Method for synthesizing 7,8-dihydro-2H-cyclopentapyrrolopyrazinone compounds

Abstract

The present invention relates to a method for the synthesis of 7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one compounds and their analogs, which are well suited for large-scale industrial production due to their simple steps, simple and safe reaction procedures, and related intermediates that are easily isolated and purified.

Description

[Technical field]

[0001] Technical Field The present invention is in the field of pharmaceutical intermediates and medicinal chemistry. In particular, the present invention relates to a method for synthesizing 7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one compounds and analogs thereof. [Background technology]

[0002] Background technology 7,8-Dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one compounds and their analogues are a novel class of pharmaceutical intermediates.

[0003] Various active compounds for use in the treatment of inflammation, immune diseases and cancer, as well as intermediates for the preparation of these compounds, such as the compound having the following structure, are provided in Chinese patent application CN 104125959 A:

[0004] [ka]

[0005] The patent application further discloses the following methods for preparing the above compounds: Method 1:

[0006] [ka]

[0007] The Wittig reaction is carried out in the first synthetic step of the method. The reaction is usually carried out in the presence of aprotic solvents and strong bases, and under anhydrous and oxygen-free conditions, etc., and produces a highly unstable Wittig reagent, which is not subjected to isolation, but is reacted directly with an aldehyde to produce compound 107a. The harsh conditions of the Wittig reaction make this method unsuitable for industrial production. Sodium azide is used in the second step of the method to introduce an amino group (compound 107b), and due to its highly toxic and explosive nature, this route poses a significant hidden safety hazard in industrial production. Method 2:

[0008] [ka]

[0009] The method also uses sodium azide, a highly toxic and explosive reagent, making it unsuitable for use in industrial production.

[0010] In addition, the above methods 1 and 2 have long reaction pathways, which are not conducive to industrial production.

[0011] The present invention provides a novel method for synthesizing 7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one compounds and their analogs (compounds of formula (I)). The method is well suited for large-scale industrial production due to its simple steps, simple and safe reaction procedures, and related intermediates are easily isolated and purified. The present invention also provides novel intermediate compounds, which can be used for the preparation of various small molecule inhibitors or their intermediates. Summary of the Invention [Means for solving the problem]

[0012] Summary of the invention: The present invention provides a method for synthesizing 7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one compounds and analogs thereof (i.e., compounds represented by formula (I)) (hereinafter referred to as the "method of the present invention").

[0013] [ka]

[0014] (Wherein, R1 and R2 are each independently hydrogen, C 1-6 alkyl, or halogen; R3 is hydrogen or C 1-6 Selected from alkyl; m and n are independently 0, 1 or 2, and m + n is 2, 3 or 4; and R4 is hydrogen or C 1-6 alkyl.)

[0015] In one aspect, the present invention provides the following synthetic route:

[0016] [ka]

[0017] (wherein the variables are defined below).

[0018] In another aspect, the present invention also provides the following specific embodiments.

[0019] Embodiment 1: Formula (I)

[0020] [ka]

[0021] (Wherein, R1 and R2 are each independently hydrogen, C 1-6 alkyl, or halogen; R3 is hydrogen or C 1-6 Selected from alkyl; m and n are independently 0, 1 or 2, and m + n is 2, 3 or 4; and R4 is hydrogen or C 1-6 alkyl.) A method for synthesizing a compound of the formula: The process is as follows: a) Compound M1

[0022] [ka]

[0023] (wherein R1, R2, R3, m, and n are as defined above, and X is a halogen or an easily removable active ester group such as -OTf, -Ots, or -Oms, preferably a halogen.) Compound M2

[0024] [ka]

[0025] (R in the formula a , R b , and R c are each independently C 1-6 alkyl.) to give compound M3

[0026] [ka]

[0027] (In the formula R1, R2, R3, m, n, R a , R b , and R c is as defined above.) obtaining b) Compound M3 is subjected to an ammonolysis reaction to produce compound M4

[0028] [ka]

[0029] (In the formula R1, R2, R3, R4, m, n, R a , and R b is as defined above.) obtaining c) reacting compound M4 under acidic conditions to obtain a compound of formula (I) A method comprising:

[0030] Embodiment 2: The method according to embodiment 1, wherein step b) is replaced by step b') as follows: Compound M3 was subjected to hydrolysis reaction to obtain compound M5.

[0031] [ka]

[0032] (In the formula R1, R2, R3, m, n, R a , and R b is as defined above.) Compound M5 is then reacted with R4NH2 (where R4 is hydrogen or C 1-6 alkyl) to give compound M4.

[0033] Embodiment 3: R1 and R2 are each independently C 1-6 The method according to embodiment 1 or 2, wherein the alkyl group is selected from alkyl or hydrogen, preferably methyl or hydrogen, and more preferably methyl.

[0034] Embodiment 4: A method according to any one of the preceding embodiments, wherein R3 is H.

[0035] Embodiment 5: R a and R bThe method of any one of the preceding embodiments, wherein each is independently selected from methyl or ethyl, preferably methyl.

[0036] Embodiment 6: R c The method of any one of the preceding embodiments, wherein is methyl or ethyl, preferably ethyl.

[0037] Embodiment 7: The method according to any one of the preceding embodiments, wherein m is 0 or 1, and n is 1 or 2; and preferably, m is 1, and n is 1.

[0038] Embodiment 8: A method according to any one of the preceding embodiments, wherein R4 is H.

[0039] Embodiment 9: The method according to any one of the preceding embodiments, wherein the cyclization reaction in step a) is carried out in a non-polar solvent such as N,N-dimethylformamide (DMF) or N-methylpyrrolidone (NMP), or a mixture thereof; and the reaction is carried out under heating conditions, preferably at a controlled temperature between 100°C and 150°C, preferably between 110°C and 130°C, and more preferably between 115°C and 125°C.

[0040] Embodiment 10: The ammonolysis reaction in step b) is carried out in an organic solvent methanol or ethanol with RNH (wherein R is hydrogen or C 1-6 The method of any one of the preceding embodiments, wherein the ammonolysis reaction is carried out under reaction conditions conventional in the art, such as using a corresponding ammonolysis agent, such as an alkyl group, such as 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,19,20,21,22,23,24,25,26,27,28,29,29; for example, the ammonolysis reaction can be carried out in a solution of ammonia in methanol.

[0041] Embodiment 11: The method of any one of the preceding embodiments, wherein the hydrolysis reaction in step b') can be carried out in the presence of a strong inorganic base, such as in a reaction solvent (e.g., an organic solvent and water), and at 50°C to 100°C (e.g., 75°C to 85°C); in particular, the strong inorganic base can be selected from potassium hydroxide, sodium hydroxide, or lithium hydroxide.

[0042] Embodiment 12: The method of any one of the preceding embodiments, wherein compound M5 in step b') is reacted with R4NH2 under alkaline conditions in the presence of any condensing agent and in a solvent; preferably, the base includes, but is not limited to, triethylamine, pyridine, 4-dimethylaminopyridine, DBU, and the like; and preferably, the condensing agent includes, but is not limited to, HBTU, DCC, EDCI, DIC, or CDI.

[0043] Embodiment 13: The method according to any one of the preceding embodiments, wherein the acid in step c) is selected from organic acids such as acetic acid, p-toluenesulfonic acid, and the like; and preferably, the reaction is carried out at a controlled temperature between 70° C. and 120° C., for example, between 95° C. and 105° C.

[0044] Embodiment 14: Compound M3

[0045] [ka]

[0046] (In the formula R1, R2, R3, m, n, R a , R b , and R c is as defined above.) A method for preparing The process is as follows: Compound M1

[0047] [ka]

[0048] (In the formula, R1, R2, R3, X, m, and n are as defined above.) Compound M2

[0049] [ka]

[0050] (R in the formula a , R b , and R c is as defined above.) to obtain compound M3. A method comprising:

[0051] Embodiment 15: The method according to embodiment 14, wherein the cyclization reaction is carried out according to embodiment 9.

[0052] EMBODIMENT 16:

[0053] [ka]

[0054] (In the formula R1, R2, R3, R4, m, n, R a , R b , and R c is as defined in 1 above.) or a salt thereof.

[0055] EMBODIMENT 17:

[0056] [ka]

[0057] or a salt thereof.

[0058] Embodiment 18: Use of a compound according to embodiment 16 or 17, or a salt thereof, in the preparation of a compound of formula (I).

[0059] Definition: Terms or symbols used in this application have the following meanings unless otherwise specified: Technical and scientific terms used herein and not specifically defined have the meanings commonly understood by POSITA to which this invention belongs.

[0060] As used herein, the term "alkyl" refers to a linear or branched saturated monovalent hydrocarbyl having 1 to 6 carbon atoms, e.g., 1, 2, 3, 4, 5, or 6 carbon atoms, preferably a linear or branched saturated monovalent hydrocarbyl having 1 to 4 carbon atoms. An alkyl having 1 to 6 carbon atoms can simply be referred to as "C 1-6 An alkyl group having 1 to 4 carbon atoms is simply represented as "C 1-4 In the present specification, the term "alkyl" is used interchangeably with "alkyl," and alkyls having other numbers of carbon atoms can also be represented in a similar manner. Examples of alkyl include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and the like.

[0061] As used herein, the term "halogen" or "halo" means fluorine (F), chlorine (Cl), bromine (Br), and iodine (I), preferably chlorine and bromine, and more preferably chlorine.

[0062] As used herein in step b'), the term "strong inorganic base" refers to an inorganic base capable of hydrolyzing a carboxylic acid ester to produce a carboxylate or carboxylic acid, including, but not limited to, potassium hydroxide, sodium hydroxide, or lithium hydroxide.

[0063] The term "easily removable active ester group" as used herein refers to an ester group prepared from an alcohol, which can be easily displaced by a nucleophile such as an amine to form a stable bond. The term "easily removable active ester group" of the present invention is preferably p-CH3-Ph-SO3-(-OTs), CF3SO3-(-OTf) or CH3SO3-(-OMs), where Ph refers to phenyl, Ts refers to p-toluenesulfonyl, Tf refers to trifluoromethanesulfonyl, and Ms refers to methylsulfonyl.

[0064] The term "condensing agent" as used herein refers to commonly used condensing agents that can facilitate the formation of amides, including, but not limited to, HBTU, DCC, EDCI, DIC, or CDI.

[0065] DBU refers to 1,8-diazabicyclo[5.4.0]undec-7-ene. HBTU refers to benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate. DCC refers to N,N'-dicyclohexylcarbodiimide. EDCI refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. DIC refers to N,N'-diisopropylcarbodiimide. CDI refers to N,N'-carbonyldiimidazole.

[0066] If a latter embodiment or technical solution refers to a former embodiment or technical solution and does not further define a variable or feature described therein, it should be understood that the variable or feature in the latter embodiment or technical solution has the same meaning or definition as the corresponding variable or feature in the former embodiment or technical solution, unless otherwise specified or explicitly contradicted by the context.

[0067] It should also be understood that the reaction of the present invention can be carried out under general reaction conditions known in the art. For example, the reaction temperature and pressure can be controlled to some extent according to the properties of the reactants until the reaction is completed.

[0068] Typically, the reaction may be carried out in a solvent, including but not limited to, an organic solvent such as methanol, ethanol, isopropanol, acetonitrile, heptane, toluene, acetone, dichloromethane, tetrahydrofuran, 2-methyloxolane, dimethylsulfoxide, N,N-dimethylformamide, ethyl acetate, ethyl ether, isopropyl ether, methyl tert-butyl ether, methylcyclopentyl ether, and any combination thereof. In appropriate cases, a mixture of an organic solvent and water may be used. Some reactions may be carried out without additional solvents, and the reaction reagent itself may be used as the solvent. For example, an acid such as acetic acid used in step c) may be used as the solvent, or other solvents may be added to the reaction.

[0069] The reaction may be carried out at an appropriate temperature, for example, from -78°C to 200°C, such as -78°C to 0°C, -20°C to 20°C, -10°C to 10°C, 10°C to 130°C, 20°C to 100°C, 40°C to 100°C, 50°C to 100°C, 60°C to 100°C, 50°C to 80°C, 70°C to 120°C, 60°C to 90°C, 110°C to 130°C, 110°C to 120°C, 100°C to 150°C, or 100°C to 200°C.

[0070] The reaction may be carried out under normal pressure, elevated pressure, or reduced pressure, as appropriate.

[0071] It should be understood that POSITA can easily detect the reaction process and thereby determine the reaction end point according to the reaction time or actual situation.

[0072] In this specification, in the event of a discrepancy between the name and structure of a compound, where both are given for a compound, the structure of the compound is to be followed unless the context indicates that the structure of the compound is incorrect and the name is correct.

[0073] The process route for synthesizing the compound of formula (I) provided by the present invention has the following beneficial effects:

[0074] 1. There are only three reaction steps in the entire process, each step has a single reaction site, and there are few side reactions; 2. The reaction conditions are mild, and the operation is simple, without using dangerous reagents such as highly toxic and flammable and explosive reagents, which makes the process route well suitable for industrial production; 3. The manufacturing process is simple and the cost is low; and / or 4. The relevant intermediates are easy to isolate and purify and can even be used directly in the subsequent reaction without purification, making the process route well suited for large-scale industrial production. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0075] Detailed Description of the Preferred Embodiments The following examples are intended to be merely illustrative and should not be considered limiting in any way. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but one skilled in the art should understand that some experimental error and deviation should be accounted for. Unless otherwise specified, parts are parts by weight, temperatures are in degrees Celsius, and pressures are at or near atmospheric pressure. All HNMR data was generated using a Varian 400-MR. Reagents used in the examples of the present invention are commercially available.

[0076] Example 1 Synthesis of ethyl 1-(2,2-dimethoxyethyl)-5,5-dimethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate

[0077] [ka]

[0078] Compound 1 (50.0 kg), compound 2 (150.0 kg), and DMF (N,N-dimethylformamide, 950 kg) were added to a 2000 L reaction kettle. The mixture was stirred and heated, and the temperature was controlled at 115°C to 125°C until the reaction was completed. The reaction liquid was cooled to room temperature and then added to water. Ethyl acetate was added, and the resulting mixture was stirred and then allowed to settle for liquid separation. The organic phase was collected and washed with saturated NaCl aqueous solution, and allowed to settle for liquid separation. The organic phase was collected. The organic phase was concentrated under reduced pressure until no distillate remained.

[0079] A mixed solvent of n-heptane / ethyl acetate was added to dissolve the distillation residue, and the solution was filtered through a silica gel pad to remove a small amount of insoluble matter. The filter cake was washed with a mixed solvent of n-heptane / ethyl acetate. The filtrates were combined. The filtrate was concentrated under reduced pressure until no liquid was evidently dripping, giving 42.8 kg of a light yellow oil, (compound 3, ethyl 1-(2,2-dimethoxyethyl)-5,5-dimethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate) (content: 57.2%, yield: 26.3%, MS (m / z) = 264.0 [M-OMe] + ) was obtained. The product was used directly in the next step without purification.

[0080] A small sample was taken for purification and the HNMR data measured on the product was as follows: 1 HNMR (400MHz, CDCl3) δ 6.73 (s, 1H), 4.54 (t, J = 5.3Hz, 1H), 4.28 - 4.18 (m, 4H), 3.35 (s, 6H), 2.54 (s, 2H), 2.42 (s, 2H), 1.32 (t, J = 7.1Hz, 3H), 1.20 (s, 6H).

[0081] Example 2 Synthesis of 1-(2,2-dimethoxyethyl)-5,5-dimethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylic acid

[0082] [ka]

[0083] Ethanol (99.0 kg), water (125.0 kg), compound 3 (25.0 kg), and LiOH.H2O (14.2 kg) were added to a 500 L reaction kettle. The mixture was heated to 75°C-85°C and stirred while maintaining the temperature constant until the reaction was complete. The reaction liquid was concentrated under reduced pressure to remove most of the ethanol. Methyl tert-butyl ether was added and the resulting mixture was stirred and then allowed to settle for liquid separation. The lower aqueous phase was collected and the aqueous phase was adjusted to pH 5-6 with aqueous hydrochloric acid, and a large amount of solid precipitated. The reaction mixture was filtered, and the filter cake was washed with water and dried to give 19.8 kg of an off-white solid, (compound 4, 1-(2,2-dimethoxyethyl)-5,5-dimethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylic acid) (purity: 91.97%, content: 91%, yield: 79.6%, MS (m / z) = 236.0 [M-OMe] + ) was obtained.

[0084] The HNMR data of the product was as follows: 1 HNMR (400MHz, CDCl3) δ 6.86 (s, 1H), 4.55 (t, J = 5.3Hz, 1H), 4.21 (d, J = 5.3Hz, 2H), 3.36 (s, 6H), 2.56 (s, 2H), 2.44 (s, 2H), 1.21 (s, 6H).

[0085] Example 3 Synthesis of 1-(2,2-dimethoxyethyl)-5,5-dimethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxamide

[0086] [ka]

[0087] DMF (102.6 kg), compound 4 (19.8 kg), and triethylamine (13.6 kg) were added to the reaction kettle. The mixture was cooled to -5°C to 5°C. HBTU (benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, 30.6 kg) was added in portions at a controlled temperature of less than 10°C. After the addition, the mixture was stirred at a constant temperature of -5°C to 5°C until the reaction of compound 4 was completed. Ammonia water was added dropwise to the reaction liquid at a controlled temperature of less than 10°C, and the resulting mixture was stirred at a constant temperature of -5°C to 5°C until the reaction was completed. The reaction liquid was poured into water, and ethyl acetate was added. The mixture was stirred and then left to stand for liquid separation. The organic phase was collected and washed with saturated NaCl aqueous solution, and left to stand for liquid separation. The organic phase was collected. The organic phase was concentrated under reduced pressure and distilled until no visible liquid was dripping, giving 18.6 kg of a bright red solid, (compound 5, 1-(2,2-dimethoxyethyl)-5,5-dimethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxamide) (purity: 94.6%, content: 94.1%, yield: 97.8%, MS (m / z) = 235.1 [M-OMe] + ) was obtained. The product was used directly in the next step without purification.

[0088] A small sample was taken for purification and the HNMR data measured on the product was as follows: 1 HNMR (400MHz, CDCl3) δ 6.40 (s, 1H), 5.42 (s, 2H), 4.61 (t, J = 5.2Hz, 1H), 4.23 (d, J = 5.2Hz, 2H), 3.36 (s, 6H), 2.55 (s, 2H), 2.42 (s, 2H), 1.20 (s, 6H).

[0089] Example 4 7,7-Dimethyl-7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one

[0090] [ka]

[0091] The intermediate compound 5 (17.5 kg) obtained in Example 3 was dissolved in acetic acid (147 kg) and then added to a 200 L reaction kettle. The temperature was controlled at 95°C to 105°C until the reaction was completed. The reaction solution was cooled to room temperature and then poured into water. A mixed solvent of ethyl acetate and ethanol was added under stirring. The mixed solution of the reaction liquid and water was extracted and then allowed to settle for liquid separation. The organic phase was collected. The organic phase was concentrated under reduced pressure to a small volume, and a large amount of solid was precipitated. n-heptane and ethyl acetate were added to the reaction kettle. The resulting mixture was heated to 40°C to 50°C and stirred while maintaining the temperature constant. The reaction mixture was subjected to hot filtration, and the filter cake was washed with a mixed solvent of n-heptane and ethyl acetate, and dried to obtain 11.1 kg of off-white solid, (compound 6, 7,7-dimethyl-7,8-dihydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one) (purity: 99.8%, content: 98.4%, yield: 83.5%, MS (m / z) = 203.0 [M+H] + ) was obtained.

[0092] The HNMR data of the product was as follows: 1 HNMR (400MHz, CDCl3) δ 10.92 (s, 1H), 6.89 (s, 1H), 6.74 (d, J = 5.6Hz, 1H), 6.51 (t, J = 4.5Hz, 1H), 2.63 (s, 2H), 2.60 (s, 2H), 1.26 (s, 6H).

Claims

1. Formula (I) 【Chemistry 1】 (In the formula: R 1 and R 2 are independently hydrogen, C 1-6 alkyl, or halogen; R 3 is hydrogen or C 1-6 Selected from alkyl; m and n are independently 0, 1, or 2, and m + n is 2, 3, or 4; and R 4 is hydrogen or C 1-6 alkyl.) A method for synthesizing a compound of the formula: The following steps: a) Compound M1 【Chemistry 2】 (R in the formula 1 , R 2 , R 3 , m, and n are as defined above, and X is a halogen or an easily removable active ester group such as -OTf, -Ots, or -Oms, preferably a halogen. Compound M2 【Transformation 3】 (R in the formula a , R b , and R c are each independently C 1-6 alkyl.) to give compound M3 【Chemistry 4】 (R in the formula 1 , R 2 , R 3 , m, n, R a , R b , and R c is as defined above.) obtaining a step of b) Compound M3 is subjected to an ammonolysis reaction to produce compound M4 【Transformation 5】 (R in the formula 1 , R 2 , R 3 , R 4 , m, n, R a , and R b is as defined above.) obtaining a step of c) reacting compound M4 under acidic conditions to obtain a compound of formula (I) A method comprising:

2. 10. The method of claim 1, wherein step b) is replaced by step b') as follows: Compound M3 was subjected to hydrolysis reaction to obtain compound M5 【Transformation 6】 (R in the formula 1 , R 2 , R 3 , m, n, R a , and R b is as defined in claim 1. Compound M5 is then added to R 4 NH 2 (where R 4 is hydrogen or C 1-6 alkyl) to give compound M4.

3. R 1 and R 2 are each independently C 1-6 3. The method according to claim 1 or 2, wherein the alkyl is selected from alkyl or hydrogen, preferably methyl or hydrogen, and more preferably methyl.

4. R 3 The method of claim 3 , wherein

5. R a and R b 4. The method of claim 3, wherein each is independently selected from methyl or ethyl, preferably methyl.

6. R c 4. The method of claim 3, wherein is methyl or ethyl, preferably ethyl.

7. 4. The method of claim 3, wherein m is 0 or 1 and n is 1 or 2; and preferably m is 1 and n is 1.

8. R 4 The method of claim 3 , wherein

9. The method according to claim 3, wherein the cyclization reaction in step a) is carried out in a non-polar solvent such as N,N-dimethylformamide (DMF) or N-methylpyrrolidone (NMP), or a mixture thereof; and the reaction is carried out under heating conditions, preferably at a temperature controlled between 100°C and 150°C, preferably between 110°C and 130°C, and more preferably between 115°C and 125°C.

10. The ammonolysis reaction in step b) is carried out in an organic solvent, methanol or ethanol, by 4 NH 2 (where R 4 is hydrogen or C 1-6 4. The method according to claim 3, wherein the ammonolysis reaction is carried out under reaction conditions conventional in the art, such as using a corresponding ammonolysis agent, such as ammonia, selected from alkyl groups; for example, the ammonolysis reaction can be carried out in a solution of ammonia in methanol.

11. 4. The method according to claim 3, wherein the hydrolysis reaction in step b') can be carried out in the presence of a strong inorganic base in a reaction solvent, such as an organic solvent and water, and at 50°C to 100°C; in particular, the strong inorganic base can be selected from potassium hydroxide, sodium hydroxide, or lithium hydroxide.

12. In step b′), compound M5 is reacted with R 4 NH 2 4. The method of claim 3, wherein the base preferably includes, but is not limited to, triethylamine, pyridine, 4-dimethylaminopyridine, DBU, and the like; and the condensing agent preferably includes, but is not limited to, HBTU, DCC, EDCI, DIC, or CDI.

13. 4. The method according to claim 3, wherein the acid in step c) is selected from organic acids such as acetic acid, p-toluenesulfonic acid, etc.; and preferably, the reaction is carried out at a controlled temperature between 70°C and 120°C, for example, between 95°C and 105°C.

14. Compound M3 【Transformation 7】 (R in the formula 1 , R 2 , R 3 , m, n, R a , R b , and R c is as defined in claim 1.

1. A method for preparing The following steps: Compound M1 【Transformation 8】 (R in the formula 1 , R 2 , R 3 , X, m, and n are as defined in claim 1. Compound M2 【Chemistry 9】 (R in the formula a , R b , and R c is as defined in claim 1. to obtain compound M3. A method comprising:

15. The cyclization reaction is carried out according to claim 9. Compound M3 【Transformation 7】 wherein R 1 and R 2 are each independently selected from hydrogen, C 1-6 alkyl, or halogen; R 3 is selected from hydrogen or C 1-6 alkyl; m and n are independently 0, 1, or 2, and m + n is 2, 3, or 4; and R a , R b , and R c are each independently selected from C 1-6 alkyl.

1. A method for preparing The following steps: Compound M1 【Transformation 8】 (wherein R 1 , R 2 , R 3 , m, and n are as defined above, and X is a halogen or an easily removable active ester group such as -OTf, -Ots, or -Oms, preferably a halogen.) Compound M2 【Chemistry 9】 (wherein R a , R b , and R c are as defined above.) to obtain compound M3. A method comprising: 【Request Item 16】 【Chemistry 10】 (R in the formula 1 , R 2 , R 3 , R 4 , m, n, R a , R b , and R c is as defined in claim 1. A compound selected from the group consisting of: 【Request Item 17】 【Chemistry 11】 A compound selected from the group consisting of:

18. 18. Use of a compound according to claim 16 or 17, or a salt thereof, in the preparation of a compound of formula (I) according to claim 1.

19. A pharmaceutical intermediate used in the preparation of a compound of formula (I) according to claim 1, comprising a compound according to claim 16 or 17 or a salt thereof.

20. A method for preparing a compound of formula (I) according to claim 1, comprising using a compound according to claim 16 or 17 or a salt thereof.

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