer, 6760002S)

5)384-孔微板(PerkinElmer，6007290) 5) 384-well microplate (PerkinElmer, 6007290)

6)BSA(上海生工，A600332-0100) 6) BSA (Shanghai Shenggong, A600332-0100)

7)吐溫-20(Diamond，A100777-0500) 7) Tween-20 (Diamond, A100777-0500)

8)GST-TEV-SOS1(564-1049)(維亞生物科技，SOS1-191010) 8) GST-TEV-SOS1 (564-1049) (Via Biotechnology, SOS1-191010)

9)KRAS G12D、KRAS G12V(由上海磐超生物科技有限公司生產提供) 9) KRAS G12D, KRAS G12V (produced by Shanghai Panchao Biotechnology Co., Ltd.)

10)磷酸鹽緩衝液(PBS)PH7.4(上海源培生物科技股份有限公司，B320) 10) Phosphate Buffered Saline (PBS) PH7.4 (Shanghai Yuanpei Biotechnology Co., Ltd., B320)

11)多功能酶標儀(PerkinElmer，Envision) 11) Multi-function microplate reader (PerkinElmer, Envision)

2、實驗步驟 2. Experimental steps

實驗準備： Experiment preparation:

1)實驗開始之前先配製實驗緩衝液：1 x PBS+0.1%BSA+0.05%吐溫-20。 1) Prepare the experimental buffer before starting the experiment: 1 x PBS+0.1%BSA+0.05%Tween-20.

2)KRAS G12D、KRAS-G12V蛋白用生物素標記試劑盒進行生物素標記。 2) The KRAS G12D and KRAS-G12V proteins were biotin-labeled with a biotin labeling kit.

實驗步驟： Experimental steps:

1)先將生物素標記後的KRAS G12V或KRAS G12D蛋白分別與SOS1蛋白(GST-TEV-SOS1(564-1049)(維亞生物科技，SOS1-191010))和GDP混合室溫孵育備用。 1) First, the biotin-labeled KRAS G12V or KRAS G12D protein was incubated with SOS1 protein (GST-TEV-SOS1 (564-1049) (Via Biotechnology, SOS1-191010)) and GDP at room temperature for use.

2)將AlphaLISA谷胱甘肽受體珠和AlphaScreen鏈黴親和素供體珠在使用前1：1混合成40μg/mL備用。 2) Mix AlphaLISA glutathione acceptor beads and AlphaScreen streptavidin donor beads 1:1 to 40 μg/mL before use.

3)將化合物用實驗緩衝液配製成起始濃度為40μM，5倍梯度稀釋，10個梯度系列濃度點。 3) Compounds were prepared with experimental buffer to an initial concentration of 40 μM, 5-fold gradient dilution, and 10 gradient series concentration points.

4)在384-孔微板中，每孔加入10μL KRAS G12V或KRAS G12D蛋白與SOS1和GDP混合物和5μL稀釋好的化合物，室溫，避光孵育30分鐘。 4) In a 384-well microplate, add 10 μL of KRAS G12V or KRAS G12D protein, SOS1 and GDP mixture and 5 μL of the diluted compound to each well, and incubate at room temperature for 30 minutes in the dark.

5)然後每孔加入5μL AlphaLISA谷胱甘肽受體珠和AlphaScreen鏈黴親和素供體珠混合物，室溫，避光孵育60分鐘。 5) Then add 5 μL of AlphaLISA glutathione acceptor beads and AlphaScreen streptavidin donor beads mixture to each well, and incubate at room temperature for 60 minutes in the dark.

6)在多功能酶標儀上讀取螢光值。 6) Read the fluorescence value on the multi-function microplate reader.

7)用Graphpad Prism計算得到化合物的IC₅₀值。 7) Calculate the _IC50 value of the compound with Graphpad Prism.

3、實驗數據 3. Experimental data

本公開化合物抑制KRAS蛋白各亞型G12D或G12V與SOS1蛋白間的相互作用能力，測得的IC₅₀值見表1。 The compounds of the present disclosure inhibit the interaction ability between each subtype G12D or G12V of KRAS protein and SOS1 protein, and the measured _IC50 values are shown in Table 1.

表1 本公開化合物抑制KRAS蛋白各亞型G12D或G12V與SOS1蛋白間的相互作用能力的IC₅₀值

Table 1 IC ₅₀ values of the compounds of the present disclosure for the ability to inhibit the interaction between each subtype G12D or G12V of KRAS protein and SOS1 protein

結論：本公開化合物能很好的抑制KRAS蛋白各亞型G12D或G12V與SOS1蛋白間的相互作用。 Conclusion: The disclosed compounds can well inhibit the interaction between each subtype G12D or G12V of KRAS protein and SOS1 protein.

測試例2 H358細胞ERK磷酸化抑制生物學評價 Test Example 2 Biological evaluation of ERK phosphorylation inhibition in H358 cells

1、測試目的 1. Test purpose

本實驗藉由檢測化合物對細胞ERK磷酸化抑制作用，根據IC₅₀大小評價本公開化合物對KRAS靶點(含G12C突變)的抑制作用。 In this experiment, the inhibitory effect of the compounds on cellular ERK phosphorylation was detected, and the inhibitory effect of the disclosed compounds on KRAS targets (containing G12C mutation) was evaluated according to the IC ₅₀ size.

2、實驗方法 2. Experimental method

H358細胞(ATCC，CRL-5807)用含有10%胎牛血清的RPMI1640(Hyclone，SH30809.01)完全培養基進行培養。實驗第一天，使用完全培養基將H358細胞以25,000個/孔的密度種於96孔板，每孔190μL細胞懸液，放置37℃，5% CO₂細胞培養箱培養過夜。第二天，每孔加入10μL用完全培養基配製的梯度稀釋的待測化合物，化合物的終濃度是從10μM開始進行5倍梯度稀釋的9個濃度點，設置含有0.1% DMSO的空白對照，孔板放置37℃，5% CO₂的細胞培養箱孵育1個小時。1小時後，取出96孔細胞培養板，吸掉培養基，每孔加入200μL PBS(上海源培生物科技股份有限公司，B320)洗一遍。吸掉PBS，每孔加入50μL含封閉液(blocking reagent，Cisbio，64KB1AAC)的裂解緩衝液(lysis buffer，Cisbio，64KL1FDF)，孔板放置振盪器上室溫震盪裂解40分鐘。裂解後用移液器吹打混勻，每孔各轉移16μL裂解液分別至兩塊HTRF 96孔檢測板(Cisbio，66PL96100)中，之後兩塊板分別加入4μL預混的phospho-ERK1/2抗體溶液(Cisbio，64AERPEG)或4μL預混的total-ERK1/2抗體溶液(Cisbio，64NRKPEG)。微孔板用封板膜密封，在微孔板離心機中離心1分鐘，室溫避光孵育過夜。第三天，使用PHERAstar多功能酶標儀(BMG Labtech，S/N 471-0361)讀取337nm波長激發，665nm和620nm波長發射的螢光值。 H358 cells (ATCC, CRL-5807) were cultured in RPMI1640 (Hyclone, SH30809.01) complete medium containing 10% fetal bovine serum. On the first day of the experiment, H358 cells were seeded in a 96-well plate at a density of 25,000 cells/well in complete medium, with 190 μL of cell suspension per well, and placed in a 37°C, 5% CO ₂ cell incubator overnight. On the second day, 10 μL of the compound to be tested in a serial dilution prepared in complete medium was added to each well. The final concentration of the compound was 9 concentration points of 5-fold serial dilution starting from 10 μM, and a blank control containing 0.1% DMSO was set. Place in a 37°C, 5% CO ₂ cell incubator for 1 hour. One hour later, the 96-well cell culture plate was taken out, the medium was aspirated, and 200 μL of PBS (Shanghai Yuanpei Biotechnology Co., Ltd., B320) was added to each well for washing. PBS was aspirated, 50 μL of lysis buffer (lysis buffer, Cisbio, 64KL1FDF) containing blocking reagent (Cisbio, 64KB1AAC) was added to each well, and the plate was placed on a shaker for 40 minutes at room temperature. After lysis, pipette and mix well, transfer 16 μL of lysate per well to two HTRF 96-well detection plates (Cisbio, 66PL96100), and then add 4 μL of premixed phospho-ERK1/2 antibody solution to the two plates. (Cisbio, 64AERPEG) or 4 μL of premixed total-ERK1/2 antibody solution (Cisbio, 64NRKPEG). The microplate was sealed with sealing film, centrifuged in a microplate centrifuge for 1 minute, and incubated overnight at room temperature in the dark. On the third day, use a PHERAstar multi-plate reader (BMG Labtech, S/N 471-0361) to read the fluorescence values for excitation at 337 nm and emission at 665 nm and 620 nm.

3、數據分析 3. Data analysis

用Graphpad Prism軟體根據化合物濃度和pERK/total ERK的比值計算化合物抑制活性的IC₅₀值，結果見下表2。 _IC50 values of compound inhibitory activity were calculated according to compound concentration and pERK/total ERK ratio using Graphpad Prism software, and the results are shown in Table 2 below.

表2 H358細胞ERK磷酸化抑制活性數據

Table 2 ERK phosphorylation inhibitory activity data in H358 cells

結論：本公開化合物對H358細胞ERK磷酸化具有較好的抑制作用。 Conclusion: The disclosed compounds have a good inhibitory effect on ERK phosphorylation in H358 cells.

測試例3 H358細胞增殖抑制生物學評價 Test Example 3 Biological evaluation of H358 cell proliferation inhibition

1、測試目的 1. Test purpose

藉由測試本公開化合物對H358細胞的增殖抑制作用，評價本公開化合物對KRAS靶點(含G12C突變)的抑制作用。 By testing the proliferation inhibitory effect of the disclosed compounds on H358 cells, the inhibitory effect of the disclosed compounds on KRAS targets (containing G12C mutation) was evaluated.

2、實驗方法 2. Experimental method

H358細胞(ATCC，CRL-5807)用完全培養基即含有10%胎牛血清(Corning，35-076-CV)的RPMI1640培養基(Hyclone，SH30809.01)進行培養。實驗第一天，使用完全培養基將H358細胞以1500個細胞/孔的密度種於96低吸附板(Corning，CLS7007-24EA)，每孔90μL細胞懸液，2000rpm室溫離心5分鐘後放置37℃，5% CO₂細胞培養箱培養過夜。第二天，每孔加入10μL用完全培養基配製的梯度稀釋的待測化合物，化合物的終濃度是從10μM開始進行5倍梯度稀釋的9個濃度點，設置含有0.1% DMSO的空白對照，孔板放置37℃，5% CO₂的細胞培養箱培養120小時。第七天，取出96孔細胞培養板，每孔加入50μL CellTiter-Glo® 3D Reagent(Promega，G9682)，室溫震盪25分鐘後，吹吸混勻並取出50μL轉移至白色不透底的96孔板(PE，6005290)中，使用多功能微孔板酶標儀(PerkinElmer，VICTOR 3)讀取發光信號值。 H358 cells (ATCC, CRL-5807) were cultured in complete medium ie RPMI1640 medium (Hyclone, SH30809.01) containing 10% fetal bovine serum (Corning, 35-076-CV). On the first day of the experiment, H358 cells were seeded on 96 low-adsorption plates (Corning, CLS7007-24EA) at a density of 1500 cells/well using complete medium, 90 μL of cell suspension per well, centrifuged at 2000 rpm for 5 minutes at room temperature and placed at 37°C , 5% CO ₂ cell incubator overnight. On the second day, 10 μL of the compound to be tested in a serial dilution prepared in complete medium was added to each well. The final concentration of the compound was 9 concentration points of 5-fold serial dilution starting from 10 μM, and a blank control containing 0.1% DMSO was set. Place in a cell incubator at 37°C, 5% CO ₂ for 120 hours. On the seventh day, take out the 96-well cell culture plate, add 50 μL of CellTiter-Glo® 3D Reagent (Promega, G9682) to each well, shake at room temperature for 25 minutes, mix by pipetting, remove 50 μL and transfer to a white impermeable bottom 96-well plate (PE, 6005290), the luminescence signal value was read using a multifunctional microplate reader (PerkinElmer, VICTOR 3).

3、數據分析 3. Data analysis

用Graphpad Prism軟體計算化合物抑制活性的IC₅₀值，結果見下表3。 The _IC50 values for the inhibitory activity of the compounds were calculated using Graphpad Prism software, and the results are shown in Table 3 below.

表3 H358細胞增殖抑制活性數據

Table 3 H358 cell proliferation inhibitory activity data

結論：本公開化合物對H358細胞增殖具有較好的抑制作用。 Conclusion: The disclosed compounds have a good inhibitory effect on the proliferation of H358 cells.

藥物代謝動力學評價 Pharmacokinetic evaluation

測試例4 本公開化合物的藥物代謝動力學測試 Test Example 4 Pharmacokinetic testing of the compounds of the present disclosure

1、摘要 1. Abstract

以小鼠受試動物，應用LC/MS/MS法測定了小鼠靜脈注射給予實施例1化合物後不同時刻血漿中的藥物濃度。研究本公開化合物在小鼠體內的藥物代謝動力學行為，評價其藥動學特徵。 Using LC/MS/MS method as a mouse test animal, the drug concentration in the plasma of mice at different times after intravenous injection of the compound of Example 1 was determined. To study the pharmacokinetic behavior of the disclosed compounds in mice, and to evaluate their pharmacokinetic characteristics.

2、試驗方案 2. Test plan

2.1 試驗藥品 2.1 Test Drugs

實施例1化合物。 Compound of Example 1.

2.2 試驗動試驗動物 2.2 Experimental animals

健康成年C57小鼠18隻，雌性，購自維通利華實驗動物有限公司。 Eighteen healthy adult C57 mice, female, were purchased from Weitong Lihua Laboratory Animal Co., Ltd.

2.3 藥物配製 2.3 Drug preparation

稱取一定量藥物，加入5% DMSO+5%吐溫80+90%生理鹽水配製成液體。 Weigh a certain amount of medicine, add 5% DMSO + 5% Tween 80 + 90% normal saline to prepare a liquid.

2.4 給藥 2.4 Administration

小鼠禁食過夜後靜脈注射給藥，給藥劑量均為1mg/kg，給藥體積均為0.1mL/10g。 After overnight fasting, the mice were administered intravenously at a dose of 1 mg/kg and an administration volume of 0.1 mL/10 g.

3、操作 3. Operation

小鼠靜脈注射給藥實施例1化合物，於給藥前及給藥後5分、0.25、0.5、1.0、2.0、4.0、8.0、11.0、24.0小時採血0.1mL，置於EDTA-K2抗凝試管中，4℃、10000轉/分鐘離心1分鐘，1小時內分離血漿，於-20℃保存待測，採血至離心過程在冰浴條件下操作。 Mice were intravenously injected with the compound of Example 1, and 0.1 mL of blood was collected before administration and at 5 minutes, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 11.0, and 24.0 hours after administration, and placed in an EDTA-K2 anticoagulation test tube In the medium, centrifuge at 4°C and 10,000 rpm for 1 minute, separate the plasma within 1 hour, store it at -20°C for testing, and operate under ice bath conditions during the process of blood collection and centrifugation.

測定藥物靜脈給藥後小鼠血漿中的待測化合物含量：取給藥後各時刻的小鼠血漿25μL，加入內標溶液(100ng/ml喜樹鹼)50μL，乙腈200μL，渦旋混合5分鐘，離心15分鐘(3600轉/分鐘)，血漿樣品取上清液0.1μL進行LC/MS/MS分析。 Determination of the content of the test compound in mouse plasma after intravenous administration of the drug: take 25 μL of mouse plasma at each time after administration, add 50 μL of internal standard solution (100ng/ml camptothecin), 200 μL of acetonitrile, and vortex for 5 minutes , centrifuged for 15 minutes (3600 rpm), and 0.1 μL of the supernatant was taken from the plasma samples for LC/MS/MS analysis.

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

表4 本公開化合物的藥物代謝動力學參數

Table 4 Pharmacokinetic parameters of compounds of the present disclosure

結論：本公開化合物的藥物代謝良好，具有明顯的藥物代謝動力學優勢。 Conclusion: The compounds of the present disclosure have good drug metabolism and have obvious pharmacokinetic advantages.

測試例5 本公開化合物對人肝微粒體CYP450酶的抑制作用 Test Example 5 Inhibitory effect of compounds of the present disclosure on human liver microsomal CYP450 enzymes

本公開化合物對人肝微粒體CYP450酶的抑制作用採用如下實驗方法測定： The inhibitory effect of the compounds of the present disclosure on human liver microsomal CYP450 enzymes was determined by the following experimental methods:

1、實驗材料及儀器 1. Experimental materials and instruments

1)磷酸緩衝液(20×PBS，購買自生工) 1) Phosphate buffer solution (20×PBS, purchased from the manufacturer)

2)NADPH(ACROS，A2646-71-1) 2) NADPH (ACROS, A2646-71-1)

3)人肝微粒體(Corning Gentest，Cat No，452161，Lot No.905002,Donor35) 3) Human liver microsomes (Corning Gentest, Cat No, 452161, Lot No. 905002, Donor35)

4)ABI QTrap 4000液質兩用儀(AB Sciex) 4) ABI QTrap 4000 LC/MS (AB Sciex)

5)ZORBAX Extend-C18,3×50mm,3.5μm(美國安捷倫公司) 5) ZORBAX Extend-C18, 3×50mm, 3.5μm (Agilent, USA)

6)CYP探針受質(非那西丁，雙氯酚酸，(S)-美芬妥英，右美沙芬，睾酮) 6) CYP probe substrate (phenacetin, diclofenac, (S)-mephenytoin, dextromethorphan, testosterone)

購自Sigma-Aldrich。 Purchased from Sigma-Aldrich.

2、實驗步驟 2. Experimental steps

2.1、溶液配製 2.1. Solution preparation

1)100mM磷酸緩衝液(PBS)的配製 1) Preparation of 100mM Phosphate Buffered Saline (PBS)

取50mL濃度為2000mM的PBS溶液，加超純水950mL，稀釋至1000mL，混合均勻，即得pH 7.4的PBS溶液，放置4℃冰箱保存(保存期限為6個月)。 Take 50 mL of PBS solution with a concentration of 2000 mM, add 950 mL of ultrapure water, dilute to 1000 mL, and mix evenly to obtain a PBS solution with pH 7.4, which is stored in a refrigerator at 4°C (the shelf life is 6 months).

2)NADPH溶液的配製 2) Preparation of NADPH solution

精密稱取NADPH粉末適量，加入PBS緩衝溶液溶解，配成濃度為5mM的溶液，備用(現配現用)。 Precisely weigh an appropriate amount of NADPH powder, add PBS buffer solution to dissolve, and prepare a solution with a concentration of 5 mM, for later use (prepared and used now).

3)肝微粒體溶液的配製 3) Preparation of liver microsome solution

取人肝微粒體儲存液(濃度為20mg/mL)適量，用濃度為15mM的MgCl₂溶液稀釋至0.5mg/mL微粒體溶液，備用(現配現用)。 Take an appropriate amount of human liver microsome stock solution (concentration of 20 mg/mL) and dilute it to 0.5 mg/mL microsomal solution with 15 mM MgCl ₂ solution for later use (prepared for current use).

4)MgCl₂溶液的配製 ₄ ) Preparation of MgCl solution

稱取MgCl₂粉末適量，用PBS溶液配製成300mM的儲備液，置於4℃冰箱保存，備用。精密稱取該溶液適量，加入100mM PBS溶液稀釋成15mM的工作液，即可(現配現用)。 Weigh an appropriate amount of MgCl ₂ powder, prepare a 300 mM stock solution with PBS solution, and store it in a 4°C refrigerator for later use. Precisely weigh an appropriate amount of the solution, add 100 mM PBS solution and dilute it into a 15 mM working solution, and that's it (prepared and used now).

5)受試化合物溶液的製備 5) Preparation of test compound solutions

a.精密稱取適量的受試化合物標準品，加入DMSO配成濃度為30mM的儲備液，置於4℃冰箱保存。 a. Precisely weigh an appropriate amount of the test compound standard, add DMSO to prepare a stock solution with a concentration of 30 mM, and store in a refrigerator at 4°C.

b.精密移取該儲備液適量，加入DMSO溶液適量稀釋成濃度為10、3、1、0.3、0.03和0.003mM的系列溶液I。精密移取上述系列溶液I適量，加入乙腈適量稀釋成濃度為3、1、0.3、0.1、0.03、0.003、0.0003mM的系列溶液II。精密移取上述系列溶液II適量，加入PBS適量稀釋成濃度為150、50、15、5、1.5、0.15、0.015μM的工作液，備用。 b. Precisely pipette an appropriate amount of the stock solution, add an appropriate amount of DMSO solution to dilute to a series of solution I with a concentration of 10, 3, 1, 0.3, 0.03 and 0.003 mM. Precisely pipet an appropriate amount of the above series of solution I, add an appropriate amount of acetonitrile to dilute to a series of solution II with a concentration of 3, 1, 0.3, 0.1, 0.03, 0.003, 0.0003 mM. Precisely pipette an appropriate amount of the above-mentioned series of solutions II, add an appropriate amount of PBS to dilute to a working solution with a concentration of 150, 50, 15, 5, 1.5, 0.15, 0.015 μM, and set aside.

6)CYP探針受質和選擇性抑制劑的選擇 6) Selection of CYP probe substrates and selective inhibitors

a.探針受質儲備液的配製：稱取各探針受質適量，加入DMSO配製成儲備液，其濃度如下表5所示。 a. Preparation of probe substrate stock solution: Weigh an appropriate amount of each probe substrate, add DMSO to prepare a stock solution, and its concentration is shown in Table 5 below.

b.探針受質工作液的配製：精密移取探針受質儲備液適量，加入PBS溶液稀釋200倍，得探針受質工作液，其濃度如下表5所示。 b. Preparation of probe substrate working solution: Precisely pipette an appropriate amount of probe substrate stock solution, add PBS solution and dilute 200 times to obtain probe substrate working solution, the concentration of which is shown in Table 5 below.

表5

table 5

2.2、肝微粒體孵育及樣品製備 2.2. Incubation of liver microsomes and sample preparation

反應體系中蛋白濃度、受質和抑制劑的濃度如下表6-1和表6-2所示。 The protein concentration, substrate and inhibitor concentration in the reaction system are shown in Table 6-1 and Table 6-2 below.

表6-1

Table 6-1

表6-2

Table 6-2

2.3、操作過程 2.3. Operation process

1)精密移取人肝微粒體溶液(0.25mg/mL)40μL，探針受質溶液20μL和受試化合物溶液20μL於96孔板中，在37℃水浴中預孵育5分鐘。 1) Precisely pipette 40 μL of human liver microsome solution (0.25 mg/mL), 20 μL of probe substrate solution and 20 μL of test compound solution into a 96-well plate, and pre-incubate in a 37°C water bath for 5 minutes.

2)預孵育5分鐘後取出，加入20μL濃度為5mM的NADPH溶液，啟動反應，在37℃水浴中孵育30分鐘。每個樣本平行兩份。 2) Take out after 5 minutes of pre-incubation, add 20 μL of NADPH solution with a concentration of 5 mM, start the reaction, and incubate in a 37° C. water bath for 30 minutes. Each sample was replicated in duplicate.

3)孵育結束後，加入250μL含內標的乙腈溶液終止反應，800rpm搖10分鐘後，3700rpm離心10分鐘，精密移取上清液100μL 加入80μL蒸餾水稀釋，並於800rpm搖10分鐘，吸取上清液進行LC-MS/MS分析。 3) After the incubation, add 250 μL of acetonitrile solution containing internal standard to stop the reaction, shake at 800 rpm for 10 minutes, centrifuge at 3700 rpm for 10 minutes, and precisely pipette 100 μL of the supernatant. Add 80 μL of distilled water to dilute, and shake at 800 rpm for 10 minutes, and aspirate the supernatant for LC-MS/MS analysis.

數值經Graphpad Prism計算分別得到藥物對人肝微粒體CYP1A2非那西丁O-去乙基化、CYP2C9雙氯酚酸4’-羥基化、CYP2C19美芬妥英4’-羥基化、CYP2D6右美沙芬O-去甲基化和CYP3A4T睾酮6β-羥基化代謝抑制的IC₅₀值見表7。 The values were calculated by Graphpad Prism to obtain the drug effects on human liver microsomes CYP1A2 phenacetin O -deethylation, CYP2C9 diclofenac 4'-hydroxylation, CYP2C19 mephentoin 4'-hydroxylation, CYP2D6 dextromethorphan _IC50 values for the metabolic inhibition of Fen O -demethylation and CYP3A4T testosterone 6β-hydroxylation are shown in Table 7.

表7 本公開化合物對人肝微粒體CYP1A2非那西丁、CYP2C9雙氯酚酸、CYP2C19美芬妥英、CYP2D6右美沙芬和CYP3A4T睾酮代謝位點的抑制的IC₅₀值(單位μM)

Table 7 _IC50 values (in μM) of compounds of the present disclosure for inhibition of human liver microsomal CYP1A2 phenacetin, CYP2C9 diclofenac, CYP2C19 mephenytoin, CYP2D6 dextromethorphan and CYP3A4T testosterone metabolic sites

結論：本公開化合物30μM濃度範圍內不會發生基於CYP1A2非那西丁O-去乙基化、CYP2C9雙氯酚酸4’-羥基化、CYP2C19美芬妥英4’-羥基化、CYP2D6右美沙芬O-去甲基化和CYP3A4T睾酮6β-羥基化代謝位點的代謝性藥物相互作用。 Conclusion: The compounds of the present disclosure do not occur in the concentration range of 30 μM based on CYP1A2 phenacetin O -deethylation, CYP2C9 diclofenac 4'-hydroxylation, CYP2C19 mephentoin 4'-hydroxylation, CYP2D6 dextromethorphan Metabolic drug interactions at the Fen O -demethylation and testosterone 6β-hydroxylation metabolic sites of CYP3A4T.

測試例6 本公開化合物對hERG鉀離子通道的作用 Test Example 6 Effects of the disclosed compounds on hERG potassium channel

1、測試目的 1. Test purpose

應用手動膜片鉗技術在轉染hERG鉀通道的穩定細胞株上測試本公開化合物對hERG鉀電流的阻斷作用 The blocking effect of the compounds of the present disclosure on hERG potassium current was tested on stable cell lines transfected with hERG potassium channel using manual patch clamp technique

2、測試方法 2. Test method

2.1、細胞培養 2.1. Cell culture

本試驗所用的細胞為轉染有hERG cDNA與穩定表達hERG通道的CHO細胞系(由丹麥Sophion Bioscience公司提供)，細胞代數為P9&P11。細胞培養在含有下列成分的培養基中(皆來源於Invitrogen)：Ham’s F12培養基，10%(v/v)滅活的胎牛血清，100μg/mL潮黴素B，100μg/mL遺傳黴素。 The cells used in this experiment were CHO cell lines (provided by Sophion Bioscience, Denmark) transfected with hERG cDNA and stably expressing hERG channels, and the cell passages were P9&P11. Cells were grown in medium (all from Invitrogen) containing the following components: Ham's F12 medium, 10% (v/v) inactivated fetal bovine serum, 100 μg/mL hygromycin B, 100 μg/mL Geneticin.

CHO hERG細胞生長於含上述培養液的培養皿中，並在37℃、含5% CO₂的培養箱中進行培養。電生理實驗之前24到48小時，CHO hERG細胞被轉移到放置於培養皿中的圓形玻璃片上，並在以上相同的培養液及培養條件下生長。每個圓形玻片上CHO hERG細胞的密度需要達到絕大多數細胞是獨立、單個的要求。 CHO hERG cells were grown in petri dishes containing the above medium and cultured at 37°C in an incubator containing 5% CO ₂ . Twenty-four to 48 hours before electrophysiological experiments, CHO hERG cells were transferred to circular glass slides placed in petri dishes and grown in the same medium and culture conditions as above. The density of CHO hERG cells on each circular slide needs to be such that the vast majority of cells are independent and single.

2.2、實驗溶液 2.2. Experimental solution

表8 細胞內液和外液的組成成分

Table 8 Composition of intracellular fluid and extracellular fluid

表9 試劑詳細信息

Table 9 Reagent Details

2.3、電生理記錄系統 2.3. Electrophysiological recording system

本實驗採用手動膜片鉗系統(HEKA EPC-10信號放大器及數字轉換系統，購自德國HEKA Electronics)作全細胞電流的記錄。表面生長有CHO hERG細胞的圓形玻片被放置於倒置顯微鏡下的電生理記錄槽中。記錄槽內以細胞外液作持續灌流(大約每分鐘1毫升)。實驗過程採用常規全細胞膜片鉗電流記錄技術。如無特殊說明，實驗都是在常規室溫下進行(~25℃)。細胞鉗制在-80mV的電壓下。細胞鉗制電壓去極化到+20mV以激活hERG鉀通道，5秒後再鉗制到-50mV以消除失活並產生尾電流。尾電流峰值用作hERG電流大小的數值。上述步驟所記錄的hERG鉀電流在記錄槽內持續的細胞外液灌流下達到穩定後則可以疊加灌流待測試的藥物，直到藥物對hERG電流的抑制作用達到穩定狀態。一般以最近的連續3個電流記錄線重合作為判斷是否穩定狀態的標準。達到穩定態勢以後以細胞外液灌流沖洗直到hERG電流回復到加藥物之前的大小。一個細胞上可以測試一個或多個藥物，或者同一種藥物的多個濃度，但是在不同藥物之間需要以細胞外液沖洗。Cisapride(西沙必利，購自Sigma)被用於實驗中作為陽性對照以保證所使用的細胞質量正常。 In this experiment, a manual patch clamp system (HEKA EPC-10 signal amplifier and digital conversion system, purchased from HEKA Electronics, Germany) was used for whole-cell current recording. The round slides with CHO hERG cells grown on the surface were placed in the electrophysiological recording chamber under an inverted microscope. The recording tank was continuously perfused with extracellular fluid (approximately 1 ml per minute). experiment procedure The conventional whole-cell patch-clamp current recording technique was used. Unless otherwise specified, the experiments were carried out at normal room temperature (~25°C). Cells were clamped at -80mV. Cells were depolarized to +20 mV to activate the hERG potassium channel, and then clamped to -50 mV for 5 s to abolish inactivation and generate tail currents. The peak tail current was used as a numerical value for the magnitude of hERG current. After the hERG potassium current recorded in the above steps reaches a stable state under the continuous extracellular fluid perfusion in the recording tank, the drug to be tested can be superimposed and perfused until the inhibitory effect of the drug on the hERG current reaches a stable state. Generally, the recent coincidence of three consecutive current recording lines is used as the criterion for judging whether it is in a stable state. After reaching a steady state, the cells were perfused with extracellular fluid until the hERG current returned to the level before the drug was added. One or more drugs, or multiple concentrations of the same drug, can be tested on a cell, but need to be flushed with extracellular fluid between drugs. Cisapride (cisapride, purchased from Sigma) was used in the experiments as a positive control to ensure that the cells used were of normal quality.

2.4、試驗步驟 2.4. Test steps

為了取得化合物的IC₅₀，選擇下列濃度(30、10、3、1、0.3和0.1μM)來作測試。在試驗之前，用DMSO以梯度稀釋的方式稀釋成10、3、1、0.3和0.1mM的儲備液，用細胞外液稀釋成最終的μM測試濃度。各濃度化合物溶液中DMSO的最終濃度都為0.1%。陽性對照Cisapride(西沙比利)的測試濃度為0.1μM。所有的化合物溶液都經過常規的5到10分鐘超聲和振盪以保證化合物完全溶解。 In order to obtain the _IC50 of the compounds, the following concentrations (30, 10, 3, 1, 0.3 and 0.1 [mu]M) were selected for testing. Stock solutions of 10, 3, 1, 0.3 and 0.1 mM were serially diluted with DMSO and the final [mu]M test concentrations were diluted with extracellular fluid prior to the assay. The final concentration of DMSO in each concentration compound solution was 0.1%. The positive control Cisapride (cisapride) was tested at a concentration of 0.1 μM. All compound solutions were routinely sonicated and shaken for 5 to 10 minutes to ensure complete compound dissolution.

試驗數據由HEKA Patchmaster(V2x73.2)，Microsoft Excel以及Graphpad Prism 5.0提供的數據分析軟體進行分析。 The experimental data were analyzed by HEKA Patchmaster (V2x73.2), Microsoft Excel and data analysis software provided by Graphpad Prism 5.0.

2.5、試驗結果 2.5. Test results

本公開化合物對hERG鉀電流的阻斷作用藉由以上的試驗進行測定，測得的IC₅₀值見表10。 The blocking effect of the compounds of the present disclosure on hERG potassium current was determined by the above test, and the measured IC ₅₀ values are shown in Table 10.

表10 本公開化合物對hERG鉀離子通道的阻斷作用的IC₅₀

Table 10 _IC50 of the blocking effect of the compounds of the present disclosure on hERG potassium channel

結論：本公開化合物對hERG的抑制作用弱，可降低由hERG通路引起的副作用。 Conclusion: The disclosed compounds have weak inhibitory effect on hERG and can reduce the side effects caused by the hERG pathway.

Claims

一種通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽， A compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable of salt,

其中， in,

環A為芳基或雜芳基； Ring A is aryl or heteroaryl;

G為CR⁵或N原子； G is CR ⁵ or N atom;

R³選自氫原子、烷基、鹵烷基、羥烷基、環烷基、雜環基、芳基和雜芳基，其中該烷基、鹵烷基、羥烷基、環烷基、雜環基、芳基和雜芳基各自獨立地任選地被選自鹵素、烷基、烯基、炔基、烷氧基、鹵烷基、鹵烷氧基、氰基、胺基、硝基、羥基、羥烷基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； ^R is selected from hydrogen atom, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, Heterocyclyl, aryl, and heteroaryl are each independently optionally selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro substituted with one or more substituents in radical, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

n選自0、1、2、3、4和5。 n is selected from 0, 1, 2, 3, 4 and 5.

如請求項1所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R⁰選自鹵素、烷基、烷氧基、鹵烷基、鹵烷氧基、羥烷基、烯基、炔基、羥基、胺基、-(CH₂)_pNR⁶R⁷、環烷基氧基、雜環基氧基、環烷基、雜環基、芳基和雜芳基，其中該烷基、環烷基氧基、雜環基氧基、環烷基、雜環基、芳基和雜芳基各自獨立地任選地被選自鹵素、烷基、鹵烷基、羥基、羥烷基、烷氧基、鹵烷氧基、胺基、硝基、氰基、-S(O)₂R⁹、-C(O)R¹⁰、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基取代； The compound represented by the general formula (I) according to claim 1 or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof , or a pharmaceutically acceptable salt thereof, wherein R ^is selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, hydroxy, amino, -(CH ₂ ) _pNR6R7 , ^{cycloalkyloxy} , ^{heterocyclyloxy} , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyloxy, heterocyclyloxy , cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amine substituted with one or more substituents in group, nitro, cyano, -S(O) ₂ R ⁹ , -C(O)R ¹⁰ , cycloalkyl, heterocyclyl, aryl and heteroaryl;

R⁶、R⁷、R¹¹、R¹²、p和q如請求項1中所定義。 R ⁶ , R ⁷ , R ¹¹ , R ¹² , p and q are as defined in claim 1 .

如請求項1或2所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中G為CR⁵，R⁵如請求項1或2中所定義；較佳地，G為CH。 The compound represented by the general formula (I) according to claim 1 or 2 or its tautomer, meso, racemate, enantiomer, diastereomer, or its In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein G is CR ⁵ , and R ⁵ is as defined in claim 1 or 2; preferably, G is CH.

如請求項1至3中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其為通式(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽， The compound represented by the general formula (I) according to any one of claims 1 to 3 or its tautomer, meso, racemate, enantiomer, and diastereomer isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is the compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, non- an enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

其中，環A、R、R⁰、R¹、R³、R⁴、R⁵、R⁸和n如請求項1或2中所定義。 wherein rings A, R, R ⁰ , R ¹ , R ³ , R ⁴ , R ⁵ , R ⁸ and n are as defined in claim 1 or 2.

如請求項1至4中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R⁰選自環烷基氧基、雜環基氧基、環烷基、雜環基、芳基和雜芳基，其中該環烷基氧基、雜環基氧基、環烷基、雜環基、芳基和雜芳基各自獨立地任選地被選自羥基和-C(O)R¹⁰中的一個或多個取代基取代；R¹⁰為烷基。 The compound represented by general formula (I) according to any one of claims 1 to 4 or its tautomer, meso, racemate, enantiomer, diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁰ is selected from cycloalkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the ring Alkyloxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more selected from hydroxy and -C(O)R ¹⁰ substituted; R ¹⁰ is alkyl.

如請求項1至5中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R⁰為四氫呋喃基氧基或哌啶基，該四氫呋喃基氧基和哌啶基各自獨立地任選地被-C(O)R¹⁰和/或羥基取代，其中R¹⁰為C_1-6烷基。 The compound represented by the general formula (I) according to any one of claims 1 to 5 or its tautomer, meso, racemate, enantiomer, and diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁰ is tetrahydrofuranyloxy or piperidinyl, each of which is independently optionally -C(O)R ¹⁰ and/or hydroxy substituted, wherein R ¹⁰ is C _1-6 alkyl.

如請求項1至6中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其為通式(III)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽， The compound represented by the general formula (I) according to any one of claims 1 to 6 or its tautomer, meso, racemate, enantiomer, and diastereomer isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is the compound represented by the general formula (III) or its tautomer, meso, racemate, enantiomer, non- an enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

其中，R、R⁰、R¹、R⁴、R⁵、R⁸和n如請求項1或2中所定義。 wherein R, R ⁰ , R ¹ , R ⁴ , R ⁵ , R ⁸ and n are as defined in claim 1 or 2.

如請求項1至7中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R⁸相同或不同，各自獨立地選自鹵素、C_1-6烷基、C_1-6鹵烷基、胺基、-(CH₂)_pNR⁶R⁷和C_1-6羥烷基，其中該C_1-6鹵烷基任選地被一個或多個羥基取代；R⁶和R⁷為氫原子或C_1-6烷基，p為0、1或2。 The compound represented by the general formula (I) according to any one of claims 1 to 7 or its tautomer, meso, racemate, enantiomer, diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁸ are the same or different, each independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, amino, -(CH ₂ ) _p NR ⁶ R ⁷ and C _1-6 hydroxyalkyl, wherein the C _1-6 haloalkyl is optionally substituted by one or more hydroxyl groups; R ⁶ and R ⁷ are hydrogen atoms or C _1-6 alkanes base, p is 0, 1 or 2.

如請求項1至8中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R¹選自氫原子、C_1-6烷基和鹵素；較佳地，R¹為甲基。 The compound represented by the general formula (I) according to any one of claims 1 to 8 or its tautomer, meso, racemate, enantiomer, diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from a hydrogen atom, a C _1-6 alkyl group and a halogen; preferably, R ¹ is a methyl group.

如請求項1、2、3、5、6、8和9中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R²為氫原子或C_1-6烷基；較佳地，R²為甲基。 The compound represented by the general formula (I) according to any one of claims 1, 2, 3, 5, 6, 8 and 9 or its tautomer, meso, racemate, para Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ² is a hydrogen atom or a C _1-6 alkyl group; preferably, R ² is a methyl group.

如請求項1至6、8至10中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R³為氫原子或C_1-6烷基；較佳地，R³為氫原子。 The compound represented by the general formula (I) according to any one of claims 1 to 6 and 8 to 10 or its tautomer, meso, racemate, enantiomer, non- An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ³ is a hydrogen atom or a C _1-6 alkyl group; preferably, R ³ is a hydrogen atom.

如請求項1至11中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R⁴為氫原子。 The compound represented by the general formula (I) according to any one of claims 1 to 11 or its tautomer, meso, racemate, enantiomer, diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a hydrogen atom.

如請求項1至12中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R⁵為氫原子。 The compound represented by the general formula (I) according to any one of claims 1 to 12 or its tautomer, meso, racemate, enantiomer, diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a hydrogen atom.

如請求項1至13中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中R為C_1-6烷氧基。 The compound represented by the general formula (I) according to any one of claims 1 to 13 or its tautomer, meso, racemate, enantiomer, diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is C _1-6 alkoxy.

一種化合物，其選自以下任一結構： A compound selected from any of the following structures:

一種通式(IA)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽， A compound represented by general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable of salt,

其中X為鹵素； wherein X is halogen;

R⁰選自溴、碘、烷基、烷氧基、鹵烷基、鹵烷氧基、羥烷基、烯基、炔基、羥基、胺基、-(CH₂)_pNR⁶R⁷、雜環基氧基、環烷基、雜環基、芳基和雜芳基，其中該烷基、雜環基氧基、環烷基、雜環基、芳基和雜芳基各自獨立地任選地被選自鹵素、烷基、鹵烷基、羥基、羥烷基、烷氧基、鹵烷氧基、胺基、硝基、氰基、-S(O)₂R⁹、-C(O)R¹⁰、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基取代； R ⁰ is selected from bromine, iodine, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, hydroxyl, amino, -(CH ₂ ) _p NR ⁶ R ⁷ , Heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently any is optionally selected from halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, amine, nitro, cyano, -S(O) ^2R9 , _-C ( O) substituted with one or more substituents in R ¹⁰ , cycloalkyl, heterocyclyl, aryl and heteroaryl;

G、R⁶、R⁷、R⁹、R¹⁰、R¹¹、R¹²、p、q和R⁴如請求項1或2中所定義。 G, R ⁶ , R ⁷ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , p, q and R ⁴ are as defined in claim 1 or 2.

一種製備通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽的方法，該方法包括以下步驟： A kind of compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable A method of using the salt, the method comprising the steps of:

通式(IA)的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽與通式(IB)或其鹽反應，得到通式(I)的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽， The compound of general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof and The general formula (IB) or its salt is reacted to obtain the compound of the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or its in the form of a mixture, or a pharmaceutically acceptable salt thereof,

其中，X為鹵素； Wherein, X is halogen;

環A、G、R、R⁰、R¹、R²、R³、R⁴、R⁸和n如請求項1或2中所定義。 Rings A, G, R, R ⁰ , R ¹ , R ² , R ³ , R ⁴ , R ⁸ and n are as defined in claim 1 or 2.

一種醫藥組成物，該醫藥組成物含有治療有效量的如請求項1至15中任一項所述的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，以及一種或多種藥學上可接受的載體、稀釋劑或賦形劑。 A pharmaceutical composition containing a therapeutically effective amount of the compound described in any one of claims 1 to 15 or its tautomer, meso, racemate, Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

一種如請求項1至15中任一項所述的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽或者如請求項19所述的醫藥組成物在製備用於抑制SOS1的藥物中的用途。 A compound as claimed in any one of claims 1 to 15 or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, Use of a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 19 in the preparation of a medicament for inhibiting SOS1.

一種如請求項1至15中任一項所述的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽或者如請求項19所述的醫藥組成物在製備用於治療和/或預防癌症、炎症、RAS病、努南綜合症(NS)、伴有多斑的努南綜合症(NSML)、毛細血管畸形-動靜脈畸形綜合症(CM-AVM)、科斯特洛綜合症(CS)、心-面-皮膚綜合症(CFC)、萊格斯綜合症、遺傳性牙齦纖維瘤病、或其它增殖性疾病的藥物中的用途，較佳為癌症；該癌症較佳自黑色素瘤、皮膚癌、肝癌、腎癌、肺癌、鼻咽癌、胃癌、食道癌、結腸直腸癌、膽囊癌、膽管癌、絨毛膜上皮癌、胰腺癌、真性紅細胞增多症、兒科腫瘤、宮頸癌、卵巢癌、乳腺癌、膀胱癌、尿路上皮癌、輸尿管腫瘤、***癌、精原細胞瘤、睾丸腫瘤、白血病、頭頸瘤、子宮內膜癌、甲狀腺癌、淋巴瘤、肉瘤、骨瘤、成神經細胞瘤、神經母細胞瘤、腦瘤、骨髓瘤、星形細胞瘤、膠質母細胞瘤和膠質瘤；該RAS病較佳為1型神經纖維瘤病(NF1)；該肺癌較佳為非小細胞肺癌，進一步較佳為轉移性非小細胞肺癌；該白血病較佳為慢性淋巴細胞白血病或急性髓性白血病；該淋巴瘤較佳為瀰漫性大B細胞淋巴瘤；該骨髓瘤較佳為多發性骨髓瘤；該骨瘤較佳為骨軟骨瘤；該肝癌較佳為肝細胞癌；該結腸直腸癌較佳為結腸癌或直腸癌；該頭頸癌較佳為頭頸鱗狀細胞癌；該肉瘤較佳為骨肉瘤。 A compound as claimed in any one of claims 1 to 15 or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, Or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as claimed in claim 19 in preparation for the treatment and/or prophylaxis of cancer, inflammation, RAS disease, Noonan syndrome (NS), Noonan syndrome with multiple spots Capillary Malformation-Arteriovenous Malformation Syndrome (NSML), Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM), Costello Syndrome (CS), Cardio-Facial-Skin Syndrome (CFC), Leggers Syndrome, Hereditary Gingival Fibrosis The use in the drug of neoplastic disease or other proliferative diseases, preferably cancer; the cancer is preferably selected from melanoma, skin cancer, liver cancer, kidney cancer, lung cancer, nasopharyngeal cancer, gastric cancer, esophageal cancer, colorectal cancer, Gallbladder cancer, bile duct cancer, chorioepithelial cancer, pancreatic cancer, polycythemia vera, pediatric cancer, cervical cancer, ovarian cancer, breast cancer, bladder cancer, urothelial cancer, ureteral cancer, prostate cancer, seminoma, Testicular tumors, leukemia, head and neck tumors, endometrial cancer, thyroid cancer, lymphoma, sarcoma, osteoma, neuroblastoma, neuroblastoma, brain tumor, myeloma, astrocytoma, glioblastoma and Glioma; the RAS disease is preferably neurofibromatosis type 1 (NF1); the lung cancer is preferably non-small cell lung cancer, more preferably metastatic non-small cell lung cancer; the leukemia is preferably chronic lymphocytic leukemia or Acute myeloid leukemia; the lymphoma is preferably diffuse large B-cell lymphoma; the myeloma is preferably multiple myeloma; the osteoma is preferably osteochondroma; the liver cancer is preferably hepatocellular carcinoma; the The colorectal cancer is preferably colon cancer or rectal cancer; the head and neck cancer is preferably head and neck squamous cell carcinoma; the sarcoma is preferably osteosarcoma.