7-azaindole compound, pharmaceutical composition containing 7-azaindole compound and application of 7-azaindole compound

Abstract

The invention discloses a 7-azaindole compound as shown in a formula I, an optical isomer or pharmaceutically acceptable salt thereof, and also provides a preparation method and application thereof, and the obtained compound shows a certain Menin protein expression down-regulation effect, better cell proliferation inhibition activity and better PK effect.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and relates to a 7-azaindole compound with Menin expression down-regulation activity, and further relates to a pharmaceutical composition of the compound as an active ingredient and application thereof. BACKGROUND

[0002] AML is one of the most common leukemias in adults, accounting for about one-third of all cases. As a rapidly progressive blood and bone marrow cancer, the cancerous white blood cells of AML patients grow rapidly, which not only cannot perform normal functions, but also affect the generation of normal blood cells. The 5-year survival rate of AML patients is the lowest among all leukemia types. MLL gene rearrangement and NPM1 mutation occur in about 40% of AML patients. In addition, MLL rearrangement also occurs in acute lymphoblastic leukemia, including about 80% of infant patients.

[0003] In leukemia with KMT2A gene rearrangement and NPM1 mutation, KMT2A interacts with menin to cause abnormal expression of HOX and MEIS1 genes, thereby causing blocked hematopoietic differentiation and leukemia transformation. Blocking Menin-KMT2A interaction can disrupt the assembly of oncogenic KMT2A wild type or fusion complex on chromatin.

[0004] Menin is encoded by the MEN1 gene and mainly exists in the nucleus, as a scaffold protein, plays a variety of key roles in biological pathways such as cell growth regulation, cell cycle control, genome stability, bone development and hematopoiesis. In the nucleus, it functionally cross-talks with different binding partners to regulate gene transcription and interacts with various signaling pathways, such as TGF (SMADs), NF-kappa B, Wnt (beta-catenin) and other nuclear receptors (estrogen receptor ERa). In the cytoplasm, menin inhibits the activation of receptor tyrosine kinase AKT, SOS1 and ERK signals through various mechanisms.

[0005] Studies have found that Menin inhibitors are effective for leukemia with KMT2A rearrangement (KMT2Ar) and NPM1 mutation (NPM1c), so developing a highly efficient menin inhibitor will bring treatment hope to patients of this subtype. SUMMARY

[0006] The present application provides a class of compounds acting on a new mechanism, the compound of the present application inhibits tumor cell proliferation by down-regulating the expression of Menin protein, and is used for treating and preventing diseases related to Menin protein.

[0007] The present application provides a composition and a preparation comprising the above-mentioned 7-azaindole compound.

[0008] The application also provides a use of the compound, the composition or the preparation in the preparation of a medicament for preventing or treating a disease caused by abnormal Menin pathway.

[0009] The application adopts the following technical scheme:

[0010] The application provides a compound with a general formula I, an optical isomer thereof or a pharmaceutically acceptable salt thereof.

[0011]

[0012] Wherein:

[0013] A is selected from Wherein R2 is selected from optionally substituted hydrogen, hydroxyl, halogen, C1-C4 alkyl, halogen-substituted C1-C4 alkyl, C1-C4 alkoxy, cyano, nitro or -NR3R4, R3 and R4 are each independently hydrogen or C1-C3 alkyl; m is 0, 1, 2; q is 0, 1, 2;

[0014] Z is selected from Wherein W and X are each independently selected from N or CH; R5 and R6 are each independently selected from optionally substituted hydrogen, hydroxyl, halogen, C1-C4 alkyl, halogen-substituted C1-C4 alkyl, C1-C4 alkoxy, cyano, nitro; R7 is selected from hydrogen, C1-C4 alkyl, halogen-substituted C1-C4 alkyl, C1-C4 alkoxy, hydroxyl-substituted C1-C4 alkyl; k is 1, 2, 3, 4, 5;

[0015] E is selected from optionally substituted hydrogen, C1-C4 alkyl, halogen or Wherein R8 is selected from hydrogen, C1-C4 alkyl; p is selected from 0-5; M and Y are each independently selected from NH or O;

[0016] L is selected from Wherein g is 1, 2, 3; l is 0, 1, 2, 3;

[0017] D is selected from CH2, NH, O or S;

[0018] Q is selected from N or CH;

[0019] n is 1, 2, 3, 4;

[0020] R1 is selected from optionally substituted hydrogen, hydroxyl, halogen, C1-C4 alkyl, halogen-substituted C1-C4 alkyl, C1-C4 alkoxy, cyano, nitro.

[0021] R1is preferably hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy, cyano, nitro.

[0022] As a preference, n = 1.

[0023] As a preference, A is selected from

[0024] As a preference, L is selected from CH, -NH-C(O)-.

[0025] As a preference, E is selected from hydrogen or

[0026] As a preference, Q is selected from N.

[0027] The present application more preferably has the structure shown in general formula II-1, II-2, II-3, or an optical isomer thereof or a pharmaceutically acceptable salt thereof:

[0028]

[0029] Z is selected from wherein W, X are each independently selected from N or CH; R5, R6are each independently selected from optionally substituted hydrogen, hydroxyl, halogen, C1-C4alkyl, halogen-substituted C1-C4alkyl, C1-C4alkoxy, cyano, nitro; R7is selected from hydrogen, C1-C4alkyl, halogen-substituted C1-C4alkyl, C1-C4alkoxy, hydroxyl-substituted C1-C4alkyl; k is 1, 2, 3, 4, 5;

[0030] R2is selected from optionally substituted hydrogen, halogen, C1-C4alkyl, halogen-substituted C1-C4alkyl, C1-C4alkoxy, cyano, nitro;

[0031] R8is selected from hydrogen, C1-C4alkyl; p is selected from 1, 2, 3, 4, 5; M, Y are each independently selected from NH or O.

[0032] As a preference, Z is selected from wherein W, X are each independently selected from N or CH; R5, R6are selected from optionally substituted hydrogen; R7is selected from methyl, ethyl; k is 1, 2, 3, 4, 5.

[0033] As a preference, R2is selected from hydrogen, halogen.

[0034] As a preference, R8is selected from methyl, ethyl, propyl, isopropyl, tert-butyl; p is selected from 0, 1, 2, 3; M, Y are each independently selected from NH or O.

[0035] As a preference, the more preferred compounds of the present application have the following structure:

[0036]

[0037] As a more specific preference, k is 1, 2, 3, X is CH, and R6 is H.

[0038] The application further more preferably includes compounds of any one of the following structures:

[0039]

[0040]

[0041] Definitions and Descriptions

[0042] The following terms and phrases, as used herein, are intended to have the following meanings unless otherwise indicated. A particular term or phrase should not be construed as being indefinite or unclear in the absence of a specific definition, but should be understood in accordance with the ordinary meaning. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0043] The term "pharmaceutically acceptable" pertains to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0044] The term "pharmaceutically acceptable salt" means a salt of a compound of the application which is found to possess the specific substituents of the compounds of the application and which is prepared from relatively non-toxic, inorganic or organic acids or bases. Where the compound of the application contains relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or like salts. Where the compound of the application contains relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids, such as hydrochloric, hydrobromic, nitric, carbonic, boric, sulfuric, sulfamic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, and the like, and organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like; also salts of amino acids such as arginate, asparginate, glutamate, and the like; and salts of organic acids like glucuronic, and the like. Certain specific compounds of the application contain both basic and acidic functionalities, allowing the compounds to be converted into either base or acid addition salts.

[0045] The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound that contains an acidic or basic moiety by conventional chemical methods. Generally, the salt will be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of both.

[0046] The term "isomers" means that the compounds of the present application can occur in specific geometric or stereoisomeric forms. The present application contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)-isomers, as well as the racemic mixtures and other mixtures of the enantiomers or diastereomers, and the like. Further, where the presence of at least one asymmetric carbon atom renders the substance optically active, the application contemplates every individual enantiomeric or diastereomeric form, as well as mixtures thereof in any proportion.

[0047] The term "enantiomeric" or "optical isomer" means stereoisomers which are mirror images of one another unless otherwise stated.

[0048] The term "cis- or trans-isomer" or "geometric isomer" means stereoisomers which arise from the inability of a double bond or ring-forming carbon atom single bond to rotate freely unless otherwise stated.

[0049] The term "diastereomeric" means stereoisomers which have two or more chiral centers and are nonmirror images of one another unless otherwise stated.

[0050] "(D)" or "(+)" means dextrorotatory and "(L)" or "(-)" means levorotatory and "(DL)" or "(rac)" means racemic unless otherwise stated.

[0051] Unless otherwise stated, a solid wedge and a dashed wedge indicate the absolute configuration about a stereogenic center.

[0052] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0053] The term "substituted" means that any one or more hydrogen atoms on the designated atom is replaced with a substituent group, can include deuterium and variations of hydrogen, as long as the valency of the designated atom is properly satisfied and the resulting compound is stable. When the substituent is oxygen (i.e., =0), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that the group can or can not be substituted, and unless otherwise specified, the kinds and number of substituents are any that are chemically possible.

[0054] When any variable (e.g., R) occurs more than one time in a compound or substituent, "each occurrence" is treated as independent of the other occurrences. Thus, for example, if a group is substituted with 0-2 R groups, the group can optionally be substituted with up to two R groups, and each occurrence of R is independent of the others. Furthermore, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0055] When a substituent is recited without the word "by," it is attached to the rest of the molecule by a single bond, e.g., phenyl as a substituent is attached by any one of the carbons of the phenyl ring.

[0056] Unless otherwise specified, the term "alkyl" is used to mean straight or branched chain saturated hydrocarbon groups, which can be mono-substituted (e.g., -CH2F) or poly-substituted (e.g., -CF3), and which can be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methine). Examples of alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.

[0057] Unless otherwise specified, cycloalkyl includes any stable cyclic or polycyclic hydrocarbon group, any carbon atom is saturated, which can be mono-substituted or poly-substituted, and which can be monovalent, divalent, or multivalent. Examples of these cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclodecane, and the like.

[0058] Unless otherwise specified, the term "halogen" by itself or as part of another substituent means a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom.

[0059] Unless otherwise specified, the term "alkoxy" means an alkyl group, as defined herein, attached to the remainder of the molecule through an oxygen atom. Unless otherwise specified, C 1-5Alkoxy groups include C1, C2, C3, C4, and C5 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, sec-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. The alkoxy group can be optionally substituted with one or more substituents described herein.

[0060] In vitro experiments show that the compound provided by the present application has a certain Menin protein expression down-regulation effect, and also has good MV4-11 cell inhibition activity and PK effect, and has a good application prospect in the medical field. DETAILED DESCRIPTION

[0061] The practicability of the present application is illustrated below by examples, and those skilled in the art should understand that, according to the teaching of the prior art, the corresponding technical features are modified or replaced, which still belongs to the scope of the present application.

[0062] Synthesis of intermediate 1d in Example 1

[0063]

[0064] Step one: 4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine 1a (10 g, 35.7 mmol), morpholine (6.2 g, 71.5 mmol), N,N-diisopropylethylamine (13.8 g, 107.3 mmol) were added into the reaction bottle in turn, n-butanol was used as the solvent, and after stirring at 100°C for 12 hours, the reaction was completed. After the reaction was completed, the reaction liquid was poured into 200 mL of water, and the solid was precipitated, filtered and dried to obtain 1b, with a yield of 90%, LCMS (M+H) + = 331.2.

[0065] Step two: under nitrogen protection, intermediate 1b (8 g, 24.2 mmol), 1-N-tert-butoxycarbonylpiperidin-4-boronic acid pinacol ester (11.3 g, 36.4 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.7 g, 2.4 mmol), potassium carbonate (10.1 g, 72.7 mmol) were added into a 500 ml three-necked bottle containing 200 ml of 1,4-dioxane and 50 ml of water in turn, and the reaction system was placed at 100°C and stirred fully overnight. After the reaction was completed and cooled to room temperature, the reaction liquid was poured into 200 mL of water, extracted with ethyl acetate for 3 times, the organic layers were combined, washed with saturated sodium chloride for 2 times, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain 7.5 g of intermediate 1c in the form of a light yellow solid, with a yield of 79%, LCMS (M+H) + = 388.2.

[0066] Step 3: Intermediate 1c (7 g, 18.1 mmol) was dissolved in dichloromethane, and an equal volume of 4N hydrochloric acid in ethyl acetate was added. The reaction was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was directly rotary evaporated to give yellow solid intermediate 1d. LCMS (M+H) + = 288.1.

[0067] Synthesis of Example 2 intermediate 2e

[0068]

[0069] Step 1: p-Fluorothiophenol 2a (5 g, 39.0 mmol), 4-iodopyridine (9.6 g, 46.8 mmol), sodium tert-butoxide (7.5 g, 78.0 mmol) were added into a reaction flask in sequence, dimethyl sulfoxide was used as solvent, stirred at 80 °C for 10 hours. After the reaction was completed, the reaction liquid was poured into 300 mL water, extracted with ethyl acetate for 3 times, combined the organic layers, washed with saturated sodium chloride for 2 times, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography to give white solid 5 g of intermediate 2b, yield 62%, LCMS (M+H) + = 206.1.

[0070] Step 2: 2b (4 g, 19.5 mmol), m-CPBA (8.4 g, 48.8 mmol) were added into a reaction flask in sequence at 0 °C, dichloromethane was used as solvent, stirred at room temperature for 2 hours. After the reaction was completed, the reaction liquid was poured into 200 mL saturated aqueous sodium bicarbonate solution, extracted with dichloromethane for 3 times, combined the organic layers, washed with saturated sodium chloride for 2 times, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography to give white solid 3.6 g of intermediate 2c, yield 77.8%, LCMS (M+H) + = 238.1.

[0071] Step 3: 2c (3 g, 12.6 mmol), 3-hydroxymethylazetidine hydrochloride (2.4 g, 18.9 mmol), potassium carbonate (6.9 g, 50.5 mmol) were added into a reaction flask in sequence, acetonitrile was used as solvent, stirred at 90 °C for 24 hours. After the reaction was completed, water was added, extracted with ethyl acetate for 3 times, combined the organic layers, washed with saturated sodium chloride for 2 times, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography to give white solid 3.1 g of intermediate 2d, yield 77%, LCMS (M+H) + = 305.1.

[0072] Step four: 2d (2 g, 6.5 mmol), triethylamine (1.9 g, 19.7 mmol), methanesulfonyl chloride (1.5 g, 13.1 mmol) were added into the reaction bottle successively at 0 °C, dichloromethane as solvent, then stirred at room temperature for 3 hours, after the reaction was completed, water was added, extracted with dichloromethane for 3 times, combined organic layer, washed with saturated sodium chloride for two times, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography to obtain white solid 2g of intermediate 2e, yield 79%, LCMS (M+H) + = 383.1.

[0073] Synthesis of intermediate 3f in example 3

[0074]

[0075] Step one: under nitrogen protection, intermediate 3a (5 g, 17.8 mmol), 1-N-tert- butyloxycarbonyl piperidin-4-boronic acid pinacol ester (8.3 g, 26.8 mmol), [1,1'- bis (diphenylphosphino) ferrocene] palladium dichloride (1.3 g, 1.7 mmol), potassium carbonate (7.4 g, 53.7 mmol) were added into a 250 ml three-necked bottle containing 120 ml of 1,4-dioxane and 40 ml of water successively, the reaction system was placed at 100 °C and stirred fully overnight, after cooling to room temperature, the reaction liquid was poured into 200 ml of water, extracted with ethyl acetate for 3 times, combined organic layer, washed with saturated sodium chloride for two times, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography to obtain 5 g of intermediate 3b as a light yellow solid, yield 82%, LCMS (M+H) + = 337.1.

[0076] Step two: intermediate 3b (5 g, 14.8 mmol) was dissolved in dichloromethane, an equal volume of 4N hydrochloric acid ethyl acetate solution was added, stirred at room temperature for 2 hours, after the reaction was completed, the solvent was directly rotary evaporated to obtain yellow solid intermediate 3c, LCMS (M+H) + = 237.1.

[0077] Step three: 3c (3 g, 10.9 mmol), 2e (5.1 g, 13.1 mmol), potassium carbonate (4.5 g, 32.9 mmol) were added into the reaction bottle successively, acetonitrile as solvent, stirred at 90 °C for 24 hours, after the reaction was completed, water was added, extracted with ethyl acetate for 3 times, combined organic layer, washed with saturated sodium chloride for two times, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography to obtain 4.2 g of intermediate 3d as a white solid, yield 73%, LCMS (M+H) + = 523.2.

[0078] Step four: 3d (3 g, 5.7 mmol), 3-(Boc-amino)piperidine (1.7 g, 8.6 mmol), N, N- diisopropyl ethylamine (2.2 g, 17.2 mmol) were added into the reaction flask in turn, isopropyl alcohol as solvent, stirred at 80 °C for 10 hours. After the reaction was completed, the solvent was dried and evaporated, water was added and extracted with ethyl acetate for 3 times, the organic layer was combined, washed with saturated sodium chloride twice, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain white solid compound M-4, yield 73%, LCMS (M+H) + = 687.3.

[0079] Step five: intermediate M-4 (3 g, 4.4 mmol) was dissolved in dichloromethane, and an equal volume of 4N hydrochloric acid ethyl acetate solution was added, stirred at room temperature for 2 hours, after the reaction was completed, the solvent was directly dried and evaporated to obtain yellow solid intermediate 3f, LCMS (M+H) + = 587.2.

[0080] Synthesis of intermediate 4a in Example 4

[0081]

[0082] Step one: 3d (2 g, 3.8 mmol), 3-(Boc-aminomethyl)piperidine (1.2 g, 5.7 mmol), N, N- diisopropyl ethylamine (1.4 g, 11.4 mmol) were added into the reaction flask in turn, isopropyl alcohol as solvent, stirred at 80 °C for 10 hours. After the reaction was completed, the solvent was dried and evaporated, water was added and extracted with ethyl acetate for 3 times, the organic layer was combined, washed with saturated sodium chloride twice, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain white solid 2 g of intermediate 4a, yield 74%, LCMS (M+H) + = 701.1.

[0083] Step two: intermediate 4a (2 g, 3.3 mmol) was dissolved in dichloromethane, and an equal volume of 4N hydrochloric acid ethyl acetate solution was added, stirred at room temperature for 2 hours, after the reaction was completed, the solvent was directly dried and evaporated to obtain yellow solid intermediate 4b, LCMS (M+H) + = 601.1.

[0084] Synthesis of intermediate 5a in Example 5

[0085]

[0086] Referring to the synthesis method of intermediate 1d in Example 1, 1-N-tert-butoxycarbonyl piperidine-4-boronic acid pinacol ester was replaced by 4-Boc-amino-1-cyclohexene boronic acid pinacol ester, and finally intermediate 5a was obtained, yield 65%, ESI (M+H) += 300.1.

[0087] Synthesis of intermediate 6a in example 6

[0088]

[0089] Referring to the synthesis method of intermediate 1c in example 1, replace 1-N-tert-butoxycarbonylpiperidin-4-boronic acid pinacol ester with 2-fluoro-4-aminobenzoic acid pinacol ester to obtain intermediate 6a in a yield of 65%, ESI (M+H) + = 314.1.

[0090] Synthesis of intermediate 7a in example 7

[0091]

[0092] Referring to the synthesis method of intermediate 1c in example 1, replace 1-N-tert-butoxycarbonylpiperidin-4-boronic acid pinacol ester with 4-aminobenzoic acid pinacol ester to obtain intermediate 7a in a yield of 70%, ESI (M+H) + = 296.1.

[0093] Synthesis of intermediate 8d in example 8

[0094]

[0095] Step one: 4-methylpiperidine (3.1 g, 30.8 mmol), triethylamine (7.8 g, 77.1 mmol) were added into the reaction bottle in turn, dichloromethane was used as the solvent, and then 8a (5 g, 25.7 mmol) was slowly added. After stirring at room temperature for 2 hours, the reaction was completed. Then 200 mL of saturated aqueous sodium bicarbonate solution was added, and dichloromethane was used for extraction three times. The combined organic layers were washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain 6.2 g of white solid intermediate 8b in a yield of 93%, LCMS (M+H) + = 258.1.

[0096] Step two: 8b (5 g, 19.4 mmol), azetidine-3-carboxylic acid methyl ester hydrochloride (4.4 g, 29.1 mmol), potassium carbonate (8.1 g, 58.3 mmol) were added into the reaction bottle in turn, acetonitrile was used as the solvent, and then stirring was performed at 90°C for 24 hours. After the reaction was completed, water was added, and ethyl acetate was used for extraction three times. The combined organic layers were washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain 5.5 g of white solid intermediate 8c in a yield of 80%, LCMS (M+H) + = 353.1.

[0097] Step three: 8c (5 g, 14.1 mmol), lithium hydroxide (1.7 g, 70.9 mmol) were added into the reaction bottle successively, tetrahydrofuran and water were used as the solvent, stirred at room temperature for 5 hours. After the reaction was completed, the pH was adjusted to 5-6 with 4N hydrochloric acid aqueous solution, dichloromethane was added for extraction three times, the organic layers were combined, washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain 4.5 g of white solid intermediate 8d, with a yield of 93%, LCMS (M+H)+= 339.1.

[0098] Synthesis of intermediate 9a in Example 9

[0099]

[0100] Referring to the synthesis method of intermediate 8d in Example 8, 4-methylpiperidine was replaced by N-methylpiperazine, and finally intermediate 9a was obtained, with a yield of 88%, ESI (M+H) + = 340.1.

[0101] Synthesis of intermediate 10a in Example 10

[0102]

[0103] Step one: p-fluorothiophenol 10a (5 g, 39.0 mmol), bromocyclopropane (9.4 g, 78.1 mmol), sodium tert-butoxide (7.5 g, 78.0 mmol) were added into the reaction bottle successively, dimethyl sulfoxide was used as the solvent, stirred at 80°C for 10 hours, after the reaction was completed, 200 mL of water was added, extracted with ethyl acetate three times, the organic layers were combined, washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain 5 g of white solid intermediate 10b, with a yield of 76%, LCMS (M+H) + = 169.1.

[0104] Step two: 10b (4 g, 23.7 mmol), m-CPBA (12.3 g, 71.1 mmol) were added into the reaction bottle successively at 0°C, dichloromethane was used as the solvent, after stirring at room temperature for 2 hours. After the reaction was completed, 200 mL of saturated sodium bicarbonate aqueous solution was added, extracted with dichloromethane three times, the organic layers were combined, washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain 4.2 g of white solid intermediate 10c, with a yield of 88%, LCMS (M+H) + = 201.1.

[0105] Step 3: 10c (4 g, 19.9 mmol), methyl azetidine-3-carboxylate hydrochloride (4.5 g, 29.9 mmol), potassium carbonate (8.2 g, 59.9 mmol) were added into the reaction bottle successively, acetonitrile as solvent, stirred at 90 °C for 24 hours, after the reaction was completed, water was added, extracted with ethyl acetate for 3 times, combined organic layer, washed with saturated sodium chloride for two times, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography to obtain white solid 5.2 g of intermediate 10d, yield 88%, LCMS (M+H)+= 296.1. + = 296.1.

[0106] Step 4: 10d (5 g, 16.9 mmol), lithium hydroxide (2.1 g, 84.6 mmol) were added into the reaction bottle successively, tetrahydrofuran and water as solvent, stirred at room temperature for 5 hours. After the reaction was completed, 4N hydrochloric acid aqueous solution was used to adjust the pH to 5-6, dichloromethane was added for extraction for 3 times, combined organic layer, washed with saturated sodium chloride for two times, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography to obtain white solid 4.5 g of intermediate 10e, yield 89%, LCMS (M+H)+= 282.1.

[0107] Synthesis of intermediate 11a in example 11

[0108]

[0109] Referring to the synthesis method of intermediate 2e in example 2, 4-iodopyridine was replaced by bromocyclopropane, and finally intermediate 11a was obtained, yield 75%, ESI (M+H) + = 346.1.

[0110] Synthesis of compound M-1 in example 12

[0111]

[0112] Step: 1d (0.3 g, 0.92 mmol), 2e (0.35 g, 0.92 mmol), potassium carbonate (0.38 g, 2.78 mmol) were added into the reaction bottle successively, acetonitrile as solvent, stirred at 90 °C for 24 hours, after the reaction was completed, water was added, extracted with ethyl acetate for 3 times, combined organic layer, washed with saturated sodium chloride for two times, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography to obtain white solid 0.25 g of intermediate M-1, yield 47%, 1H NMR (400 MHz, DMSO-d6) δ 11.58 (d, J = 2.0 Hz, 1H), 8.91 - 8.59 (m, 2H), 8.07 (s, 1H), 7.80 - 7.73 (m, 2H), 7.71 - 7.64 (m, 2H), 6.58 - 6.41 (m, 2H), 6.29 (d, J = 2.0 Hz, 1H), 4.00 (t, J = 8.1 Hz, 2H), 3.75 (dd, J = 5.7, 3.7 Hz, 4H), 3.67 (dd, J = 5.7, 3.6 Hz, 4H), 3.56 (dd, J = 8.2, 5.5 Hz, 2H), 2.93 (t, J = 7.3 Hz, 1H), 2.86 (d, J = 11.1 Hz, 2H), 2.54 (d, J = 7.6 Hz, 2H), 1.99 (t, J = 11.4 Hz, 2H), 1.88 (d, J = 12.5 Hz, 2H), 1.64 (td, J = 12.3, 3.5 Hz, 2H). LC-MS (ESI): m / z 574.2 [M+H] + .

[0113] Synthesis of compound M-2 in Example 13

[0114]

[0115] Referring to the synthesis method of compound M-1 in Example 12, 2e is replaced by 11a, and finally compound M-2 is obtained in a yield of 54%, 1 H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 8.07 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 6.60 - 6.41 (m, 2H), 6.30 (d, J = 2.0 Hz, 1H), 4.01 (t, J = 7.9 Hz, 2H), 3.75 (dd, J = 5.7, 3.7 Hz, 4H), 3.67 (dd, J = 5.5, 3.4 Hz, 4H), 3.56 (dd, J = 7.9, 5.5 Hz, 2H), 2.95 (s, 1H), 2.89 (d, J = 11.0 Hz, 2H), 2.63 (s, 1H), 2.57 (d, J = 7.2 Hz, 2H), 2.01 (t, J = 11.6 Hz, 2H), 1.89 (d, J = 12.6 Hz, 2H), 1.70 - 1.57 (m, 2H), 0.98 (dd, J = 5.1, 2.2 Hz, 2H), 0.91 (dd, J = 7.9, 2.3 Hz, 2H). LC-MS (ESI): m / z 537.2 [M+H] + .

[0116] Synthesis of compound M-3 in Example 14

[0117]

[0118] Step: 3f (0.3 g, 0.48 mmol), triethylamine (0.15 g, 1.44 mmol), dimethylpyrocarbonate (0.09 g, 0.72 mmol) were added into the reaction flask at 0 °C, and stirred at room temperature for 2 h. After the reaction was completed, 200 mL of saturated aqueous sodium bicarbonate solution was added, and extracted with dichloromethane three times, and the combined organic layer was washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain 0.15 g of compound M-3 as a white solid, with a yield of 48%, 1 H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 8.90 - 8.75 (m, 2H), 8.07 (s, 1H), 7.81 - 7.75 (m, 2H), 7.71 (d, J = 8.8 Hz, 2H), 7.29 (d, J = 7.3 Hz, 1H), 6.48 (d, J = 8.9 Hz, 2H), 6.33 (s, 1H), 4.57 - 4.27 (m, 2H), 4.05 (t, J = 8.1 Hz, 2H), 3.60 (t, J = 6.8 Hz, 2H), 3.54 (s, 3H), 3.15 (d, J = 11.0 Hz, 2H), 3.05 - 2.89 (m, 4H), 2.61 (s, 2H), 2.06 (d, J = 11.3 Hz, 1H), 1.91 (d, J = 10.8 Hz, 3H), 1.81 - 1.64 (m, 3H), 1.49 (s, 2H), 1.24 (d, J = 5.9 Hz, 2H). LC-MS (ESI): m / z 645.2 [M+H] + .

[0119] Synthesis of compound M-4 of Example 15

[0120]

[0121] Referring to the synthesis method of Example 3, compound M-4 was obtained with a yield of 73%, 1H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 1H), 8.81 (d, J = 4.8 Hz, 2H), 8.06 (s, 1H), 7.81 - 7.76 (m, 2H), 7.71 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 7.4 Hz, 1H), 6.48 (d, J = 8.9 Hz, 2H), 6.41 (s, 1H), 4.44 (dd, J = 33.5, 12.9 Hz, 2H), 4.04 (t, J = 8.0 Hz, 2H), 3.71 - 3.56 (m, 2H), 3.02 (d, J = 11.5 Hz, 2H), 2.92 - 2.82 (m, 4H), 2.58 (s, 3H), 2.03 (d, J = 13.8 Hz, 3H), 1.97 - 1.85 (m, 3H), 1.78 - 1.56 (m, 4H), 1.40 (s, 9H). LC-MS (ESI): m / z 687.3 [M+H] + .

[0122] Synthesis of compound M-5

[0123]

[0124] Referring to the synthesis method of compound M-3 in Example 14, compound M-5 was obtained by replacing 3f with 4b, in a yield of 65%, 1 H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 1H), 8.81 (d, J = 4.8 Hz, 2H), 8.06 (s, 1H), 7.81 - 7.76 (m, 2H), 7.71 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 7.4 Hz, 1H), 6.48 (d, J = 8.9 Hz, 2H), 6.41 (s, 1H), 4.44 (dd, J = 33.5, 12.9 Hz, 2H), 4.04 (t, J = 8.0 Hz, 2H), 3.71 - 3.56 (m, 2H), 3.02 (d, J = 11.5 Hz, 2H), 2.92 - 2.82 (m, 4H), 2.58 (s, 3H), 2.03 (d, J = 13.8 Hz, 3H), 1.97 - 1.85 (m, 3H), 1.78 - 1.56 (m, 4H), 1.40 (s, 9H). LC-MS (ESI): m / z 687.3 [M+H] + .

[0125] Synthesis of compound M-6

[0126]

[0127] Procedure: Intermediate 5a (0.3 g, 0.89 mmol) was dissolved in 20 ml of dichloromethane, followed by the addition of N,N-diisopropylethylamine (0.34 g, 2.68 mmol), 2-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.57 g, 1.16 mmol), 8d (0.31 g, 0.89 mmol), and the reaction was allowed to proceed at room temperature for 3 hours. Saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted three times with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to give 0.2 g of compound M-6 as a white solid in 36% yield. 1 H NMR (400 MHz, DMSO-d6) δ 12.01 (d, J = 2.0 Hz, 1H), 8.26 (ddd, J = 6.1, 3.0, 1.7 Hz, 1H), 8.20 (s, 1H), 7.52 - 7.47 (m, 2H), 6.53 (d, J = 8.8 Hz, 2H), 6.24 (dd, J = 8.6, 2.1 Hz, 1H), 4.21 (d, J = 3.1 Hz, 2H), 4.15 (t, J = 8.1 Hz, 2H), 4.07 (dd, J = 7.9, 5.7 Hz, 2H), 3.97 - 3.81 (m, 4H), 3.82 - 3.75 (m, 5H), 3.74 (t, J = 5.7 Hz, 2H), 3.55 (d, J = 10.9 Hz, 2H), 2.70 (s, 2H), 2.16 - 2.11 (m, 2H), 1.75 - 1.51 (m, 2H), 1.25 (s, 1H), 1.10 (dd, J = 12.2, 3.9 Hz, 2H), 0.82 (d, J = 6.2 Hz, 3H). LC-MS (ESI): m / z 620.3 [M+H] + .

[0128] Synthesis of compound M-7

[0129]

[0130] Referring to the synthesis method of compound M-6 of Example 17, compound M-7 was obtained by replacing 8d with 9a in 61% yield, 1H NMR (400 MHz, DMSO-d6) δ 12.01 (d, J = 2.0 Hz, 1H), 8.26 (ddd, J = 6.1, 3.0, 1.7 Hz, 1H), 8.23 (s, 1H), 7.86 (t, J = 8.7 Hz, 1H), 7.78 (d, J = 14.0 Hz, 1H), 7.57 - 7.47 (m, 2H), 6.57 (d, J = 8.2 Hz, 2H), 6.51 (d, J = 1.6 Hz, 2H), 4.20 (d, J = 3.1 Hz, 2H), 4.18 (t, J = 8.2 Hz, 2H), 4.07 (t, J = 6.7 Hz, 2H), 3.94 - 3.80 (m, 4H), 3.79 - 3.68 (m, 4H), 2.80 (s, 4H), 2.70 (s, 4H), 2.34 (d, J = 4.9 Hz, 4H), 2.13 (s, 3H). LC-MS (ESI): m / z 621.2 [M+H] + .

[0131] Synthesis of compound M-8 of Example 19

[0132]

[0133] Referring to the synthesis method of compound M-6 of Example 17, 5a is replaced with 6a to obtain compound M-8 in a yield of 58%, 1 H NMR (400 MHz, DMSO-d6) δ 12.17 (s, 1H), 10.47 (s,

[0134] 1H), 8.20 (s, 1H), 7.86 (t, J = 8.7 Hz, 1H), 7.77 (dd, J = 14.0, 2.1 Hz, 1H),

[0135] 7.52 - 7.45 (m, 2H), 7.40 (dd, J = 8.6, 2.1 Hz, 1H), 6.96 (t, J = 2.0 Hz, 1H),

[0136] 6.56 (d, J = 8.8 Hz, 2H), 4.18 (t, J = 8.1 Hz, 2H), 4.06 (dd, J = 7.9, 5.7 Hz,

[0137] 2H), 3.97 - 3.82 (m, 4H), 3.80 - 3.69 (m, 5H), 3.53 (d, J = 10.9 Hz, 2H),

[0138] 2.16 - 2.01 (m, 2H), 1.78 - 1.53 (m, 2H), 1.22 (s, 1H), 1.12 (dd, J = 12.2,

[0139] 3.9 Hz, 2H), 0.84 (d, J = 6.4 Hz, 3H). LC-MS (ESI): m / z 634.2 [M+H] + .

[0140] Synthesis of compound M-9

[0141]

[0142] Referring to the synthesis method of compound M-6 in Example 17, replace 5a with 6a and 8d with 9a to obtain compound M-9 in a yield of 60%, 1 H NMR (400 MHz, DMSO-d6) δ 12.17 (s, 1H), 10.50 (s, 1H), 8.21 (d, J = 3.9 Hz, 1H), 7.86 (t, J = 8.7 Hz, 1H), 7.78 (d, J = 14.0 Hz, 1H), 7.57 - 7.47 (m, 2H), 7.41 (d, J = 8.6 Hz, 1H), 6.96 (s, 1H), 6.57 (d, J = 8.2 Hz, 2H), 4.18 (t, J = 8.2 Hz, 2H), 4.07 (t, J = 6.7 Hz, 2H), 3.94 - 3.80 (m, 4H), 3.79 - 3.68 (m, 4H), 2.80 (s, 4H), 2.34 (d, J = 4.9 Hz, 4H), 2.13 (s, 3H). LC-MS (ESI): m / z 635.2 [M+H] + .

[0143] Synthesis of compound M-10

[0144]

[0145] Referring to the synthesis method of compound M-6 in Example 17, replace 5a with 6a and 8d with 9a to obtain compound M-9 in a yield of 60%, 1H NMR (400 MHz, DMSO-d6) δ 12.14 (d, J = 2.1 Hz, 1H), 10.20 (s, 1H), 8.14 (s, 1H), 7.83 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.9 Hz, 2H), 7.59 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 2.1 Hz, 1H), 6.64 - 6.47 (m, 2H), 4.14 (t, J = 8.2 Hz, 2H), 4.03 (dd, J = 7.8, 5.8 Hz, 2H), 3.84 (t, J = 4.8 Hz, 4H), 3.71 (dd, J = 5.8, 3.8 Hz, 4H), 2.67 - 2.60 (m, 1H), 0.99 (dd, J = 5.1, 2.2 Hz, 2H), 0.92 (dd, J = 7.8, 2.3 Hz, 2H). LC-MS (ESI): m / z 559.2 [M+H] + .

[0146] Example 22 Menin protein expression down-regulation test

[0147] Huh7 cells were trypsinized and centrifuged at 1000 r for 5 min. The culture medium was discarded and 1 ml of new culture medium was added for reconstitution, and the number of cells was counted using a hemocytometer. Two ml of culture medium was added to each well of a six-well plate, and then 0.5-0.6 million cells were added to each well. The six-well plate was shaken in a cross pattern and was placed in a 37°C incubator for culture. The drug was configured to 1 mM, and one well of DMSO was set as a control in each six-well plate, and the rest of the wells were added with the drug. Fifteen microliters of DMSO and the drug were added to each well, and the concentration of the drug was 10 μg / mL. After 24 hours of drug addition, the protein was extracted. The culture medium was discarded, 1 ml of PBS was added to each well for washing, and the PBS was discarded. One hundred microliters of protein lysis solution was added for lysis, and after lysis for 30-40 min, centrifugation was performed at 15000 r for 10-20 min. The supernatant was transferred to another centrifuge tube. The BCA working solution was configured according to A:B = 50:1, and 100 μl of BCA working solution and 10 μl of extracted protein were added to each well of a 96-well plate. Incubation was performed in a 37°C incubator for 30 min, and the enzyme label instrument was used to test the od value. The protein concentration was calculated according to the protein standard curve, and then the sample loading amount was fixed. According to the protein concentration, the system was diluted with PBS to 40 μl, and then 10 μl of 5x loading buffer was added. The sample was boiled in a 100°C metal bath for 5-10 min. After removal, centrifugation was performed at 15000 r for 5 min.

[0148] The running buffer was added to the electrophoresis tank, 10-15 μl was loaded into each well of the 12-well precast gel, and constant voltage running was performed at 160 v for 45 min. The PVDF membrane was activated in a methanol solution for 10 s, the gel was cut according to the size of the target protein and the internal reference protein, and the membrane was clamped in the order of white bottom-sponge-membrane-gel-sponge-black bottom. The transfer solution was added to the electrophoresis tank, and constant current transfer was performed at 250 mA for 90 min. 5% skimmed milk was prepared with tbst, and the PVDF membrane was blocked with 5% skimmed milk for 2 h. After 2 h, the membrane was washed with tbst three times, each for 10 min. The primary antibody was diluted with the primary antibody diluent at 1:3000, 5 ml of the primary antibody was added to each membrane, and it was blocked at 4°C overnight. The primary antibody was recovered, and the membrane was washed with tbst three times, each for 10 min. The secondary antibody was diluted with 5% skimmed milk at 1:5000. 5 ml of the secondary antibody was added to each membrane for one hour, and then the membrane was washed with tbst three times, each for 10 min. The developing solution was prepared according to 1:1, and the developing solution was added to the membrane and incubated for 30 s, and then it was placed in the developing instrument for development. The Menin protein down-regulation rate of the compound was calculated according to the formula: target protein gray value of the required compound / gap gray value of the required compound / target protein gray value of DMSO / gap gray value of DMSO.

[0149] Table 1 Menin protein down-regulation rate of the compound

[0150]

[0151] a: between 0 and 20; b: between 20 and 40; c: between 40 and 100.

[0152] Example 22 MV4-11 cell proliferation inhibition experiment

[0153] MV4-11 cells were cultured with IMDM plus 10% fetal bovine serum and collected, and the cell concentration was diluted according to the action time of 7 days, 180 μL of cell suspension was added to each well of the 96-well cell plate, so that the number of cells was 2000, and a blank group without cells was set up only with IMDM plus 10% fetal bovine serum medium. 10 μL of DMSO with a final concentration of 0.2% was added to the control cell well, and the test compound was diluted by 3 times gradient from 10 mM stock solution, and 10 μL was also added to the compound cell well (the final concentration of DMSO was 0.2%). The cells were incubated in a 37°C, 5% CO2 incubator for 7 days. After the reaction solution was prepared according to the MTS kit, 20 μL was added to each well, and it was incubated in a 37°C, 5% CO2 incubator for 3-4 hours. The absorbance value (OD 490 ) at 490 nm was read by the enzyme-labeled plate, and the absorbance value (OD 690 ) at 690 nm was taken as the background value. The OD 490 was obtained by subtracting the OD 690 from the OD 490 . 690 DMSOor OD compound. The inhibition rate of the compound is calculated according to the formula: inhibition rate = (OD DMSO - OD 化合物 ) / (OD DMSO - OD 空白 ) x 100%. The proliferation inhibition IC 50 is fitted by GraphPad Prism 5.0. The experiment is repeated three times, and the average and standard deviation are calculated by using three parallel experiments each time, and the results are shown in Table 2.

[0154] Table 2: Compound inhibition of MV4-11 cell proliferation activity

[0155]

[0156] a: between 0-100 nM; b: between 100-300 nM; c: between 300-1000 nM; d: between 1-10 μM.

[0157] As can be seen from the test data in Table 1, the compound represented by formula I has a better inhibitory effect on the growth of human myelomonocytic leukemia MV-4-11 cells. It has potential for use in the preparation of drugs for treating and preventing leukemia.

[0158] Example 23: In vivo exposure amount detection of animals

[0159] Objectives of the experiment:

[0160] IG: Test the exposure level of M-10 in the plasma of SD Rat at a dose of 20 mg / kg.

[0161] Method of the experiment:

[0162] Standard curve and quality control sample preparation: 1 mg of the compound is diluted with 1 mL of DMSO, and blank acetonitrile is used to dilute the compound to a concentration of 200, 100, 50, 20, 10, 5, 2, 1, 0.5, 0.2, 0.1 and 0.05 μg / mL, respectively. Take 2.5 μL of the standard working solution, add 47.5 μL of blank acetonitrile, and then add 200 μL of 5 ng / mL loratadine acetonitrile solution to prepare the standard sample. After vortex oscillation for 2-3 min, centrifuge at 13500 rpm at 4°C for 10 min, and take the supernatant.

[0163] Unknown sample preparation: Take 50 μL of the plasma sample, add 200 μL of 5 ng / mL loratadine acetonitrile solution, vortex oscillate for 2-3 min, then centrifuge at 13500 rcf at 4°C for 10 min, and take the supernatant for LC-MS / MS analysis.

[0164]

[0165] Results of the experiment:

[0166] From the data in the above table, it can be seen that our compounds have certain level of exposure in vivo and can be developed for oral administration.

Claims

1. A 7-azaindole compound, characterized in that, A compound having the structure of Formula I, an optical isomer thereof, or a pharmaceutically acceptable salt thereof: wherein: A is selected from wherein R2is selected from hydrogen, hydroxyl, halogen, C1-C4 alkyl, halogen-substituted C1-C4 alkyl, C1-C4 alkoxy, cyano, nitro, or -NR3R4, each of R3 and R4 independently represents hydrogen or C1-C3 alkyl; m is 0, 1, 2; q is 0, 1, 2; Z is selected from wherein W, X are each independently selected from N or CH; R5, R6are each independently selected from hydrogen, hydroxyl, halogen, C1-C4alkyl, halogen-substituted C1-C4alkyl, C1-C4alkoxy, cyano, nitro; R7is selected from hydrogen, C1-C4alkyl, halogen-substituted C1-C4alkyl, C1-C4alkoxy, hydroxyl-substituted C1-C4alkyl; k is 1, 2, 3, 4, 5; E is selected from hydrogen, C1-C4alkyl, halogen or wherein R8is selected from hydrogen, C1-C4alkyl; p is selected from 1, 2, 3, 4, 5; M, Y are each independently selected from NH or O; L is selected from wherein g is 1, 2, 3; I is 0, 1, 2, 3; D is selected from CH2, NH, O, or S; Q is selected from N or CH; n is 1, 2, 3, 4; R1 is selected from hydrogen, hydroxyl, halogen, C1-C4 alkyl, halogen-substituted C1-C4 alkyl, C1-C4 alkoxy, cyano, nitro.

2. The 7-azaindole compound according to claim 1, wherein R1is hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy, cyano, nitro; n = 1 ; A is selected from L is selected from CH, -NH-C(O)-; E is selected from hydrogen or Q is selected from N.

3. The 7-azaindole compound according to claim 1, wherein The compound has the structure of Formula II-1, II-2, or II-3, an optical isomer thereof, or a pharmaceutically acceptable salt thereof: Z is selected from wherein W, X are each independently selected from N or CH; R5, R6are each independently selected from optionally substituted hydrogen, hydroxyl, halogen, C1-C4alkyl, halogen-substituted C1-C4alkyl, C1-C4alkoxy, cyano, nitro; R7is selected from hydrogen, C1-C4alkyl, halogen-substituted C1-C4alkyl, C1-C4alkoxy, hydroxyl-substituted C1-C4alkyl; k is 1, 2, 3, 4, 5; R2 is selected from hydrogen, halogen, C1-C4 alkyl, halogen-substituted C1-C4 alkyl, C1-C4 alkoxy, cyano, nitro; R8 is selected from hydrogen, C1-C4 alkyl; p is selected from 0-3; each of M and Y is independently selected from NH or O.

4. The 7-azaindole compound according to claim 1, wherein The compound is selected from the following compounds:

5. A pharmaceutical composition, characterized by, The compound is selected from the following compounds:

6. A pharmaceutical preparation, characterized by, The pharmaceutical composition comprises at least one active ingredient selected from the compound of any one of claims 1-4, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

7. Use of a compound of any one of claims 1-4 in the manufacture of a medicament for treating a disease by down-regulating Menin protein expression.

8. Use according to claim 7, characterized in that, The medicament is a tumor treatment medicament.

9. Use according to claim 7, characterized in that, The medicament is a hematological tumor and solid tumor treatment medicament.

10. Use according to claim 7, characterized in that, The medicament is a leukemia and liver cancer treatment medicament.

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