Quinazoline derivatives, their preparation methods, pharmaceutical compositions and uses

Abstract

The present invention discloses a quinazoline derivative, a preparation method thereof, a pharmaceutical composition and an application. Specifically, the present invention discloses a compound represented by Formula I, a solvate thereof, a pharmaceutically acceptable salt thereof or a solvate of a pharmaceutically acceptable salt thereof. The compound represented by Formula I has a novel structure and excellent inhibitory effects on wild-type ALK and TRKA.

Description

[0001] This application claims the priority of Chinese Patent Application No. 2022103415985 with the filing date of March 28, 2022. This application incorporates the entire text of the above-mentioned Chinese patent application by reference. Technical Field

[0002] The present invention relates to a quinazoline derivative, a preparation method thereof, a pharmaceutical composition and an application. Background Art

[0003] The incidence and mortality of lung cancer rank first among all malignant tumors. There has always been a need to discover new compounds with better activity and higher selectivity in the field of targeted therapy for lung cancer. The most common type of lung cancer is non-small cell lung cancer, accounting for 80-85%. Genes related to non-small cell lung cancer mainly include NTRK (NeuroTrophin Receptor Kinase), ALK (Anaplastic Lymphoma kinase), etc. The "golden mutation" - the ALK gene shows higher efficacy and a more significant cure rate compared to targeted therapy for EGFR gene mutations because it is mutually exclusive with other driver genes. In addition, NTRK gene fusions have been found in both common cancer tissues and rare tumors, so NTRK has achieved a true "broad spectrum". Currently, there are already marketed drugs for both ALK and NTRK, indicating their good druggability. Therefore, designing and synthesizing ALK / TRK (tropomyosin receptor kinase) dual-target drugs has certain theoretical significance and application value.

[0004] Currently, there are mainly three generations of ALK inhibitors on the market: the first-generation crizotinib, the second-generation alectinib, ceritinib, brigatinib, and the third-generation lorlatinib. In 2011, the FDA approved the marketing of crizotinib for the treatment of patients with locally advanced or metastatic non-small cell lung cancer positive for ALK, filling the gap in the field of targeted drugs for ALK-positive non-small cell lung cancer at that time. In 2017, the FDA approved the marketing of ceritinib and brigatinib for the treatment of patients with ALK-positive non-small cell lung cancer whose tumor condition has progressed or who cannot tolerate treatment with crizotinib. In 2018, the FDA approved the marketing of lorlatinib for the treatment of ALK-positive non-small cell lung cancer with continuous disease progression, metastatic disease patients who have received crizotinib and at least one other ALK inhibitor, or patients whose disease has progressed to metastatic disease after receiving alectinib or ceritinib.

[0005] There are mainly two drugs for TRK inhibitors: Larotrectinib and Entrectinib, which were respectively approved by the FDA for marketing in 2018 and 2019, and are used to treat adult and pediatric patients with solid tumors having NTRK gene fusions rather than specific cancer types. The research on Entrectinib targeting the ALK target is in the clinical stage. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide a novel quinazoline derivative, a preparation method, a pharmaceutical composition and an application. The indazole derivative of the present invention has excellent inhibitory effects on wild-type ALK and TRKA (wherein, the IC 50 values for wild-type ALK and TRKA are both in the nanomolar level).

[0007] The present invention solves the above technical problem through the following methods.

[0008] The present invention provides a compound represented by Formula I, its solvate, its pharmaceutically acceptable salt or a solvate of its pharmaceutically acceptable salt;

[0009]

[0010] Wherein, R 1 is halogen, 3- to 8-membered heterocycloalkyl, 3- to 8-membered heterocycloalkyl substituted by one or more R 1-1 , -NR 1 -4 R 1-5 , 5- to 8-membered heterocycloalkenyl, 5- to 8-membered heterocycloalkenyl substituted by one or more R 1-2 or C1-C6 alkyl substituted by one or more R 1-3 ;

[0011] R 1-3 is independently 3- to 8-membered heterocycloalkyl or 3- to 8-membered heterocycloalkyl substituted by one or more R a ;

[0012] R 1-1 , R 1-2 and R a are each independently C1-C6 alkyl or -NR b R c ;

[0013] R 1-4 and R 1-5 are each independently C1-C6 alkyl or C1-C6 alkyl substituted by one or more R d ;

[0014] R dFor-NR e R f ;

[0015] R b , R c , R e and R f Each is independently a C1-C6 alkyl group;

[0016] R 2 H, -NR 2-1 R 2-2 or a 3- to 8-membered heterocycloalkyl group;

[0017] R 2-1 and R 2-2 Each is independently H, C1-C6 alkyl or 3-8 membered heterocycloalkyl;

[0018] X is a connecting key, -CR x1 R x2 -, -O- or -O-CR x3 R x4 -; R x1 , R x2 , R x3 and R x4 Each group is independently H or C1-C6 alkyl;

[0019] R 3 C6~C 14 Aryl or C6~C 14 Aryl; wherein the halogen is denoted as M and the number of halogens is denoted as n;

[0020] In the 3- to 8-membered heterocycloalkyl and 5- to 8-membered heterocycloalkenyl, the types of the heteroatoms are independently selected from one or more of N, O and S, and the number of the heteroatoms is independently 1, 2 or 3.

[0021] In one embodiment, R 1 In the above, the halogen may be F, Cl, Br or I, such as F or Br.

[0022] In one embodiment, R 1 and R 1-3 In the 3- to 8-membered heterocycloalkyl, the type of the heteroatom can be independently N and / or O, preferably N, N and O; the number of the heteroatom can be independently 1 or 2.

[0023] In one embodiment, R 1 and R 1-3Among them, the 3- to 8-membered heterocycloalkyl group can be independently a 5- to 7-membered heterocycloalkyl group, such as pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl or a 7-membered heterocycloalkyl group containing 2 N atoms, and more preferably

[0024] In one embodiment, R 1 and R 1-3 Among them, in the 5- to 8-membered heteroalkenyl group, the types of the heteroatoms can be independently N; the number of the heteroatoms can be independently 1.

[0025] In one embodiment, R 1 and R 1-3 Among them, the 5- to 8-membered heteroalkenyl group can be independently a 6-membered heteroalkenyl group, such as a 6-membered heteroalkenyl group containing 1 N atom, and more preferably

[0026] In one embodiment, R 1 Among them, the C1-C6 alkyl group can be a C1-C3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl, and preferably methyl.

[0027] In one embodiment, R 1-1 , R 1-2 and R a Among them, the C1-C6 alkyl group can be independently a C1-C3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl, and preferably methyl or ethyl.

[0028] In one embodiment, R 1-4 and R 1-5 Among them, the C1-C6 alkyl group can be independently a C1-C3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl, and preferably methyl or ethyl.

[0029] In one embodiment, R b , R c , R e and R f Among them, the C1-C6 alkyl group can be independently a C1-C3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl, and preferably methyl.

[0030] In one embodiment, R 1It can be a halogen, a piperazinyl group substituted by methyl, an ethyl-substituted piperazinyl group, a piperidyl group, a morpholinyl group, a methyl-substituted morpholinyl group, a methyl-substituted 7-membered heterocyclic alkyl group containing 2 N atoms, a methyl-substituted 6-membered heteroalkenyl group containing 1 N atom, a methyl-substituted piperidyl group, a pyrrolidinyl group substituted by dimethylamino, an amino group substituted by methyl and dimethylaminoethyl, a methyl-substituted piperazinyl-CH2-, a morpholinyl-CH2-, a methyl-substituted morpholinyl-CH2-, a methyl-substituted 7-membered heterocyclic alkyl group containing 2 N atoms-CH2-, a methyl-substituted piperidyl group-CH2- or a pyrrolidinyl group substituted by dimethylamino-CH2-, such as F, Br,

[0031] In one embodiment, R 2 、R 2-1 and R 2-2 Among them, in the 3- to 8-membered heterocyclic alkyl group, the types of the heteroatoms can be independently N and / or O; the number of the heteroatoms can be independently 1 or 2.

[0032] In one embodiment, in R 2 Among them, the 3- to 8-membered heterocyclic alkyl group can contain an N atom, and the N atom can be located at the site in the ring connected to the parent nucleus.

[0033] In one embodiment, R 2 、R 2-1 and R 2-2 Among them, the 3- to 8-membered heterocyclic alkyl group can be independently a 4- to 6-membered heterocyclic alkyl group, such as tetrahydropyranyl, morpholinyl, azetidinyl or piperidyl, more preferably

[0034] In one embodiment, R 2-1 and R 2-2 Among them, the C1-C6 alkyl group can be independently a C1-C3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl, and is preferably methyl.

[0035] In one embodiment, R 2 can be H, dimethylamino, morpholinyl, an amino group substituted by tetrahydropyranyl, azetidinyl or piperidyl, such as H,

[0036] In one embodiment, R x1 、R x2 、R x3 and R x4 Among them, the C1-C6 alkyl group can be independently a C1-C3 alkyl group, such as methyl, ethyl, n-propyl or isopropyl, and is preferably methyl.

[0037] In one embodiment, Rx1 , R x2 , R x3 and R x4 may each independently be H or methyl.

[0038] In one embodiment, X may be a linking bond, -CH2-, -O-, or -O-CHCH3-, for example, a linking bond, -CH2-, -O-, or

[0039] In one embodiment, R 3 in, the C6-C 14 aryl may be C6-C 10 aryl, such as phenyl.

[0040] In one embodiment, R 3 in, the number of the halogens is denoted as n, and the n may be 2 or 3.

[0041] In one embodiment, R 3 in, the halogen is denoted as M, and the M may be selected from one or more of F, Cl, Br, and I, preferably F and / or Cl.

[0042] In one embodiment, R 3 may be a fluorine-substituted phenyl or a phenyl substituted by fluorine and chlorine together, more specifically or

[0043] In one embodiment, R 1 is a 3- to 8-membered heterocycloalkyl or a 3- to 8-membered heterocycloalkyl substituted by one or more R 1-1 ; in the 3- to 8-membered heterocycloalkyl, the types of the heteroatoms are preferably N and O, and the number of the heteroatoms is preferably 2; preferably, the 3- to 8-membered heterocycloalkyl is morpholinyl, for example

[0044] In one embodiment, R 1-1 is a C1-C6 alkyl.

[0045] In one embodiment, X is CH2.

[0046] In one embodiment, R 1 is a 3- to 8-membered heterocycloalkyl or a 3- to 8-membered heterocycloalkyl substituted by one or more R 1-1 ; preferably, it is a 3- to 8-membered heterocycloalkyl containing N and O atoms or a 3- to 8-membered heterocycloalkyl containing N and O atoms and substituted by one or more R 1-1 ; for example, morpholinyl or morpholinyl substituted by one or more methyl groups, more specifically X is CH2.

[0047] In one embodiment, R 1 is a 3- to 8-membered heterocycloalkyl group substituted by one or more R 1-1 ; in the 3- to 8-membered heterocycloalkyl group, the type of the heteroatom is preferably N, and the number of the heteroatoms is preferably 2; preferably, the 3- to 8-membered heterocycloalkyl group is a morpholinyl group, for example

[0048] In one embodiment, X is -O- or -O-CR x3 R x4 , for example -O- or

[0049] In one embodiment, R 1 is a 3- to 8-membered heterocycloalkyl group substituted by one or more R 1-1 ; preferably, it is a 3- to 8-membered heterocycloalkyl group containing 2 N atoms substituted by one or more R 1-1 , such as a piperazinyl group substituted by one or more methyl groups, more specifically

[0050] X is -O- or -O-CR x3 R x4 -, for example -O- or

[0051] In one embodiment, R 1 is a 3- to 8-membered heterocycloalkyl group substituted by one or more R 1-1 ; in the 3- to 8-membered heterocycloalkyl group, the type of the heteroatom is preferably N, and the number of the heteroatoms is preferably 1; preferably, the 3- to 8-membered heterocycloalkyl group is a piperidinyl group, for example

[0052] In one embodiment, X is -O-CR x3 R x4 -, for example

[0053] In one embodiment, R 1 is a 3- to 8-membered heterocycloalkyl group substituted by one or more R 1-1 ; preferably, it is a 3- to 8-membered heterocycloalkyl group containing 1 N atom substituted by one or more R 1-1 , such as a piperidinyl group substituted by one or more methyl groups, more specifically

[0054] X is -O-CR x3 R x4 -, for example

[0055] In one embodiment, R2 -NR 2-1 R 2-2 or a 3- to 8-membered heterocycloalkyl group, such as a dimethylamino group, a morpholino group, a tetrahydropyranyl-substituted amino group, an azetidinyl group or a piperidinyl group, more preferably

[0056] In one embodiment, the compound represented by Formula I may be any one of the following structures:

[0057]

[0058] wherein the definitions of each letter and group are as defined in the present invention.

[0059] In one embodiment, the compound represented by Formula I is any one of the following compounds:

[0060]

[0061] The present invention also provides a method for preparing a compound represented by Formula I, which comprises the following steps: in a solvent, the compound represented by Formula 1 reacts with the compound represented by Formula 2 as shown below, and that's it;

[0062]

[0063] wherein Y is a halogen, such as F, Cl, Br or I, preferably Cl; the definitions of the remaining substituents in the above formulas are as described above.

[0064] In one embodiment, the method for preparing the compound represented by Formula I comprises the following steps: in a solvent, under the action of a palladium catalyst, a ligand and a base, the compound represented by Formula 1 and the compound represented by Formula 2 react, and that's it.

[0065] In one embodiment, in the method for preparing the compound represented by Formula I, the solvent can be a solvent commonly used in such reactions in the art, such as a hydrocarbon solvent, more preferably a benzene solvent, and preferably toluene.

[0066] In one embodiment, in the method for preparing the compound represented by Formula I, the palladium catalyst can be a palladium catalyst commonly used in such reactions in the art, such as a divalent palladium catalyst, and preferably palladium acetate.

[0067] In one embodiment, in the method for preparing the compound represented by Formula I, the ligand can be a ligand commonly used in such reactions in the art, such as BINAP.

[0068] In one embodiment, in the method for preparing the compound represented by Formula I, the base can be a ligand commonly used in such reactions in the art, such as a carbonate of an alkali metal, and preferably cesium carbonate.

[0069] The present invention also provides a pharmaceutical composition, which comprises substance P and pharmaceutically acceptable excipients; the substance P is a compound represented by the above formula I, its solvate, its pharmaceutically acceptable salt or a solvate of its pharmaceutically acceptable salt.

[0070] The present invention also provides the use of the above substance P or the above pharmaceutical composition in the preparation of an ALK and / or TRK inhibitor.

[0071] The present invention also provides the use of the above substance P or the above pharmaceutical composition in the preparation of a drug for preventing and / or treating diseases related to ALK and / or TRK.

[0072] In one embodiment, the diseases related to ALK and / or TRK may be cancer, pain, neurological diseases, autoimmune diseases and inflammation.

[0073] In one embodiment, the cancer may be lung cancer, such as non-small cell lung cancer.

[0074] In one embodiment, the TRK may be TRKA.

[0075] Unless otherwise specified, the terms used in the present invention have the following meanings:

[0076] The term "heterocycloalkyl" refers to a cyclic group having a specified number of ring atoms (e.g., 3 to 8-membered), a specified number of heteroatoms (e.g., 1, 2 or 3), a specified type of heteroatoms (one or more of N, O and S), and each ring is saturated.

[0077] The term "heterocycloalkenyl" refers to a partially unsaturated monocyclic or polycyclic cyclic group formed by carbon atoms and at least one heteroatom, wherein the heteroatoms are independently selected from N, O or S, and examples include but are not limited to

[0078] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0079] The term "alkyl" is a straight-chain or branched-chain saturated aliphatic hydrocarbon group. The terms "C1-C6 alkyl" and "C1-C3 alkyl" refer to straight-chain or branched-chain alkyl groups having 1 to 6 carbon atoms and 1 - 3 carbon atoms, respectively, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl.

[0080] The term "aryl" refers to an aromatic group of a conjugated hydrocarbon ring system composed of carbon atoms that satisfies the 4n + 2 rule, and each ring has aromaticity. In one embodiment, "aryl" refers to an aromatic group having 6 to 14 (preferably 6 - 10) carbon atoms. Examples of aryl include but are not limited to phenyl or naphthyl, etc.

[0081] "R-CH2-" means that one H in -CH3 is replaced by R to form an R-substituted methyl group. For example, morpholinyl-CH2- means a methyl group substituted by a morpholinyl group.

[0082] In the structural fragment means that this structural fragment is connected to other fragments in the molecule through this site.

[0083] The term "one or more" means 1, 2, 3, 4, 5, 6, 7, 8, 9 or more.

[0084] In addition, it should be noted that, unless otherwise clearly indicated, the description method "… independently is" adopted in the present invention should be understood in a broad sense, which means that the described individuals are independent of each other and can independently be the same or different specific groups.

[0085] The term "solvate" refers to a substance formed after a compound crystallizes with a solvent (including but not limited to: water, methanol, ethanol, etc.). Solvates are divided into stoichiometric solvates and non-stoichiometric solvates.

[0086] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for use by patients) acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. Pharmaceutically acceptable base addition salts include but are not limited to sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, bismuth salts, ammonium salts, etc. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. The pharmaceutically acceptable acids include inorganic acids and organic acids. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977), or, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0087] The term "solvate of a pharmaceutically acceptable salt" refers to a substance formed by the combination of a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for use in patients) acid or base, and a solvent (including but not limited to: water, methanol, ethanol, etc.). Among them, the pharmaceutically acceptable salt has the same meaning as the above-mentioned term "pharmaceutically acceptable salt".

[0088] The term "pharmaceutical excipient" or "pharmaceutically acceptable carrier" refers to excipients and additives used in the production of drugs and the formulation of prescriptions, and all substances contained in pharmaceutical preparations except the active ingredient. Reference can be made to the fourth part of the Pharmacopoeia of the People's Republic of China (2015 edition), or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition). Excipients are mainly used to provide a safe, stable, and functional pharmaceutical composition, and can also provide methods to enable the active ingredient to dissolve at the desired rate after the subject receives the administration, or to promote the effective absorption of the active ingredient after the subject receives the administration of the composition. The said pharmaceutical excipients can be inert fillers, or provide certain functions, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition. The said pharmaceutical excipients can include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesives, glidants, wetting agents, gelling agents, absorption retardants, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweetening agents.

[0089] The term "treatment" refers to therapeutic or palliative measures. When referring to a specific disease or disorder, treatment means: (1) alleviating one or more biological manifestations of the disease or disorder, (2) interfering with (a) one or more points in the biological cascade that causes or gives rise to the disorder or (b) one or more biological manifestations of the disorder, (3) improving one or more symptoms, effects, or side effects associated with the disorder, or one or more symptoms, effects, or side effects associated with the disorder or its treatment, or (4) slowing down the development of the disorder or one or more biological manifestations of the disorder. "Treatment" can also mean prolonging the survival period compared to the expected survival without treatment.

[0090] The term "prevention" refers to a reduction in the risk of acquiring or developing a disease or disorder.

[0091] On the basis of conforming to the common knowledge in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain various preferred examples of the present invention.

[0092] The reagents and raw materials used in the present invention are all commercially available.

[0093] The positive and progressive effects of the present invention are as follows: The compound shown in Formula I of the present invention exhibits excellent inhibitory activities against ALK and TRKA, and the IC 50 values for wild-type ALK and TRKA are both in the nanomolar range. Detailed implementation mode

[0094] The present invention will be further illustrated by the following examples, but the present invention is not limited to the scope of the described examples. For the experimental methods without specific conditions in the following examples, they are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0095] In the following examples, the preparation methods of intermediates 4-1 to 18-1, 22-1, 24-1, 26-1 to 29-1 are the same as that of intermediate 3-6, and the preparation methods of intermediates 19-1 to 20-1 are the same as those of intermediates 1 to 4.

[0096] Example 1 Synthesis of Compound 1

[0097]

[0098] Synthesis route

[0099]

[0100] 1) To a toluene solution of compound 1-1 (5.12 g, 31.04 mmol) with magnetic stirring, compound 1-2 (7.1 g, 34.15 mmol), Pd(PPh3)4 (700 mg, 0.61 mmol) and potassium phosphate (13.2 g, 62.18 mmol) were successively added, and the mixture was refluxed at 105 °C under a nitrogen atmosphere for 4 h. After monitoring the reaction by TLC and the reaction was completed, the reaction solution was naturally cooled to room temperature, quenched with water (100 mL), extracted with ethyl acetate (200 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (PE / EA = 40 / 1) to obtain intermediate 1-3 (light brown solid; 5.8 g; yield: 76%);

[0101] 2) To a n-butanol solution of intermediate 1-3 (4.7 g, 19.0) with magnetic stirring, 85% hydrazine hydrate (5.6 mL, 95.0 mmol) was added, and the mixture was refluxed at 120 °C for 14 h. After monitoring the reaction by TLC and the reaction was completed, the reaction solution was naturally cooled to room temperature, quenched with water (100 mL), extracted with ethyl acetate (200 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (PE / EA = 40 / 1) to obtain intermediate 1-4 (white solid; 4.7 g; yield: 96%);

[0102] 3) Dissolve intermediate 1-4 (427.8 mg, 1.65 mmol) in toluene (5 ml). Sequentially add compound 4-chloro-7-fluoroquinazoline (200 mg, 1.1 mmol), Pd(OAc)2 (24.7 mg, 0.11 mmol), BINAP (68.5 mg, 0.11 mmol), and Cs2CO3 (0.72 g, 2.2 mmol) to the solution. Heat the reaction solution to 110 °C and stir for 6 h at this temperature. After monitoring the reaction by TLC until completion, allow the reaction solution to cool to room temperature naturally. Quench the reaction with water (100 mL), extract with ethyl acetate (200 mL), collect the organic phase, dry the organic phase over anhydrous sodium sulfate, filter, and rotary evaporate to obtain the crude product. Purify the crude product by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 1 (brown solid; 0.3 g; yield: 66.7%). 1 1H-NMR (400 MHz, CDCl3, δ ppm): 12.4 (s, 1H), 8.72 (s, 1H), 8.54 (s, 1H), 8.42 (dd, J = 9.2, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.64 (dd, J = 2.4, 1H), 7.47 (dd, J = 8.0 Hz, 1H), 7.43 (dd, J = 9.2 Hz, 2.4 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.01 - 7.08 (m, 3H), 4.14 (s, 2H). ES-API (m / z): [M+H] + : 406.5.

[0103] Synthesis of Compound 2 in Example 2

[0104]

[0105] Synthetic Route

[0106]

[0107] Under nitrogen protection, intermediate 1-4 (318.89 mg, 1.23 mmol) (refer to Example 1) was dissolved in toluene (5 ml) solution. To the solution were successively added compound 4-bromo-7-fluoroquinazoline (200 mg, 0.82 mmol), Pd(OAc)2 (18.41 mg, 0.08 mmol), BINAP (51.06 mg, 0.08 mmol), and Cs2CO3 (0.53, 1.64 mmol). The reaction solution was heated to 110 °C and stirred at this temperature for 6 h. After monitoring the reaction by TLC and the reaction was completed, the reaction solution was naturally cooled to room temperature, quenched with water (100 mL), extracted with ethyl acetate (200 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 1 (brown solid; 0.25 g; yield: 68.79%). 1 1H-NMR (400 MHz, DMSO-d6, δ ppm): 12.5 (s, 1H), 8.55 (s, 1H), 8.42 (s, 1H), 8.16 (dd, J = 9.2, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.58 (dd, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 6.94 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 7.12 (dd, J = 2.8, 1H), 7.04 - 7.09 (m, 3H), 4.24 (s, 2H). ES-API (m / z): [M+H] + : 466.2.

[0108] Synthesis of Compound 3 in Example 3

[0109]

[0110] Synthetic Route

[0111]

[0112] 1) Intermediate 3-1 (5 g, 27.01 mmol) with magnetic stirring was dissolved in DMF (50 mL), cooled to 0 °C, potassium carbonate (7.5 g, 54.02 mmol) was added, and after stirring for 5 min, methyl iodide (11.5 g, 81.03 mmol) was added. The reaction was monitored by TLC, the reaction solution was concentrated, extracted with ethyl acetate (500 ml) and water (200 ml), and the organic phase was dried to obtain intermediate 3-2 (orange liquid 5 g, yield 92.59%);

[0113] 2) Dissolve the intermediate 3-2 (5 g, 25.11 mmol) with magnetic stirring in a DMF solution, add N-methylpiperazine (3.8 g, 37.66 mmol), and react overnight at room temperature. Extract the reaction solution with ethyl acetate (500 ml) and water (200 ml), and dry the organic layer to obtain the intermediate 3-3 (brown solid, 7 g, yield 93.52%);

[0114] 3) Dissolve the intermediate 3-3 (7 g, 23.54 mmol) in a methanol-tetrahydrofuran (2:1, 200 mL) solution, add palladium on carbon (1.4 g, 20%), and react overnight under a hydrogen atmosphere. Filter the palladium on carbon from the reaction solution with diatomaceous earth, and concentrate to obtain the intermediate 3-4 (white solid, 5.7 g, yield 98.26%);

[0115] 4) Dissolve the intermediate 3-4 (5 g, 20.05 mmol) with magnetic stirring in methanol (20 mL), add trimethyl orthoformate (4.25 g, 40.1 mmol) and ammonium acetate (3.1 g, 40.1 mmol), heat under reflux at 110 °C for 8 h until the reaction is complete. Concentrate the reaction solution and perform column chromatography to obtain the intermediate 3-5 (white solid, 2.8 g, yield 56.8%);

[0116] 5) Dissolve the intermediate 3-5 (2.8 g, 11.46 mmol) with magnetic stirring in phosphorus oxychloride (10 mL) solution, react at 105 °C for 9 h, quench the reaction with water (100 mL), adjust the pH to neutral with sodium carbonate, extract the aqueous layer with ethyl acetate (3 * 200 mL), and dry the organic phase to obtain the intermediate J (brown solid, 2.3 g, yield 76%);

[0117] 6) Dissolve the intermediate 3-6 (200 mg, 0.76 mmol) (refer to Example 1) in a toluene (5 ml) solution. Sequentially add compound 1-4 (295 mg, 1.14 mmol), Pd(OAc)2 (18 mg, 0.08 mmol), BINAP (49.8 mg, 0.08 mmol), and Cs2CO3 (0.5 g, 1.52 mmol) to the solution. Heat the reaction solution to 110 °C and stir at this temperature for 6 h. After monitoring the reaction by TLC until it is complete, allow the reaction solution to cool naturally to room temperature, quench the reaction with water (100 mL), extract with ethyl acetate (200 mL), collect the organic phase, dry the organic phase over anhydrous sodium sulfate, filter, and rotary evaporate to obtain the crude product. The crude product is purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 1 (light brown solid; 0.28 g; yield: 75.9%). 1H-NMR(400MHz, DMSO-d6, δ ppm): 8.77 (s, 1H), 8.57 (s, 1H), 8.45 (dd, J = 9.2, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.67 (dd, J = 2.4, 1H), 7.42 - 7.52 (m, 2H), 7.27 (d, J = 8.0 Hz, 1H), 7.01 - 7.08 (m, 3H), 4.14 (s, 2H), 3.42 (s, 4H), 2.54 (s, 4H), 2.27 (s, 3H). ES-API (m / z): [M + H] + : 486.5.

[0118] Synthesis of Compound 4 in Example 4

[0119]

[0120] Synthesis Route

[0121]

[0122] Under nitrogen protection, dissolve intermediate 4-1 (295 mg, 1.14 mmol) (refer to Example 3, replace 3-6 with intermediate 4-1) in toluene (5 ml) solution. Sequentially add 1-4 (200 mg, 0.76 mmol), Pd(OAc)2 (18 mg, 0.08 mmol), BINAP (49.8 mg, 0.08 mmol), and Cs2CO3 (0.5 g, 1.52 mmol) to the solution. Heat the reaction solution to 110 °C and stir for 6 h at this temperature. After monitoring the reaction by TLC until it is completed, allow the reaction solution to cool to room temperature naturally. Quench the reaction with water (100 mL), extract with ethyl acetate (200 mL), collect the organic phase, dry the organic phase over anhydrous sodium sulfate, filter, and rotary evaporate to obtain the crude product. The crude product is purified by column chromatography (DCM / MeOH = 40 / 1) to obtain Compound 4 (brown solid; 0.28 g; yield: 75.9%). 1 H-NMR(400MHz, DMSO-d6, δ ppm): 8.76 (s, 1H), 8.54 (s, 1H), 8.41 (dd, J = 9.2, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.64 (dd, J = 2.4, 1H), 7.42 - 7.56 (m, 2H), 7.24 (d, J = 8.0 Hz, 1H), 7.07 - 7.17 (m, 3H), 4.12 (s, 2H), 3.45 (s, 4H), 2.52 (s, 4H), 2.17 (q, J = 4.0 Hz, 2H), 1.03 (t, J = 4.0 Hz, 3H). ES-API (m / z): [M + H] + : 499.9.

[0123] Synthesis of Compound 5 in Example 5

[0124]

[0125] Synthesis Route

[0126]

[0127] Under nitrogen protection, Intermediate 5-1 (200 mg, 0.81 mmol) (refer to Example 3, Intermediate 5-1 replaces 3-6) was dissolved in toluene (5 ml) solution. To the solution were successively added Intermediate 1-4 (316 mg, 1.22 mmol), Pd(OAc)2 (18 mg, 0.08 mmol), BINAP (49.8 mg, 0.08 mmol), and Cs2CO3 (0.52 g, 1.62 mmol). The reaction solution was heated to 110 °C and stirred at this temperature for 6 h. After monitoring the reaction by TLC until it was completed, the reaction solution was naturally cooled to room temperature, quenched with water (100 mL), extracted with ethyl acetate (200 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain Compound 5 (brown solid; 0.26 g; yield: 69.5%). 1 1H-NMR (400 MHz, DMSO-d6, δ ppm): 8.73 (s, 1H), 8.55 (s, 1H), 8.42 (dd, J = 9.2, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.67 (dd, J = 2.4, 1H), 7.43 - 7.56 (m, 2H), 7.27 (d, J = 8.0 Hz, 1H), 7.05 - 7.13 (m, 3H), 4.17 (s, 2H), 3.55 (s, 4H), 1.56 - 1.71 (m, 6H). ES-API (m / z): [M + H] + : 471.2.

[0128] Synthesis of Compound 6 in Example 6

[0129]

[0130] Synthesis Route

[0131]

[0132] Under nitrogen protection, intermediate 6-1 (200 mg, 0.80 mmol) (refer to Example 3, intermediate 6-1 replaces 3-6) was dissolved in toluene (5 ml) solution. Intermediate 1-4 (311.1 mg, 1.2 mmol), Pd(OAc)2 (18 mg, 0.08 mmol), BINAP (49.8 mg, 0.08 mmol), and Cs2CO3 (0.52 g, 1.6 mmol) were successively added to the solution. The reaction solution was heated to 110 °C and stirred at this temperature for 6 h. After monitoring the reaction by TLC and the reaction was completed, the reaction solution was naturally cooled to room temperature, quenched with water (100 mL), extracted with ethyl acetate (200 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 5 (brown solid; 0.27 g; yield: 71.5%). 1 1H-NMR(400MHz, DMSO-d6, δ ppm): 8.71 (s, 1H), 8.54 (s, 1H), 8.45 (dd, J = 9.2, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.63 (dd, J = 2.4, 1H), 7.47 - 7.57 (m, 2H), 7.23 (d, J = 8.0 Hz, 1H), 7.05 - 7.15 (m, 3H), 4.14 (s, 2H), 3.27 (t, J = 9.6 Hz, 4H), 2.53 (t, J = 9.6 Hz, 4H). ES-API (m / z): [M + H] + : 473.2.

[0133] Synthesis of Compound 7 in Example 7

[0134]

[0135] Synthetic Route

[0136]

[0137] Under nitrogen protection, dissolve intermediate 7-1 (200 mg, 0.72 mmol) (refer to Example 3, replace 3-6 with intermediate 7-1) in toluene (5 ml) solution. Add intermediate 1-4 (280 mg, 1.08 mmol), Pd(OAc)2 (15.7 mg, 0.07 mmol), BINAP (43.6 mg, 0.07 mmol), and Cs2CO3 (0.47 g, 1.44 mmol) to the solution in sequence. Heat the reaction solution to 110 °C and stir for 6 h at this temperature. After monitoring the reaction by TLC until it is completed, let the reaction solution cool to room temperature naturally. Quench the reaction with water (100 mL), extract with ethyl acetate (200 mL), collect the organic phase, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate by rotary evaporation to obtain the crude product. The crude product is purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 5 (light brown solid; 0.24 g; yield: 67.3%). 1 1H-NMR (400 MHz, DMSO-d6, δ ppm): 8.73 (s, 1H), 8.58 (s, 1H), 8.45 (dd, J = 9.2, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.62 (dd, J = 2.4, 1H), 7.47 - 7.57 (m, 2H), 7.22 (d, J = 8.0 Hz, 1H), 7.02 - 7.12 (m, 3H), 4.17 (s, 2H), 3.22 - 3.32 (m, 2H), 2.62 (dd, J = 12.4, 2.0 Hz, 2H), 2.17 (dd, J = 12.2, 10.2 Hz, 2H), 1.25 (d, J = 6.2 Hz, 6H). ES-API (m / z): [M+H] + : 501.2.

[0138] Synthesis of Compound 8 in Example 8

[0139]

[0140] Synthetic Route

[0141]

[0142] Under nitrogen protection, dissolve intermediate 8-1 (200 mg, 0.72 mmol) (refer to Example 3, replace 3-6 with intermediate 8-1) in toluene (5 ml) solution. Sequentially add intermediate 1-4 (280 mg, 1.08 mmol), Pd(OAc)2 (15.7 mg, 0.07 mmol), BINAP (43.6 mg, 0.07 mmol), and Cs2CO3 (0.47 g, 1.44 mmol) to the solution. Heat the reaction solution to 110 °C and stir for 6 h at this temperature. After monitoring the reaction by TLC and it is completed, let the reaction solution cool to room temperature naturally. Quench the reaction with water (100 mL), extract with ethyl acetate (200 mL), collect the organic phase. The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation to obtain the crude product. The crude product is purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 5 (light brown solid; 0.23 g; yield: 64.9%). 1 1H-NMR (400 MHz, DMSO-d6, δ ppm): 8.76 (s, 1H), 8.57 (s, 1H), 8.46 (dd, J = 9.2, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.62 (dd, J = 2.4, 1H), 7.43 - 7.59 (m, 2H), 7.24 (d, J = 8.0 Hz, 1H), 7.05 - 7.18 (m, 3H), 4.14 (s, 2H), 2.92 - 3.14 (m, 4H), 2.57 - 2.67 (m, 4H), 2.34 (s, 3H), 1.76 - 1.84 (m, 2H). ES-API (m / z): [M+H] + : 500.2.

[0143] Synthesis of Compound 9 in Example 9

[0144]

[0145] Synthesis Route

[0146] Under nitrogen protection,

[0147] Dissolve intermediate 9-1 (200 mg, 0.72 mmol) (refer to Example 3, replace 3-6 with intermediate 9-1) in toluene (5 ml) solution. Sequentially add intermediate 1-4 (280 mg, 1.08 mmol), Pd(OAc)2 (15.7 mg, 0.07 mmol), BINAP (43.6 mg, 0.07 mmol), and Cs2CO3 (0.47 g, 1.44 mmol) to the solution. Heat the reaction solution to 110 °C and stir for 6 h at this temperature. After monitoring the reaction by TLC until it is completed, allow the reaction solution to cool naturally to room temperature. Quench the reaction with water (100 mL), extract with ethyl acetate (200 mL), collect the organic phase, dry the organic phase over anhydrous sodium sulfate, filter, and rotary evaporate to obtain the crude product. The crude product is purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 5 (brown solid; 0.27 g; yield: 75.6%). 1 1H-NMR (400 MHz, DMSO-d6, δ ppm): 12.2 (s, 1H), 8.75 (s, 1H), 8.44 - 8.54 (m, 2H), 7.95 (d, J = 8.0 Hz, 1H), 7.65 (dd, J = 2.4, 1H), 7.42 (dd, J = 8.0 Hz, 1H), 7.44 (dd, J = 9.2 Hz, 2.4 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.01 - 7.09 (m, 3H), 4.17 (s, 2H), 3.05 - 3.13 (m, 4H), 2.70 - 2.76 (m, 1H), 2.24 (s, 6H), 1.60 - 1.68 (m, 2H). ES-API (m / z): [M+H] + : 500.2.

[0148] Synthesis of Compound 10 in Example 10

[0149]

[0150] Synthetic Route

[0151]

[0152] Under nitrogen protection, dissolve intermediate 10-1 (200 mg, 0.76 mmol) (refer to Example 3, replace 3-6 with intermediate 10-1) in toluene (5 ml) solution. Add intermediate 1-4 (295.6 mg, 1.14 mmol), Pd(OAc)2 (18 mg, 0.08 mmol), BINAP (49.8 mg, 0.08 mmol), and Cs2CO3 (0.5 g, 1.52 mmol) to the solution in sequence. Heat the reaction solution to 110 °C and stir for 6 h at this temperature. After monitoring the reaction by TLC until it is completed, let the reaction solution cool to room temperature naturally. Quench the reaction with water (100 mL), extract with ethyl acetate (200 mL), collect the organic phase, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate by rotary evaporation to obtain the crude product. The crude product is purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 5 (brown solid; 0.23 g; yield: 62.1%). 1 1H-NMR (400 MHz, DMSO-d6, δ ppm): 12.1 (s, 1H), 8.71 (s, 1H), 8.38 - 8.42 (m, 2H), 7.88 (d, J = 8.0 Hz, 1H), 7.59 (dd, J = 2.4, 1H), 7.37 (dd, J = 8.0 Hz, 1H), 7.36 (dd, J = 9.2 Hz, 2.4 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 6.95 - 7.09 (m, 3H), 4.15 (s, 2H), 3.47 (t, J = 4.0 Hz, 2H), 3.35 (t, J = 4.0 Hz, 2H), 2.65 (s, 3H), 2.24 (s, 6H). ES-API (m / z): [M + H] + : 488.2.

[0153] Synthesis of Compound 11 in Example 11

[0154]

[0155] Synthesis Route

[0156]

[0157] Under nitrogen protection, dissolve intermediate 11-1 (200 mg, 0.77 mmol) (refer to Example 3, replace 3-6 with intermediate 11-1) in toluene (5 ml) solution. Sequentially add intermediate 1-4 (300.7 mg, 1.16 mmol), Pd(OAc)2 (18 mg, 0.08 mmol), BINAP (49.8 mg, 0.08 mmol), and Cs2CO3 (0.5 g, 1.54 mmol) to the solution. Heat the reaction solution to 110 °C and stir for 6 h at this temperature. After monitoring the reaction by TLC until it is completed, let the reaction solution cool naturally to room temperature. Quench the reaction with water (100 mL), extract with ethyl acetate (200 mL), collect the organic phase, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate by rotary evaporation to obtain the crude product. The crude product is purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 5 (light brown solid; 0.25 g; yield: 66.4%). 1 1H-NMR (400 MHz, DMSO-d6, δ ppm): 8.75 (s, 1H), 8.50 - 8.62 (m, 2H), 7.93 (d, J = 8.0 Hz, 1H), 7.64 (dd, J = 2.4, 1H), 7.47 (dd, J = 8.0 Hz, 1H), 7.42 (dd, J = 9.2 Hz, 2.4 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.02 - 7.09 (m, 3H), 6.14 (t, J = 6.4 Hz, 1H), 4.18 (s, 2H), 3.32 (t, J = 4.0 Hz, 2H), 2.57 (t, J = 4.0 Hz, 2H), 2.26 (s, 3H), 1.94 (t, J = 3.6 Hz, 2H). ES-API (m / z): [M+H] + : 483.2.

[0158] Synthesis of Compound 12 in Example 12

[0159]

[0160] Synthetic Route

[0161]

[0162] Under nitrogen protection, dissolve intermediate 12-1 (200 mg, 0.76 mmol) (refer to Example 3, replace 3-6 with intermediate 12-1) in toluene (5 ml) solution. Add intermediate 1-4 (295.6 mg, 1.14 mmol), Pd(OAc)2 (18 mg, 0.08 mmol), BINAP (49.8 mg, 0.08 mmol), and Cs2CO3 (0.5 g, 1.52 mmol) to the solution in sequence. Heat the reaction solution to 110 °C and stir for 6 h at this temperature. After monitoring the reaction by TLC until it is completed, let the reaction solution cool to room temperature naturally. Quench the reaction with water (100 mL), extract with ethyl acetate (200 mL), collect the organic phase, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate by rotary evaporation to obtain the crude product. The crude product is purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 5 (light brown solid; 0.25 g; yield: 68.3%). 1 1H-NMR (400 MHz, DMSO-d6, δ ppm): 8.73 (s, 1H), 8.42 - 8.53 (m, 2H), 7.98 (d, J = 8.0 Hz, 1H), 7.64 (dd, J = 2.4, 1H), 7.42 (dd, J = 8.0 Hz, 1H), 7.45 (dd, J = 9.2 Hz, 2.4 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.00 - 7.09 (m, 3H), 4.17 (s, 2H), 2.68 - 2.72 (m, 1H), 2.45 - 2.53 (m, 4H), 2.14 (s, 3H), 1.60 - 1.68 (m, 1H). ES-API (m / z): [M+H] + : 485.2.

[0163] Synthesis of Compound 13 in Example 13

[0164]

[0165] Synthetic Route

[0166]

[0167] Under nitrogen protection, dissolve intermediate 13-1 (200 mg, 0.72 mmol) (refer to Example 3, replace 3-6 with intermediate 13-1) in toluene (5 ml) solution. Add intermediate 1-4 (280 mg, 1.08 mmol), Pd(OAc)2 (18 mg, 0.07 mmol), BINAP (49.8 mg, 0.07 mmol), and Cs2CO3 (0.47 g, 1.44 mmol) to the solution in sequence. Heat the reaction solution to 110 °C and stir for 6 h at this temperature. After monitoring the reaction by TLC until it is completed, let the reaction solution cool to room temperature naturally. Quench the reaction with water (100 mL), extract with ethyl acetate (200 mL), collect the organic phase, dry the organic phase over anhydrous sodium sulfate, filter, and rotary evaporate to obtain the crude product. The crude product is purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 5 (brown solid; 0.24 g; yield: 64.7%). 1 1H-NMR (400 MHz, DMSO-d6, δ ppm): 12.4 (s, 1H), 8.71 (s, 1H), 8.47 - 8.56 (m, 2H), 7.92 (d, J = 8.0 Hz, 1H), 7.66 (dd, J = 2.4, 1H), 7.44 (dd, J = 8.0 Hz, 1H), 7.41 (dd, J = 9.2 Hz, 2.4 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.01 - 7.11 (m, 3H), 4.23 (s, 2H), 3.61 (s, 2H), 2.42 (t, J = 2.4 Hz, 4H), 2.37 (t, J = 2.4, 4H), 2.15 (s, 3H). ES-API (m / z): [M + H] + : 500.2.

[0168] Synthesis of Compound 14 in Example 14

[0169]

[0170] Synthetic Route

[0171]

[0172] Under nitrogen protection, dissolve intermediate 14-1 (264 mg, 1 mmol) (refer to Example 3, replace 3-6 with intermediate 14-1) in toluene (5 ml) solution. Add intermediate 1-4 (181 mg, 0.7 mmol), Pd(OAc)2 (22.4 mg, 0.1 mmol), BINAP (62.3 mg, 0.1 mmol), and Cs2CO3 (0.65 g, 2 mmol) to the solution in sequence. Heat the reaction solution to 110 °C and stir for 6 h at this temperature. After monitoring the reaction by TLC and the reaction is completed, cool the reaction solution to room temperature naturally. Quench the reaction with water (100 mL), extract with ethyl acetate (200 mL), collect the organic phase, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate by rotary evaporation to obtain the crude product. The crude product is purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 14 (brown solid; 0.2 g; yield: 58%). 1 1H-NMR (400 MHz, DMSO-d6, δ ppm): 12.6 (s, 1H), 8.72 (s, 1H), 8.47 - 8.56 (m, 2H), 7.96 (d, J = 8.0 Hz, 1H), 7.65 (dd, J = 2.4, 1H), 7.47 - 7.51 (m, 2H), 7.23 (d, J = 8.0 Hz, 1H), 7.02 - 7.12 (m, 3H), 4.14 (s, 2H), 3.65 (s, 2H), 3.52 (s, 4H), 2.47 (s, 1H). ES-API (m / z): [M + H] + : 487.2.

[0173] Synthesis of Compound 15 in Example 15

[0174]

[0175] Synthetic Route

[0176]

[0177] Under nitrogen protection, dissolve intermediate 15-1 (276 mg, 1 mmol) (refer to Example 3, replace 3-6 with intermediate 15-1) in toluene (5 ml) solution. Sequentially add intermediate 1-4 (181 mg, 0.7 mmol), Pd(OAc)2 (22.4 mg, 0.1 mmol), BINAP (62.3 mg, 0.1 mmol), and Cs2CO3 (0.65 g, 2 mmol) to the solution. Heat the reaction solution to 110 °C and stir for 6 h at this temperature. After monitoring the reaction by TLC until it is completed, let the reaction solution cool to room temperature naturally. Quench the reaction with water (100 mL), extract with ethyl acetate (200 mL), collect the organic phase, dry the organic phase over anhydrous sodium sulfate, filter, and rotary evaporate to obtain the crude product. The crude product is purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 15 (brown solid; 0.24 g; yield: 67%). 1 1H-NMR (400 MHz, DMSO-d6, δ ppm): 8.71 (s, 1H), 8.54 (s, 1H), 8.42 (dd, J = 9.2, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.62 (dd, J = 2.4, 1H), 7.48 - 7.55 (m, 2H), 7.21 (d, J = 8.0 Hz, 1H), 7.02 - 7.14 (m, 3H), 4.18 (s, 2H), 3.58 (s, 2H), 2.47 - 2.50 (m, 4H), 1.92 - 1.99 (m, 1H), 1.45 - 1.48 (m, 4H), 1.19 (d, J = 4.0 Hz, 3H). ES-API (m / z): [M+H] + : 499.2

[0178] Synthesis of Compound 16 in Example 16

[0179]

[0180] Synthetic Route

[0181]

[0182] Under nitrogen protection, dissolve intermediate 16-1 (300 mg, 1 mmol) (refer to Example 3, replace 3-6 with intermediate 16-1) in toluene (5 ml) solution. Add intermediate 1-4 (181 mg, 0.7 mmol), Pd(OAc)2 (22.4 mg, 0.1 mmol), BINAP (62.3 mg, 0.1 mmol), and Cs2CO3 (0.65 g, 2 mmol) to the solution in sequence. Heat the reaction solution to 110 °C and stir for 6 h at this temperature. After monitoring the reaction by TLC until it is completed, let the reaction solution cool to room temperature naturally. Quench the reaction with water (100 mL), extract with ethyl acetate (200 mL), collect the organic phase, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate by rotary evaporation to obtain the crude product. The crude product is purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 16 (light brown solid; 0.23 g; yield: 64%). 1 1H-NMR (400 MHz, DMSO-d6, δ ppm): 12.4 (s, 1H), 8.76 (s, 1H), 8.40 - 8.51 (m, 2H), 7.90 (d, J = 8.0 Hz, 1H), 7.61 (dd, J = 2.4, 1H), 7.43 - 7.52 (m, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.02 - 7.09 (m, 3H), 4.18 (s, 2H), 3.62 (m, 2H), 3.57 - 3.27 (m, 2H), 2.67 (dd, J = 12.4, 2.0 Hz, 2H), 2.17 (dd, J = 12.2, 10.2 Hz, 2H), 1.26 (d, J = 6.2 Hz, 6H). ES-API (m / z): [M + H] + : 514.5.

[0183] Synthesis of Compound 17 in Example 17

[0184]

[0185] Synthetic Route

[0186]

[0187] Under nitrogen protection, dissolve intermediate 17-1 (346 mg, 1 mmol) (refer to Example 3, replace 3-6 with intermediate 17-1) in toluene (5 ml) solution. Add intermediate 1-4 (181 mg, 0.7 mmol), Pd(OAc)2 (22.4 mg, 0.1 mmol), BINAP (62.3 mg, 0.1 mmol), and Cs2CO3 (0.65 g, 2 mmol) to the solution in sequence. Heat the reaction solution to 110 °C and stir for 6 h at this temperature. After monitoring the reaction by TLC and the reaction is completed, let the reaction solution cool to room temperature naturally. Quench the reaction with water (100 mL), extract with ethyl acetate (200 mL), collect the organic phase. The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation to obtain the crude product. The crude product is purified by column chromatography (DCM / MeOH = 40 / 1) to obtain Compound 17 (light brown solid; 0.19; yield: 52%). 1 1H-NMR (400 MHz, DMSO-d6, δ ppm): 8.64 (s, 1H), 8.44 - 8.53 (m, 2H), 7.97 (d, J = 8.0 Hz, 1H), 7.62 (dd, J = 2.4, 1H), 7.42 - 7.52 (m, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.07 - 7.15 (m, 3H), 4.15 (s, 2H), 3.61 (m, 2H), 2.94 - 3.18 (m, 4H), 2.51 - 2.67 (m, 4H), 2.34 (s, 3H), 1.76 - 1.86 (m, 2H). ES-API (m / z): [M+H] + : 514.3.

[0188] Synthesis of Compound 18 in Example 18

[0189]

[0190] Synthetic route

[0191]

[0192] Under nitrogen protection, dissolve intermediate 18-1 (346 mg, 1 mmol) (refer to Example 3, replace 3-6 with intermediate 18-1) in toluene (5 ml) solution. Add intermediate 1-4 (181 mg, 0.7 mmol), Pd(OAc)2 (22.4 mg, 0.1 mmol), BINAP (62.3 mg, 0.1 mmol), and Cs2CO3 (0.65 g, 2 mmol) to the solution in sequence. Heat the reaction solution to 110 °C and stir for 6 h at this temperature. After monitoring the reaction by TLC and the reaction is completed, let the reaction solution cool to room temperature naturally. Quench the reaction with water (100 mL), extract with ethyl acetate (200 mL), collect the organic phase, dry the organic phase over anhydrous sodium sulfate, filter, and rotary evaporate to obtain the crude product. The crude product is purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 18 (brown solid; 0.22 g; yield: 62%). 1 1H-NMR (400 MHz, DMSO-d6, δ ppm): 8.74 (s, 1H), 8.47 - 8.57 (m, 2H), 7.92 (d, J = 8.0 Hz, 1H), 7.67 (dd, J = 2.4, 1H), 7.43 - 7.53 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.01 - 7.11 (m, 3H), 4.17 (s, 2H), 3.65 (s, 2H), 3.14 - 3.28 (m, 4H), 2.71 - 2.81 (m, 1H), 2.24 (s, 6H), 1.51 - 1.61 (m, 2H). ES-API (m / z): [M+H] + : 514.4.

[0193] Example 19 Synthesis of Compound 19

[0194]

[0195] Synthesis Route

[0196]

[0197] Under nitrogen protection, dissolve intermediate 19-1 (200 mg, 0.82 mmol) (refer to Example 3, replace 1-4 with intermediate 19-1) in toluene (5 ml) solution. Add intermediate 3-6 (143.63 mg, 0.55 mmol), Pd(OAc)2 (18 mg, 0.08 mmol), BINAP (49.8 mg, 0.08 mmol), and Cs2CO3 (0.5 g, 1.64 mmol) to the solution in sequence. Heat the reaction solution to 110 °C and stir for 6 h at this temperature. After monitoring the reaction by TLC and the reaction is completed, let the reaction solution cool to room temperature naturally. Quench the reaction with water (100 mL), extract with ethyl acetate (200 mL), collect the organic phase, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. The crude product is purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 19 (brown solid; 0.18 g; yield: 69.23%). 1 1H-NMR (400 MHz, DMSO-d6, δ ppm): 8.76 (s, 1H), 8.35 (s, 1H), 8.27 (dd, J = 9.2 Hz, 1H), 7.77–7.87 (m, 2H), 7.54 (dd, J = 2.4 Hz, 1H), 7.38 (ddd, J = 9.2 Hz, 2.4 Hz, 1H), 7.18–7.32 (m, 3H), 3.45 (s, 4H), 2.52 (s, 4H), 2.26 (s, 3H). ES-API (m / z): [M+H] + : 472.3.

[0198] Example 20 Synthesis of Compound 20

[0199]

[0200] Synthesis Route

[0201]

[0202] Under nitrogen protection, dissolve intermediate 20-1 (200 mg, 0.76 mmol) (refer to Example 3, replace 1-4 with intermediate 20-1) in toluene (5 ml) solution. Add intermediate 3-6 (167.63 mg, 0.64 mmol), Pd(OAc)2 (18 mg, 0.08 mmol), BINAP (49.8 mg, 0.08 mmol), and Cs2CO3 (0.5 g, 1.64 mmol) to the solution in sequence. Heat the reaction solution to 110 °C and stir for 6 h at this temperature. After monitoring the reaction by TLC until it is completed, let the reaction solution cool to room temperature naturally. Quench the reaction with water (100 mL), extract with ethyl acetate (200 mL), collect the organic phase, dry the organic phase over anhydrous sodium sulfate, filter, and rotary evaporate to obtain the crude product. The crude product is purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 20 (light brown solid; 0.2 g; yield: 67%). 1 1H-NMR (400 MHz, DMSO-d6, δ ppm): 12.88 (s, 1H), 8.54 (s, 1H), 8.43 (s, 1H), 8.17 (dd, J = 9.2 Hz, 1H), 7.55 (dd, J = 8.9, 0.49 Hz, 1H), 7.42 (s, 1H), 7.12 - 7.24 (m, 2H), 6.93 (tt, J = 9.31, 2.27 Hz, 1H), 6.86 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 6.63 (dd, J = 8.84, 2.26 Hz, 2H), 3.45 (s, 4H), 2.52 (s, 4H), 2.26 (s, 3H). ES-API (m / z): [M+H] + : 488.5.

[0203] Synthesis of Compound 21 in Example 21

[0204]

[0205] Synthetic Route

[0206]

[0207] Under nitrogen protection, intermediate 21-1 (300 mg, 0.88 mmol) (refer to Example 3, replace 1-4 with intermediate 21-1) was dissolved in toluene (5 ml). Intermediate 3-6 (155 mg, 0.59 mmol), Pd(OAc)2 (20 mg, 0.09 mmol), BINAP (56 mg, 0.09 mmol), and Cs2CO3 (0.6 g, 1.76 mmol) were successively added to the solution. The reaction solution was heated to 110 °C and stirred at this temperature for 6 h. After monitoring the reaction by TLC until it ended, the reaction solution was naturally cooled to room temperature, quenched with water (100 mL), extracted with ethyl acetate (200 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 21 (light brown solid; 0.24 g; yield: 70%). 1 1H-NMR (400 MHz, DMSO-d6, δ ppm): 12.47 (s, 1H), 8.52 (s, 1H), 8.42 (s, 1H), 7.92 - 8.07 (m, 2H), 7.58 (dd, J = 8.8, 5.2 Hz, 1H), 7.45 - 7.51 (m, 1H), 7.43 (dd, J = 8.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.12 (dd, J = 2.8 Hz, 1H), 6.96 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 6.19 (q, J = 6.8 Hz, 1H), 3.45 (s, 4H), 2.52 (s, 4H), 2.26 (s, 3H), 1.74 (d, J = 6.4 Hz, 3H). ES-API (m / z): [M + H] + : 566.4.

[0208] Synthesis of Compound 22 in Example 22

[0209]

[0210] Synthetic Route

[0211]

[0212] Under nitrogen protection, intermediate 22-1 (250 mg, 1 mmol) (refer to Example 20, replace 3-6 with intermediate 22-1) was dissolved in toluene (5 ml) solution. Intermediate 20-1 (183 mg, 0.7 mmol), Pd(OAc)2 (22.4 mg, 0.1 mmol), BINAP (62.3 mg, 0.1 mmol), and Cs2CO3 (0.65 g, 2 mmol) were successively added to the solution. The reaction solution was heated to 110 °C and stirred at this temperature for 6 h. After monitoring the reaction by TLC until it ended, the reaction solution was naturally cooled to room temperature, quenched with water (100 mL), extracted with ethyl acetate (200 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 22 (brown solid; 0.2 g; yield: 42.2%). 1 1H-NMR(400MHz, DMSO-d6, δ ppm): 8.55 (s, 1H), 8.44 (s, 1H), 8.12 (dd, J = 9.2 Hz, 1H), 7.57 (dd, J = 8.9, 0.49 Hz, 1H), 7.42 (s, 1H), 7.27 (dd, J = 8.90, 2.32 Hz, 1H), 7.15 (dd, J = 2.8 Hz, 1H), 6.82 - 6.92 (m, 2H), 6.67 (dd, J = 8.84, 2.26 Hz, 2H), 3.21 (t, J = 9.6 Hz, 4H), 2.5 (t, J = 9.6 Hz, 4H). ES-API (m / z): [M + H] + : 475.3.

[0213] Synthesis of Compound 23 in Example 23

[0214]

[0215] Synthetic Route

[0216]

[0217] Under nitrogen protection, dissolve intermediate 22-1 (250 mg, 1 mmol) (refer to Example 21, replace 3-6 with intermediate 22-1) in toluene (5 ml) solution. Add intermediate 21-1 (238 mg, 0.7 mmol), Pd(OAc)2 (22.4 mg, 0.1 mmol), BINAP (62.3 mg, 0.1 mmol), and Cs2CO3 (0.65 g, 2 mmol) to the solution in sequence. Heat the reaction solution to 110 °C and stir for 6 h at this temperature. After monitoring the reaction by TLC until it is completed, let the reaction solution cool to room temperature naturally. Quench the reaction with water (100 mL), extract with ethyl acetate (200 mL), collect the organic phase, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate by rotary evaporation to obtain the crude product. The crude product is purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 23 (brown solid; 0.24 g; yield: 62.06%). 1 1H-NMR (400 MHz, DMSO-d6, δ ppm): 8.55 (s, 1H), 8.42 (s, 1H), 8.14 (dd, J = 9.2 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.52 (dd, J = 8.8, 5.2 Hz, 1H), 7.41 - 7.51 (m, 2H), 7.24 (d, J = 8.0 Hz, 1H), 7.12 (dd, J = 2.8 Hz, 1H), 6.91 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 6.15 (q, J = 6.8 Hz, 1H), 3.74 (s, 4H), 3.24 (s, 4H), 1.77 (d, J = 6.4 Hz, 3H). ES-API (m / z): [M+H] + : 553.2.

[0218] Synthesis of Compound 24 in Example 24

[0219]

[0220] Synthesis Route

[0221]

[0222] Under nitrogen protection, intermediate 24-1 (270 mg, 1 mmol) (refer to Example 20, replace 3-6 with intermediate 24-1) was dissolved in toluene (5 ml) solution. Intermediate 20-1 (183 mg, 0.7 mmol), Pd(OAc)2 (22.4 mg, 0.1 mmol), BINAP (62.3 mg, 0.1 mmol), and Cs2CO3 (0.65 g, 2 mmol) were successively added to the solution. The reaction solution was heated to 110 °C and stirred at this temperature for 6 h. After monitoring the reaction by TLC until it ended, the reaction solution was naturally cooled to room temperature, quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 24 (brown solid; 0.23 g; yield: 67.65%). 1 1H-NMR (400 MHz, DMSO-d6, δ ppm): 8.56 (s, 1H), 8.42 (s, 1H), 8.14 (dd, J = 9.2 Hz, 1H), 7.54 (dd, J = 8.9, 0.49 Hz, 1H), 7.32 (s, 1H), 7.22 (dd, J = 8.90, 2.32 Hz, 1H), 7.11 (dd, J = 2.8 Hz, 1H), 6.72 - 6.82 (m, 2H), 6.62 (dd, J = 8.84, 2.26 Hz, 2H), 3.15 (m, 2H), 3.04 (m, 2H), 1.57 (m, 2H), 1.72 (m, 1H), 1.31 (m, 2H), 1.04 (d, J = 4.0, 3H). ES-API (m / z): [M+H] + : 487.2.

[0223] Synthesis of Compound 25 in Example 25

[0224]

[0225] Synthetic Route

[0226]

[0227] Under nitrogen protection, intermediate 24-1 (270 mg, 1 mmol) (refer to Example 21, replace 3-6 with intermediate 24-1) was dissolved in toluene (5 ml) solution. Intermediate 21-1 (238 mg, 0.7 mmol), Pd(OAc)2 (22.4 mg, 0.1 mmol), BINAP (62.3 mg, 0.1 mmol), and Cs2CO3 (0.65 g, 2 mmol) were successively added to the solution. The reaction solution was heated to 110 °C and stirred at this temperature for 6 h. After monitoring the reaction by TLC until it was completed, the reaction solution was naturally cooled to room temperature, quenched with water (100 mL), extracted with ethyl acetate (200 mL), and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation to obtain a crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 25 (brown solid; 0.24 g; yield: 60%). 1 1H-NMR (400 MHz, DMSO-d6, δ ppm): 8.56 (s, 1H), 8.44 (s, 1H), 8.17 (dd, J = 9.2 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.41 - 7.51 (m, 3H), 7.21 (d, J = 8.0 Hz, 1H), 6.91 - 7.13 (m, 3H), 3.15 (m, 2H), 3.04 (m, 2H), 1.57 (m, 2H), 1.72 - 1.82 (m, 4H), 1.31 (m, 2H), 1.04 (d, J = 4.0, 3H). ES-API (m / z): [M+H] + : 565.5.

[0228] Synthesis of Compound 26 in Example 26

[0229]

[0230] Synthetic Route

[0231]

[0232] Under nitrogen protection, dissolve intermediate 26-1 (300 mg, 1 mmol) (refer to Example 3, replace 3-6 with intermediate 26-1) in toluene (5 ml) solution. Sequentially add intermediate 1-4 (181 mg, 0.7 mmol), Pd(OAc)2 (22.4 mg, 0.1 mmol), BINAP (62.3 mg, 0.1 mmol), and Cs2CO3 (0.65 g, 2 mmol) to the solution. Heat the reaction solution to 110 °C and stir for 6 h at this temperature. After monitoring the reaction by TLC and the reaction is completed, let the reaction solution cool to room temperature naturally. Quench the reaction with water (100 mL), extract with ethyl acetate (200 mL), collect the organic phase. The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation to obtain the crude product. The crude product is purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 26 (brown solid; 0.15 g; yield: 58%). 1 1H-NMR (400 MHz, DMSO-d6, δ ppm): 8.74 (s, 1H), 8.48 (dd, J = 9.2, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.64 (dd, J = 2.4, 1H), 7.47 - 7.52 (m, 2H), 7.27 (d, J = 8.0 Hz, 1H), 7.07 - 7.16 (m, 3H), 4.15 (s, 2H), 3.47 (s, 4H), 3.07 (s, 6H), 2.55 (s, 4H), 2.24 (s, 3H). ES-API (m / z): [M + H] + : 569.5.

[0233] Synthesis of Compound 27 in Example 27

[0234]

[0235] Synthesis Route

[0236]

[0237] Under nitrogen protection, dissolve intermediate 27-1 (350 mg, 1 mmol) (refer to Example 3, replace 3-6 with intermediate 27-1) in toluene (5 ml) solution. Add intermediate 1-4 (181 mg, 0.7 mmol), Pd(OAc)2 (22.4 mg, 0.1 mmol), BINAP (62.3 mg, 0.1 mmol), and Cs2CO3 (0.65 g, 2 mmol) to the solution in sequence. Heat the reaction solution to 110 °C and stir for 6 h at this temperature. After monitoring the reaction by TLC until it is completed, let the reaction solution cool to room temperature naturally. Quench the reaction with water (100 mL), extract with ethyl acetate (200 mL), collect the organic phase, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate by rotary evaporation to obtain the crude product. The crude product is purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 27 (brown solid; 0.23 g; yield: 57.5%). 1 1H-NMR (400 MHz, DMSO-d6, δ ppm): 8.74 (s, 1H), 8.41 (dd, J = 9.2, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.67 (dd, J = 2.4, 1H), 7.44 - 7.57 (m, 2H), 7.27 (d, J = 8.0 Hz, 1H), 6.68 - 7.08 (m, 3H), 4.15 (s, 2H), 3.77 (s, 4H), 3.42 (s, 4H), 3.27 (s, 4H), 2.57 (s, 4H), 2.24 (s, 3H). ES-API (m / z): [M+H] + : 570.3.

[0238] Synthesis of Compound 28 in Example 28

[0239]

[0240] Synthesis Route

[0241]

[0242] Under nitrogen protection, dissolve intermediate 28-1 (360 mg, 1 mmol) (refer to Example 3, replace 3-6 with intermediate 28-1) in toluene (5 ml) solution. Add intermediate 1-4 (181 mg, 0.7 mmol), Pd(OAc)2 (22.4 mg, 0.1 mmol), BINAP (62.3 mg, 0.1 mmol), and Cs2CO3 (0.65 g, 2 mmol) to the solution in sequence. Heat the reaction solution to 110 °C and stir for 6 h at this temperature. After monitoring the reaction by TLC until it is completed, let the reaction solution cool to room temperature naturally. Quench the reaction with water (100 mL), extract with ethyl acetate (200 mL), collect the organic phase, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate by rotary evaporation to obtain the crude product. The crude product is purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 28 (light brown solid; 0.25 g; yield: 60.98%). 1 1H-NMR (400 MHz, DMSO-d6, δ ppm): 8.77 (s, 1H), 8.45 (dd, J = 9.2, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.62 (dd, J = 2.4, 1H), 7.44 - 7.54 (m, 2H), 7.25 (d, J = 8.0 Hz, 1H), 7.08 - 7.18 (m, 3H), 4.13 (s, 2H), 3.57 (s, 4H), 3.45 (s, 4H), 2.67 - 2.77 (m, 5H), 2.26 (s, 3H), 1.92 (m, 4H). ES-API (m / z): [M+H] + : 584.4.

[0243] Synthesis of Compound 29 in Example 29

[0244]

[0245] Synthetic Route

[0246]

[0247] Under nitrogen protection, dissolve intermediate 29-1 (320 mg, 1 mmol) (refer to Example 3, replace 3-6 with intermediate 29-1) in toluene (5 ml) solution. Add intermediate 1-4 (181 mg, 0.7 mmol), Pd(OAc)2 (22.4 mg, 0.1 mmol), BINAP (62.3 mg, 0.1 mmol), and Cs2CO3 (0.65 g, 2 mmol) to the solution in sequence. Heat the reaction solution to 110 °C and stir for 6 h at this temperature. After monitoring the reaction by TLC until it is completed, let the reaction solution cool to room temperature naturally. Quench the reaction with water (100 mL), extract with ethyl acetate (200 mL), collect the organic phase, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate by rotary evaporation to obtain the crude product. The crude product is purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 29 (light brown solid; 0.21 g; yield: 55.56%). 1 1H-NMR (400 MHz, DMSO-d6, δ ppm): 8.74 (s, 1H), 8.47 (dd, J = 9.2, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.63 (dd, J = 2.4, 1H), 7.45 - 7.55 (m, 2H), 7.27 (d, J = 8.0 Hz, 1H), 7.03 - 7.13 (m, 3H), 4.17 (s, 2H), 3.74 (m, 4H), 3.45 (s, 4H), 2.53 (s, 4H), 2.26 (s, 3H), 2.04 (m, 2H). ES-API (m / z): [M+H] + : 541.3.

[0248] Synthesis of Compound 30 in Example 30

[0249]

[0250] Synthesis Route

[0251]

[0252] Under nitrogen protection, intermediate 30-1 (346 mg, 1 mmol) (refer to Example 3, intermediate 30-1 replaces 3-6) was dissolved in toluene (5 ml) solution. Intermediate 1-4 (181 mg, 0.7 mmol), Pd(OAc)2 (22.4 mg, 0.1 mmol), BINAP (62.3 mg, 0.1 mmol), and Cs2CO3 (0.65 g, 2 mmol) were successively added to the solution. The reaction solution was heated to 110 °C and stirred at this temperature for 6 h. After monitoring the reaction by TLC until it was completed, the reaction solution was naturally cooled to room temperature, quenched with water (100 mL), extracted with ethyl acetate (200 mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation to obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 40 / 1) to obtain compound 30 (brown solid; 0.22 g; yield: 55.3%). 1 1H-NMR (400 MHz, DMSO-d6, δ ppm): 8.74 (s, 1H), 8.42 (dd, J = 9.2, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.65 (dd, J = 2.4, 1H), 7.41 - 7.54 (m, 2H), 7.25 (d, J = 8.0 Hz, 1H), 7.01 - 7.12 (m, 3H), 4.15 (s, 2H), 3.87 (t, J = 4.0 Hz, 4H), 3.42 (s, 4H), 2.54 (s, 4H), 2.26 (s, 3H), 1.62 (m, 4H), 1.43 (m, 2H). ES-API (m / z): [M+H] + : 569.3.

[0253] Effect Example 1 In vitro kinase inhibitory activity

[0254] 1.1 Screening of ALK inhibitory activity

[0255] Dilute the ALK stock solution at 50 ng / μL with kinase buffer (50 mM HEPES, 10 mM MgCl2, 2 mM DTT, 1 mM EGTA, 0.01% Tween 20). Add 6 μL of the working solution at 0.0668 ng / μL at 1.67× per well (final concentration 0.04 ng / μL). Use a nanoliter pipettor to add different compounds dissolved in DMSO to the wells, so that the final concentration of the compounds is 1000 nM to 0.244 nM, with a 4-fold gradient and a total of 7 concentrations. At the same time, set up blank control wells (without enzyme) and negative control wells (with enzyme, adding solvent DMSO). After the enzyme reacts with the compound or solvent for 30 min, mix 5× 50 μM ATP (final concentration 10 μM) and 5× 0.5 μM substrate (final concentration 0.1 μM, U Light-poly GT) prepared with kinase buffer in a 1:1 ratio and add 4 μL per well to the wells; seal the plate with a sealing film. After reacting at room temperature for 2 h, add 5 μL of 4× 40 mM EDTA (final concentration 10 mM) per well, for 5 min at room temperature, then add 5 μL of 4× 8 nM detection reagent (final concentration 2 nM, PT66) per well, and incubate at room temperature for 1 hour; read the plate with a PE instrument (excitation 320 nm, emission 665 nm), and use four-parameter fitting to calculate the IC 50 。

[0256] 1.2 Screening for TRKA inhibitory activity

[0257] There are three subtypes of the TRK protein, TRKA, TRKB, and TRKC, and TRKA here is one of the subtypes

[0258] Dilute the TRKA stock solution with 1x kinase buffer (50 mM HEPES pH 7.5, 10 mM MgCl2, 0.01% Tween-20, 0.01% BSA). Dilute the compound with 100% DMSO to 10 nM - 1000 nM, and use a nanoliter pipettor to transfer 100 μl of this compound dilution to the wells of a 96-well plate. In the same 384-well Echo plate, add 50 μl of 100% DMSO to 2 empty wells respectively as the compound-free control and the enzyme-free control. Label the plate as the source plate. Transfer 100 nl from the 384-well Echo plate to the 384-well detection plate. Prepare a 2x substrate solution by adding the polypeptide and ATP in 1x kinase base buffer, start the reaction by adding 5 μl of the 2x substrate solution per well, react at room temperature for 1 hour, prepare the detection solution at 2-fold final concentration in antibody dilution buffer, and add 10 μl of the detection solution per well to stop the reaction, and incubate at room temperature for 1 hour. Read the plate with an Envision instrument (excitation 340 nm, emission 520 nm and 495 nm), and use four-parameter fitting to calculate the IC 50 。The results are shown in Table 1.

[0259] Table 1: Results of in vitro kinase inhibitory activity

[0260]

[0261]

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof; Among them, R 1 is halogen, 3- to 8-membered heterocycloalkyl, 3- to 8-membered heterocycloalkyl substituted with one or more R 1-1 substituents, -NR 1-4 R 1-5 , 5- to 8-membered heterocycloalkenyl, 5- to 8-membered heterocycloalkenyl substituted with one or more R 1-2 substituents or C1-C6 alkyl substituted with one or more R 1-3 substituents; R 1-3 independently a 3- to 8-membered heterocycloalkyl or a 3- to 8-membered heterocycloalkyl substituted with one or more R a substituents; R 1-1 , R 1-2 and R a Each independently is C1-C6 alkyl or -NR b R c ; R 1-4 and R 1-5 each independently is a C1-C6 alkyl group or a C1-C6 alkyl group substituted by one or more R d substituents; R d is -NR e R f ; R b 、R c 、R e and R f each independently represents a C1-C6 alkyl group; R 2 is H, -NR 2-1 R 2-2 or 3- to 8-membered heterocycloalkyl; R 2-1 and R 2-2 each independently is H, C1-C6 alkyl or 3-8 membered heterocycloalkyl; X is a linking group, -CR x1 R x2 -, -O-, or -O-CR x3 R x4 -; R x1 、R x2 、R x3 and R x4 each group is independently H or a C1-C6 alkyl group; R 3 is C6-C 14 aryl or C6-C aryl substituted by one or more halogens 14 ; where the halogen is denoted as M and the number of halogens is denoted as n; In the 3- to 8-membered heterocycloalkyl group and 5- to 8-membered heterocycloalkenyl group described above, the types of heteroatoms are each independently selected from one or more of N, O, and S, and the number of heteroatoms is independently 1, 2, or 3.

2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1)R 1 wherein the halogen is F, Cl, Br or I; (2)R 1 and R 1-3 In the 3- to 8-membered heterocycloalkyl group, the types of the heteroatoms are independently N and / or O; (3)R 1 and R 1-3 In the 3- to 8-membered heterocycloalkyl group, the number of the heteroatoms is independently 1 or 2; (4)R 1 and R 1-3 wherein the 3- to 8-membered heterocycloalkyl group is independently a 5- to 7-membered heterocycloalkyl group; (5)R 1 and R 1-3 in the 5- to 8-membered heteroalkenyl group, the types of the heteroatoms are independently N; (6)R 1 and R 1-3 In the 5- to 8-membered heteroalkenyl group, the number of the heteroatoms is independently 1; (7)R 1 and R 1-3 in which the 5- to 8-membered heteroalkenyl is independently a 6-membered heteroalkenyl; (8)R 1 In the formula, the C1-C6 alkyl group is a C1-C3 alkyl group; (9)R 1-1 、R 1-2 and R a In, the C1-C6 alkyl groups are independently C1-C3 alkyl groups; (10)R 1-4 and R 1-5 wherein the C1-C6 alkyl groups are independently C1-C3 alkyl groups; (11)R b 、R c 、R e and R f Among them, the C1-C6 alkyl groups mentioned are independently C1-C3 alkyl groups; (12)R 2 、R 2-1 and R 2-2 In R 2 , R 2-1 and R 2-2 , in the 3- to 8-membered heterocycloalkyl group, the types of the heteroatoms are independently N and / or O; (13)R 2 、R 2-1 and R 2-2 In, in the 3- to 8-membered heterocycloalkyl group, the number of the heteroatoms is independently 1 or 2; (14)R 2 、R 2-1 and R 2-2 Among them, the 3- to 8-membered heterocycloalkyl group is a 4- to 6-membered heterocycloalkyl group; (15)R 2-1 and R 2-2 wherein the C1-C6 alkyl groups are independently C1-C3 alkyl groups; (16)R x1 、R x2 、R x3 and R x4 Among them, the C1-C6 alkyl groups mentioned are independently C1-C3 alkyl groups; (17) R 3 Among them, the C6-C 14 aryl is C6-C 10 aryl; (18)R 3 Among them, the number of the halogens is denoted as n, and n is two or three; (19)R 3 Among them, the halogen is denoted as M, and the M is selected from one or more of F, Cl, Br, and I.

3. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that, It satisfies one or more of the following conditions: (1)R 1 wherein the halogen is F or Br; (2)R 1 and R 1-3 wherein the 3- to 8-membered heterocycloalkyl group is independently a pyrrolidinyl group, a piperazinyl group, a piperidinyl group, a morpholinyl group or a 7-membered heterocycloalkyl group containing 2 N atoms; (3)R 1 and R 1-3 Among them, the 5- to 8-membered heteroalkenyl is independently a 6-membered heteroalkenyl containing 1 N atom; (4)R 1 wherein, the C1-C6 alkyl group is methyl, ethyl, n-propyl or isopropyl; (5)R 1-1 、R 1-2 and R a wherein the C1-C6 alkyl groups are independently methyl, ethyl, n-propyl or isopropyl; (6)R 1-4 and R 1-5 wherein the C1-C6 alkyl groups are independently methyl, ethyl, n-propyl or isopropyl; (7)R b 、R c 、R e and R f wherein the C1-C6 alkyl groups are independently methyl, ethyl, n-propyl or isopropyl; (8)R 2 、R 2-1 and R 2-2 Among them, the 3- to 8-membered heterocyclic alkyl groups are independently tetrahydropyranyl, morpholinyl, azetidinyl or piperidinyl; (9)R 2-1 and R 2-2 wherein the C1-C6 alkyl groups are independently methyl, ethyl, n-propyl or isopropyl; (10)R x1 、R x2 、R x3 and R x4 wherein the C1-C6 alkyl groups are independently methyl, ethyl, n-propyl or isopropyl; (11)R 3 Among them, the C6-C 14 aryl is phenyl; (12)R 3 In which, the said M is F and / or Cl.

4. The compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 3, wherein, It satisfies one or more of the following conditions: (1)R 1 and R 1-3 in, the 3- to 8-membered heterocycloalkyl is independently (2)R 1 and R 1-3 in, the 5- to 8-membered heteroalkenyl groups are independently (3)R 1 In the formula, C1-C6 alkyl is methyl; (4)R 1-1 、R 1-2 and R a wherein the C1-C6 alkyl groups are independently methyl or ethyl; (5)R 1-4 and R 1-5 wherein the C1-C6 alkyl groups are independently methyl or ethyl; (6)R b 、R c 、R e and R f wherein the C1-C6 alkyl groups are independently methyl; (7)R 2 In this formula, the 3- to 8-membered heterocyclic alkyl group contains an N atom, and the N atom is located at the site in the ring that is connected to the parent nucleus; (8)R 2-1 and R 2-2 in which the 3- to 8-membered heteroalkyl group is independently (9)R 2-1 and R 2-2 in which the C1-C6 alkyl group is independently methyl; (10)R x1 、R x2 、R x3 and R x4 Among them, the C1-C6 alkyl groups mentioned are independently methyl groups.

5. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 3, characterized in that, R 2 In the formula, the 3- to 8-membered heterocycloalkyl is 6. The compound of formula I as described in claim 3 or a pharmaceutically acceptable salt thereof, characterized in that, It satisfies one or more of the following conditions: (1)R 1 is halogen, methyl-substituted piperazinyl, ethyl-substituted piperazinyl, piperidinyl, morpholinyl, methyl-substituted morpholinyl, methyl-substituted 7-membered heterocyclic alkyl containing 2 N atoms, methyl-substituted 6-membered heterocyclic alkenyl containing 1 N atom, methyl-substituted piperidinyl, dimethylamino-substituted pyrrolidinyl, amino substituted by methyl and dimethylaminoethyl, methyl-substituted piperazinyl-CH2-, morpholinyl-CH2-, methyl-substituted morpholinyl-CH2-, methyl-substituted 7-membered heterocyclic alkyl containing 2 N atoms-CH2-, methyl-substituted piperidinyl-CH2- or dimethylamino-substituted pyrrolidinyl-CH2-; (2)R 2 is an amino group, azetidinyl or piperidinyl substituted by H, dimethylamino, morpholinyl, tetrahydropyranyl; (3)R x1 、R x2 、R x3 and R x4 each independently is H or methyl; (4) X is a linking bond, -CH2-, -O-, or -O-CHCH3-; (5)R 3 is a fluorine-substituted phenyl group or a phenyl group substituted by both fluorine and chlorine.

7. The compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 5, characterized in that, It satisfies one or more of the following conditions: (1)R 1 is F, Br, (2)R 2 is H, (3) X is a connecting key, -CH2-, -O- or (4)R 3 For 8. The compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, R 1 is a morpholinyl group or a morpholinyl group substituted with a methyl group.

9. The compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 1, wherein, R 1 is X is CH2.

10. The compound of formula I as described in claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, It is any one of the following schemes: Scheme 1: R 1 is a 3- to 8-membered heterocycloalkyl group substituted by one or more R 1-1 ; X is -O- or -O-CR x3 R x4 -; Scheme 2: R 1 is a 3- to 8-membered heterocycloalkyl group substituted by one or more R 1-1 ; X is -O-CR x3 R x4 -; Scheme 3: R 2 is -NR 2-1 R 2-2 or 3 - to 8 - membered heteroalkyl; Scheme 4: R 1 is a 3- to 8-membered heterocycloalkyl group or a 3- to 8-membered heterocycloalkyl group substituted by one or more R 1-1 ; X is CH2.

11. The compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 10, wherein It is any one of the following schemes: Scheme 1: R 1 is a 3- to 8-membered heterocyclic alkyl group containing 2 N atoms substituted by one or more R 1-1 ; X is -O- or -O-CR x3 R x4 -; Scheme 2: R 1 is a 3- to 8-membered heterocycloalkyl group containing 1 nitrogen atom and substituted by one or more R 1-1 ; X is -O-CR x3 R x4 -; Scheme 3: R 2 is dimethylamino, morpholino, tetrahydropyranyl-substituted amino, azetidinyl or piperidinyl; Scheme 4: R 1 is a 3- to 8-membered heteroalkyl group containing N and O atoms or a 3- to 8-membered heteroalkyl group containing N and O atoms substituted by one or more R 1-1 ; X is CH2.

12. The compound of formula I as claimed in claim 10 or a pharmaceutically acceptable salt thereof, characterized in that, It is any one of the following schemes: Scheme 1: R 1 is a piperazinyl group substituted by one or more methyl groups; X is -O- or -O-CR x3 R x4 -; Scheme 2: R 1 is a piperidinyl group substituted by one or more methyl groups; X is -O-CR x3 R x4 -; Solution 3: R 2 For Scheme 4: R 1 is a morpholinyl group or a morpholinyl group substituted by one or more methyl groups; X is CH2.

13. The compound of formula I as claimed in claim 10 or a pharmaceutically acceptable salt thereof, characterized in that, It is any one of the following schemes: Solution 1: R 1 For X is -O- or -O-CR x3 R x4 -; Solution 2: R 1 For X is -O-CR x3 R x4 -; Solution 3: R 2 For Solution 4: R 1 is X is CH2.

14. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 10, characterized in that, It satisfies one or both of the following conditions: (1)In Solution 1, X is -O- or (2) In Solution 2, X is 15. The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, characterized in that, The compound of formula I described above is any one of the following structures: wherein, R 1 , R 2 , X and R 3 are all defined as described in any one of claims 1 to 14; M is selected from one or more of F, Cl, Br, and I; n is 2 or 3.

16. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The compound of formula I described above is any one of the following compounds:

17. A method for preparing a compound represented by formula I as described in any one of claims 1 to 16, characterized in that, It comprises the following steps: In a solvent, the compound of formula 1 and the compound of formula 2 are subjected to the reaction shown below, and that's it; Wherein, Y is a halogen; the definitions of the remaining substituents in each of the above formulas are as described in any one of claims 1 to 16.

18. The preparation method of the compound shown in Formula I as described in claim 17, characterized in that, Y is F, Cl, Br, or I.

19. The preparation method of the compound represented by Formula I as described in claim 17, characterized in that, Y is Cl.

20. The preparation method of the compound shown in Formula I as described in claim 17, characterized in that, The preparation method of the compound of formula I described above comprises the following steps: In a solvent, under the action of a palladium catalyst, a ligand, and a base, the compound of formula 1 and the compound of formula 2 are reacted, and that's it.

21. The preparation method of the compound shown in Formula I as described in claim 20, characterized in that, The solvent described above is a hydrocarbon solvent.

22. The preparation method of the compound shown in Formula I as described in claim 20, characterized in that, The solvent described above is a benzene solvent.

23. The preparation method of the compound shown in Formula I as described in claim 20, characterized in that, The solvent described above is toluene.

24. The preparation method of the compound shown in Formula I as described in claim 20, characterized in that, The palladium catalyst described above is a divalent palladium catalyst.

25. The preparation method of the compound shown in Formula I as described in claim 20, characterized in that, The palladium catalyst described above is palladium acetate.

26. The preparation method of the compound shown in Formula I as described in claim 20, characterized in that, The ligand described above is BINAP.

27. The method for preparing the compound represented by formula I as described in claim 20, characterized in that, The base described above is a carbonate of an alkali metal.

28. The preparation method of the compound shown in Formula I as described in claim 20, characterized in that, The base described above is cesium carbonate.

29. A pharmaceutical composition, characterized in that, It comprises substance P and a pharmaceutically acceptable excipient; the substance P is the compound of formula I described in any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof.

30. Use of a compound of formula I described in any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition described in claim 29 in the preparation of an ALK and / or TRK inhibitor, or in the preparation of a drug for preventing and / or treating diseases related to ALK and / or TRK.

31. The application according to claim 30, wherein The diseases related to ALK and / or TRK described above are cancer, pain, neurological diseases, autoimmune diseases, and inflammation.

32. The application according to claim 30, characterized in that, The diseases related to ALK and / or TRK described above are cancer, pain, neurological diseases, autoimmune diseases, and inflammation; the cancer is lung cancer.

33. The application according to claim 30, wherein, The diseases related to ALK and / or TRK described above are cancer, pain, neurological diseases, autoimmune diseases, and inflammation; the cancer is non-small cell lung cancer.

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