Preparation method for complement factor d inhibitor, intermediate thereof, and preparation method for intermediate

Abstract

Disclosed in the present invention are a preparation method for a complement factor D inhibitor, an intermediate thereof, and a preparation method for an intermediate. The present invention provides a preparation method for a new complement factor D inhibitor, a new intermediate, and a preparation method for an intermediate. The selectivity of a reaction is improved by means of the new intermediate, the material conversion rate of each step of a route is high, a reaction type is common, the length of the route is moderate, and the obtained products can all be purified by means of a conventional method to obtain a target product, thereby reducing the production costs, and facilitating industrial production.

Description

Process for the preparation of a complement factor D inhibitor, intermediates thereof and process for the preparation of intermediates

[0001] This application claims priority to Chinese patent application 202411126120.6, filed on August 16, 2024. This application incorporates the entirety of the aforementioned Chinese patent application. TECHNICAL FIELD

[0002] The present application belongs to the field of pharmaceutical compound preparation methods, and specifically relates to a process for the preparation of a complement factor D inhibitor, intermediates thereof and process for the preparation of intermediates. BACKGROUND

[0003] Complement is a protein widely present in human and vertebrate serum, tissue fluid and cell membrane surface, mediates immune and inflammatory reactions, and is mostly a glycoprotein produced by liver cells, macrophages and intestinal mucosal epithelial cells and other cells. Complement is the necessary complement for antibodies to achieve their cytolysis, hence the name complement, but it actually mediates specific and non-specific immunity. The three activation pathways of the complement system include the classical pathway, the mannose-binding lectin pathway (MBL) and the alternative (side) pathway. Complement factor D plays an early and core role in the cascade activation of the complement side pathway. The activation of the side complement pathway is initiated by the spontaneous hydrolysis of the thioester bond in C3 to produce C3(H2O), and C3(H2O) associates with factor B to form a C3(H2O)B complex. The role of complement factor D is to break factor B in the C3(H2O)B complex to form Ba and Bb. Bb, in addition to binding with C3b to form C3 convertase, also participates in the proliferation of pre-activated B lymphocytes, while Ba inhibits its proliferation. D factor has high expression level in fat, can stimulate glucose transport and promote the accumulation of triglycerides in adipocytes, and inhibit lipolysis.

[0004] Complement system disorder plays an important role in the pathogenesis of IgA nephropathy (IgAN), lupus nephritis (LN) and paroxysmal nocturnal hemoglobinuria (PNH). Complement components and immune deposits are often found in the kidney pathological examination of IgAN and LN, complement is the direct cause of PNH hemolysis, C5aR participates in the amplification of complement system damage, complement factor B (CFB) and complement factor D (CFD) are key components of the complement side pathway and directly participate in the regulation of complement activation. Therefore, C5aR, CFB and CFD are closely related to the pathogenesis of IgAN, LN and PNH.

[0005] Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening blood disorder characterized by complement-driven hemolysis, thrombosis, and impaired bone marrow function, leading to anemia, fatigue, and other debilitating symptoms that can severely impact patients' quality of life. Currently, the main drugs for PNH on the market are monoclonal antibody drugs Soliris and Ultomiris. Among them, Soliris was first approved for marketing in 2007, and has been approved for the treatment of a variety of ultra-rare diseases, including: paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), generalized myasthenia gravis (gMG), opticospinal cord spectrum disorder (NMOSD). Ultomiris is an upgraded product of Soliris, a second-generation, long-acting C5 complement inhibitor, which was first approved for marketing at the end of 2018, and the approved indications include: paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS). A large proportion of PNH patients are still anemic and dependent on blood transfusions with current anti-C5 standard of care therapy. In addition, small molecule Voydeya (danicopan) was also approved by the Japanese Ministry of Health, Labor and Welfare (MHLW) and FDA in 2024, as an additional therapy to the standard therapy complement factor C5 inhibitor Ultomiris or Soliris for a subset of patients with paroxysmal nocturnal hemoglobinuria (PNH) who experience significant extracellular hemolysis (EVH) when treated with C5 inhibitors.

[0006] A compound that can be a complement factor D inhibitor is disclosed in PCT application WO2023051793A1, which has a good inhibitory effect on complement factor D. The application also discloses a preparation method of the compound, wherein some steps have no difference in reaction site activity, resulting in the generation of excessive coupling impurities and low reaction yield. The product is obtained by column chromatography separation and purification in multiple steps in the preparation process, which is not suitable for industrial production. Therefore, it is still of value to study a preparation method of the compound that improves the material conversion rate of each step, explores a preparation route with moderate length and simple purification steps, and is convenient for industrial production. SUMMARY

[0007] The technical problem to be solved by the present application is to overcome the defects of the prior art. The present application provides a new preparation method of a complement factor D inhibitor, intermediates thereof and a preparation method of the intermediates. The preparation method has the advantages of simple operation, high reaction yield and high purity, and has good application prospect in industrial production.

[0008] The present application provides a preparation method of a compound represented by formula IN-02, which comprises the following step A2):

[0009] The compound IN-01 is reacted with the compound M-03 to form a compound of the formula IN-02,

[0010] wherein:

[0011] R 1 is H;

[0012] R 2 and R 3 are each independently H, C 1-6 alkyl or C 2-1 alkyl substituted by 1, 2 or 3 R 1-6 ; each R 2-1 is independently halogen or -OH, the halogen preferably being F;

[0013] R 4 is H or halogen; m is 0 or 1 ;

[0014] R B is -B(OH)2or

[0015] R 5 , R 7 and R 9 are each independently H or halogen;

[0016] n is 0 or 1 ;

[0017] L is -(CR a R b ) q ; q is 0 or 1 ;

[0018] R a and R b are each independently H, D or halogen;

[0019] R c is H or C 1-6 alkyl.

[0020] The present application provides a process for the preparation of a compound of the formula IN-02, comprising the following steps:

[0021] A1 ) the compound M-01 is reacted with the compound M-02 in the presence of a base to form the compound IN-01,

[0022] A2) the compound IN-01 is reacted with the compound M-03 to form a compound of the formula IN-02,

[0023] wherein:

[0024] R 1 is H;

[0025] R 2 and R 3 each independently H, C 1-6 alkyl or C 2-1 alkyl substituted with 1, 2, or 3 R 1-6 each R 2-1 independently halogen or -OH, the halogen preferably being F;

[0026] R 4 is H or halogen; m is 0 or 1;

[0027] R B is -B(OH)2or

[0028] R 5 , R 7 , and R 9 each independently H or halogen, the halogen preferably being F;

[0029] n is 0 or 1;

[0030] L is -(CR a R b ) q -; q is 0 or 1;

[0031] R a and R b each independently H, D, or halogen;

[0032] R c is H or C 1-6 alkyl.

[0033] In certain preferred embodiments of the application, certain groups in the compounds (e.g., M-01-M-04, IN-01-IN-04, compounds of Formula (I)) are defined as follows, and groups not mentioned are as described in any embodiment of the application (simply "in an embodiment of the application" or "according to an embodiment of the application").

[0034] In an embodiment of the application, each said C 1-6 alkyl is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, or s-butyl; preferably methyl or ethyl.

[0035] In an embodiment of the application, each said halogen is independently fluorine, chlorine, bromine, or iodine; for example, fluorine.

[0036] In an embodiment of the application, R 2 and R 3each independently is hydrogen, methyl, -CH2OH, -CH2CH2OH, -CH2F, -CHF2, or ethyl; preferably hydrogen.

[0037] In an embodiment of the present application, R 4 is H or F; preferably H.

[0038] In an embodiment of the present application, R B is -B(OH)2.

[0039] In an embodiment of the present application, R 5 , R 7 , and R 9 each independently is H or F; preferably H.

[0040] In an embodiment of the present application, q is 1.

[0041] In an embodiment of the present application, R a and R b each independently is H.

[0042] In an embodiment of the present application, R c is H, methyl, or ethyl; for example, H.

[0043] In an embodiment of the present application, compound M-01 is

[0044] In an embodiment of the present application, compound M-02 is

[0045] In an embodiment of the present application, compound IN-01 is

[0046] In an embodiment of the present application, compound M-03 is

[0047] In an embodiment of the present application, the compound of formula IN-02 is

[0048] The present application also provides a method for preparing a compound of formula (I), comprising the following steps:

[0049] A1) reacting compound M-01 with compound M-02 in the presence of a base to form compound IN-01,

[0050] A2) reacting compound IN-01 with compound M-03 to form a compound of formula IN-02,

[0051] A3) reacting compound IN-02 with compound M-04 to form compound IN-03 or a salt thereof; for example, reacting compound IN-02 with compound M-04 to form compound IN-03;

[0052] A4) removing the amino protecting group Boc from compound IN-03 or a salt thereof to form compound IN-04 or a compound of formula (I); preferably, removing the amino protecting group Boc from compound IN-03 to form compound IN-04 or a compound of formula (I);

[0053] A5) subjecting compound IN-04 to a hydrolysis reaction to form a compound of formula (I),

[0054] wherein, when R c is H, the method comprises steps A1), A2), A3) and A4); when R c is C 1-6 alkyl, the method comprises steps A1), A2), A3), A4) and A5);

[0055] R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 9 , R c , L, m and n have the definitions described in any aspect of the present application;

[0056] M-04 is R 6 -H or a salt thereof; for example, R 6 -H or a hydrochloride salt thereof; and further for example, R 6 -H;

[0057] R 6 is "8-11 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S, and having 1, 2 or 3 substituents selected from hydroxyl and C 6-1 alkyl", or "8-11 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S, and having 1, 2 or 3 substituents selected from hydroxyl and C 6-1 alkyl", each R 1-6 is independently hydroxyl or C

[0058] R 10 is -COOH.

[0059] In the present application, when R cWhen R is H, step A4) is the reaction of compound IN-03 or a salt thereof to remove the amino protecting group Boc to form a compound of formula (I).

[0060] In one embodiment of the present application, R 6 is "8-11 membered heterocycloalkyl having 1 heteroatom which is N".

[0061] In one embodiment of the present application, M-04 is R6-H.HCl.

[0062] In one embodiment of the present application, M-04 is

[0063] In one embodiment of the present application, compound IN-03 is oxalate.

[0064] In one embodiment of the present application, the oxalate, wherein the molar ratio of compound IN-04 and oxalic acid is 1:1.

[0065] In one embodiment of the present application, compound IN-04 is

[0066] According to an embodiment of the present application, when R c is H, the method for preparing a compound of formula (I) comprises steps A1), A2), A3) and A4).

[0067] According to an embodiment of the present application, when R c is C 1-6 alkyl, the method for preparing a compound of formula (I) comprises steps A1), A2), A3), A4) and A5).

[0068] According to an embodiment of the present application, R c is H, methyl, ethyl, n-propyl or isopropyl.

[0069] In one embodiment of the present application, R 6 is 1, 2 or 3 R 6-1substituted 6-azaspiro[2.5]octyl, 5-azaspiro[2.5]octyl, 6-azaspiro[3.4]octyl, 2-azaspiro[3.4]octyl, 2-oxa-6-azaspiro[3.4]octyl, 6-oxa-2-azaspiro[3.4]octyl, 4-oxa-7-azaspiro[2.5]octyl, 2-azaspiro[4.4]nonyl, 2-azaspiro[3.5]nonyl, 2-oxa-7-azaspiro[3.5]nonyl, 1-oxa-7-azaspiro[3.5]nonyl, 7-azaspiro[3.5]nonyl, 2,7- diazaspiro[3.5]nonyl, 2-oxa-8-azaspiro[4.5]decyl, 3-oxa-9-azaspiro[5.5]undecyl, 2-oxa-9-azaspiro[5.5]undecyl, 3,9-diazaspiro[5.5]undecyl, 3-azabicyclo[3.2.1]octyl, 3-azaspiro[5,5]undecyl, 8-azaspiro[4.5]decyl, or 1-oxa-6-azaspiro[3,4]octyl; each R 6-1 independently hydroxyl or C 1-6 alkyl.

[0070] According to an embodiment of the present application, each R 6-1 independently hydroxyl, methyl, ethyl, n-propyl, or i-propyl.

[0071] In one aspect of the present application, R 6 is

[0072] In exemplary embodiments, the compound of formula (I) of the present application is selected from the following structures:

[0073] In the preparation method of the compound shown in the formula IN-02 or formula (I), in the step A1), the base is a conventional base for such reactions in the art; preferably one, two or more of alkali metal carbonate, alkali metal bicarbonate, alkali metal hydroxide, alkali metal alkoxide, alkali metal carboxylate, alkali metal fluoride, alkali metal phosphate or organic amine base; the alkali metal carbonate can be cesium carbonate, potassium carbonate or sodium carbonate; the alkali metal bicarbonate can be sodium bicarbonate or potassium bicarbonate; the alkali metal hydroxide can be lithium hydroxide, potassium hydroxide or sodium hydroxide; the alkali metal alkoxide can be sodium methoxide, sodium ethoxide, potassium tert-butoxide or sodium tert-butoxide; the alkali metal carboxylate can be potassium acetate; the alkali metal fluoride can be potassium fluoride or cesium fluoride; the alkali metal phosphate can be potassium phosphate or sodium phosphate; and the organic amine base can be triethylamine or N,N-diisopropylethylamine.

[0074] In the preparation method of the compound shown in the formula IN-02 or formula (I), in the step A1), the base is one, two or more of cesium carbonate, potassium carbonate, lithium hydroxide, sodium methoxide, potassium hydroxide, sodium carbonate, potassium acetate, sodium bicarbonate, potassium bicarbonate, potassium fluoride, cesium fluoride, sodium hydroxide, triethylamine, N,N-diisopropylethylamine, sodium methoxide, sodium ethoxide, potassium tert-butoxide or sodium tert-butoxide, and preferably one, two or more of cesium carbonate, potassium carbonate or potassium hydroxide.

[0075] In the preparation method of the compound shown in the formula IN-02 or formula (I), in the step A1), the solvent for the reaction is a conventional solvent for such reactions in the art; preferably one or more of amide solvents, alcohol solvents or water; further preferably DMF, or a mixed solvent of alcohol solvents and water, and further preferably DMF, or a mixed solvent of ethanol and water.

[0076] In the preparation method of the compound shown in the formula IN-02 or formula (I), in the step A1), the molar ratio of the compound M-01 to the compound M-02 is a conventional molar ratio for such reactions in the art; preferably 1.00:(1.00-2.00), further preferably 1.00:(1.00-1.50), and still preferably 1.00:1.20 or 1.00:1.00.

[0077] In the preparation method of the compound shown in the formula IN-02 or formula (I), in the step A1), the molar ratio of the compound M-01 to the base is a conventional molar ratio for such reactions in the art; preferably 1.00:(1.50-4.00), and further preferably 1.00:3.00 or 1.00:2.00.

[0078] The preparation method of the compound represented by the formula IN-02 or formula (I), in the step A1), the molar volume ratio of the compound M-01 to the solvent of the reaction is the conventional molar volume ratio of the reaction in the art; preferably 0.20-0.60 mmol / mL; further preferably 0.27 mmol / mL or 0.44 mmol / mL.

[0079] The preparation method of the compound represented by the formula IN-02 or formula (I), in the step A1), the temperature of the reaction is the conventional temperature of the reaction in the art; preferably 15-60°C; further preferably 25-35°C or 50°C.

[0080] In an aspect of the present application, the preparation method of the compound represented by the formula IN-02 or formula (I), in the step A2), the reaction occurs in the presence of a base and a catalyst in a solvent.

[0081] The preparation method of the compound represented by the formula IN-02 or formula (I), in the step A2), the reaction is a Suzuki coupling reaction, and the molar ratio of the compound IN-01 to the compound M-03 is the conventional molar ratio of the reaction in the art; preferably 1.00:(1.00-1.20), and more preferably 1.00:(1.00-1.10), such as 1.00:1.02 or 1.00:1.05.

[0082] The preparation method of the compound represented by the formula IN-02 or formula (I), in the step A2), the temperature of the reaction is the conventional temperature of the reaction in the art; preferably 30-80°C; further preferably 40-80°C or 40-60°C, and more preferably 30-40°C, 50°C or 55°C.

[0083] The preparation method of the compound represented by the formula IN-02 or formula (I), in the step A2), the solvent of the reaction is the conventional solvent of the reaction in the art; preferably a mixture of at least one of nitrile solvents or ether solvents and water; further preferably a mixture of at least one of acetonitrile, ethylene glycol dimethyl ether or tetrahydrofuran and water, and more preferably a mixture of acetonitrile and water.

[0084] In the process for preparing the compound of formula IN-02 or formula (I), in the step A2), the base is a conventional base for such reaction in the art; preferably one, two or more of an alkali metal carbonate, an alkali metal bicarbonate, an alkali metal hydroxide, an alkali metal alkoxide, an alkali metal carboxylate, an alkali metal fluoride, an alkali metal phosphate or an organic amine base; the alkali metal carbonate can be cesium carbonate, potassium carbonate or sodium carbonate; the alkali metal bicarbonate can be sodium bicarbonate or potassium bicarbonate; the alkali metal hydroxide can be lithium hydroxide, potassium hydroxide or sodium hydroxide; the alkali metal alkoxide can be sodium methoxide, sodium ethoxide, potassium tert-butoxide or sodium tert-butoxide; the alkali metal carboxylate can be potassium acetate; the alkali metal fluoride can be potassium fluoride or cesium fluoride; the alkali metal phosphate can be potassium phosphate or sodium phosphate; the organic amine base can be triethylamine or N,N-diisopropylethylamine.

[0085] Preferably, the base is an alkali metal carbonate and / or an alkali metal hydroxide; preferably an alkali metal carbonate; more preferably potassium carbonate; for example, anhydrous potassium carbonate.

[0086] In the process for preparing the compound of formula IN-02 or formula (I), in the step A2), the catalyst for the reaction is a conventional catalyst for such reaction in the art; preferably a palladium catalyst; preferably 1,1'-bis(diphenylphosphino)ferrocene palladium chloride dichloromethane complex or 1,1'-bis(diphenylphosphino)ferrocene palladium chloride.

[0087] In the process for preparing the compound of formula IN-02 or formula (I), in the step A2), the molar ratio of the compound of formula IN-01 to the base for the reaction is a conventional molar ratio for such reaction in the art; preferably 1.00:(1.00-4.00), more preferably 1.00:1.50 or 1.00:2.50.

[0088] In the process for preparing the compound of formula IN-02 or formula (I), in the step A2), the molar ratio of the compound of formula IN-01 to the catalyst for the reaction is a conventional molar ratio for such reaction in the art; preferably 1.00:(0.01-0.05), more preferably 1.00:0.03 or 1.00:0.02.

[0089] In the process for preparing the compound of formula IN-02 or formula (I), in the step A2), the molar volume ratio of the compound of formula IN-01 to the solvent for the reaction is a conventional molar volume ratio for such reaction in the art; preferably 0.04-0.40 mmol / mL; more preferably 0.14 mmol / mL, 0.25 mmol / mL or 0.24 mmol / mL.

[0090] In an embodiment of the present application, the method for preparing the compound of formula IN-02 or formula (I), in step A2), the reaction further comprises the following post-treatment steps: adjusting pH = 6-8 (for example, adjusting with dilute hydrochloric acid), distillation (for example, distillation under reduced pressure), extraction (for example, saturated salt and an ethereal solvent (for example, methyl tert-butyl ether)), removing palladium from the organic phase, removing water, removing tar, removing pigment, and recrystallization (for example, recrystallization from an ethereal solvent (for example, methyl tert-butyl ether) and an alkane solvent (for example, n-heptane)).

[0091] In an embodiment of the present application, the method for preparing the compound of formula (I), in step A3), the reaction occurs in the presence of a catalyst, a ligand, and a base in a solvent.

[0092] In the method for preparing the compound of formula (I), in step A3), the base is a conventional base for such reactions in the art; preferably, an alkali metal carbonate, an alkali metal phosphate, or an alkali metal alcoholate.

[0093] In the method for preparing the compound of formula (I), in step A3), the solvent is a conventional solvent for such reactions in the art; preferably, one or more of an ethereal solvent, an amide solvent, or a benzene solvent.

[0094] In an embodiment of the present application, the method for preparing the compound of formula (I), in step A3), the reaction is a Buchwald coupling reaction.

[0095] In an embodiment of the present application, the method for preparing the compound of formula (I), in step A3), the reaction is carried out in the presence of a Pd catalyst, the Pd catalyst is Pd2(dba)3; the reaction requires the use of a ligand, the ligand is RuPhos, XPhos, BINAP, or SPhos, preferably RuPhos; the reaction is carried out in the presence of a base, the base is cesium carbonate, potassium phosphate, or potassium tert-butoxide, preferably cesium carbonate; the solvent for the reaction is N,N-dimethylacetamide, ethylene glycol dimethyl ether, 1,4-dioxane, or toluene, preferably toluene.

[0096] In an embodiment of the present application, the method for preparing the compound of formula (I), when R c is H, in step A3), the solvent for the reaction is a benzene solvent; preferably, toluene.

[0097] In an embodiment of the present application, the method for preparing the compound of formula (I), when R c is H, in step A3), the temperature for the reaction is 80-110°C; preferably, 95°C.

[0098] In a certain embodiment of the present application, the preparation method of the compound of formula (I), when R c is H, in step A3), the reaction further comprises the following steps: reacting compound IN-03 with oxalic acid to form the oxalate salt of compound IN-03.

[0099] In a certain embodiment of the present application, the preparation method of the compound of formula (I), when R c is H, in step A3), the molar ratio of compound IN-03 to oxalic acid is 1.00:(1.00-2.00); preferably 1.00:1.20.

[0100] In a certain embodiment of the present application, the preparation method of the compound of formula (I), when R c is H, in step A3), the reaction further comprises the following steps: dilution (for example, the dilution solvent is water), pH adjustment (for example, citric acid solution to adjust the solution pH to 3), extraction (for example, the solvent is a benzene solvent; preferably toluene), concentration, dissolution (for example, ester solvent and sodium bisulfite solution; preferably ethyl acetate and 10% sodium bisulfite solution), stirring at 30-60°C (for example, 45°C), cooling to -5-10°C (for example, 0-5°C), adding oxalic acid and precipitating, stirring and filtering, washing the filter cake with an ester solvent (for example, ethyl acetate), drying, dispersing (for example, an alkane solvent, preferably dichloromethane), heating to reflux, cooling and stirring, filtering, and drying to obtain the oxalate salt of compound IN-03.

[0101] In the preparation method of the compound of formula (I), in step A3), the molar ratio of compound IN-02 to compound M-04 is the conventional molar ratio of such reactions in the art; preferably 1.00:(1.00-2.00), further preferably 1.00:(1.50-2.00); and still preferably 1.00:1.50.

[0102] In the preparation method of the compound of formula (I), in step A3), the molar ratio of compound IN-02 to compound M-04 is 1.00:(1.00-1.50); for example, 1.00:1.10 or 1.00:1.5.

[0103] In an embodiment of the present application, the method for preparing the compound of formula (I), in step A4), the reaction of removing the amino-protecting group Boc is carried out in an acidic system, which is hydrogen chloride in methanol, hydrogen chloride in 1,4-dioxane, hydrogen chloride in ethyl acetate, trifluoroacetic acid in dichloromethane or hydrochloric acid, preferably hydrogen chloride in methanol, hydrogen chloride in 1,4-dioxane, hydrogen chloride in ethyl acetate or trifluoroacetic acid in dichloromethane, and more preferably hydrogen chloride in 1,4-dioxane.

[0104] In an embodiment of the present application, the method for preparing the compound of formula (I), when R c is H, in step A4), the reaction is carried out in an acidic system, which is hydrochloric acid; preferably 6.0 M hydrochloric acid.

[0105] In an embodiment of the present application, the method for preparing the compound of formula (I), when R c is H, in step A4), the reaction is carried out at a temperature of 30-60°C; preferably 45-50°C.

[0106] In an embodiment of the present application, the method for preparing the compound of formula (I), in step A5), the hydrolysis reaction is carried out in the presence of a base in a solvent; the solvent is a conventional solvent for such reaction in the art; preferably a mixture of an alcohol solvent and / or water; the alcohol solvent can be methanol.

[0107] In an embodiment of the present application, the method for preparing the compound of formula (I), in step A5), the hydrolysis reaction is carried out in the presence of a base. The base is an inorganic base, which can be an alkali metal hydroxide; preferably one, two or more of NaOH, KOH or LiOH, and more preferably NaOH.

[0108] In the method for preparing the compound of formula IN-02 or formula (I) of the present application, the amount of the solvent can not be specifically limited, as long as it does not affect the reaction.

[0109] The present application also provides a method for preparing the compound of formula (I), which comprises steps A2), A3), A4) and A5) as described in any of the embodiments of the present application; wherein, when R c is H, the method comprises steps A2), A3) and A4); when R c is C 1-6 alkyl, the method comprises steps A2), A3), A4) and A5).

[0110] The application provides a preparation method of a compound shown in formula IA, which comprises the following steps:

[0111] A1') the compound M-01A is reacted with the compound M-02A under the action of a base to generate the compound IN-01A,

[0112] A2') the compound IN-01A is subjected to a Suzuki reaction with the compound M-03A to generate the compound IN-02A,

[0113] A3') the compound IN-02A is subjected to a Buchwald coupling reaction with the compound M-04A to generate the compound IN-03A,

[0114] A4') the compound IN-03A is removed from an amino protecting group Boc in an acidic system to generate the compound IN-04A,

[0115] and

[0116] A5') the compound IN-04A is subjected to a hydrolysis reaction under the action of a base to obtain the compound shown in formula IA,

[0117] wherein, R B is -B(OH)2 or

[0118] R c is C 1-3 alkyl, preferably methyl or ethyl;

[0119] In step A1'), the base is one, two or more of cesium carbonate, potassium carbonate, lithium hydroxide, sodium methoxide, potassium hydroxide, sodium carbonate, potassium acetate, potassium phosphate, sodium phosphate, sodium bicarbonate, potassium bicarbonate, potassium fluoride, cesium fluoride, sodium hydroxide, triethylamine, N,N-diisopropyl ethylamine, sodium methoxide, sodium ethoxide, potassium tert-butoxide or sodium tert-butoxide, preferably one, two or more of cesium carbonate, potassium carbonate, lithium hydroxide, sodium methoxide, potassium hydroxide, sodium carbonate, potassium acetate, sodium bicarbonate, potassium bicarbonate, potassium fluoride, cesium fluoride, sodium hydroxide, triethylamine, N,N-diisopropyl ethylamine, sodium methoxide, sodium ethoxide, potassium tert-butoxide or sodium tert-butoxide, and further preferably one, two or more of cesium carbonate, potassium carbonate or potassium hydroxide; the solvent system of the reaction is DMF, or a mixed solvent of an alcohol and water, preferably DMF, or a mixed solvent of ethanol and water;

[0120] In step A2'), the molar ratio of the compound IN-01A to the compound M-03A in the Suzuki reaction is 1.00:(1.00-1.20), preferably 1.00:(1.00-1.10), for example 1.00:1.02 or 1.00:1.05; the temperature of the reaction is 40-80°C, preferably 40-60°C, for example 55°C; the solvent of the reaction is a mixed solvent of at least one of acetonitrile, ethylene glycol dimethyl ether or tetrahydrofuran and water, preferably a mixed solvent of acetonitrile and water;

[0121] In step A3'), the Buchwald coupling reaction is carried out in the presence of a Pd catalyst, which is Pd2(dba)3; the Buchwald coupling reaction needs to use a ligand, which is RuPhos, XPhos, BINAP or SPhos, preferably RuPhos; the Buchwald coupling reaction is carried out in the presence of a base, which is cesium carbonate, potassium phosphate or potassium tert-butoxide, preferably cesium carbonate; the solvent of the Buchwald coupling reaction is N,N-dimethylacetamide, ethylene glycol dimethyl ether, 1,4-dioxane or toluene, preferably toluene;

[0122] In step A4'), the acid system is a methanol solution of hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, an ethyl acetate solution of hydrogen chloride or a dichloromethane solution of trifluoroacetic acid, preferably a 1,4-dioxane solution of hydrogen chloride.

[0123] In step A5'), the base is an inorganic base, which is one, two or more of NaOH, KOH or LiOH, preferably NaOH.

[0124] The present application also provides a preparation method of the compound shown in formula IA, which comprises the following steps:

[0125] A1”) in a solvent, in the presence of a base, the compound M-01A is reacted with the compound M-02B to generate the compound IN-01B,

[0126] A2”) in a solvent, in the presence of a base and a catalyst, the compound IN-01B is subjected to Suzuki reaction with the compound M-03A to generate the compound IN-02B,

[0127] A3”) in a solvent, in the presence of a catalyst, a ligand and a base, the compound IN-02B is subjected to coupling reaction with the compound M-04A to generate the oxalate of the compound IN-03B,

[0128] A4") in the presence of an acid, the oxalate salt of compound IN-03B is reacted in an acidic system to generate compound IA,

[0129] wherein, in step A1");

[0130] said base is an alkali metal hydroxide; preferably potassium hydroxide;

[0131] said solvent is a mixed solvent of an alcohol solvent and water; preferably a mixed solvent of ethanol and water;

[0132] the molar ratio of compound M-01A to compound M-02B is 1.00:(1.00-1.50), preferably 1.00:1.00;

[0133] the molar ratio of compound M-01A to the base is 1.00:(1.50-4.00), preferably 1.00:2.00;

[0134] the temperature of the reaction is 15-60°C; preferably 50°C;

[0135] in step A2");

[0136] said solvent is a mixed solvent of a nitrile solvent and water; preferably a mixed solvent of acetonitrile and water;

[0137] said base is an alkali metal carbonate; further preferably potassium carbonate; for example, anhydrous potassium carbonate;

[0138] said catalyst is a palladium catalyst; preferably 1,1'-bis(diphenylphosphino) ferrocene palladium dichloride complex or 1,1'-bis(diphenylphosphino) ferrocene palladium chloride;

[0139] the molar ratio of compound IN-01B to compound M-03A is 1.00:(1.00-1.20), preferably 1.00:1.00;

[0140] the temperature of the reaction is 30-80°C; preferably 30-40°C;

[0141] the molar ratio of compound IN-01B to the base is 1.00:(1.00-4.00), preferably 1.00:2.50;

[0142] the molar ratio of compound IN-01B to the catalyst is 1.00:(0.01-0.05), preferably 1.00:0.03;

[0143] R B is -B(OH)2or

[0144] in step A3");

[0145] the solvent is a benzene solvent; preferably toluene;

[0146] the catalyst is a Pd catalyst; preferably Pd2(dba)3;

[0147] the ligand is RuPhos, XPhos, BINAP or SPhos, preferably RuPhos;

[0148] the base is an alkali metal carbonate; preferably cesium carbonate;

[0149] the molar ratio of the compound IN-02B to the compound M-04A is 1.00:(1.0-2.0), preferably 1.00:1.50;

[0150] the temperature of the reaction is 80-110°C; preferably 95°C;

[0151] Preferably, the reaction further comprises the step that the compound IN-03B reacts with oxalic acid to generate an oxalate salt of the compound IN-03B;

[0152] the molar ratio of the compound IN-03B to the oxalic acid is 1.00:(1.00-2.00); preferably 1.00:1.20;

[0153] in step A4");

[0154] the acid is hydrochloric acid, preferably 6.0M hydrochloric acid;

[0155] the temperature of the reaction is 30-60°C; preferably 45-50°C.

[0156] In an embodiment of the present application, there is further provided a method for preparing the compound M-01 in the method for preparing the compound shown as formula IN-02, which comprises the following steps:

[0157] B1) the compound SM-1 is subjected to a reduction reaction under the action of a Lewis acid to generate the compound M-01-1;

[0158] B2) the compound M-01-1 is subjected to a reaction with a nucleophile to generate the compound M-01;

[0159] wherein R 5 and R 7 have the definitions described in any of the schemes of the present application.

[0160] In an embodiment of the present application, there is provided a method for preparing the compound M-01A in the method for preparing the compound shown as formula IA, which comprises the following steps:

[0161] B1') compound SM-1A is subjected to a reduction reaction under the action of a Lewis acid to generate compound M-01-1A;

[0162] B2') compound M-01-1A is subjected to a reaction with a nucleophile to generate compound M-01.

[0163] According to the preparation method of compound M-01 or compound M-01A according to the present application, wherein the Lewis acid is one, two or more of BF3, AlCl3, FeCl3, SnCl4 or ZnCl2; the reducing agent of the reduction reaction is NaBH4, LiAlH4 or LiBH4; the solvent of the reduction reaction is tetrahydrofuran, toluene or 2-methyltetrahydrofuran; and the nucleophile is HBr.

[0164] In an embodiment of the present application, the preparation method of compound M-03A in the preparation method of the compound shown in formula IA is also provided, which comprises the following steps: compound SM-2A is subjected to a reaction with BocNH2 under the action of an acid and a reducing agent to generate compound M-03A:

[0165] wherein, R B is -B(OH)2 or the acid is trifluoroacetic acid, and the reducing agent is triethylsilane.

[0166] In an embodiment of the present application, the preparation method of compound M-04A in the preparation method of the compound shown in formula IA is also provided, which comprises the following steps:

[0167] C1) compound SM-3A is subjected to a reaction with bromoform under the action of a base to generate compound M-04-1A;

[0168] C2) compound M-04-1A is subjected to a hydrogenation reaction under the action of a catalyst to generate compound M-04-2A;

[0169] C3) compound M-04-2A is subjected to a deprotection of an amino protecting group Boc in an acidic system to generate compound M-04A.

[0170] According to the preparation method of compound M-04A according to the present application, wherein in step C1), the base is tetrabutylammonium bromide (TBAB); wherein in step C2), the catalyst of the hydrogenation reaction is palladium on carbon; and wherein in step C3), the acidic system is a 1,4-dioxane solution of hydrogen chloride.

[0171] The present application also provides a compound shown in formula IN-01, which is an intermediate for preparing the compound shown in formula (I),

[0172] wherein R 7 is H, R 5 , R c , R 9 , L and n have the meaning according to any of the embodiments of the present application.

[0173] According to an embodiment of the present application, the compound of formula IN-01 has the structure shown below, Advantages

[0174] The present application provides a preparation method of a complement factor D inhibitor and intermediates thereof, wherein the intermediates are stable in nature, high in reaction selectivity, good in yield and high in product purity, the preparation method is simple, the reaction raw materials are common and easy to obtain, each intermediate product can be purified by a conventional method, and the industrial production is facilitated, thereby further promoting the industrialization of the complement factor D inhibitor.

[0175] Definitions and explanations of terms

[0176] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The complete disclosures of all patents, patent applications, publications, and publications cited herein are incorporated by reference in their entirety.

[0177] The "room temperature" recorded in the specification of the present application should be understood as the ambient temperature at the time of the experiment, for example, 10-35°C, preferably 25°C±5°C.

[0178] "More" appearing in the present application means three or more.

[0179] "More" appearing in the present application means three or more.

[0180] When any variable (e.g., R 1-1 ) occurs more than one time in a compound, its definition in each occurrence is independent of its definition elsewhere unless otherwise stated. 1-1 Thus, if a group is substituted with 1, 2, or 3 R 1-1 groups, that is, the group can be substituted with up to 3 R 1-1 groups, the definition of R 1-1 at each occurrence is independent of the definition of R 1-6 at each occurrence. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0181] The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group having the indicated number of carbon atoms. In some embodiments, the alkyl group is a C 1-6 alkyl group, for example, a C 1-5alkyl, C 1-4 alkyl, C 1-3 alkyl, C 1-2 alkyl, etc.; in other embodiments, the alkyl group is C 1-3 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, sec-butyl, n-pentyl, n-hexyl, and the like.

[0182] The term "heterocycloalkyl" refers to a saturated cyclic group having the specified number of ring atoms (e.g., 7-12 ring atoms), and in which the ring atoms include at least one heteroatom independently selected from nitrogen, oxygen, and sulfur, which is a monocyclic, bridged ring, or spirocyclic ring system. Preferably, the number of heteroatoms in the heterocycloalkyl group is one, two, or three. The carbon and heteroatoms of the heterocycloalkyl group can optionally be oxidized to form an oxo or thia group or other oxidized linkage (e.g., C(=0), S(=0), S(=0)2, or N-oxide, etc.), or a nitrogen atom can be quaternized. The heterocycloalkyl group can be attached to the remainder of the compound through a ring carbon atom or a ring heteroatom. In some embodiments, the heterocycloalkyl group is an 8-11 membered heterocycloalkyl group having one, two, or three heteroatoms selected from N, O, and S, and one or two heteroatoms. In other embodiments, the heterocycloalkyl group is an 8-10 membered heterocycloalkyl group having one, two, or three heteroatoms selected from N, O, and S, and one or two heteroatoms. Heterocycloalkyl groups include, but are not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, 6-azaspiro[2.5]octyl, 5-azaspiro[2.5]octyl, 6-azaspiro[3.4]octyl, 2-azaspiro[3.4]octyl, 2-oxa-6-azaspiro[3.4]octyl, 6-oxa-2-azaspiro[3.4]octyl, 4-oxa-7-azaspiro[2.5]octyl, 2-azaspiro[4.4]nonyl, 2-azaspiro[3.5]nonyl, 2-oxa-7-azaspiro[3.5]nonyl, 1-oxa-7-azaspiro[3.5]nonyl, 7-azaspiro[3.5]nonyl, 2,7-diazaspiro[3.5]nonyl, 2-oxa-8-azaspiro[4.5]decyl, 3-oxa-9-azaspiro[5.5]undecyl, 2-oxa-9-azaspiro[5.5]undecyl, 3,9-diazaspiro[5.5]undecyl, 3-azabicyclo[3.2.1]octyl, 3-azaspiro[5,5]undecyl, 8-azaspiro[4.5]decyl, 1-oxa-6-azaspiro[3,4]octyl, and the like.

[0183] The term "halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0184] The target compound can be isolated according to known methods, for example, by extraction, filtration, recrystallization, or column chromatography. DETAILED DESCRIPTION

[0185] The technical solutions of the present application will be further described in detail below in combination with specific examples. It should be understood that the following examples are only illustratively described and explained, and should not be interpreted as limiting the scope of protection of the present application. Any technology realized based on the above description of the present application is covered within the scope of protection intended by the present application.

[0186] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0187] Reagent abbreviation explanation:

[0188] DMF: N,N-dimethylformamide

[0189] TBAB: tetrabutylammonium bromide

[0190] Pd / C: palladium on carbon

[0191] Pd(dppf)Cl2·CH2Cl2: 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride dichloromethane complex

[0192] Ruphos: 2-dicyclohexylphospho-2',6'-diisopropoxy-1,1'-biphenyl

[0193] Pd2(dba)3: tris(dibenzylideneacetone)dipalladium

[0194] XPhos: 2-dicyclohexylphospho-2',4',6'-triisopropyl biphenyl

[0195] BINAP: S-(-)-1,1'-binaphthalene-2,2'-bis(diphenylphosphine)

[0196] SPhos: 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl

[0197] Example 1, Method 1 for preparing compound IA

[0198] Step 1. Preparation of compound IN-01A1

[0199] Into a reaction kettle, N,N-dimethylformamide (265.44 kg) was charged, stirring was started, and the temperature was lowered to 20±5°C. Then cesium carbonate (53.2 kg) and M-02A1 (15.4 kg) were charged, and the temperature in the kettle was controlled to be 15-25°C during the feeding. Then M-01A1 (28 kg) was added in batches at this temperature, and the reaction was carried out at 25-35°C. After the reaction was completed as detected by the control test, the temperature was lowered to 10-20°C, and water (796.32 kg) was slowly added, and a large amount of solid was precipitated. After the addition was completed, the temperature was kept at 10-20°C for crystallization. The solid was filtered, and the filter cake was rinsed with water (300.0 kg) until the pH of the filtrate was 7-8. After the filter cake was slurried with methyl tert-butyl ether and n-heptane, drying was carried out to obtain compound IN-01A1 (30.8 kg, yield 85%, purity 97.6%). LC-MS [M+H] + = 461.0.

[0200] Step 2. Preparation of compound IN-02A1

[0201] Into a reaction kettle, acetonitrile (300.0 kg) and water (69.0 kg) were charged, stirring was started, and anhydrous potassium carbonate (13.1 kg), IN-01A1 (30.0 kg), M-03A1 (15.9 kg) and Pd(dppf)Cl2·CH2Cl2 (1.05 kg) were sequentially charged, and the temperature in the kettle was controlled to be 25±5°C during the feeding. After the feeding was completed, N2 was replaced, and the reaction was carried out at 55°C. After the reaction was completed as detected by the control test, 1M dilute hydrochloric acid was added dropwise to adjust the pH to 6-8. The reaction solution was distilled under reduced pressure, and saturated brine (150 kg) and methyl tert-butyl ether (150 kg) were added to the concentrated solution for extraction and separation. After the organic phase was subjected to palladium removal, water removal, tar removal, and pigment removal, it was evaporated to dryness. The concentrate was recrystallized with methyl tert-butyl ether and n-heptane, and dried to obtain compound IN-02A1 (29.06 kg, yield 78%, purity 94.9%). LC-MS [M+H-100] + = 441.90.

[0202] Step 3. Preparation of compound IN-03A1

[0203] Into a reaction kettle, add ethylene glycol dimethyl ether (60 kg), IN-02A1 (13.7 kg), M-04A (5.25 kg) and cesium carbonate (29 kg), after nitrogen bubbling, add Ruphos (1.15 kg) and Pd2(dba)3 (0.70 kg). After the completion of feeding, the temperature is raised to 80-90 °C for reaction. After the end of reaction detected by on-line control, the temperature is adjusted to 15-25 °C, add methyl tert-butyl ether (53 kg) and water (50 kg), and separate the liquid. The upper organic phase is filtered, and the internal temperature is controlled to be ≤50 °C. The reaction solution is concentrated. The concentrated reaction solution is diluted with ethyl acetate, and the temperature is controlled at 20-30 °C. 1M hydrogen chloride ethyl acetate solution (26 kg) is added dropwise, stirred for 2-4 hours, methyl tert-butyl ether (110 kg) is added dropwise, and stirred for 3-6 hours after the completion of dropwise addition. The system is centrifuged to obtain a filter cake, which is rinsed with methyl tert-butyl ether (20 kg). The obtained filter cake is compound IN-03A1 (11.60 kg, yield 70%, purity 94.5%). LC-MS [M+H] + = 571.10.

[0204] Step 4 and 5. Preparation of compound IA

[0205] Into a reaction kettle, add 1,4-dioxane (15 kg), and start stirring. Add IN-03A1 (10.7 kg). The temperature is controlled at 15-25 °C, 4M hydrogen chloride 1,4-dioxane solution (26.5 kg) is added dropwise, and the reaction is continued at 25 °C after the completion of feeding. After the end of reaction detected by on-line control, add water (26 kg) and methyl tert-butyl ether (40 kg), stir and stand to separate the liquid, take the water phase, add methanol (27 kg) to the water phase, control the temperature at 15-25 °C, and add 50% sodium hydroxide aqueous solution (7.5 kg) in batches. After the completion of addition, the reaction is continued at the same temperature. After the end of reaction detected by on-line control, the reaction solution is concentrated. The concentrated reaction solution is diluted with methanol and dichloromethane, the temperature is controlled at 0-25 °C, and the pH is adjusted to 3-4 with 6M hydrochloric acid. The temperature is controlled at 0-25 °C, the pH of the system is adjusted to 7-8 with 7% sodium bicarbonate aqueous solution. The temperature is controlled at 15-25 °C, and the system is stirred for 10-30 minutes. After standing, the lower organic phase is separated. The obtained organic phase is washed with water twice, transferred to a reaction kettle, the temperature is controlled at 15-25 °C, and the system is stirred for 8-16 hours to crystallize. The obtained solid is rinsed with dichloromethane and dried under vacuum to obtain compound IA (3.3 kg, yield 41%, purity 99.8%). LC-MS [M+H] + = 457.25.

[0206] Example 2, preparation method 2 of compound IA

[0207] The preparation method 2 of compound IA is the same as the preparation method 1 in Example 1, except that M-02A1 is replaced by M-02A2.

[0208] Example 3, Preparation Method 3 of Compound IA

[0209] Step 1. Preparation of compound IN-01B

[0210] Into a reaction flask was added M-01A (40 g, 0.106 mol) and M-02B (19.43 g, 0.106 mol), then a mixed solvent of ethanol and water (240 mL, ethanol / water = 2 / 1) and potassium hydroxide (11.872 g, 0.212 mol) were added, and the reaction was stirred at 50°C for 2 h, then potassium hydroxide (5.936 g, 0.106 mol) was added, and the reaction was continued. After the reaction was completed by sampling, a saturated citric acid solution was added to adjust the pH to about 3-5, and a solid was precipitated. The solid was filtered, and the filter cake was washed with water. The filter cake was dissolved in water by adding sodium hydroxide solution, and extracted with ethyl acetate. The water phase was separated, and the pH of the water phase was adjusted to be acidic, and a solid was precipitated. The solid was filtered to obtain a solid, which was dried under vacuum to obtain compound IN-01B (36.16 g, yield 76%, purity 98%).

[0211] Step 2. Preparation of compound IN-02B

[0212] Compound IN-01B (100 g, 0.224 mol) was added to acetonitrile (300 mL), and a solution of potassium carbonate (77.3 g, 0.559 mol) in water (150 mL) was added dropwise to the reaction solution, and Pd(dppf)Cl2 (4.917, 6.72 mmol) was added. The reaction was heated to 30-40°C, and M-03A1 (67.49 g, 0.224 mol) was dissolved in a mixed solvent of acetonitrile and water (440 mL, acetonitrile / water = 3 / 7) and added dropwise to the reaction solution, and the dropwise addition was controlled for 1.5-2 h. After the dropwise addition was completed, the reaction was stirred at 30-40°C. After the reaction was completed by sampling, a 20% citric acid aqueous solution was slowly added to adjust the pH to 3-5, and a large amount of solid was precipitated. After stirring for 2 h, the solid was filtered to obtain a solid crude product. The solid crude product was washed with water, and the water was removed by vacuum drying. Then, ethyl acetate (800 mL) was added and heated to 70°C, and the reaction was refluxed for 2 h. The temperature was slowly lowered to 0-5°C, and the reaction was stirred for 12 h. The product was filtered to obtain a white solid powder. The product was dried under vacuum at 40°C to obtain compound IN-02B (36.16 g, yield 82%, purity 99.4%).

[0213] Step 3. Preparation of compound IN-03B oxalate salt

[0214] IN-02B (50 g, 0.112 mol), M-04A (24.74 g, 0.167 mol), cesium carbonate (164.2 g, 0.504 mol), Pd2(dba)3(10.256 g, 0.0112 mol), RuPhos (10.45 g, 0.0224 mol) and toluene (500 mL) were charged into a reaction flask, after nitrogen replacement, the reaction was stirred at 95 °C. After sampling detection, the reaction was complete, water was added for dilution, citric acid solution was added to adjust the pH of the solution to about 3, the organic phase was separated, the aqueous phase was extracted with toluene twice, and the organic phase was combined. The organic phase was concentrated. The residue after concentration was dissolved in ethyl acetate (500 mL), 10% sodium bisulfite solution (500 mL) was added to the obtained solution, and then heated to 45 °C and stirred overnight. The reaction solution was slowly cooled to 0-5 °C, oxalic acid (12.1 g, 0.134 mol) was slowly added under stirring, solid slowly precipitated, after stirring at constant temperature for 8 h, filtration was carried out, and the filter cake was rinsed with ethyl acetate. The obtained filter cake was dried, dispersed in dichloromethane (500 mL), the obtained suspension was heated to 50 °C and refluxed for 1 h, slowly cooled to room temperature and stirred for 3 h, then cooled to 0-5 °C and stirred for 12 h, filtered, and the product IN-03B oxalate (46.64 g, yield 75%, purity 99.7%) was obtained after vacuum drying.

[0215] Step 4. Preparation of compound IA

[0216] The IN-03B oxalate (39.0 g, 60.30 mmol) was added to a reaction flask, hydrochloric acid (468 mL, 6.0 M) was added, after stirring was started, heating to 45-50 °C was carried out, and reaction was carried out for 2-3 h. After HPLC detection, the raw material was reacted, the temperature was cooled to 0-10 °C, sodium bicarbonate solution was added to adjust the pH to 7-8, stirring was carried out for about 30 min, dichloromethane (200 mL x 2) was used for extraction, the combined organic phase was washed with saturated sodium chloride aqueous solution (200 mL), anhydrous sodium sulfate was used for drying, filtration was carried out, and the filtrate was concentrated under reduced pressure. n-Heptane was added to the residue after concentration, stirring was carried out at room temperature for 2 h, filtration was carried out, and the filter cake was dried to obtain compound IA (29.5 g, yield 94%, purity 99.6%).

[0217] Example 4, preparation of compound M-01A

[0218] Step 1. Preparation of compound M-01-1A

[0219] Into a reaction kettle, add tetrahydrofuran (124.6 kg), stir and cool to -5 °C, then add 3-bromo-5-iodobenzoic acid (SM-1A, 20 kg) and boron trifluoride etherate (43.52 kg) in sequence, control the temperature at -5 ± 5 °C. Add sodium borohydride (5.5 kg) in batches, control the temperature at ≤15 °C. After the addition is completed, keep the temperature at 15 ± 5 °C for reaction. After the reaction is completed as monitored by the control test, cool to -10 ± 5 °C, slowly add water, and solid precipitates, during which the temperature in the kettle is controlled at ≤10 °C. After the addition is completed, keep the temperature at 0-10 °C for crystallization for 2 h, then centrifuge, filter, wash the filter cake with water, collect the filter cake, and dry to obtain compound M-01-1A (16.4 kg, yield 85.4%, purity 98.9%).

[0220] Step 2. Preparation of compound M-01A

[0221] Into a reaction kettle, add hydrobromic acid (73.3 kg, purity 48%), start stirring, and warm to 70 °C, then add compound M-01-1A (16.4 kg). Warm to 115 ± 5 °C and keep the temperature for 2 h for reaction. After TLC monitoring shows that there is no raw material left, slowly cool to about 30 °C, add dichloromethane, extract and separate, concentrate the organic phase under reduced pressure to obtain a crude product. The crude product is slurried with n-heptane and dried to obtain compound M-01A (15.6 kg, yield 79.0%, purity 98.8%).

[0222] Example 5, Preparation of compound M-03A1

[0223] Into a reaction kettle, add acetonitrile (235.8 kg), start stirring, and add compound SM-2A1 (30.0 kg), tert-butyl carbamate (30.6 kg), and triethylsilane (34.8 kg) in sequence, start N2purging, slowly add trifluoroacetic acid (45.6 kg) dropwise, and control the temperature in the kettle at ≤10 °C during the process. After the addition is completed, warm the temperature in the kettle to 20-25 °C for reaction, and stop N2purging after the temperature in the kettle is increased to 20 °C. After the reaction is completed as monitored by the control test, add 25% sodium hydroxide aqueous solution dropwise to adjust pH to 6-7, and extract twice with n-heptane. Take the lower acetonitrile / water phase, adjust pH to 8-9 with 25% sodium hydroxide aqueous solution, dissolve the residue obtained after acetonitrile / water phase is distilled under reduced pressure with acetonitrile, slowly stir the obtained solution to be uniform, then add 1M dilute hydrochloric acid (120.0 kg) dropwise, warm to 20 ± 5 °C for crystallization for 10-12 h. After the crystallization is completed, centrifuge, filter, wash the filter cake with clean water until it is neutral, and dry the filter cake under vacuum to obtain compound M-03A1 (35.5 kg, yield 60.1%, purity 99.68%).

[0224] Example 6, Preparation of compound M-04A

[0225] Step 1. Preparation of compound M-04-1A

[0226] Into a reactor, dichloromethane (116 kg), bromoform (73.6 kg) and water (25 kg) were charged, and stirring was started. Then, compound SM-3A (25 kg) and tetrabutylammonium bromide (4.12 kg) were added. The temperature was lowered to 5 °C, and a previously prepared sodium hydroxide aqueous solution (30.62 kg of sodium hydroxide dissolved in 37.5 kg of water) was added dropwise while controlling the temperature at 15 °C. After the addition was completed, the temperature was raised to 40-47 °C, and the reaction was continued until the control test was passed. The temperature was lowered to 5 °C, and the pH was adjusted to 5-6 with dilute hydrochloric acid while controlling the temperature at 15 °C or lower. Then, dichloromethane was added for extraction, and the organic phases were combined and concentrated to obtain a crude product. The crude product was dissolved by adding methyl tert-butyl ether, filtered through diatomaceous earth, and the filtrate was concentrated to obtain a crude product. The crude product was recrystallized from isopropanol and water, and the obtained crystals were slurried with n-heptane. The mixture was centrifuged, filtered, and the filter cake was dried to obtain compound M-04-1A (26.6 kg, yield 59.5%, purity 99.3%).

[0227] Step 2. Preparation of compound M-04-2A

[0228] Into a hydrogenation reactor, 5% palladium-carbon (0.7 kg) was immersed with isopropanol (5.5 kg), and stirring was started. The temperature was lowered to ≤20 °C, and potassium hydroxide (3.2 kg) and a previously prepared potassium methoxide solution in isopropanol (27.5 kg of isopropanol dissolved in 8.0 kg of potassium methoxide) were added. Then, compound M-04-1A (7.0 kg) and isopropanol (22.0 kg) were slowly added. After the addition was completed, the reactor was purged with hydrogen three times, and the temperature was raised to 80 °C. The reaction was continued until the control test was passed. After the reaction was completed, the temperature was lowered to 20 °C, and the reactor was purged with nitrogen three times. After the pressure was released, the reaction solution was filtered through diatomaceous earth. The filtrate was slowly added to a previously prepared aqueous acetic acid solution (pre-cooled to 5 °C) while controlling the temperature in the reactor at ≤10 °C. After the addition was completed, the mixture was crystallized for 2 h, and then centrifuged, filtered, and the filter cake was dried in vacuo to obtain compound M-04-2A (2.71 kg, yield 67.6%, purity 98.2%).

[0229] Step 3. Preparation of compound M-04A

[0230] Into a reactor, 9.98 kg of a 1,4-dioxane solution of hydrogen chloride was charged, and stirring was started. The temperature was lowered to 0-5 °C. Then, compound M-04-2A (2.66 kg) was added in portions while controlling the temperature at ≤25 °C. After the addition was completed, the reaction was continued at 25 °C until the control test was passed. The reaction solution was crystallized for 1 h. The mixture was filtered, the filter cake was rinsed with n-heptane, and the filter cake was dried in vacuo to obtain compound M-04A (1.71 kg, yield 92.0%, purity 99.4%).

[0231] Example 7, Method 1 for preparing compound IN-02A1

[0232] Compound IN-01A1 (5 g, 10.84 mmol), compound M-03A1 (2.721 g, 10.84 mmol), acetonitrile (37.5 mL), water (7.5 mL), potassium carbonate (2.247 g, 16.26 mmol) and Pd(dppf)Cl2CH2Cl2(265.57 mg, 0.33 mmol) were sequentially added to a reaction flask, and the mixture was stirred at 50°C for 16 h under nitrogen. The HPLC analysis showed that 90% of IN-02A1 was generated.

[0233] Example 8, Preparation Method 2 of Compound IN-02A1

[0234] Compound 2-(2-((3,5-dibromobenzyl)oxy)phenyl)acetic acid methyl ester (5 g, 12.07 mmol), compound M-03A1 (3.182 g, 12.68 mmol), acetonitrile (20 mL), water (20 mL), potassium carbonate (4.17 g, 30.175 mmol) and Pd(dppf)Cl2CH2Cl2(295.7 mg, 0.36 mmol) were sequentially added to a reaction flask, and the mixture was stirred at 50°C for 16 h under nitrogen. The HPLC analysis showed that 65% of IN-02A1 was generated.

[0235] The above describes the embodiments of the present application. However, the present application is not limited to the above-described embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A process for the preparation of a compound of formula IN-02 comprising the steps of A2)： The compound IN-01 is reacted with the compound M-03 to form a compound of formula IN-02, wherein: R 1 is H; R 2 and R 3 each independently H, C 1-6 alkyl or C 2-1 alkyl substituted by 1, 2 or 3 R 1-6 each R 2-1 independently halogen or -OH, the halogen preferably being F; R 4 R is H or halogen; m is 0 or 1; R B is -B(OH)2or R 5 , R 7 , and R 9 are each independently H or halo; n is 0 or 1; L is -(CR a R b ) q -; q is 0 or 1 ; R a and R b each independently H, D, or halogen; R c is H or C 1-6 alkyl.

2. The process according to claim 1 for the preparation of a compound of formula IN-02, wherein it further comprises the following steps: A1 ) the compound M-01 reacts with the compound M-02 in the presence of a base to form the compound IN-01, wherein: R 5 , R 7 , and R 9 are each independently H or halo; n is 0 or 1; L is -(CR a R b ) q -; q is 0 or 1 ; R a and R b each independently H, D, or halogen; R c is H or C 1-6 alkyl.

3. Process for the preparation of a compound of formula IN-02 according to claim 1 or 2, characterized in that, one or more of the following conditions are met: (1) R 2 and R 3 each independently is hydrogen, methyl, -CH2OH, -CH2CH2OH, -CH2F, -CHF2, or ethyl; (2) R 4 is H or F; (3) R B is -B(OH)2; (4) R 5 , R 7 , and R 9 are each independently H or F; (5) q is 1; (6) R a and R b each independently H; (7) R c is H, methyl or ethyl; (8) in the step A2), the reaction occurs in the presence of a base and a catalyst; (9) in the step A2), the temperature of the reaction is 30-80°C.

4. The process according to claim 3 for the preparation of a compound of formula IN-02, wherein one or more of the following conditions are met: (1) R 2 and R 3 each independently is hydrogen; (2) R 4 is H; (3) R 5 , R 7 , and R 9 are each independently H; (4) R c is H; (5) in the step A1), the base is one, two or more of alkali metal carbonate, alkali metal bicarbonate, alkali metal hydroxide, alkali metal alcoholate, alkali metal carboxylate, alkali metal fluoride, alkali metal phosphate or organic amine base; (6) in the step A1), the solvent of the reaction is one or more of amide solvent, alcohol solvent or water; (7) in the step A1), the temperature of the reaction is 15-60°C; (8) in the step A2), the solvent of the reaction is a mixed solvent of at least one of nitrile solvent or ether solvent and water; (9) in the step A2), the base of the reaction is one, two or more of alkali metal carbonate, alkali metal bicarbonate, alkali metal hydroxide, alkali metal alcoholate, alkali metal carboxylate, alkali metal fluoride, alkali metal phosphate or organic amine base; (10) in the step A2), the catalyst of the reaction is a palladium catalyst.

5. The process according to claim 4 for the preparation of a compound of formula IN-02, wherein one or more of the following conditions are met: (1) in the step A2), the reaction is Suzuki coupling reaction, and the molar ratio of the compound IN-01 to the compound M-03 is 1.00:(1.00-1.20); (2) in the step A1) and step A2), the alkali metal carbonate is cesium carbonate, potassium carbonate or sodium carbonate; (3) in the step A1) and step A2), the alkali metal bicarbonate is sodium bicarbonate or potassium bicarbonate; (4) in the step A1) and step A2), the alkali metal hydroxide is lithium hydroxide, potassium hydroxide or sodium hydroxide; (5) in the step A1) and step A2), the alkali metal alcoholate is sodium methoxide, sodium ethoxide, potassium tert-butoxide or sodium tert-butoxide; (6) in the step A1) and step A2), the alkali metal carboxylate is potassium acetate; (7) in the step A1) and step A2), the alkali metal fluoride is potassium fluoride or cesium fluoride; (8) in the step A1) and step A2), the alkali metal phosphate is potassium phosphate or sodium phosphate; (9) in the step A1) and step A2), the organic amine base is triethylamine or N,N-diisopropylethylamine; (10) in the step A1), the solvent system of the reaction is DMF, or a mixed solvent of alcohol solvent and water; (11) in the step A1), the temperature of the reaction is 25-35°C or 50°C; (12) in the step A2), the molar ratio of the compound IN-01 to the compound M-03 is 1.00:(1.00-1.10); (13) in the step A2), the temperature of the reaction is 40-80°C or 40-60°C; (14) In the step A2), the solvent of the reaction is a mixed solvent of at least one of acetonitrile, ethylene glycol dimethyl ether or tetrahydrofuran and water; (15) In the step A2), the catalyst of the reaction is 1,1'-bis(diphenylphosphino) ferrocene palladium dichloride methane complex or 1,1'-bis(diphenylphosphino) ferrocene palladium chloride.

6. Process for the preparation of a compound of formula IN-02 according to any one of claims 1 to 5, characterized in that, One or more of the following conditions are met: (1) In the step A1), the base is one, two or more of cesium carbonate, potassium carbonate, lithium hydroxide, sodium methoxide, potassium hydroxide, sodium carbonate, potassium acetate, sodium bicarbonate, potassium bicarbonate, potassium fluoride, cesium fluoride, sodium hydroxide, triethylamine, N,N-diisopropylethylamine, sodium methoxide, sodium ethoxide, potassium tert-butoxide or sodium tert-butoxide, and preferably one, two or more of cesium carbonate, potassium carbonate or potassium hydroxide; (2) In the step A1), the solvent system of the reaction is DMF, or a mixed solvent of ethanol and water; (4) In the step A2), the molar ratio of the compound IN-01 to the compound M-03 is 1.00:1.02 or 1.00:1.05; (5) In the step A2), the temperature of the reaction is 30-40℃, 50℃ or 55℃; (6) In the step A2), the solvent of the reaction is a mixed solvent of acetonitrile and water; (7) In the step A2), the base of the reaction is an alkali metal carbonate and / or an alkali metal hydroxide; preferably an alkali metal carbonate; and more preferably potassium carbonate; for example, anhydrous potassium carbonate; (8) the compound M-01 is (9) the compound M-02 is (10) the compound IN-01 is (11) the compound M-03 is (12) compounds represented by formula IN-02 are 7. A method for preparing a compound of formula (I) ###0002### (I) characterized in that, The preparation method of the compound represented by the formula IN-02 in any one of claims 1-6 further comprises the following steps: A3) reacting compound IN-02 with compound M-04 to form compound IN-03, or a salt thereof; for example, reacting compound IN-02 with compound M-04 to form compound IN-03; A4) removing the amino protecting group Boc from compound IN-03 or a salt thereof to form compound IN-04 or a compound of formula (I); A5) the compound IN-04 undergoes a hydrolysis reaction to form a compound represented by formula (I), R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 9 , R c , L, m and n each independently have the definition as described in any one of claims 1 to 6; wherein when R c is H, its preparation process comprises steps A2), A3) and A4) or A1 ), A2), A3) and A4); for example steps A1 ), A2), A3) and A4); when R c is C 1-6 alkyl, its preparation process comprises steps A2), A3), A4) and A5) or A1 ), A2), A3), A4) and A5); for example A1 ), A2), A3), A4) and A5); M-04 is R 6 H or a salt thereof; R 6 is "8-11 membered heterocycloalkyl, wherein the heteroatoms are selected from 1, 2 or 3 of N, O and S, the number of heteroatoms is 1, 2 or 3, and the heterocycloalkyl is substituted by 1, 2 or 3 R 6-1 substituted "8-11 membered heterocycloalkyl, wherein the heteroatoms are selected from 1, 2 or 3 of N, O and S, the number of heteroatoms is 1, 2 or 3, and the heterocycloalkyl is substituted by 1, 2 or 3 R 6-1 independently is hydroxyl or C 1-6 alkyl, and the heterocycloalkyl is a bridged or spirocyclic ring; R 10 is -COOH.

8. The method for preparing the compound of formula (I) according to claim 7, characterized in that, One or more of the following conditions are met: (1) In the step A4), it comprises the following step: compound IN-03 is removed from the amino protecting group Boc to generate compound IN-04 or the compound of formula (I); (2) R 6 is "8-11 membered heterocycloalkyl having 1 heteroatom which is N"; (3) the compound IN-03 is oxalate salt of (4) the compound IN-04 is (5) the compound represented by formula (I) is selected from the group consisting of the following structures: (6) In the step A3), the reaction occurs in the presence of a catalyst, a ligand and a base in a solvent; (7) In the step A5), the hydrolysis reaction occurs in the presence of a base in a solvent.

9. The method for preparing the compound of formula (I) according to claim 7 or 8, characterized in that, One or more of the following conditions are met: (1) M-04 is R6-H or a hydrochloride salt thereof; for example, R6-H; the R6-H hydrochloride salt is, for example, R6-H.HCl; preferably, M-04 is (2) In the step A3), the reaction is a Buchwald coupling reaction; (3) In the step A3), the reaction is carried out in the presence of a Pd catalyst, which is Pd2(dba)3; the reaction needs to use a ligand, which is RuPhos, XPhos, BINAP or SPhos; the reaction is carried out in the presence of a base, which is an alkali metal carbonate, an alkali metal phosphate or an alkali metal alcoholate; (4) In the step A3), the solvent is one or more of an ether solvent, an amide solvent or a benzene solvent; (5) In the step A4), the reaction of removing the amino protecting group Boc occurs in an acidic system, which is hydrogen chloride in methanol, hydrogen chloride in 1,4-dioxane, hydrogen chloride in ethyl acetate, trifluoroacetic acid in dichloromethane or hydrochloric acid; (6) In the step A5), the hydrolysis reaction occurs under the action of a base, and the base is an inorganic base; the inorganic base is an alkali metal hydroxide; (7) In the step A3), the molar ratio of the compound IN-02 to the compound M-04 is 1.00: (1.00-2.00); (8) In the step A5), the solvent is a mixed solvent of an alcohol solvent and / or water.

10. The method for preparing the compound of formula (I) according to claim 9, characterized in that, The preparation method meets one or more of the following conditions: (1) R 6 is 1, 2, or 3 R 6-1 substituted with 6-azaspiro[2.5]octyl, 5-azaspiro[2.5]octyl, 6-azaspiro[3.4]octyl, 2-azaspiro[3.4]octyl, 2-oxa-6-azaspiro[3.4]octyl, 6-oxa-2-azaspiro[3.4]octyl, 4-oxa-7-azaspiro[2.5]octyl, 2-azaspiro[4.4]nonyl, 2-azaspiro[3.5]nonyl, 2-oxa-7-azaspiro[3.5]nonyl, 1-oxa-7-azaspiro[3.5]nonyl, 7-azaspiro[3.5]nonyl, 2,7- diazaspiro[3.5]nonyl, 2-oxa-8-azaspiro[4.5]decyl, 3-oxa-9-azaspiro[5.5]undecyl, 2-oxa-9-azaspiro[5.5]undecyl, 3,9-diazaspiro[5.5]undecyl, 3-azabicyclo[3.2.1]octyl, 3-azaspiro[5,5]undecyl, 8-azaspiro[4.5]decyl, or 1-oxa-6-azaspiro[3,4]octyl; each R 6-1 is independently hydroxyl, methyl, ethyl, n-propyl, or i-propyl; (2) In the step A3), the ligand is RuPhos; (3) In the step A3), the base is cesium carbonate, potassium phosphate or potassium tert-butoxide; (4) In the step A4), the acid system is a methanol solution of hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, an ethyl acetate solution of hydrogen chloride or a dichloromethane solution of trifluoroacetic acid, and is further preferably a 1,4-dioxane solution of hydrogen chloride; (5) In the step A5), the base is one, two or more of NaOH, KOH or LiOH; (6) In the step A3), the molar ratio of the compound IN-02 to the compound M-04 is 1.00: (1.00-1.50); (7) In the step A5), the alcohol solvent is methanol.

11. The method for preparing the compound of formula (I) according to claim 10, characterized in that, The preparation method meets one or more of the following conditions: (1) R 6 To (2) In the step A3), the base is cesium carbonate; (3) In the step A3), the molar ratio of the compound IN-02 to the compound M-04 is 1.0:1.5; (4) when R c is H, in step A3) the solvent of the reaction is a benzene solvent; preferably toluene; (5) when R c is H, in step A3) the temperature of the reaction is between 80 and 110°C; preferably 95°C; (6) when R c when R is H, in step A3), the reaction further comprises the step of reacting compound IN-03 with oxalic acid to form an oxalate salt of compound IN-03; Preferably, the molar ratio of the compound IN-03 to the oxalic acid is 1.00: (1.00-2.00); preferably 1.00:1.20; (7) when R c is H, in step A4) the reaction takes place in an acidic system, which is hydrochloric acid; preferably 6.0 M hydrochloric acid; (8) when R c when R is H, the temperature of the reaction in step A4) is 30-60 °C; preferably 45-50 °C; (9) In the step A5), the base is NaOH.

12. A method for preparing a compound of formula IA, characterized in that, It comprises any one of the following schemes: Scheme 1: comprising the following steps: A1') Compound M-01A reacts with compound M-02A in the presence of a base to form compound IN-01A, A2') Compound IN-01A is subjected to a Suzuki reaction with compound M-03A to produce compound IN-02A, A3') Buchwald coupling reaction of compound IN-02A with compound M-04A to form compound IN-03A, A4') Compound IN-03A is deprotected of the amino protecting group Boc in an acidic system to give compound IN-04A, and A5') Compound IN-04A is subjected to a hydrolysis reaction in the presence of a base to obtain a compound represented by formula IA, wherein R is -B(OH)2or B ​ R c is C 1-3 alkyl; In the step A1'), the base is one, two or more of cesium carbonate, potassium carbonate, lithium hydroxide, sodium methoxide, potassium hydroxide, sodium carbonate, potassium acetate, potassium phosphate, sodium phosphate, sodium bicarbonate, potassium bicarbonate, potassium fluoride, cesium fluoride, sodium hydroxide, triethylamine, N, N-diisopropyl ethylamine, sodium methoxide, sodium ethoxide, potassium tert-butoxide or sodium tert-butoxide; the solvent system of the reaction is DMF, or a mixed solvent of an alcohol solvent and water; In the step A2'), the molar ratio of the compound IN-01A to the compound M-03A in the Suzuki reaction is 1.00: (1.00-1.20), the temperature of the reaction is 40-80°C, and the solvent of the reaction is a mixed solvent of at least one of acetonitrile, ethylene glycol dimethyl ether or tetrahydrofuran and water; In Step A3'), the Buchwald coupling reaction is carried out in the presence of a Pd catalyst, which is Pd2(dba)3; the Buchwald coupling reaction requires the use of a ligand, which is RuPhos, XPhos, BINAP or SPhos; the Buchwald coupling reaction is carried out in the presence of a base, which is cesium carbonate, potassium phosphate or potassium tert-butoxide; the solvent for the Buchwald coupling reaction is N,N-dimethylacetamide, ethylene glycol dimethyl ether, 1,4-dioxane or toluene; In Step A4'), the acidic system is hydrogen chloride in methanol, hydrogen chloride in 1,4-dioxane, hydrogen chloride in ethyl acetate or trifluoroacetic acid in dichloromethane; In Step A5'), the base is an inorganic base, which is one, two or more of NaOH, KOH or LiOH; Scheme 2 comprises the following steps: A1") reacting compound M-01A with compound M-02B in a solvent in the presence of a base to form compound IN-01B, A2") Suzuki reaction of compound IN-01 B with compound M-03 A in the presence of a base and a catalyst in a solvent to form compound IN-02B, A3”) in a solvent, a coupling reaction of compound IN-02B with compound M-04A in the presence of a catalyst, a ligand and a base to form an oxalate salt of compound IN-03B, A4") the oxalate salt of compound IN-03B reacts in the presence of an acid in an acidic system to form compound IA, In Step A1"), the base is an alkali metal hydroxide; The base is an alkali metal hydroxide; The solvent is a mixture of an alcoholic solvent and water; In Step A2"), the base is an alkali metal carbonate; The solvent is a mixture of a nitrile solvent and water; The base is an alkali metal carbonate; The catalyst is a palladium catalyst; The molar ratio of the compound IN-01B to the compound M-03A is 1.00:(1.00-1.20); The temperature for the reaction is 30-80°C; R B is -B(OH)2or In Step A3"), the solvent is a benzene solvent; The catalyst is a palladium catalyst; The ligand is RuPhos, XPhos, BINAP or SPhos; The base is an alkali metal carbonate; The molar ratio of the compound IN-02B to the compound M-04A is 1.00:(1.0-2.0); The temperature for the reaction is 80-110°C; In Step A4"), the acid is hydrochloric acid, The temperature for the reaction is 30-60°C. The preparation method satisfies one or more of the following conditions: (2) In Step A1'), the base is one, two or more of cesium carbonate, potassium carbonate, lithium hydroxide, sodium methoxide, potassium hydroxide, sodium carbonate, potassium acetate, sodium bicarbonate, potassium bicarbonate, potassium fluoride, cesium fluoride, sodium hydroxide, triethylamine, N,N-diisopropylethylamine, sodium methoxide, sodium ethoxide, potassium tert-butoxide or sodium tert-butoxide; preferably, the base is one, two or more of cesium carbonate, potassium carbonate or potassium hydroxide; 13. The method of claim 12, wherein the compound of Formula IA is prepared by the process of: ###0002### Formula IA (3) In Step A1'), the solvent system for the reaction is DMF, or a mixture of ethanol and water; (1) in Scheme 1, R c is methyl or ethyl; (4) In Step A2'), the molar ratio of the compound IN-01A to the compound M-03A in the Suzuki reaction is preferably 1.00:(1.00-1.10), for example 1.00:1.02 or 1.00:1.05; (5) In Step A2'), the temperature for the reaction is 40-60°C, for example 55°C; (6) In Step A2'), the solvent for the reaction is a mixture of acetonitrile and water; (7) In Step A3'), the ligand is RuPhos; ​ ​ (8) In the step A3'), the base is cesium carbonate; (9) In the step A3'), the solvent is toluene; (10) In the step A4'), the acidic system is hydrogen chloride in 1,4-dioxane; (11) In the step A5'), the base is NaOH; (12) In the step A1"), the base is potassium hydroxide; (13) In the step A1"), the solvent is a mixture of ethanol and water; (14) In the step A2"), the solvent is a mixture of acetonitrile and water; (15) In the step A2"), the base is potassium carbonate; (16) In the step A2"), the catalyst is 1,1'-bis(diphenylphosphino) ferrocene palladium(II) chloride dichloromethane complex or 1,1'-bis(diphenylphosphino) ferrocene palladium(II) chloride; (17) In the step A2"), the molar ratio of the compound IN-01B to the compound M-03A is 1.00:1.00; (18) In the step A2"), the temperature of the reaction is 30-40 °C; (19) In the step A3"), the solvent is toluene; (20) In the step A3"), the catalyst is Pd2(dba)3; (21) In the step A3"), the ligand is RuPhos; (22) In the step A3"), the base is cesium carbonate; (23) In the step A3"), the molar ratio of the compound IN-02B to the compound M-04A is 1.00:1.50; (24) In the step A3"), the temperature of the reaction is 95 °C; (25) In the step A3"), the reaction further comprises the following step: the compound IN-03B is reacted with oxalic acid to form the oxalate salt of the compound IN-03B; preferably, the molar ratio of the compound IN-03B to the oxalic acid is 1.00:(1.00-2.00); preferably 1.00:1.20; (26) In the step A4"), the acid is 6.0 M hydrochloric acid; (27) In the step A4"), the temperature of the reaction is 45-50 °C.

14. A compound of formula IN-01, which is an intermediate for the preparation of a compound of formula (I), wherein, R 5 , R 7 , R 9 , R c , L and n are independently defined as in any one of claims 1-4; Preferably, R 5 is H or halogen, preferably F; R 7 is H; R 9 is H or halogen, preferably F; n is 0 or 1; L is -(CR a R b ) q -; q is 1; R a and R b each independently H, D, or halogen, preferably F; R c is H or C 1-6 alkyl, said C 1-6 alkyl is preferably methyl or ethyl.

15. The compound of formula IN-01 according to claim 14, characterized in that, The compound of Formula IN-01 has the structure shown below:

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