Process for preparation of substituted spirooxindole derivatives

Abstract

The present invention relates to a process for the preparation of a compound of formula (A) or a pharmaceutically acceptable salt or solvate thereof. The compounds of formula (A) and pharmaceutical compositions are useful as SARS-CoV-23CLpro inhibitors. # imgabs0 #

Description

[0001] Inventors: Zhu Kaicheng, Wang Tao, Zhang Xin, Peng Xiaowen, Shen Ruichao, Zhang Jiajun, Li Wei, Cao Hui, Gao Xuri, Wang Guoqiang, George G. Wu and Yat Sun Or

[0002] Related Applications

[0003] This application claims the benefit of U.S. Provisional Application No. 63 / 321,244, filed on March 18, 2022. The entire teachings of the above application are incorporated herein by reference. Technical Field

[0004] The present invention generally relates to methods and intermediates for preparing biologically active molecules, and in particular for synthesizing certain SARS-CoV-23 CLpro inhibitors. Background Art

[0005] Coronaviruses are enveloped, positive-single-stranded RNA viruses. The genomic RNA of CoVs has a 5'-cap structure and a 3'-poly-A tail and contains at least 6 open reading frames (ORFs). The first ORF (ORF 1a / b) directly translates two polyproteins: pp1a and pp1ab. These polyproteins are processed into 16 non-structural proteins by the 3C-like protease (3CLpro), also known as the main protease (Mpro). These non-structural proteins are involved in the production of subgenomic RNA encoding four structural proteins, namely envelope proteins, membrane proteins, spike proteins, and nucleocapsid proteins, as well as other auxiliary proteins. Therefore, it can be understood that the 3C-like protease plays a key role in the coronavirus life cycle.

[0006] 3CLpro is a cysteine ​​protease that participates in most cleavage events in the precursor polyprotein. Active 3CLpro is a homodimer containing two protomers with a cysteine-histidine dyad between domains I and II. 3CLpro is conserved among coronaviruses, and some common features are shared among 3CLpro substrates of different coronaviruses. Since 3CLpro has no human homolog, it is an ideal antiviral target. Although compounds that inhibit 3CLpro activity have been reported, they have not yet been approved as treatments for coronaviruses (see WO2004101742A2, US2005 / 0143320A1, US2006 / 0014821A1, US2009 / 0137818A1, WO2013049382A2, WO2013166319A1, WO2018042343, WO2018023054, WO2022013684, WO2021252644, WO2022020711, WO2022020242, US11,174,231B1, US11,124,497B1, WO2005113580 and WO2006061714).

[0007] There is a need in the art for novel therapeutic agents for treating, ameliorating or preventing SARS-CoV-2 infection. The present invention provides a method for preparing novel compounds that can inhibit or prevent the replication of SARS-CoV-2 virus and are therefore useful for treating COVID-19 (see PCT / US21 / 60247).

[0008] The synthesis of substituted spirooxindoles and their intermediates has been previously disclosed (see PCT / US21 / 60247, WO2019086142, WO2020221811, WO2020221826, J.Med.Chem.2012,55,9069). However, due to safety issues associated with certain intermediates, the instability of certain intermediates, and the lack of purification methods other than column chromatography, large-scale production using previous methods is very challenging. Therefore, there is an urgent need to develop a safe and effective method for large-scale preparation of these new substituted spirooxindoles derivatives. Summary of the invention

[0009] The present invention provides a method for preparing a compound of formula (A):

[0010]

[0011] wherein R1 is selected from hydrogen, Cl, F, optionally substituted methyl and optionally substituted methoxy; R2 is selected from hydrogen, optionally substituted -C1-C6 alkyl and optionally substituted -C1-C6 alkylaryl. Preferably, R1 is H or F; R2 is isobutyl, cyclopropylmethyl, 2,2-dimethylpropyl or benzyl. More preferably, R1 is F; R2 is isobutyl.

[0012] The present invention also relates to a process for large-scale production of the compound of formula (A) with increased product yield and improved scalability.

[0013] In some embodiments, the present invention is directed to a method of isolating the compound of formula (A) as a toluene solvate or an amorphous solid. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] The above and other objects, features and advantages of the present invention will become apparent from the following more particular description of the preferred embodiments of the present invention, as shown in the accompanying drawings, in which like reference numerals refer to the same parts in different views. The accompanying drawings are not necessarily drawn to scale, emphasis instead being placed upon illustrating the principles of the present invention.

[0015] Figure 1 This is a schematic diagram of the flow reaction process described in Example 9.

[0016] Figure 2 This is the X-ray powder diffraction pattern of the amorphous form of Compound 1 prepared in Example 19.

[0017] Figure 3 This is the DSC thermogram of the amorphous form of Compound 1 prepared in Example 19. DETAILED DESCRIPTION

[0018] The present invention provides a method for preparing a compound of formula (A),

[0019]

[0020] wherein R1 is selected from hydrogen, Cl, F, optionally substituted methyl and optionally substituted methoxy; R2 is selected from hydrogen, optionally substituted -C1-C6 alkyl and optionally substituted -C1-C6 alkylaryl. Preferably, R1 is H or F; R2 is isobutyl, cyclopropylmethyl, 2,2-dimethylpropyl or benzyl. More preferably, R1 is F; R2 is isobutyl.

[0021] In a preferred embodiment, the compound of formula (A) is represented by formula (AI):

[0022]

[0023] In one embodiment, the compound of formula (A) is compound (I):

[0024]

[0025] In one embodiment, the method for preparing the compound of formula (A) comprises the following steps:

[0026] (a) reacting a compound of formula (W) with formaldehyde to produce a compound of formula (B):

[0027]

[0028] wherein G1 is C1-C6-alkyl or aryl, preferably methyl, ethyl or phenyl, more preferably methyl; (b) converting the compound of formula (B) into a compound of formula (C):

[0029]

[0030] (c) rearranging the compound of formula (C) to produce a compound of formula (D-1):

[0031]

[0032] (d) converting the compound of formula (D-1) into compound (e-1):

[0033]

[0034] (e) converting compound (e-1) into a compound of formula (F-1):

[0035]

[0036] Wherein X is selected from Cl - Br - and CF3CO2 - Anion, preferably X is Cl - ;

[0037] (f) reacting a compound of formula (F-1) with a compound of formula (K) to produce a compound of formula (L):

[0038]

[0039] wherein PG1 is selected from -Boc, -Cbz, -C(O)OMe, -C(O)OEt, -Fmoc, -Troc, -Moz, -Pnz and -Teoc, preferably PG1 is -Boc or -Cbz, more preferably PG1 is -Cbz; R2 is as defined above, preferably isobutyl;

[0040]

[0041] (g) converting the compound of formula (L) into a compound of formula (M) or a salt thereof, optionally in the presence of a suitable acid:

[0042]

[0043] (h) reacting a compound of formula (M) or a salt thereof with a compound of formula (J) or a salt thereof,

[0044]

[0045] wherein R1 is as defined above, preferably hydrogen or F, to provide a compound of formula (N):

[0046] and

[0047] (i) converting the compound of formula (N) into the compound of formula (A):

[0048]

[0049] In a preferred embodiment of the above method, R1 is F, R2 is isobutyl, G1 is methyl, X is Cl - , PG1 is Cbz.

[0050] Step (a)

[0051] In a preferred embodiment, step (a) is carried out in a suitable solvent, such as but not limited to methanol, tert-butyl alcohol, acetonitrile, acetone, dichloromethane, chloroform, dimethylformamide, dimethyl sulfoxide, dioxane, ethyl acetate, heptane, hexane, methyl tert-butyl ether, tetrahydrofuran and toluene, or a mixture of two or more thereof. Preferably, the solvent is methanol.

[0052] In one embodiment, the reaction is carried out at a temperature of about 0° C. to about 100° C., preferably about 45° C. to about 85° C., more preferably about 65° C. In one embodiment, step a) is carried out for about half an hour to about 1 day, preferably about half an hour to about 5 hours, more preferably about 1 hour.

[0053] In a preferred embodiment, the process of the present invention further comprises isolating the compound of formula (B), preferably in substantially pure form.

[0054] Step (b)

[0055] In step (b), compound (b) is reacted with a suitable Boc protecting agent, such as but not limited to tert-butylphenyl carbonate, di-tert-butyl dicarbonate, N-(tert-butoxycarbonyloxy)phthalimide or 1-tert-butoxycarbonyl-1,2,4-triazole. Preferably, the Boc protecting agent is di-tert-butyl dicarbonate (Boc anhydride).

[0056] Preferably, step (b) is carried out in the presence of a suitable base such as, but not limited to, triethylamine, diisopropylethylamine, sodium bicarbonate or N-methylmorpholine. The preferred base is triethylamine.

[0057] In a preferred embodiment, step (b) is carried out in a solvent. Suitable solvents include, but are not limited to, 2-methyl THF, tert-butyl alcohol, acetonitrile, acetone, dichloromethane, chloroform, dimethylformamide, dimethyl sulfoxide, dioxane, ethyl acetate, heptane, hexane, methyl tert-butyl ether, tetrahydrofuran, water and toluene, or a mixture of two or more thereof. Preferably, the solvent is 2-methyl THF (2-Me THF) and water as a cosolvent. Preferably, the volume ratio of 2-methyl THF to water is 4:1.

[0058] In one embodiment, the reaction of step (b) is carried out at a temperature of about -10°C to about 60°C, preferably about 0°C to about 40°C, more preferably about 5°C to about 25°C. In one embodiment, step (b) is carried out for about 1 h to about 24 h, preferably about 1 h to about 10 h, more preferably about 5 h.

[0059] In a preferred embodiment, the process of the present invention further comprises isolating the compound of formula (C), preferably in substantially pure form.

[0060] Step (c)

[0061] In step (c), the compound of formula (C) is reacted with an oxidizing agent to produce a compound of formula (D-1). In some embodiments, the reaction also produces a compound of formula (D-2), which is a diastereomer of the compound of formula (D-1).

[0062]

[0063] Preferably, the reaction produces the compound of formula (D-1) in the form of diastereoisomer excess. The weight ratio of the compound of formula (D-1) and the compound of formula (D-2) produced is preferably about 55:45 to 95:5, more preferably about 6:1 to about 8:1.

[0064] Suitable oxidizing agents include, but are not limited to, N-bromosuccinimide (NBS), hydrogen peroxide, m-chloroperbenzoic acid (m-CPBA), potassium peroxymonosulfate (Oxone), 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selecfluor), tert-butyl hypochlorite, N-iodosuccinimide (NIS), etc. The preferred oxidizing agent is N-bromosuccinimide (NBS).

[0065] In some embodiments, step (c) is performed in the presence of a suitable acid, such as but not limited to acetic acid, formic acid, trifluoroacetic acid, benzoic acid, hydrochloric acid, phosphonic acid, sulfuric acid, p-toluenesulfonic acid, etc. The preferred acid is acetic acid.

[0066] In a preferred embodiment of step (c), the oxidizing agent is N-bromosuccinimide (NBS) and the acid is acetic acid.

[0067] In a preferred embodiment, step (c) is carried out in a solvent. Suitable solvents include, but are not limited to, dichloromethane, chloroform, dioxane, ethyl acetate, heptane, hexane, methyl tert-butyl ether, tetrahydrofuran (THF), 2-methyl THF, water and toluene, or a mixture of two or more thereof. Preferably, the solvent is a mixture of 2-methyl THF, THF and water. Preferably, the volume ratio of 2-methyl THF / THF / water is about 3.5 / 1.5 / 1.

[0068] In one embodiment, the reaction is carried out at a temperature of about -40°C to about 30°C, preferably about -30°C to about -10°C, more preferably about -30°C. In one embodiment, step (c) is carried out for about 30 min to about 3 h, preferably about 30 min to about 1 h, more preferably about 30 min.

[0069] In one embodiment, the compound of formula (D-1) is the major product. In a preferred embodiment, the process of the present invention further comprises separating the compound of formula (D-1) and the compound of formula (D-2).

[0070] Step (d)

[0071] The compound of formula (D-1) is converted to a compound of formula (e-1) by reacting with an ammonolysis reagent. In some embodiments, in step (d), the compound of formula (D-1) is reacted with an ammonolysis reagent as a mixture with a compound of formula (D-2) to produce compound (e-1) and compound (e-2).

[0072]

[0073] In some embodiments of step (d), compound (e-1) is produced in a diastereomeric excess. In some embodiments, the weight ratio of compound (e-1) and compound (e-2) produced is about 55:45 to 95:5, preferably about 6:1 to 8:1.

[0074] Suitable ammonolysis agents include, but are not limited to, ammonia, ammonium hydroxide, etc. The preferred ammonolysis agent is ammonia.

[0075] In a preferred embodiment, step (d) is carried out in a solvent. Suitable solvents include, but are not limited to, dichloromethane, chloroform, dioxane, ethyl acetate, heptane, hexane, methyl tert-butyl ether, tetrahydrofuran, methanol, ethanol, propanol and toluene, or a mixture of two or more thereof. Preferably, the solvent is methanol.

[0076] In one embodiment, the reaction is carried out at a temperature of about 20° C. to about 60° C., preferably about 40° C. to about 60° C., more preferably about 45° C. In one embodiment, step (d) is carried out for about 2 days to about 7 days, preferably about 3 days to about 5 days, more preferably about 5 days.

[0077] In one embodiment, compound (e-1) is the major product. In a preferred embodiment, the method of the present invention further comprises separating compound (e-1) and compound (e-2).

[0078] Step (e)

[0079] In some embodiments of step (e), compound (e-1) is reacted with an acid as a mixture with compound (e-2) to produce a mixture of a compound of formula (F-1) and a compound of formula (F-2):

[0080]

[0081] In some embodiments of step (e), the compound of formula (F-1) is produced in a diastereomeric excess. In some embodiments, the weight ratio of the compound of formula (F-1) and the compound of formula (F-2) produced is about 55:45 to 95:5, preferably about 6:1 to 8:1.

[0082] Suitable acids include, but are not limited to, hydrogen chloride, hydrogen bromide, trifluoroacetic acid, etc. The preferred acid is hydrogen chloride or hydrogen chloride generated in situ by reacting acetyl chloride with an alkyl alcohol.

[0083] In a preferred embodiment, step (e) is carried out in a solvent. Suitable solvents include, but are not limited to, dichloromethane, chloroform, dioxane, ethyl acetate, heptane, hexane, methyl tert-butyl ether, acetonitrile, acetone, N,N-dimethylformamide, tetrahydrofuran and toluene, and mixtures of two or more thereof. Preferably, the solvent is N,N-dimethylformamide or N,N-dimethylformamide and one or more co-solvents selected from toluene, acetonitrile, ethyl acetate and dichloromethane. In some embodiments of step (e), the mixture of the compound of formula (F-1) and the compound of formula (F-2) is formed as a DMF solvate.

[0084] In one embodiment, the reaction is carried out at a temperature of about 0° C. to about 40° C., preferably about 10° C. to about 30° C., more preferably about 25° C. In one embodiment, step (e) is carried out for about 30 min to about 10 h, preferably about 5 h to about 3 days, more preferably about 2 days.

[0085] In one embodiment, the compound of formula (F-1) is separated from the compound of formula (F-2) by recrystallizing a mixture of the compound of formula (F-1) and the compound of formula (F-2). The recrystallization is preferably carried out at a temperature of about 20°C to about 100°C, more preferably about 50°C to about 85°C, and most preferably about 55°C. The preferred solvent for recrystallization is N,N-dimethylformamide (DMF).

[0086] In a preferred embodiment, the process of the present invention further comprises isolating the compound of formula (F-1), preferably in substantially pure form.

[0087] Step (f)

[0088] The compound of formula (F-1) from step (e) is preferably reacted with a compound of formula (K) in the presence of an amide coupling agent. Suitable amide coupling agents include, but are not limited to, acetic anhydride, pivaloyl chloride, ethyl chloroformate (ECF), isobutyl chloroformate (IBCF), Boc anhydride or di-tert-butyl dicarbonate (Boc2O), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, methanesulfonyl chloride (MsCl), p-toluenesulfonyl chloride (TsCl), n-propanephosphonic anhydride (T3P), ethylmethylphosphonic anhydride (EMPA), 1,1'-carbonyldiimidazole (CDI), N,N'- Dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), (1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide hydrochloride (EDC), 1-hydroxy-7-azabenzotriazole (HOAt), 1-hydroxybenzotriazole (HOBt), ((benzotriazol-1-yloxy)tris-(dimethylamino)phosphonium hexafluorophosphate (BOP), N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b ]pyridin-1-ylmethylene]-N-methylmethanium hexafluorophosphate N-oxide (HATU), N-[(1H-benzotriazol-1-yl)-(dimethylamino)methylene]-N-methylmethanamine tetrafluoroborate N-oxide (TBTU), 2-(2-oxo-1(2H)-pyridinyl-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), O-[(cyano(ethoxycarbonyl)methyleneamino]-N,N,N',N'-tetramethyl Urea tetrafluoroborate (TOTU), N-[(1H-benzotriazole-1-yl)(dimethylamino)-methylene]-N-methylmethanium hexafluorophosphate N-oxide (HBTU), cyanuric chloride, 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride (DMTMM), or boric acid. Preferably, the coupling agent is n-propanephosphonic anhydride (T3P).

[0089] In some embodiments, step (f) is performed in the presence of a suitable base, such as, but not limited to, triethylamine, diisopropylethylamine, or N-methylmorpholine. A preferred base is N-methylmorpholine.

[0090] In some embodiments, step (f) is performed in the presence of a coupling agent and a suitable base. Preferably, the coupling agent is n-propanephosphonic anhydride (T3P) and the base is N-methylmorpholine.

[0091] In a preferred embodiment, step (f) is carried out in a solvent. Suitable solvents include, but are not limited to, methanol, ethanol, acetonitrile, dichloromethane, chloroform, dioxane, ethyl acetate, heptane, hexane, methyl tert-butyl ether, tetrahydrofuran, N,N-dimethylformamide and toluene, or a mixture of two or more thereof. Preferably, the solvent is N,N-dimethylformamide.

[0092] In some embodiments, step (f) is performed at a suitable temperature, for example, about -10°C to about 30°C, preferably about -10°C to about 10°C, more preferably about 0°C. In one embodiment, step (f) is performed for about 1 h to about 24 h, preferably about 4 h.

[0093] In a preferred embodiment, the process of the present invention further comprises isolating the compound of formula (L), preferably in substantially pure form.

[0094] Step (g)

[0095] Preferably, the compound of formula (L) is converted into a compound of formula (M) by reacting with a hydrogen source. In the embodiment where PG1 is Cbz, Fmoc, Moz or Pnz, the hydrogen source can be hydrogen, ammonium formate, etc. In some embodiments, the reaction is carried out in the presence of a catalyst, such as but not limited to carbon-supported palladium, carbon-supported palladium hydroxide or Raney nickel (Raneynickel). Preferably, the hydrogen source is H2, and the catalyst is carbon-supported palladium. In some embodiments, the reaction is carried out under a suitable hydrogen pressure, such as but not limited to about 0.5 atmosphere to about 10 atmospheres, preferably about 1 atmosphere to 5 atmospheres.

[0096] In some embodiments, the compound of formula (L) is reacted with a hydrogen source in the presence of a suitable acid, such as, but not limited to, hydrogen chloride, hydrogen bromide, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, acetic acid, or a combination of two or more thereof, to remove the PG1 group and generate a salt form of the compound of formula (M). The preferred acid is hydrogen bromide in acetic acid.

[0097] In some embodiments where PG1 is Cbz, Fmoc, Moz or Pnz, the hydrogen source is H2, the catalyst is palladium on carbon, and the reaction is carried out in the presence of a suitable acid, such as but not limited to p-toluenesulfonic acid or methanesulfonic acid, to remove the PG1 group and generate a salt form of the compound of formula (M).

[0098] In a preferred embodiment, step (g) is carried out in a solvent. Suitable solvents include, but are not limited to, acetonitrile, acetone, dichloromethane, dimethylformamide, dimethyl sulfoxide, dioxane, ethyl acetate, heptane, hexane, methanol, methyl tert-butyl ether, ethanol, tetrahydrofuran, N,N-dimethylformamide, toluene, acetic acid, and mixtures of two or more thereof. Preferred solvents include methanol, acetic acid, and N,N-dimethylformamide.

[0099] In some embodiments, step (g) is performed at a suitable temperature, for example, about -20°C to about 50°C, preferably about 0°C to about 30°C. In one embodiment, the reaction is performed for about 1 h to about 24 h, preferably about 1 h to about 8 h.

[0100] In some embodiments, the compound of formula (M) or its salt form is used directly in the next step without further isolation.

[0101] In a preferred embodiment, the process of the present invention further comprises isolating the compound of formula (M) or a salt form thereof, preferably in substantially pure form.

[0102] Step (h)

[0103] The compound of formula (M) or its salt is preferably reacted with the compound of formula (J) or its salt in the presence of an amide coupling agent. Suitable amide coupling agents include, but are not limited to, acetic anhydride, pivaloyl chloride, ethyl chloroformate (ECF), isobutyl chloroformate (IBCF), Boc anhydride or di-tert-butyl dicarbonate (Boc2O), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, methanesulfonyl chloride (MsCl), p-toluenesulfonyl chloride (TsCl), n-propanephosphonic anhydride (T3P), ethyl methylphosphonic anhydride (EMPA), 1,1'-carbonyldiimidazole (CDI), N,N'-dicyclohexylcarbodiimide (DCC) 、N,N'-diisopropylcarbodiimide (DIC), (1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide hydrochloride (EDC), 1-hydroxy-7-azabenzotriazole (HOAt), 1-hydroxybenzotriazole (HOBt), ((benzotriazol-1-yloxy)tris-(dimethylamino)phosphonium hexafluorophosphate (BOP), N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanium hexafluorophosphate N- oxide (HATU), N-[(1H-benzotriazol-1-yl)-(dimethylamino)methylene]-N-methylmethanamine tetrafluoroborate N-oxide (TBTU), 2-(2-oxo-1(2H)-pyridinyl-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), O-[(cyano(ethoxycarbonyl)methyleneamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU), N-[(1H-benzotriazol-1-yl)(dimethylamino)-methylene]-N-methylmethanamine tetrafluoroborate N-oxide (TBTU), 2-(2-oxo-1(2H)-pyridinyl-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), ]-N-methylmethanium hexafluorophosphate N-oxide (HBTU), cyanuric chloride, 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride (DMTMM), or boric acid. Preferably, the coupling agent is N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanium hexafluorophosphate N-oxide (HATU).

[0104] Preferred salts of the compound of formula (J) include potassium and sodium salts. Preferred salts of the compound of formula (M) include acetate, chloride and bromide salts.

[0105] In some embodiments, step (h) is performed in the presence of a suitable base, such as but not limited to triethylamine, diisopropylethylamine or N-methylmorpholine. A preferred base is N-methylmorpholine.

[0106] In some embodiments, step (h) is performed in the presence of an amide coupling agent and a suitable base, wherein the amide coupling agent is HATU and the base is N-methylmorpholine.

[0107] In a preferred embodiment, step (h) is carried out in a solvent, such as but not limited to acetonitrile, acetone, chloroform, dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide, dioxane, ethyl acetate, heptane, hexane, methanol, methyl tert-butyl ether, tetrachloromethane, tetrahydrofuran, toluene or a mixture of two or more thereof. Preferably, the solvent is N,N-dimethylformamide.

[0108] Step (h) is performed at a suitable temperature, for example about 0° C. to about 50° C., preferably about 20° C. to about 30° C., more preferably about 25° C. In one embodiment, step (h) is performed for about 1 h to about 24 h, preferably about 3 h to about 12 h.

[0109] In a preferred embodiment, the process of the present invention further comprises isolating the compound of formula (N), preferably in substantially pure form.

[0110] Step (i)

[0111] The compound of formula (N) is converted into the compound of formula (A) by reacting with a dehydrating agent. Suitable dehydrating agents include, but are not limited to, n-propanephosphonic anhydride (T3P), trifluoroacetic anhydride (TFAA), methyl N-(triethylammoniumsulfonyl)carbamate (Burgess reagent), phosphorus oxide (P2O5). The preferred dehydrating agent is trifluoroacetic anhydride (TFAA).

[0112] In some embodiments, step (i) is carried out in the presence of a suitable base, such as but not limited to triethylamine, diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), imidazole, pyridine, 2,6-lutidine, ethyl nicotinate, N-methylpiperazine or 1-methylimidazole. The preferred base is triethylamine.

[0113] In some embodiments, step (i) is performed in the presence of a dehydrating agent and a base, wherein the dehydrating agent is trifluoroacetic anhydride (TFAA) and the base is triethylamine.

[0114] In a preferred embodiment, step (i) is carried out in a solvent. Suitable solvents include, but are not limited to, acetonitrile, acetone, dichloromethane, dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, dioxane, ethyl acetate, heptane, hexane, methyl tert-butyl ether, tetrahydrofuran, toluene, and mixtures of two or more thereof. The preferred solvent is ethyl acetate.

[0115] In some embodiments, step (i) is performed at a suitable temperature, such as about -10°C to about 10°C, preferably about -5°C to about 5°C, more preferably about 0°C. In one embodiment, step (i) is performed for about 30 min to about 2 h, preferably about 1 h.

[0116] In a preferred embodiment, the process of the present invention further comprises isolating the compound of formula (A), preferably in substantially pure form.

[0117] In some embodiments, the present invention provides a method for producing a compound of formula (A), comprising steps (f), (g), (h) and (i) above.

[0118] In some embodiments, the present invention provides a method for producing a compound of formula (A), comprising steps (h) and (i) above.

[0119] In one embodiment, the present invention provides a method for preparing a compound of formula (J) or a salt thereof

[0120]

[0121] The following steps are involved:

[0122] (J-1) reducing the compound of formula (Ga) to produce a compound of formula (Gb):

[0123]

[0124] (J-2) Oxidizing the compound of formula (Gb) to produce a compound of formula (G):

[0125]

[0126] (J-3) reacting a compound of formula (G) with a compound of formula (G-1) in the presence of a base to produce a compound of formula (H):

[0127]

[0128] Wherein R3 is methyl, ethyl or benzyl;

[0129] (J-4) Converting the compound of formula (H) to the compound of formula (I) by Hemetsberger indole cyclization:

[0130] and (J-5) reacting the compound of formula (I) with a base to obtain a compound of formula (J) or a salt thereof:

[0131]

[0132] In another embodiment, the present invention provides a method for preparing a compound of formula (J) or a salt thereof:

[0133] The following steps are involved:

[0134] (J-1) reducing the compound of formula (Ga) to produce a compound of formula (Gb):

[0135]

[0136] (J-2) Oxidizing the compound of formula (Gb) to produce a compound of formula (G):

[0137]

[0138] (J-2a) reacting the compound of formula (G) with sodium bisulfite to produce a compound of formula (Gc):

[0139]

[0140] (J-2b) reacting a compound of formula (Gc) with a base to produce a compound of formula (G):

[0141]

[0142] (J-3) reacting a compound of formula (G) with a compound of formula (G-1) in the presence of a base to produce a compound of formula (H):

[0143]

[0144] Wherein R3 is methyl, ethyl or benzyl;

[0145] (J-4) Converting the compound of formula (H) to the compound of formula (I) by Hemetsberger indole cyclization:

[0146] and

[0147] (J-5) reacting the compound of formula (I) with a base to obtain a compound of formula (J) or a salt thereof:

[0148]

[0149] Step (J-1)

[0150] The compound of formula (Ga) is preferably reduced by reaction with a reducing agent. Suitable reducing agents include, but are not limited to, lithium aluminum hydride, lithium borohydride, sodium borohydride, diisobutylaluminum hydride, borane-tetrahydrofuran complex, borane-dimethyl sulfide complex, etc. Preferably, the reducing agent is sodium borohydride or borane-tetrahydrofuran complex.

[0151] In a preferred embodiment, step (J-1) is carried out in a solvent. Suitable solvents include, but are not limited to, acetonitrile, acetone, dichloromethane, dimethylformamide, dimethyl sulfoxide, dioxane, ethyl acetate, heptane, hexane, methyl tert-butyl ether, tetrahydrofuran, toluene, and mixtures of two or more thereof. The preferred solvent is tetrahydrofuran.

[0152] In one embodiment, the reaction of step (J-1) is carried out at a suitable temperature, for example, about -20°C to about 50°C, preferably about -5°C to about 25°C. In one embodiment, the reaction is carried out for about 0.5h to about 12h, preferably about 2h to 6h.

[0153] In some embodiments, the methods of the present invention further comprise isolating the compound of formula (Gb), preferably in substantially pure form.

[0154] Step (J-2)

[0155] The compound of formula (Gb) is oxidized by reacting with an oxidant. Suitable oxidants include, but are not limited to, trichloroisocyanuric acid, sodium hypochlorite (NaClO) containing TEMPO, sodium hypochlorite containing TEMPO, oxalyl chloride containing dimethyl sulfoxide, manganese oxide, chromium trioxide, pyridinium chlorochromate (PCC), sodium perchlorate, Dess-Martin periodinane (DMP), etc. A preferred oxidant is sodium hypochlorite containing TEMPO.

[0156] In a preferred embodiment, the reaction of step (J-2) occurs in a solvent. Suitable solvents include, but are not limited to, acetonitrile, acetone, dichloromethane, dimethylformamide, dimethyl sulfoxide, dioxane, ethyl acetate, heptane, hexane, methyl tert-butyl ether, tetrahydrofuran, toluene, and mixtures of two or more thereof. A preferred solvent is methyl tert-butyl ether (MTBE).

[0157] The reaction of step (J-2) is carried out at a suitable temperature, for example, about -20°C to about 50°C, preferably about -10°C to about 10°C, more preferably about -5°C to about 5°C. In some embodiments, the reaction in step (J-2) is carried out for about 10 min to about 10 h, preferably about 30 min to about 3 h.

[0158] Step (J-2a)

[0159] In one embodiment, the reaction of step (J-2a) occurs in a solvent. Suitable solvents include, but are not limited to, acetonitrile, dioxane, ethyl acetate, methyl tert-butyl ether, tetrahydrofuran, toluene, methanol, ethanol, water, and mixtures of two or more thereof. Preferred solvents are mixtures of MTBE, EtOH, and water.

[0160] In one embodiment, the reaction of step (J-2a) is carried out at a suitable temperature, for example, about 0° C. to about 60° C., preferably about 20° C. to about 40° C. In one embodiment, the reaction is carried out for about 0.5 h to about 12 h, preferably about 2 to 6 h.

[0161] Step (J-2b)

[0162] Step (J-2b) is carried out in the presence of a suitable base, such as but not limited to sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, lithium diisopropylamide, 2,2,6,6-tetramethylpiperidinium lithium, sodium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, triethylamine, diisopropylethylamine, etc. Preferably, the base is sodium carbonate.

[0163] In one embodiment, the reaction of step (J-2b) occurs in a solvent. Suitable solvents include, but are not limited to, acetonitrile, acetone, dimethyl sulfoxide, dioxane, ethyl acetate, methyl tert-butyl ether, tetrahydrofuran, toluene, ethanol, water, and mixtures of two or more thereof. A preferred solvent is methyl tert-butyl ether (MTBE) or a mixture of MTBE and water.

[0164] In one embodiment, the reaction of step (J-2b) is carried out at a suitable temperature, for example, about 0° C. to about 40° C., preferably about 20° C. to about 25° C. In one embodiment, the reaction is carried out for about 0.5 h to about 12 h, preferably about 2 to 6 h.

[0165] In some embodiments, the methods of the present invention further comprise isolating the compound of formula (G), preferably in substantially pure form.

[0166] Step (J-3)

[0167] Step (J-3) is carried out in the presence of a suitable base, such as but not limited to sodium methoxide, sodium ethoxide, sodium tert-butoxide, lithium diisopropylamide, 2,2,6,6-tetramethylpiperidinium lithium, sodium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, etc. Preferably, the base is sodium methoxide or sodium ethoxide.

[0168] In a preferred embodiment, step (J-3) is carried out in the presence of a sacrificial electrophilic reagent, such as, but not limited to, CF3CO2Et, ethyl trichloroacetate or ethyl formate, to prevent hydrolysis in the base-catalyzed condensation reaction, thereby increasing the yield. A preferred sacrificial electrophilic reagent is CF3CO2Et.

[0169] In a preferred embodiment, step (J-3) is carried out in a suitable solvent, such as but not limited to dichloromethane, chloroform, dioxane, ethyl acetate, heptane, hexane, methyl tert-butyl ether, tetrahydrofuran, methanol, ethanol or toluene and a mixture of two or more thereof. Preferably, the solvent is methanol or ethanol. More preferably, the solvent is methanol.

[0170] In a preferred embodiment, step (J-3) is carried out in the presence of sodium methoxide or sodium ethoxide as base, methanol or ethanol as solvent and CF3CO2Et as sacrificial electrophile.

[0171] The reaction of step (J-3) is carried out at a suitable temperature, for example, about -10°C to about 10°C, preferably about -5°C to about 10°C, and more preferably about 0°C. In one embodiment, step (J-3) is carried out for about 30 min to about 10 h, preferably about 5 h to about 24 h, and more preferably about 8 h to about 14 h.

[0172] In some embodiments, the methods of the present invention further comprise isolating the compound of formula (H), preferably in substantially pure form.

[0173] Step (J-4)

[0174] In step (J-4), the compound of formula (H) is heated to produce a reactive intermediate which can cyclize to form a compound of formula (I).

[0175] In a preferred embodiment, step (J-4) is carried out in a solvent. Suitable solvents include, but are not limited to, trimethylbenzene, dichloromethane, chloroform, dioxane, ethyl acetate, heptane, hexane, methyl tert-butyl ether, tetrahydrofuran, methanol, xylene and toluene, and mixtures of two or more thereof. Preferably, the solvent is a mixture of xylene and methanol. Preferably, the volume ratio of xylene to methanol is greater than 1. More preferably, the volume ratio of xylene to methanol is 5:1.

[0176] In some embodiments, in step (J-4), the reaction is carried out in a flow reactor with adjustable flow rate, reaction retention time, reaction temperature and pressure by continuous flow chemistry technology to prepare the compound of formula (I). Step (J-4) is carried out at a suitable temperature, for example, from about 100°C to about 300°C, preferably from about 150°C to about 250°C, more preferably from about 200°C. In one embodiment, the residence time of step (J-4) is from about 10 min to about 6 h, preferably about 25 min.

[0177] In a preferred embodiment, the process of the present invention further comprises isolating the compound of formula (I), preferably in substantially pure form.

[0178] Step (J-5)

[0179] Step (J-5) is to saponify the ester of the compound of formula (I) in the presence of a suitable base, and then treat with an acid to form a compound of formula (J). Suitable bases include, but are not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide, or a combination of two or more thereof. A preferred base is sodium hydroxide. A suitable acid includes, but is not limited to, hydrogen chloride, hydrogen bromide, sulfuric acid, and a combination of two or more thereof. A preferred acid is hydrogen chloride.

[0180] In a preferred embodiment, step (J-5) is carried out in a solvent. Suitable solvents include, but are not limited to, dichloromethane, chloroform, dioxane, ethyl acetate, heptane, hexane, methyl tert-butyl ether, tetrahydrofuran, water, toluene, and mixtures of two or more thereof. Preferably, the solvent is a mixture of tetrahydrofuran and water or a mixture of MTBE and water.

[0181] In some embodiments, step (J-5) is performed at a suitable temperature, for example, about 30° C. to about 100° C., preferably about 55° C. to about 65° C., and more preferably about 65° C. In one embodiment, step (J-5) is performed for about 1 h to about 3 days, preferably about 10 h to about 2 days, and more preferably about 24 h.

[0182] In a preferred embodiment, the process of the present invention further comprises isolating the compound of formula (J), preferably in substantially pure form.

[0183] In some embodiments, the present invention provides a method for producing a compound of formula (A), comprising the above steps (a), (b), (c), (d), (e), (f), (g), (J-1), (J-2), (J-3), (J-4), (J-5), (h) and (i).

[0184] In some embodiments, the present invention provides a method for producing a compound of formula (A), comprising the above steps (a), (b), (c), (d), (e), (f), (g), (J-1), (J-2), (J-2a), (J-2b), (J-3), (J-4), (J-5), (h) and (i).

[0185] In some embodiments, the present invention provides a method for producing a compound of formula (A), comprising the above steps (a), (b), (c), (d), (e), (f), (g), (J-3), (J-4), (J-5), (h) and (i).

[0186] In one embodiment, the present invention provides a process for preparing compound (I).

[0187]

[0188] The method comprises the following steps:

[0189] (1) reacting compound (w) with formaldehyde to generate compound (b):

[0190]

[0191] (2) Converting compound (b) into compound (c):

[0192]

[0193] (3) Converting compound (c) into a mixture of compound (d-1) and compound (d-2) by rearrangement reaction:

[0194]

[0195] wherein one of the two diastereomers (d-1) and (d-2) is in diastereomeric excess, for example, a diastereomeric excess of at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95%;

[0196] (4) converting the mixture of compound (d-1) and compound (d-2) into a mixture of the following substances:

[0197] (5) Compound (e-1) and Compound (e-2):

[0198]

[0199] wherein one of compound (e-1) and compound (e-2) is produced in diastereomeric excess, for example, a diastereomeric excess of at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95%;

[0200] (6) Converting a mixture of compound (e-1) and compound (e-2) into a hydrochloride of compound (f-1) and a hydrochloride of compound (f-2) as a mixture of diastereomers:

[0201]

[0202] wherein one of compound (f-1) and compound (f-2) is produced in diastereomeric excess, for example, a diastereomeric excess of at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95%;

[0203] (7) Reaction of compound (f-1) with compound (k)

[0204]

[0205] Producing compound (l):

[0206]

[0207] (8) Converting compound (1) into compound (m):

[0208]

[0209] Alternatively, compound (l) is converted into a salt form of compound (m) with a suitable acid;

[0210] (9) reacting a compound of formula (m) or a salt form of the compound of formula (m) with an indole acid compound (j) or a salt thereof,

[0211]

[0212] To provide compound (n):

[0213] and

[0214] (10) Converting compound (n) into compound (I):

[0215]

[0216] Step (1)

[0217] In a preferred embodiment, step (1) is carried out in a suitable solvent, such as but not limited to methanol, tert-butyl alcohol, acetonitrile, acetone, dichloromethane, chloroform, dimethylformamide, dimethyl sulfoxide, dioxane, ethyl acetate, heptane, hexane, methyl tert-butyl ether, tetrahydrofuran and toluene, or a mixture of two or more thereof. Preferably, the solvent is methanol.

[0218] In one embodiment, the reaction is carried out at a temperature of about 0° C. to about 100° C., preferably about 45° C. to about 85° C., more preferably about 65° C. In one embodiment, step 1) is carried out for about half an hour to about 1 day, preferably about half an hour to about 5 hours, more preferably about 1 hour.

[0219] In a preferred embodiment, the process of the present invention further comprises isolating compound (b), preferably in substantially pure form.

[0220] Step (2)

[0221] In step (2), compound (b) is reacted with a suitable Boc protecting agent, such as but not limited to tert-butylphenyl carbonate, di-tert-butyl dicarbonate, N-(tert-butoxycarbonyloxy)phthalimide or 1-tert-butoxycarbonyl-1,2,4-triazole. Preferably, the Boc protecting agent is di-tert-butyl dicarbonate (Boc anhydride).

[0222] Step (2) is preferably carried out in the presence of a suitable base, such as but not limited to triethylamine, diisopropylethylamine, sodium bicarbonate or N-methylmorpholine. The preferred base is triethylamine.

[0223] In a preferred embodiment, step (2) is carried out in a solvent. Suitable solvents include, but are not limited to, 2-methyl THF, tert-butyl alcohol, acetonitrile, acetone, dichloromethane, chloroform, dimethylformamide, dimethyl sulfoxide, dioxane, ethyl acetate, heptane, hexane, methyl tert-butyl ether, tetrahydrofuran, water and toluene, or a mixture of two or more thereof. Preferably, the solvent is 2-methyl THF and water as a co-solvent. Preferably, the volume ratio of 2-methyl THF to water is 4:1.

[0224] In one embodiment, the reaction of step (2) is carried out at a temperature of about -10°C to about 60°C, preferably about 0°C to about 40°C, more preferably about 5°C to about 25°C. In one embodiment, step (b) is carried out for about 1 h to about 24 h, preferably about 1 h to about 10 h, more preferably about 5 h.

[0225] In a preferred embodiment, the process of the present invention further comprises isolating compound (c), preferably in substantially pure form.

[0226] Step (3)

[0227] In step (3), compound (c) reacts with an oxidant to produce a mixture of compound (d-1) and compound (d-2). Preferably, the reaction produces an excess of diastereoisomer compound (d-1). The weight ratio of the produced compound (d-1) to compound (d-2) is preferably about 55:45 to 95:5, more preferably about 6:1 to about 8:1.

[0228] Suitable oxidizing agents include, but are not limited to, N-bromosuccinimide (NBS), hydrogen peroxide, m-chloroperbenzoic acid (m-CPBA), potassium peroxymonosulfate (Oxone), 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selecfluor), tert-butyl hypochlorite, N-iodosuccinimide (NIS), etc. The preferred oxidizing agent is N-bromosuccinimide (NBS).

[0229] In some embodiments, step (3) is performed in the presence of a suitable acid, such as but not limited to acetic acid, formic acid, trifluoroacetic acid, benzoic acid, hydrochloric acid, phosphonic acid, sulfuric acid, p-toluenesulfonic acid, etc. The preferred acid is acetic acid.

[0230] In a preferred embodiment of step (3), the oxidizing agent is N-bromosuccinimide (NBS) and the acid is acetic acid.

[0231] In a preferred embodiment, step (3) is carried out in a solvent. Suitable solvents include, but are not limited to, dichloromethane, chloroform, dioxane, ethyl acetate, heptane, hexane, methyl tert-butyl ether, tetrahydrofuran (THF), 2-methyl THF, water and toluene, or a mixture of two or more thereof. Preferably, the solvent is a mixture of 2-methyl THF, THF and water. Preferably, the volume ratio of 2-methyl THF / THF / water is about 3.5 / 1.5 / 1.

[0232] In one embodiment, the reaction is carried out at a temperature of about -40°C to about 30°C, preferably about -30°C to about -10°C, more preferably about -30°C. In one embodiment, step (c) is carried out for about 30 min to about 3 h, preferably about 30 min to about 1 h, more preferably about 30 min.

[0233] In one embodiment, compound (d-1) is the major product. In a preferred embodiment, the method of the present invention further comprises separating compound (d-1) and compound (d-2).

[0234] Step (4)

[0235] The mixture of compound (d-1) and compound (d-2) is preferably converted into a mixture of compound (e-1) and compound (e-2) by reacting with an aminolysis reagent. In some embodiments of step (4), compound (e-1) is produced in the form of diastereoisomer excess. In some embodiments, the weight ratio of compound (e-1) to compound (e-2) is about 55:45 to 95:5, preferably about 6:1 to 8:1.

[0236] Suitable ammonolysis agents include, but are not limited to, ammonia, ammonium hydroxide, etc. The preferred ammonolysis agent is ammonia.

[0237] In a preferred embodiment, step (4) is carried out in a solvent. Suitable solvents include, but are not limited to, dichloromethane, chloroform, dioxane, ethyl acetate, heptane, hexane, methyl tert-butyl ether, tetrahydrofuran, methanol, ethanol, propanol and toluene, or a mixture of two or more thereof. Preferably, the solvent is methanol.

[0238] In one embodiment, the reaction is carried out at a temperature of about 20° C. to about 60° C., preferably about 40° C. to about 60° C., more preferably about 45° C. In one embodiment, step (d) is carried out for about 2 days to about 7 days, preferably about 3 days to about 5 days, more preferably about 5 days.

[0239] In one embodiment, compound (e-1) is the major product. In a preferred embodiment, the method of the present invention further comprises separating compound (e-1) and compound (e-2).

[0240] Step (5)

[0241] The mixture of compounds (e-1) and (e-2) is reacted with an acid to produce a mixture of compounds (f-1) and (f-2). In some embodiments of step (e), compound (f-1) is produced in a diastereoisomer excess. In some embodiments, the weight ratio of the produced compound (f-1) to compound (f-2) is about 55:45 to 95:5, preferably about 6:1 to 8:1.

[0242] Suitable acids include, but are not limited to, hydrogen chloride, hydrogen bromide, trifluoroacetic acid, etc. The preferred acid is hydrogen chloride or hydrogen chloride generated in situ by the reaction of acetyl chloride and an alkyl alcohol.

[0243] In a preferred embodiment, step (5) is carried out in a solvent. Suitable solvents include, but are not limited to, dichloromethane, chloroform, dioxane, ethyl acetate, heptane, hexane, methyl tert-butyl ether, acetonitrile, acetone, N,N-dimethylformamide, tetrahydrofuran and toluene, and mixtures of two or more thereof. Preferably, the solvent is N,N-dimethylformamide or N,N-dimethylformamide and one or more co-solvents selected from toluene, acetonitrile, ethyl acetate and dichloromethane. In some embodiments of step (e), the mixture of compound (f-1) and compound (f-2) is formed as a DMF solvate.

[0244] In one embodiment, the reaction is carried out at a temperature of about 0° C. to about 40° C., preferably about 10° C. to about 30° C., more preferably about 25° C. In one embodiment, step (e) is carried out for about 30 min to about 10 h, preferably about 5 h to about 3 days, more preferably about 2 days.

[0245] In one embodiment, compound (f-1) is separated from compound (f-2) by recrystallizing a mixture of compound (f-1) and compound (f-2). The recrystallization is preferably carried out at a temperature of about 20°C to about 100°C, more preferably about 50°C to about 85°C, and most preferably about 55°C. The preferred solvent for recrystallization is N,N-dimethylformamide (DMF).

[0246] In a preferred embodiment, the method of the present invention further comprises isolating compound (f-1), preferably in substantially pure form.

[0247] Step (6)

[0248] Compound (f-1) is preferably reacted with compound (k) in the presence of an amide coupling agent. Suitable amide coupling agents include, but are not limited to, acetic anhydride, pivaloyl chloride, ethyl chloroformate (ECF), isobutyl chloroformate (IBCF), Boc anhydride or di-tert-butyl dicarbonate (Boc2O), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, methanesulfonyl chloride (MsCl), p-toluenesulfonyl chloride (TsCl), n-propanephosphonic anhydride (T3P), ethyl methylphosphonic anhydride (EMPA), 1,1'-carbonyldiimidazole (CDI), N,N'- Dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), (1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide hydrochloride (EDC), 1-hydroxy-7-azabenzotriazole (HOAt), 1-hydroxybenzotriazole (HOBt), ((benzotriazol-1-yloxy)tris-(dimethylamino)phosphonium hexafluorophosphate (BOP), N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b ]pyridin-1-ylmethylene]-N-methylmethanium hexafluorophosphate N-oxide (HATU), N-[(1H-benzotriazol-1-yl)-(dimethylamino)methylene]-N-methylmethanamine tetrafluoroborate N-oxide (TBTU), 2-(2-oxo-1(2H)-pyridinyl-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), O-[(cyano(ethoxycarbonyl)methyleneamino]-N,N,N',N'-tetramethyl Urea tetrafluoroborate (TOTU), N-[(1H-benzotriazole-1-yl)(dimethylamino)-methylene]-N-methylmethanium hexafluorophosphate N-oxide (HBTU), cyanuric chloride, 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride (DMTMM), or boric acid. Preferably, the coupling agent is n-propanephosphonic anhydride (T3P).

[0249] In some embodiments, step (6) is performed in the presence of a suitable base, such as but not limited to triethylamine, diisopropylethylamine or N-methylmorpholine. The preferred base is N-methylmorpholine.

[0250] In some embodiments, step (6) is performed in the presence of a coupling agent and a suitable base. Preferably, the coupling agent is n-propanephosphonic anhydride (T3P) and the base is N-methylmorpholine.

[0251] In a preferred embodiment, step (6) is carried out in a solvent. Suitable solvents include, but are not limited to, methanol, ethanol, acetonitrile, dichloromethane, chloroform, dioxane, ethyl acetate, heptane, hexane, methyl tert-butyl ether, tetrahydrofuran, N,N-dimethylformamide and toluene, or a mixture of two or more thereof. Preferably, the solvent is N,N-dimethylformamide.

[0252] In some embodiments, step (6) is performed at a suitable temperature, for example, about -10°C to about 30°C, preferably about -10°C to about 10°C, more preferably about 0°C. In one embodiment, step (6) is performed for about 1 h to about 24 h, preferably about 4 h.

[0253] In a preferred embodiment, the process of the present invention further comprises isolating compound (1), preferably in substantially pure form.

[0254] Step (7)

[0255] Compound (l) is preferably converted into compound (m) by reaction with a hydrogen source (e.g., hydrogen, ammonium formate, etc.), a catalyst (e.g., but not limited to, palladium on carbon, palladium hydroxide on carbon, or Raney nickel), optionally in the presence of a suitable acid (e.g., but not limited to, hydrogen chloride, hydrogen bromide, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, acetic acid, etc.). Preferably, the hydrogen source is H2, and the catalyst is palladium on carbon. More preferably, the hydrogen source is H2, and the catalyst is palladium on carbon, and the reaction is carried out in the presence of p-toluenesulfonic acid to remove the Cbz group and form p-toluenesulfonic acid of compound (m).

[0256] In some embodiments, the reaction is carried out under a suitable hydrogen pressure, such as, but not limited to, about 0.5 atmosphere to about 10 atmospheres, preferably about 1 atmosphere to 5 atmospheres.

[0257] In a preferred embodiment, step (7) is carried out in a solvent. Suitable solvents include, but are not limited to, acetonitrile, acetone, dichloromethane, dimethylformamide, dimethyl sulfoxide, dioxane, ethyl acetate, heptane, hexane, methanol, methyl tert-butyl ether, ethanol, tetrahydrofuran, N,N-dimethylformamide, toluene, acetic acid, and mixtures of two or more thereof. Preferred solvents include methanol, acetic acid, and N,N-dimethylformamide.

[0258] In some embodiments, step (7) is performed at a suitable temperature, for example, about -20°C to about 50°C, preferably about 0°C to about 30°C. In one embodiment, the reaction is performed for about 1 h to about 24 h, preferably about 1 h to about 8 h.

[0259] In some embodiments, compound (m) or its salt form is used directly in the next step without further isolation.

[0260] In a preferred embodiment, the method of the present invention further comprises isolating compound (m) or a salt form thereof, preferably in substantially pure form.

[0261] Step (8)

[0262] Compound (m) or its salt is preferably reacted with compound (j) in the presence of an amide coupling agent. Suitable amide coupling agents include, but are not limited to, acetic anhydride, pivaloyl chloride, ethyl chloroformate (ECF), isobutyl chloroformate (IBCF), Boc anhydride or di-tert-butyl dicarbonate (Boc2O), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, methanesulfonyl chloride (MsCl), p-toluenesulfonyl chloride (TsCl), n-propanephosphonic anhydride (T3P), ethylmethylphosphonic anhydride (EMPA), 1,1'-carbonyldiimidazole (CDI), N,N'-dicyclohexylcarbodiimide (DCC) 、N,N'-diisopropylcarbodiimide (DIC), (1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide hydrochloride (EDC), 1-hydroxy-7-azabenzotriazole (HOAt), 1-hydroxybenzotriazole (HOBt), ((benzotriazol-1-yloxy)tris-(dimethylamino)phosphonium hexafluorophosphate (BOP), N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanium hexafluorophosphate N- oxide (HATU), N-[(1H-benzotriazol-1-yl)-(dimethylamino)methylene]-N-methylmethanamine tetrafluoroborate N-oxide (TBTU), 2-(2-oxo-1(2H)-pyridinyl-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), O-[(cyano(ethoxycarbonyl)methyleneamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU), N-[(1H-benzotriazol-1-yl)(dimethylamino)-methylene] -N-methylmethanium hexafluorophosphate N-oxide (HBTU), cyanuric chloride, 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride (DMTMM), and boric acid. Preferably, the coupling agent is N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanium hexafluorophosphate N-oxide (HATU).

[0263] In some embodiments, step (8) is performed in the presence of a suitable base, such as but not limited to triethylamine, diisopropylethylamine or N-methylmorpholine. A preferred base is N-methylmorpholine.

[0264] In some embodiments, step (8) is performed in the presence of an amide coupling agent and a suitable base, wherein the amide coupling agent is HATU and the base is N-methylmorpholine.

[0265] Preferred salts of the compound of formula (j) include potassium and sodium salts. Preferred salts of the compound of formula (m) include acetate, chloride and bromide salts.

[0266] In a preferred embodiment, step (8) occurs in a solvent such as, but not limited to, acetonitrile, acetone, chloroform, dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide, dioxane, ethyl acetate, heptane, hexane, methanol, methyl tert-butyl ether, tetrachloromethane, tetrahydrofuran, toluene, or a mixture of two or more thereof. Preferably, the solvent is N,N-dimethylformamide.

[0267] Step (8) is performed at a suitable temperature, for example, about 0° C. to about 50° C., preferably about 20° C. to about 30° C., more preferably about 25° C. In one embodiment, step (8) is performed for about 1 h to about 24 h, preferably about 3 h to about 12 h.

[0268] In a preferred embodiment, the method of the present invention further comprises isolating compound (n), preferably in substantially pure form.

[0269] Step (9)

[0270] Compound (n) is converted into compound (I) by reacting with a dehydrating agent. Suitable dehydrating agents include, but are not limited to, n-propanephosphonic anhydride (T3P), trifluoroacetic anhydride (TFAA), methyl N-(triethylammoniumsulfonyl)carbamate (Burgess reagent), phosphorus oxide (P2O5). The preferred dehydrating agent is trifluoroacetic anhydride (TFAA).

[0271] In some embodiments, step (9) is carried out in the presence of a suitable base, such as but not limited to triethylamine, diisopropylethylamine, N-methylmorpholine, 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), imidazole, pyridine, 2,6-lutidine, ethyl nicotinate, N-methylpiperazine or 1-methylimidazole. The preferred base is triethylamine.

[0272] In some embodiments, step (9) is performed in the presence of a dehydrating agent and a base, wherein the dehydrating agent is trifluoroacetic anhydride (TFAA) and the base is triethylamine.

[0273] In a preferred embodiment, step (9) is carried out in a solvent. Suitable solvents include, but are not limited to, acetonitrile, acetone, dichloromethane, dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, dioxane, ethyl acetate, heptane, hexane, methyl tert-butyl ether, tetrahydrofuran, toluene, and mixtures of two or more thereof. The preferred solvent is ethyl acetate.

[0274] In some embodiments, step (9) is performed at a suitable temperature, for example, about -10°C to about 10°C, preferably about -5°C to about 5°C, more preferably about 0°C. In one embodiment, step (9) is performed for about 30 min to about 2 h, preferably about 1 h.

[0275] In a preferred embodiment, the process of the present invention further comprises isolating compound (I), preferably in substantially pure form.

[0276] In some embodiments, the present invention further provides a method for purifying compound (I) by crystallization. The method includes dissolving compound (I) in a suitable solvent at a temperature of about 20°C to about 80°C, preferably about 45°C to about 55°C, more preferably about 50°C. The resulting solution is then cooled to a temperature of, for example, about 10°C to 25°C, thereby inducing compound (I) to crystallize. Suitable solvents for crystallization include anisole, toluene, xylene, and a mixture of two or more thereof. Preferably, the solvent is toluene. Compound (I) is preferably separated as a corresponding toluene solvate.

[0277] The present invention further provides a method for preparing an amorphous form of compound (I). The method comprises: (ia) adding a first solvent to a toluene solvate of compound (I) to produce a solution; (ib) removing a portion of the first solvent and toluene from the solution, for example by distillation; (ic) repeating steps (ia) and (ib) until a toluene concentration of no greater than a predetermined value, for example 0.1% (wt / wt) of compound (I) solution is produced. The resulting solution is then mixed with a second solvent insoluble in compound (I) to produce an amorphous form of compound (I). Suitable first solvent / second solvent pairs include EtOH / water, isopropanol / water, acetone / water and MTBE / n-heptane, preferably, the first solvent is ethanol and the second solvent is water.

[0278] The method of crystallizing Compound (I) and optionally the method of preparing an amorphous form of Compound (I) may be carried out on Compound (I) prepared by the methods described herein.

[0279] In some embodiments, the present invention provides a method for producing compound (I), comprising steps (6), (7), (8) and (9) above.

[0280] In some embodiments, the present invention provides a method for producing compound (I), comprising steps (8) and (9) above.

[0281] In one embodiment, the present invention provides a method for preparing compound (j) or a salt thereof

[0282]

[0283] The method comprises the following steps:

[0284] (j-1) Reducing compound (ga) to produce compound (gb):

[0285]

[0286] (j-2) Oxidizing compound (gb) to produce compound (g):

[0287]

[0288] (j-3) Compound (g) is reacted with ethyl 2-azidoacetate in the presence of sodium methoxide as a base to produce a mixture of compound (h-1) and compound (h-2):

[0289]

[0290] wherein one of compound (h-1) and compound (h-2) is produced in excess, for example, in excess of at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95%;

[0291] (j-4) Converting a mixture of compound (h-1) and compound (h-2) into a mixture of compound (i-1) and compound (i-2) by Hemetsberger indole cyclization:

[0292]

[0293] wherein one of compound (i-1) and compound (i-2) is produced in excess, for example, in excess of at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95%; and

[0294] (j-5) reacting a mixture of compound (i-1) and compound (i-2) with a base to obtain compound (j) or a salt thereof:

[0295]

[0296] In another embodiment, the present invention provides a method for preparing compound (j) or a salt thereof

[0297] The method comprises the following steps:

[0298] (j-1) Reducing compound (ga) to produce compound (gb):

[0299]

[0300] (j-2) Oxidizing compound (gb) to produce compound (g):

[0301]

[0302] (j-2a) reacting compound (g) with sodium bisulfite to produce compound (gc):

[0303] (j-2b) reacting compound (gc) with a base to produce compound (g):

[0304]

[0305] (j-3) Compound (g) is reacted with ethyl 2-azidoacetate in the presence of sodium methoxide as a base to produce a mixture of compound (h-1) and compound (h-2):

[0306]

[0307] wherein one of compound (h-1) and compound (h-2) is produced in excess, for example, in excess of at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95%;

[0308] (j-4) Converting a mixture of compound (h-1) and compound (h-2) into a mixture of compound (i-1) and compound (i-2) by Hemetsberger indole cyclization:

[0309]

[0310] wherein one of compound (i-1) and compound (i-2) is produced in excess, for example, in excess of at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95%; and

[0311] (j-5) reacting a mixture of compound (i-1) and compound (i-2) with a base to obtain compound (j) or a salt thereof:

[0312]

[0313] Step (j-1)

[0314] Compound (ga) is preferably reduced by reacting with a reducing agent. Suitable reducing agents include, but are not limited to, lithium aluminum hydride, lithium borohydride, sodium borohydride, diisobutylaluminum hydride, borane-tetrahydrofuran complex, borane-dimethyl sulfide complex, etc. Preferably, the reducing agent is sodium borohydride or borane-tetrahydrofuran complex.

[0315] In a preferred embodiment, step (j-1) is carried out in a solvent. Suitable solvents include, but are not limited to, acetonitrile, acetone, dichloromethane, dimethylformamide, dimethyl sulfoxide, dioxane, ethyl acetate, heptane, hexane, methyl tert-butyl ether, tetrahydrofuran, toluene, and mixtures of two or more thereof. The preferred solvent is tetrahydrofuran.

[0316] In one embodiment, the reaction of step (j-1) is carried out at a suitable temperature, for example, about -20°C to about 50°C, preferably about -5°C to about 25°C. In one embodiment, the reaction is carried out for about 0.5h to about 12h, preferably about 2 to 6h.

[0317] In some embodiments, the methods of the present invention further comprise isolating compound (gb), preferably in substantially pure form.

[0318] Step (j-2)

[0319] Compound (gb) is oxidized by reacting with an oxidant. Suitable oxidants include, but are not limited to, trichloroisocyanuric acid, sodium hypochlorite (NaClO) containing TEMPO, sodium hypochlorite containing TEMPO, oxalyl chloride containing dimethyl sulfoxide, manganese oxide, chromium trioxide, pyridinium chlorochromate (PCC), sodium perchlorate, Dess-Martin periodate (DMP), etc. A preferred oxidant is sodium hypochlorite containing TEMPO.

[0320] In a preferred embodiment, the reaction of step (j-2) occurs in a solvent. Suitable solvents include, but are not limited to, acetonitrile, acetone, dichloromethane, dimethylformamide, dimethyl sulfoxide, dioxane, ethyl acetate, heptane, hexane, methyl tert-butyl ether, tetrahydrofuran, toluene, and mixtures of two or more thereof. The preferred solvent is methyl tert-butyl ether (MTBE).

[0321] The reaction of step (j-2) is carried out at a suitable temperature, for example, about -20°C to about 50°C, preferably about -10°C to about 10°C, more preferably about -5°C to about 5°C. In some embodiments, the reaction of step (j-2) is carried out for about 10 min to about 10 h, preferably about 30 min to about 3 h.

[0322] Step (j-2a)

[0323] In one embodiment, the reaction of step (j-2a) occurs in a solvent. Suitable solvents include, but are not limited to, acetonitrile, dioxane, ethyl acetate, methyl tert-butyl ether, tetrahydrofuran, toluene, EtOH, water, and mixtures of two or more thereof. Preferred solvents are mixtures of MTBE, EtOH, and water.

[0324] In one embodiment, the reaction of step (j-2a) is carried out at a suitable temperature, for example, about 0° C. to about 60° C., preferably about 20° C. to about 40° C. In one embodiment, the reaction is carried out for about 0.5 h to about 12 h, preferably about 2 to 6 h.

[0325] Step (j-2b)

[0326] Step (j-2b) is carried out in the presence of a suitable base, such as but not limited to sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, lithium diisopropylamide, 2,2,6,6-tetramethylpiperidinium lithium, sodium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, triethylamine, diisopropylethylamine, etc. Preferably, the base is sodium carbonate.

[0327] In one embodiment, the reaction in step (j-2b) occurs in a solvent. Suitable solvents include, but are not limited to, acetonitrile, acetone, dimethyl sulfoxide, dioxane, ethyl acetate, methyl tert-butyl ether, tetrahydrofuran, toluene, ethanol, water, and mixtures of two or more thereof. A preferred solvent is methyl tert-butyl ether (MTBE) or a mixture of MTBE and water.

[0328] In one embodiment, the reaction of step (j-2b) is carried out at a suitable temperature, for example, about 0° C. to about 40° C., preferably about 20° C. to about 25° C. In one embodiment, the reaction is carried out for about 0.5 h to about 12 h, preferably about 2 to 6 h.

[0329] In some embodiments, the methods of the present invention further comprise isolating compound (g), preferably in substantially pure form.

[0330] Step (j-3)

[0331] In a preferred embodiment, step (j-3) is carried out in the presence of a sacrificial electrophilic reagent, such as, but not limited to, CF3CO2Et, ethyl trichloroacetate or ethyl formate, to prevent hydrolysis in the base-catalyzed condensation reaction, thereby increasing the yield. A preferred sacrificial electrophilic reagent is CF3CO2Et.

[0332] In a preferred embodiment, step (j-3) is carried out in a suitable solvent, such as but not limited to dichloromethane, chloroform, dioxane, ethyl acetate, heptane, hexane, methyl tert-butyl ether, tetrahydrofuran, methanol, ethanol or toluene, and a mixture of two or more thereof. Preferably, the solvent is methanol or ethanol. More preferably, the solvent is methanol.

[0333] The reaction of step (j-3) is carried out at a suitable temperature, for example, about -10°C to about 10°C, preferably about -5°C to about 10°C, and more preferably about 0°C. In one embodiment, step (j-3) is carried out for about 30 min to about 10 h, preferably about 5 h to about 24 h, and more preferably about 8 h to about 14 h.

[0334] In some embodiments, the methods of the present invention further comprise isolating compound (h-1), preferably in substantially pure form.

[0335] Step (j-4)

[0336] In step (j-4), compound (h-1) is heated to produce a reactive intermediate which can cyclize to form compound (i-1) and compound (i-2).

[0337] In a preferred embodiment, step (j-4) is carried out in a solvent. Suitable solvents include, but are not limited to, trimethylbenzene, dichloromethane, chloroform, dioxane, ethyl acetate, heptane, hexane, methyl tert-butyl ether, tetrahydrofuran, methanol, xylene and toluene, and mixtures of two or more thereof. Preferably, the solvent is a mixture of xylene and methanol. Preferably, the volume ratio of xylene to methanol is greater than 1. More preferably, the volume ratio of xylene to methanol is 5:1.

[0338] In some embodiments, step (j-4) is carried out in a flow reactor, compound (i-1) and compound (i-2) are prepared by continuous flow chemistry technology, and carried out at a suitable temperature, for example, about 100° C. to about 300° C., preferably about 150° C. to about 250° C., more preferably about 200° C. In one embodiment, step (j-4) is carried out with a residence time of about 10 min to about 6 h, preferably about 25 min.

[0339] In a preferred embodiment, the method of the present invention further comprises isolating compound (i-1), preferably in substantially pure form.

[0340] Step (j-5)

[0341] Step (j-5) is to saponify compound (i-1) and / or compound (i-2) in the presence of a suitable base, and then treat with an acid to form compound (j). Suitable bases include, but are not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide, or a combination of two or more thereof. The preferred base is sodium hydroxide. Suitable acids include, but are not limited to, hydrogen chloride, hydrogen bromide, sulfuric acid, and a combination of two or more thereof. The preferred acid is hydrogen chloride.

[0342] In a preferred embodiment, step (j-5) is carried out in a solvent. Suitable solvents include, but are not limited to, dichloromethane, chloroform, dioxane, ethyl acetate, heptane, hexane, methyl tert-butyl ether, tetrahydrofuran, water, toluene, and mixtures of two or more thereof. Preferably, the solvent is a mixture of tetrahydrofuran and water or a mixture of MTBE and water.

[0343] In some embodiments, step (j-5) is performed at a suitable temperature, for example, about 30° C. to about 100° C., preferably about 55° C. to about 65° C., and more preferably about 65° C. In one embodiment, step (j-5) is performed for about 1 h to about 3 days, preferably about 10 h to about 2 days, and more preferably about 24 h.

[0344] In a preferred embodiment, the method of the present invention further comprises isolating compound (j), preferably in substantially pure form.

[0345] In some embodiments, the present invention provides a method for preparing compound (I), comprising the above steps (1), (2), (3), (4), (5), (6), (7), (j-1), (j-2), (j-3), (j-4), (j-5), (8) and (9).

[0346] In some embodiments, the present invention provides a method for preparing compound (I), comprising the above steps (1), (2), (3), (4), (5), (6), (7), (j-1), (j-2), (j-2a), (j-2b), (j-3), (j-4), (j-5), (8) and (9).

[0347] In some embodiments, the present invention provides a method for producing compound (I), comprising the above steps (1), (2), (3), (4), (5), (6), (7), (j-3), (j-4), (j-5), (8) and (9).

[0348] Definition

[0349] Listed below are definitions of various terms used to describe the present invention. Whether used alone or in combination with other terms, these definitions apply to the terms used throughout the specification and claims, unless otherwise limited in specific cases.

[0350] As used herein, the term "alkoxy", when used alone or in combination with other terms, unless otherwise indicated, refers to an alkyl group having the specified number of carbon atoms connected to the rest of the molecule through an oxygen atom, such as methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and higher homologs and isomers. Preferred alkoxy is (C1-C3) alkoxy.

[0351] The terms "heterocycle" or "heterocycloalkyl" are used interchangeably and refer to a non-aromatic ring or a bicyclic or tricyclic fused, bridged or spiro ring system wherein (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur and nitrogen, (ii) each ring system may be saturated or unsaturated, (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may optionally be quaternized, (v) any of the above rings may be fused to an aromatic ring, and (vi) the remaining ring atoms are carbon atoms which may be optionally substituted with oxo or optionally substituted with an exocyclic olefinic bond, an imine bond or an oxime double bond. Representative heterocycloalkyl includes but is not limited to 1,3-dioxolane, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, 2-azabicyclo [2.2.1] -heptyl, 8-azabicyclo [3.2.1] octyl, 5-azaspiro [2.5] octyl, 1-oxa-7-azaspiro [4.4] nonyl, 7-oxoxo oxacycloheptan-4-yl (7-oxooxepan-4-yl) and tetrahydrofuranyl. These heterocyclic groups can be further substituted. Heteroaryl or heterocyclic groups can be C-connected or N-connected (if possible).

[0352] An "aliphatic" group is a non-aromatic moiety composed of any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, and optionally contains one or more unsaturated units, such as double bonds and / or triple bonds. Examples of aliphatic groups are functional groups such as alkyl, alkenyl, alkynyl, O, OH, NH, NH2, C(O), S(O)2, C(O)O, C(O)NH, OC(O)O, OC(O)NH, OC(O)NH2, S(O)2NH, S(O)2NH2, NHC(O)NH2, NHC(O)C(O)NH, NHS(O)2NH, NHS(O)2NH2, C(O)NHS(O)2, C(O)NHS(O)2NH, or C(O)NHS(O)2NH2, etc., groups containing one or more functional groups, non-aromatic hydrocarbons (optionally substituted), and groups in which one or more carbons of the non-aromatic hydrocarbons (optionally substituted) are substituted with functional groups. The carbon atoms of the aliphatic group may be optionally substituted with oxo. The aliphatic group may be linear, branched, cyclic or a combination thereof, and preferably contains from about 1 to about 24 carbon atoms, more typically from about 1 to about 12 carbon atoms. In addition to aliphatic hydrocarbon groups, as used herein, aliphatic groups clearly include, for example, alkoxyalkyl, polyalkoxyalkyl, such as polyalkylene glycols, polyamines and polyimines. The aliphatic group may be optionally substituted.

[0353] The term "sulfonyl" refers to a group of the formula R a -SO2- group, where R a is alkyl, alkenyl, alkynyl or aryl, each optionally substituted. a is an optionally substituted alkyl group or an optionally substituted aryl group.

[0354] The term "phosphoryl" refers to a group of the formula (R b )2P(O)-, where R b is an alkyl-O-, alkenyl-O-, alkynyl-O- or aryl-O- group, each optionally substituted. b is optionally substituted alkyl, for example C1-C3-alkyl.

[0355] The term "substituted" means that one, two, three or more hydrogen atoms are independently replaced by substituents, including but not limited to -F, -Cl, -Br, -I, -OH, C1-C 12 -alkyl; C2-C 12 -alkenyl, C2-C 12 -alkynyl, protected hydroxyl, -NO2, -N3, -CN, -NH2, protected amino, oxo, thio, -NH-C1-C 12 -alkyl, -NH-C2-C8-alkenyl, -NH-C2-C8-alkynyl, -NH-C3-C 12-cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -O-C1-C 12 -alkyl, -O-C2-C8-alkenyl, -O-C2-C8-alkynyl, -O-C3-C 12 -cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycloalkyl, -C(O)-C1-C 12 -alkyl, -C(O)-C2-C8-alkenyl, -C(O)-C2-C8-alkynyl, -C(O)-C3-C 12 -cycloalkyl, -C(O)-aryl, -C(O)-heteroaryl, -C(O)-heterocycloalkyl, -CONH2, -CONH-C1-C 12 -alkyl, -CONH-C2-C8-alkenyl, -CONH-C2-C8-alkynyl, -CONH-C3-C 12 -cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -OCO2-C1-C 12 -alkyl, -OCO2-C2-C8-alkenyl, -OCO2-C2-C8-alkynyl, -OCO2-C3-C 12 -cycloalkyl, -OCO2-aryl, -OCO2-heteroaryl, -OCO2-heterocycloalkyl, -CO2-C1-C 12 Alkyl, -CO2-C2-C8 alkenyl, -CO2-C2-C8 alkynyl, CO2-C3-C 12 -cycloalkyl, -CO2-aryl, CO2-heteroaryl, CO2-heterocycloalkyl, -OCONH2, -OCONH-C1-C 12 -alkyl, -OCONH-C2-C8-alkenyl, -OCONH-C2-C8-alkynyl, -OCONH-C3-C 12 -cycloalkyl, -OCONH-aryl, -OCONH-heteroaryl, -OCONH-heterocycloalkyl, -NHC(O)H, -NHC(O)-C1-C 12 -alkyl, -NHC(O)-C2-C8-alkenyl, -NHC(O)-C2-C8-alkynyl, -NHC(O)-C3-C 12 -cycloalkyl, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)-heterocycloalkyl, -NHCO2-C1-C 12 -alkyl, -NHCO2-C2-C8-alkenyl, -NHCO2-C2-C8-alkynyl, -NHCO2-C3-C 12-cycloalkyl, -NHCO2-aryl, -NHCO2-heteroaryl, -NHCO2-heterocycloalkyl, -NHC(O)NH2, -NHC(O)NH-C1-C 12 -alkyl, -NHC(O)NH-C2-C8-alkenyl, -NHC(O)NH-C2-C8-alkynyl, -NHC(O)NH-C3-C 12 -cycloalkyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, -NHC(O)NH-heterocycloalkyl, NHC(S)NH2, -NHC(S)NH-C1-C 12 -alkyl, -NHC(S)NH-C2-C8-alkenyl, -NHC(S)NH-C2-C8-alkynyl, -NHC(S)NH-C3-C 12 -cycloalkyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH-heterocycloalkyl, -NHC(NH)NH2, -NHC(NH)NH-C1-C 12 -alkyl, -NHC(NH)NH-C2-C8-alkenyl, -NHC(NH)NH-C2-C8-alkynyl, -NHC(NH)NH-C3-C 12 -cycloalkyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NH-heterocycloalkyl, -NHC(NH)-C1-C 12 -alkyl, -NHC(NH)-C2-C8-alkenyl, -NHC(NH)-C2-C8-alkynyl, -NHC(NH)-C3-C 12 -cycloalkyl, -NHC(NH)-aryl, -NHC(NH)-heteroaryl, -NHC(NH)-heterocycloalkyl, -C(NH)NH-C1-C 12 -alkyl, -C(NH)NH-C2-C8-alkenyl, -C(NH)NH-C2-C8-alkynyl, -C(NH)NH-C3-C 12 -cycloalkyl, -C(NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NH-heterocycloalkyl, -S(O)-C1-C 12 -alkyl, -S(O)-C2-C8-alkenyl, -S(O)-C2-C8-alkynyl, -S(O)-C3-C 12 -cycloalkyl, -S(O)-aryl, -S(O)-heteroaryl, -S(O)-heterocycloalkyl, -SO2NH2, -SO2NH-C1-C 12 -alkyl, -SO2NH-C2-C8-alkenyl, -SO2NH-C2-C8-alkynyl, -SO2NH-C3-C 12-cycloalkyl, -SO2NH-aryl, -SO2NH-heteroaryl, -SO2NH-heterocycloalkyl, -NHSO2-C1-C 12 -alkyl, -NHSO2-C2-C8-alkenyl, -NHSO2-C2-C8-alkynyl, -NHSO2-C3-C 12 -cycloalkyl, -NHSO2-aryl, -NHSO2-heteroaryl, -NHSO2-heterocycloalkyl, -CH2NH2, -CH2SO2CH3, -aryl, -aralkyl, -heteroaryl, -heteroaralkyl, -heterocycloalkyl, -C3-C 12 -cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-C1-C 12 -alkyl, -S-C2-C8-alkenyl, -S-C2-C8-alkynyl, -S-C3-C 12 -cycloalkyl, -S-aryl, -S-heteroaryl, -S-heterocycloalkyl or methylthio-methyl. It should be understood that aryl, heteroaryl, alkyl, cycloalkyl, etc. may be further substituted.

[0356]

[0046] The terms "halo" or "halogen," as used herein alone or as part of another substituent, refer to a fluorine, chlorine, bromine, or iodine atom.

[0357] As used herein, the term "optionally substituted" means that the referenced group may be substituted or unsubstituted. In one embodiment, the referenced group is optionally substituted with zero substituents, i.e., the referenced group is unsubstituted. In another embodiment, the referenced group is optionally substituted with one or more additional groups individually and independently selected from the groups described herein.

[0358] The term "hydrogen" includes hydrogen and deuterium. In addition, the atoms described include other isotopes of that atom as long as the resulting compound is pharmaceutically acceptable.

[0359] In some embodiments, the compound of each formula herein is defined as including isotope-labeled compounds. "Isotope-labeled compound" is a compound in which at least one atomic position is enriched with a specific isotope of a specified element, and its enrichment level is significantly higher than the natural abundance of the isotope. For example, one or more hydrogen atom positions in the compound can be enriched with deuterium to a level significantly greater than the natural abundance of deuterium, for example, enriched to at least 1%, preferably at least 20% or at least 50%. For example, this deuterated compound may be metabolized more slowly than its non-deuterated analog, and therefore shows a longer half-life when administered to a subject. This compound can be synthesized using methods known in the art, for example, by using deuterated raw materials. Unless otherwise indicated, isotope-labeled compounds are pharmaceutically acceptable.

[0360] The term "hydroxyl activating group" as used herein refers to a labile chemical moiety known in the art that activates a hydroxyl group so that it will dissociate during a synthetic process, such as a substitution or elimination reaction. Examples of hydroxyl activating groups include, but are not limited to, methanesulfonate, toluenesulfonate, triflate, p-nitrobenzoate, phosphonate, and the like.

[0361] As used herein, the term "activated hydroxyl" refers to a hydroxyl group activated with a hydroxyl activating group as defined above, including, for example, mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups.

[0362] As used herein, the term "hydroxy protecting group" refers to an unstable chemical moiety known in the art that is used to protect a hydroxyl group from undesirable reactions during the synthesis process. After the synthesis steps, the hydroxy protecting group described herein can be selectively removed. Typical hydroxy protecting groups known in the art are described in TH Greene and PGM Wuts, Pr otectiveGroupsinOrganicSynthesis , 3rd edition, John Wiley & Sons, New York (1999). Examples of hydroxyl protecting groups include benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, tert-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, allyl, benzyl, triphenylmethyl (trityl), methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-(trimethylsilyl)-ethoxymethyl, methylsulfonyl, trimethylsilyl, triisopropylsilyl, and the like.

[0363] The term "protected hydroxy" as used herein refers to a hydroxy group protected by a hydroxy protecting group as defined above, including, for example, benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups.

[0364] The term "hydroxy prodrug group" as used herein refers to a prodrug group known in the art that changes the physicochemical properties of the parent drug in a temporary manner by covering or masking the hydroxyl group, thereby changing its biological properties. After the synthetic steps described, the hydroxy prodrug group described herein must be able to return to the hydroxyl group in vivo. Typical hydroxy prodrug groups known in the art are described in Kenneth B. Sloan, Prodrugs,Topical and Ocular Drug Delivery, (Drugs and Pharmaceutical Sciences; Vol. 53), Marcel Dekker, Inc., New York (1992) and SS Dharmashwar and VJ Stella, "Prodrugs of Alcohols and Phenols," Prodrugs Challenges and Rewards Part-2 , (Biotechnology: Pharmaceutical Aspects), edited by VJ Stell et al., published by Springer and AAPSPress, 2007, pp. 31-99.

[0365] As used herein, the term "amino protecting group" refers to a labile chemical moiety known in the art that is used to protect an amino group from undesirable reactions during the synthesis process. The amino protecting groups described herein may be selectively removed after the synthetic steps described. Typical amino protecting groups known in the art are described in TH Greene and PGM Wuts, Prot ectiveGroupsinOrganicSynthesis , 3rd edition, John Wiley & Sons, New York (1999). Examples of amino protecting groups include, but are not limited to, methoxycarbonyl, tert-butyloxycarbonyl, 9-fluorenyl-methoxycarbonyl, benzyloxycarbonyl, and the like.

[0366] The term "protected amino" as used herein refers to an amino group protected by an amino protecting group as defined above.

[0367] The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction. For example, representative leaving groups include chloro, bromo and iodo; sulfonate groups, such as mesylate, tosylate, bromobenzenesulfonate, nosylate, etc.; and acyloxy groups, such as acetoxy, trifluoroacetoxy, etc.

[0368] As used herein, the term "aprotic solvent" refers to a solvent that is relatively inert to proton activity, i.e., does not act as a proton donor. Examples include, but are not limited to, hydrocarbons (such as hexane and toluene), such as halogenated hydrocarbons (such as dichloromethane, vinyl chloride, chloroform, etc.), heterocyclic compounds (such as tetrahydrofuran and N-methylpyrrolidone), and ethers (such as diethyl ether, bismethoxymethyl ether). These compounds are well known to those skilled in the art, and it is obvious to those skilled in the art that for specific compounds and reaction conditions, a single solvent or a mixture thereof may be preferred, depending on factors such as the solubility of the reagents, the reactivity of the reagents, and the preferred temperature range. Further discussion of aprotic solvents can be found in organic chemistry textbooks or professional monographs, for example: OrganicSolventsPhysicalPropertiesandMethodsofPurification , 4th edition, edited by John A. Riddick et al., Volume 2, TechniquesofChemistry Series , John Wiley & Sons, NY, 1986.

[0369] As used herein, the term "protic solvent" refers to a solvent that tends to donate protons, such as alcohols, such as methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, etc. These solvents are well known to those skilled in the art, and it is obvious to those skilled in the art that for specific compounds and reaction conditions, a single solvent or a mixture thereof may be preferred, depending on factors such as the solubility of the reagents, the reactivity of the reagents, and the preferred temperature range. Further discussion of protic solvents can be found in organic chemistry textbooks or professional monographs, for example: OrganicSolventsPhysica lPropertiesand MethodsofPurification , 4th edition, edited by John A. Riddick et al., Volume 2, Techniques ofChemistrySeries , John Wiley & Sons, NY, 1986.

[0370] The combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable compounds. As used herein, the term "stable" refers to compounds that have stability sufficient to allow manufacturing and maintain the integrity of the compound for a sufficient period of time to be used for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

[0371] The synthesized compound can be separated from the reaction mixture and further purified by methods such as column chromatography, high pressure liquid chromatography or recrystallization. As will be appreciated by those skilled in the art, other methods for synthesizing the general formula compounds herein will be apparent to those of ordinary skill in the art. In addition, the various synthesis steps can be carried out in an alternating order or sequence to obtain the desired compound.

[0372] Synthetic chemistry transformations and protecting group methods (protection and deprotection) for synthesizing the compounds described herein are known in the art and include, for example, those described by R. Larock, Comprehensive Organic Transformations , 2nd edition, Wiley-VCH (1999); TW Greene and PGM Wuts, Protective Groups in Organic Synthesis , 3rd edition, John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis , John Wiley and Sons (1994); and L. Paquette et al., Encyclopedia of Reagents for Organic Synthesis , John Wiley and Sons (1995), and subsequent editions.

[0373] The compounds described herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms which may be defined, based on absolute stereochemistry, as (R)- or (S)-, or, for amino acids, as (D)- or (L)-. The present invention is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optical isomers may be prepared from their respective optically active precursors by the methods described above or by resolution of the racemic mixtures. Resolution may be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques known to those skilled in the art. Further details on resolution may be found in Jacques et al. Enantiomers,Racemates,andResolutions (John Wiley & Sons, 1981). When the compounds described herein contain olefinic double bonds, other unsaturated bonds, or other centers of geometric asymmetry, unless otherwise specified, the compounds include E and Z geometric isomers or cis and trans isomers. Likewise, all tautomeric forms are also included. Tautomers may be cyclic or acyclic. The configuration of any carbon-carbon double bond appearing herein is selected only for convenience and is not intended to specify a particular configuration unless so described herein; therefore, any carbon-carbon double bond or carbon-heteroatom double bond described herein as trans may be cis, trans, or a mixture of any proportion of the two.

[0374] Some compounds of the present invention may also exist in different stable conformational forms that are separable. Torsional asymmetry due to limited rotation around an asymmetric single bond (e.g., due to steric hindrance or ring strain) may allow separation of different conformers. The present invention includes each conformer of these compounds and mixtures thereof.

[0375] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and have a reasonable benefit / risk ratio within the scope of reasonable medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts described in detail by SM Berge et al. in J. Pharmaceutical Sciences, 66: 1-19 (1977). Salts can be prepared in situ during the final separation and purification of the compounds of the present invention, or prepared separately by reacting the free base functional group with a suitable organic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts, which are salts of amino groups formed with inorganic acids (such as hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid and perchloric acid) or with organic acids (such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid) or by using other methods used in the art (such as ion exchange). Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane-propionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyls having 1 to 6 carbon atoms, sulfonates and aryl sulfonates, where appropriate.

[0376] As used herein, the term "pharmaceutically acceptable ester" refers to esters that hydrolyze in vivo, including those that readily decompose in the human body to produce the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic acids, alkenoic acids, cycloalkanoic acids, and alkanedioic acids, wherein each alkyl or alkenyl moiety advantageously has no more than 6 carbon atoms. Examples of specific esters include, but are not limited to, esters of C1-C6-alkanoic acids, such as acetates, propionates, butyrates, and pivalates.

[0377] Abbreviation

[0378] Abbreviations that may be used in the scheme descriptions and examples that follow are:

[0379] DMAP: dimethylaminopyridine;

[0380] DMF: dimethylformamide;

[0381] DCM: dichloromethane;

[0382] AcOH: acetic acid;

[0383] EtOAc or EA: ethyl acetate;

[0384] Cbz: benzyloxycarbonyl;

[0385] HCl: hydrogen chloride;

[0386] HBr: hydrogen bromide;

[0387] NaHCO3: sodium bicarbonate;

[0388] HPLC: high pressure liquid chromatography;

[0389] MeOH: methanol;

[0390] MTBE: tert-butyl methyl ether;

[0391] EtOH: ethanol;

[0392] Fmoc: fluorenylmethoxycarbonyl;

[0393] Troc: 2,2,2-trichloroethoxycarbonyl;

[0394] Moz: p-methoxybenzyloxycarbonyl;

[0395] Pnz: p-nitrobenzyloxycarbonyl;

[0396] Teoc: 2-(trimethylsilyl)ethoxycarbonyl;

[0397] NMM: N-methylmorpholine;

[0398] HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate;

[0399] NBS: N-bromosuccinimide;

[0400] Rp: hydroxyl protecting group;

[0401] TEA: triethylamine;

[0402] THF: tetrahydrofuran;

[0403] 2-MeTHF: 2-methyltetrahydrofuran;

[0404] TFAA: trifluoroacetic anhydride;

[0405] TsOH: p-toluenesulfonic acid;

[0406] TPP or PPh3: triphenylphosphine;

[0407] T3P: n-propanephosphonic anhydride;

[0408] Boc: tert-butoxycarbonyl;

[0409] Bz: benzyl;

[0410] Ph: phenyl;

[0411] PhMe: Toluene.

[0412] All other abbreviations used herein, not specifically described above, should be consistent with the meanings given by ordinary technicians in the field.

[0413] Synthesis Scheme

[0414] The present invention will be better understood in conjunction with Schemes 1, 2 and 3, wherein R1, R2 and R3 are as defined above, unless otherwise indicated. It is obvious to one of ordinary skill in the art that the method of the present invention can be implemented by replacing appropriate reactants, and the order of the steps themselves can be changed.

[0415] The chemical route for the synthesis of the amide hydrochloride salt (f-1) is summarized in Scheme 1. Commercially available compound (a) can be reacted with formaldehyde to undergo a Pictet-Spengler reaction to form a bicyclic compound (b) as an HCl salt. Compound (b) can be protected to generate compound (c) as a Boc amine. Compound (c) can be treated with NBS to arrange to generate spirooxindole compound (d-1) and compound (d-2) as a diastereoisomer mixture, which are converted to the corresponding amide compound (e-1) and compound (e-2) by aminolysis. The mixture of compound (e-1) and (e-2) is treated with HCl to cleave the Boc group, followed by recrystallization in DMF to produce the key intermediate compound (f-1) in the form of a high-purity DMF solvate.

[0416] Solution 1

[0417]

[0418] The chemical route for synthesizing 2-indolecarboxylic acid ester compound (j) is summarized in Scheme 2. Commercially available compound (ga) is reduced and then oxidized to obtain compound (g). In the presence of a base and a sacrificial electrophile (i.e., ethyl trifluoroacetate), compound (g) reacts with ethyl 2-azidoacetate to undergo a condensation reaction to form acrylate compound (h). Compound (h) is then subjected to Hemetsberger indole cyclization using a continuous flow chemistry method to obtain compound (i) in the form of a 2-indolecarboxylic acid ester. Saponification of compound (i) provides compound (j), a key intermediate of 2-indolecarboxylic acid.

[0419] Solution 2

[0420]

[0421] An alternative chemical route to synthesize 2-indolecarboxylic acid ester compound (j) is summarized in Scheme 2a. Commercially available compound (ga) can be reduced to alcohol (gb). Oxidation affords compound (g). Compound (g) reacts with sodium bisulfite to form its sodium bisulfite salt (gc). Sodium bisulfite (gc) releases compound (g) upon treatment with a base (i.e., sodium carbonate), which reacts with ethyl 2-azidoacetate in the presence of a base and a sacrificial electrophile (i.e., ethyl trifluoroacetate) to undergo a condensation reaction to form acrylate compound (h). Compound (h) is then subjected to a Hemetsberger indole cyclization using a continuous flow chemistry method to afford compound (i) in the form of a 2-indolecarboxylic acid ester. Saponification of compound (i) provides compound (j), a key intermediate for 2-indolecarboxylic acid.

[0422] Option 2a

[0423]

[0424] The chemical route for synthesizing 2-indolecarboxylate compound (i) is summarized in Scheme 3. Compound (f-1) can be reacted with commercially available compound (k) under amide coupling conditions to obtain compound (l). A suspension of compound (l) and Pd / C catalyst in methanol is stirred under a hydrogen atmosphere to allow the Cbz deprotection reaction to produce secondary amine compound (m-1). Alternatively, a suspension of compound (l) and Pd / C catalyst in methanol is stirred in the presence of an acid under a hydrogen atmosphere to obtain compound (m-2) in the form of an acid salt. Alternatively, compound (l) can be treated with a strong acid (e.g., HBr in HOAc) to allow the Cbz deprotection reaction to produce secondary amine compound (m-3) in the form of an acid salt. A mixture of compound (m-1), compound (j), a coupling agent (i.e., HATU) and a base (i.e., NMM) in DMF is stirred to complete the coupling reaction to obtain compound (n). Similar reaction conditions are also applicable to compound (m-2) or (m-3) to obtain compound (n). Compound (n) can be subjected to a dehydration reaction to convert the amide into a nitrile, which can be further purified by toluene crystallization to obtain a toluene-solidified compound (o). The separated toluene solvate solid is dissolved in EtOH and added to water to form a suspension. The amorphous solid product is filtered, washed with water, and dried to obtain compound (i) in the form of an amorphous solid.

[0425] Solution 3

[0426]

[0427] The compounds and methods of the present invention will be understood in conjunction with the following exemplary methods by which the compounds of the present invention can be prepared. It should be understood that any reaction described herein in any variation thereof can be combined with one or more other reactions in their respective variations, substantially similar to Scheme 1 above.

[0428] Example

[0429] The compounds and methods of the present invention will be better understood in conjunction with the following examples, which are intended for illustration only and do not limit the scope of the present invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art, and may be made without departing from the spirit of the present invention and the scope of the appended claims, including but not limited to changes and modifications associated with the chemical structures, substituents, derivatives, preparations and / or methods of the present invention.

[0430] Example 1. Preparation of methyl ester (b)

[0431]

[0432] To a stirred solution of compound a (70.0 kg, 274.8 mol, 1.0 equiv) in MeOH (700 L) was added a 37 wt % aqueous formaldehyde solution (24.6 kg, 302.3 mol, 1.1 equiv) at 65 ° C within 1 h, and the resulting solution was stirred at 65 ° C for 30 min. HPLC showed that compound b was completely consumed. The reaction mixture was concentrated in vacuo to about 60 kg, and a white solid was precipitated. MTBE (840 L) was added, and the resulting white suspension was stirred at 20 ° C for 2 h. The mixture was filtered, the filter cake was washed with MTBE (70 L), and dried under vacuum to obtain compound b (71.0 kg, 100.0% purity, 98.9% content, 95.7% yield) in the form of a methyl ester. 1 H-NMR (300MHz,CDCl3): 1 HNMR (400MHz, DMSO): δ11.19(s,1H),10.24(s,2H),7.48(d,J=7.8Hz,1H),7.37(d,J=8.1Hz,1H),7.16-7.06(m,1H),7.06 -6.96(m,1H),4.63(dd,J=10.1,5.3Hz,1H),4.40(s,2H),3.83(s,3H),3.33-3.26(m,1H),3.07(dd,J=15.9,10.1Hz,1H).

[0433] Example 2. Preparation of Boc amine (c)

[0434]

[0435] To a stirred suspension of compound b (70.0 kg, assay: 98.9%, 259.6 mol, 1.0 equiv) in 2-MeTHF (643.8 kg) at 5°C was added TEA (54.2 kg, 535.6 mol, 2.06 equiv) and H2O (156.8 kg). The resulting solution was stirred at 5-10°C for 20 min. (Boc)2O (61.8 kg, 283.2 mol, 1.09 equiv) was added. The reaction mixture was heated to 25°C and stirred at 25°C for 5 h. The reaction mixture was cooled to 5°C and 7 wt% aqueous HCl (208.5 kg, 400.0 mol, 1.54 equiv) was slowly added. The mixture was separated and the aqueous layer was extracted with 2-methylTHF (100 kg). The combined organic layers were washed with 5% sodium bicarbonate solution (109.1 kg) and 5% aqueous NaCl solution (144.8 kg) to give a solution of compound c in 2-methyltetrahydrofuran (690.2 kg), which was used in the next step without further purification.

[0436] 1 H NMR (300MHz, CDCl3): δ8.69 (s, 0.5H), 8.05 (s, 0.5H), 7.50 (d, J = 7.6Hz, 1H), 7.36- 7.26(m,1H),7.21-7.05(m,2H),5.44(d,J=5.5Hz,0.5H),5.23(d,J=5.3Hz,0.5H), 4.93(d,J=16.1Hz,0.5H), 4.83(d,J=16.2Hz,0.5H), 4.57(dd,J=16.1,11.1Hz,1H) ,3.62(d,J=8.7Hz,3H),3.44(d,J=15.6Hz,1H),3.12(m,1H),1.55(d,J=3.0Hz,9H).

[0437] Example 3. Preparation of Compound (d-1) and Compound (d-2) as a mixture of diastereomers

[0438]

[0439] To a solution of compound (c) in 2-MeTHF (688.5 kg, 259.6 mol, 1.0 eq.) was added H2O (220.6 kg) and THF (312.3 kg) at 0°C, and AcOH (113.0 kg, 1881.7 mol, 7.2 eq.) was added at 0°C. The turbid mixture was cooled to -30°C, while it became a milky solution. NBS (46.9 kg, 263.5 mol, 1.0 eq.) was added in 10 portions at -30°C at intervals of 20 min. The milky mixture became a yellow turbid solution and was stirred at -30°C for 30 min. HPLC showed that compound 3 was completely consumed. The turbid yellow solution was warmed to -10°C and poured into a stirred 15 wt% K2CO3 aqueous solution (1156.5 kg). The mixture was separated and the aqueous layer was extracted with DCM (370.6 kg). The combined organic layers were washed with 15wt% K2CO3 aqueous solution (289.4kg) and 10wt% NaCl aqueous solution (286.4kg×3), and concentrated to 1 / 4 volume under vacuum. DCM, THF and 2-MeTHF were removed by azeotropic distillation with MeOH (221.5kg×3) to obtain a solution (174.1kg) of compound (d-1) and compound (d-2) in MeOH, which was directly used in the next step.

[0440] 1H NMR (400MHz, DMSO): δ10.66(s,1H),7.23(t,J=7.7Hz,1H),7.08(dd,J=15.3,7.2Hz, 1H),7.00(dd,J=10.2,4.5Hz,1H),6.90(d,J=7.7Hz,1H),6.84(d,J=7.6Hz,1H),4.6 1(dt,J=13.8,8.5Hz,1H),3.71(d,J=12.5Hz,3H),3.54(dt,J=26.9,10.1Hz,2H),2. 39(dd,J=12.8,8.0Hz,1H),2.25(ddd,J=18.5,12.8,9.1Hz,1H),1.41-1.36(m,9H).

[0441] Example 4. Preparation of Amide Compound (e-1) and Compound (e-2) as a Diastereoisomer Mixture

[0442]

[0443] At 25°C, to a solution of compound (d-1) and compound (d-2) in MeOH (174.2 kg, 259.6 mol, 1.0 equivalent) was added a solution of 7N NH3 in MeOH (568.1 kg, 20 equivalents), and the reaction mixture was stirred in an autoclave at 50-55°C for 5 days. The mixture was cooled and concentrated to half volume under vacuum. DMF (172.4 kg) and PhMe (93.5 kg) were added, and the mixture was concentrated under vacuum to give a dark brown solution (222.1 kg) of compound (e-1) and compound (e-2) in DMF and toluene, which was used in the next step without further purification.

[0444] 1 H NMR (400MHz, DMSO): δ10.65(s,1H),7.51(d,J=7.0Hz,1H),7.24(t,J=7.6Hz,1H),7.09(d,J=25.4Hz,1H),7.04 -6.94(m,2H),6.92(t,J=5.5Hz,1H),4.50-4.36(m,1H),3.57-3.50(m,2H),2.20(t,J=6.8Hz,2H),1.38(m,9H).

[0445] Example 5. Preparation of compound (f-1)

[0446]

[0447] A solution of 4M HCl in EA (440.8kg) was added to DCM (2288.5kg) at 25°C, and a solution of compounds (e-1) and (e-2) in DMF and PhMe (222.1kg, 259.6mol) and acetonitrile (135.5kg) were added at 25°C. The reaction mixture was stirred at 25±5°C for 2 days. HPLC showed that the reaction was complete. The mixture was filtered, the filter cake was washed with DCM (357.5kg), and dried under vacuum to give a crude product (72.1kg). The crude product was added to hot DMF (205.0kg) at 55°C, and the mixture was stirred at 55°C for 3h. The mixture was then cooled to 10±5°C within 6h, and then stirred for 2h. The mixture was filtered, the filter cake was washed with DMF (67.8 kg) and DCM (228.9 kg), and dried in vacuo at 30°C to give a pale yellow solid compound (f-1) (40.0 kg, purity 99.5%, content 76.3%, yield over 4 steps 43.5%). 1 H NMR (400MHz, DMSO): δ11.00(s,1H),10.78(s,1H),9.06(s,1H),8.03(s,1H ),7.77(s,1H),7.63(d,J=7.4Hz,1H),7.27(td,J=7.7,1.0Hz,1H),7.04(t d,J=7.6,0.8Hz,1H),6.91(d,J=7.7Hz,1H),4.64(dd,J=11.0,7.3Hz,1H), 3.59(d,J=12.3Hz,1H), 3.45(d,J=12.2Hz,1H), 2.47(m,1H), 2.22(m,1H).

[0448] Example 6. Preparation of compound (gb)

[0449]

[0450] Compound (ga) (340.0 kg, 1.0 equivalent) and THF (1513.0 L, 5 V) were charged into reactor 1 (R1). Reactor 1 was cooled to 0-10°C. Sodium borohydride (87.7 kg, 1.2 equivalent) was added to R1 at 0-10°C and stirred at 0-10°C for 1-2 h. Boron trifluoride-THF (324.0 kg, 1.2 equivalent) was added dropwise to R1 at 0-10°C (0-5°C is recommended) and stirred at 0-10°C for 0.5-1 h. R1 was heated to 15-25°C and stirred for 2-3 h. Samples were taken for IPC (HPLC) (quenched with saturated NH4Cl aqueous solution, EP-038282-A≤2.0%). Water (1500L, 4.4V) and NH4Cl (550.8kg) were charged into reactor 2 (R2) to prepare an aqueous NH4Cl solution. The reaction mixture of R1 was slowly added to the aqueous NH4Cl solution of R2 at 20-30°C, and R2 was stirred at 20-30°C for 2-3h. After separation, the organic phase of R2 was collected and the aqueous phase was transferred to R1. R2 was concentrated to below 50°C until no obvious distillate was precipitated. MTBE (1360L, 4V) was added to R1, and R1 was stirred for 0.5h. After separation, the organic phase was collected and transferred to R2. MTBE (1360L, 4V) was added to R1, and MTBE was transferred to R2. The slurry in R2 was stirred at 20-30°C for 10-20min. After filtration, the filter cake was washed with MTBE (340L, 1V). All filtrates in R1 were collected and the crude compound (gb) was used directly in the next step.

[0451] Example 7. Preparation of compound (g)

[0452]

[0453] In R1, NaHCO3 (324.4 kg, 2.0 equivalents) and TEMPO (1.5 kg, 0.005 equivalents) are added to the solution of compound (gb) from the previous step (Example 6). R1 ​​is cooled to -5 to 5°C (0°C is recommended), and then a 10% NaClO aqueous solution is added dropwise to R1 at -5 to 5°C (0°C is recommended). R1 ​​is stirred at -5 to 5°C (0°C is recommended) for 2 to 3 hours. Samples are taken for IPC (HPLC) (the top organic phase is detected, and compound (gb) ≤ 2.0%). If compound (gb) > 2.0%, 10% NaClO aqueous solution is added until the IPC result is qualified. Na2SO3 (10.2 kg) and water (23.8 kg) are added to reactor 2 (R2) to prepare a 30% Na2SO3 aqueous solution. Before filtering the slurry, quench the reaction in R1 with a 30% aqueous Na2SO3 solution in R2 (detected with KI-starch paper). After filtration, wash the filter cake with MTBE (340L, 1V) and collect all the filtrate in R2. Add anhydrous magnesium sulfate (39.1kg) to R2 and stir at 20-30°C for 20-30min. After filtration, wash the filter cake with MTBE (340L, 1V) and collect all the filtrate in R1. The aldehyde (g) in the MBTE solution can be used for experiment 20. Alternatively, concentrate R1 to no obvious distillate below 30°C to obtain the crude compound (g) as an orange oil, which is transferred to the distillation reactor R3. R3 is distilled at a vacuum degree of ≤0.085MPa at a temperature below 30°C until no obvious distillate is produced, and then distilled at a vacuum degree of ≥0.090MPa at 60-100°C (70-80°C is recommended) to collect the distillate. Purified compound (g) (273.6 kg, 88% yield) was obtained as a colorless to orange oil.

[0454] 1 H-NMR(CDCl3): δ10.23(s,1H),7.64-7.70(m,1H),7.04-7.10(m,1H).

[0455] Example 8. Preparation of Compounds (h-1) and (h-2) as Acrylates

[0456]

[0457] Compound (g) (100 kg, pure, 1.0 equivalent, prepared using the method in Experiment 7) or compound (g) (100 kg in MeOH solution, prepared using the method in Experiment 21), CF3CO2Et (133.1 kg, 1.5 equivalent) and MeOH (150 L, 1.5 V) were added to the reactor. The reactor was cooled to -5 to 5°C (-5 to 0°C is recommended), and ethyl azidoacetate (96.8 kg, 1.2 equivalent) was added at -5 to 5°C (0°C is recommended). MeONa (56.2 kg, 0.5 equivalent, 30 wt% in MeOH) was then added dropwise to the reactor at -5 to 0°C. The reaction mixture was stirred at -5 to 5°C for 2 to 3 h, and then MeONa (56.2 kg, 0.5 equivalent, 30 wt% in MeOH) was added dropwise to the reactor at -5 to 0°C. The mixture was stirred at -5 to 5°C for 2 to 3 h, and then MeONa (56.2 kg, 0.5 equivalent, 30 wt% in methanol solution) was added dropwise at -5 to 0°C. The reaction mixture was stirred at -5 to 5°C for 2 to 3 h, and then stirred at 0 to 10°C (5°C is recommended) for 8 to 14 h. At 0 to 10°C, the reaction mixture was slowly added to 2.5 wt% NH4Cl (aqueous solution) in R2. After filtration, the filter cake was collected and washed with water (600 L, 3V×2). The crude compounds (h-1) and (h-2) were used directly in the next step without further purification.

[0458] 1 H NMR (400MHz, DMSO-d6): δ3.85-3.90 (s, 3H), 6.75-6.86 (s, 1H), 7.53-7.74 (td, J=6.9, 10.6Hz, 1H), 8.17-8.31 (ddd, J=6.9, 9.2, 12.1Hz, 1H).

[0459] Example 9. Preparation of indole-2-carboxylic acid methyl / ethyl ester (i-1) / (i-2)

[0460]

[0461] Solution A: Xylene (20V) is charged into the R1 reactor. R1 is adjusted to 5°C (0-10°C). The wet cake of the mixture of compounds (h-1) and (h-2) is charged into R1. Stir for 1h (0.5-1.5h) at 5°C (0-10°C), then process water (5V) is added to R1 at 5°C (0-10°C). Stir for 20min (10-30min) at 5°C (0-10°C), and stand for 20min (10-30min) at 5°C (0-10°C) to allow phase separation. The bottom aqueous layer is removed. The upper organic layer is filtered and used as solution A.

[0462] Solution B: Methanol (5V) was used as solution B

[0463] Flow procedure (10L equipment) Figure 1 As shown, the description is as follows:

[0464] The above solution A was transferred to FLV1 (1, flow tank 1) in batches through a filter. Fresh methanol (solution B) was transferred to FLV2 (4, flow tank 2). FLR1 (flowing liquid reactor 1) was placed in oven 1 (3), and FLR1 was controlled at 195-205°C (target 200°C). The post-heating pipe (FLR2) was placed in a water / ethylene glycol tank (7), and the post-heating pipe (FLR2) was controlled at 50-60°C (target 55°C) by a temperature control device. The pressure value of the back pressure valve (8) was set at 1.8-2.0 MPa. The flow rates of pump 1 (2) and pump 2 (5) were set according to a residence time of 25 min. Then, solution A in FLV1 was continuously transferred to FLR1 by pump 1 through valve (6), and the methanol solvent in FLV2 was transferred to FLR2 by pump 2 through valve (6), and the solution in FLR2 was transferred to the product tank (9).

[0465] Take samples for IPC (HPLC, once every 2 to 6 hours). After the flow process is completed, add the combined reaction mixture to the reactor and concentrate to below 70°C without obvious distillate (collect the distillate for recycling). Add xylene (4.3 kg, 5V) to the reactor and concentrate to below 70°C without obvious distillate (collect the distillate for recycling). Add xylene (2.6 kg, 3V) to R1, and then cool the reaction mixture to -5 to 5°C (0 to 5°C is recommended) and stir at -5 to 5°C for 2 to 5 hours. After centrifugation, wash the crude filter cake with xylene (0.43 kg, 0.5V), and the resulting crude mixture of compound (i-1) and compound (i-2) (a mixture of methyl ester and ethyl ester in a ratio of about 9 / 1) is directly used in the next step without further purification.

[0466] NMR: 1 H NMR (300MHz, DMSO-d6) δ12.87 (s, 1H), 7.08 (d, J = 2.7Hz, 1H), 7.02 (ddd, J = 11.5, 9.7, 5.2Hz, 1H), 3.75 (s, 3H).

[0467] Example 10. Preparation of indole-2-carboxylic acid compound (j)

[0468]

[0469] Sodium hydroxide (22 kg, 2.5 equivalents) and H2O (100 kg, 10 V) were charged into the R1 reactor to prepare an aqueous sodium hydroxide solution. A crude mixture of i-1 / i-2 (50 kg, 1.0 equivalents) and MTBE (18.5 kg, 0.5 V) were charged into the R1 reactor. R1 was heated to 55-65°C and stirred at this temperature for 3-6 h. After the reaction was completed, R1 was cooled to 0-10°C. Aqueous hydrochloric acid solution (36%, 72 kg) and H2O (43 kg) were added to R2 to prepare a 2N HCl aqueous solution. 2N HCl aqueous solution was slowly added from R2 to R1 until the pH value of the R1 solution was less than 3. R1 was stirred at 15-25°C for 0.5-1.0 h, the slurry was filtered, and the filter cake was washed with H2O (10 kg). The filter cake was vacuum dried at 60-70°C to obtain compound J as an off-white solid. 1 H-NMR (300MHz, DMSO-d6): δ13.48(s,br,1H),12.86(s,1H),7.12-7.21(m,2H).

[0470] Example 11. Preparation of Compound (1)

[0471]

[0472] Under nitrogen atmosphere, DMF (480kg, 5V) was added to the reactor, and then compound (f-1, 100kg net weight, 1.0 equivalent) and compound (k) (110kg, 1.1 equivalent) were added to the reactor at about 20°C. The reactor was cooled to 0±5°C. At 0±5°C, NMM (113kg, 3.0 equivalent) was added dropwise to the reaction system within 30min. At 0±5°C, a DMF solution of T3P (1.5 equivalent) was added dropwise to the reaction system within 1h. The solution was stirred for at least 4h, and the reaction progress was monitored by HPLC. Once completed, the reaction mixture was added dropwise to a 2% aqueous sodium bicarbonate solution (25.0V) at 20±5°C. Then, stirred for at least 2h. The mixture was filtered and the filter cake was washed with water. The filter cake was slurried with process water (2000kg, 20V) for 3h at 20°C, then filtered and washed with water. The filter cake was dried at 60±5°C to give the product of compound (1) as an off-white solid with a yield of 90-93%.

[0473] 1H NMR(300MHz,DMSO-d6)δ10.72(d,J=6.6Hz,1H),7.52(s,1H),7.30(q,J=4.5,3.6Hz,2H),7.26-7.17(m,2H) ,7.14(dd,J=7.1,2.4Hz,1H),7.06(d,J=10.6Hz,1H),7.01-6.85(m,3H),6.80(d,J=7.3Hz,1H),4.86(dd,J =15.5,11.9Hz,2H),4.68-4.50(m,2H),3.95(d,J=10.2Hz,1H),3.73(d,J=10.2Hz,1H),2.80(d,J=6.1Hz,3 H), 2.33-2.11(m,2H),1.63(ddd,J=13.9,9.5,4.8Hz,1H),1.56-1.35(m,2H),0.87(dd,J=14.5,6.2Hz,6H).

[0474] Example 12. Preparation of free N-methylamine form of compound (m-1)

[0475]

[0476] Under N2, methanol (395.0 kg, 5V) was charged into the R1 reactor, followed by compound (l) (100 kg, 1.0 equivalent). The reaction mixture was stirred at 20°C (15-25°C) for 30 min, and then palladium on activated carbon (10 kg) was added to R1. R1 was rinsed with methanol (79.0 kg, 1V) under N2 and cooled to 0°C (-5-5°C). The reaction mixture was stirred at 0°C (-5-5°C) for 8h (5-12h) under H2 (1-5 atmospheres). Once the reaction was complete, the mixture was filtered with diatomaceous earth (50.0 kg), the filtrate was transferred to the R2 reactor at -5-5°C, the filter cake was washed with methanol (1V×2), and the filtrates were combined. The solution in the R2 reactor was concentrated to 2-3V under vacuum at below 12°C, and cold THF (890.0 kg, 10V) was added to the R2 reactor at 0-10°C. The mixture was concentrated in the R2 reactor under vacuum at below 12° C. to 3-4 V. Once precipitation was observed, cold THF (178 kg, 2 V) was added to the reactor R2 at -5-5° C., followed by the addition of n-heptane (683.0 g, 10 V) dropwise into the reactor R2 over 1 h (1-2 h).

[0477] The mixture in the R2 reactor was stirred at 0°C (-5 to 5°C) for 2h (1 to 2h) and filtered. The filter cake was rinsed with n-heptane (136.6kg, 2V), and the wet filter cake was dried at 60°C (55 to 65°C) for 72h to obtain a white solid compound (m-1) with a yield of 80-85%.

[0478] 1 H NMR(400MHz,DMSO-d6)δ10.72(s,1H),7.55-7.40(m,1H),7.31-7.17(m,1H),7 .06-6.95(m,2H),6.93(dd,J=7.6,2.0Hz,2H),4.78-4.51(m,1H),4.03(d,J=10 .3Hz,1H),3.66(d,J=10.2Hz,1H),3.28(dd,J=8.4,5.6Hz,1H),2.19(d,J=9.0H z, 2H), 2.12 (d, J = 5.6Hz, 3H), 1.40-1.12 (m, 3H), 0.84 (dd, J = 17.5, 6.6Hz, 6H).

[0479] Example 13. Preparation of Compound (m-2)

[0480]

[0481] Under N2, DMF (39.5 kg, 5V) was charged into the R1 reactor, followed by compound (l) (10 kg, 1.0 equivalent) and TsOH (1.0-1.1 equivalent). The reaction mixture was stirred at 20°C (15-25°C) for 30 min, and then palladium on activated carbon (1 kg) was added to the reactor R1. The reactor R1 was rinsed with DMF (7.9 kg, 1V) under N2 and cooled to 0°C (-5-5°C). The reaction mixture was stirred at 0°C (-5-5°C) for 8h (5-12h) under H2 (1-5 atmospheres). Once the reaction was complete, the mixture was filtered with diatomaceous earth (5 kg), and the filtrate (m-2) was directly transferred to the next step without purification.

[0482] Example 14. Preparation of Compound (m-3)

[0483]

[0484] At 25°C, AcOH (10 L, 2.0 V) was charged into the reactor, followed by compound (1) (5 kg, 1.0 eq.). A solution of HBr in AcOH (7.5 L, 1.5 V, 5.0 eq.) was added dropwise to the reactor at 20-30°C, and the reaction mixture was stirred at 20-30°C for at least 2 h. Once the reaction was complete, the reaction solution was diluted with acetone (10 L, 2 V) at 25°C. The resulting solution was then added dropwise to MTBE (100 L, 20 V) at 25°C. The slurry was stirred at 25°C for at least 2 h and then filtered. The filter cake was rinsed with MTBE (10 L, 2 V) and the filter cake was re-slurried three times at 25°C with acetone / DCM (1:10, 100 L, 20 V). The material was filtered, rinsed with DCM (10 L, 2 V), and the filter cake was dried at 40±5° C. to afford the product, compound (m-3), as an off-white solid in about 90% yield. 1 H-NMR (300MHz, Methanol-d4) δ7.31 (td, J=7.6, 1.4Hz, 1H), 7.19-7.12 (m, 1H), 7. 08(td,J=7.5,1.1Hz,1H),7.02(d,J=7.7Hz,1H),5.01(s,1H),4.33(t,J=6.6Hz,1 H),4.11(d,J=10.1Hz,1H),3.91(d,J=10.0Hz,1H),2.68(s,3H),2.49(dd,J=8.8, 2.6Hz, 2H), 2.01-1.79 (m, 2H), 1.30 (dd, J = 4.7, 2.6Hz, 1H), 1.03 (t, J = 6.6Hz, 6H).

[0485] Example 15. Preparation of (3R,5'S)-1'-(N-methyl-N-(4,6,7-trifluoro-1H-indole-2-carbonyl)-L-leucyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (Compound (N))

[0486]

[0487] DMF (760 kg, 8 V) was added to the reaction at 0°C (-5 to 5°C), followed by compound (j) (63 kg, 1.05 eq.), N-methylmorpholine (56 kg, 2 eq.), HATU (106 kg, 1.0 eq.), and compound (m-1) (100 kg, 1.0 eq.). The reactor was rinsed with DMF (190 kg, 2 V) and heated to 25°C (20 to 30°C), and stirred at 25°C (20 to 30°C) for 5 h (3 to 6 h). Afterwards, additional HATU (0.1 eq.) was added and the reaction mixture was stirred for 16-24 h. 25% ammonium hydroxide (38 kg) was added to the reaction mixture at 25°C (20 to 30°C), and stirred at 25°C (20 to 30°C) for 2 h (1 to 3 h). Then, the reaction mixture was added to 20-30°C water (5000kg, 50V) within 2h, and the resulting slurry was stirred at 25°C (20-30°C) for 2h (1-5h). The mixture was filtered and the filter cake was rinsed with water (500kg, 5V). The filter cake was dissolved in ethyl acetate (1350kg, 15V) and washed three times with 10% sodium chloride solution (500kg). The organic layer was separated to 1.5-2.5V under vacuum at a temperature not exceeding 45°C. The solution was cooled to 25°C (20-30°C) and dichloromethane (660kg, 5V) was added. The mixture was stirred at 25°C (20-30°C) for 2h (2-5h) to form a slurry. At 25°C (20-30°C), n-heptane (137 kg, 2 V) was added dropwise within 0.5 h (0.5-2 h), and stirred at 25°C (20-30°C) for another 2 h (1-3 h). The reaction mixture was filtered and the wet cake was rinsed with DCM / heptane (5 / 2). The wet cake was dried at 50°C (45-55°C) for 20 h (15-25 h) to obtain a white solid compound (n) with a yield of 80-85%.

[0488] 1H NMR(300MHz,DMSO-d6)δ12.46(s,1H),10.68(s,1H),7.56(s,1H),7.15-7.00(m,3H),6.91(t ,J=4.4Hz,2H),6.84(d,J=7.7Hz,1H),6.55(d,J=2.8Hz,1H),5.34(t,J=7.3Hz,1H),4.63(dd, J=9.8,8.0Hz,1H),3.83(q,J=10.3Hz,2H),3.45(qd,J=7.0,5.1Hz,1H),3.16(s,3H),2.35-2. 13(m,2H), 1.69(t,J=7.1Hz,2H), 1.56(dq,J=13.1,6.5Hz,1H), 0.93(dd,J=12.2,6.3Hz,6H).

[0489] Example 16. Preparation of (3R,5'S)-1'-(N-methyl-N-(4,6,7-trifluoro-1H-indole-2-carbonyl)-L-leucyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (Compound (N))

[0490]

[0491] At about 0-10°C, a DMF solution of compound (m-2) (1 kg, 1.0 eq) was added to the reactor. Compound (l) (600 g, 1.0 eq), NMM (3.00 eq, 850 g) and HATU (1.00 eq, 1.06 kg) were added to the reactor while maintaining the temperature at 0-10°C. The reactants were heated to 20±5°C and stirred at 20±5°C for at least 6 h. HATU (0.20 eq, 210 g) was added to the reactor at 20±5°C and stirred at 20±5°C for at least 6 h. 25% ammonium hydroxide (390 g, 1.0 eq) was added to the reaction mixture at 20°C and stirred at 20°C for 2 h (1-3 h). EtOAc (14.0 V) and water (14 V) were added at about 25°C within 20 min, and the solution was stirred for at least 30 min. The aqueous phase was extracted three times with EtOAc, the organic phases were combined, and the organic phases were washed three times with 10% NaCl aqueous solution at 20±5°C. The organic phase was concentrated to 6V, and then EtOH (7.0V) was added. The EtOAc-EtOH solvent exchange was repeated three times and concentrated to 5V, and then water (7.0V) was added at 20±5°C. The mixture was cooled to 0-10°C and stirred for 1h, and then filtered. The filter cake was dissolved in ethyl acetate (15V) and washed three times with 10% sodium chloride solution. Under vacuum, at a temperature not exceeding 45°C, the organic layer was concentrated to 2-3V. The solution was cooled to 25°C (20-30°C), and dichloromethane (5V) was added. The mixture was stirred at 25°C (20-30°C) for 2h (2-5h) to form a slurry. At 25°C (20-30°C), n-heptane (2V) was added dropwise within 0.5h (0.5-2h), and stirred at 25°C (20-30°C) for another 2h (1-3h). The reaction mixture was filtered and the wet cake was rinsed with DCM / heptane (5 / 2). The wet cake was dried at 50°C (45-55°C) for 20h (15-25h) to obtain a white solid compound (n) with a total yield of about 70-75% in two steps.

[0492] 1H NMR(300MHz,DMSO-d6)δ12.46(s,1H),10.68(s,1H),7.56(s,1H),7.15-7.00(m,3H),6.91(t ,J=4.4Hz,2H),6.84(d,J=7.7Hz,1H),6.55(d,J=2.8Hz,1H),5.34(t,J=7.3Hz,1H),4.63(dd, J=9.8,8.0Hz,1H),3.83(q,J=10.3Hz,2H),3.45(qd,J=7.0,5.1Hz,1H),3.16(s,3H),2.35-2. 13(m,2H), 1.69(t,J=7.1Hz,2H), 1.56(dq,J=13.1,6.5Hz,1H), 0.93(dd,J=12.2,6.3Hz,6H).

[0493] Example 17. Preparation of (3R,5'S)-1'-(N-methyl-N-(4,6,7-trifluoro-1H-indole-2-carbonyl)-L-leucyl)-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamide (Compound (N))

[0494]

[0495] At 25°C, DMF (10.0V) was added to the reactor, followed by compound (l) (4.4kg, 1.0 equivalent), NMM (3.0 equivalent), compound (m-3) (1.0 equivalent) and HATU (1.0 equivalent) at 20-25°C. The reaction mixture was stirred at 20-25°C for at least 12h. Once the reaction was complete, aqueous ammonium hydroxide solution (1.0 equivalent) was added to the reaction system at 20-25°C, followed by stirring at 20-25°C for at least 2h. The reaction mixture was then added to water (220kg, 50V) at 20-30°C within 2h, and the resulting slurry was stirred at 25°C (20-30°C) for 2h (1-5h). The mixture was filtered and the filter cake was rinsed with water (22kg, 5V). The filter cake was dissolved in ethyl acetate (135g, 15V) and washed three times with 10% sodium chloride solution (22kg). At a temperature not exceeding 45°C, the organic layer is separated to 1.5-2.5V under vacuum. The solution is cooled to 25°C (20-30°C) and dichloromethane (5V) is added. The mixture is stirred at 25°C (20-30°C) for 2h (2-5h) to form a slurry. At 25°C (20-30°C), n-heptane (2V) is added dropwise within 0.5h (0.5-2h), and stirred at 25°C (20-30°C) for another 2h (1-3h). The reaction mixture is filtered and the wet cake is rinsed with DCM / heptane (5 / 2). The wet cake is dried at 50°C (45-55°C) for 20h (15-25h) to obtain a white solid compound (n) with a yield of 80-85%.

[0496] 1 H NMR(300MHz,DMSO-d6)δ12.46(s,1H),10.68(s,1H),7.56(s,1H),7.15-7.00(m,3H),6.91(t ,J=4.4Hz,2H),6.84(d,J=7.7Hz,1H),6.55(d,J=2.8Hz,1H),5.34(t,J=7.3Hz,1H),4.63(dd, J=9.8,8.0Hz,1H),3.83(q,J=10.3Hz,2H),3.45(qd,J=7.0,5.1Hz,1H),3.16(s,3H),2.35-2. 13(m,2H), 1.69(t,J=7.1Hz,2H), 1.56(dq,J=13.1,6.5Hz,1H), 0.93(dd,J=12.2,6.3Hz,6H).

[0497] Example 18. Preparation of N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentan-2-yl)-4,6,7-trifluoro-N-methyl-1H-indole-2-carboxamide toluene solvate (Compound (I))

[0498]

[0499] Ethyl acetate (630 kg, 10 V) was added to the reactor (R1), followed by compound (n) (70 kg). Ensure that the water content is less than 0.20% (w / w). The reaction was cooled to 0°C (-5-5°C), then triethylamine (89.6 kg) was added, followed by trifluoroacetic anhydride (92.4 kg) at 0°C (-5-5°C). The reaction was stirred at 0°C (-5-5°C) for 1 h (0.5-2 h). Once the reaction was complete, the reaction mixture was slowly added to 0.2N HCl aqueous solution (700 kg) at 0°C (-5-5°C) within 1 h. The resulting solution was stirred at 0°C (-5-5°C) for 30 min and the organic layer was separated. 1% ammonium hydroxide aqueous solution (700 kg) was added to the organic layer and stirred at 20°C for 30 min (15-25°C). The organic layer was separated and washed four times with 10% brine. The organic layer was then separated and distilled to 2-3 V. Toluene-ethyl acetate exchange was performed until precipitation was observed at 3-4V. Toluene (5-6V) was then added and the slurry was stirred at 50°C for 2h. The solution was then cooled to 20°C within 1-2h and stirred at 20°C (15-25°C) for 10h (6-14h). The reaction mixture was filtered and the wet cake was rinsed with toluene (120kg, 2V). The wet cake was then dried at 50°C (45-55°C) for 48h to obtain the desired compound (o) as a white solid with a yield of 80-85%.

[0500] 1H NMR (400MHz, Acetone-d6) δ11.17(s,1H),9.65(s,1H),7.02(dd,J=13.7,7.3Hz,2H),6.94(dd,J=6.0,3.5 Hz,1H),6.92-6.85(m,2H),6.81(t,J=7.5Hz,1H),5.56(dd,J=9.4,5.6Hz,1H),5.21(t,J=8.3Hz,1H),4.25 (d,J=10.7Hz,1H),3.99(d,J=10.6Hz,1H),3.43(s,3H),2.79-2.61(m,2H),1.93(ddd,J=14.4,9.5,5.1Hz ,1H), 1.79(ddd,J=14.2,8.7,5.6Hz,1H), 1.64(dpd,J=8.7,6.6,5.1Hz,1H), 0.98(dd,J=18.5,6.6Hz,6H).

[0501] Example 19. Preparation of N-((S)-1-((3R,5'S)-5'-cyano-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-yl)-4-methyl-1-oxopentan-2-yl)-4,6,7-trifluoro-N-methyl-1H-indole-2-carboxamide - Amorphous Form (Compound (I))

[0502]

[0503] At 20-30°C, toluene solvate compound (I) (60 kg, net weight) and ethanol (10 times volume (V)) are added to a reactor. The mixture is stirred at 20-30°C for 0.5-1h to obtain a clear solution. The solution is distilled to about 5V at a certain temperature (NMT 50°C) and re-injected into ethanol (5V). The distillation is repeated until the residual toluene content is ≤0.1% w / w. At 20°C (15-25°C), the ethanol solution of the compound (5-6V) is added to water (15V) within 1-2h and stirred at 15-25°C for 1h (0.5-2h). The slurry is filtered and the wet cake is rinsed with pure water (2V). The wet cake is then dried at 50°C (45-55°C) for 48-72h to obtain a white to off-white amorphous solid compound (I) with a yield of 95-97%.

[0504] 1H NMR (400MHz, Acetone-d6) δ11.17(s,1H),9.65(s,1H),7.02(dd,J=13.7,7.3Hz,2H),6.94(dd,J=6.0,3.5 Hz,1H),6.92-6.85(m,2H),6.81(t,J=7.5Hz,1H),5.56(dd,J=9.4,5.6Hz,1H),5.21(t,J=8.3Hz,1H),4.25 (d,J=10.7Hz,1H),3.99(d,J=10.6Hz,1H),3.43(s,3H),2.79-2.61(m,2H),1.93(ddd,J=14.4,9.5,5.1Hz ,1H), 1.79(ddd,J=14.2,8.7,5.6Hz,1H), 1.64(dpd,J=8.7,6.6,5.1Hz,1H), 0.98(dd,J=18.5,6.6Hz,6H).

[0505] The amorphous form of Compound (I) was physically characterized using powder X-ray diffraction (PXRD) analysis and differential scanning calorimetry (DSC) analysis. Figure 2 As shown, it is shown that compound (I) is amorphous. Figure 3 As shown, the glass transition midpoint is 98.29°C.

[0506] Example 20. Preparation of sodium hydroxy(2,4,5-trifluorophenyl)methanesulfonate (gc)

[0507]

[0508] Method A: 2,4,5-trifluorobenzaldehyde (100 g pure, obtained by distillation in Experiment 7) was added to reactor R1, followed by MTBE (500 mL) and EtOH (600 mL). Sodium bisulfite (71.5 g) and water (100 g) were added to reactor R2. The mixture in R2 was heated to 40°C and stirred for 20 min to form a clear solution. The solution in R1 was heated to 40°C. The solution in R2 was transferred to R1 within 1 h, and the mixture obtained in R1 was stirred at 40°C for another 2 h. The mixture in R1 was cooled to 20°C within 1 h and stirred at 20°C for another 1 h. The wet cake was filtered and washed with ethanol (80 g). The cake was dried at 50°C to obtain compound (gc) as a white solid.

[0509] Method B: A 100 g MTBE solution (100 mL) of 2,4,5-trifluorobenzaldehyde prepared by the procedure of Example 7 was added to the R1 reactor, followed by MTBE (400 mL) and EtOH (600 mL). Sodium bisulfite (71.5 g) and water (100 g) were added to the R2 reactor. The mixture in R2 was heated to 40 ° C and stirred for 20 min to form a clear solution. The solution in R1 was heated to 40 ° C. The R2 solution was transferred to R1 within 1 h, and the mixture obtained in R1 was stirred at 40 ° C for another 2 h. The mixture in R1 was cooled to 20 ° C within 1 h and stirred at 20 ° C for another 1 h. The wet cake was filtered and washed with ethanol (80 g). The cake was dried at 50 ° C to obtain compound (gc) as a white solid.

[0510] Example 21. Preparation of Compound g from Sodium Hydroxy(2,4,5-trifluorophenyl)methanesulfonate (gc)

[0511]

[0512] Compound gc (100 g) and methyl tert-butyl ether (MTBE, 400 mL) were added to the R1 reactor, followed by water (500 mL) and sodium carbonate (48 g). The mixture in R1 was stirred at 25 ° C for 2 h to form a two-phase solution. The upper layer (organic layer) was separated and the bottom layer (aqueous layer) was removed. The aqueous layer was extracted with MTEB and the organic layers were combined. The combined organic layers can be treated by the following two methods to obtain compound (g).

[0513] Method A: The organic layer is concentrated to below 30°C with no obvious distillate. A crude compound (g) is obtained as an orange oil, and the crude compound (g) is transferred to a distillation reactor R3. R3 is distilled at below 30°C under a vacuum of ≤0.085 MPa until no obvious distillate is obtained, and then R3 is distilled at 60-100°C (recommended 70-80°C) under a vacuum of ≥0.090 MPa, and the distillate is collected. A purified compound (g) is obtained as a colorless to orange oil.

[0514] (Same procedure as in Example 7)

[0515] Method B: Methanol was added to the organic layer. After solvent exchange from MTBE to methanol, compound (g) in methanol solution was used for the next condensation reaction to form compound (h), see Experiment 8.

[0516] While the invention has been particularly shown and described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made without departing from the scope of the invention as encompassed by the following claims.

Claims

1. A method for preparing a compound of formula (A), wherein R1 is selected from hydrogen, Cl, F, optionally substituted methyl and optionally substituted methoxy; R2 is selected from hydrogen, optionally substituted -C1-C6 alkyl and optionally substituted -C1-C6 alkylaryl, The method comprises the following steps: a) reacting a compound of formula (W) with formaldehyde to produce a compound of formula (B): Wherein G1 is methyl, ethyl or phenyl; b) converting the compound of formula (B) into a compound of formula (C): c) rearranging the compound of formula (C) to produce a compound of formula (D-1): d) converting the compound of formula (D-1) into compound (e-1): e) converting compound (e-1) into a compound of formula (F-1): Wherein X is selected from Cl - Br - and CF3CO2 - anions; f) reacting a compound of formula (F-1) with a compound of formula (K) to produce a compound of formula (L): wherein PG1 is selected from -Boc, -Cbz, -C(O)OMe, -C(O)OEt, -Fmoc, -Troc, -Moz, -Pnz and -Teoc, g) converting the compound of formula (L), optionally in the presence of a suitable acid, into a compound of formula (M) or a salt thereof: Alternatively, the compound of formula (L) is converted into a salt form of the compound of formula (M) with a suitable acid; (J-1) reducing the compound of formula (Ga) to produce a compound of formula (Gb): (J-2) Oxidizing the compound of formula (Gb) to produce a compound of formula (G): (J-3) reacting a compound of formula (G) with a compound of formula (G-1) in the presence of a base to produce a compound of formula (H): Wherein R3 is methyl, ethyl or benzyl; (J-4) Converting the compound of formula (H) to the compound of formula (I) by Hemetsberger indole cyclization: (J-5) reacting compound (I) with a base to obtain a compound of formula (J) or a salt thereof: h) reacting a compound of formula (M) or a salt thereof with a compound of formula (J) or a salt thereof to provide a compound of formula (N): Where R1 is as defined above, and i) converting the compound of formula (N) into a compound of formula (A):

2. The method according to claim 1, wherein R1 is F and R2 is isobutyl.

3. The method according to claim 2, wherein G1 is methyl, X is Cl - , and PG1 is Cbz.

4. The method according to any one of claims 1 to 3, wherein In step (b), the reaction is carried out in the presence of di-tert-butyl dicarbonate (Boc anhydride) as a Boc protecting agent and triethylamine as a base; In step (c), the reaction is carried out in the presence of N-bromosuccinimide (NBS) and acetic acid at a temperature of about -30°C, and the ratio of the diastereomer (d-1) to the diastereomer (d-2) is 6:1 to 8:1; In step (d), the reaction is carried out in methanol in the presence of ammonia, and the ratio of the diastereomer (e-1) to the diastereomer (e-2) is 6:1 to 8:1; In step (e), the reaction is carried out in ethyl acetate in the presence of hydrogen chloride, and the salt form of compound (f-1) and hydrogen chloride is isolated by crystallization in N,N-dimethylformamide (DMF); In step (f), the reaction is carried out in the presence of n-propanephosphonic anhydride (T3P) and N-methylmorpholine; In step (g), PG1 is Cbz, and the reaction is carried out in the presence of H2 as a hydrogen source, palladium on carbon as a catalyst, optionally in the presence of p-toluenesulfonic acid; or, in step (g), the reaction is carried out in acetic acid in the presence of hydrogen bromide; In step (J-1), the reducing agent is sodium borohydride and borane-tetrahydrofuran complex; In step (J-2), the oxidant is sodium hypochlorite containing TEMPO; In step (J-3), wherein R3 is ethyl, and the reaction is carried out in the presence of sodium methoxide or sodium ethoxide as a base and CF3CO2Et as a sacrificial electrophile; In step (J-4), the reaction is carried out in a solvent mixture of xylene and methanol in a flow chemical reactor, the volume ratio of xylene to methanol is 5:1, the reaction temperature is about 200° C., and the reaction time is about 25 min; In step (J-5), the reaction is carried out in the presence of sodium hydroxide, and then in the presence of hydrogen chloride; In step (h), the reaction is carried out in the presence of N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanium hexafluorophosphate N-oxide (HATU) and N-methylmorpholine; and In step (i), the reaction is carried out in the presence of trifluoroacetic anhydride (TFAA) and triethylamine.

5. A method for preparing a compound of formula (A), wherein R1 is selected from hydrogen, Cl, F, optionally substituted methyl and optionally substituted methoxy; R2 is selected from hydrogen, optionally substituted -C1-C6 alkyl and optionally substituted -C1-C6 alkylaryl, The method comprises the following steps: a) reacting a compound of formula (W) with formaldehyde to produce a compound of formula (B): Wherein G1 is methyl, ethyl or phenyl; b) converting the compound of formula (B) into a compound of formula (C): c) rearranging the compound of formula (C) to produce a compound of formula (D-1): d) converting the compound of formula (D-1) into compound (e-1): e) converting compound (e-1) into a compound of formula (F-1): Wherein X is selected from Cl - Br - and CF3CO2 - anions; f) reacting a compound of formula (F-1) with a compound of formula (K) to produce a compound of formula (L): wherein PG1 is selected from -Boc, -Cbz, -C(O)OMe, -C(O)OEt, -Fmoc, -Troc, -Moz, -Pnz and -Teoc, g) converting the compound of formula (L), optionally in the presence of a suitable acid, into a compound of formula (M) or a salt thereof: Alternatively, the compound of formula (L) is converted into a salt form of the compound of formula (M) with a suitable acid; h) reacting a compound of formula (M) or a salt thereof with a compound of formula (J) or a salt thereof to provide a compound of formula (N): Where R1 is as defined above, and i) converting the compound of formula (N) into a compound of formula (A):

6. The method according to claim 5, wherein R1 is F and R2 is isobutyl.

7. The method according to claim 6, wherein G1 is methyl, X is Cl - , and PG1 is Cbz.

8. The method according to any one of claims 5 to 7, wherein In step (b), the reaction is carried out in the presence of di-tert-butyl dicarbonate (Boc anhydride) as a Boc protecting agent and triethylamine as a base; In step (c), the reaction is carried out in the presence of N-bromosuccinimide (NBS) and acetic acid at a temperature of about -30°C, and the ratio of the diastereomer (d-1) to the diastereomer (d-2) is 6:1 to 8:1; In step (d), the reaction is carried out in methanol in the presence of ammonia, and the ratio of the diastereomer (e-1) to the diastereomer (e-2) is 6:1 to 8:1; In step (e), the reaction is carried out in ethyl acetate in the presence of hydrogen chloride, and the salt form of compound (f-1) and hydrogen chloride is isolated by crystallization in N,N-dimethylformamide (DMF); In step (f), the reaction is carried out in the presence of n-propanephosphonic anhydride (T3P) and N-methylmorpholine; In step (g), wherein PG1 is Cbz, and the reaction is carried out in the presence of H2 as a hydrogen source, palladium on carbon as a catalyst, optionally in the presence of p-toluenesulfonic acid; or, in step (g), the reaction is carried out in acetic acid in the presence of hydrogen bromide; In step (h), the reaction is carried out in the presence of N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanium hexafluorophosphate N-oxide (HATU) and N-methylmorpholine; and In step (i), the reaction is carried out in the presence of trifluoroacetic anhydride (TFAA) and triethylamine.

9. A method for preparing a compound of formula (A), wherein R1 is selected from hydrogen, Cl, F, optionally substituted methyl and optionally substituted methoxy; R2 is selected from hydrogen, optionally substituted -C1-C6 alkyl and optionally substituted -C1-C6 alkylaryl, The method comprises the following steps: (a) reacting a compound of formula (W) with formaldehyde to produce a compound of formula (B): Wherein G1 is C1-C6-alkyl or aryl; (b) converting the compound of formula (B) into a compound of formula (C): (c) rearranging the compound of formula (C) to produce a compound of formula (D-1): (d) converting the compound of formula (D-1) into compound (e-1): (e) converting compound (e-1) into a compound of formula (F-1): Wherein X is selected from Cl - Br - and CF3CO2 - anions; (f) reacting a compound of formula (F-1) with a compound of formula (K) to produce a compound of formula (L): wherein PG1 is selected from -Boc, -Cbz, -C(O)OMe, -C(O)OEt, -Fmoc, -Troc, -Moz, -Pnz and -Teoc, R2 is as defined above, (g) converting the compound of formula (L) into a compound of formula (M) or a salt thereof, optionally in the presence of a suitable acid: (h) reacting a compound of formula (M) or a salt thereof with a compound of formula (J) or a salt thereof to provide a compound of formula (N): wherein R1 is as defined above, preferably hydrogen or F, and (i) converting the compound of formula (N) into the compound of formula (A).

10. The method of claim 9, wherein R1 is fluorine and R2 is isobutyl.

11. The method according to claim 10, wherein G1 is methyl, X is Cl - , and PG1 is Cbz.

12. A method for preparing a compound of formula (A), wherein R1 is selected from hydrogen, Cl, F, optionally substituted methyl and optionally substituted methoxy; R2 is selected from hydrogen, optionally substituted -C1-C6 alkyl and optionally substituted -C1-C6 alkylaryl, The method comprises the following steps: a) reacting a compound of formula (W) with formaldehyde to produce a compound of formula (B): Wherein G1 is C1-C6-alkyl or aryl; b) converting the compound of formula (B) into a compound of formula (C): c) rearranging the compound of formula (C) to produce a compound of formula (D-1): d) converting the compound of formula (D-1) into compound (e-1): e) converting compound (e-1) into a compound of formula (F-1): Wherein X is selected from Cl - Br - and CF3CO2 - anions; f) reacting a compound of formula (F-1) with a compound of formula (K) to produce a compound of formula (L): wherein PG1 is selected from -Boc, -Cbz, -C(O)OMe, -C(O)OEt, -Fmoc, -Troc, -Moz, -Pnz and -Teoc, g) converting the compound of formula (L), optionally in the presence of a suitable acid, into a compound of formula (M) or a salt thereof: Alternatively, the compound of formula (L) is converted into a salt form of the compound of formula (M) using a suitable acid; (J-1) the compound of formula (Ga) is reduced to produce a compound of formula (Gb): (J-2) Oxidizing the compound of formula (Gb) to produce a compound of formula (G): (J-2a) reacting the compound of formula (G) with sodium bisulfite to produce a compound of formula (Gc): (J-2b) reacting a compound of formula (Gc) with a base to produce a compound of formula (G): (J-3) reacting a compound of formula (G) with a compound of formula (G-1) in the presence of a base to produce a compound of formula (H): Wherein R3 is methyl, ethyl or benzyl; (J-4) Converting the compound of formula (H) to the compound of formula (I) by Hemetsberger indole cyclization: (J-5) reacting compound (I) with a base to obtain a compound of formula (J) or a salt thereof: h) reacting a compound of formula (M) or a salt thereof with a compound of formula (J) or a salt thereof to provide a compound of formula (N): Where R1 is as defined above, and i) converting the compound of formula (N) into the compound of formula (A).

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