Process for preparing substituted spirooxindole derivatives

Abstract

The present invention relates to a compound of formula (A) [Formula 1] JPEG2025509663000160.jpg3949 or a pharma-ceutically acceptable salt or solvate thereof. The compounds of formula (A) and pharmaceutical compositions are useful as SARS-CoV-2 3CL pro-inhibitors.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 321,244, filed March 18, 2022, the entire teachings of which are incorporated herein by reference.

[0002] The present invention relates generally to methods and intermediates useful for the preparation of biologically active molecules, in particular for the synthesis of certain SARS-CoV-2 3CLpro inhibitors. [Background technology]

[0003] Coronaviruses are enveloped, positive-sense, single-stranded RNA viruses. The genomic RNA of CoVs has a 5' cap structure and a 3' polyA tail and contains at least six open reading frames (ORFs). The first ORF (ORF 1a / b) directly translates two polyproteins: pp1a and pp1ab. These polyproteins are processed into 16 nonstructural proteins by the 3C-like protease (3CLpro), also known as the main protease (Mpro). These nonstructural proteins are involved in the production of subgenomic RNAs that code for the four structural proteins, namely the envelope, membrane, spike and nucleocapsid proteins, among other accessory proteins. As a result, it is understood that the 3C-like protease plays a key role in the coronavirus life cycle.

[0004] 3CLpro is a cysteine ​​protease responsible for most cleavage events within the precursor polyprotein. Active 3CLpro is a homodimer containing two protomers and is characterized by a Cys-His dyad located between domains I and II. 3CLpro is conserved among coronaviruses, and several common features are shared among the substrates of 3CLpro in various coronaviruses. The absence of a human homolog of 3CLpro makes it an ideal antiviral target. Compounds have been reported to inhibit 3CLpro activity, but they have not been approved as coronavirus therapies. (International Publication No. WO 2004101742(A2), U.S. Patent Application Publication No. 2005 / 0143320(A1), U.S. Patent Application Publication No. 2006 / 0014821(A1), U.S. Patent Application Publication No. 2009 / 0137818(A1), International Publication No. 2013049382(A2), International Publication No. 2013166319(A1), International Publication No. 2018042343, International Publication No. (see WO 2018023054, WO 2022013684, WO 2021252644, WO 2022020711, WO 2022020242, U.S. Patent No. 11,174,231(B1), U.S. Patent No. 11,124,497(B1), WO 2005113580, and WO 2006061714).

[0005] There is a need in the art for novel therapeutic agents that treat, ameliorate, or prevent SARS-CoV-2 infection. The present invention provides methods of novel compounds that act in inhibiting or preventing SARS-CoV-2 viral replication and thus are used to treat COVID-19 (see PCT / US21 / 60247).

[0006] The synthesis of substituted spirooxindoles and their intermediates has been previously published (see PCT / US21 / 60247, WO2019086142, WO2020221811, WO2020221826, J.Med.Chem.2012,55,9069). However, scale-up using previous methods is very difficult due to safety concerns associated with certain intermediates, instability of certain intermediates, as well as the lack of purification methods other than column chromatography. Therefore, there is a strong need to develop safe and efficient methods for the large-scale preparation of these novel substituted spirooxindole derivatives. Summary of the Invention

[0007] The present invention relates to a compound of formula (A) [ka] (wherein R1 is selected from the group consisting of hydrogen, Cl, F, optionally substituted methyl, and optionally substituted methoxy; and R2 is selected from the group consisting of 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 and R2 is isobutyl.

[0008] The present invention further relates to processes with increased product yields and improved scalability for the large-scale manufacture of compounds of formula (A).

[0009] In certain embodiments, the present invention relates to methods for isolating the compound of formula (A) as a toluene solvate or an amorphous solid.

[0010] The foregoing and other objects, features and advantages of the present invention will become apparent from the following more particular description of preferred embodiments of the invention, as illustrated in the accompanying drawings, in which like reference characters refer to the same parts throughout the different views, and in which the drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention. [Brief description of the drawings]

[0011] [Figure 1] FIG. 1 is a schematic diagram of the flow reaction process described in Example 9. [Diagram 2] FIG. 1 is an X-ray powder diffraction pattern of the amorphous form of Compound 1 prepared in Example 19. [Diagram 3] 1 is a DSC thermogram of the amorphous form of Compound 1 prepared in Example 19. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] The present invention relates to a compound of formula (A) [ka] (wherein R1 is selected from the group consisting of hydrogen, Cl, F, optionally substituted methyl, and optionally substituted methoxy; and R2 is selected from the group consisting of hydrogen, optionally substituted -C1-C6 alkyl, and optionally substituted -C1-C6 alkylaryl). Preferably, R1 is H or F and R2 is isobutyl, cyclopropylmethyl, 2,2-dimethylpropyl or benzyl. More preferably, R1 is F and R2 is isobutyl.

[0013] In a preferred embodiment, the compound of formula (A) has the formula (AI) [ka] As shown by:

[0014] In one embodiment, the compound of formula (A) is compound (I): [ka] It is.

[0015] In one embodiment, the process for preparing a compound of formula (A) comprises: (a) reacting a compound of formula (W) with formaldehyde to produce a compound of formula (B); [ka] (wherein G1 is C1-C6-alkyl or aryl, preferably methyl, ethyl or phenyl, more preferably methyl); (b) converting a compound of formula (B) to a compound of formula (C); [ka] (c) subjecting the compound of formula (C) to a rearrangement to produce a compound of formula (D-1); [ka] (d) converting the compound of formula (D-1) into compound (e-1); [ka] (e) converting compound (e-1) into a compound of formula (F-1); [ka] (Wherein, X is Cl - , Br - and CF3CO2 - Preferably, X is an anion selected from Cl - ), (f) Reacting the compound of formula (F-1) with a compound of formula (K) [ka] 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, and R2 is as defined above, preferably isobutyl. to produce a compound of formula (L); [ka] (g) converting a compound of formula (L) into a compound of formula (M) or a salt thereof, optionally in the presence of a suitable acid; [ka] (h) reacting a compound of formula (M) or a salt thereof with a compound of formula (J) or a salt thereof [ka] wherein R1 is as defined above and is preferably hydrogen or F, to obtain a compound of formula (N); [ka] (i) converting a compound of formula (N) to a compound of formula (A); [ka] Includes.

[0016] In one preferred embodiment of the aforementioned method, R1 is F, R2 is isobutyl, G1 is methyl, and X is Cl. - and PG1 is Cbz.

[0017] Process (a) In a preferred embodiment, step (a) occurs in a suitable solvent, such as, but not limited to, methanol, t-butyl alcohol, acetonitrile, acetone, dichloromethane, chloroform, dimethylformamide, dimethylsulfoxide, dioxane, ethyl acetate, heptane, hexane, methyl t-butyl ether, tetrahydrofuran, and toluene, or a mixture of two or more thereof. Preferably, the solvent is methanol.

[0018] 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 a period of about 30 minutes to about 1 day, preferably about 30 minutes to about 5 hours, more preferably about 1 hour.

[0019] In a preferred embodiment, the process of the invention further comprises isolating the compound of formula (B), preferably in substantially pure form.

[0020] Process (b) 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).

[0021] Step (b) preferably occurs in the presence of a suitable base, such as, but not limited to, triethylamine, diisopropylethylamine, sodium bicarbonate or N-methylmorpholine. A preferred base is triethylamine.

[0022] In a preferred embodiment, step (b) occurs in a solvent. Suitable solvents include, but are not limited to, 2-Me THF, t-butyl alcohol, acetonitrile, acetone, dichloromethane, chloroform, dimethylformamide, dimethylsulfoxide, dioxane, ethyl acetate, heptane, hexane, methyl t-butyl ether, tetrahydrofuran, water, and toluene, or a mixture of two or more thereof. Preferably, the solvent is 2-Me THF and water as a co-solvent. Preferably, the volume ratio of 2-Me THF to water is 4:1.

[0023] In one embodiment, the reaction in step (b) is carried out at a temperature of about −10° C. to about 60° C., preferably about 0° C. to about 40° C., and more preferably about 5° C. to about 25° C. In one embodiment, step (b) is carried out for a period of about 1 hour to about 24 hours, preferably about 1 hour to about 10 hours, and more preferably about 5 hours.

[0024] In a preferred embodiment, the process of the invention further comprises isolating the compound of formula (C), preferably in substantially pure form.

[0025] Process (c) In step (c), the compound of formula (C) is reacted with an oxidizing agent to produce a compound of formula (D-1). In certain embodiments, this reaction also produces a compound of formula (D-2), which is a diastereomer of the compound of formula (D-1). [ka]

[0026] Preferably, the compound of formula (D-1) is produced in diastereomeric excess by this reaction. The weight ratio of the compound of formula (D-1) produced to the compound of formula (D-2) is preferably about 55:45 to 95:5, more preferably about 6:1 to about 8:1.

[0027] Suitable oxidizing agents include, but are not limited to, N-bromosuccinimide (NBS), hydrogen peroxide, meta-chloroperbenzoic acid (m-CPBA), potassium peroxymonosulfate (Oxone), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selecfluor), tert-butyl hypochlorite, N-iodosuccinimide (NIS), etc. A preferred oxidizing agent is N-bromosuccinimide (NBS).

[0028] In certain embodiments, step (c) occurs 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. A preferred acid is acetic acid.

[0029] In a preferred embodiment of step (c), the oxidizing agent is N-bromosuccinimide (NBS) and the acid is acetic acid.

[0030] In a preferred embodiment, step (c) occurs in a solvent. Suitable solvents include, but are not limited to, dichloromethane, chloroform, dioxane, ethyl acetate, heptane, hexane, methyl t-butyl ether, tetrahydrofuran (THF), 2-Me THF, water and toluene, or a mixture of two or more thereof. Preferably, the solvent is a mixture of 2-Me THF, THF and water. Preferably, the volume ratio of 2-Me THF / THF / water is approximately 3.5 / 1.5 / 1.

[0031] 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 a period of about 30 minutes to about 3 hours, preferably about 30 minutes to about 1 hour, more preferably about 30 minutes.

[0032] In one embodiment, the compound of formula (D-1) is the major product. In a preferred embodiment, the method of the present invention further comprises isolating the compound of formula (D-1) and the compound of formula (D-2).

[0033] Process (d) The compound of formula (D-1) is converted to the compound of formula (e-1) by reaction with an ammonolysis reagent. In certain embodiments, in step (d), the compound of formula (D-1) is reacted with an ammonolysis reagent in a mixture with the compound of formula (D-2), resulting in the production of both compound (e-1) and compound (e-2). [ka]

[0034] In a specific embodiment of step (d), compound (e-1) is prepared in diastereomeric excess. In a specific embodiment, the weight ratio of compound (e-1) to compound (e-2) prepared is about 55:45 to 95:5, preferably about 6:1 to 8:1.

[0035] Suitable ammonolysis reagents include, but are not limited to, ammonia, ammonium hydroxide, etc. The preferred ammonolysis reagent is ammonia.

[0036] In a preferred embodiment, step (d) occurs in a solvent. Suitable solvents include, but are not limited to, dichloromethane, chloroform, dioxane, ethyl acetate, heptane, hexane, methyl t-butyl ether, tetrahydrofuran, methanol, ethanol, propanol, and toluene, or a mixture of two or more thereof. Preferably, the solvent is methanol.

[0037] 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 a period of about 2 days to about 7 days, preferably about 3 days to about 5 days, more preferably about 5 days.

[0038] In one embodiment, compound formula (e-1) is the major product. In a preferred embodiment, the method of the present invention further comprises isolating compound (e-1) and compound (e-2).

[0039] Process (e) In certain embodiments of step (e), compound (e-1) is reacted with an acid in a mixture with compound (e-2) to produce a mixture of compounds of formula (F-1) and formula (F-2). [ka]

[0040] In certain embodiments of step (e), the compound of formula (F-1) is prepared in diastereomeric excess. In certain embodiments, the weight ratio of the compound of formula (F-1) to the compound of formula (F-2) prepared is preferably about 55:45 to 95:5, more preferably about 6:1 to about 8:1.

[0041] Suitable acids include, but are not limited to, hydrogen chloride, hydrogen bromide, trifluoroacetic acid, etc. A preferred acid is hydrogen chloride or hydrogen chloride generated in situ from the reaction of acetyl chloride with an alkyl alcohol.

[0042] In a preferred embodiment, step (e) occurs in a solvent. Suitable solvents include, but are not limited to, dichloromethane, chloroform, dioxane, ethyl acetate, heptane, hexane, methyl t-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 with one or more co-solvents selected from toluene, acetonitrile, ethyl acetate, and dichloromethane. In a certain embodiment 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.

[0043] 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 a period of about 30 minutes to about 10 hours, preferably about 5 hours to about 3 days, more preferably about 2 days.

[0044] 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 the recrystallization is N,N-dimethylformamide (DMF).

[0045] In a preferred embodiment, the process of the present invention further comprises isolating the compound of formula (F-1), preferably in substantially pure form.

[0046] Process (f) The compound of formula (F-1) from step (e) is preferably reacted with the 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), ethylmethylphosphinic 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) N-[(1H-benzotriazol-1-yl)-(dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU), N-[(1H-benzotriazol-1-yl)-(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate N-oxide (TBTU), 2-(2-oxo-1(2H)-pyridyl-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), O-[(cyano(ethoxycarbonyl)methyl) N-[(1H-benzotriazol-1-yl)(dimethylamino)-methylene]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU), N-[(1H-benzotriazol-1-yl)(dimethylamino)-methylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HBTU), cyanuric chloride, 2-chloro-4,6-dimethoxy-1,3,5 triazine (CDMT), 4-(4,6-dimethoxy-1,3,5 triazin-2-yl)-4-methylmorpholinium chloride (DMTMM), or boric acid.Preferably, the coupling agent is n-propanephosphonic anhydride (T3P).

[0047] In certain embodiments, step (f) occurs in the presence of a suitable base, such as, but not limited to, triethylamine, diisopropylethylamine, or N-methylmorpholine. A preferred base is N-methylmorpholine.

[0048] In certain embodiments, step (f) occurs 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.

[0049] In a preferred embodiment, step (f) occurs in a solvent. Suitable solvents include, but are not limited to, methanol, ethanol, acetonitrile, dichloromethane, chloroform, dioxane, ethyl acetate, heptane, hexane, methyl t-butyl ether, tetrahydrofuran, N,N-dimethylformamide and toluene, or a mixture of two or more thereof. Preferably, the solvent is N,N-dimethylformamide.

[0050] In certain embodiments, step (f) is carried out at a suitable temperature, such as from about −10° C. to about 30° C., preferably from about −10° C. to about 10° C., and more preferably at about 0° C. In one embodiment, step (f) is carried out for a period of from about 1 hour to about 24 hours, preferably for about 4 hours.

[0051] In a preferred embodiment, the process of the invention further comprises isolating the compound of formula (L), preferably in substantially pure form.

[0052] Process (g) The compound of formula (L) is preferably converted to the compound of formula (M) by reaction with a hydrogen source. In embodiments where PG1 is Cbz, Fmoc, Moz or Pnz, the hydrogen source can be hydrogen, ammonium formate, and the like. In certain embodiments, the reaction proceeds in the presence of a catalyst, such as, but not limited to, palladium on carbon, palladium hydroxide on carbon, or Raney nickel. Preferably, the hydrogen source is H2 and the catalyst is palladium on carbon. In certain embodiments, the reaction is carried out under a suitable hydrogen pressure, such as, but not limited to, about 0.5 atm to about 10 atm, preferably about 1 atm to 5 atm.

[0053] In certain 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 produce a salt form of the compound of formula (M). A preferred acid is hydrogen bromide in acetic acid.

[0054] In certain 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, which removes the PG1 group and produces a salt form of the compound of formula (M).

[0055] In a preferred embodiment, step (g) occurs in a solvent. Suitable solvents include, but are not limited to, acetonitrile, acetone, dichloromethane, dimethylformamide, dimethylsulfoxide, dioxane, ethyl acetate, heptane, hexane, methanol, methyl t-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.

[0056] In certain embodiments, step (g) is carried out at a suitable temperature, such as from about −20° C. to about 50° C., preferably from about 0° C. to about 30° C. In one embodiment, the reaction is carried out over a period of from about 1 hour to about 24 hours, preferably from about 1 hour to about 8 hours.

[0057] In certain embodiments, the compound of formula (M) or a salt form thereof is used directly in the next step without further isolation.

[0058] 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.

[0059] Process (h) 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), ethylmethylphosphinic 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) N-[(1H-benzotriazol-1-yl)-(dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU), N-[(1H-benzotriazol-1-yl)-(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate N-oxide (TBTU), 2-(2-oxo-1(2H)-pyridyl-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), O-[(cyano(ethoxycarbonyl)methyl) [(1H-benzotriazol-1-yl)(dimethylamino)-methylene]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU), N-[(1H-benzotriazol-1-yl)(dimethylamino)-methylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HBTU), cyanuric chloride, 2-chloro-4,6-dimethoxy-1,3,5 triazine (CDMT), 4-(4,6-dimethoxy-1,3,5 triazin-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-methylmethanaminium hexafluorophosphate N-oxide (HATU).

[0060] 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.

[0061] In certain embodiments, step (h) occurs in the presence of a suitable base, such as, but not limited to, triethylamine, diisopropylethylamine, or N-methylmorpholine. A preferred base is N-methylmorpholine.

[0062] In certain embodiments, step (h) occurs in the presence of an amide coupling agent and a suitable base, where the amide coupling agent is HATU and the base is N-methylmorpholine.

[0063] In a preferred embodiment, step (h) occurs in a solvent such as, but not limited to, acetonitrile, acetone, chloroform, dichloromethane, N,N-dimethylformamide, dimethylsulfoxide, dioxane, ethyl acetate, heptane, hexane, methanol, methyl t-butyl ether, tetrachloromethane, tetrahydrofuran, toluene, or a mixture of two or more thereof. Preferably, the solvent is N,N-dimethylformamide.

[0064] Step (h) is carried out at a suitable temperature, for example, from about 0° C. to about 50° C., preferably from about 20° C. to about 30° C., more preferably about 25° C. In one embodiment, step (h) is carried out for a period of from about 1 hour to about 24 hours, preferably from about 3 hours to about 12 hours.

[0065] In a preferred embodiment, the process of the invention further comprises isolating the compound of formula (N), preferably in substantially pure form.

[0066] Process (i) The compound of formula (N) is converted to the compound of formula (A) by reaction with a dehydrating reagent. Suitable dehydrating reagents include, but are not limited to, n-propylphosphonic anhydride (T3P), trifluoroacetic anhydride (TFAA), methyl N-(triethylammonium sulfonyl)carbamate (Burgess reagent), and phosphorus oxide (PO5). A preferred dehydrating reagent is trifluoroacetic anhydride (TFAA).

[0067] In certain embodiments, step (i) occurs 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. A preferred base is triethylamine.

[0068] In certain embodiments, step (i) occurs in the presence of a dehydrating reagent and a base, where the dehydrating reagent is trifluoroacetic anhydride (TFAA) and the base is triethylamine.

[0069] In a preferred embodiment, step (i) occurs in a solvent. Suitable solvents include, but are not limited to, acetonitrile, acetone, dichloromethane, dichloroethane, N,N-dimethylformamide, dimethylsulfoxide, N-methyl-2-pyrrolidone, dioxane, ethyl acetate, heptane, hexane, methyl t-butyl ether, tetrahydrofuran, toluene, and mixtures of two or more thereof. A preferred solvent is ethyl acetate.

[0070] In certain embodiments, step (i) is carried out at a suitable temperature, such as from about −10° C. to about 10° C., preferably from about −5° C. to about 5° C., and more preferably at about 0° C. In one embodiment, step (i) is carried out over a period of from about 30 minutes to about 2 hours, preferably for about 1 hour.

[0071] In a preferred embodiment, the process of the invention further comprises isolating the compound of formula (A), preferably in substantially pure form.

[0072] In certain embodiments, the present invention provides a method for preparing a compound of formula (A), comprising steps (f), (g), (h) and (i) above.

[0073] In certain embodiments, the present invention provides a method for preparing a compound of formula (A), comprising steps (h) and (i) above.

[0074] In one embodiment, the present invention provides a compound of formula (J) or a salt thereof [ka] and providing a method for preparing (J-1) reducing a compound of formula (Ga) to produce a compound of formula (Gb); [ka] (J-2) a step of oxidizing a compound of formula (Gb) to produce a compound of formula (G); [ka] (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); [ka] wherein R3 is methyl, ethyl or benzyl; (J-4) converting the compound of formula (H) to a compound of formula (I) via Hemetsberger indole cyclization; [ka] (J-5) reacting the compound of formula (I) with a base to obtain a compound of formula (J) or a salt thereof; [ka] Includes.

[0075] In another embodiment, the present invention provides a compound of formula (J) or a salt thereof [ka] and providing a method for preparing (J-1) reducing a compound of formula (Ga) to produce a compound of formula (Gb); [ka] (J-2) a step of oxidizing a compound of formula (Gb) to produce a compound of formula (G); [ka] (J-2a) reacting a compound of formula (G) with sodium hydrogen sulfite to produce a compound of formula (Gc); [ka] (J-2b) reacting a compound of formula (Gc) with a base to produce a compound of formula (G); [ka] (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); [ka] wherein R3 is methyl, ethyl or benzyl; (J-4) converting the compound of formula (H) to a compound of formula (I) via Hemetsberger indole cyclization; [ka] (J-5) reacting the compound of formula (I) with a base to obtain a compound of formula (J) or a salt thereof; [ka] Includes.

[0076] Process (J-1) 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-dimethylsulfide complex, etc. Preferably, the reducing agent is sodium borohydride or borane-tetrahydrofuran complex.

[0077] In a preferred embodiment, step (J-1) occurs in a solvent. Suitable solvents include, but are not limited to, acetonitrile, acetone, dichloromethane, dimethylformamide, dimethylsulfoxide, dioxane, ethyl acetate, heptane, hexane, methyl t-butyl ether, tetrahydrofuran, toluene, and mixtures of two or more thereof. A preferred solvent is tetrahydrofuran.

[0078] In one embodiment, the reaction in step (J-1) is carried out at a suitable temperature, for example, from about −20° C. to about 50° C., preferably from about −5° C. to about 25° C. In one embodiment, the reaction is carried out over a period of from about 0.5 hours to about 12 hours, preferably from about 2 to 6 hours.

[0079] In certain embodiments, the methods of the invention further comprise isolating the compound of formula (Gb), preferably in substantially pure form.

[0080] Process (J-2) The compound of formula (Gb) is oxidized by reaction with an oxidizing agent. Suitable oxidizing agents include, but are not limited to, trichloroisocyanuric acid with TEMPO, sodium hypochlorite (NaClO), sodium hypochlorite with TEMPO, oxalyl chloride with dimethylsulfoxide, manganese oxide, chromium trioxide, pyridinium chlorochromate (PCC), sodium perchloride, Dess-Martin periodinane (DMP), and the like. A preferred oxidizing agent is sodium hypochlorite with TEMPO.

[0081] In a preferred embodiment, the reaction in step (J-2) occurs in a solvent. Suitable solvents include, but are not limited to, acetonitrile, acetone, dichloromethane, dimethylformamide, dimethylsulfoxide, dioxane, ethyl acetate, heptane, hexane, methyl t-butyl ether, tetrahydrofuran, toluene, and mixtures of two or more thereof. A preferred solvent is methyl tert-butyl ether (MTBE).

[0082] The reaction in 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., and more preferably about −5° C. to about 5° C. In a particular embodiment, the reaction in step (J-2) is carried out for a period of about 10 minutes to about 10 hours, preferably about 30 minutes to about 3 hours.

[0083] Process (J-2a) In one embodiment, the reaction in 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, MeOH, EtOH, water, and mixtures of two or more thereof. A preferred solvent is a mixture of MTBE, EtOH, and water.

[0084] In one embodiment, the reaction in step (J-2a) is carried out at a suitable temperature, for example, from about 0° C. to about 60° C., preferably from about 20° C. to about 40° C. In one embodiment, the reaction is carried out over a period of from about 0.5 hours to about 12 hours, preferably from about 2 to 6 hours.

[0085] Process (J-2b) Step (J-2b) occurs 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, lithium 2,2,6,6-tetramethylpiperidide, sodium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, triethylamine, diisopropylethylamine, etc. Preferably, the base is sodium carbonate.

[0086] In one embodiment, the reaction in step (J-2b) occurs in a solvent. Suitable solvents include, but are not limited to, acetonitrile, acetone, dimethylsulfoxide, dioxane, ethyl acetate, methyl tert-butyl ether, tetrahydrofuran, toluene, EtOH, water, and mixtures of two or more thereof. A preferred solvent is methyl tert-butyl ether (MTBE) or a mixture of MTBE and water.

[0087] In one embodiment, the reaction in step (J-2b) is carried out at a suitable temperature, for example, from about 0° C. to about 40° C., preferably from about 20° C. to about 25° C. In one embodiment, the reaction is carried out over a period of from about 0.5 hours to about 12 hours, preferably from about 2 to 6 hours.

[0088] In certain embodiments, the methods of the invention further comprise isolating the compound of formula (G), preferably in substantially pure form.

[0089] Process (J-3) Step (J-3) occurs in the presence of a suitable base, such as, but not limited to, sodium methoxide, sodium ethoxide, sodium tert-butoxide, lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidide, sodium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, etc. Preferably, the base is sodium methoxide or sodium ethoxide.

[0090] In a preferred embodiment, step (J-3) occurs in the presence of a sacrificial electrophile, such as, but not limited to, CF3CO2Et, ethyl trichloroacetate or ethyl formate, to prevent hydrolysis in the base-catalyzed condensation reaction and thereby improve the yield. A preferred sacrificial electrophile is CF3CO2Et.

[0091] In a preferred embodiment, step (J-3) occurs in a suitable solvent, such as, but not limited to, dichloromethane, chloroform, dioxane, ethyl acetate, heptane, hexane, methyl t-butyl ether, tetrahydrofuran, methanol, ethanol, or toluene, and mixtures of two or more thereof. Preferably, the solvent is methanol or ethanol. More preferably, the solvent is methanol.

[0092] In a preferred embodiment, step (J-3) occurs in the presence of sodium methoxide or sodium ethoxide as a base, methanol or ethanol as a solvent, and CF3CO2Et as a sacrificial electrophile.

[0093] The reaction in 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., more preferably about 0° C. In one embodiment, step (J-3) is carried out for a period of about 30 minutes to about 10 hours, preferably about 5 hours to about 24 hours, more preferably about 8 hours to about 14 hours.

[0094] In certain embodiments, the methods of the invention further comprise isolating the compound of formula (H), preferably in substantially pure form.

[0095] Process (J-4) In step (J-4), the compound of formula (H) is heated to generate an activated intermediate, which can cyclize to form a compound of formula (I).

[0096] In a preferred embodiment, step (J-4) occurs in a solvent. Suitable solvents include, but are not limited to, trimethylbenzene, dichloromethane, chloroform, dioxane, ethyl acetate, heptane, hexane, methyl t-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.

[0097] In a particular embodiment, in step (J-4), the compound of formula (I) is prepared via continuous flow chemistry techniques by carrying out the reaction in a flow reactor with adjustable flow rate, reaction retention time, reaction temperature and pressure. Step (J-4) is 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 minutes to about 6 hours, preferably about 25 minutes.

[0098] In a preferred embodiment, the process of the invention further comprises isolating the compound of formula (I), preferably in substantially pure form.

[0099] Process (J-5) Step (J-5) is the saponification of the ester of the compound of formula (I) in the presence of a suitable base, followed by treatment 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. Suitable acids include, but are not limited to, hydrogen chloride, hydrogen bromide, sulfuric acid, and a combination of two or more thereof. A preferred acid is hydrogen chloride.

[0100] In a preferred embodiment, step (J-5) occurs in a solvent. Suitable solvents include, but are not limited to, dichloromethane, chloroform, dioxane, ethyl acetate, heptane, hexane, methyl t-butyl ether, tetrahydrofuran, water, toluene, and mixtures of two or more thereof. Preferably, the solvent is a mixture of tetrahydrofuran and water or MTBE and water.

[0101] In a particular embodiment, step (J-5) is carried out at a suitable temperature, for example, about 30° C. to about 100° C., preferably about 55° C. to about 65° C., more preferably about 65° C. In one embodiment, step (J-5) is carried out for a period of about 1 hour to about 3 days, preferably about 10 hours to about 2 days, more preferably about 24 hours.

[0102] In a preferred embodiment, the process of the invention further comprises isolating the compound of formula (J), preferably in substantially pure form.

[0103] In certain embodiments, the present invention provides a method for preparing 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).

[0104] In certain embodiments, the present invention provides a method for preparing 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).

[0105] In certain embodiments, the present invention provides a method for preparing a compound of formula (A), comprising steps (a), (b), (c), (d), (e), (f), (g), (J-3), (J-4), (J-5), (h), and (i) above.

[0106] In one embodiment, the present invention provides compound (I): [ka] A method for preparing the compound is provided. The method comprises: (1) reacting compound (w) with formaldehyde to produce compound (b); [ka] (2) converting compound (b) into compound (c); [ka] (3) converting compound (c) into a mixture of compound (d-1) and compound (d-2) via a rearrangement reaction, [ka] wherein one of the two diastereomers (d-1) and (d-2) is in diastereomeric excess, for example at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 95% diastereomeric excess; (4) a step of converting a mixture of compound (d-1) and compound (d-2) into (5) a mixture of compound (e-1) and compound (e-2), [ka] wherein one of compound (e-1) and compound (e-2) is prepared in diastereomeric excess, for example in at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90 or 95% diastereomeric excess; (6) converting the 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, [ka] wherein one of compound (f-1) and compound (f-2) is prepared in diastereomeric excess, for example, in at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90 or 95% diastereomeric excess; (7) Reacting compound (f-1) with compound (k) [ka] A step of producing compound (l); [ka] (8) converting compound (l) into compound (m); [ka] Alternatively, converting compound (l) to a salt form of compound (m) using a suitable acid; (9) reacting a compound of formula (m) or a salt form of a compound of formula (m) with an indole acid compound (j) or a salt thereof, [ka] Obtaining compound (n); [ka] (10) converting compound (n) into compound (I); [ka] Includes.

[0107] Process (1) In a preferred embodiment, step (1) occurs in a suitable solvent, such as, but not limited to, methanol, t-butyl alcohol, acetonitrile, acetone, dichloromethane, chloroform, dimethylformamide, dimethylsulfoxide, dioxane, ethyl acetate, heptane, hexane, methyl t-butyl ether, tetrahydrofuran, and toluene, or a mixture of two or more thereof. Preferably, the solvent is methanol.

[0108] 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 a period of about 30 minutes to about 1 day, preferably about 30 minutes to about 5 hours, more preferably about 1 hour.

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

[0110] Process (2) 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).

[0111] Step (2) preferably occurs in the presence of a suitable base, such as, but not limited to, triethylamine, diisopropylethylamine, sodium bicarbonate, or N-methylmorpholine. A preferred base is triethylamine.

[0112] In a preferred embodiment, step (2) occurs in a solvent. Suitable solvents include, but are not limited to, 2-Me THF, t-butyl alcohol, acetonitrile, acetone, dichloromethane, chloroform, dimethylformamide, dimethylsulfoxide, dioxane, ethyl acetate, heptane, hexane, methyl t-butyl ether, tetrahydrofuran, water, and toluene, or a mixture of two or more thereof. Preferably, the solvent is 2-Me THF and water as a co-solvent. Preferably, the volume ratio of 2-Me THF to water is 4:1.

[0113] In one embodiment, the reaction in step (2) is carried out at a temperature of about −10° C. to about 60° C., preferably about 0° C. to about 40° C., and more preferably about 5° C. to about 25° C. In one embodiment, step (b) is carried out for a period of about 1 hour to about 24 hours, preferably about 1 hour to about 10 hours, and more preferably about 5 hours.

[0114] In a preferred embodiment, the process of the invention further comprises isolating compound (c), preferably in substantially pure form.

[0115] Process (3) In step (3), compound (c) is reacted with an oxidizing agent to produce a mixture of compound (d-1) and compound (d-2). Preferably, the compound of formula (d-1) is produced in diastereomeric excess by this reaction. 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.

[0116] Suitable oxidizing agents include, but are not limited to, N-bromosuccinimide (NBS), hydrogen peroxide, meta-chloroperbenzoic acid (m-CPBA), potassium peroxymonosulfate (Oxone), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selecfluor), tert-butyl hypochlorite, N-iodosuccinimide (NIS), etc. A preferred oxidizing agent is N-bromosuccinimide (NBS).

[0117] In certain embodiments, step (3) occurs 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. A preferred acid is acetic acid.

[0118] In a preferred embodiment of step (3), the oxidizing agent is N-bromosuccinimide (NBS) and the acid is acetic acid.

[0119] In a preferred embodiment, step (3) occurs in a solvent. Suitable solvents include, but are not limited to, dichloromethane, chloroform, dioxane, ethyl acetate, heptane, hexane, methyl t-butyl ether, tetrahydrofuran (THF), 2-Me THF, water and toluene, or a mixture of two or more thereof. Preferably, the solvent is a mixture of 2-Me THF, THF and water. Preferably, the volume ratio of 2-Me THF / THF / water is approximately 3.5 / 1.5 / 1.

[0120] 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 a period of about 30 minutes to about 3 hours, preferably about 30 minutes to about 1 hour, more preferably about 30 minutes.

[0121] In one embodiment, compound (d-1) is the major product. In a preferred embodiment, the method of the present invention further comprises isolating compound (d-1) and compound (d-2).

[0122] Process (4) The mixture of compound (d-1) and compound (d-2) is preferably converted to a mixture of compound (e-1) and compound (e-2) by reaction with an ammonolysis reagent. In certain embodiments of step (4), compound (e-1) is prepared in diastereomeric excess. In certain 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.

[0123] Suitable ammonolysis reagents include, but are not limited to, ammonia, ammonium hydroxide, etc. The preferred ammonolysis reagent is ammonia.

[0124] In a preferred embodiment, step (4) occurs in a solvent. Suitable solvents include, but are not limited to, dichloromethane, chloroform, dioxane, ethyl acetate, heptane, hexane, methyl t-butyl ether, tetrahydrofuran, methanol, ethanol, propanol, and toluene, or a mixture of two or more thereof. Preferably, the solvent is methanol.

[0125] 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 a period of about 2 days to about 7 days, preferably about 3 days to about 5 days, more preferably about 5 days.

[0126] In one embodiment, compound formula (e-1) is the major product. In a preferred embodiment, the method of the present invention further comprises isolating compound (e-1) and compound (e-2).

[0127] Process (5) 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 certain embodiments of step (e), compound (f-1) is produced in diastereomeric excess. In certain embodiments, the weight ratio of compound (f-1) and compound (f-2) produced is about 55:45 to 95:5, preferably about 6:1 to 8:1.

[0128] 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 from the reaction of acetyl chloride with an alkyl alcohol.

[0129] In a preferred embodiment, step (5) occurs in a solvent. Suitable solvents include, but are not limited to, dichloromethane, chloroform, dioxane, ethyl acetate, heptane, hexane, methyl t-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 with one or more co-solvents selected from toluene, acetonitrile, ethyl acetate, and dichloromethane. In certain embodiments of step (e), the mixture of compound (f-1) and compound (f-2) is formed as a DMF solvate.

[0130] 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 a period of about 30 minutes to about 10 hours, preferably about 5 hours to about 3 days, more preferably about 2 days.

[0131] 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).

[0132] In a preferred embodiment, the process of the present invention further comprises isolating compound (f-1), preferably in substantially pure form.

[0133] Process (6) 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), ethylmethylphosphinic anhydride (EMPA), 1,1'-carbonyldiimidazoline, ... (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-methylmethanaminium hexafluorophosphate N-oxide (HATU), N-[(1H-benzotriazol-1-yl)-(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate N-oxide (TBTU), 2-(2-oxo-1(2H)-pyridyl-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), O-[(cyano(ethoxycarbonyl)methyleneamino]-N,N,N',N'-tetramethyluronium Examples of the coupling agent include tetrafluoroborate (TOTU), N-[(1H-benzotriazol-1-yl)(dimethylamino)-methylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HBTU), cyanuric chloride, 2-chloro-4,6-dimethoxy-1,3,5 triazine (CDMT), 4-(4,6-dimethoxy-1,3,5 triazin-2-yl)-4-methylmorpholinium chloride (DMTMM), or boric acid.Preferably, the coupling agent is n-propanephosphonic anhydride (T3P).

[0134] In certain embodiments, step (6) occurs in the presence of a suitable base, such as, but not limited to, triethylamine, diisopropylethylamine, or N-methylmorpholine. A preferred base is N-methylmorpholine.

[0135] In certain embodiments, step (6) occurs 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.

[0136] In a preferred embodiment, step (6) occurs in a solvent. Suitable solvents include, but are not limited to, methanol, ethanol, acetonitrile, dichloromethane, chloroform, dioxane, ethyl acetate, heptane, hexane, methyl t-butyl ether, tetrahydrofuran, N,N-dimethylformamide and toluene, or a mixture of two or more thereof. Preferably, the solvent is N,N-dimethylformamide.

[0137] In certain embodiments, step (6) is carried out at a suitable temperature, such as from about −10° C. to about 30° C., preferably from about −10° C. to about 10° C., and more preferably at about 0° C. In one embodiment, step (6) is carried out for a period of from about 1 hour to about 24 hours, preferably for about 4 hours.

[0138] In a preferred embodiment, the process of the invention further comprises isolating compound (l), preferably in substantially pure form.

[0139] Process (7) Compound (l) is preferably converted to compound (m) by reaction with hydrogen, a hydrogen source such as ammonium formate, a catalyst such as, but not limited to, palladium on carbon, palladium hydroxide on carbon, or Raney nickel, optionally 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, etc. Preferably, the hydrogen source is H2 and the catalyst is palladium on carbon. More preferably, the hydrogen source is H2, the catalyst is palladium on carbon, and the reaction is carried out in the presence of p-toluenesulfonic acid, which removes the Cbz group and forms the p-toluenesulfonic acid of compound (m).

[0140] In certain embodiments, the reaction is carried out under a suitable hydrogen pressure, such as, but not limited to, about 0.5 atm to about 10 atm, preferably about 1 atm to 5 atm.

[0141] In a preferred embodiment, step (7) occurs in a solvent. Suitable solvents include, but are not limited to, acetonitrile, acetone, dichloromethane, dimethylformamide, dimethylsulfoxide, dioxane, ethyl acetate, heptane, hexane, methanol, methyl t-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.

[0142] In certain embodiments, step (7) is carried out at a suitable temperature, such as from about −20° C. to about 50° C., preferably from about 0° C. to about 30° C. In one embodiment, the reaction is carried out over a period of from about 1 hour to about 24 hours, preferably from about 1 hour to about 8 hours.

[0143] In certain embodiments, compound (m) or a salt form thereof is used directly for the next step without further separation.

[0144] In a preferred embodiment, the process of the present invention further comprises isolating compound (m) or a salt form thereof, preferably in substantially pure form.

[0145] Process (8) Compound (m) or a salt form thereof 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), ethylmethylphosphinic 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) N-[(1H-benzotriazol-1-yl)-(dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU), N-[(1H-benzotriazol-1-yl)-(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate N-oxide (TBTU), 2-(2-oxo-1(2H)-pyridyl-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), O-[(cyano(ethoxycarbonyl)methyl) [(1H-benzotriazol-1-yl)(dimethylamino)-methylene]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU), N-[(1H-benzotriazol-1-yl)(dimethylamino)-methylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HBTU), cyanuric chloride, 2-chloro-4,6-dimethoxy-1,3,5 triazine (CDMT), 4-(4,6-dimethoxy-1,3,5 triazin-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-methylmethanaminium hexafluorophosphate N-oxide (HATU).

[0146] In certain embodiments, step (8) occurs in the presence of a suitable base, such as, but not limited to, triethylamine, diisopropylethylamine, or N-methylmorpholine. A preferred base is N-methylmorpholine.

[0147] In certain embodiments, step (8) occurs in the presence of an amide coupling agent and a suitable base, where the amide coupling agent is HATU and the base is N-methylmorpholine.

[0148] 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.

[0149] In a preferred embodiment, step (8) occurs in a solvent such as, but not limited to, acetonitrile, acetone, chloroform, dichloromethane, N,N-dimethylformamide, dimethylsulfoxide, dioxane, ethyl acetate, heptane, hexane, methanol, methyl t-butyl ether, tetrachloromethane, tetrahydrofuran, toluene, or a mixture of two or more thereof. Preferably, the solvent is N,N-dimethylformamide.

[0150] Step (8) is carried out at a suitable temperature, for example, from about 0° C. to about 50° C., preferably from about 20° C. to about 30° C., and more preferably about 25° C. In one embodiment, step (8) is carried out for a period of from about 1 hour to about 24 hours, preferably from about 3 hours to about 12 hours.

[0151] In a preferred embodiment, the process of the invention further comprises isolating compound (n), preferably in substantially pure form.

[0152] Process (9) Compound (n) is converted to compound (I) by reaction with a dehydrating reagent. Suitable dehydrating reagents include, but are not limited to, n-propylphosphonic anhydride (T3P), trifluoroacetic anhydride (TFAA), methyl N-(triethylammonium sulfonyl)carbamate (Burgess reagent), and phosphorus oxide (PO5). A preferred dehydrating reagent is trifluoroacetic anhydride (TFAA).

[0153] In certain embodiments, step (9) occurs 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. A preferred base is triethylamine.

[0154] In certain embodiments, step (9) occurs in the presence of a dehydrating reagent and a base, where the dehydrating reagent is trifluoroacetic anhydride (TFAA) and the base is triethylamine.

[0155] In a preferred embodiment, step (9) occurs in a solvent. Suitable solvents include, but are not limited to, acetonitrile, acetone, dichloromethane, dichloroethane, N,N-dimethylformamide, dimethylsulfoxide, N-methyl-2-pyrrolidone, dioxane, ethyl acetate, heptane, hexane, methyl t-butyl ether, tetrahydrofuran, toluene, and mixtures of two or more thereof. A preferred solvent is ethyl acetate.

[0156] In certain embodiments, step (9) is carried out at a suitable temperature, such as from about −10° C. to about 10° C., preferably from about −5° C. to about 5° C., and more preferably at about 0° C. In one embodiment, step (9) is carried out for a period of from about 30 minutes to about 2 hours, preferably for about 1 hour.

[0157] In a preferred embodiment, the process of the present invention further comprises isolating compound (I), preferably in substantially pure form.

[0158] In certain 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, for example, to a temperature of about 10 to 25°C, thereby inducing crystallization of compound (I). Solvents suitable for crystallization include anisole, toluene, xylene, and mixtures of two or more thereof. Preferably, the solvent is toluene. Compound (I) is preferably isolated as the corresponding toluene solvate.

[0159] The present invention further provides a method for preparing an amorphous form of compound (I). The method includes the steps of (ia) adding a first solvent to a toluene solvate of compound (I) to prepare a solution, (ib) removing the first solvent and a portion of the toluene from the solution, for example by distillation, and (ic) repeating steps (ia) and (ib) until a solution of compound (I) is prepared with a toluene concentration below a predetermined value, such as 0.1% (wt / wt). The resulting solution is then mixed with a second solvent that is a non-solvent for compound (I) to prepare an amorphous form of compound (I). Suitable first solvent / second solvent pairs include EtOH / water, isopropanol / water, acetone / water, and MTBE / n-heptane, and preferably, the first solvent is ethanol and the second solvent is water.

[0160] The methods of crystallizing Compound (I) and optionally preparing amorphous forms of Compound (I) can be carried out on Compound (I) as prepared by the methods described herein.

[0161] In certain embodiments, the present invention provides a method for producing compound (I), comprising steps (6), (7), (8) and (9) above.

[0162] In certain embodiments, the present invention provides a method for producing compound (I), comprising steps (8) and (9) above.

[0163] In one embodiment, the present invention relates to compound (j) or a salt thereof. [ka] and providing a method for preparing The method comprises: (j-1) reducing compound (ga) to produce compound (gb); [ka] (j-2) a step of oxidizing compound (gb) to produce compound (g); [ka] (j-3) A process for producing a mixture of compounds (h-1) and (h-2) by reacting compound (g) with ethyl 2-azidoacetate in the presence of sodium methoxide as a base, [ka] wherein one of compound (h-1) and compound (h-2) is produced in excess, for example at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90 or 95% excess; (j-4) A process for converting a mixture of compound (h-1) and compound (h-2) into a mixture of compound (i-1) and compound (i-2) via Hemetsberger indole cyclization, [ka] wherein one of compound (i-1) and compound (i-2) is produced in excess, for example at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90 or 95% excess; (j-5) reacting the mixture of compound (i-1) and compound (i-2) with a base to obtain compound (j) or a salt thereof; [ka] Includes.

[0164] In another embodiment, the present invention relates to compound (j) or a salt thereof. [ka] and providing a method for preparing The method comprises: (j-1) reducing compound (ga) to produce compound (gb); [ka] (j-2) a step of producing compound (g) by oxidizing compound (gb); [ka] (j-2a) reacting compound (g) with sodium hydrogen sulfite to produce compound (gc); [ka] (j-2b) reacting compound (gc) with a base to produce compound (g); [ka] (j-3) A process for producing a mixture of compounds (h-1) and (h-2) by reacting compound (g) with ethyl 2-azidoacetate in the presence of sodium methoxide as a base, [ka] wherein one of compound (h-1) and compound (h-2) is produced in excess, for example at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90 or 95% excess; (j-4) A process for converting a mixture of compound (h-1) and compound (h-2) into a mixture of compound (i-1) and compound (i-2) via Hemetsberger indole cyclization, [ka] wherein one of compound (i-1) and compound (i-2) is produced in excess, for example at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90 or 95% excess; (j-5) reacting a mixture of compound (i-1) and compound (i-2) with a base to obtain compound (j) or a salt thereof; [ka] Includes.

[0165] Process (j-1) Compound (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-dimethylsulfide complex, etc. Preferably, the reducing agent is sodium borohydride or borane-tetrahydrofuran complex.

[0166] In a preferred embodiment, step (j-1) occurs in a solvent. Suitable solvents include, but are not limited to, acetonitrile, acetone, dichloromethane, dimethylformamide, dimethylsulfoxide, dioxane, ethyl acetate, heptane, hexane, methyl t-butyl ether, tetrahydrofuran, toluene, and mixtures of two or more thereof. A preferred solvent is tetrahydrofuran.

[0167] In one embodiment, the reaction in step (j-1) is carried out at a suitable temperature, for example, from about −20° C. to about 50° C., preferably from about −5° C. to about 25° C. In one embodiment, the reaction is carried out over a period of from about 0.5 hours to about 12 hours, preferably from about 2 to 6 hours.

[0168] In certain embodiments, the methods of the invention further comprise isolating compound (gb), preferably in substantially pure form.

[0169] Process (j-2) Compound (gb) is oxidized by reaction with an oxidizing agent. Suitable oxidizing agents include, but are not limited to, trichloroisocyanuric acid with TEMPO, sodium hypochlorite (NaClO), sodium hypochlorite with TEMPO, oxalyl chloride with dimethylsulfoxide, manganese oxide, chromium trioxide, pyridinium chlorochromate (PCC), sodium perchloride, Dess-Martin periodinane (DMP), and the like. A preferred oxidizing agent is sodium hypochlorite with TEMPO.

[0170] In a preferred embodiment, the reaction in step (j-2) occurs in a solvent. Suitable solvents include, but are not limited to, acetonitrile, acetone, dichloromethane, dimethylformamide, dimethylsulfoxide, dioxane, ethyl acetate, heptane, hexane, methyl t-butyl ether, tetrahydrofuran, toluene, and mixtures of two or more thereof. A preferred solvent is methyl tert-butyl ether (MTBE).

[0171] The reaction in 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., and more preferably about −5° C. to about 5° C. In a particular embodiment, the reaction in step (j-2) is carried out for a period of about 10 minutes to about 10 hours, preferably about 30 minutes to about 3 hours.

[0172] Process (j-2a) In one embodiment, the reaction in 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. A preferred solvent is a mixture of MTBE, EtOH, and water.

[0173] In one embodiment, the reaction in step (j-2a) is carried out at a suitable temperature, for example, from about 0° C. to about 60° C., preferably from about 20° C. to about 40° C. In one embodiment, the reaction is carried out over a period of from about 0.5 hours to about 12 hours, preferably from about 2 to 6 hours.

[0174] Process (j-2b) Step (j-2b) occurs 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, lithium 2,2,6,6-tetramethylpiperidide, sodium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, triethylamine, diisopropylethylamine, etc. Preferably, the base is sodium carbonate.

[0175] In one embodiment, the reaction in step (j-2b) occurs in a solvent. Suitable solvents include, but are not limited to, acetonitrile, acetone, dimethylsulfoxide, dioxane, ethyl acetate, methyl tert-butyl ether, tetrahydrofuran, toluene, EtOH, water, and mixtures of two or more thereof. A preferred solvent is methyl tert-butyl ether (MTBE) or a mixture of MTBE and water.

[0176] In one embodiment, the reaction in step (j-2b) is carried out at a suitable temperature, for example, from about 0° C. to about 40° C., preferably from about 20° C. to about 25° C. In one embodiment, the reaction is carried out over a period of from about 0.5 hours to about 12 hours, preferably from about 2 to 6 hours.

[0177] In certain embodiments, the methods of the invention further comprise isolating compound (g), preferably in substantially pure form.

[0178] Process (j-3) In a preferred embodiment, step (j-3) occurs in the presence of a sacrificial electrophile, such as, but not limited to, CF3CO2Et, ethyl trichloroacetate or ethyl formate, to prevent hydrolysis in the base-catalyzed condensation reaction and thereby improve the yield. A preferred sacrificial electrophile is CF3CO2Et.

[0179] In a preferred embodiment, step (j-3) occurs in a suitable solvent, such as, but not limited to, dichloromethane, chloroform, dioxane, ethyl acetate, heptane, hexane, methyl t-butyl ether, tetrahydrofuran, methanol, ethanol, or toluene, and mixtures of two or more thereof. Preferably, the solvent is methanol or ethanol. More preferably, the solvent is methanol.

[0180] The reaction in 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., more preferably about 0° C. In one embodiment, step (j-3) is carried out for a period of about 30 minutes to about 10 hours, preferably about 5 hours to about 24 hours, more preferably about 8 hours to about 14 hours.

[0181] In certain embodiments, the methods of the present invention further comprise isolating compound (h-1), preferably in substantially pure form.

[0182] Process (j-4) In step (j-4), compound (h-1) is heated to generate an activated intermediate, which can cyclize to form compound (i-1) and compound (i-2).

[0183] In a preferred embodiment, step (j-4) occurs in a solvent. Suitable solvents include, but are not limited to, trimethylbenzene, dichloromethane, chloroform, dioxane, ethyl acetate, heptane, hexane, methyl t-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.

[0184] In a particular embodiment, step (j-4) is carried out in a flow reactor, and compound (i-1) and compound (i-2) are prepared by continuous flow chemistry techniques and are 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 about 200° C. In one embodiment, step (j-4) is carried out with a residence time of from about 10 minutes to about 6 hours, preferably about 25 minutes.

[0185] In a preferred embodiment, the process of the present invention further comprises isolating compound (i-1), preferably in substantially pure form.

[0186] Process (j-5) Step (j-5) is the saponification of compound (i-1) and / or compound (i-2) in the presence of a suitable base, followed by treatment 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. A 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. A preferred acid is hydrogen chloride.

[0187] In a preferred embodiment, step (j-5) occurs in a solvent. Suitable solvents include, but are not limited to, dichloromethane, chloroform, dioxane, ethyl acetate, heptane, hexane, methyl t-butyl ether, tetrahydrofuran, water, toluene, and mixtures of two or more thereof. Preferably, the solvent is a mixture of tetrahydrofuran and water or MTBE and water.

[0188] In a particular embodiment, step (j-5) is carried out at a suitable temperature, for example, about 30° C. to about 100° C., preferably about 55° C. to about 65° C., more preferably about 65° C. In one embodiment, step (J-5) is carried out for a period of about 1 hour to about 3 days, preferably about 10 hours to about 2 days, more preferably about 24 hours.

[0189] In a preferred embodiment, the process of the invention further comprises isolating compound (j), preferably in substantially pure form.

[0190] In a certain embodiment, the present invention provides a method for producing 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).

[0191] In a certain embodiment, the present invention provides a method for producing 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).

[0192] In a certain embodiment, 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).

[0193] definition Listed below are definitions of various terms used to describe this invention. These definitions apply to those terms as they are used throughout the specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0194] As used herein, the term "alkoxy", used alone or in combination with other terms, unless otherwise specified, refers to an alkyl group having the specified number of carbon atoms attached to the remainder of the molecule through an oxygen atom, e.g., methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and higher homologs and isomers. Preferred alkoxy is (C1-C3)alkoxy.

[0195] The terms "heterocyclic" or "heterocycloalkyl" may be used interchangeably and refer to non-aromatic rings or bicyclic or tricyclic fused, bridged, or spiro systems, where (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur, and nitrogen, (ii) each ring system can be saturated or unsaturated, (iii) the nitrogen and sulfur heteroatoms can be optionally oxidized, (iv) the nitrogen heteroatom can be optionally quaternized, (v) any of the above rings can be fused to an aromatic ring, and (vi) the remaining ring atoms are optionally oxo-substituted or optionally substituted with an exocyclic olefin, imine, or oxime double bond. Representative heterocycloalkyl groups include, but are not limited to, 1,3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinozalinyl, pyridazinonyl, 2-azabicyclo[2.2.1]-heptyl, 8-azabicyclo[3.2.1]octyl, 5-azaspiro[2.5]octyl, 1-oxa-7-azaspiro[4.4]nonanyl, 7-oxoxoxepan-4-yl, and tetrahydrofuryl. Such heterocyclic groups may be further substituted. Heteroaryl or heterocyclic groups may be C-linked or N-linked (where possible).

[0196] An "aliphatic" group is a non-aromatic moiety composed of any combination of carbon, hydrogen, halogen, oxygen, nitrogen or other atoms, and may contain one or more units of unsaturation, such as double and / or triple bonds. Examples of aliphatic groups include 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, groups containing one or more functional groups, non-aromatic hydrocarbons (optionally substituted), and groups in which one or more carbons of a non-aromatic hydrocarbon (optionally substituted) are replaced by a functional group. The carbon atoms of the aliphatic group may be oxo-substituted. 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 expressly include, for example, alkoxyalkyl, polyalkoxyalkyl, such as polyalkylene glycols, polyamines, and polyimines. The aliphatic group may be substituted.

[0197] The term "sulfonyl group" refers to a group of the formula R a -SO2-(wherein, R a R is an alkyl, alkenyl, alkynyl or aryl group, each of which may be substituted. a is optionally substituted alkyl or optionally substituted aryl.

[0198] The term "phosphoryl group" refers to a group of the formula (R b )2P(O)- group, where R b is an alkyl-O-, alkenyl-O-, alkynyl-O- or aryl-O- group, each of which is optionally substituted. bis optionally substituted alkyl, for example C1-C3-alkyl.

[0199] The term "substituted" refers to a group in which one, two, three, or more hydrogen atoms have been replaced with, but not limited to, -F, -Cl, -Br, -I, -OH, C1-C 12 -Alkyl, C2-C 12 -Alkenyl, C2-C 12 -Alkynyl, protected hydroxy, -NO2, -N3, -CN, -NH2, protected amino, oxo, thioxo, -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-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 12Alkyl, -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-heterocyclo-alkyl, -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)-heterocyclo-alkyl, -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, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C3~C 12-Cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-C 12 -Alkyl, -S-C2~C8-alkenyl, -S-C2~C8-alkynyl, -S-C3~C 12 It refers to substitution by being independently replaced with substituents such as -cycloalkyl, -S-aryl, -S-heteroaryl, -S-heterocycloalkyl, or methylthio-methyl. It is understood that the aryl, heteroaryl, alkyl, cycloalkyl, etc. can be further substituted.

[0200] The terms "halo" or "halogen," as used herein, alone or as part of another substituent, refer to a fluorine, chlorine, bromine, or iodine atom.

[0201] The term "optionally substituted" as used herein means that the referenced group can be substituted or unsubstituted. In one embodiment, the referenced group can be substituted with 0 substituents, i.e., the referenced group is unsubstituted. In another embodiment, the referenced group can be substituted with one or more additional groups individually and independently selected from the groups described herein.

[0202] The term "hydrogen" includes hydrogen and deuterium. Furthermore, the recitation of an atom includes other isotopes of that atom so long as the resulting compound is pharma- cetically acceptable.

[0203] In certain embodiments, the compounds of each formula herein are defined to include isotopically labeled compounds. An "isotopically labeled compound" is a compound in which at least one atomic position is enriched in a particular isotope of a specified element to a level significantly greater than the natural abundance of that isotope. For example, one or more hydrogen atom positions in a compound can be enriched with deuterium to a level significantly greater than the natural abundance of deuterium, for example, to a level of at least 1%, preferably at least 20% or at least 50%. Such deuterated compounds can, for example, be metabolized more slowly than their non-deuterated analogues, and therefore can exhibit a longer half-life when administered to a subject. Such compounds can be synthesized using methods known in the art, for example, by using deuterated starting materials. Unless otherwise stated, isotopically labeled compounds can be pharma- ceutically acceptable.

[0204] As used herein, the term "hydroxy activating group" refers to a labile chemical moiety, which is known in the art to activate a hydroxyl group so that it is eliminated during a synthetic procedure, such as a substitution or elimination reaction. Examples of hydroxyl activating groups include, but are not limited to, mesylates, tosylates, triflates, p-nitrobenzoates, phosphonates, and the like.

[0205] The term "activated hydroxyl" as used herein refers to a hydroxy group that has been activated with a hydroxyl activating group as defined above, including, for example, a mesylate, tosylate, triflate, p-nitrobenzoate, or phosphonate group.

[0206] The term "hydroxy protecting group" as used herein refers to a labile chemical moiety, which is known in the art to protect hydroxyl groups from undesired reactions during synthetic procedures. After said synthetic procedures, the hydroxy protecting groups described herein can be selectively removed. Hydroxy protecting groups known in the art are generally described in TH Greene and PG M Huts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, New York (1999). Examples of hydroxyl protecting groups include benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, tert-butoxy-carbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, allyl, benzyl, triphenyl-methyl(trityl), methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-(trimethylsilyl)-ethoxymethyl, methanesulfonyl, trimethylsilyl, triisopropylsilyl, and the like.

[0207] The term "protected hydroxy" as used herein refers to a hydroxy group protected with a hydroxy-protecting group, as defined above, which includes, for example, benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups.

[0208] The term "hydroxy prodrug group" as used herein refers to a promoiety group, which is known in the art to temporarily change the physicochemical and therefore biological properties of the parent drug by covering or masking the hydroxy group. After the synthesis procedure, the hydroxy prodrug group described herein must be able to revert to the hydroxy group in vivo. Hydroxy prodrug groups known in the art are generally described in Kenneth B. Sloan, Prodrugs, Topical and Ocular Drug Delivery, (Drugs and the Pharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York (1992), and in Prodrugs Challenges and Rewards Part-2, (Biotechnology: Pharmaceutical Aspects), "Prodrugs of Alcohols and Phenols" by SSDhareshwar and VJ Stella, eds. VJ Stella, et al., Springer and AAPS Press, 2007, pp. 31-99.

[0209] The term "amino protecting group" as used herein refers to a labile chemical moiety, which is known in the art to protect amino groups from undesired reactions during synthetic procedures. After said synthetic procedures, the amino protecting groups described herein can be selectively removed. Amino protecting groups known in the art are generally described in TH Greene and PGM Huts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, New York (1999). Examples of amino protecting groups include, but are not limited to, methoxycarbonyl, t-butoxycarbonyl, 9-fluorenyl-methoxycarbonyl, benzyloxycarbonyl, and the like.

[0210] The term "protected amino" as used herein refers to an amino group protected with an amino-protecting group as defined above.

[0211] The term "leaving group" means a functional group or atom that can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction. By way of example, representative leaving groups include chloro, bromo, and iodo groups; sulfonate ester groups, such as mesylate, tosylate, brosylate, nosylate; and acyloxy groups, such as acetoxy, trifluoroacetoxy, and the like.

[0212] The term "aprotic solvent" as used herein 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, halogenated hydrocarbons such as methylene chloride, ethylene chloride, chloroform, heterocyclic compounds such as tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether. Such compounds are well known to those skilled in the art, and it will be clear to those skilled in the art that individual solvents or mixtures thereof may be preferred for certain compounds and reaction conditions, depending on factors such as, for example, 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 specialized monographs, such as Organic Solvents Physical Properties and Methods of Purification, 4th Edition (edited by John A. Riddick et al.), Vol. II in Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.

[0213] The term "protic solvent" as used herein refers to a solvent that tends to provide a proton, such as an alcohol, e.g., methanol, ethanol, propanol, isopropanol, butanol, t-butanol, etc. Such solvents are well known to those skilled in the art, and it will be apparent to those skilled in the art that individual solvents or mixtures thereof may be preferred for certain compounds and reaction conditions, depending on factors such as, for example, the solubility of the reagents, the reactivity of the reagents, and the preferred temperature range. Further discussion of protogenic solvents can be found in organic chemistry textbooks or specialized monographs, such as Organic Solvents Physical Properties and Methods of Purification, 4th Edition (ed. John A. Riddick et al.), Vol. II, in Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.

[0214] 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 a compound that has sufficient stability to permit its manufacture and maintains its integrity for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

[0215] The synthesized compounds can be separated from the reaction mixture and further purified by methods such as column chromatography, high pressure liquid chromatography, or recrystallization. As can be appreciated by those skilled in the art, additional methods of synthesizing the compounds of the formulas herein will be apparent to those skilled in the art. Additionally, various synthetic steps can be performed in an alternative order or sequence to obtain the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, 2nd Edition Wiley-VCH (1999); T. W. Greene and P. G. Muts, 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, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and successive editions thereof.

[0216] The compounds described herein contain one or more asymmetric centers and therefore give rise to enantiomers, diastereomers, and other stereoisomers, which may be defined in terms of absolute stereochemistry as (R)- or (S)-, or for amino acids as (D)- or (L)-. The present invention is meant 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 procedures described above, or by resolving the racemic mixture. 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 regarding resolution may be found in Jacques, et al., Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). When the compounds described herein contain olefinic double bonds, other unsaturation, or other centers of geometrical asymmetry, it is intended that the compounds include both E and Z geometric isomers or cis and trans isomers, unless otherwise specified. Likewise, all tautomeric forms are intended to be included. Tautomers may be cyclic or acyclic. Any carbon-carbon double bond configurations appearing herein are merely selected for convenience and are not intended to designate a particular configuration unless otherwise stated in the text. Thus, any carbon-carbon double bond or carbon-heteroatom double bond shown herein as trans may be cis, trans, or a mixture of the two in any ratio.

[0217] Certain compounds of the present invention may also exist in different stable conformational forms that may be separable. Torsional asymmetry due to restricted rotation around a chiral single bond, for example due to steric hindrance or ring strain, may allow the separation of different conformers. The present invention includes each conformational isomer of these compounds and mixtures thereof.

[0218] The term "pharmaceutically acceptable salts" as used herein refers to salts that are suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., within the scope of sound medical judgment, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. have described pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19 (1977). Salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or separately by reacting the free base function with a suitable organic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts that are salts of amino groups formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or 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 pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane-propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobiotin, and the like. Representative salts include, but are not limited to, phosphate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, picrate, 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, and the like.Further pharma- ceutically acceptable salts include, where appropriate, 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 arylsulfonates.

[0219] The term "pharmaceutical acceptable ester" as used herein refers to esters that hydrolyze in vivo, including those that decompose readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, each alkyl or alkenyl moiety advantageously having 6 or fewer carbon atoms. Examples of specific esters include, but are not limited to, esters of C1-C6-alkanoic acids, such as acetate, propionate, butyrate and pivalate esters.

[0220] Abbreviation Abbreviations that may be used in the description of the following schemes and examples are as follows: DMAP: Dimethylaminopyridine DMF: Dimethylformamide DCM: dichloromethane AcOH: acetic acid EtOAc or EA: Ethyl acetate Cbz: benzyloxycarbonyl HCl: Hydrogen chloride HBr: Hydrogen bromide NaHCO3: Sodium bicarbonate HPLC: High Pressure Liquid Chromatography MeOH: Methanol MTBE: tert-butyl methyl ether EtOH: Ethanol Fmoc: fluorenylmethoxycarbonyl Troc: 2,2,2-trichloroethoxycarbonyl Moz: p-Methoxybenzyloxycarbonyl Pnz: p-nitrobenzyloxycarbonyl Teoc: 2-(trimethylsilyl)ethoxycarbonyl NMM: N-methylmorpholine HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate N-Bromosuccinimide (NBS) Rp: hydroxyl protecting group TEA: Triethylamine THF: tetrahydrofuran 2-Me THF: 2-methyltetrahydrofuran TFAA: Trifluoroacetic anhydride TsOH: p-toluenesulfonic acid TPP or PPh3: Triphenylphosphine T3P: n-propanephosphonic anhydride Boc: t-butoxycarbonyl Bz: Benzyl Ph: Phenyl PhMe: Toluene

[0221] All other abbreviations used herein not specifically defined above are intended to accord the meaning ascribed to them by one of ordinary skill in the art.

[0222] Synthesis scheme The present invention will be better understood in conjunction with Schemes 1, 2, and 3, in which R1, R2, and R3 are as defined above unless otherwise indicated. It will be readily apparent to one skilled in the art that the process of the present invention can be carried out by appropriate substitution of reactants, and the order of the steps themselves can be varied.

[0223] The chemical route for the synthesis of amide HCl salt (f-1) is summarized in Scheme 1. Commercially available compound (a) can be reacted with formaldehyde to undergo the Pictet-Spengler reaction to form 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 undergo configuration, which can generate spirooxindole compound (d-1) and compound (d-2) as a mixture of diastereomers, which were converted to the corresponding amide compound (e-1) and compound (e-2) via aminolysis. A mixture of compounds (e-1) and (e-2) was treated with HCl to cleave the Boc group, followed by recrystallization in DMF to generate the key intermediate compound (f-1) as a highly pure DMF solvate. [ka]

[0224] The chemical route to the synthesis of 2-indole carboxylate compound (j) is summarized in Scheme 2. Commercially available compound (ga) can be reduced and then oxidized to obtain compound (g). Compound (g) undergoes a condensation reaction with 2-azidoethyl acetate in the presence of a base and a sacrificial electrophile (i.e., ethyl trifluoroacetate) to form acrylate compound (h). Compound (h) is then subjected to Hemetsberger indole cyclization using a continuous flow chemical process to obtain compound (i) as a 2-indole carboxylate. Saponification of compound (i) leads to key intermediate compound (j) as a 2-indole carboxylic acid. [ka]

[0225] An alternative chemical route to the synthesis of 2-indole carboxylate compound (j) is summarized in Scheme 2a. Commercially available compound (ga) can be reduced to alcohol (gb), which can be oxidized to obtain compound (g). Compound (g) reacts with sodium bisulfite to form its sodium bisulfite salt (gc). After treatment with a base (i.e., sodium carbonate), sodium bisulfite (gc) liberates compound (g), which undergoes a condensation reaction with ethyl 2-azidoacetate in the presence of a base and a sacrificial electrophile (i.e., ethyl trifluoroacetate) to form acrylate compound (h). Compound (h) is then subjected to Hemetsberger indole cyclization using a continuous flow chemical process to obtain compound (i) as a 2-indole carboxylate. Saponification of compound (i) leads to the key intermediate compound (j) as a 2-indole carboxylic acid. [ka]

[0226] The chemical route to the synthesis of 2-indole carboxylate compound (I) is summarized in Scheme 3. Compound (f-1) can be reacted with commercially available compound (k) under amide coupling conditions to give compound (l). A suspension of compound (l) and Pd / C catalyst in methanol can be stirred under hydrogen atmosphere to give secondary amine compound (m-1) by Cbz deprotection reaction. Alternatively, a suspension of compound (l) and Pd / C catalyst in methanol can be stirred under hydrogen atmosphere in the presence of acid to give compound (m-2) as an acid salt. Alternatively, compound (l) can be treated with strong acid (such as HBr in HOAc) to give secondary amine compound (m-3) by Cbz deprotection reaction as an acid salt. A mixture of compound (m-1), compound (j), coupling reagent (i.e., HATU) and base (i.e., NMM) in DMF can be stirred to complete the coupling reaction to give compound (n). Similar reaction conditions can be applied to compound (m-2) or (m-3) to obtain compound (n). Compound (n) can undergo a dehydration reaction to convert the amide to a nitrile, which can be further purified by toluene crystallization to obtain compound (o) as a toluene solate. The isolated toluene solvate solid is dissolved in EtOH and added to water to form a suspension. The amorphous solid product is filtered and Washing with water and drying gave compound (I) as an amorphous solid. [ka]

[0227] The compounds and methods of the present invention will be understood with reference to the following exemplary methods by which the compounds of the present invention can be prepared. It will be understood that any of the reactions described herein can be combined with one or more of the other reactions, in any of their variations, which are substantially similar to Scheme 1 above. EXAMPLES

[0228] The compounds and methods of the present invention will be better understood in connection with the following examples, which are intended as illustrative only and not limiting the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art, and such changes and modifications, including but not limited to those relating to the chemical structures, substituents, derivatives, formulations and / or methods of the invention, can be made without departing from the spirit of the invention and the scope of the appended claims.

[0229] Example 1. Preparation of methyl ester (b) [ka] To a stirred solution of compound a (70.0 kg, 274.8 mol, 1.0 equiv.) in MeOH (700 L) was added 37 wt. % aqueous formaldehyde (24.6 kg, 302.3 mol, 1.1 equiv.) dropwise 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 approximately 60 kg, and a white solid precipitated. MTBE (840 L) was added, and the resulting white suspension was stirred at 20° C. for 2 h. The mixture was filtered, and the filter cake was washed with MTBE (70 L) and dried in vacuo to give compound b as the methyl ester (71.0 kg, 100.0% purity, 98.9% assay, 95.7% yield).

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[0230] Example 2. Preparation of Boc amine (c) [ka] To a stirred suspension of compound b (70.0 kg, assay: 98.9%, 259.6 mol, 1.0 equiv) in 2-Me THF (643.8 kg) was added TEA (54.2 kg, 535.6 mol, 2.06 equiv) at 5 °C and HO (156.8 kg) was added. 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 warmed 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 further extracted with 2-Me THF (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 2-methyltetrahydrofuran solution containing compound c (690.2 kg), which was used in the next step without further purification.

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[0231] Example 3. Preparation of compound (d-1) and compound (d-2) as a diastereomeric mixture [ka] To a solution of compound (c) in 2-Me THF (688.5 kg, 259.6 mol, 1.0 equiv.) was added HO (220.6 kg) and THF (312.3 kg) at 0° C., and AcOH (113.0 kg, 1881.7 mol, 7.2 equiv.) was added at 0° C. The cloudy mixture was cooled to −30° C. and became a milky solution. NBS (46.9 kg, 263.5 mol, 1.0 equiv.) was added in 10 portions at 20 min intervals at −30° C. The milky mixture became a yellow cloudy solution and was stirred at −30° C. for 30 min. HPLC showed that compound 3 was completely consumed. The cloudy yellow solution was warmed to −10° C. and poured into a stirring 15 wt % aqueous KCO solution (1156.5 kg). The mixture was separated, and the aqueous layer was further extracted with DCM (370.6 kg). The combined organic layers were washed with 15 wt% K2CO3 aqueous solution (289.4 kg) and 10 wt% NaCl aqueous solution (286.4 kg x 3), and concentrated in vacuum to 1 / 4 volume. DCM, THF and 2-Me THF were removed by azeotropic distillation with MeOH (221.5 kg x 3) to obtain a solution of compound (d-1) and compound (d-2) in MeOH (174.1 kg), which was used directly in the next step.

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[0232] Example 4. Preparation of compound (e-1) and compound (e-2) as a diastereomeric mixture [ka] To a solution of compound (d-1) and compound (d-2) in MeOH (174.2 kg, 259.6 mol, 1.0 equiv.), 7N NH3 in MeOH (568.1 kg, 20 equiv.) was added at 25°C, and the reaction mixture was stirred in an autoclave at 50-55°C for 5 days. The mixture was cooled and concentrated in vacuum to half the volume. DMF (172.4 kg) and PhMe (93.5 kg) were added, and the mixture was concentrated in vacuum to give a dark brown solution of compound (e-1) and compound (e-2) in DMF and toluene (222.1 kg), which was used in the next step without further purification.

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[0233] Example 5. Preparation of compound (f-1) [ka] To DCM (2288.5 kg) was added EA containing 4M HCl (440.8 kg) at 25° C., and a DMF solution containing compounds (e-1) and (e-2), PhMe (222.1 kg, 259.6 mol) and acetonitrile (135.5 kg) was added at 25° C. The reaction mixture was stirred at 25±5° C. for 2 days. HPLC showed the reaction was complete. The mixture was filtered, and the filter cake was washed with DCM (357.5 kg) and dried in vacuum to obtain crude product (72.1 kg). The crude product was added to hot DMF (205.0 kg) at 55° C., and the mixture was stirred at 55° C. for 3 hours. The mixture was then cooled to 10±5° C. within 6 hours and then stirred for 2 hours. The mixture was filtered, and the filter cake was washed with DMF (67.8 kg) and DCM (228.9 kg), and dried in vacuum at 30° C. to give compound (f-1) (40.0 kg, 99.5% purity, 76.3% assay, 43.9% yield over four steps) as a yellowish solid.

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[0234] Example 6. Preparation of compound (gb) [ka] Charge compound (ga) (340.0 kg, 1.0 equiv.) and THF (1513.0 L, 5 V) into reactor 1 (R1). Cool reactor 1 to 0-10 °C. Add NaBH4 (87.7 kg, 1.2 equiv.) to R1 at 0-10 °C and stir at 0-10 °C for 1-2 h. Add BF3-THF (324.0 kg, 1.2 equiv.) dropwise to R1 at 0-10 °C (0-5 °C recommended) and stir at 0-10 °C for 0.5-1 h. Warm R1 to 15-25 °C and stir for 2-3 h. Sample for IPC (HPLC) (quenched with saturated aqueous NH4Cl, EP-038282-A ≦2.0%). Water (1500 L, 4.4 V) and NH4Cl (550.8 kg) were charged into reactor 2 (R2) to prepare an aqueous NH4Cl solution. The reaction mixture in R1 was slowly added to the aqueous NH4Cl solution in R2 at 20-30 °C, and R2 was stirred at 20-30 °C for 2-3 h. After separation, the organic phase was collected in R2 and the aqueous phase was converted and placed in R1. R2 was concentrated until no obvious distillate was present below 50 °C. MTBE (1360 L, 4 V) was added to R1, and R1 was stirred for 0.5 h. After separation, the organic phase was collected and transferred to R2. MTBE (1360 L, 4 V) was added to R1, and MTBE was transferred to R2. The slurry in R2 was stirred at 20-30 °C for 10-20 min. After filtration, the cake was washed with MTBE (340 L, 1 V). All the filtrate in R1 was collected and the crude compound (gb) was used directly in the next step.

[0235] Example 7. Preparation of compound (g) [ka] NaHCO3 (324.4 kg, 2.0 equiv.) and TEMPO (1.5 kg, 0.005 equiv.) to a solution of compound (gb) from the previous step (Example 6) in R1. Cool R1 to -5-5°C (0°C recommended) and add 10% aqueous NaClO dropwise to R1 at -5-5°C (0°C recommended). Stir R1 at -5-5°C (0°C recommended) for 2-3 hours. Sample for IPC (HPLC) (top organic phase, detect compound (gb) ≤ 2.0%). If compound (gb) > 2.0%, add 10% aqueous NaClO until IPC result is qualified. Add Na2SO3 (10.2 kg) and water (23.8 kg) to reactor 2 (R2) to make 30% aqueous Na2SO3. After the reaction in R1 was quenched with 30% Na2SO3 aqueous solution in R2 (detected by KI-starch test paper), the slurry was filtered. After filtration, the cake was washed with MTBE (340 L, 1 V) and all the filtrate was collected in R2. Anhydrous MgSO4 (39.1 kg) was added to R2 and stirred at 20-30 °C for 20-30 min. After filtration, the cake was washed with MTBE (340 L, 1 V) and all the filtrate was collected in R1. The MBTE solution containing aldehyde (g) can be used in experiment 20. Alternatively, R1 was concentrated below 30 °C until no obvious distillate was obtained to obtain crude compound (g) as an orange oil, which was transferred to distillation reactor R3. R3 was distilled under reduced pressure of 0.085 MPa or less at <30°C until no obvious distillate was produced, then distilled under reduced pressure of 0.090 MPa or more at 60-100°C (70-80°C recommended) to recover the distillate. Purified compound (g) (273.6 kg, 88% yield) was obtained as a colorless to orange oil.

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[0236] Example 8. Preparation of compounds (h-1) and (h-2) as acrylates [ka] The reactor was charged with compound (g) (100 kg, neat, 1.0 equiv., prepared using the procedure in run 7, or compound (g), 100 kg in MeOH solution, prepared using the procedure in run 21, CF3CO2Et (133.1 kg, 1.5 equiv.) and MeOH (150 L, 1.5 V). The reactor was cooled to -5 to 5 °C (-5 to 0 °C recommended) and ethyl azide acetate (96.8 kg, 1.2 equiv.) was added at -5 to 5 °C (0 °C recommended). MeONa (56.2 kg, 0.5 equiv., 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, after which Me ONa (56.2 kg, 0.5 equiv., 30 wt.% in MeOH) was added dropwise to the reactor at -5-0°C. The mixture was stirred at -5-5°C for 2-3 h, then MeONa (56.2 kg, 0.5 equiv., 30 wt.% in MeOH) was added dropwise at -5-0°C. The reaction mixture was stirred at -5-5°C for 2-3 h, then at 0-10°C (5°C recommended) for 8-14 h. The reaction mixture was slowly added to 2.5 wt.% NH4Cl (aq) in R2 at 0-10°C. After filtration, the cake was collected and washed with water (600 L, 3Vx2). The crude compounds (h-1) and (h-2) were used directly in the next step without further purification.

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[0237] Example 9. Preparation of methyl / ethyl indole-2-carboxylates (i-1) / (i-2) [ka]

[0238] Solution A: Xylene (20V) was charged into reactor R1. R1 was adjusted to 5°C (0-10°C). A wet cake of a mixture of compounds (h-1) and (h-2) was charged into R1. After stirring at 5°C (0-10°C) for 1 hour (0.5-1.5 hours), process water (5V) was charged into R1 at 5°C (0-10°C). The mixture was stirred at 5°C (0-10°C) for 20 minutes (10-30 minutes), and then allowed to stand at 5°C (0-10°C) for 20 minutes (10-30 minutes) to perform phase separation.

[0239] The bottom aqueous layer was removed. The top organic layer was filtered and used as solution A.

[0240] Solution B: and MeOH (5V) was used as solution B.

[0241] The flow procedure (10 L facility) is shown diagrammatically in Figure 1 and described below.

[0242] The above solution A was transferred in batches to FLV1 (1, flowing liquid tank 1) through a filter. Fresh methanol (solution B) was transferred to FLV2 (4, flowing liquid 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 tube (FLR2) was placed in a water / EG bath (7) and the post-heating tube (FLR2) was controlled at 50-60 °C by a temperature control unit (target 55 °C). The pressure value of the back pressure valve (8) was set to 1.8-2.0 MPa. The flow rates of pump 1 (2) and pump 2 (5) were set based on a residence time of 25 minutes. Then, solution A in FLV1 was continuously transferred to FLR1 by pump 1 through valve (6), MeOH 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), respectively.

[0243] Samples were taken for IPC (HPLC, every 2-6 hours). After the flow process was finished, the combined reaction mixture was charged into the reactor and concentrated until no obvious distillate was observed below 70 °C (the distillate was collected for recycling). Xylene (4.3 kg, 5 V) was added to the reactor and concentrated until no obvious distillate was observed below 70 °C (the distillate was collected for recycling). Xylene (2.6 kg, 3 V) was added to R1, and then the reaction mixture was cooled to -5-5 °C (0-5 °C is recommended) and stirred at -5-5 °C for 2-5 hours. After centrifugation, the crude cake was washed with xylene (0.43 kg, 0.5 V), and the resulting crude mixture of compound (i-1) and compound (i-2) (a mixture of methyl esters and ethyl esters, the ratio is about 9 / 1) was used directly in the next step without further purification. NMR:

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[0244] Example 10. Preparation of indole-2-carboxylic acid compound (j) [ka] NaOH (22 kg, 2.5 equiv.) and H2O (100 kg, 10 V) were charged into reactor R1 to make aqueous NaOH solution. A crude mixture of i-1 / i-2 (50 kg, 1.0 equiv.) and MTBE (18.5 kg, 0.5 V) was charged into reactor R1. R1 was heated to 55-65 °C and stirred at such temperature for 3-6 h. After completion of the reaction, R1 was cooled to 0-10 °C. Aqueous HCl solution (36%, 72 kg) and H2O (43 kg) were charged into R2 to make 2N aqueous HCl solution. 2N aqueous HCl solution was slowly added from R2 to R1 until the pH of the solution in R1 was less than 3. R1 was stirred at 15-25 °C for 0.5-1.0 h. The slurry was filtered and the cake was washed with H2O (10 kg). The cake was dried in vacuum at 60-70° C. to give compound J as an off-white solid.

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[0245] Example 11. Preparation of compound (l) [ka] Under nitrogen atmosphere, DMF (480 kg, 5V) was added to the reactor followed by compound (f-1, net weight 100 kg, 1.0 eq) and compound (k) (110 kg, 1.1 eq) at approximately 20°C. The reactor was cooled to 0±5°C. NMM (113 kg, 3.0 eq) was added dropwise to the reaction at 0±5°C over 30 minutes. T3P in DMF (1.5 eq) was added dropwise to the reaction at 0±5°C over 1 hour. The solution was stirred for at least 4 hours and the progress of the reaction was monitored by HPLC. Upon completion, the reaction mixture was added dropwise to 2% NaHCO3 aqueous solution (25.0v) at 20±5°C. It was then stirred for at least 2 hours. The mixture was filtered and the cake was washed with water. The filter cake was slurried with process water (2000 kg, 20 V) at 20° C. for 3 h, then filtered and washed with water. The cake was dried at 60±5° C. to give the compound (l) product as an off-white solid in 90-93% yield.

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[0246] Example 12. Preparation of compound (m-1) as the free N-methylamine [ka] MeOH was charged to reactor R1 under N2 (395.0 kg, 5 V) followed by compound (l) (100 kg, 1.0 equiv). The reaction mixture was stirred at 20°C (15-25°C) for 30 min, after which palladium on activated carbon (10 kg) was added to R1. R1 was rinsed with MeOH (79.0 kg, 1 V) under N2 and cooled to 0°C (-5-5°C). The reaction mixture was stirred under H2 (1-5 atm) at 0°C (-5-5°C) for 8 h (5-12 h). Once the reaction was complete, the mixture was filtered through Celite (50.0 kg) and the filtrate was transferred to reactor R2 at -5-5°C. The filter cake was washed with MeOH (1V X 2) and the filtrates were combined. The solution in reactor R2 was concentrated under vacuum below 12 °C to 2-3 V and cold THF (890.0 kg, 10 V) was added to reactor R2 at 0-10 °C. The mixture was concentrated under vacuum below 12 °C to 3-4 V in reactor R2. When precipitation was observed, cold THF (178 kg, 2 V) was added to reactor R2 at -5-5 °C and then n-heptane (683.0 g, 10 V) was added dropwise to reactor R2 over 1 h (1-2 h).

[0247] The mixture in reactor R2 was stirred at 0°C (-5~5°C) for 2 hours (1~2 hours) and filtered. The cake was rinsed with n-heptane (136.6 kg, 2V) and the wet cake was dried at 60°C (55~65°C) for 72 hours to obtain compound (m-1) as a white solid in 80~85% yield.

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[0248] Example 13. Preparation of compound (m-2) [ka] DMF was charged (39.5 kg, 5 V) under N2 into reactor R1, followed by compound (l) (10 kg, 1.0 equiv.) and TsOH (1.0-1.1 equiv.). The reaction mixture was stirred at 20°C (15-25°C) for 30 min, after which palladium on activated carbon (1 kg) was added to reactor R1. Reactor R1 was rinsed with DMF (7.9 kg, 1 V) under N2 and cooled to 0°C (-5-5°C). The reaction mixture was stirred under H2 (1-5 atm) at 0°C (-5-5°C) for 8 h (5-12 h). Once the reaction was complete, the mixture was filtered through Celite (5 kg) and the filtrate (m-2) could be sent to the next step without purification.

[0249] Example 14. Preparation of compound (m-3) [ka] AcOH (10 L, 2.0 V) was charged to the reactor at 25 °C, followed by compound (l) (5 kg, 1.0 equiv). AcOH with HBr (7.5 L, 1.5 V, 5.0 equiv) 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 cake was rinsed with MTBE (10 L, 2 V), and the cake was reslurried three times with acetone / DCM (1:10, 100 L, 20 V) at 25 °C. The material was filtered, rinsed with DCM (10 L, 2V) and the cake was dried at 40±5° C. to give the product compound (m-3) as an off-white solid in about 90% yield.

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[0250] 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)) [ka] 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 equiv.) and N-methylmorpholine (56 kg, 2 equiv.), HATU (106 kg, 1.0 equiv.) and compound (m-1) (100 kg, 1.0 equiv.). The reactor was rinsed with DMF (190 kg, 2 V), warmed to 25 °C (20 to 30 °C), and stirred at 25 °C (20 to 30 °C) for 5 h (3 to 6 h). Then, additional HATU (0.1 equiv.) was added and the reaction mixture was stirred for 16 to 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). The reaction mixture was then added to water (5000 kg, 50 V) over 2 h at 20-30 °C and the resulting slurry was stirred at 25 °C (20-30 °C) for 2 h (1-5 h). The mixture was filtered and the cake was rinsed with water (500 kg, 5 V). The cake was dissolved in ethyl acetate (1350 kg, 15 V) and washed three times with 10% sodium chloride solution (500 kg). The organic layer was separated under vacuum at 45 °C or below to 1.5-2.5 V. The solution was cooled to 25 °C (20-30 °C) and dichloromethane (660 kg, 5 V) was added. The mixture was stirred at 25 °C (20-30 °C) for 2 h (2-5 h) to form a slurry. n-Heptane (137 kg, 2V) was added dropwise over 0.5 h (0.5-2 h) at 25°C (20-30°C) and stirred for an additional 2 h (1-3 h) at 25°C (20-30°C). 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 give compound (n) as a white solid in 80-85% yield.

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[0251] 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)) [ka] A DMF solution of compound (m-2) (1 kg, 1.0 equiv.) was added to the reactor at approximately 0-10 °C. Compound (l) (600 g, 1.0 equiv.), NMM (3.00 equiv. 850 g) and HATU (1.00 equiv., 1.06 kg) were added to the reactor while maintaining the temperature at 0-10 °C. The reactor was warmed to 20 ± 5 °C and stirred at 20 ± 5 °C for at least 6 hours. HATU (0.20 equiv., 210 g) was added to the reactor at 20 ± 5 °C and stirred at 20 ± 5 °C for at least 6 hours. 25% ammonium hydroxide (390 g, 1.0 equiv.) was added to the reaction mixture at 20 °C and stirred at 20 °C for 2 hours (1-3 hours). EtOAc (14.0V) and water (14V) were added over 20 min at approximately 25°C and the solution was stirred for at least 30 min. The aqueous phase was extracted 3 times with EtOAc and the organic phases were combined and washed 3 times with 10% aqueous NaCl at 20±5°C. The organic phase was concentrated to 6V and then charged with EtOH (7.0V). The EtOAc-EtOH solvent exchange was repeated 3 times and concentrated to 5V, after which water (7.0v) was added at 20±5°C. The mixture was cooled to 0-10°C, stirred for 1 h and then filtered. The filter cake was dissolved in ethyl acetate (15V) and washed 3 times with 10% sodium chloride solution. The organic layer was concentrated in vacuo to 2-3V at up to 45°C. 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 2 hours (2-5 hours) to form a slurry. n-Heptane (2V) was added dropwise over 0.5 hours (0.5-2 hours) at 25°C (20-30°C) and stirred for another 2 hours (1-3 hours) at 25°C (20-30°C). 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 hours (15-25 hours) to give compound (n) as a white solid in about 70-75% yield over two steps.

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[0252] 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)) [ka] DMF (10.0v) was added to the reactor at 25°C, followed by compound (l) (4.4kg, 1.0eq), NMM (3.0eq), compound (m-3) (1.0eq) and HATU (1.0eq) at 20-25°C. The reaction mixture was stirred at 20-25°C for at least 12 hours. Once the reaction was complete, aqueous ammonium hydroxide (1.0eq) was charged to the reaction system at 20-25°C, followed by stirring at 20-25°C for at least 2 hours. The reaction mixture was then added to water (220kg, 50v) at 20-30°C over 2 hours, and the resulting slurry was stirred at 25°C (20-30°C) for 2 hours (1-5 hours). The mixture was filtered and the cake was rinsed with water (22kg, 5v). The cake was dissolved in ethyl acetate (135 g, 15 V) and washed three times with 10% sodium chloride solution (22 kg). The organic layer was separated under vacuum below 45 °C to 1.5-2.5 V. The solution was cooled to 25 °C (20-30 °C) and dichloromethane (5 V) was added. The mixture was stirred at 25 °C (20-30 °C) for 2 h (2-5 h) to form a slurry. n-Heptane (2 V) was added dropwise over 0.5 h (0.5-2 h) at 25 °C (20-30 °C) and stirred for an additional 2 h (1-3 h) at 25 °C (20-30 °C). 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 hours (15-25 hours) to give compound (n) as a white solid in 80-85% yield.

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[0253] 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)) [ka] Ethyl acetate (630 kg, 10V) 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 mass was cooled to 0°C (-5 to 5°C) and then triethylamine (89.6 kg) was added followed by trifluoroacetic anhydride (92.4 kg) at 0°C (-5 to 5°C). The reaction mass was stirred at 0°C (-5 to 5°C) for 1 hour (0.5 to 2 hours). Once the reaction was complete, the reaction mixture was slowly added to 0.2N aqueous HCl solution (700 kg) over 1 hour at 0°C (-5 to 5°C). The resulting solution was stirred at 0°C (-5 to 5°C) for 30 minutes and the organic layer was separated. 1% aqueous ammonium hydroxide solution (700 kg) was added to the organic layer and stirred at 20°C for 30 minutes (15 to 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. A toluene-EtOAc exchange was performed until precipitation was observed at 3-4 V. Toluene (5-6 V) was then added and the slurry was stirred at 50 °C for 2 h. The solution was then cooled to 20 °C over 1-2 h and stirred at 20 °C (15-25 °C) for 10 h (6-14 h). The reaction mixture was filtered and the wet cake was rinsed with toluene (120 kg, 2 V). The wet cake was then dried at 50 °C (45-55 °C) for 48 h to give the desired compound (o) as a white solid in 80-85% yield.

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[0254] 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)) [ka] Toluene solvate compound (I) (60 kg, net weight) and ethanol (10 volumes (V)) were added to the reactor at 20-30 °C. The mixture was stirred at 20-30 °C for 0.5-1 h to obtain a clear solution. The solution was distilled at any temperature (NMT 50 °C) to approximately 5 V and recharged with ethanol (5 V). Distillation was repeated until the residual toluene level was below 0.1% w / w. EtOH solution containing compound (5-6 V) was added to water (15 V) over 1-2 h at 20 °C (15-25 °C) and stirred at 15-25 °C for 1 h (0.5-2 h). The slurry was filtered and the wet cake was rinsed with purified water (2 V). The wet cake was then dried at 50 °C (45-55 °C) for 48-72 h to obtain compound (I) as a white to off-white amorphous solid in 95-97% yield.

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[0255] Powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) analyses were used to physically characterize the amorphous form of Compound (I). The X-ray diffractogram is shown in Figure 2, which indicated that Compound (I) was amorphous. The DSC thermogram is shown in Figure 3, which showed a glass transition with a midpoint at 98.29°C.

[0256] Example 20. Preparation of sodium hydroxy(2,4,5-trifluorophenyl)methanesulfonate (gc) [ka]

[0257] Method A: 2,4,5-trifluorobenzaldehyde (100 g neat, obtained by distillation of run 7) was added to reactor R1, followed by MTBE (500 mL) and EtOH (600 mL). NaHSO3 (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 minutes to form a clear solution. The solution in R1 was heated to 40° C. The solution in R2 was transferred to R1 over 1 hour and the resulting mixture in R1 was stirred at 40° C. for an additional 2 hours. The mixture in R1 was cooled to 20° C. over 1 hour and stirred at 20° C. for an additional 1 hour. The wet cake was filtered and washed with ethanol (80 g). The cake was dried at 50° C. to give compound (gc) as a white solid.

[0258] Method B: 100 g of 2,4,5-trifluorobenzaldehyde in MTBE solution (100 mL), prepared from the procedure of Example 7, was added to reactor R1, followed by MTBE (400 mL) and EtOH (600 mL). NaHSO3 (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 minutes to form a clear solution. The solution in R1 was heated to 40° C. The solution in R2 was transferred to R1 over 1 hour, and the resulting mixture in R1 was stirred at 40° C. for an additional 2 hours. The mixture in R1 was cooled to 20° C. over 1 hour and stirred at 20° C. for an additional 1 hour. 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.

[0259] Example 21. Preparation of compound g from sodium hydroxy(2,4,5-trifluorophenyl)methanesulfonate (gc) [ka] Compound gc (100 g) and methyl tert-butyl ether (MTBE, 400 mL) were added to reactor R1, followed by water (500 mL) and sodium carbonate (48 g). The mixture in R1 was stirred at 25° C. for 2 hours to form a two-phase solution. The upper layer (organic layer) was separated and the lower 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 in the following two ways to obtain compound (g).

[0260] Method A: The organic layer was concentrated to no obvious distillate below 30°C. Crude compound (g) was obtained as an orange oil and transferred to distillation reactor R3. R3 was distilled under vacuum ≤ 0.085MPa until no obvious distillate below 30°C, then R3 was distilled at 60-100°C (recommended 70-80°C) under vacuum ≥ 0.090MPa and the distillate was collected. Purified compound (g) was obtained as a colorless to orange oil (same procedure as in Example 7).

[0261] Method B: Methanol was added to the organic layer. After solvent exchange from MTBE to methanol, the methanol solution containing compound (g) can be used in a subsequent condensation reaction to form compound (h). See Experiment 8.

[0262] While the present 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 therein without departing from the scope of the invention as encompassed by the appended claims.

Claims

1. Compound of formula (A) 【Chemistry 1】 (In the formula, R １ is selected from the group consisting of hydrogen, Cl, F, optionally substituted methyl, and optionally substituted methoxy; R ２ is hydrogen, optionally substituted -C １ ~C ６ Alkyl and optionally substituted -C １ ~C ６ alkylaryl) A method for producing The method further comprising: a) reacting a compound of formula (W) with formaldehyde to produce a compound of formula (B); 【Chemistry 2】 (In the formula, G １ is methyl, ethyl or phenyl); b) converting said compound of formula (B) to a compound of formula (C); 【Chemistry 3】 c) subjecting the compound of formula (C) to a rearrangement to produce a compound of formula (D-1); 【Chemistry 4】 d) converting the compound of formula (D-1) into compound (e-1); 【Chemistry 5】 e) converting said compound (e-1) into a compound of formula (F-1); 【Chemistry 6】 (Wherein, X is Cl － , B － and C.F. ３ CO ２ － an anion selected from the group consisting of f) Reacting the compound of formula (F-1) with a compound of formula (K) 【Chemistry 7】 (In the formula, PG １ is selected from the group consisting of -Boc, -Cbz, -C(O)OMe, -C(O)OEt, -Fmoc, -Troc, -Moz, -Pnz and -Teoc. to produce a compound of formula (L); 【Chemistry 8】 g) converting said compound of formula (L) into a compound of formula (M) or a salt thereof, optionally in the presence of a suitable acid; 【Chemistry 9】 Alternatively, converting a compound of formula (L) into a salt form of a compound of formula (M) using a suitable acid; (J-1) reducing the compound of formula (Ga) to produce a compound of formula (G-b); 【Chemistry 10】 (J-2) a step of oxidizing the compound of formula (G-b) to produce a compound of formula (G); 【Chemistry 11】 (J-3) reacting the compound of formula (G) with a compound of formula (G-1) in the presence of a base to produce a compound of formula (H); 【Chemistry 12】 (In the formula, R ３ is methyl, ethyl or benzyl); (J-4) converting the compound of formula (H) into a compound of formula (I) via Hemetsberger indole cyclization; 【Chemistry 13】 (J-5) reacting the compound (I) with a base to obtain a compound of formula (J) or a salt thereof; 【Chemistry 14】 h) reacting the compound of formula (M) or a salt thereof with a compound of formula (J) or a salt thereof 【Chemistry 15】 (In the formula, R １ is as defined above), to obtain a compound of formula (N); 【Chemistry 16】 i) converting said compound of formula (N) into said compound of formula (A); 【Chemistry 17】 A method comprising:

2. R １ is F and R ２ The method of claim 1 , wherein is isobutyl.

3. G １ is methyl and X is Cl － And P.G. １ The method of claim 2 , wherein is Cbz.

4. In step (b), the reaction is carried out in the presence of di-tert-butyl dicarbonate (Boc anhydride) as a Boc-protecting reagent and triethylamine as a base; In step (c), the reaction is carried out in the presence of N-bromosuccinimide (NBS), acetic acid at a temperature of about −30° C., and the ratio of diastereomer (d-1) to diastereomer (d-2) is 6:1 to 8:1; In step (d), the reaction is carried out in the presence of ammonia in methanol, and the ratio of diastereomer (e-1) to diastereomer (e-2) is 6:1 to 8:1; In step (e), the reaction is carried out in the presence of hydrogen chloride in ethyl acetate, and the salt form of the compound (f-1) containing 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), PG １ is Cbz, and the reaction is carried out using H ２ in the presence of palladium on carbon as a catalyst, optionally in the presence of p-toluenesulfonic acid; or in step (g), the reaction is carried out in the presence of hydrogen bromide in acetic acid; In the step (J-1), the reducing agent is sodium borohydride and a borane-tetrahydrofuran complex; In step (J-2), the oxidizing agent is sodium hypochlorite containing TEMPO; In step (J-3), R ３ is ethyl, and the reaction is carried out using sodium methoxide or sodium ethoxide as the base and CF as the sacrificial electrophile. ３ CO ２ In the presence of Et, In step (J-4), the reaction is carried out in a flow chemical reactor in a solvent mixture of xylene and methanol, the volume ratio of xylene to methanol is 5:1 when the reaction temperature is about 200° C. and the reaction time is less than about 25 minutes; 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-methylmethanaminium hexafluorophosphate N-oxide (HATU) and N-methylmorpholine; The process according to any one of claims 1 to 3, wherein in step (i), the reaction is carried out in the presence of trifluoroacetic anhydride (TFAA) and triethylamine.

5. Compound of formula (A) 【Chemistry 18】 (In the formula, R １ is selected from the group consisting of hydrogen, Cl, F, optionally substituted methyl, and optionally substituted methoxy; R ２ is hydrogen, optionally substituted -C １ ~C ６ Alkyl and optionally substituted -C １ ~C ６ alkylaryl) A method for producing The method further comprising: a) reacting a compound of formula (W) with formaldehyde to produce a compound of formula (B); 【Chemistry 19】 (In the formula, G １ is methyl, ethyl or phenyl); b) converting said compound of formula (B) to a compound of formula (C); 【Chemistry 20】 c) subjecting the compound of formula (C) to a rearrangement to produce a compound of formula (D-1); 【Chemistry 21】 d) converting the compound of formula (D-1) into compound (e-1); 【Chemical 22】 e) converting said compound (e-1) into a compound of formula (F-1); 【Chemistry 23】 (Wherein, X is Cl － , B － and C.F. ３ CO ２ － an anion selected from the group consisting of f) Reacting the compound of formula (F-1) with a compound of formula (K) 【Chemistry 24】 (In the formula, PG １ is selected from the group consisting of -Boc, -Cbz, -C(O)OMe, -C(O)OEt, -Fmoc, -Troc, -Moz, -Pnz and -Teoc. to produce a compound of formula (L); 【Chemistry 25】 g) converting said compound of formula (L) into a compound of formula (M) or a salt thereof, optionally in the presence of a suitable acid; 【Chemistry 26】 Alternatively, converting a compound of formula (L) into a salt form of a compound of formula (M) using a suitable acid; h) reacting the compound of formula (M) or a salt thereof with a compound of formula (J) or a salt thereof 【Chemical 27】 (In the formula, R １ is as defined above), to obtain a compound of formula (N); 【Chemistry 28】 i) converting said compound of formula (N) into said compound of formula (A); 【Chemical 29】 A method comprising:

6. R １ is F and R ２ The method of claim 5 , wherein is isobutyl.

7. G １ is methyl and X is Cl － And P.G. １ The method of claim 6 , wherein is Cbz.

8. In step (b), the reaction is carried out in the presence of di-tert-butyl dicarbonate (Boc anhydride) as a Boc-protecting reagent and triethylamine as a base; In step (c), the reaction is carried out in the presence of N-bromosuccinimide (NBS), acetic acid at a temperature of about −30° C., and the ratio of diastereomer (d-1) to diastereomer (d-2) is 6:1 to 8:1; In step (d), the reaction is carried out in the presence of ammonia in methanol, and the ratio of diastereomer (e-1) to diastereomer (e-2) is 6:1 to 8:1; In step (e), the reaction is carried out in the presence of hydrogen chloride in ethyl acetate, and the salt form of the compound (f-1) containing 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), PG １ is Cbz, and the reaction is carried out using H ２ in the presence of palladium on carbon as a catalyst, optionally in the presence of p-toluenesulfonic acid; or in step (g), the reaction is carried out in the presence of hydrogen bromide in acetic acid; 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-methylmethanaminium hexafluorophosphate N-oxide (HATU) and N-methylmorpholine; The process according to any one of claims 5 to 7, wherein in step (i), the reaction is carried out in the presence of trifluoroacetic anhydride (TFAA) and triethylamine.

9. Compound of formula (A) 【Chemistry 30】 (In the formula, R １ is selected from the group consisting of hydrogen, Cl, F, optionally substituted methyl, and optionally substituted methoxy; R ２ is hydrogen, optionally substituted -C １ ~C ６ Alkyl and optionally substituted -C １ ~C ６ alkylaryl) A method for preparing The method further comprising: (a) reacting a compound of formula (W) with formaldehyde to produce a compound of formula (B); 【Chemistry 31】 (In the formula, G １ is C １ ~C ６ -alkyl or aryl), (b) converting said compound of formula (B) to a compound of formula (C); 【Chemistry 32】 (c) subjecting the compound of formula (C) to a rearrangement to produce a compound of formula (D-1); 【Chemical 33】 (d) converting the compound of formula (D-1) into compound (e-1); 【Chemical 34】 (e) converting compound (e-1) into a compound of formula (F-1); 【Chemistry 35】 (Wherein, X is Cl － , B － and C.F. ３ CO ２ － an anion selected from (f) Reacting the compound of formula (F-1) with a compound of formula (K) 【Chemical 36】 (In the formula, PG １ is selected from -Boc, -Cbz, -C(O)OMe, -C(O)OEt, -Fmoc, -Troc, -Moz, -Pnz, and -Teoc; R ２ is as defined above) to produce a compound of formula (L); 【Chemical 37】 (g) converting said compound of formula (L) into a compound of formula (M) or a salt thereof, optionally in the presence of a suitable acid; 【Chemical 38】 (h) reacting the compound of formula (M) or a salt thereof with a compound of formula (J) or a salt thereof 【Chemical 39】 (In the formula, R １ is as defined above and is preferably hydrogen or F), to obtain a compound of formula (N); 【Chemistry 40】 (i) converting said compound of formula (N) into said compound of formula (A); A method comprising:

10. R １ is fluorine, R ２ The method of claim 9 , wherein is isobutyl.

11. G １ is methyl and X is Cl － And P.G. １ The method of claim 10, wherein is Cbz.

12. Compound of formula (A) 【Chemistry 41】 (In the formula, R １ is selected from the group consisting of hydrogen, Cl, F, optionally substituted methyl, and optionally substituted methoxy; R ２ is hydrogen, optionally substituted -C １ ~C ６ Alkyl and optionally substituted -C １ ~C ６ alkylaryl) A method for producing The method further comprising: a) reacting a compound of formula (W) with formaldehyde to produce a compound of formula (B); 【Chemistry 42】 (In the formula, G １ is C １ ~C ６ -alkyl or aryl), b) converting said compound of formula (B) to a compound of formula (C); 【Chemistry 43】 c) subjecting the compound of formula (C) to a rearrangement to produce a compound of formula (D-1); 【Chemistry 44】 d) converting the compound of formula (D-1) into compound (e-1); 【Chemistry 45】 e) converting said compound (e-1) into a compound of formula (F-1); 【Chemistry 46】 (Wherein, X is Cl － , B － and C.F. ３ CO ２ － an anion selected from the group consisting of f) Reacting the compound of formula (F-1) with a compound of formula (K) 【Chemistry 47】 (In the formula, PG １ is selected from the group consisting of -Boc, -Cbz, -C(O)OMe, -C(O)OEt, -Fmoc, -Troc, -Moz, -Pnz and -Teoc. to produce a compound of formula (L); 【Chemistry 48】 g) converting said compound of formula (L) into a compound of formula (M) or a salt thereof, optionally in the presence of a suitable acid; 【Chemistry 49】 Alternatively, converting a compound of formula (L) into a salt form of a compound of formula (M) using a suitable acid; (J-1) reducing the compound of formula (Ga) to produce a compound of formula (G-b); 【Chemistry 50】 (J-2) a step of oxidizing the compound of formula (G-b) to produce a compound of formula (G); 【Chemistry 51】 (J-2a) reacting the compound of formula (G) with sodium hydrogen sulfite to produce a compound of formula (G-c); 【Chemistry 52】 (J-2b) reacting the compound of formula (G-c) with a base to produce a compound of formula (G); 【Chemistry 53】 (J-3) reacting the compound of formula (G) with a compound of formula (G-1) in the presence of a base to produce a compound of formula (H); 【Chemical 54】 (In the formula, R ３ is methyl, ethyl or benzyl); (J-4) converting the compound of formula (H) into a compound of formula (I) via Hemetsberger indole cyclization; 【Chemistry 55】 (J-5) reacting the compound (I) with a base to obtain a compound of formula (J) or a salt thereof; 【Chemistry 56】 h) reacting the compound of formula (M) or a salt thereof with a compound of formula (J) or a salt thereof 【Chemistry 57】 (In the formula, R １ is as defined above), to obtain a compound of formula (N); 【Chemistry 58】 i) converting said compound of formula (N) into said compound of formula (A); A method comprising:

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