Pyrrolopyrimidine compound and application thereof

Abstract

The invention relates to the field of medicines, in particular to a pyrrolopyrimidine compound and application thereof. The pyrrolopyrimidine compound has a structure as shown in a formula (I): # imgabs0 #. The pyrrolopyrimidine compound disclosed by the invention has good solubility, an excellent FAK inhibition effect and a remarkable inhibition effect on the growth of tumor cells (MDA-MB-231, SKOV3 and HepG2).

Description

Technical Field

[0001] The present invention relates to the field of medicine, and particularly to a pyrrolopyrimidine compound and its application. Background Art

[0002] Focal Adhesion Kinase (FAK), also known as Protein Tyrosine Kinase 2 (PTK2), is a non-receptor tyrosine kinase that plays a central role in the regulation of integrin and growth factor receptor signaling pathways. FAK participates in various physiological and pathological processes such as embryonic development, tissue repair, and angiogenesis by regulating processes such as cell adhesion, migration, proliferation, survival, and invasion.

[0003] Currently, the research and development of FAK inhibitors mainly focuses on the field of small molecule compounds, including pyrimidine derivatives, pyrazole derivatives, and aminopyridine derivatives. Although a variety of FAK inhibitors have entered clinical research, there are still many problems. For example, the selectivity is insufficient, and some inhibitors have cross-inhibition on FAK homologous kinases (such as PYK2), resulting in off-target effects; long-term use of a single inhibitor is prone to drug resistance, and combination therapy may increase the risk of organ toxicity. Therefore, it is of great significance to provide a novel pyrrolopyrimidine compound and its stereoisomers or pharmaceutically acceptable salts as FAK inhibitors in the field of medicine. Summary of the Invention

[0004] Based on the above, the present invention provides a pyrrolopyrimidine compound and its application.

[0005] To achieve the above object, the present invention provides the following solutions:

[0006] The present invention provides a compound (pyrrolopyrimidine compound) represented by formula (I):

[0007] or its stereoisomers or pharmaceutically acceptable salts;

[0008] Wherein, R1 is selected from hydrogen, deuterium, halogen, nitro, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or C1-C3 deuterated alkoxy;

[0009] R 2-1 、R 2-2 、R 2-3 、R 2-4 and R 2-5 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, nitro, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, or C1-C3 deuterated alkoxy;

[0010] L is selected from a bond, -CO-, -CH2CO-, -NHCO- or -CH2-;

[0011] R3 is selected from hydrogen, deuterium, halogen, hydroxy, nitro, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or C1-C3 deuterated alkoxy;

[0012] R 3-1 is selected from hydrogen, deuterium, halogen, hydroxy, nitro, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 deuterated alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl or -P(=O)(OR 4-1 )(OR 4-2 ), and the C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 deuterated alkoxy, C 3-1 cycloalkyl and 3-8 membered heterocycloalkyl in R 3-8 are optionally substituted by one or more R5;

[0013] R 4-1 and R 4-2 are each independently selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 deuterated alkyl;

[0014] R5 is selected from hydrogen, deuterium, halogen, hydroxy, nitro, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 deuterated alkoxy, C1-C3 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, -COOR 5-1 、-C(=S)SCH2CH2NR 5-2 R 5-3 , and the C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 deuterated alkoxy, C1-C3 hydroxyalkyl, C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl are optionally substituted by one or more of hydrogen, deuterium, halogen, hydroxy, nitro, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 deuterated alkoxy, C1-C3 hydroxyalkyl;

[0015] R 5-1 、R5-2 and R 5-3 are each independently selected from hydrogen, C1-C4 alkyl, C1-C3 haloalkyl or C1-C3 deuterated alkyl;

[0016] x is 0, 1, 2, 3 or 4.

[0017] In a preferred embodiment of the present invention, the compound has the structure shown in formula (II-1) or formula (II-2):

[0018]

[0019] wherein,

[0020] R 3-2 , R 3-3 , R 3-4 and R 3-5 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, nitro, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or C1-C3 deuterated alkoxy;

[0021] R 2-1 , R 2-3 , L, R 3-1 is the same as R in claim 1 2-1 , R 2-3 , L, R 3-1 .

[0022] In a preferred embodiment of the present invention, R 2-1 in the compound is selected from C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 deuterated alkyl; preferably, R 2-1 is selected from methyl or ethyl;

[0023] and / or, R 2-3 is selected from hydrogen, deuterium, halogen, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 deuterated alkyl; preferably, R 2-3 is selected from hydrogen, fluorine, chlorine or methyl.

[0024] In a preferred embodiment of the present invention, R 3-2 , R 3-3 , R 3-4 and R 3-5 are each independently selected from hydrogen, chlorine or methoxy;

[0025] R 3-1 is selected from C1-C3 alkyl, C1-C3 alkoxy, 3-8 membered heterocycloalkyl or -P(=O)(OR 4-1 )(OR 4-2), the 3- to 8-membered heterocycloalkyl is optionally substituted with one or more R5;

[0026] R 4-1 and R 4-2 are each independently selected from C1-C3 alkyl;

[0027] R5 is selected from hydrogen, C1-C3 alkyl, C1-C3 hydroxyalkyl, 3- to 8-membered heterocycloalkyl, -COOR 5-1 , -C(=S)SCH2CH2NR 5- 2R 5-3 ; More preferably, R5 is C1-C3 alkyl.

[0028] R 5-1 , R 5-2 and R 5-3 are each independently selected from C1-C4 alkyl.

[0029] In a preferred embodiment of the present invention, in the compound, R 3-1 is selected from methyl, methoxy, or -P(=O)(OCH2CH3)(OCH2CH3), and the is optionally substituted with one or more R5;

[0030] R5 is selected from hydrogen, methyl, -CH2CH2OH, -COO-tert-butyl, -C(=S)SCH2CH2N(CH3)2.

[0031] In a further preferred embodiment of the present invention, R 3-1 is selected from methyl, methoxy,

[0032] or -P(=O)(OCH2CH3)(OCH2CH3).

[0033] In a preferred embodiment of the present invention, in the compound, -L-R 3-1 is selected from methoxy,

[0034] -CH2P(=O)(OCH2CH3)(OCH2CH3), or -NHCOCH3.

[0035] In a preferred embodiment of the present invention, the compound has the structure shown in formula (III):

[0036]

[0037] In a preferred embodiment of the present invention, the compound is one of the following structural formulas:

[0038]

[0039]

[0040]

[0041] The present invention also provides a pharmaceutical composition, the active ingredient of which comprises the above-mentioned compound, or its stereoisomer or its pharmaceutically acceptable salt.

[0042] The pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0043] The present invention also provides the use of the above-mentioned compound in the preparation of a FAK inhibitor, or in the preparation of a drug for treating breast cancer, ovarian cancer or liver cancer.

[0044] The present invention discloses the following technical effects:

[0045] The pyrrolopyrimidine compound of the present invention has good solubility, excellent FAK inhibitory effect and significant inhibitory effect on the growth of tumor cells (MDA-MB-231, SKOV3, HepG2). Detailed Description of the Invention

[0046] The various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be construed as a limitation of the present invention, but rather as a more detailed description of certain aspects, characteristics and embodiments of the present invention.

[0047] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0048] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched-chain group containing 1 to 4 carbon atoms, preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl.

[0049] The term "cycloalkyl" refers to a saturated monocyclic or polycyclic hydrocarbon, and the cycloalkyl ring contains 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0050] The term "heterocycloalkyl" refers to a saturated monocyclic or polycyclic hydrocarbon substituent, which contains 3 to 8 ring atoms, and one or more of the ring atoms are selected from nitrogen, oxygen, C(O), S(O)(=NH) or S(O) ma heteroatom (where m is an integer from 0 to 2), provided that the ring moiety does not include -O-O-, -O-S- or -S-S-, and the remaining ring atoms are carbon.

[0051] The term "alkoxy" means -O-(alkyl), where alkyl is as defined above.

[0052] The term "halogen" means fluorine, chlorine, bromine or iodine.

[0053] The term "deuterated alkyl" means an alkyl group substituted with one or more deuteriums, where alkyl is as defined above.

[0054] The term "haloalkyl" means an alkyl group substituted with one or more halogens, where alkyl is as defined above.

[0055] The term "haloalkoxy" means an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.

[0056] The term "deuterated alkoxy" means an alkoxy group substituted with one or more deuteriums, where alkoxy is as defined above.

[0057] The term "hydroxyalkyl" means an alkyl group substituted with one or more hydroxyl groups, where alkyl is as defined above.

[0058] Phrases such as "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" all convey the same meaning, namely that X can be any one or more of A, B and C.

[0059] "Optional" or "optionally" means that the subsequent described event or circumstance may but need not occur, and this description includes the cases where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl" means that the alkyl may but need not be present, and this description includes the cases where the heterocyclic group is substituted with an alkyl and the cases where the heterocyclic group is not substituted with an alkyl.

[0060] "Substituted" means that one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 - 3 hydrogen atoms, are independently replaced by the corresponding number of substituents. It goes without saying that the substituents are only at their possible chemical positions, and those skilled in the art can determine (by experiment or theory) what substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with a free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (such as olefinic) bond.

[0061] "Pharmaceutical composition" refers to a mixture containing one or more compounds described in the present invention or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration to an organism, promote the absorption of the active ingredient and thus exert its biological activity.

[0062] "Pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, which has safety and effectiveness when used in mammals and has the due biological activity.

[0063] The technical solutions described in the present invention are all conventional solutions in the art unless otherwise specified. The reagents or raw materials used are all purchased from commercial channels or are publicly available unless otherwise specified.

[0064] The technical solutions provided by the present invention will be described in detail below in conjunction with the examples, but they should not be construed as limiting the scope of protection of the present invention.

[0065] The preparation method of the compounds represented by formulas (I)-(III) involved in the examples of the present invention is completed through two key reactions, and the reaction route is shown in formula (IV):

[0066]

[0067] The introduction of the 4-substituted amino group in the first step, that is, the preparation of compound B, is obtained by the following method: raw material A reacts with 1-1.5 equivalents of amine reagent in a suitable solvent under the catalysis of a basic reagent through a nucleophilic substitution reaction;

[0068] Among them, raw material A is selected from 5-R1-2,4-dichloropyrrolo[2,3-d]pyrimidine purchased or self-made, and the substituent R1 can be -H, -CN, -Cl, -F, -CH3, -CH2CH3 or -OCH3, etc.;

[0069] The amine reagent is a substituted aniline, R 2-1 、R 2-2 、R 2-3 、R 2-4 and R 2-5 each independently selected from hydrogen, deuterium, halogen, hydroxyl, nitro, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or C1-C3 deuterated alkoxy;

[0070] The solvent is selected from ethanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, dioxane, or N,N-dimethylformamide, etc.;

[0071] The basic reagent is selected from pyridine, triethylamine, N,N-diisopropylethylamine, potassium carbonate, cesium carbonate, etc.

[0072] The introduction of the 2-position substituted amino group in the second step, i.e., the preparation of the compound shown in formula (I), is obtained by the following method: Raw material B reacts with 1 - 1.5 equivalents of an amine reagent in a suitable solvent under the catalysis of a palladium reagent and a phosphorus-containing ligand through a coupling reaction;

[0073] Among them, in the substituted aniline reagent, the substituent R3 is independently selected from hydrogen, deuterium, halogen, hydroxyl, nitro, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or C1-C3 deuterated alkoxy; R3-1 is selected from hydrogen, deuterium, halogen, hydroxyl, nitro, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 deuterated alkoxy, C3-8 cycloalkyl, 3-8 membered heteroalkyl or -P(=O)(OR 4-1 )(OR 4-2 ), and the C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 deuterated alkoxy, C3-8 cycloalkyl and 3-8 membered heteroalkyl are optionally substituted by one or more R5; R 4-1 and R 4-2 are each independently selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 deuterated alkyl; R5 is independently selected from hydrogen, deuterium, halogen, hydroxyl, nitro, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 deuterated alkoxy, C1-C3 hydroxyalkyl, C3-8 cycloalkyl, 3-8 membered heteroalkyl, -COOR 5-1 , -C(=S)SCH2CH2NR 5-2 R 5-3 , and the C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 deuterated alkoxy, C1-C3 hydroxyalkyl, C3-8 cycloalkyl and 3-8 membered heteroalkyl are optionally substituted by one or more of hydrogen, deuterium, halogen, hydroxyl, nitro, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 deuterated alkoxy, C1-C3 hydroxyalkyl; R 5-1 , R 5-2 and R 5-3 are each independently selected from hydrogen, C1-C4 alkyl, C1-C3 haloalkyl or C1-C3 deuterated alkyl; x is 0, 1, 2, 3 or 4.

[0074] The solvent is selected from ethanol, isopropanol, n-butanol, tert-butanol, tetrahydrofuran, dioxane, or N,N-dimethylformamide, etc.;

[0075] The palladium reagent is selected from palladium acetate, palladium chloride, tris(dibenzylideneacetone)dipalladium, tetrakis(triphenylphosphine)palladium, etc.;

[0076] The phosphorus-containing ligand is selected from Ph3P, Xantphos, Xphos, BINAP, etc.

[0077] Example 1

[0078]

[0079] (1) 2,4-Dichloro-5-fluoro-pyrrolo[2,3-d]pyrimidine (317.24 mg, 1.54 mmol) and 2-amino-N-methylbenzamide (278.6 mg, 1.86 mmol, 1.2 eq) were dissolved in 25 ml of MeCN, and DIPEA (0.53 ml, 3.08 mmol, 2 eq) was added. Stir with an external bath under reflux. After reacting for 40 h, the reaction was stopped, stirred at room temperature overnight, and then filtered to obtain B-1: 353.4 mg, with a yield of 48.4%. m.p. >250 °C. 1 1H NMR (400 MHz, DMSO-d6) δ 11.98 (s, 1H), 11.93 (s, 1H), 8.85–8.77 (m, 1H), 8.72 (d, J = 8.5 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.30 (s, 1H), 7.16 (t, J = 7.6 Hz, 1H), 2.81 (d, J = 4.5 Hz, 3H). ESI-MS m / z 319.9 [M+H] + .

[0080] (2) B-1 (180 mg, 0.564 mmol), 4-(4-morpholinyl)aniline (84 mg, 0.470 mmol), potassium carbonate (195 mg, 1.41 mmol), Xphos (22 mg, 0.047 mmol), and Pd2(dba)3 (22 mg, 0.0235 mmol) were dissolved in 6 mL of tert-butanol, protected by nitrogen, and stirred with an external bath at 100 °C. After reacting for 15 h, the reaction was stopped. The reaction solution was concentrated by rotary evaporation and then purified by column chromatography. The eluent was dichloromethane:methanol = 20:1, and 65 mg of the compound of Example 1 was obtained, with a yield of 30%. 11H NMR (400 MHz, DMSO-d6) δ 11.44 (s, 1H), 11.00 (s, 1H), 9.03 (d, J = 8.4 Hz, 1H), 8.81 (s, 1H), 8.68 (q, J = 4.1 Hz, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.63 (d, J = 8.7 Hz, 2H), 7.47 (t, J = 7.9 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 6.88 (d, J = 8.8 Hz, 2H), 6.82 (s, 1H), 3.78–3.71 (m, 4H), 3.08–3.01 (m, 4H), 2.81 (d, J = 4.4 Hz, 3H). ESI-MS m / z 462.2 [M+H] + .

[0081] Example 2

[0082]

[0083] B-1 (150 mg, 0.47 mmol), 4-(4-methylpiperazinyl)aniline (108 mg, 0.564 mmol), potassium carbonate (195 mg, 1.41 mmol), Xphos (22 mg, 0.047 mmol), and Pd2(dba)3 (22 mg, 0.0235 mmol) were dissolved in 6 mL of tert-butanol, protected by nitrogen, and stirred with an external bath at 100 °C. After reacting for 15 h, the reaction was stopped. The reaction solution was concentrated in vacuo and then purified by column chromatography. The eluent was dichloromethane:methanol = 24:1, and 16 mg of the compound of Example 2 was obtained, with a yield of 7.2%. 1 1H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 11.01 (s, 1H), 9.05 (d, J = 9.4 Hz, 1H), 8.81 (s, 1H), 8.75–8.66 (m, 1H), 7.73 (d, J = 8.7 Hz, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.48 (t, J = 8.1 Hz, 1H), 7.09 (t, J = 8.0 Hz, 1H), 6.89 (d, J = 8.8 Hz, 2H), 6.83 (s, 1H), 3.12–3.05 (m, 4H), 2.82 (d, J = 4.3 Hz, 3H), 2.50–2.44 (m, 4H), 2.24 (s, 3H). ESI-MS m / z: 475.2 [M+H] + .

[0084] Example 3

[0085]

[0086] B-1 (150 mg, 0.47 mmol), 2-[4-(4-aminophenyl)piperazin-1-yl]ethanol (125 mg, 0.564 mmol), potassium carbonate (195 mg, 1.41 mmol), Xphos (22 mg, 0.047 mmol) and Pd2(dba)3 (22 mg, 0.0235 mmol) were dissolved in 6 mL of tert-butanol, protected by nitrogen, and stirred with an external bath at 100 °C. The reaction was stopped after 15 h. The reaction solution was concentrated in vacuo and then purified by column chromatography. The eluent was dichloromethane:methanol = 24:1. The compound of Example 3 was obtained: 67 mg, yield 28.6%. 1 H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 10.98 (s, 1H), 9.03 (d, J = 8.3 Hz, 1H), 8.77 (s, 1H), 8.67 (q, J = 4.5 Hz, 1H), 7.71 (d, J = 8 Hz, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.46 (t, J = 8.0 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 6.87 (d, J = 9.0 Hz, 2H), 6.81 (s, 1H), 4.42 (s, 1H), 3.54 (s, 2H), 3.06 (s, 4H), 2.81 (d, J = 4.4 Hz, 3H), 2.57 (s, 4H), 2.45 (t, J = 6.0 Hz, 2H). ESI-MS m / z: 505.2 [M+H] + .

[0087] Example 4

[0088]

[0089] B-1 (150 mg, 0.47 mmol), 3,4,5-trimethoxyaniline (103 mg, 0.564 mmol), potassium carbonate (195 mg, 1.41 mmol), Xphos (22 mg, 0.047 mmol) and Pd2(dba)3 (22 mg, 0.0235 mmol) were dissolved in 6 mL of tert-butanol, protected by nitrogen, and stirred with an external bath at 100 °C. The reaction was stopped after 15 h. The reaction solution was concentrated in vacuo and then purified by column chromatography. The eluent was dichloromethane:ethyl acetate = 3:1. The compound of Example 4 was obtained: 20 mg, yield 9.1%. 11H NMR (400 MHz, DMSO-d6) δ 11.53 (s, 1H), 11.10 (s, 1H), 9.09 (d, J = 8.5 Hz, 1H), 8.98 (s, 1H), 8.71 (q, J = 4.5 Hz, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.48 (t, J = 8.1 Hz, 1H), 7.26 (s, 2H), 7.09 (t, J = 7.8 Hz, 1H), 6.91 (t, J = 2.1 Hz, 1H), 3.76 (s, 6H), 3.63 (s, 3H), 2.82 (d, J = 4.4 Hz, 3H). ESI-MS m / z: 467.2 [M+H] + 。

[0090] Example 5

[0091]

[0092] B-1 (150 mg, 0.47 mmol), 2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (171.6 mg, 0.564 mmol), potassium carbonate (195 mg, 1.41 mmol), Xphos (22 mg, 0.047 mmol) and Pd2(dba)3 (22 mg, 0.0235 mmol) were dissolved in 6 mL of tert-butanol, protected by nitrogen, and stirred at 100 °C in an external bath. After reacting for 15 h, the reaction was stopped. The reaction solution was concentrated in vacuo and then subjected to column chromatography. The polarity of the eluent was dichloromethane:methanol = 24:1, and the compound of Example 5 was obtained: 30 mg, yield 10.9%. 1 1H NMR (600 MHz, DMSO-d6) δ 11.42 (s, 1H), 10.98 (s, 1H), 8.84 (d, J = 8.4 Hz, 1H), 8.70 (q, J = 4.7 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.50 (s, 1H), 7.41 (t, J = 7.7 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 6.80 (t, J = 2.2 Hz, 1H), 6.69–6.62 (m, 1H), 6.49 (dd, J = 8.7, 2.0 Hz, 1H), 3.81 (s, 3H), 3.72 (d, J = 11.4 Hz, 2H), 2.82 (s, 6H), 2.80 (d, J = 4.4 Hz, 3H), 2.65 (t, J = 11.5 Hz, 2H), 2.51 (s, 4H), 1.91 (s, 2H), 1.61 (s, 2H). ESI-MS m / z: 588.3 [M+H] + .

[0093] Example 6

[0094]

[0095] B-1 (150 mg, 0.47 mmol), diethyl (4-aminobenzyl)phosphonate (137 mg, 0.564 mmol), potassium carbonate (195 mg, 1.41 mmol), Xphos (22 mg, 0.047 mmol), and Pd2(dba)3 (22 mg, 0.0235 mmol) were dissolved in 6 mL of tert-butanol. Under nitrogen protection, the mixture was stirred with an external bath at 100 °C. After reacting for 15 h, the reaction was stopped. The reaction solution was concentrated in vacuo and then purified by column chromatography. The eluent was dichloromethane:methanol = 26:1, and 60 mg of the compound of Example 6 was obtained, with a yield of 25%. 1 H NMR (400 MHz, DMSO-d6) δ 11.49 (s, 1H), 11.11 (s, 1H), 9.07 (s, 1H), 9.03 (d, J = 9.1 Hz, 1H), 8.76–8.69 (m, 1H), 7.78–7.69 (m, 3H), 7.55–7.47 (m, 1H), 7.16 (d, J = 6.5 Hz, 2H), 7.14–7.07 (m, 1H), 6.89 (s, 1H), 3.96 (m, 4H), 3.18 (s, 1H), 3.13 (s, 1H), 2.82 (d, J = 4.4 Hz, 3H), 1.19 (t, J = 7.1 Hz, 6H). ESI-MS m / z: 527.2 [M+H] + .

[0096] Example 7

[0097]

[0098] B-1 (150 mg, 0.47 mmol), 3-(4-morpholinyl)aniline (100 mg, 0.564 mmol), potassium carbonate (195 mg, 1.41 mmol), Xphos (22 mg, 0.047 mmol), and Pd2(dba)3 (22 mg, 0.0235 mmol) were dissolved in 6 mL of tert-butanol. Under nitrogen protection, the mixture was stirred with an external bath at 100 °C. After reacting for 15 h, the reaction was stopped. The reaction solution was concentrated in vacuo and then purified by column chromatography. The eluent was dichloromethane:methanol = 20:1, and 36 mg of the compound of Example 7 was obtained, with a yield of 17%. 11H NMR (400 MHz, DMSO-d6) δ 11.49 (s, 1H), 11.07 (s, 1H), 9.15–9.00 (m, 1H), 8.91 (s, 1H), 8.68 (q, J = 4.1 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.52–7.39 (m, 2H), 7.32 (d, J = 8.0 Hz, 1H), 7.09 (q, J = 7.4, 6.8 Hz, 2H), 6.88 (s, 1H), 6.51 (d, J = 7.2 Hz, 1H), 3.81–3.66 (m, 4H), 3.16–3.02 (m, 4H), 2.81 (d, J = 4.4 Hz, 3H). ESI-MS m / z 462.2 [M+H] + .

[0099] Example 8

[0100]

[0101] B-1 (150 mg, 0.47 mmol), 3-(4-methylpiperazin-1-yl)aniline (107 mg, 0.564 mmol), potassium carbonate (195 mg, 1.41 mmol), Xphos (22 mg, 0.047 mmol) and Pd2(dba)3 (22 mg, 0.0235 mmol) were dissolved in 6 mL of tert-butanol, protected by nitrogen, and stirred with an external bath at 100 °C. After reacting for 15 h, the reaction was stopped. After the reaction solution was evaporated to dryness, it was subjected to column chromatography. The eluent was dichloromethane:methanol = 20:1, and 40 mg of the compound of Example 8 was obtained, with a yield of 18%. 1 1H NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1H), 11.09 (s, 1H), 9.07 (d, J = 8.5 Hz, 1H), 8.90 (s, 1H), 8.70 (d, J = 4.6 Hz, 1H), 7.73 (d, J = 9.4 Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.40 (s, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.08 (t, J = 8.2 Hz, 2H), 6.88 (s, 1H), 6.51 (d, J = 8.3 Hz, 1H), 3.13 (s, 4H), 2.81 (d, J = 4.8 Hz, 3H), 2.50–2.46 (m, 4H), 2.27 (s, 3H). ESI-MS m / z: 475.2 [M+H] + .

[0102] Example 9

[0103]

[0104] B-1 (150 mg, 0.47 mmol), 4-aminophenyl morpholin-4-ylmethanone (116 mg, 0.564 mmol), potassium carbonate (195 mg, 1.41 mmol), Xphos (22 mg, 0.047 mmol) and Pd2(dba)3 (22 mg, 0.0235 mmol) were dissolved in 6 mL of tert-butanol, protected by nitrogen, and stirred with an external bath at 100 °C. After reacting for 15 h, the reaction was stopped. The reaction solution was concentrated in vacuo and then subjected to column chromatography. The eluent was dichloromethane:methanol = 20:1, and the compound of Example 9 was obtained: 64 mg, yield 27.8%. 1 H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 11.19 (s, 1H), 9.35 (s, 1H), 8.99 (d, J = 8.2 Hz, 1H), 8.70 (q, J = 4.8, 4.4 Hz, 1H), 7.89 (d, J = 8.5 Hz, 2H), 7.73 (d, J = 7.0 Hz, 1H), 7.51 (t, J = 8.4 Hz, 1H), 7.33 (d, J = 8.5 Hz, 2H), 7.11 (t, J = 7.7 Hz, 1H), 6.92 (t, J = 2.2 Hz, 1H), 3.65–3.57 (m, 4H), 3.53 (s, 4H), 2.81 (d, J = 4.4 Hz, 3H). ESI-MS m / z 490.2 [M+H] + .

[0105] Example 10

[0106]

[0107] B-1 (150 mg, 0.47 mmol), 4-[(4-methyl-1-piperazinyl)carbonyl]aniline (123 mg, 0.564 mmol), potassium carbonate (195 mg, 1.41 mmol), Xphos (22 mg, 0.047 mmol) and Pd2(dba)3 (22 mg, 0.0235 mmol) were dissolved in 6 mL of tert-butanol, protected by nitrogen, and stirred with an external bath at 100 °C. After reacting for 15 h, the reaction was stopped. The reaction solution was concentrated in vacuo and then subjected to column chromatography. The eluent was dichloromethane:methanol = 20:1, and the compound of Example 10 was obtained: 78 mg, yield 33%. 11H NMR (400 MHz, DMSO-d6) δ 11.49 (s, 1H), 11.19 (s, 1H), 9.33 (s, 1H), 8.98 (d, J = 8.4 Hz, 1H), 8.70 (d, J = 3.0 Hz, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 7.8 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.30 (d, J = 8.6 Hz, 2H), 7.11 (t, J = 7.5 Hz, 1H), 6.92 (s, 1H), 3.51 (s, 4H), 2.81 (d, J = 3.9 Hz, 3H), 2.31 (s, 4H), 2.20 (s, 3H). ESI-MS m / z 503.2 [M+H] + .

[0108] Example 11

[0109]

[0110] B-1 (150 mg, 0.47 mmol), (4-aminophenyl)(4-(2-hydroxyethyl)piperazin-1-yl)methanone (141 mg, 0.564 mmol), potassium carbonate (195 mg, 1.41 mmol), Xphos (22 mg, 0.047 mmol) and Pd2(dba)3 (22 mg, 0.0235 mmol) were dissolved in 6 mL of tert-butanol, protected by nitrogen, and stirred at 100 °C in an external bath. After reacting for 15 h, the reaction was stopped. The reaction solution was concentrated to dryness and then subjected to column chromatography. The eluent was dichloromethane:methanol = 20:1, and the compound of Example 11 was obtained: 65 mg, with a yield of 26%. 1 1H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 11.19 (s, 1H), 9.34 (s, 1H), 8.98 (d, J = 8.0 Hz, 1H), 8.71 (s, 1H), 7.88 (d, J = 9.0 Hz, 2H), 7.73 (d, J = 8.0 Hz, 1H), 7.51 (t, J = 8.5 Hz, 1H), 7.30 (d, J = 8.8 Hz, 2H), 7.10 (t, J = 7.0 Hz, 1H), 6.92 (s, 1H), 4.45 (s, 1H), 3.50 (s, 6H), 2.81 (s, 3H), 2.43 (s, 6H). ESI-MS m / z: 533.2 [M+H] + .

[0111] Example 12

[0112]

[0113] B-1 (150 mg, 0.47 mmol), 4-(4-aminobenzoyl)piperazine-1-carbodithioic acid 2-(dimethylamino)ethyl ester (198 mg, 0.564 mmol), potassium carbonate (195 mg, 1.41 mmol), Xphos (22 mg, 0.047 mmol) and Pd2(dba)3 (22 mg, 0.0235 mmol) were dissolved in 6 mL of tert-butanol, protected by nitrogen, and stirred with an external bath at 100 °C. After reacting for 15 h, the reaction was stopped. The reaction solution was concentrated in vacuo and then subjected to column chromatography. The eluent was dichloromethane:methanol = 20:1, and the compound of Example 12 was obtained: 39 mg, yield 13%. 1 HNMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 11.22 (s, 1H), 9.40 (s, 1H), 9.00 (d, J = 8.5 Hz, 1H), 8.73 (q, J = 5.2 Hz, 1H), 7.93 (d, J = 8.3 Hz, 2H), 7.76 (d, J = 7.9 Hz, 1H), 7.54 (t, J = 7.9 Hz, 1H), 7.41 (d, J = 8.3 Hz, 2H), 7.13 (t, J = 7.7 Hz, 1H), 6.95 (s, 1H), 4.33 (s, 2H), 4.05 (s, 2H), 3.69 (s, 4H), 3.43 (t, J = 6.7 Hz, 2H), 2.83 (d, J = 4.4 Hz, 3H), 2.58 (t, J = 7.0 Hz, 2H), 2.22 (s, 6H). ESI-MS m / z: 636.2 [M+H] + .

[0114] Example 13

[0115]

[0116] B-1 (150 mg, 0.47 mmol), 4-aminobenzoylpiperazine (115 mg, 0.564 mmol), potassium carbonate (195 mg, 1.41 mmol), Xphos (22 mg, 0.047 mmol) and Pd2(dba)3 (22 mg, 0.0235 mmol) were dissolved in 6 mL of tert-butanol, protected by nitrogen, and stirred with an external bath at 100 °C. After reacting for 15 h, the reaction was stopped. The reaction solution was concentrated in vacuo and then subjected to column chromatography. The eluent was dichloromethane:methanol = 20:1, and the compound of Example 13 was obtained: 44 mg, yield 19%. 11H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 11.20 (s, 1H), 9.33 (s, 1H), 8.99 (d, J = 8.4 Hz, 1H), 8.72 (q, J = 4.4 Hz, 1H), 7.87 (d, J = 8.5 Hz, 2H), 7.73 (d, J = 7.6 Hz, 1H), 7.51 (t, J = 7.7 Hz, 1H), 7.29 (d, J = 8.5 Hz, 2H), 7.10 (t, J = 7.5 Hz, 1H), 6.92 (s, 1H), 3.43 (s, 4H), 2.81 (d, J = 4.4 Hz, 3H), 2.69 (s, 4H). ESI-MS m / z: 489.2 [M+H] + .

[0117] Example 14

[0118]

[0119] B-1 (150 mg, 0.47 mmol), tert-butyl 4-(4-aminobenzoyl)piperazine-1-carboxylate (172 mg, 0.564 mmol), potassium carbonate (195 mg, 1.41 mmol), Xphos (22 mg, 0.047 mmol) and Pd2(dba)3 (22 mg, 0.0235 mmol) were dissolved in 6 mL of tert-butanol, protected by nitrogen, and stirred with an external bath at 100 °C. After reacting for 15 h, the reaction was stopped. The reaction solution was concentrated in vacuo and then purified by column chromatography. The eluent was dichloromethane:methanol = 20:1, and the compound of Example 14 was obtained: 199 mg, yield 72%. 1 1H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 11.20 (s, 1H), 9.35 (s, 1H), 8.98 (d, J = 8.6 Hz, 1H), 8.71 (s, 1H), 7.89 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 8.8 Hz, 1H), 7.57–7.48 (m, 1H), 7.33 (d, J = 8.7 Hz, 2H), 7.15–7.07 (m, 1H), 6.92 (s, 1H), 3.50 (s, 4H), 3.37 (s, 4H), 2.80 (s, 3H), 1.41 (s, 9H). ESI-MS m / z: 589.3 [M+H] + .

[0120] Example 15

[0121]

[0122] B-1 (150 mg, 0.47 mmol), 3-(morpholine-4-carbonyl)aniline (116 mg, 0.564 mmol), potassium carbonate (195 mg, 1.41 mmol), Xphos (22 mg, 0.047 mmol), and Pd2(dba)3 (22 mg, 0.0235 mmol) were dissolved in 6 mL of tert-butanol, protected by nitrogen, and stirred with an external bath at 100 °C. After reacting for 15 h, the reaction was stopped. The reaction solution was concentrated by rotary evaporation and then purified by column chromatography. The eluent was dichloromethane:methanol = 20:1, and 75 mg of the compound of Example 15 was obtained, with a yield of 33%. 1 H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 11.14 (s, 1H), 9.22 (s, 1H), 8.99 (d, J = 8.4 Hz, 1H), 8.69 (s, 1H), 7.91 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 6.92 (d, J = 7.3 Hz, 2H), 3.59 (s, 6H), 3.39 (s, 2H), 2.81 (s, 3H). ESI-MS m / z: 490.19 [M + H] + .

[0123] Example 16

[0124]

[0125] B-1 (150 mg, 0.47 mmol), 3-[(4-methyl-1-piperazinyl)carbonyl]aniline (123 mg, 0.564 mmol), potassium carbonate (195 mg, 1.41 mmol), Xphos (22 mg, 0.047 mmol), and Pd2(dba)3 (22 mg, 0.0235 mmol) were dissolved in 6 mL of tert-butanol, protected by nitrogen, and stirred with an external bath at 100 °C. After reacting for 15 h, the reaction was stopped. The reaction solution was concentrated by rotary evaporation and then purified by column chromatography. The eluent was dichloromethane:methanol = 20:1, and 70 mg of the compound of Example 16 was obtained, with a yield of 30%. 11H NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1H), 11.11 (s, 1H), 9.22 (s, 1H), 8.98 (d, J = 8.4 Hz, 1H), 8.77–8.64 (m, 1H), 7.95–7.81 (m, 2H), 7.73 (d, J = 9.5 Hz, 1H), 7.48 (t, J = 8.6 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.18–7.05 (m, 1H), 6.96–6.79 (m, 2H), 3.60 (s, 2H), 3.36 (s, 2H), 2.81 (d, J = 4.4 Hz, 3H), 2.28 (s, 4H), 2.18 (s, 3H). ESI-MS m / z: 503.22 [M+H] + .

[0126] Example 17

[0127]

[0128] B-1 (150 mg, 0.47 mmol), 2-(4-aminophenyl)-1-morpholinoethan-1-one (124 mg, 0.564 mmol), potassium carbonate (195 mg, 1.41 mmol), Xphos (22 mg, 0.047 mmol) and Pd2(dba)3 (22 mg, 0.0235 mmol) were dissolved in 6 mL of tert-butanol, protected by nitrogen, and stirred with an external bath at 100 °C. After reacting for 15 h, the reaction was stopped. After the reaction solution was evaporated to dryness, it was subjected to column chromatography. The eluent was dichloromethane:methanol = 20:1, and the compound of Example 17 was obtained: 28 mg, yield 11.7%. 1 1H NMR (400 MHz, DMSO-d6) δ 11.47 (s, 1H), 11.09 (s, 1H), 9.07–8.99 (m, 2H), 8.74–8.68 (m, 1H), 7.73 (dd, J = 8.3, 3.3 Hz, 3H), 7.49 (t, J = 7.0 Hz, 1H), 7.10 (m, 3H), 6.88 (s, 1H), 3.66 (s, 2H), 3.60–3.43 (m, 8H), 2.82 (d, J = 4.5 Hz, 3H). ESI-MS m / z 504.2 [M+H] + .

[0129] Example 18

[0130]

[0131] B-1 (150 mg, 0.47 mmol), 2-(4-aminophenyl)-1-(4-methylpiperazin-1-yl)ethan-1-one (131 mg, 0.564 mmol), potassium carbonate (195 mg, 1.41 mmol), Xphos (22 mg, 0.047 mmol) and Pd2(dba)3 (22 mg, 0.0235 mmol) were dissolved in 6 mL of tert-butanol, protected by nitrogen, and stirred with an external bath at 100 °C. After reacting for 15 h, the reaction was stopped. The reaction solution was concentrated by rotary evaporation and then subjected to column chromatography. The eluent was dichloromethane:methanol = 20:1, and the compound of Example 18 was obtained: 89 mg, with a yield of 37%. 1 HNMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 11.09 (s, 1H), 9.03 (d, J = 9.9 Hz, 2H), 8.71 (q, J = 5.1, 4.5 Hz, 1H), 7.76–7.71 (m, 3H), 7.49 (t, J = 7.9 Hz, 1H), 7.12 (dd, J = 7.8, 2.9 Hz, 3H), 6.88 (s, 1H), 3.65 (s, 2H), 3.48 (d, J = 3.9 Hz, 4H), 2.82 (d, J = 4.4 Hz, 3H), 2.23 (dd, J = 8.7, 5.0 Hz, 4H), 2.16 (s, 3H). ESI-MS m / z 517.2 [M+H] + .

[0132] Example 19

[0133]

[0134] B-1 (150 mg, 0.47 mmol), 2-(4-aminophenyl)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethan-1-one (148 mg, 0.564 mmol), potassium carbonate (195 mg, 1.41 mmol), Xphos (22 mg, 0.047 mmol) and Pd2(dba)3 (22 mg, 0.0235 mmol) were dissolved in 6 mL of tert-butanol, protected by nitrogen, and stirred with an external bath at 100 °C. After reacting for 15 h, the reaction was stopped. The reaction solution was concentrated by rotary evaporation and then subjected to column chromatography. The eluent was dichloromethane:methanol = 20:1, and the compound of Example 19 was obtained: 89 mg, with a yield of 35%. 1HNMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 11.10 (s, 1H), 9.10–8.94 (m, 2H), 8.75–8.64 (m, 1H), 7.76–7.66 (m, 3H), 7.48 (t, J = 7.7 Hz, 1H), 7.09 (t, J = 8.5 Hz, 3H), 6.87 (s, 1H), 4.43 (t, J = 5.8 Hz, 1H), 3.63 (s, 2H), 3.52–3.39 (m, 6H), 2.81 (d, J = 4.2 Hz, 3H), 2.38–2.25 (m, 6H). ESI-MS m / z: 547.2 [M+H] + .

[0135] Example 20

[0136]

[0137] B-1 (150 mg, 0.47 mmol), 2-(4-aminophenyl)-1-(piperazin-1-yl)ethan-1-one (123 mg, 0.564 mmol), potassium carbonate (195 mg, 1.41 mmol), Xphos (22 mg, 0.047 mmol) and Pd2(dba)3 (22 mg, 0.0235 mmol) were dissolved in 6 mL of tert-butanol, protected by nitrogen, and stirred with an external bath at 100 °C. After reacting for 15 h, the reaction was stopped. The reaction solution was concentrated to dryness and then subjected to column chromatography. The eluent was dichloromethane:methanol = 20:1, and the compound of Example 20 was obtained: 47 mg, with a yield of 20%. 1 HNMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 11.10 (s, 1H), 9.09–8.98 (m, 2H), 8.73 (s, 1H), 7.78–7.68 (m, 3H), 7.48 (t, J = 7.7 Hz, 1H), 7.16–7.06 (m, 3H), 6.87 (s, 1H), 3.64 (s, 2H), 3.47 (s, 4H), 2.81 (s, 3H), 2.72 (s, 2H), 2.67 (s, 2H). ESI-MS m / z: 503.22 [M+H] + .

[0138] Example 21

[0139]

[0140] B-1 (150 mg, 0.47 mmol), 2-(3-aminophenyl)-1-morpholin-4-yl-ethanone (124 mg, 0.564 mmol), potassium carbonate (195 mg, 1.41 mmol), Xphos (22 mg, 0.047 mmol), and Pd2(dba)3 (22 mg, 0.0235 mmol) were dissolved in 6 mL of tert-butanol. Under nitrogen protection, the mixture was stirred with an external bath at 100 °C. After reacting for 15 h, the reaction was stopped. The reaction solution was concentrated in vacuo and then purified by column chromatography. The eluent was dichloromethane:methanol = 20:1, and the compound of Example 21 was obtained: 71 mg, yield 30%. 1 H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 11.09 (s, 1H), 9.10 (s, 1H), 9.02 (d, J = 8.4 Hz, 1H), 8.71 (d, J = 4.6 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.50 (d, J = 7.1 Hz, 2H), 7.21 (d, J = 7.8 Hz, 1H), 7.10 (d, J = 7.5 Hz, 1H), 6.89 (t, J = 2.5 Hz, 1H), 6.77 (d, J = 7.5 Hz, 1H), 3.66 (s, 2H), 3.55 (d, J = 4.6 Hz, 2H), 3.47 (s, 6H), 2.81 (d, J = 4.4 Hz, 3H). ESI-MS m / z: 504.21 [M + H] + .

[0141] Example 22

[0142]

[0143] B-1 (150 mg, 0.47 mmol), 2-(3-aminophenyl)-1-(4-methylpiperazin-1-yl)ethan-1-one (131 mg, 0.564 mmol), potassium carbonate (195 mg, 1.41 mmol), Xphos (22 mg, 0.047 mmol), and Pd2(dba)3 (22 mg, 0.0235 mmol) were dissolved in 6 mL of tert-butanol. Under nitrogen protection, the mixture was stirred with an external bath at 100 °C. After reacting for 15 h, the reaction was stopped. The reaction solution was concentrated in vacuo and then purified by column chromatography. The eluent was dichloromethane:methanol = 20:1, and the compound of Example 22 was obtained: 80 mg, yield 33%. 11H NMR (400 MHz, DMSO-d6) δ 11.52 (s, 1H), 11.13 (s, 1H), 9.10 (s, 1H), 9.05 (d, J = 8.4 Hz, 1H), 8.72 (d, J = 4.6 Hz, 1H), 7.84 (d, J = 2.7 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.53–7.48 (m, 2H), 7.21 (t, J = 7.9 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 6.90 (t, J = 2.5 Hz, 1H), 6.78 (d, J = 7.5 Hz, 1H), 3.67 (s, 2H), 3.48 (t, J = 4.8 Hz, 4H), 2.83 (d, J = 4.5 Hz, 3H), 2.27 (d, J = 4.7 Hz, 2H), 2.22 (d, J = 5.0 Hz, 2H), 2.16 (s, 3H). ESI-MS m / z: 517.24 [M+H] + .

[0144] Example 23

[0145]

[0146] B-1 (150 mg, 0.47 mmol), 2-(3-aminophenyl)-1-(piperazin-1-yl)ethan-1-one (123 mg, 0.564 mmol), potassium carbonate (195 mg, 1.41 mmol), Xphos (22 mg, 0.047 mmol), and Pd2(dba)3 (22 mg, 0.0235 mmol) were dissolved in 6 mL of tert-butanol, protected by nitrogen, and stirred at 100 °C in an external bath. After reacting for 15 h, the reaction was stopped. The reaction solution was concentrated by rotary evaporation and then purified by column chromatography. The eluent was dichloromethane:methanol = 20:1, and 54 mg of the compound of Example 23 was obtained, with a yield of 23%. 1 1H NMR (400 MHz, DMSO-d6) δ 11.49 (s, 1H), 11.19 (s, 1H), 9.06 (s, 1H), 9.04 (d, J = 8.5 Hz, 1H), 8.73–8.62 (m, 1H), 7.78 (d, J = 7.5 Hz, 1H), 7.72 (d, J = 7.4 Hz, 1H), 7.53 (s, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.19 (t, J = 7.7 Hz, 1H), 7.08 (t, J = 7.3 Hz, 1H), 6.87 (s, 1H), 6.76 (d, J = 7.2 Hz, 1H), 3.65 (s, 2H), 3.42 (s, 4H), 2.81 (d, J = 3.8 Hz, 3H), 2.72–2.55 (m, 4H). ESI-MS m / z 503.22: [M+H] + .

[0147] Example 24

[0148]

[0149] B-1 (150 mg, 0.47 mmol), 2-(5-amino-2-chlorophenyl)-1-(4-methylpiperazin-1-yl)ethan-1-one (150 mg, 0.564 mmol), potassium carbonate (195 mg, 1.41 mmol), Xphos (22 mg, 0.047 mmol) and Pd2(dba)3 (22 mg, 0.0235 mmol) were dissolved in 6 mL of tert-butanol, protected by nitrogen, and stirred with an external bath at 100 °C. After reacting for 15 h, the reaction was stopped. After the reaction solution was concentrated to dryness by rotary evaporation, column chromatography was carried out. The eluent was dichloromethane:methanol = 20:1, and the compound of Example 24 was obtained: 90 mg, yield 35%. 1 HNMR(400MHz,DMSO-d6)δ11.50(s,1H),11.18(s,1H),9.22(s,1H),8.97(d,J = 8.4Hz,1H),8.69(q,J = 3.9Hz,1H),7.83(dd,J = 8.8,2.5Hz,1H),7.73(dd,J = 7.9,1.2Hz,1H),7.62(d,J = 2.5Hz,1H),7.54–7.44(m,1H),7.27(d,J = 8.8Hz,1H),7.09(t,J = 7.5Hz,1H),6.90(t,J = 2.3Hz,1H),3.71(s,2H),3.55–3.48(m,4H),2.81(d,J = 4.5Hz,3H),2.33–2.27(m,4H),2.19(s,3H).ESI-MS m / z:551.20[M + H] + .

[0150] Example 25

[0151]

[0152] B-1 (150 mg, 0.47 mmol), 2-(5-amino-2-chlorophenyl)-1-(piperazin-1-yl)ethan-1-one (142 mg, 0.564 mmol), potassium carbonate (195 mg, 1.41 mmol), Xphos (22 mg, 0.047 mmol) and Pd2(dba)3 (22 mg, 0.0235 mmol) were dissolved in 6 mL of tert-butanol, protected by nitrogen, and stirred with an external bath at 100 °C. After reacting for 15 h, the reaction was stopped. After the reaction solution was concentrated to dryness by rotary evaporation, column chromatography was carried out. The eluent was dichloromethane:methanol = 20:1, and the compound of Example 25 was obtained: 48 mg, yield 19%. 1HNMR(400MHz, DMSO-d6) δ 11.50 (s, 1H), 11.31 (s, 1H), 9.22 (s, 1H), 8.99 (d, J = 8.4 Hz, 1H), 8.70 (d, J = 4.3 Hz, 1H), 7.81 (s, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.67–7.57 (m, 1H), 7.50 (t, J = 7.7 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 6.89 (s, 1H), 3.70 (s, 2H), 3.51 (s, 1H), 3.45 (s, 4H), 2.81 (d, J = 4.4 Hz, 3H), 2.74–2.65 (m, 4H). ESI-MS m / z: 537.19 [M+H] + .

[0153] Example 26

[0154]

[0155] (1) 2,4-Dichloro-5-fluoro-pyrrolo[2,3-d]pyrimidine (317 mg, 1.54 mmol) and 2-amino-N-ethyl-benzamide (305 mg, 1.86 mmol) were dissolved in 25 ml of MeCN, and DIPEA (0.53 ml, 3.08 mmol, 2 eq) was added. The reaction mixture was heated under reflux with stirring in an external bath. After 40 h of reaction, the reaction was stopped, stirred overnight at room temperature, and then filtered to obtain white solid B-2: 190 mg, yield 37%. 1 HNMR(400MHz, DMSO-d6) δ 11.94 (s, 1H), 11.91 (s, 1H), 8.84 (s, 1H), 8.71 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.57 (t, J = 7.9 Hz, 1H), 7.31 (s, 1H), 7.16 (t, J = 7.5 Hz, 1H), 3.34–3.27 (m, 2H), 1.14 (t, J = 7.2 Hz, 3H). ESI-MS m / z: 334.08 [M+H] + .

[0156] (2) B-2 (157 mg, 0.47 mmol), m-aminacetanilide (85 mg, 0.564 mmol), potassium carbonate (195 mg, 1.41 mmol), Xphos (22 mg, 0.047 mmol), and Pd2(dba)3 (22 mg, 0.0235 mmol) were dissolved in 6 mL of tert-butanol, protected by nitrogen, and stirred with an external bath at 100 °C. The reaction was stopped after 15 h. After the reaction solution was evaporated to dryness, column chromatography was performed. The eluent was dichloromethane:methanol = 20:1, and 21 mg of the compound of Example 26 was obtained, with a yield of 10%. 1 H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 11.10 (s, 1H), 9.85 (s, 1H), 9.13 (s, 1H), 9.08 (d, J = 8.2 Hz, 1H), 8.75 (s, 1H), 7.81 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.22–7.10 (m, 2H), 7.08 (d, J = 7.5 Hz, 1H), 6.88 (s, 1H), 3.34–3.25 (m, 2H), 2.04 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H). ESI-MS m / z: 448.18 [M+H] + .

[0157] Example 27

[0158]

[0159] (1) 2,4-Dichloro-5-fluoro-pyrrolo[2,3-d]pyrimidine (317 mg, 1.54 mmol) and 2-amino-N,5-dimethylbenzamide (305 mg, 1.86 mmol) were dissolved in 25 ml of MeCN, and DIPEA (0.53 ml, 3.08 mmol, 2 eq) was added. The mixture was stirred with an external bath under reflux. The reaction was stopped after 40 h. After stirring at room temperature overnight, filtration was performed to obtain 323 mg of white solid B-3, with a yield of 63%. 1 H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 11.84 (s, 1H), 8.79 (s, 1H), 8.59 (d, J = 8.4 Hz, 1H), 7.60 (s, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.29 (s, 1H), 2.80 (d, J = 3.7 Hz, 3H), 2.33 (s, 3H). ESI-MS m / z: 334.08 [M+H] + .

[0160] (2) B-3 (157 mg, 0.47 mmol), m-aminacetanilide (85 mg, 0.564 mmol), potassium carbonate (195 mg, 1.41 mmol), Xphos (22 mg, 0.047 mmol), and Pd2(dba)3 (22 mg, 0.0235 mmol) were dissolved in 6 mL of tert-butanol. Under nitrogen protection, the mixture was stirred with an external bath at 100 °C. After reacting for 15 h, the reaction was stopped. The reaction solution was concentrated by rotary evaporation and then subjected to column chromatography. The eluent was dichloromethane:methanol = 20:1, and the compound of Example 27 was obtained: 44 mg, with a yield of 21%. 1 H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H), 11.04 (s, 1H), 9.84 (s, 1H), 9.07 (s, 1H), 8.94 (d, J = 8.0 Hz, 1H), 8.66 (s, 1H), 7.78 (s, 1H), 7.62 (d, J = 7.2 Hz, 1H), 7.55 (s, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.21–7.08 (m, 2H), 6.85 (s, 1H), 2.79 (s, 3H), 2.33 (s, 3H), 2.03 (s, 3H). ESI-MS m / z: 448.18 [M + H] + .

[0161] Example 28

[0162]

[0163] (1) 2,4-Dichloro-5-fluoro-pyrrolo[2,3-d]pyrimidine (317 mg, 1.54 mmol) and 2-amino-5-fluoro-N-methylbenzamide (312 mg, 1.86 mmol) were dissolved in 25 ml of MeCN, and DIPEA (0.53 ml, 3.08 mmol, 2 eq) was added. The mixture was stirred with an external bath under reflux. After reacting for 40 h, the reaction was stopped. After stirring at room temperature overnight, the mixture was filtered to obtain white solid B-4: 264 mg, with a yield of 51%. 1 HNMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 11.77 (s, 1H), 8.86 (s, 1H), 8.71 (dd, J = 7.7, 5.7 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.30 (s, 1H), 2.80 (d, J = 3.3 Hz, 3H). ESI-MS m / z: 338.05 [M + H] + .

[0164] (2) B-4 (158 mg, 0.47 mmol), m-aminacetanilide (85 mg, 0.564 mmol), potassium carbonate (195 mg, 1.41 mmol), Xphos (22 mg, 0.047 mmol) and Pd2(dba)3 (22 mg, 0.0235 mmol) were dissolved in 6 mL of tert-butanol, protected by nitrogen, and stirred with an external bath at 100 °C. After reacting for 15 h, the reaction was stopped. After the reaction solution was evaporated to dryness, it was subjected to column chromatography. The eluent was dichloromethane:methanol = 20:1, and the compound of Example 28 was obtained: 42 mg, yield 20%. 1 H NMR (400 MHz, DMSO-d6) δ 11.35 (s, 1H), 11.08 (s, 1H), 9.83 (s, 1H), 9.10 (s, 2H), 8.77 (d, J = 4.5 Hz, 1H), 7.79 (s, 1H), 7.59 (t, J = 10.4 Hz, 2H), 7.26 (t, J = 7.2 Hz, 1H), 7.16 (t, J = 8.0 Hz, 1H), 7.08 (d, J = 7.9 Hz, 1H), 6.86 (s, 1H), 2.79 (d, J = 4.4 Hz, 3H), 2.02 (s, 3H). ESI-MS m / z: 452.16 [M+H] + .

[0165] Example 29

[0166]

[0167] (1) 2,4-Dichloro-5-fluoro-pyrrolo[2,3-d]pyrimidine (317 mg, 1.54 mmol) and 2-amino-5-chloro-N-methylbenzamide (342 mg, 1.86 mmol) were dissolved in 25 ml of MeCN, and DIPEA (0.53 ml, 3.08 mmol, 2 eq) was added. Stirred with an external bath under reflux, the reaction was stopped after 40 h, stirred at room temperature overnight and then filtered to obtain white solid B-5: 223 mg, yield 41%.

[0168] (2) B-5 (166 mg, 0.47 mmol), m-aminacetanilide (85 mg, 0.564 mmol), potassium carbonate (195 mg, 1.41 mmol), Xphos (22 mg, 0.047 mmol) and Pd2(dba)3 (22 mg, 0.0235 mmol) were dissolved in 6 mL of tert-butanol, protected by nitrogen, and stirred with an external bath at 100 °C. After reacting for 15 h, the reaction was stopped. After the reaction solution was evaporated to dryness, it was subjected to column chromatography. The eluent was dichloromethane:methanol = 20:1, and the compound of Example 29 was obtained: 48 mg, yield 22%. 11H NMR (400 MHz, DMSO-d6) δ 11.51 (s, 1H), 11.13 (s, 1H), 9.86 (s, 1H), 9.15 (t, J = 4.0 Hz, 2H), 8.85 (d, J = 4.0 Hz, 1H), 7.82 (d, J = 6.5 Hz, 2H), 7.60 (d, J = 8.3 Hz, 1H), 7.44 (d, J = 9.0 Hz, 1H), 7.18 (t, J = 8.0 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.89 (s, 1H), 2.81 (d, J = 3.9 Hz, 3H), 2.04 (s, 3H). ESI-MS m / z: 468.13 [M+H] + .

[0169] Effect Verification Example 1: Adhesion Plaque Kinase (FAK) Inhibition Activity Test

[0170] Experimental Method: A 50 μL reaction system was composed of 40 mM Tris (pH 7.4), 10 nM MgCl2, 0.1 mg / mL BSA, 1 mM DTT, 10 μM ATP, 240 ng FAK, 0.2 mg / mL Poly(Glu1Tyr), and the compound to be tested at various concentrations. The concentration gradient of the compound was 0.1 nM, 0.33 nM, 1 nM, 3.3 nM, 10 nM, 33 nM, 100 nM, 333 nM, 1 μM. After the reaction system reacted at 30 °C for 120 min, 50 μL of Kinase-Glo Plus detection reagent was added to the system, and the reaction was carried out at 30 °C for 10 min. The luminescence was detected in the Luminecesce mode of an MD-SpectraMax M5 multi-functional microplate reader, and the data was collected. According to the formula enzyme activity % = [(Lu 无酶 —Lu 加药 ) / (Lu 无酶 —Lu 有酶无药 )]*100%, the enzyme activity at each concentration was calculated, and then processed with Graphpad Prism5 software to fit and obtain the IC 50 value.

[0171] The experimental results showed that the above compound had significant inhibitory activity against adhesion plaque kinase (FAK) (as shown in Table 1).

[0172] Table 1. Half-maximal inhibitory concentration (IC 50 ) of the compounds in Examples 1-29 against FAK

[0173]

[0174]

[0175] In Table 1, PF-562271, an FAK inhibitor that has entered clinical research, is used as a positive control.

[0176] Effect verification example 2: Anti-tumor cell proliferation activity test

[0177] Experimental method: Tumor cells were routinely cultured in DMEM medium supplemented with 10% fetal bovine serum (FBS) in a sterile incubator at 37°C and 5% carbon dioxide saturated humidity. After the experiment started, cells in the logarithmic growth phase were taken, digested with 0.25% trypsin, and the cell concentration was adjusted to 50,000 cells / mL with medium after centrifugation. Then, the cells were inoculated into a 96-well culture plate, 100 μL of cell suspension per well, and cultured overnight in the incubator to allow the cells to adhere to the wall. After that, different concentrations of the test drug were added to the wells, with concentration gradients of 100 μΜ, 50 μΜ, 20 μΜ, 10 μΜ, 1 μΜ, and 0.1 μΜ, and there were 4 replicates for each concentration. At the same time, a negative control without drug addition was set. The cells after adding the drug were cultured in an incubator at 37°C and 5% carbon dioxide saturated humidity. After 48 h, 10 μL of 5 mg / mL MTT solution was added to each well and cultured for another 4 h. After sufficient reaction to form formazan crystals, the culture medium was aspirated, and 150 μL of DMSO was added to each well to dissolve the formazan. After thorough mixing, the absorbance OD value at a wavelength of 490 nM of each well was measured with an enzyme-linked immunosorbent assay (ELISA) reader. According to the formula, the cell proliferation inhibition rate % = [(OD 阴性 - OD 给药 ) / (OD 阴性 - OD 调零 )] * 100%, the proliferation inhibition rate of each concentration was calculated, and then processed with Graphpad Prism5 software to fit and obtain the IC 50 value.

[0178] The experimental results showed that the above compounds significantly inhibited the growth of tumor cells (as shown in Table 2)

[0179] Table 2. Half-maximal inhibitory concentration (IC50) of the compounds in Examples 1 - 29 against tumor cell lines

[0180]

[0181]

[0182] Effect verification example 3: Solubility experiment

[0183] Determination method: Drawing of the standard curve of the test compound: Weigh accurately about 1 mg of the test compound standard, dissolve it with DMSO to prepare a 20 mg / mL solution, and then dilute it with chromatographic grade methanol to 6 concentrations (200 μg / mL, 100 μg / mL, 50 μg / mL, 25 μg / mL, 12.5 μg / mL, 6.25 μg / mL). After filtering through a 0.22 μm ultrafiltration membrane, perform on-machine detection. Take the area under the curve (Area) as the abscissa, denoted as x, and the concentration of the test compound (μg / mL) as the ordinate, denoted as y, to draw the standard curve of each compound. Preparation of the test compound: Take a small amount of the compound (about 0.5 mg) in a 5 mL centrifuge tube, number it in sequence, add 2 mL of PBS solution to the centrifuge tube, and seal the centrifuge tube with a sealing film; place the centrifuge tube in an ultrasonic device and ultrasonicate at 37 °C for 30 min to fully dissolve the compound, then let it stand at room temperature for 1 h; take the supernatant, filter it through a 0.22 μm ultrafiltration membrane and perform on-machine detection; substitute the area under the curve into the corresponding standard curve to calculate the solubility of each compound in PBS.

[0184] The experimental results show that the solubility of some of the above compounds is acceptable (as shown in Table 3)

[0185] Table 3. Solubility data of the compounds in some embodiments

[0186]

[0187] The embodiments described above are only descriptions of the preferred modes of the present invention, and do not limit the scope of the present invention. Without departing from the design spirit of the present invention, various deformations and improvements made by those of ordinary skill in the art to the technical solutions of the present invention shall fall within the protection scope determined by the claims of the present invention.

Claims

1. A compound represented by formula (I): or a stereoisomer thereof or a pharmaceutically acceptable salt thereof; Among them, R1 is selected from hydrogen, deuterium, halogen, nitro, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or C1-C3 deuterated alkoxy; R 2-1 , R 2-2 , R 2-3 , R 2-4 and R 2-5 Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, nitro, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or C1-C3 deuterated alkoxy; L is selected from a bond, -CO-, -CH2CO-, -NHCO- or -CH2-; R3 is selected from hydrogen, deuterium, halogen, hydroxy, nitro, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or C1-C3 deuterated alkoxy; R 3-1 selected from hydrogen, deuterium, halogen, hydroxy, nitro, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 deuterated alkoxy, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl or -P(=O)(OR 4-1 )(OR 4-2 ), where the C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 deuterated alkoxy, C 3-1 cycloalkyl and 3-8 membered heterocycloalkyl in R 3-8 are optionally substituted with one or more R5; R 4-1 and R 4-2 are each independently selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 deuterated alkyl; R5 is selected from hydrogen, deuterium, halogen, hydroxy, nitro, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 deuterated alkoxy, C1-C3 hydroxyalkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, -COOR 5-1 , -C(=S)SCH2CH2NR 5-2 R 5-3 , and the C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 deuterated alkoxy, C1-C3 hydroxyalkyl, C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl are optionally substituted by one or more of hydrogen, deuterium, halogen, hydroxy, nitro, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 deuterated alkoxy, C1-C3 hydroxyalkyl; R 5-1 、R 5-2 and R 5-3 are each independently selected from hydrogen, C1-C4 alkyl, C1-C3 haloalkyl or C1-C3 deuterated alkyl; x is 0, 1, 2, 3 or 4.

2. The compound according to claim 1, having a structure represented by formula (II-1) or formula (II-2): Wherein, R 3-2 、R 3-3 、R 3-4 and R 3-5 are each independently selected from hydrogen, deuterium, halogen, hydroxy, nitro, cyano, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy or C1-C3 deuterated alkoxy; R 2-1 、R 2-3 、L、R 3-1 Same as R in Claim 1 2-1 、R 2-3 、L、R 3-1 。 3. The compound according to claim 2, wherein R 2-1 is selected from C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 deuterated alkyl; and / or, R 2-3 is selected from hydrogen, deuterium, halogen, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 deuterated alkyl.

4. The compound according to claim 2, wherein R 3-2 , R 3-3 , R 3-4 and R 3-5 are each independently selected from hydrogen, chlorine or methoxy; R 3-1 selected from C1-C3 alkyl, C1-C3 alkoxy, 3-8 membered heterocycloalkyl or -P(=O)(OR 4-1 )(OR 4-2 ), wherein the 3-8 membered heterocycloalkyl is optionally substituted with one or more R5; R 4-1 and R 4-2 each independently selected from C1-C3 alkyl; R5 is selected from hydrogen, C1-C3 alkyl, C1-C3 hydroxyalkyl, 3-8 membered heterocycloalkyl, -COOR 5-1 , -C(=S)SCH2CH2NR 5-2 R 5-3 ; R 5-1 、R 5-2 and R 5-3 are each independently selected from C1-C4 alkyl groups.

5. The compound according to claim 2, wherein R 3-1 is selected from methyl, methoxy, or -P(=O)(OCH2CH3)(OCH2CH3), wherein the is optionally substituted with one or more R5; R5 is selected from hydrogen, methyl, -CH2CH2OH, -COO-tert-butyl, -C(=S)SCH2CH2N(CH3)2.

6. The compound according to claim 2, wherein -L-R 3-1 is selected from methoxy, -CH2P(=O)(OCH2CH3)(OCH2CH3), or -NHCOCH3.

7. The compound according to claim 2, having a structure represented by formula (III):

8. The compound according to claim 2, being one of the following structural formulas:

9. A pharmaceutical composition, characterized in that, The active ingredient comprises the compound according to any one of claims 1 to 8, or its stereoisomer or its pharmaceutically acceptable salt.

10. Use of the compound according to any one of claims 1 to 8 in the preparation of a FAK inhibitor or a medicament for treating breast cancer, ovarian cancer or liver cancer.

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