Methods for preparing PSMA conjugates

Abstract

To provide processes for preparing compounds that are useful in the treatment of disease, such as cancer, in mammals.SOLUTION: The present invention provides processes for preparing compounds of formula I capable of targeting PSMA-expressing cells and useful in the treatment of diseases caused by PSMA-expressing cells, such as prostate cancer.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. Provisional Patent Application No. 62 / 850,119, filed May 20, 2019. No. 62 / 910,777, filed October 4, 2019; and Benefit of U.S. Provisional Patent Application No. 62 / 912,353, filed October 8, 2019; Priority is claimed, the entire disclosure of which is incorporated herein by reference.

[0002] The present disclosure relates to methods for preparing compounds useful for treating diseases such as cancer in mammals. In particular, the invention described herein is capable of targeting PSMA-expressing cells. and to develop compounds useful for treating diseases caused by PSMA-expressing cells, such as prostate cancer. It also relates to a method for preparation. [Background technology]

[0003] The prostate is a male reproductive organ that provides nutrients to the sperm that are introduced into the vagina during reproduction. The prostate gland functions to produce and store semen, providing fluid for the ejaculation and secretion of sperm. may develop either malignant (cancerous) or benign (non-cancerous) tumors. Prostate cancer is one of the most common cancers in men in the Western world and the second most common among American men. The current treatment methods for prostate cancer include hormone therapy, radiation therapy, and These include chemotherapy, surgery, photodynamic therapy, and combination therapy. Many of these treatments impact the quality of life of men diagnosed with prostate cancer, especially those over the age of 50. For example, the use of hormone drugs often comes with side effects such as osteoporosis and liver damage. Such side effects may be more selective or specific to the tissue causing the pathology. and can be mitigated by the use of treatments that avoid non-target tissues such as bone or liver.

[0004] Prostate-specific membrane antigen (PSMA) is a biomarker that is overexpressed in prostate cancer. PSMA has a significantly lower incidence of malignant prostate cancer compared to other organs in the human body, such as the kidney, proximal small intestine, and salivary glands. It is overexpressed in glandular tissues. PSMA is a cancer inhibitor that inhibits the proliferation and proliferation of lung, colon, breast, kidney, liver and pancreatic cancers. It is also expressed in neovasculature in many non-prostate solid tumors, including prostate cancer, but not in normal vasculature. PSMA is also minimally expressed in the brain. 18), a transmembrane domain (amino acids 19–43), and an extensive extracellular domain (amino acids 44-750), a type II cell surface membrane-associated glycoprotein with a molecular weight of approximately 110 kD. The functions of the intracellular segment and the transmembrane domain are not currently considered important. It is believed that the extracellular domain is involved in several different activities. SMA plays a role in the central nervous system, where PSMA acts as a stimulator of N-acetylglucosamine (NAc), a stimulator of acetylcholine (AS), and acetylcholine (AS). Metabolizes N-acetylglutamic acid (NAAG) to glutamic acid and N-acetylaspartic acid. PSMA also plays a role in the proximal small intestine, where it is involved in the synthesis of poly-γ-glutamine. Removes gamma-linked glutamate from acid folates and alpha-linked glutamate from peptides and small molecules However, the specific function of PSMA in prostate cancer cells remains unclear. .

[0005] Unlike many other membrane-bound proteins, PSMA does not bind to cells like vitamin receptors. It is rapidly internalized into cells in a manner similar to that of surface-bound receptors. They are internalized through coated pits and then recycled to the cell surface or transported to lysosomes. Thus, diagnostic, imaging, and therapeutic agents can be directed to PSMA-expressing cells, e.g. For example, it can be targeted to PSMA for delivery into prostate cancer cells.

[0006] Described herein are methods for preparing compounds capable of binding to PSMA. Compounds that can target PSMA for diagnosis, imaging, and therapeutic delivery. Also described herein are methods for preparing the

[0007] The conjugates prepared by the methods described herein have high affinity for PSMA. The compounds prepared by the methods described herein are unexpectedly found to exhibit compatibility with 1,2-dichlorophenyl 2,3-dichlorophenyl 2,4-dichlorophenyl 2,5-dichlorophenyl 2,6-dichlorophenyl 2,7-dichlorophenyl 2,7-dichlorophenyl 2,8-dichlorophenyl 2,7 ... has been shown to prevent diseases caused by pathogenic cells that express PSMA, such as prostate cancer cells. It has also been found to be effective in treating

[0008] It has been disclosed that certain conjugates exhibit high affinity for PSMA. The conjugates are induced by pathogenic cells expressing PSMA, such as prostate cancer cells. It is also disclosed that such conjugates are effective in treating diseases such as One of them is described in International Publication No. 2015 / 055318 A1, [ka] (also known as PSMA-617).

[0009] The demand for drugs such as PSMA-617 means lower costs, higher purity and larger quantities There is a need to provide a synthesis method capable of providing such products. Methods for preparing compounds capable of binding to PSMA, such as A-617, are provided herein. This will be stated in the specification. Summary of the Invention

[0010] In one aspect, the present disclosure provides a method for the treatment of diseases, particularly cancer, in mammals, including humans. Methods for preparing the compounds are provided.

[0011] In one embodiment, the present disclosure provides a method for treating a mammal, including a human, in need of such treatment. The present invention provides a method for preparing a compound for treating abnormal cell proliferation caused by

[0012] In another embodiment, the abnormal cell growth is cancer. In another embodiment, the cancer is prostate cancer. , metastatic prostate cancer, and metastatic castration-resistant prostate cancer.

[0013] In another aspect, the present disclosure provides a compound of formula I [ka] A method for preparing the compound is provided.

[0014] Further embodiments, features, and advantages of the present disclosure will become apparent from the following detailed description and from the present disclosure. It will become apparent through practice that the compounds of the present disclosure may be any of the following listed clauses: Any of the embodiments described herein may be implemented in any of the following ways: In conjunction with any other embodiment described herein to the extent that the embodiments are not mutually exclusive. It will be appreciated that it can be used.

[0015] 1. Formula I [ka] A process for preparing a compound of the formula: Formula A [ka] contacting the resin-based compound of formula A' with a first deprotecting agent in a polar aprotic solvent to produce a compound of formula A' [ka] or providing a resin-based compound of b. A resin-based compound of formula A' is mixed with a resin-based compound of formula B [ka] in the presence of an organic solvent and a base to form a compound of formula C [ka] or providing a resin-based compound of c. contacting the resin-based compound of formula C with a second deprotecting agent in the presence of an organic solvent to produce a compound of formula C' [ka] or providing a resin-based compound of d. Reacting a resin-based compound of formula C' in the presence of a polar aprotic solvent, a coupling agent and a base. Below, P.G. 1 -3-(2-naphthyl)-L-alanine to form a compound of formula D [ka] or providing a resin-based compound of e. contacting the resin-based compound of formula D with a first deprotecting agent in a polar aprotic solvent; Formula D' [ka] or providing a resin-based compound of f. reacting a resin-based compound of formula D' with a polar aprotic solvent, a coupling agent, and a base in the presence of the Under PG 1 - contacting with tranexamic acid to form a compound of formula E [ka] or providing a resin-based compound of g. contacting the resin-based compound of Formula E with a first deprotecting agent in a polar aprotic solvent; Formula E' [ka] or providing a resin-based compound of h. Resin-based compound of formula E' with a compound of formula E 2’ [ka] in the presence of a polar aprotic solvent, a coupling agent, and a base, formula F [ka] or providing a resin-based compound of i. contacting a resin-based compound of formula F with a third deprotecting and / or cleaving agent in an organic solvent; This includes In the ceremony, P.G. 1 and P.G. 2 is an amine protecting group, LG is a leaving group, and R 1 is C1 -C4 alkyl or cyclohexyl.

[0016] 2. The first deprotecting agent in step (a) is piperidine, morpholine, 1,8-diazabicin 5.4.0-dichloro-7-ene (DBU), diethylamine (DEA), dicyclo Hexamine, 4-methylpiperidine (4MP), tris(2-aminoethyl)amine, 2. The method according to clause 1, wherein said amino acid sequence is selected from the group consisting of lysine and collidine.

[0017] 3. The first deprotecting agent in step (e) is piperidine, morpholine, 1,8-diazabicin 5.4.0-dichloro-7-ene (DBU), diethylamine (DEA), dicyclo Hexamine, 4-methylpiperidine (4MP), tris(2-aminoethyl)amine, Item 11. The method according to any one of the preceding claims, wherein the lysine is selected from the group consisting of lysine and collidine.

[0018] 4. The first deprotecting agent in step (g) is piperidine, morpholine, 1,8-diazabicin 5.4.0-dichloro-7-ene (DBU), diethylamine (DEA), dicyclo Hexamine, 4-methylpiperidine (4MP), tris(2-aminoethyl)amine, Item 11. The method according to any one of the preceding claims, wherein the lysine is selected from the group consisting of lysine and collidine.

[0019] 5. The method according to any one of the preceding paragraphs, wherein the first deprotecting agent in step (a) is piperidine. Law.

[0020] 6. The method according to any one of the preceding paragraphs, wherein the first deprotecting agent in step (e) is piperidine. Law.

[0021] 7. The method according to any one of the preceding paragraphs, wherein the first deprotecting agent in step (g) is piperidine. Law.

[0022] 8. The polar aprotic solvent in step (a) is dimethylformamide (DMF), N-methyl NMP, dichloromethane (DCM), dichloromethane / dimethyl Dimethylformamide mixture, acetonitrile (ACN), acetonitrile / dimethylformamide and dimethyl sulfoxide (DMSO). 2. The method according to any one of claims 1 to 11.

[0023] 9. The polar aprotic solvent in step (d) is dimethylformamide (DMF), N-methyl NMP, dichloromethane (DCM), dichloromethane / dimethyl Dimethylformamide mixture, acetonitrile (ACN), acetonitrile / dimethylformamide and dimethyl sulfoxide (DMSO). 2. The method according to any one of claims 1 to 11.

[0024] 10. The polar aprotic solvent in step (e) is dimethylformamide (DMF), N- Methyl-2-pyrrolidone (NMP), dichloromethane (DCM), dichloromethane / dimeth Dimethylformamide mixture, acetonitrile (ACN), acetonitrile / dimethylformamide amide mixture, and dimethyl sulfoxide (DMSO), 2. The method according to claim 1 .

[0025] 11. The polar aprotic solvent in step (f) is dimethylformamide (DMF), N- Methyl-2-pyrrolidone (NMP), dichloromethane (DCM), dichloromethane / dimeth Dimethylformamide mixture, acetonitrile (ACN), acetonitrile / dimethylformamide amide mixture, and dimethyl sulfoxide (DMSO), 2. The method according to claim 1 .

[0026] 12. The polar aprotic solvent in step (g) is dimethylformamide (DMF), N- Methyl-2-pyrrolidone (NMP), dichloromethane (DCM), dichloromethane / dimeth Dimethylformamide mixture, acetonitrile (ACN), acetonitrile / dimethylformamide amide mixture, and dimethyl sulfoxide (DMSO), 2. The method according to claim 1 .

[0027] 13. The polar aprotic solvent in step (h) is dimethylformamide (DMF), N- Methyl-2-pyrrolidone (NMP), dichloromethane (DCM), dichloromethane / dimeth Dimethylformamide mixture, acetonitrile (ACN), acetonitrile / dimethylformamide amide mixture, and dimethyl sulfoxide (DMSO), 2. The method according to claim 1 .

[0028] 14. The polar aprotic solvent in step (a) is dimethylformamide (DMF); 2. The method according to any one of the preceding claims.

[0029] 15. The polar aprotic solvent in step (d) is dimethylformamide (DMF); 2. The method according to any one of the preceding claims.

[0030] 16. The polar aprotic solvent in step (e) is dimethylformamide (DMF); 2. The method according to any one of the preceding claims.

[0031] 17. The polar aprotic solvent in step (f) is dimethylformamide (DMF). 2. The method according to any one of the preceding claims.

[0032] 18. The polar aprotic solvent in step (g) is dimethylformamide (DMF). 2. The method according to any one of the preceding claims.

[0033] 19. The polar aprotic solvent in step (h) is dimethylformamide (DMF). 2. The method according to any one of the preceding claims.

[0034] 20. The base in step (b) is N,N-diisopropylethylamine ( i Pr2NEt) , triethylamine (TEA), 4-methylmorpholine (NMM), imidazole, pyridinium Item 10. The method according to any one of the preceding claims, wherein the ribozyme is selected from the group consisting of ribozyme, ...

[0035] 21. The base in step (d) is N,N-diisopropylethylamine ( i Pr2NEt) , triethylamine (TEA), 4-methylmorpholine (NMM), imidazole, pyridinium Item 10. The method according to any one of the preceding claims, wherein the ribozyme is selected from the group consisting of ribozyme, ...

[0036] 22. The base in step (f) is N,N-diisopropylethylamine ( i Pr2NEt) , triethylamine (TEA), 4-methylmorpholine (NMM), imidazole, pyridinium Item 10. The method according to any one of the preceding claims, wherein the ribozyme is selected from the group consisting of ribozyme, ...

[0037] 23. The base in step (h) is N,N-diisopropylethylamine ( i Pr2NEt) , triethylamine (TEA), 4-methylmorpholine (NMM), imidazole, pyridinium Item 10. The method according to any one of the preceding claims, wherein the ribozyme is selected from the group consisting of ribozyme, ...

[0038] 24. The base in step (b) is N,N-diisopropylethylamine ( i Pr2NEt) Item 11. The method according to any one of the preceding items, wherein

[0039] 25. The base in step (d) is N,N-diisopropylethylamine ( i Pr2NEt) Item 11. The method according to any one of the preceding items, wherein

[0040] 26. The base in step (f) is N,N-diisopropylethylamine ( i Pr2NEt) Item 11. The method according to any one of the preceding items, wherein

[0041] 27. The base in step (h) is N,N-diisopropylethylamine ( i Pr2NEt) Item 11. The method according to any one of the preceding items, wherein

[0042] 28. The second deprotecting agent in step (c) is trifluoroacetic acid (TFA), acetic acid, trifluoro Perfluoroethanol, hexafluoroisopropanol, dichloromethane, and combinations thereof The method according to any one of the preceding claims, wherein the combination is selected from the group consisting of:

[0043] 29. The second deprotecting agent in step (c) is trifluoroacetic acid (TFA) or acetic acid and trifluoroacetic acid. 2. The method according to any one of the preceding claims, wherein the mixture is with ethyl alcohol.

[0044] 30. The coupling agent in step (d) is benzotriazol-1-yl-oxytripycin. Lolidinophosphonium hexafluorophosphate (PyBOP), 1-[bis(dimethyl (amino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- Oxidohexafluorophosphate (HATU), 2-(1H-benzotriazole- 1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBT U), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl Hexafluorophosphate (HBTU), 2-chloro-4,6-dimethoxy- 1,3,5-Triazine (CDMT), N-[(5-chloro-3-oxido-1H-benzo[ 1-(4-Morpholinylmethylene)-N-methylmethanamine Hexafluorophosphate (HDMC), 1-cyano-2-ethoxy-2-oxoethane (Dimethylamino)morpholino-carbenium hexafluorophos Phosphate (COMU), Dimethylamino (triazolo[4,5-b]pyridin-3-yl OXY)METHYLIDENE]-DIMETHYLAZANIUM;TETRAFLUOROBORATE (TATU), N ,N,N',N'-Tetramethyl-S-(1-oxide-2-pyridyl)thiouronium Tetrafluoroborate (TOTT), N-ethoxycarbonyl-2-ethoxy-1,2 -dihydroquinoline (EEDQ), 1-propanephosphonic anhydride (T3P), and 4- (4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholinyl The method according to any one of the preceding claims, wherein the compound is selected from the group consisting of dimethyl taurate chloride (DMTMM) and dimethyl taurate chloride (DMTMM). Law.

[0045] 31. The coupling agent in step (f) is benzotriazol-1-yl-oxytripycin. Lolidinophosphonium hexafluorophosphate (PyBOP), 1-[bis(dimethyl (amino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- Oxidohexafluorophosphate (HATU), 2-(1H-benzotriazole- 1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBT U), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl Hexafluorophosphate (HBTU), 2-chloro-4,6-dimethoxy- 1,3,5-Triazine (CDMT), N-[(5-chloro-3-oxido-1H-benzo[ 1-(4-Morpholinylmethylene)-N-methylmethanamine Hexafluorophosphate (HDMC), 1-cyano-2-ethoxy-2-oxoethane (Dimethylamino)morpholino-carbenium hexafluorophos Phosphate (COMU), Dimethylamino (triazolo[4,5-b]pyridin-3-yl OXY)METHYLIDENE]-DIMETHYLAZANIUM;TETRAFLUOROBORATE (TATU), N ,N,N',N'-Tetramethyl-S-(1-oxide-2-pyridyl)thiouronium Tetrafluoroborate (TOTT), N-ethoxycarbonyl-2-ethoxy-1,2 -dihydroquinoline (EEDQ), 1-propanephosphonic anhydride (T3P), and 4- (4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholinyl The method according to any one of the preceding claims, wherein the compound is selected from the group consisting of dimethyl taurate chloride (DMTMM) and dimethyl taurate chloride (DMTMM). Law.

[0046] 32. The coupling agent in step (h) is benzotriazol-1-yl-oxytripycin. Lolidinophosphonium hexafluorophosphate (PyBOP), 1-[bis(dimethyl (amino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- Oxidohexafluorophosphate (HATU), 2-(1H-benzotriazole- 1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBT U), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl Hexafluorophosphate (HBTU), 2-chloro-4,6-dimethoxy- 1,3,5-Triazine (CDMT), N-[(5-chloro-3-oxido-1H-benzo[ 1-(4-Morpholinylmethylene)-N-methylmethanamine Hexafluorophosphate (HDMC), 1-cyano-2-ethoxy-2-oxoethane (Dimethylamino)morpholino-carbenium hexafluorophos Phosphate (COMU), Dimethylamino (triazolo[4,5-b]pyridin-3-yl OXY)METHYLIDENE]-DIMETHYLAZANIUM;TETRAFLUOROBORATE (TATU), N ,N,N',N'-Tetramethyl-S-(1-oxide-2-pyridyl)thiouronium Tetrafluoroborate (TOTT), N-ethoxycarbonyl-2-ethoxy-1,2 -dihydroquinoline (EEDQ), 1-propanephosphonic anhydride (T3P), and 4- (4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholinyl The method according to any one of the preceding claims, wherein the compound is selected from the group consisting of dimethyl taurate chloride (DMTMM) and dimethyl taurate chloride (DMTMM). Law.

[0047] 33. The coupling agent in step (d) is benzotriazol-1-yl-oxytripycin. Any of the preceding paragraphs, which is lolidinophosphonium hexafluorophosphate (PyBOP). 2. The method according to claim 1.

[0048] 34. The coupling agent in step (f) is benzotriazol-1-yl-oxytripycin. Any of the preceding paragraphs, which is lolidinophosphonium hexafluorophosphate (PyBOP). 2. The method according to claim 1.

[0049] 35. The coupling agent in step (h) is benzotriazol-1-yl-oxytripycin. Any of the preceding paragraphs, which is lolidinophosphonium hexafluorophosphate (PyBOP). 2. The method according to claim 1.

[0050] 36. The third deprotecting agent in step (i) is trifluoroacetic acid (TFA), hydrofluoric acid ( HF), triflic acid (TfOH), trifluoroacetic acid (TFA) / water / triisopropanol Pyridylane mixture, trifluoroacetic acid (TFA) / dichloromethane (DCM) mixture, Triethylsaline (TES), indole, phenol Any one of the preceding items selected from the group consisting of anisole / anisole mixtures and thioanisole. The method according to claim 5.

[0051] 37. The third deprotecting agent in step (i) is trifluoroacetic acid (TFA) / water / triisopropyl Item 11. The method of any one of the preceding claims, wherein the pyrsilane is a mixture.

[0052] 38. The cleavage reagent in step (i) is trifluoroacetic acid (TFA) or trifluoroacetic acid (T Item 11. The method of any one of the preceding claims, wherein the FA) / water / triisopropylsilane mixture.

[0053] 39. The cleavage reagent in step (i) is trifluoroacetic acid (TFA) / water / triisopropyl silyl Item 11. The method of any one of the preceding, wherein the orchid is a mixture.

[0054] 40. The organic solvent in step (b) is CH2Cl2, THF, diethyl ether, MeOH , EtOH, acetone, acetonitrile. The method according to

[0055] 41. The organic solvent in step (c) is CH2Cl2, THF, diethyl ether, MeOH , EtOH, acetone, acetonitrile. The method described above.

[0056] 42. The organic solvent in step (i) is CH2Cl2, THF, diethyl ether, MeOH , EtOH, acetone, acetonitrile. The method described above.

[0057] 43. The method according to any one of the preceding claims, wherein the organic solvent in step (b) is CH2Cl2. .

[0058] 44. The method according to any one of the preceding claims, wherein the organic solvent in step (c) is CH2Cl2. .

[0059] 45. The method according to any one of the preceding claims, wherein the organic solvent in step (i) is CH2Cl2. .

[0060] 46. ​​PG 1 9-Fluorenylmethyl-carbonyl (Fmoc) or t-Butylcarbamate Item 11. The method according to any one of the preceding items, wherein the aryl group is phenyl (Boc).

[0061] 47. PG 1 is 9-fluorenylmethyl-carbonyl (Fmoc), 2. The method according to claim 1 .

[0062] 48. PG 2 is monomethoxytrityl (MMt) or 4-methyltrityl (Mtt) 2. The method according to any one of the preceding claims.

[0063] 49. PG 2 is 4-methyltrityl (Mtt), Law.

[0064] 50. LG, [ka] and * Item 11. The method of any one of the preceding, wherein represents a point of attachment to the remainder of the compound.

[0065] 51. R 1 Item 11. The method of any one of the preceding, wherein is t-butyl.

[0066] 52. Formula 1 [ka] A method for preparing a compound of the formula: a. Formula I [ka] contacting the resin-based compound of formula 2 with a first deprotecting agent in the presence of a solvent to form a compound of formula 2 [ka] or providing a resin-based compound of b. The resin-based compound of formula 2 is mixed with a compound of formula 3 [ka] in the presence of an organic solvent and a base to form a compound of formula 4 [ka] or providing a resin-based compound of c. contacting the resin-based compound of formula 4 with a second deprotecting agent in the presence of an organic solvent to produce a compound of formula 5 [ka] or providing a resin-based compound of d. The resin-based compound of formula 5 is reacted with a compound of formula 6 [ka] in the presence of a solvent, a coupling agent, and optionally a base and / or an additive. By contacting, the compound of formula 7 [ka] or providing a resin-based compound of e. contacting the resin-based compound of formula 7 with a third deprotecting agent in the presence of a solvent to produce a compound of formula 8. [ka] or providing a resin-based compound of f. The resin-based compound of formula 8 is reacted with a compound of formula 9 [ka] in the presence of a solvent, a coupling agent, and optionally a base and / or an additive. By contacting, the formula 10 [ka] or providing a resin-based compound of g. reacting the resin-based compound of formula 10 with at least one third deprotecting agent and and / or a cleavage reagent to provide a compound of formula I. one or more of In the formula, PG, PG1 and P.G. 4 is an amine protecting group, PG 2 , P.G. 3 , and P.G. 5 teeth is a carbonyl protecting group, and LG of compound C is a leaving group.

[0067] 53. P.G., P.G. 1 and P.G. 4 However, 9-fluorenylmethyl-carbonyl (Fmoc) , benzyl carbamate (Cbz), t-butyloxycarbonyl (Boc), acetone amide, trifluoroacetamide, p-toluenesulfonamide, triphenylmethyl ( triphemylmethyl), monomethoxytrityl (MMt), and 4-methyl 53. The method of claim 52, wherein said aryl group is selected from the group consisting of trityl (Mtt).

[0068] 54. The method according to claim 52 or 53, wherein PG is 9-fluorenylmethyl-carbonyl. method.

[0069] 55. PG 1 is monomethoxytrityl (MMt) or 4-methyltrityl (Mtt) 55. The method according to any one of clauses 52 to 54.

[0070] 56. PG 1 Any one of clauses 52 to 55, wherein The method according to

[0071] 57. PG 4 Any of the above items 52 to 56, wherein the compound is 9-fluorenylmethyl-carbonyl. 2. The method according to claim 1.

[0072] 58. PG 2 , P.G. 3 , and P.G. 5Each of the above items 52 to 57 is t-butyl. 2. The method according to any one of claims 1 to 11.

[0073] 59. The LG of compound C is made from imidazolyl, 4-nitrophenoxy, and phenoxy. 59. The method according to any one of clauses 52 to 58, selected.

[0074] 60. The first deprotecting agent in step (a) is 9-fluorenylmethyl-carbonyl (Fmo c), benzyl carbamate (Cbz), t-butyloxycarbonyl (Boc), acetonitrile amide, trifluoroacetamide, p-toluenesulfonamide, triphenylmethy triphemylmethyl, monomethoxytrityl (MMt), and 4-methyltrityl a reagent capable of removing a protecting group selected from the group consisting of trityl (Mtt) or 60. The method of any one of clauses 52 to 59, wherein the method comprises a mixture of reagents.

[0075] 61. The first deprotecting agent in step (a) removes the 9-fluorenylmethyl-carbonyl. The method according to any one of clauses 52 to 60, comprising a reagent or a mixture of reagents capable of Law.

[0076] 62. The first deprotecting agent in step (a) is piperidine, morpholine, 1,8-diazabis(2,3-dihydropyridine), Chloro[5.4.0]undec-7-ene (DBU), diethylamine (DEA), dicyclohexyl hexamine, 4-methylpiperidine (4MP), tris(2-aminoethyl)amine, Any one of the above items 52 to 61, selected from the group consisting of pyridine and collidine. Method of posting.

[0077] 63. Any one of clauses 52 to 62, wherein the first deprotecting agent in step (a) is piperidine. The method according to claim 5.

[0078] 64. Any one of clauses 52 to 63, wherein the solvent in step (a) is a polar aprotic solvent. The method according to claim 5.

[0079] 65. The solvent in step (a) is dimethylformamide (DMF), N-methyl-2-pyrrolidone (N-methyl-2-pyrrolidone), NMP, dichloromethane (DCM), dichloromethane / dimethylformamide mixture, acetonitrile (ACN), acetonitrile / dimethylformamide mixture, and Any of the items 52 to 64 is selected from the group consisting of dimethyl sulfoxide (DMSO) and dimethyl sulfoxide (DMSO). 2. The method according to claim 1 .

[0080] 66. The base in step (b) is N,N-diisopropylethylamine ( i Pr2NEt) , triethylamine (TEA), 4-methylmorpholine (NMM), imidazole, pyridinium 66. The method according to any one of claims 52 to 65, wherein the compound is selected from the group consisting of acyl amine, ... method.

[0081] 67. The organic solvent in step (b) is CH2Cl2, THF, diethyl ether, MeOH , EtOH, acetone, and acetonitrile. 2. The method according to claim 1 .

[0082] 68. The second deprotecting agent in step (c) is 9-fluorenylmethyl-carbonyl (Fmo c), benzyl carbamate (Cbz), t-butyloxycarbonyl (Boc), acetonitrile amide, trifluoroacetamide, p-toluenesulfonamide, triphenylmethy triphemylmethyl, monomethoxytrityl (MMt), and 4-methyltrityl a reagent capable of removing a protecting group selected from the group consisting of trityl (Mtt) or 68. The method of any one of clauses 52 to 67, wherein the method comprises a mixture of reagents.

[0083] 69. The second deprotecting agent in step (c) removes 4-methyltrityl (Mtt). 69. The method of any one of clauses 52 to 68, comprising a reagent or mixture of reagents capable of:

[0084] 70. The second deprotecting agent in step (c) is trifluoroacetic acid (TFA), acetic acid, 2,2, 2-Trifluoroethanol, hexafluoroisopropanol, and combinations thereof 70. The method according to any one of clauses 52 to 69, wherein the method is selected from the group consisting of:

[0085] 71. The second deprotecting agent in step (c) is acetic acid and 2,2,2-trifluoroethanol. 71. The method according to any one of clauses 52 to 70, wherein the mixture is

[0086] 72. The organic solvent in step (c) is CH2Cl2, THF, diethyl ether, MeOH , EtOH, acetone, and acetonitrile. 2. The method according to claim 1 .

[0087] 73. The coupling agent in step (d) is benzotriazol-1-yloxy-tri s(Dimethylamino)-phosphonium hexafluorophosphate (BOP), benzotriazole Riazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 7-aza-benzotriazol-1-yloxy-tripyrrolidino- Sulfonium hexafluorophosphate (PyAOP), ethyl cyano(hydroxyimide Acetato-O2)-tri-(1-pyrrolidinyl)-phosphonium hexafluorophosphonium Phosphate (PyOxim), Bromo-tripyrrolidino-phosphonium hexafluorophos Phosphate (PyBrOP), 3-(diethoxy-phosphoryloxy)-1,2,3-benzophenone Zo[d]triazin-4(3H)-one (DEPBT), 1-[bis(dimethylamino) methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide Hexafluorophosphate (HATU), 2-(1H-benzotriazol-1-yl) -1,1,3,3-Tetramethyluronium tetrafluoroborate (TBTU), 2- (1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium Hexafluorophosphate (HBTU), 2-(6-chloro-1H-benzotriazole -1-yl)-N,N,N',N'-tetramethylaminium hexafluorophosphate HCTU, 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT ), N-[(5-chloro-3-oxido-1H-benzotriazol-1-yl)-4- Morpholinylmethylene]-N-methylmethanaminium hexafluorophosphate (H DMC), 1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethyl a Amino-morpholino-carbenium hexafluorophosphate (COMU), dimethyl a Amino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethyl a N,N,N',N'-Tetramethyl-S -(1-Oxido-2-pyridyl)thiouronium tetrafluoroborate (TOTT) , tetramethylfluoroformamidinium hexafluorophosphate (TFFH), N-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), 1- Propanephosphonic anhydride (T3P), 4-(4,6-dimethoxy-1,3,5-trimethylphenyl) Dicyclohexyl)-4-methyl-morpholinium chloride (DMTMM), Diisopropylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), (N-(3 -dimethylaminopropyl)-N'-ethylcarbodiimide (EDAC), and 1,1' - Carbonyldimidizole (CDI) 73. The method according to any one of clauses 52 to 72, wherein the compound is selected from the group consisting of:

[0088] 74. The base in step (d) is N,N-diisopropylethylamine ( i Pr2NEt) , triethylamine (TEA), 4-methylmorpholine (NMM), imidazole, pyridinium 74. The method according to any one of claims 52 to 73, wherein the compound is selected from the group consisting of acyl amine, ... method.

[0089] 75. The additive in step (d), if present, is 1-hydroxybenzotriazole. HOBt, 1-Hydroxybenzotriazole-6-sulfonamidomethyl resin H Cl(HOBt-6-sulfonamidomethyl resin HCl), Hydroxy-3,4-dihydr 4-Oxo-1,2,3-benzotriazine (HOOBt), N-Hydroxysuccinimide 1-Hydroxy-7-aza-1H-benzotriazole (HOAt ), ethyl 2-cyano-2-(hydroxymino)acetate and 4-(N,N-dimethylamino)pyridine (DMAP). 75. The method according to any one of clauses 52 to 74.

[0090] 76. Any one of clauses 52 to 75, wherein the solvent in step (d) is a polar aprotic solvent. The method according to claim 5.

[0091] 77. The solvent in step (d) is dimethylformamide (DMF), N-methyl-2-pyrrolidone (N-Pyridoxal), NMP, dichloromethane (DCM), dichloromethane / dimethylformamide mixture, acetonitrile (ACN), acetonitrile / dimethylformamide mixture, and Any of the items 52 to 76 is selected from the group consisting of dimethyl sulfoxide (DMSO) and dimethyl sulfoxide (DMSO). 2. The method according to claim 1 .

[0092] 78. The third deprotecting agent in step (e) is 9-fluorenylmethyl-carbonyl (Fmo c), benzyl carbamate (Cbz), t-butyloxycarbonyl (Boc), acetonitrile amide, trifluoroacetamide, p-toluenesulfonamide, triphenylmethy triphemylmethyl, monomethoxytrityl (MMt), and 4-methyltrityl a reagent capable of removing a protecting group selected from the group consisting of trityl (Mtt) or 78. The method of any one of clauses 52 to 77, wherein the method comprises a mixture of reagents.

[0093] 79. The third deprotecting agent in step (e) removes the 9-fluorenylmethyl-carbonyl. The method according to any one of clauses 52 to 78, comprising a reagent or mixture of reagents capable of Law.

[0094] 80. The first deprotecting agent in step (e) is piperidine, morpholine, 1,8-diazabis(2-phenylpropanediol). Chloro[5.4.0]undec-7-ene (DBU), diethylamine (DEA), dicyclohexyl hexamine, 4-methylpiperidine (4MP), tris(2-aminoethyl)amine, Any one of the above claims 52 to 79, wherein the compound is selected from the group consisting of pyridine and collidine. Method of posting.

[0095] 81. Any one of clauses 52 to 80, wherein the first deprotecting agent in step (e) is piperidine. The method according to claim 5.

[0096] 82. Any one of clauses 52 to 81, wherein the solvent in step (e) is a polar aprotic solvent. The method according to claim 5.

[0097] 83. The solvent in step (e) is dimethylformamide (DMF), N-methyl-2-pyrrolidone (N-Pyridoxal), NMP, dichloromethane (DCM), dichloromethane / dimethylformamide mixture, acetonitrile (ACN), acetonitrile / dimethylformamide mixture, and Any of the items 52 to 82, selected from the group consisting of dimethyl sulfoxide (DMSO) and dimethyl sulfoxide (DMSO). 2. The method according to claim 1 .

[0098] 84. The coupling agent in step (f) is benzotriazol-1-yloxy-tris(benzotriazol-1-yloxy). (Dimethylamino)-phosphonium hexafluorophosphate (BOP), benzotri Azol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate ( PyBOP), 7-aza-benzotriazol-1-yloxy-tripyrrolidino-phos PyAOP, Ethylcyano(hydroxyimino )Acetato-O2)-tri-(1-pyrrolidinyl)-phosphonium hexafluorophosphine PyOxim, bromo-tripyrrolidino-phosphonium hexafluorophosphine PyBrOP, 3-(diethoxy-phosphoryloxy)-1,2,3-benzoate [d]Triazin-4(3H)-one (DEPBT), 1-[bis(dimethylamino)methyl 1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexa Fluorophosphate (HATU), 2-(1H-benzotriazol-1-yl)- 1,1,3,3-Tetramethyluronium tetrafluoroborate (TBTU), 2-( 1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexahydrate Fluorophosphate (HBTU), 2-(6-chloro-1H-benzotriazole- 1-yl)-N,N,N',N'-tetramethylaminium hexafluorophosphate (HCTU), 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) , N-[(5-chloro-3-oxido-1H-benzotriazol-1-yl)-4-methyl [Folylmethylene]-N-methylmethanaminium hexafluorophosphate (HD MC), 1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamine No-morpholino-carbenium hexafluorophosphate (COMU), dimethylamine No(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylaza Nitium tetrafluoroborate (TATU), N,N,N',N'-tetramethyl-S- (1-oxido-2-pyridyl)thiouronium tetrafluoroborate (TOTT), Tetramethylfluoroformamidinium hexafluorophosphate (TFFH), N -Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), 1-propanol Propanephosphonic anhydride (T3P), 4-(4,6-dimethoxy-1,3,5-triazolidinediamine 2-methyl-4-methyl-morpholinium chloride (DMTMM), dicyclohexyl Diisopropylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), (N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide (EDAC), and 1,1'- Consists of carbonyldimidizole (CDI) 84. The method according to any one of clauses 52 to 83, selected from the group:

[0099] 85. The base in step (f), when present, is N,N-diisopropylethylamine. hmm( i PrNEt), triethylamine (TEA), 4-methylmorpholine (NMM) 52 to 84, wherein the aryl group is selected from the group consisting of imidazole, pyridine, and collidine. 2. The method according to any one of claims 1 to 11.

[0100] 86. The additive in step (f), if present, is 1-hydroxybenzotriazole. HOBt, 1-Hydroxybenzotriazole-6-sulfonamidomethyl resin H Cl(HOBt-6-sulfonamidomethyl resin HCl), Hydroxy-3,4-dihydr 4-Oxo-1,2,3-benzotriazine (HOOBt), N-Hydroxysuccinimide 1-Hydroxy-7-aza-1H-benzotriazole (HOAt ), ethyl 2-cyano-2-(hydroxymino)acetate and 4-(N,N-dimethylamino)pyridine (DMAP). 86. The method according to any one of Items 52 to 85.

[0101] 87. Any of clauses 52 to 86, wherein the solvent in step (f) is a polar aprotic solvent. 2. The method according to claim 1 .

[0102] 88. The solvent in step (f) is dimethylformamide (DMF), N-methyl-2 -NMP, dichloromethane (DCM), dichloromethane / dimethylform Amide mixture, acetonitrile (ACN), acetonitrile / dimethylformamide mixture and dimethyl sulfoxide (DMSO), 88. The method of any one of clauses 52 to 87, wherein the solvent is

[0103] 89. The third deprotecting agent in step (g) is t-butyl, benzyl, 2-chlorotrityl ( 2-Cl-Trt), 2,4-dimethoxybenzyl (Dmb), allyl, 1,1-dimethyl A protecting group selected from the group consisting of p-aryl (Dma), and p-nitrobenzyl (pNB). Any one of clauses 52 to 88, which is a reagent or a mixture of reagents capable of removing a group. The method described above.

[0104] 90. The third deprotecting agent in step (g) is trifluoroacetic acid (TFA), hydrofluoric acid ( HF), triflic acid (TfOH), trifluoroacetic acid (TFA) / water / triisopropanol Pyridylane mixture, trifluoroacetic acid (TFA) / dichloromethane (DCM) mixture, Triethylsaline (TES), indole, phenol / anisole mixture, and thioanisole. 2. The method according to any one of claims 1 to 11.

[0105] 91. The third deprotecting agent in step (g) is trifluoroacetic acid (TFA) / water / triisopropyl 91. The method according to any one of clauses 52 to 90, wherein the isopropylsilane mixture.

[0106] 92. The cleavage reagent in step (g) is trifluoroacetic acid (TFA) or trifluoroacetic acid ( TFA) / water / triisopropylsilane mixture according to any one of clauses 52 to 91. The method described.

[0107] 93. The cleavage reagent in step (g) is trifluoroacetic acid (TFA) / water / triisopropyl silyl 93. The method of any one of clauses 52 to 92, wherein the orchid is a mixture.

[0108] 94. The organic solvent in step (g) is CH2Cl2, THF, diethyl ether, MeOH , EtOH, acetone, and acetonitrile. 2. The method according to claim 1 .

[0109] 95. A compound of formula 6, a solvent, a coupling agent, and a tertiary amine are mixed together prior to contacting with a resin-based compound of formula 5. and optionally combining a base and / or an additive, [ka] forming a mixture containing an activated compound of the formula: 5. The method according to any one of clauses 52 to 94.

[0110] 96. Formula 6' [ka] (wherein LG of compound 6' is a leaving group) prior to in situ formation of an activated compound of formula or at the same time, a compound of a resin-based compound of formula 5, a compound of formula 6, a solvent, coupling Any of the methods according to any of clauses 52 to 94, wherein the agent and, optionally, the base and / or the additive are contacted together. 2. The method according to any one of claims 1 to 11.

[0111] 97. LG of compound 6' is 1-(λ 1 -Oxidaneyl)-1H-benzo[d][1 ,2,3]triazole, 3-(λ 1 -Oxidantyl)-3H-[1,2,3]thiazolinol Zolo[4,5-b]pyridine, Ethyl cyano(hydroxyimino)acetate (Oxym a), bromide, 3-(λ 1 -Oxidaneyl)benzo[d][1,2,3]triazine 4 (3H)-one, 6-chloro-1-(λ 1 -Oxidaneyl)-1H-benzo[d][1 ,2,3]triazole, 2,4-dimethoxy-6-(λ 1 -Oxidantyl)-1,3 ,5-triazine, ethabonic acid, propylphosphonic acid, dicyclohexylurea, 1-(3 -(Dimethyl-λ 4 -azanyl)propyl)-3-ethylurea, and imidazolyl 97. The method of claim 95 or 96, wherein the compound is selected from the group consisting of:

[0112] 98. The compound 6' according to any one of clauses 95 to 97, wherein LG is imidazolyl. How to.

[0113] 99. A compound of formula 9, a solvent, a coupling agent, and a tertiary amine are added to the resin-based compound of formula H prior to contacting the resin-based compound of formula H. and optionally combining a base and / or an additive, [ka] forming a mixture containing an activated compound of the formula: 2. The method according to any one of the preceding claims.

[0114] 100. Formula 9' [ka] (wherein LG of compound 9′ is a leaving group) prior to in situ formation of an activated compound of formula or at the same time, a resin-based compound of formula 8, a compound of formula 9, a solvent, a coupling agent, and Any one of clauses 52 to 98, optionally together with a base and / or an additive. The method described above.

[0115] 101. LG of compound 9' is 1-(λ 1 -Oxidaneyl)-1H-benzo[d][ 1,2,3]triazole, 3-(λ 1 -Oxidaneyl)-3H-[1,2,3]trimethyl Azolo[4,5-b]pyridine, Ethyl cyano(hydroxyimino)acetate (Oxy ma), bromide, 3-(λ 1 -Oxidaneyl)benzo[d][1,2,3]triazine -4(3H)-one, 6-chloro-1-(λ 1 -Oxidaneyl)-1H-benzo[d] [1,2,3]triazole, 2,4-dimethoxy-6-(λ 1 -Oxidantyl)-1 ,3,5-triazine, ethaboic acid, propylphosphonic acid, dicyclohexylurea, 1- (3-(dimethyl-λ 4 -azanyl)propyl)-3-ethylurea, and imidazolyl 101. The method of claim 99 or 100, wherein the compound is selected from the group consisting of:

[0116] 102. The compound 9' according to any one of clauses 99 to 101, wherein LG is imidazolyl. The method described.

[0117] 103. Formula 4 [ka] (In the formula, PG 1 is an amine protecting group, PG 2 and P.G. 3 are each independently (Xyl protecting group) Resin-based compound.

[0118] 104. Formula 5 [ka] (In the formula, PG 2 and P.G. 3 are each independently a carboxyl protecting group. Resin-based compound.

[0119] 105. Formula 7 [ka] (In the formula, PG 2 and P.G. 3 are each independently a carboxy protecting group, PG 4 A (protecting group) Resin-based compound.

[0120] 106. Formula 8 [ka] (In the formula, PG 2 and P.G. 3 are each independently a carboxy protecting group. Resin-based compound.

[0121] 107. Formula 10 [ka] (In the formula, each PG 2 , P.G. 3 , and P.G. 5 are independently carboxyl protecting groups. Resin-based compound.

[0122] 108. PG 1 and P.G. 4 When present, 9-fluorenylmethyl-carbonyl ( Fmoc), benzyl carbamate (Cbz), t-butyloxycarbonyl (Boc) , acetamide, trifluoroacetamide, p-toluenesulfonamide, triphenyl triphemylmethyl, monomethoxytrityl (MMt), and 4-methyltrityl (Mtt) 13. The resin-based compound according to claim 12 .

[0123] 109. PG 1 If present, monomethoxytrityl (MMt) or 4-methyltrityl 109. The resin-based compound according to any one of clauses 103 to 108, which is lithyl (Mtt).

[0124] 110. PG 1 When present, it is 4-methyltrityl (Mtt). 110. The resin-based compound according to any one of items 1 to 109.

[0125] 111. PG 4 is, if present, 9-fluorenylmethyl-carbonyl; 111. The resin-based compound according to any one of items 103 to 110.

[0126] 112. P.G. 2 , P.G. 3 , and P.G. 5 where present, each is t-butyl; Item 103. A resin-based compound according to any one of items 103 to 111.

[0127] 113. Formula C [ka] (In the formula, PG 2 is an amine protecting group, and each R 1 is C1-C4 alkyl or cyclohexyl A resin-based compound that is silane.

[0128] 114. Formula C' [ka] (In the formula, each R 1 is C1-C4 alkyl or cyclohexyl) Resin-based compound.

[0129] 115. Formula D [ka] (In the formula, PG 1 is an amine protecting group, and each R 1 is C1-C4 alkyl or cyclohexyl It is Sil. Resin-based compound.

[0130] 116. Formula D' [ka] (In the formula, each R 1 is C1-C4 alkyl or cyclohexyl) Resin-based compound.

[0131] 117. Formula E [ka] (In the formula, PG 1 is an amine protecting group, and each R 1 is C1-C4 alkyl or cyclohexyl It is Sil. Resin-based compound.

[0132] 118. Formula E' [ka] (In the formula, each R 1 is C1-C4 alkyl or cyclohexyl) Resin-based compound.

[0133] 119. Formula F [ka] (In the formula, each R 1 is C1-C4 alkyl or cyclohexyl) Resin-based compound.

[0134] 120. PG 1 9-Fluorenylmethyl-carbonyl (Fmoc) or t-Butylcarbonyl 118. The resin-based compound according to claim 115 or 117, wherein the compound is carboxyl (Boc).

[0135] 121. P.G. 1 is 9-fluorenylmethyl-carbonyl (Fmoc), 5, 117 or 120. A resin-based compound according to any one of claims 5, 117 or 120.

[0136] 122. P.G. 2 Monomethoxytrityl (MMt) or 4-methyltrityl (Mtt) Item 113. The resin-based compound according to item 113,

[0137] 123. PG 2 is 4-methyltrityl (Mtt), Resin-based compound.

[0138] 124. R 1 is t-butyl compound.

[0139] definition As used herein, the term "alkyl" refers to an optionally branched, 1 to 4 carbon The alkyl radicals include a chain of carbon atoms containing atoms such as aryl, aryl, aryl and aryl groups, and may be referred to as "lower alkyls." Exemplary alkyl radicals include those containing aryl, aryl, aryl and aryl groups. The alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl. Examples of butyl groups include, but are not limited to, butyl, sec-butyl, and tert-butyl.

[0140] As used herein, unless otherwise indicated, the term "abnormal cell growth" refers to a cell that is Refers to cell proliferation that is independent of regulatory mechanisms (e.g., loss of contact inhibition).

[0141] The term "subject" refers to a mammalian patient in need of such treatment, such as a human.

[0142] As used herein, the term "protecting group" or "PG" refers to an amine or hydroxyl These functional groups are introduced into molecules through chemical modification, providing chemoselectivity in subsequent chemical reactions. Such protecting groups refer to any group commonly known to those skilled in the art that can provide the Then, at a later point in the synthesis, it is removed from the functional group to provide further opportunities for reaction at such functional groups. or in the case of the final product, such functional groups can be unmasked. It will be appreciated that protecting groups can be prepared by, for example, Wuts, PGM, Greene, T .W.,Greene,TW,& John Wiley & Sons.(200 6).Greene's protective groups in organic synthesis. Hoboken, NJ: Wiley-Interscience Those skilled in the art can introduce such protecting groups onto functional groups. The chemical process conditions will be readily recognized as suitable amine protection agents useful in connection with the present disclosure. The groups include 9-fluorenylmethyl-carbonyl (Fmoc) and t-butylcarbonyl. Examples of aryl esters include, but are not limited to, Boc.

[0143] As used herein, the term "leaving group" of "LG" refers to a heterolytic bond cleavage group. Leaving groups refer to any group commonly known to those skilled in the art that leaves with a pair of electrons at It may be an anion or a neutral molecule, but in either case the leaving group is at the heteroatom of the bond. It is important to be able to stabilize the additional electron density that arises from the solution. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0144] Before the present disclosure is further described, it is to be understood that this disclosure is not limited to particular embodiments described, but rather Therefore, it should be understood that variations may occur. The terms used in this specification refer to specific embodiments, limited only by the scope of the claims. It should also be understood that this is for illustrative purposes only and is not intended to be limiting.

[0145] Unless otherwise defined, all technical and scientific terms used herein are within the meaning of the present disclosure. has the same meaning as commonly understood by a person skilled in the art to which it pertains. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety. The definitions set forth in this section are incorporated herein by reference. Any definition contrary to or otherwise inconsistent with any definition set forth in any license, application, or other publication. Where applicable, the definitions set forth in this section shall prevail over the definitions incorporated herein by reference. is also given priority.

[0146] As used in this specification and the appended claims, the singular forms "a," "a "n" and "the" include plural referents unless the context clearly dictates otherwise. Further, the claims may be drafted to exclude any optional element. Accordingly, this statement should not be construed as a recitation or "negative" limitation of any claim element. Serve as a precedent to the use of exclusive terms such as "sole" or "only" in connection with the use of It is meant to stand.

[0147] Synthesis method Method 1: In some embodiments, the present disclosure provides a compound of formula I [ka] The present invention provides a method for preparing a compound of the formula: Formula A [ka] contacting the resin-based compound of formula A' with a first deprotecting agent in a polar aprotic solvent to produce a compound of formula A' [ka] or providing a resin-based compound of b. A resin-based compound of formula A' is mixed with a resin-based compound of formula B [ka] in the presence of an organic solvent and a base. [ka] or providing a resin-based compound of formula C: c. contacting the resin-based compound of formula C with a second deprotecting agent in the presence of an organic solvent to produce a compound of formula C' [ka] or providing a resin-based compound of d. The resin-based compound of formula C' is reacted with a polar aprotic solvent, a coupling agent, and a base to form a cyclohexane-dichloromethane (CD-1H-cyclohexane) copolymer. Currently PG 1 -3-(2-naphthyl)-L-alanine to form a compound of formula D [ka] or providing a resin-based compound of e. contacting the resin-based compound of formula D with a first deprotecting agent in a polar aprotic solvent; Formula D' [ka] or providing a resin-based compound of f. A resin-based compound of formula D' is reacted with a polar aprotic solvent, a coupling agent, and a base in the presence of the base. Currently PG 1 - contacting with tranexamic acid to form a compound of formula E [ka] or providing a resin-based compound of g. contacting the resin-based compound of Formula E with a first deprotecting agent in a polar aprotic solvent; Formula E' [ka] or providing a resin-based compound of h. Resin-based compound of formula E' with a compound of formula E 2’ [ka] in the presence of a polar aprotic solvent, a coupling agent, and a base, formula F [ka] or providing a resin-based compound of i. contacting a resin-based compound of formula F with a third deprotecting and / or cleaving agent in an organic solvent; To make Including, In the ceremony, P.G. 1 and P.G. 2 is an amine protecting group, LG is a leaving group, and R 1 is C1 ~C4 alkyl or cyclohexyl.

[0148] Method 2: Alternatively, in some embodiments, the present disclosure provides a compound represented by formula 1 [ka] The present invention provides a method for preparing a compound of the formula: a. Formula 1 [ka] contacting the resin-based compound of formula 2 with a first deprotecting agent in the presence of a solvent to form a compound of formula 2 [ka] or providing a resin-based compound of b. The resin-based compound of formula 2 is mixed with a compound of formula 3 [ka] in the presence of an organic solvent and a base to form a compound of formula 4 [ka] or providing a resin-based compound of c. contacting the resin-based compound of formula 4 with a second deprotecting agent in the presence of an organic solvent to produce a compound of formula 5 [ka] or providing a resin-based compound of d. The resin-based compound of formula 5 is reacted with a compound of formula 6 [ka] in the presence of a solvent, a coupling agent, and optionally a base and / or an additive. By contacting, the compound of formula 7 [ka] or providing a resin-based compound of e. contacting the resin-based compound of formula 7 with a third deprotecting agent in the presence of a solvent to produce a compound of formula 8. [ka] or providing a resin-based compound of f. The resin-based compound of formula 8 is reacted with a compound of formula 9 [ka] in the presence of a solvent, a coupling agent, and optionally a base and / or an additive. By contacting, the formula 10 [ka] or providing a resin-based compound of g. reacting the resin-based compound of formula 10 with at least one third deprotecting agent and and / or a cleavage reagent to provide a compound of formula I. one or more of In the formula, PG, PG 1 and P.G. 4 is an amine protecting group, PG 2 , P.G. 3 , and P.G. 5 teeth is a carboxyl protecting group, and LG of compound C is a leaving group.

[0149] The present disclosure relates to a method for preparing a compound of formula I as described in the above paragraph (by method 1 or method 2). The present invention provides a method for producing a medicament for use in a pharmaceutical composition comprising the steps of: It will be appreciated that the present disclosure also provides a method for producing a compound of formula (a) comprising steps (a) and (b). Alternatively, the present disclosure provides a method for preparing a compound of formula I comprising steps (b) and (c) Alternatively, the present disclosure provides a method for preparing a compound of formula I, comprising the steps ( Alternatively, the present invention provides a method for preparing a compound of formula I, comprising steps (c) and (d). The figure provides a method for preparing a compound of formula I, comprising steps (d) and (e). Alternatively, the present disclosure relates to a method for preparing a compound of formula I, comprising steps (e) and (f). Alternatively, the present disclosure provides a method for preparing a compound of formula I, comprising steps (f) and (g). Alternatively, the present disclosure provides a method for preparing a compound of formula I, comprising steps (g) and (h). Alternatively, the present disclosure provides a method for preparing a product comprising steps (h) and (i). Alternatively, the present disclosure provides a method for preparing a compound of formula I, comprising steps (a), ( Alternatively, the present invention provides a method for preparing a compound of formula I, comprising steps (a) and (b). The present invention provides a method for preparing a compound of formula I, comprising steps (b), (c) and (d). Alternatively, the present disclosure provides a method for preparing a compound of formula I, comprising steps (c), (d) and (e). Alternatively, the present disclosure provides a method for comprising steps (d), (e) and (f). Alternatively, the present disclosure provides a method for preparing a compound of formula I, comprising steps (e), ( Alternatively, the present invention provides a method for preparing a compound of formula I, comprising steps (f) and (g). The present invention provides a method for preparing a compound of formula I, comprising steps (d), (e) and (f). Alternatively, the present disclosure provides a method for preparing a compound of formula I, comprising steps (f), (g) and (h). Alternatively, the present disclosure provides a method for comprising steps (d), (e) and (f). Alternatively, the present disclosure provides a method for preparing a compound of formula I, comprising steps (g), ( Alternatively, the present invention provides a method for preparing a compound of formula I, comprising steps (i) and (h). The illustration includes steps (a), (b), (c), (d), (e), (f), (g), and (h). The present invention provides methods for preparing compounds of formula I, including

[0150] In various embodiments described herein, the protecting group used in the preparation of compound (I) It will be appreciated by those skilled in the art that the selection of groups may be selected from a variety of alternatives known in the art. It will be appreciated that any protecting group may be used in an orthogonal protecting strategy. It will be appreciated that the protecting group scheme will be selected. Cross-protection is a strategy that allows the deprotection of one or more of multiple protecting groups. Here, protecting groups are used to selectively react one with another using a dedicated set of reaction conditions. Each is removed one at a time or is prevented from affecting the others using a dedicated set of reaction conditions. are removed together as a subset of all protecting groups used in the synthesis without affecting the .

[0151] In step (a) of method 1, PG on a resin-based compound of formula A 1 is 9-fluorenyl and protecting groups such as t-butylcarbonyl (Fmoc) or t-butylcarbonyl (Boc). Earned, PG 2 is 4-methyltrityl (Mtt) or monomethoxytrityl (MMt), etc. The first deprotecting agent in step (a) of method 1 can be an orthogonal protecting group of PG 1 and / or PG 2 Depending on the identity of the deprotecting agent, it may be an acidic or basic deprotecting agent. The first deprotecting agent is piperidine, morpholine, 1,8-diazabicyclo[5.4.0]urethane, Decan-7-ene (DBU), diethylamine (DEA), dicyclohexamine, 4-methyl- tris(2-aminoethyl)amine, pyridine, or colloidal In particular, the first deprotecting agent may be a basic deprotecting agent such as TFA, HCl, or H Suitable deprotecting agents for step (a) of method 1 may be acidic deprotecting agents such as 3PO4. The conditions are, for example, Wuts, PGM, Greene, TW, Greene, TW,& John Wiley & Sons.(2006).Greene's protective groups in organic synthesis. Hoboken, NJ: Wiley-Interscience. In step (a) of method 1, the base used to remove the Fmoc group is piperidine. The polar aprotic solvent in step (a) of method 1 can be any of the polar aprotic solvents known in the art. The solvent may be a polar aprotic solvent. Suitable polar aprotic solvents include dimethylformamide, Dimethyl ether (DMF), N-methyl-2-pyrrolidone (NMP), dichloromethane (DCM ), dichloromethane / dimethylformamide mixture, acetonitrile (ACN), acetonitrile Nitrile / dimethylformamide mixtures and dimethyl sulfoxide (DMSO) The step (a) of method 1 can be carried out at room temperature, under cooling, or under heating. It will be appreciated that the method can be carried out at any temperature, such as under conditions typically used in solid phase synthesis. The deprotection step (a) of method 1 may be carried out for about 5 minutes to about 200 minutes, or about 10 minutes to about 10 minutes. 0 minutes, or about 40 minutes to about 60 minutes to about 15 minutes, or about 30 minutes, or about 90 minutes, etc. Following the deprotection step (a) of Method 1, the compound of formula A' prepared in step (a) can be The resin-based compound may be prepared using a solvent such as DMF, IPA, or CH2Cl2, which are commonly known in the art. It can be washed with a reagent.

[0152] In step (b) of method 1, R on the compound of formula B 1 is C1-C4 alkyl, preferably LG may be tert-butyl or cyclohexyl, and LG may be an active ester or the like. Suitable active esters known in the art include 4-nitrophenyl, 2,4 ,5-trichlorophenyl, NHS ester, benzotriazyl, etc. In some embodiments, LG is a 4-nitrophenyl ester. R 1 The choice is PG 1 , P.G. 2 and / or be orthogonal to the choice of resin bead connection. It will be appreciated that in step (b) of method 1, the base may be any suitable base as described in the art for the urea forming reaction. The base may be any base commonly known in the art. Suitable bases include N,N-diisopropyl isopropylethylamine ( i PrNEt), triethylamine (TEA), 4-methyl These include morpholine (NMM), imidazole, pyridine, and collidine. The step (b) of method 1 can be carried out in a solvent, such as an organic solvent. The solvent may be any solvent commonly known in the art for resin-based synthesis. Suitable organic solvents include CH2Cl2, THF, diethyl ether, MeOH, E Examples of solvents include, but are not limited to, tOH, acetone, and acetonitrile. In some embodiments, the solvent is CH2Cl2. Step (b) of method 1 is carried out at room temperature under cooling. The reaction can be carried out at any temperature commonly used in solid phase synthesis, such as under elevated or elevated temperature. It will be appreciated that the deprotection step (b) of method 1 can be carried out for about 5 minutes to about 200 minutes, or About 10 minutes to about 100 minutes, or about 40 minutes to about 60 minutes to about 15 minutes, or about 30 minutes, or about 90 minutes The deprotection step (a) of Method 1 can be followed by the deprotection of the compound prepared in step (b). The resin-based compound of formula C prepared above was dissolved in DMF, IPA, CH2Cl2, or other solvents commonly used in the art. The material can be washed with reagents known in the art.

[0153] In step (c) of method 1, the second deprotecting agent is PG 1 and / or PG 2 Aiden Depending on the activity, the deprotection agent may be an acidic deprotection agent, a basic deprotection agent, or other deprotection agent. In some embodiments, the second deprotecting agent may be an acidic deprotecting agent. Suitable acidic deprotecting agents include Examples include, but are not limited to, TFA, HCl, or H3PO4. In some embodiments, the second deprotecting agent in step (c) of method 1 is trifluoroacetic acid ( TFA), acetic acid, trifluoroethanol, hexafluoroisopropanol, dichloro methane, and combinations thereof. In some embodiments, The second deprotection is 2 In some embodiments, the β-amino acid is TFA, such as when β-amino acid is Mtt. The second deprotection is PG 2 For example, when Mtt is used, acetic acid and trifluoroethanol are used. In some embodiments, the second deprotecting agent is a mixture of PG 2 is alloc For example, a suitable deprotection agent for step (c) of method 1 may be a palladium deprotection agent. The agents and conditions are described, for example, in Wuts, PGM, Greene, TW, Green e,TW,& John Wiley & Sons.(2006).Greene 's protective groups in organic synthesis Hoboken, NJ: Wiley-Interscience. Mtt can be cleaved using an acidic deprotection agent (TFA). Other suitable acidic deprotection agents include The following are examples of the fluorochemicals: acetic acid, trifluoroethanol, dichloromethane, hexafluoroisopropanol These include, but are not limited to, dichloromethane, dichloromethane, and combinations thereof. Step (c) of method 1 can be carried out in a solvent, such as an organic solvent. The solvent may be any solvent generally known in the art for the synthesis of azeotropic solvents. Examples include CH2Cl2, THF, diethyl ether, MeOH, EtOH, acetone, and acetone. In some embodiments, the solvent may be acetonitrile or the like. The solvent is CH2Cl2.

[0154] In step (d), PG 1 -PG on 3-(2-naphthyl)-L-alanine 1 [ka] is 9-fluorenylmethyl-carbonyl (Fmoc) or t-butylcarbonyl (Bo c) may be a protecting group such as PG 1 The selection of is carried out in accordance with step (a) of method 1 above. In step (d) of method 1, the polar aprotic solvent is a solvent that is known in the art to The solvent may be any commonly known polar aprotic solvent. The solvents used were N-methyl-2-pyrrolidone (NMP), dichloromethane (DCM), and dichloromethane (DCM). Dimethylformamide / dimethylformamide mixture, acetonitrile (ACN), acetonitrile / dimethylformamide mixture, and dimethyl sulfoxide (DMSO). In some embodiments, the polar aprotic solvent is DMF. Suitable bases include triethylamine (TEA), 4-methylmorpholine (NM M), imidazole, pyridine, and collidine. In some embodiments, the base in step (d) of method 1 is N,N-diisopropyl Ethylamine ( i Coupling agents are used for resin-based synthesis. The coupling agent may be any coupling agent commonly known in the art. The agents include HATU, TBTU, HBTU, CDMT, HDMC, COMU, and TATU. Some examples include, but are not limited to, TOTT, T3P, and DMTMM. In an embodiment, the coupling agent in step (d) of method 1 is (PyBOP). Step (d) of method 1 can be carried out under room temperature, cooled, or heated conditions, as commonly used in solid phase synthesis. It will be appreciated that the coupling step of Method 1 ( d) is about 5 minutes to about 200 minutes, or about 10 minutes to about 100 minutes, or about 40 minutes to about 60 minutes to about The coupling may be performed for a period of about 15 minutes, about 30 minutes, or about 90 minutes. Following the mixing step (d), the resin-based compound of formula D produced in step (d) of method 1 is mixed with DM F, IPA, CH2Cl2, or other reagents commonly known in the art. can.

[0155] In step (e) of method 1, PG on a resin-based compound of formula D 1 is 9-fluorenyl and protecting groups such as t-butylcarbonyl (Fmoc) or t-butylcarbonyl (Boc). Earned, PG 2 is 4-methyltrityl (Mtt) or monomethoxytrityl (MMt), etc. The first deprotecting agent in step (e) of method 1 can be an orthogonal protecting group of PG 1 and / or PG 2 Depending on the identity of the protective agent, it may be an acidic or basic protective agent. The deprotection agents are piperidine, morpholine, and 1,8-diazabicyclo[5.4.0]undecane. Carboxy-7-ene (DBU), diethylamine (DEA), dicyclohexamine, 4-methyl Piperidine (4MP), tris(2-aminoethyl)amine, pyridine, or collidine The first deprotection agent can be any basic deprotection agent. In particular, the first deprotection agent can be TFA, HCl, or H3P Suitable deprotecting agents and conditions for step (e) of method 1 include: For example, Wuts, PGM, Greene, TW, Greene, T. W.,& John Wiley & Sons.(2006).Greene's p. rotective groups in organic synthesis.Ho Boken, NJ: Wiley-Interscience. The polar aprotic solvent in step (e) of method 1 can be any polar aprotic solvent known in the art. Suitable polar aprotic solvents include dimethylformamide (DM F), N-methyl-2-pyrrolidone (NMP), dichloromethane (DCM), Acetonitrile (ACN), acetonitrile / dimethylformamide mixture, dimethylformamide mixture, and dimethyl sulfoxide (DMSO), The method 1, step (e) may be carried out under solid conditions, such as at room temperature, under cooling, or under heating. It will be appreciated that the method can be carried out at any temperature commonly used in phase synthesis. The deprotection step (e) of method 1 can be carried out for about 5 minutes to about 200 minutes, or about 10 minutes to about 100 minutes, or about 4 minutes. It can be performed for a period of time such as 0 minutes to about 60 minutes to about 45 minutes, or about 60 minutes, or about 90 minutes. Following the deprotection step (e) of Method 1, a resin-based compound of formula D' prepared in step (e) of Method 1 may be prepared. The mixture is washed with reagents commonly known in the art, such as DMF, IPA, CH2Cl2, etc. It can be purified.

[0156] In step (f) of the first method, PG 1 -PG on tranexamic acid reagent 1 teeth, [ka] 9-Fluorenylmethyl-carbonyl (Fmoc) or t-Butylcarbonyl (Boc) It may be a protecting group such as PG 1 For the selection of the above, see step (a) of Method 1. In step (f) of method 1, the polar aprotic solvent is a solvent generally known in the art. The solvent may be any polar aprotic solvent known in the art. Suitable polar aprotic solvents are Examples include N-methyl-2-pyrrolidone (NMP), dichloromethane (DCM), and dichloromethane (DCM). Methane / dimethylformamide mixture, acetonitrile (ACN), acetonitrile / dimethylformamide methylformamide mixture, and dimethyl sulfoxide (DMSO). In some embodiments, the polar aprotic solvent is DMF. Suitable bases include triethylamine (TEA), 4-methylmorpholine (NMM), Examples of suitable amines include, but are not limited to, imidazole, pyridine, and collidine. In some embodiments, the base in step (f) of method 1 is N,N-diisopropylethyl ether. amine ( i Coupling agents are used in the art for resin-based synthesis. The coupling agent may be any coupling agent commonly known in the art. The following are the cases: HATU, TBTU, HBTU, CDMT, HDMC, COMU, TATU, T Some implementations include, but are not limited to, OTT, T3P, and DMTMM. In one embodiment, the coupling agent in step (f) of Method 1 is (PyBOP). Step (f) may be carried out under any of the conditions commonly used in solid phase synthesis, such as at room temperature, under cooling, or under warm conditions. It will be appreciated that the coupling step (f) of method 1 can be carried out at a temperature of About 5 minutes to about 200 minutes, about 10 minutes to about 100 minutes, or about 40 minutes to about 60 minutes to about 15 minutes The coupling can be carried out for a period of time such as about 10 minutes, about 30 minutes, or about 90 minutes. Following step (f), the resin-based compound of formula E prepared in step (f) of method 1 is dissolved in DMF, It can be washed with reagents commonly known in the art such as IPA, CH2Cl2, etc. do.

[0157] In step (g) of method 1, PG on the resin-based compound of formula E 1 is 9-fluorenyl and protecting groups such as t-butylcarbonyl (Fmoc) or t-butylcarbonyl (Boc). Earned, PG 2 is 4-methyltrityl (Mtt) or monomethoxytrityl (MMt), etc. The first deprotecting agent in step (g) of method 1 can be an orthogonal protecting group of PG 1 and / or PG 2 Depending on the identity of the protective agent, it may be an acidic or basic protective agent. The deprotection agents are piperidine, morpholine, and 1,8-diazabicyclo[5.4.0]undecane. Carboxy-7-ene (DBU), diethylamine (DEA), dicyclohexamine, 4-methyl Piperidine (4MP), tris(2-aminoethyl)amine, pyridine, or collidine The first deprotection agent can be any basic deprotection agent. In particular, the first deprotection agent can be TFA, HCl, or H3P Suitable deprotecting agents and conditions for step (g) of method 1 include: For example, Wuts, PGM, Greene, TW, Greene, T. W.,& John Wiley & Sons.(2006).Greene's p. rotective groups in organic synthesis.Ho Boken, NJ: Wiley-Interscience. The polar aprotic solvent in step (g) of method 1 can be any polar aprotic solvent known in the art. Suitable polar aprotic solvents include dimethylformamide (DM F), N-methyl-2-pyrrolidone (NMP), dichloromethane (DCM), Acetonitrile (ACN), acetonitrile / dimethylformamide mixture, dimethylformamide mixture, and dimethyl sulfoxide (DMSO), The method (g) may be carried out under a solid state, for example, at room temperature, under cooling, or under heating. It will be appreciated that the method can be carried out at any temperature commonly used in phase synthesis. The deprotection step (g) of method 1 can be carried out for about 5 minutes to about 200 minutes, or about 10 minutes to about 100 minutes, or about 4 minutes. It can be performed for a period of time such as 0 minutes to about 60 minutes to about 45 minutes, or about 60 minutes, or about 90 minutes. Following the deprotection step (g) of Method 1, a resin-based compound of formula E′ prepared in step (g) of Method 1 is The mixture is washed with reagents commonly known in the art, such as DMF, IPA, CH2Cl2, etc. It can be purified.

[0158] In step (h) of method 1, the polar aprotic solvent is a solvent generally known in the art. The solvent may be any polar aprotic solvent that is suitable for use in the preparation of ethanol. Suitable polar aprotic solvents include N -Methyl-2-pyrrolidone (NMP), dichloromethane (DCM), dichloromethane / di Methylformamide mixture, acetonitrile (ACN), acetonitrile / dimethylformamide These include, but are not limited to, dimethyl sulfoxide (DMSO), dimethyl sulphoxide (DMSO), and dimethyl sulphoxide (DMSO). In some embodiments, the polar aprotic solvent is DMF. The groups include triethylamine (TEA), 4-methylmorpholine (NMM), imidazoline, Some examples include, but are not limited to, ethanol, pyridine, and collidine. In one embodiment, the base in step (h) of method 1 is N,N-diisopropylethylamine ( i Coupling agents are well known in the art for resin-based synthesis. The coupling agent may be any commonly known coupling agent. Suitable coupling agents include H ATU, TBTU, HBTU, CDMT, HDMC, COMU, TATU, TOTT, T In some embodiments, the method includes, but is not limited to, 3P, DMTMM. The coupling agent in step (h) of method 1 is (PyBOP). ) can be carried out at any temperature commonly used in solid phase synthesis, including room temperature, cooled, or heated conditions. It will be appreciated that the coupling step (h) of method 1 can be carried out in about 5 minutes. ~ about 200 minutes, or about 10 minutes to about 100 minutes, or about 40 minutes to about 60 minutes to about 15 minutes, or about The coupling step (h) of method 1 can be carried out for a period of time such as about 30 minutes, or about 90 minutes. Next, the resin-based compound of formula F prepared in step (h) of method 1 is dissolved in DMF, IPA, CH The solution can be washed with reagents commonly known in the art, such as 2Cl2.

[0159] In step (i) of method 1, the third deprotecting agent may be the same as or different from the cleavage reagent. In some embodiments, the third deprotecting agent may be, for example, R 1 Cyclohexyl where the cleavage reagent can be TFA, HF or TfOH. In the embodiment, for example, R 1 A third deprotecting agent and a cleavage agent, such as when is tert-butyl. The cleaving agents can both be TFA. In some embodiments, the third deprotecting agent and the cleaving agent The cleavage reagent can be a mixture of TFA, water, and triisopropylsilane in both cases. A suitable deprotection agent for this is trifluoroacetic acid (TFA) / dichloromethane (DCM) mixture. Compound, triethylsaline (TES), indole, Examples include, but are not limited to, phenol / anisole mixtures, and thioanisole. Step (i) of method 1 can be carried out in a solvent, such as an organic solvent. The solvent may be any solvent generally known in the art for lipid-based synthesis. The solvents are CH2Cl2, THF, diethyl ether, MeOH, EtOH, and acetone. , acetonitrile, and the like. In some embodiments, , the solvent is CH2Cl2.

[0160] In step (a) of method 2, PG on the resin-based compound of formula 1 can be a protecting group, in particular , 9-fluorenylmethyl-carbonyl (Fmoc), benzyl carbamate (Cbz) , t-butyloxycarbonyl (Boc), acetamide, trifluoroacetamide, p-Toluenesulfonamide, triphemylmethyl , monomethoxytrityl (MMt), or 4-methyltrityl (Mtt) In step (a) of method 2, PG may be a protecting group. 1 is a protecting group, in particular, 9-fluoro Fluorenylmethyl-carbonyl (Fmoc), benzyl carbamate (Cbz), t-Bu Boc, acetamide, trifluoroacetamide, p-toluamide Ethylsulfonamide, triphemylmethyl, monomethacrylate orthogonal to PG, such as 4-methyltrityl (Mtt) or 4-methyltrityl (MMt). In some embodiments, PG can be a 9-fluorenylmethyl- butylcarbonyl (Fmoc) or t-butylcarbonyl (Boc), 1 teeth, Orthogonal protecting groups such as 4-methyltrityl (Mtt) or monomethoxytrityl (MMt) It's fine.

[0161] The first deprotecting agent in step (a) of method 2 is a deprotecting agent for an amine protecting group, such as 9-fluorenyl Benzyl carbamate (Cbz), t-butyloxy Dicarbonyl (Boc), acetamide, trifluoroacetamide, p-toluenesulfonyl triphemylmethyl, monomethacrylate Reagents capable of removing trityl (MMt) or 4-methyltrityl (Mtt) In some embodiments, the first deprotection of step (a) of method 2 may be a mixture of reagents. The agent is a reagent or a mixture of reagents capable of removing 9-fluorenylmethyl-carbonyl In some embodiments, the first deprotecting agent of step (a) of method 2 comprises PG and / or PG 1 Depending on the identity of the deprotecting agent, it may be an acidic or basic deprotecting agent. The first deprotecting agent is a basic deprotecting agent, such as piperidine, morpholine, 1,8-diaza Bicyclo[5.4.0]undec-7-ene (DBU), diethylamine (DEA), Cyclohexamine, 4-methylpiperidine (4MP), tris(2-aminoethyl)amine In particular, the first deprotecting agent may be an acidic deprotecting agent, e.g. For example, TFA, HCl, or H3PO4 may be used. Protective agents and conditions are described, for example, in Wuts, PGM, Greene, TW, Gre ene,TW,& John Wiley & Sons.(2006).Gree ne's protective groups in organic synthesis sis.Hoboken, NJ:Wiley-Interscience. can be done.

[0162] In some embodiments of step (a) of method 2, a 2-aminopropyl group is used to remove the Fmoc group. The base can be an amine base, such as piperidine. The polar aprotic solvent in step (a) may be any polar aprotic solvent known in the art. Suitable polar aprotic solvents include dimethylformamide (DMF). , N-methyl-2-pyrrolidone (NMP), dichloromethane (DCM), dichloromethane / Dimethylformamide mixture, Acetonitrile (ACN), Acetonitrile / Dimethyl Formamide mixture, and dimethyl sulfoxide (DMSO), etc. The step (a) can be carried out under conditions generally used in solid phase synthesis, such as at room temperature, under cooling, or under heating. It will be appreciated that the deprotection of method 2 can be carried out at any temperature used in the method. Step (a) may be carried out for about 5 minutes to about 200 minutes, or about 10 minutes to about 100 minutes, or about 40 minutes to about 60 minutes. The desorption of the cellulose may be performed for a period of time ranging from about 15 minutes to about 15 minutes, about 30 minutes, or about 90 minutes. Following protection step (a), the resin-based compound of formula B prepared in step (a) of method 2 is reacted with DM F, IPA, CH2Cl2, or other reagents commonly known in the art. can.

[0163] In step (b) of method 2, PG on the compound of formula 3 2 and / or PG 3 are respectively may independently be a carboxy protecting group, and LG is a leaving group such as an active ester. Suitable activated esters known in the art include imidazolyl, 4-nitrophenoxy, Phenoxy, 2,4,5-trichlorophenyl, NHS ester, benzotriazyl, etc. In some embodiments, the LG of compound 3 is an imino group. In some embodiments, the aryloxy group is selected from dazolyl, 4-nitrophenoxy, and phenoxy. In the compound 3, LG is a 4-nitrophenyl ester. 2 and / or PG 3 The choice is PG and PG 1 It will be appreciated that the choice of In terms of form, PG 2 and / or PG 3 In step (b) of method 2, In the present invention, the base is any base commonly known in the art for urea forming reactions. Suitable bases include N,N-diisopropylethylamine ( i PrNEt), Triethylamine (TEA), 4-methylmorpholine (NMM), imidazole, pyridinium Examples of suitable amines include, but are not limited to, riboflavin, and collidine.

[0164] Step (b) of method 2 can be carried out in a solvent, such as an organic solvent. The solvent may be any solvent generally known in the art for the synthesis of bases. Examples include CH2Cl2, THF, diethyl ether, MeOH, EtOH, acetone, In some embodiments, the solvent may be acetonitrile or the like. The solvent is CH2Cl2. Step (b) of Method 2 can be carried out at room temperature, under cooling, or under warm conditions. It will be appreciated that the reaction can be carried out at any temperature commonly used in solid phase synthesis, such as at any temperature. The deprotection step (b) of method 2 may be carried out for about 5 minutes to about 200 minutes, or about 10 minutes to about 100 minutes. For a period of about 40 minutes to about 60 minutes to about 15 minutes, about 30 minutes, or about 90 minutes, etc. Following step (b) of method 2, the resin-based compound of formula 4 produced in step (b) can be The material is washed with reagents commonly known in the art, such as DMF, IPA, CH2Cl2, etc. It is possible.

[0165] In step (c) of method 2, the second deprotecting agent is 9-fluorenylmethyl-carbonyl Fmoc, benzyl carbamate (Cbz), t-butyloxycarbonyl (Bo c) Acetamide, trifluoroacetamide, p-toluenesulfonamide, trifluoroacetamide triphemylmethyl, monomethoxytrityl (MMt), and 4-methyltrityl (Mtt). In some embodiments, the second deprotecting agent can be a reagent or mixture of reagents capable of reacting with 4 -methyltrityl (Mtt) can be any reagent or mixture of reagents capable of removing methyltrityl (Mtt). In some embodiments, the second deprotecting agent is PG 1 , P.G. 2 and / or PG 3 Idea Depending on the identity of the compound, the deprotecting agent may be an acidic deprotecting agent, a basic deprotecting agent, or another deprotecting agent. In some embodiments, the second deprotection agent can be an acidic deprotection agent. Agents include, but are not limited to, TFA, HCl, or H3PO4. In some embodiments, the second deprotecting agent in step (c) of method 2 is a trifluoro Acetic acid (TFA), acetic acid, trifluoroethanol, hexafluoroisopropanol, and and combinations thereof. In some embodiments, the second deprotection Mamoru is PG 2 is TFA, such as when is Mtt. The second deprotection in step (c) is 2 For example, when Mtt is used, acetic acid and trifluoroacetate are used. Suitable deprotection agents and conditions for step (c) of method 2. For example, Wuts, PGM, Greene, TW, Greene, TW .,& John Wiley & Sons.(2006).Greene's pr otective groups in organic synthesis.Hob Oaken, NJ: Wiley-Interscience. Step (c) of 2 can be carried out in a solvent, such as an organic solvent. The organic solvent can be a resin-based solvent. Suitable organic solvents include any solvent generally known in the art for the synthesis of CH2Cl2, THF, diethyl ether, MeOH, EtOH, acetone, acetonitrile In some embodiments, the solvent includes, but is not limited to, nitriles, etc. , CH2Cl2. Following the deprotection step (c) of Method 2, The resin-based compound of formula 5 was dissolved in a solvent commonly used in the art, such as DMF, IPA, or CH2Cl2. It can be washed with known reagents.

[0166] In step (d) of method 2, PG 4 is a protecting group, particularly an amine protecting group, 9-fluorenyl Benzyl carbamate (Cbz), t-butyloxy Dicarbonyl (Boc), acetamide, trifluoroacetamide, p-toluenesulfonyl triphemylmethyl, monomethacrylate Trityl (MMt), and 4-methyltrityl (Mtt). Well, P.G. 4 9-fluorenylmethyl-carbonyl (Fmoc) or t-butylcarbamate It can be bonyl (Boc). PG 4 For the selection of the above, see step (a) of Method 2. In step (d) of method 2, the solvent can be a polar aprotic solvent. In some embodiments, the polar aprotic solvent is any solvent commonly known in the art. The solvent may be any polar aprotic solvent. Suitable polar aprotic solvents include dimethyl Formamide (DMF), N-methyl-2-pyrrolidone (NMP), dichloromethane (D CM), dichloromethane / dimethylformamide mixture, acetonitrile (ACN), Acetonitrile / dimethylformamide mixture and dimethyl sulfoxide (DMSO) In some embodiments, polar aprotic solvents include, but are not limited to, is DMF. Suitable bases for use in step (d) of method 2 include N,N-diphenylmethane, Isopropylethylamine ( i PrNEt), triethylamine (TEA), 4-methyl These include non-morpholine (NMM), imidazole, pyridine, and collidine. In some embodiments, the base in step (d) is an N,N-diamino isopropylethylamine ( i PrNEt).

[0167] The coupling agent may be any of those commonly known in the art for resin-based synthesis. Suitable coupling agents for use in step (d) of method 2 include Benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium Hexafluorophosphate (BOP), Benzotriazol-1-yl-oxytripy Lolidinophosphonium hexafluorophosphate (PyBOP), 7-aza-benzothiazide Triazol-1-yloxy-tripyrrolidino-phosphonium hexafluorophosphate (PyAOP), Ethyl cyano(hydroxyimino)acetato-O2)-tri-(1- Pyrrolidinyl)-phosphonium hexafluorophosphate (PyOxim), bromo- Tripyrrolidino-phosphonium hexafluorophosphate (PyBrOP), 3-(di Ethoxy-phosphoryloxy)-1,2,3-benzo[d]triazine-4(3H)-o DEPBT, 1-[bis(dimethylamino)methylene]-1H-1,2,3-trimethylphenyl Azolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU ), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluron tetrafluoroborate (TBTU), 2-(1H-benzotriazole-1-yl) HBTU)-1,1,3,3-tetramethyluronium hexafluorophosphate ), 2-(6-chloro-1H-benzotriazol-1-yl)-N,N,N',N'- Tetramethylaminium hexafluorophosphate (HCTU), 2-chloro-4,6 -Dimethoxy-1,3,5-triazine (CDMT), N-[(5-chloro-3-oxy Do-1H-benzotriazol-1-yl)-4-morpholinylmethylene]-N-methyl Methanaminium hexafluorophosphate (HDMC), 1-cyano-2-ethoxy -2-Oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexa Fluorophosphate (COMU), dimethylamino (triazolo[4,5-b]pyridine Dimethylazanium tetrafluoroborate (T ATU), N,N,N',N'-tetramethyl-S-(1-oxido-2-pyridyl)thio Auronium tetrafluoroborate (TOTT), Tetramethylfluoroformamide Trifluoroethylene hexafluorophosphate (TFFH), N-ethoxycarbonyl-2-ethoxy 1,2-dihydroquinoline (EEDQ), 1-propanephosphonic anhydride (T3P) , 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-mol Dicyclohexylcarbodiimide (DCC), dicyclohexylcarbodimide (DMTMM), N-(3-dimethylaminopropyl)-N'-isopropylcarbodiimide (DIC), Ethylcarbodiimide (EDAC), or 1,1'-carbonyldiimidizole (carb These include, but are not limited to, cyclodextrin (CDI). In some embodiments, the coupling agent in step (d) of method 2 is HATU, TBTU, H BTU, CDMT, HDMC, COMU, TATU, TOTT, T3P, or DMTMM In some embodiments, the coupling agent in step (d) of method 2 can be (PyBOP).

[0168] It will be appreciated that step (d) of method 2 can be carried out in the presence of an additive. Suitable additives include 1-hydroxybenzotriazole (HOBt), 1-hydroxybenzotriazole (1H2O4), HOBt-6-sulfonamide methyl resin HCl (HOBt-6-sulfonamide methyl resin Amidomethyl Resin HCl), Hydroxy-3,4-dihydro-4-oxo-1,2,3 -benzotriazine (HOOBt), N-hydroxysuccinimide (NHS), 1- hydroxy-7-aza-1H-benzotriazole (HOAt), ethyl 2-cyano-2- (Hydroxymino)acetate, or 4-(N,N-dimethyl Examples of suitable dimethylaminopyridine (DMAP) include, but are not limited to, dimethylaminopyridine (DMAP). (d) is at any temperature commonly used in solid phase synthesis, such as room temperature, cooled, or heated conditions. It will be appreciated that the coupling step (d) of method 2 can be carried out in a reaction mixture of about 5 minutes to about 200 minutes, or about 10 minutes to about 100 minutes, or about 40 minutes to about 60 minutes to about 15 minutes, or The coupling step of Method 2 ( Following step (d), the resin-based compound of formula 7 prepared in step (d) of method 2 is dissolved in DMF, IPA, The mixture can be washed with reagents commonly known in the art, such as, for example, CH2Cl2.

[0169] In step (e) of method 2, PG on the resin-based compound of formula 7 4 is 9-fluorenyl Fmoc, benzyl carbamate (Cbz), t-butyloxycarbonyl Carbonyl (Boc), acetamide, trifluoroacetamide, p-toluenesulfone Amide, triphemylmethyl, monomethoxytrimethyl The protecting group may be an amine protecting group such as 4-methyltrityl (MMt), and 4-methyltrityl (Mtt). The third deprotecting agent in step (e) of 2 is 9-fluorenylmethyl-carbonyl (Fm oc), benzyl carbamate (Cbz), t-butyloxycarbonyl (Boc), Cetoamide, trifluoroacetamide, p-toluenesulfonamide, triphenylmethane triphemylmethyl, monomethoxytrityl (MMt), and 4- A reagent capable of removing a protecting group selected from the group consisting of methyltrityl (Mtt) or a mixture of reagents. In some embodiments, PG 4 is 9-fluorenyl In some embodiments, the third deprotecting agent can be ethyl-carbonyl (Fmoc). may be the third deprotecting agent in step (e) of method 2, 9-fluorenylmethyl-carbonyl In some embodiments, the third The deprotecting agent can be an acidic or basic protecting agent. In some embodiments, the third deprotecting agent The agents are piperidine, morpholine, 1,8-diazabicyclo[5.4.0]undeca-7- Diethylamine (DEA), dicyclohexamine, 4-methylpiperidinyl A base such as 4MP, tris(2-aminoethyl)amine, pyridine, or collidine In some embodiments, the third deprotecting agent can be a reactive deprotecting agent such as TFA, HCl, or H3PO4. The protective agents and conditions are described, for example, in Wuts, PGM, Greene, TW, Greene ne,TW,& John Wiley & Sons.(2006).Green e's protective groups in organic synthesis Hoboken, NJ: Wiley-Interscience. can.

[0170] In some embodiments, step (e) of method 2 is carried out in a solvent, such as a polar aprotic solvent. The polar aprotic solvent in step (e) of method 2 can be any of the polar aprotic solvents known in the art. The solvent may be any polar aprotic solvent. Suitable polar aprotic solvents include dichloromethane, Dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), dichloromethane (DCM), dichloromethane / dimethylformamide mixture, acetonitrile (ACN) , acetonitrile / dimethylformamide mixture, and dimethyl sulfoxide (DMSO The step (e) of the method 2 includes, but is not limited to, a method of: The reaction can be carried out at any temperature commonly used in solid phase synthesis, such as under elevated or elevated temperature conditions. It will be appreciated that the deprotection step (e) of method 2 can be carried out in a period of about 5 minutes to about 200 minutes, or in a period of about 10 minutes. About 100 minutes, about 40 minutes to about 60 minutes to about 45 minutes, about 60 minutes, about 90 minutes, etc. The deprotection step (e) of Method 2 can be followed by the deprotection step (e) of Method 2. The resin-based compound of formula 9 thus prepared was dissolved in a solvent commonly used in the art, such as DMF, IPA, or CH2Cl2. The material can be washed with reagents known in the art.

[0171] In step (f) of method 2, PG 5 may be a carboxy protecting group. In the embodiment, PG 5 can be t-butyl. PG 5 For the selection, see Method 2 above. In step (f) of method 2, the solvent is a polar aprotic In some embodiments, the polar aprotic solvent can be a solvent generally known in the art. The solvent may be any polar aprotic solvent known in the art. Suitable polar aprotic solvents are Examples of solvents include dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), and diphenyl Dichloromethane (DCM), dichloromethane / dimethylformamide mixture, acetonitrile ACN, acetonitrile / dimethylformamide mixture, and dimethylsulfoxide In some embodiments, polar dimethyl sulfoxide (DMSO) may be used. The aprotic solvent is DMF. Suitable bases for use in step (f) include N , N-Diisopropylethylamine ( i PrNEt), triethylamine (TEA), 4-methylmorpholine (NMM), imidazole, pyridine, and collidine. In some embodiments, the base in step (f) of method 2 is, but is not limited to, is N,N-diisopropylethylamine ( i PrNEt). The coupling agent may be any of those commonly known in the art for resin-based synthesis. Suitable coupling agents for use in step (f) of method 2 may be The agent is benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium. Hexafluorophosphate (BOP), Benzotriazol-1-yl-oxytrimethyl Pyrrolidinophosphonium hexafluorophosphate (PyBOP), 7-aza-benzo Triazol-1-yloxy-tripyrrolidino-phosphonium hexafluorophosphate PyAOP, ethyl cyano(hydroxyimino)acetato-O2)-tri-(1 -pyrrolidinyl)-phosphonium hexafluorophosphate (PyOxim), bromo -Tripyrrolidino-phosphonium hexafluorophosphate (PyBrOP), 3-( Diethoxy-phosphoryloxy)-1,2,3-benzo[d]triazine-4(3H)- DEPBT, 1-[bis(dimethylamino)methylene]-1H-1,2,3-tetramethylbutane Riazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HAT U), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl Tetrafluoroborate (TBTU), 2-(1H-benzotriazole-1- yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBT U), 2-(6-chloro-1H-benzotriazol-1-yl)-N,N,N',N' -Tetramethylaminium hexafluorophosphate (HCTU), 2-chloro-4, 6-Dimethoxy-1,3,5-triazine (CDMT), N-[(5-chloro-3-oxo Cido-1H-benzotriazol-1-yl)-4-morpholinylmethylene]-N-methyl Luminetanaminium hexafluorophosphate (HDMC), 1-cyano-2-ethoxy dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), dimethylamino (triazolo[4,5-b]pi Lysine-3-yloxy)methylidene]-dimethylazanium tetrafluoroborate ( TATU), N,N,N',N'-tetramethyl-S-(1-oxido-2-pyridyl) Thiouronium tetrafluoroborate (TOTT), tetramethylfluoroformamide Trifluoroethylene hexafluorophosphate (TFFH), N-ethoxycarbonyl-2-ethoxy 1,2-dihydroquinoline (EEDQ), 1-propanephosphonic anhydride (T3P ), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl- Dicyclohexylcarbodiimide (DCC), diphenyl ether Isopropylcarbodiimide (DIC), (N-(3-dimethylaminopropyl)-N' -Ethylcarbodiimide (EDAC), and 1,1'-carbonyldiimidizole (car These include, but are not limited to, benzoyldimidizole (CDI). In some embodiments, the coupling agent in step (f) of method 2 is HATU, TBTU, HBTU, CDMT, HDMC, COMU, TATU, TOTT, T3P, or DMTM In some embodiments, the coupling agent in step (f) of method 2 can be , (PyBOP).

[0172] It will be appreciated that step (f) of method 2 can be carried out in the presence of an additive. Suitable additives include 1-hydroxybenzotriazole (HOBt), 1-hydroxybenzotriazole (1H2O4), HOBt-6-sulfonamide methyl resin HCl (HOBt-6-sulfonamide methyl resin Amidomethyl Resin HCl), Hydroxy-3,4-dihydro-4-oxo-1,2,3 -benzotriazine (HOOBt), N-hydroxysuccinimide (NHS), 1- hydroxy-7-aza-1H-benzotriazole (HOAt), ethyl 2-cyano-2- (Hydroxymino)acetate, or 4-(N,N-dimethyl Examples of suitable dimethylaminopyridine (DMAP) include, but are not limited to, dimethylaminopyridine (DMAP). (f) is any temperature commonly used in solid phase synthesis, such as room temperature, cooled, or heated conditions. It will be appreciated that the coupling step (f) of method 2 can be carried out in a reaction mixture of about 5 minutes to about 200 minutes, or about 10 minutes to about 100 minutes, or about 40 minutes to about 60 minutes to about 15 minutes, or The coupling step of Method 2 ( Following step (f), the resin-based compound of formula 10 prepared in step (f) of method 2 is dissolved in DMF, IP The solution can be washed with reagents commonly known in the art, such as HCl, HCl A, or CH2Cl2.

[0173] In step (g) of method 2, PG on the resin-based compound of formula 10 2 , P.G. 3 and / or P G 5 may each be a protecting group, such as a carboxyl protecting group. The third deprotecting agent in step (g) of method 2 is t-butyl, benzyl, 2-chlorotrimethylsilyl. (2Cl-Trt), 2,4-dimethoxybenzyl (Dmb), allyl, 1,1-dimethyl A protective group selected from the group consisting of dimethyl allyl (Dma) and p-nitrobenzyl (pNB). It may be any reagent or mixture of reagents capable of removing a protecting group. In some embodiments, , P.G. 2 , P.G. 3 , and P.G. 5 Each of is a t-butyl group. The third deprotecting agent in 2 , P.G. 3 , and / or P.G. 5 In response to the identity of In some embodiments, the third deprotecting agent is It may be an acidic deprotecting agent such as TFA, HCl, or H3PO4. The third deprotection agent is trifluoroacetic acid (TFA), hydrofluoric acid (HF), trifluoroacetic acid (TFA), trifluoroacetic acid (TfOH), trifluoroacetic acid (TFA) / water / triisopropylsilane mixture , trifluoroacetic acid (TFA) / dichloromethane (DCM) mixture, triethylsaline ( triethylsaline (TES), indole, phenol / anisole mixture Suitable compounds for step (g) may be selected from the group consisting of thioanisole, thioanisole, and thioanisole. Suitable deprotection agents and conditions are described, for example, in Wuts, PGM, Greene, TW, G reene,TW,& John Wiley & Sons.(2006).Gr eene's protective groups in organic synt hesis. Hoboken, NJ: Wiley-Interscience. In some embodiments, the third deprotecting agent in step (g) of method 2 is a trimethylsilyl group. A mixture of fluoroacetic acid (TFA) / water / triisopropylsilane. In one embodiment, the cleavage reagent in step (g) of method 2 is trifluoroacetic acid (TFA) / water / triisopropyl ether. Propyl silane mixture.

[0174] The organic solvent in step (g) of method 2 can be any organic solvent known in the art. Suitable organic solvents include CH2Cl2, THF, diethyl ether, Examples include, but are not limited to, ether, MeOH, EtOH, acetone, and acetonitrile. The step (g) of method 2 can be carried out at room temperature, under cooling, or under heating, or the like, by solid phase synthesis. It will be appreciated that the deprotection of Method 2 can be carried out at any temperature commonly used. The protection step (g) is carried out for about 5 minutes to about 200 minutes, or about 10 minutes to about 100 minutes, or about 40 minutes to about 6 minutes. It can be performed for a period of time such as from 0 minutes to about 45 minutes, or about 60 minutes, or about 90 minutes.

[0175] Method 2, specific embodiment: PSMA 617(I) was synthesized using solid-phase peptide synthesis technology as shown in the following scheme: It can be prepared using: [ka] [ka]

[0176] The following reagents and intermediates can be used: [ka]

[0177] Three chemical transformations take place: by mixing the resin with a base in a polar aprotic solvent, The Fmoc protecting group was removed from the Fmoc-Lys(Mtt)-Wang resin (2-1) by The resin is then washed with a solvent. The ester hydrochloride (3') can be reacted with, for example, a base and carbonyldiimidazole, p-nitrophenyl Activated urea or cation can be used to convert phenyl chloroformate, phenyl chloroformate, etc. The deprotected compound 2-2 is mixed with a solution of 2-3. Once the conversion to 4 is complete, the resin is washed with an organic solvent.

[0178] The resin was mixed with a mixture of 2,2,2-trifluoroethanol, acetic acid and dichloromethane. The methyltrityl protecting group is removed from 2-4 by reacting with 2-4 with the trityl group removed. The resin is then washed with a polar aprotic solvent. In a solvent, (2S)-2-(9-fluorenylmethyloxycarbonylamino)-3-naphthalene talen-2-yl-propionic acid (2-6), a base, and a phosphonium salt activator. After conversion to 2-7, the resin is mixed with an activator, such as, but not limited to, a polar non-promoter. Wash with toluene.

[0179] Fmoc protection from 2-7 by mixing the resin with base in a polar aprotic solvent The deprotected compound 2-8 is reacted with a polar aprotic solvent to remove the aryl group and wash the resin with a solvent. 2-9, with an activating agent such as, but not limited to, a base and a phosphonium salt activating agent. After conversion to 2-10, the resin is washed with polar aprotic and organic solvents. .

[0180] The tert-butyl group was removed and the reaction was carried out with trifluoroacetic acid, triisopropylsilane, and water. The resin is cut by mixing it with the mixture. The liquid is separated from the cut resin and the organic solvent is added. The crude PSMA 617 was purified by column chromatography and The material is desalted using an 18 column and an acetonitrile / water gradient eluent. is evaporated or distilled from the aqueous solution under vacuum, and PSMA 617(I) is obtained by lyophilization. Isolate from solution. EXAMPLES

[0181] The examples and preparations provided below further illustrate and describe certain aspects of the embodiments of the present disclosure. It is understood that the scope of the present disclosure is in no way limited by the scope of the following examples. should be done.

[0182] Abbreviation The examples described herein are referred to by the following abbreviations known to those of skill in the art: Use materials including, but not limited to:

[0183] [Table 1-1]

[0184] Example 1a: Preparation of AB2 Compound AB2 was prepared according to the following synthetic scheme: [ka] 403 mg of 4-nitrophenyl chloroformate (2.0 mmol, 0.95 equiv.) 621 mg of L- Glutamic acid di-tert-butyl ester hydrochloride (2.1 mmol, 1.0 equiv.) was added to a stirring The solution was cooled to 0°C and then diluted with 5 mL of CH2Cl2. 0.730 mL of diisopropylethylamine ( i PrNEt) (4.2 mmol, 2 A solution of 1.0 eq. was added dropwise using a pressure equalizing addition funnel. i Pr2NEt addition is complete The reaction mixture was then stirred for 30 minutes, warmed to room temperature, and stirred for an additional 30 minutes. The mixture was evaporated to give the crude product as an oily residue which could be further purified. The mixture was used without further rinsing and kept under high vacuum until desired.

[0185] Example 1b: Alternative preparation of AB2 Add 0.891 g of 4-nitrophenyl chloroformate (4.42 mmol) to the reaction vessel. and 15 mL of dichloromethane (CH2Cl2) and purged with argon. The vessel was fitted with a temperature probe and the solution was cooled to below -10°C using an IPA / ice bath. In a flask, 1.44 g of L-glutamic acid di-tert-butyl ester hydrochloride ( 4.87 mmol) in 15 mL of dichloromethane (CH2Cl2), followed by 1. 54 mL of diisopropylethylamine ( i PrNEt) (8.84 mmol) was added. The L-glutamic acid di-tert-butyl ester hydrochloride solution was stored at -11°C to -5°C. While maintaining the temperature, add dropwise to the cooled 4-nitrophenyl chloroformate solution. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 4 h, at which time the UPLC / MS was used to show that the reaction was complete. The reaction mixture was used without further purification. Used.

[0186] Example 2: Preparation of PSMA-617 The compound of formula I is Fmoc-Lys(N-4-methoxytrityl)-2-chlorotrityl The compound of formula I was prepared by SPPS starting from 1,2-dichloro- ... The mixture was prepared according to the following procedure: [ka] [ka]

[0187] The following Tables 1 and 2 show the results of the above synthetic skis made according to the methods described herein. Here is a summary of the program:

[0188] [Table 1-2]

[0189] [Table 2]

[0190] Pretreatment process: Prior to use in the synthesis process, peptide synthesis vessels were loaded with Fmoc-Lys(Mtt)-Wang 2.00 g (1.08 mmol) of resin (resin loading=0.54 mmol / g) was added. The resin was washed with 20 mL of dimethylformamide (DMF) for 5 min, then the liquid was removed from the vessel. The washing step was repeated one more time.

[0191] Step 1: Urea formation Add the soluble resin to the peptide synthesis vessel. Add DMF (approximately 20 mL) for Fmoc deprotection. A solution of 20% piperidine in 10 mL of ethyl acetate was added. Argon was bubbled through the solution for 15 minutes and then vented. 20% piperidine in DMF (approximately 20 mL) was added, and aeration was continued for 5 minutes, after which the mixture was drained. The resin was washed with DMF (approximately 20 mL × 3), followed by IPA (approximately The mixture was washed with 20 mL x 3) and finally with CH2Cl2 (approximately 20 mL x 3). The crude residue was dissolved in 60 mL of CH2Cl2 and half the volume was added to the deprotected lysine resin. I i PrNEt was added. Argon was bubbled through the solution for 45 minutes and then vented. of crude AB2 solution, followed by i Add PrNEt to the resin and keep argon in the solution for an additional 30 min. The reaction vessel was then drained and the resin was washed with CH2Cl2 (approximately 20 mL x 3). Then, it was washed with IPA (about 20 mL x 3) and again with CH2Cl2 (about 20 mL x 3).

[0192] Alternative urea formation: The lysine resin was added to the peptide synthesis vessel. The AB2 reaction mixture from Example 1b was added to 0. 188mL i The reaction mixture was added to the resin along with PrNEt (1.08 mmol). The mixture was stirred overnight (about 18 hours). The resin was washed with CH2Cl2 (about 20 mL x 3).

[0193] Step 2: Mtt deprotection 2% TFA in CH2Cl2 (approximately 20 mL) was added and argon was bubbled through the solution for 5 min. A small amount of CH2Cl2 was added to the reaction vessel to maintain the same volume in case of vigorous aeration. The yellow solution was drained and repeated five times. The resin was washed with fresh C until the filtrate remained clear. The mixture was washed with H2Cl2. A 2% solution of TFA in CH2Cl2 was added again. If it remained bright, the reaction mixture was drained and the next coupling step was carried out. If so, wash the resin with fresh CH2Cl2 until clear and a clear reaction solution is obtained. This process was repeated until the resin was completely dissolved in DMF (approximately 20 mL x 3).

[0194] Alternative Mtt deprotection 112 mL of CH2Cl2, 32 mL of 2,2,2-trifluoroethanol (TFE ) and 16 mL of acetic acid (AcOH) solution were prepared. The mixture was stirred for about 1 hour, and the solution was added to the resin in the peptide synthesis vessel. The synthesis vessel was drained. This procedure was repeated one more time. 20 mL of AcOH-TFE The solution was added to the resin in the peptide synthesis vessel and the mixture was stirred overnight. The vessel was drained. 20 mL of AcOH-TFE solution was added to the resin in the peptide synthesis vessel. The mixture was stirred for about 1 hour. The liquid was drained from the peptide synthesis vessel. The resin was washed with 3x CH2Cl2, 3x 2-propanol (IPA), and 3x 2-propanol (IPA). × Washed with DMF.

[0195] Step 3: Amino coupling A solution of amino acid in DMF (approximately 20 mL), i Peptide synthesis using Pr2NEt and PyBOP The resin was added to the vessel. Argon was bubbled through the solution for 1 hour and then vented. The resin was diluted with DMF (approximately 20 mL x 3), followed by washing with IPA (approx. 20 mL x 3) and again with DMF (approx. 20 mL x 3). did.

[0196] Alternative Amino Coupling A solution of amino acid in DMF (approximately 20 mL), PyBOP in DMF (approximately 20 mL), and i PrNEt was added to the peptide synthesis vessel containing the resin. The mixture was stirred for approximately 4 hours. The resin was then washed with DMF (approximately 20 mL x 3), followed by The mixture was then washed with IPA (approximately 20 mL x 3).

[0197] Step 4: Fmoc deprotection A deprotection step was performed before each amino acid coupling step (2% TF in CH2Cl2). In addition to Mtt deprotection using A), in DMF (approximately 20 mL) for Fmoc deprotection A solution of 20% piperidine was added. Argon was bubbled through the solution for 15 minutes and then vented. 20% piperidine in DMF (approximately 20 mL) was added, and aeration was continued for 5 min, after which the mixture was drained. (2x). The resin was washed with DMF (approximately 20 mL x 3), followed by IPA (approximately 20 mL x 3) and then washed again with 10 mL of DMF. It was washed with DMF (approximately 20 mL x 3).

[0198] Alternative FMOC deprotection An alternative deprotection step was performed before each amino acid coupling step (in addition to Mtt deprotection). To the resin was added a solution of 20% piperidine in DMF (approximately 20 mL). Stir for approximately 10 minutes. The liquid was drained from the reaction vessel and the process was repeated two more times. The resin was washed with DMF (approximately 20 mL x 3), followed by IPA (approximately 20 mL x 3). Therefore, the resin was dissolved in DMF (approximately 20 mL × 3) or alternatively in CH2Cl2 (approximately 20 mL × 3). ) and further washed.

[0199] Process 5: Resin cutting The resin was washed with CH2Cl2 (approximately 20 mL × 3) and drained. 25 mL of cleavage reagent (9 5% TFA, 2.5% H2O, 2.5% triisopropylsilane) in a peptide synthesis volume Add to the vessel, bubble with argon for 1 h, vent, and then centrifuge with fresh cleavage reagent (10 mL, 15 min). This was repeated twice. The filtrate was stirred overnight at room temperature under argon. 10 ml of reaction mixture remained. The product was triturated in 40 mL of diethyl ether and centrifuged. The solution was decanted from the resulting pellet. The pellet was dissolved in 50 mL of diethyl ether. The previous step was repeated twice by resuspending and centrifuging. The pellet was then flushed with argon. It was dried over stream and then under high vacuum.

[0200] Alternative Resin Cutting 42 mL of trifluoroacetic acid (TFA), 0.90 mL of water, and 3.0 mL of trifluoroacetic acid A mixture of triisopropylsilane (TIPS) was prepared and added to the resin in the peptide synthesis vessel. The mixture was stirred for 6 hours (the last hour was warmed to 30°C in a water bath). The resin was filtered. The solid was washed with 2 mL of TFA. The filtrate and the product containing the washings were combined. The mixture was washed with 420 mL of methyl tert-butyl ether (MTBE) cooled at 37° C. The product was collected by filtration. The solid was washed with 5 mL of MTBE. The solid was dried under vacuum to give To provide 1.19 g of crude compound of formula I.

[0201] Purification step 1 The resulting powder was dissolved in a small amount of DMSO and loaded onto a C18 column. Reverse-phase chromatography (0-55% acetonitrile in 50 mM ammonium carbonate buffer) The acetonitrile was evaporated under reduced pressure, and the remaining aqueous buffer solution was The liquid was frozen and removed by lyophilization. 256 mg (49.2%) of the desired product was obtained. Recovered as a white powder.

[0202] Purification step 2 Compounds of formula I were analyzed using mobile phase A = 0.1% TFA in water and mobile phase B = acetonitrile (A CN) (flow rate = 45 mL / min, 1 CV = 90 mL, collection wavelength at 275 nm) The product was purified using an iotage 60g C18 ULTRA column. 3mL of ACN Load the crude PSMA-617 in 20 mL of 0.1% TFA in water onto the column. Purification was performed at 1 CV 15% B, 7 CV 15% B to 25% B, and held at 25% B. The product peak began to elute at approximately 5 CV and fractions were collected. Examine and combine acceptable product fractions (≥98% at 275 nm) and centrifuge the product solution on a rotary centrifuge. The mixture was concentrated using a -evaporator to remove ACN (final volume = 59 mL). Compounds were desalted using a Biotage 30g C18 ULTRA column and The column was run with mobile phase A = 0.1% AcOH in water and mobile phase B = ACN (flow rate = 25 mL / min). , 1CV=45mL, collection wavelength at 275nm). 17 (59 mL) was mixed with 0.28 g of ammonium acetate, 0.36 mL of AcOH, and 3 The PSMA-617 solution was loaded onto the column and the column was run for 5 CV. The column was washed with 39% B. The product was eluted from the column with 3 CV 39% B. The peak was eluted with 6 CV and one fraction was collected. The product solution was evaporated using a rotary evaporator. The ACN was removed by concentration using 100% NaCl. The solid was isolated by lyophilization to give 0.675 g. A compound of formula I was provided.

[0203] Example 3: Characterization of PSMA-617 by Nuclear Magnetic Resonance and High Resolution MS ES+(TOF) Characterization: 1 H NMR(D6-DMSO): 8.03(t, 1H), 7.88(t, 1H), 7. 84(d, 1H), 7.69-7.80(m, 2H), 7.69(s, 1H), 7.43 -7.47(m, 2H), 7.39(dd, 1H), 6.29-6.33(m, 2H), 4.50-4.52(m, 1H), 4.08-4.11(m, 1H), 3.99-4.0 2(m, 1H), 3.46(br s, 6H), 3.13(br s, 2H), 3.10 (d, 1H), 2.89-3.04(m, 17H), 2.68(s, 4H), 2.22- 2.27(m, 2H), 2.07(s, 1H), 1.91(s, 1H), 1.57~1. 74(m,5H),1.46~1.50(m,2H),1.31~1.35(m,3H) ,1.22~1.26(m,3H),1.06~1.12(m,1H),0.80~0. 82(m,2H).

[0204] Note: Six carboxylic acid protons are spread across the spectrum, including residual acetic acid (1.91 ppm). and an additional resonance from acetonitrile (2.07 ppm).

[0205] 13 C NMR(D6-DMSO):175.09, 174.52, 174.14, 17 3.73, 170.99, 170.55, 170.11, 169.64, 157.26, 135.78, 132.86, 131.70, 127.81, 127.37, 127.3 2, 127.24, 127.22, 125.83, 125.24, 57.80, 55.3 4, 54.86, 53.85, 52.33, 51.78, 51.24, 50.52, 49 .96, 49.84, 44.54, 43.77, 38.14, 37.86, 36.81, 31.65, 30.05, 29.61, 29.50, 28.63, 28.56, 28.3 8, 27.69, 22.41.

[0206] Note: Residual acetic acid (171.88 ppm, 20.98 ppm) and acetonitrile (1.06 There is an additional resonance from 1000 to 8 ppm.

[0207] High resolution MS ES+(TOF):M+H + =1042.5067m / z (theoretical value 104 2.5096m / z)

Claims

1. Formula I 【Chemistry 1】 A process for preparing a compound of the formula: a) Formula A 【Chemistry 2】 contacting the resin-based compound of formula A' with a first deprotecting agent in a polar aprotic solvent to form a 【Chemistry 3】 or providing a resin-based compound of b) reacting a resin-based compound of formula A′ with a compound of formula B 【Chemistry 4】 in the presence of an organic solvent and a base to form a compound of formula C 【Chemistry 5】 or providing a resin-based compound of c) contacting the resin-based compound of formula C with a second deprotecting agent in the presence of an organic solvent to form a compound of formula C ’ 【Chemistry 6】 or providing a resin-based compound of d) reacting a resin-based compound of formula C' with a polar aprotic solvent, a coupling agent, and a base; In the presence of PG １ -3-(2-naphthyl)-L-alanine to form a compound of formula D 【Chemistry 7】 or providing a resin-based compound of e) contacting the resin-based compound of formula D with a first deprotecting agent in a polar aprotic solvent; , formula D' 【Chemistry 8】 or providing a resin-based compound of f) reacting a resin-based compound of formula D' with a polar aprotic solvent, a coupling agent and a base in the presence of the base; Currently PG １ - tranexamic acid to form a compound of formula E 【Chemistry 9】 or providing a resin-based compound of g) contacting the resin-based compound of formula E with a first deprotecting agent in a polar aprotic solvent; , formula E' 【Chemistry 10】 or providing a resin-based compound of h) reacting a resin-based compound of formula E′ with a compound of formula E ２’ 【Chemistry 11】 in the presence of a polar aprotic solvent, a coupling agent, and a base, Formula F 【Chemistry 12】 or providing a resin-based compound of i) reacting said resin-based compound of formula F with a third deprotecting agent and / or cleaving agent in an organic solvent; contacting the In the formula, P.G. １ and P.G. ２ is an amine protecting group, LG is a leaving group, R １ is C １ ~C ４ alkyl or cyclohexyl.

2. The first deprotecting agent in step (a) is selected from the group consisting of piperidine, morpholine, 1,8-diazabicin 5.4.0]undec-7-ene (DBU), diethylamine (DEA), dicyclo Hexamine, 4-methylpiperidine (4MP), tris(2-aminoethyl)amine, 2. The method of claim 1, wherein the amino acid sequence is selected from the group consisting of lysine and collidine.

3. 3. The method of claim 2, wherein the first deprotecting agent in step (a) is piperidine.

4. The polar aprotic solvent in step (a) is dimethylformamide (DMF), N-methyl NMP, dichloromethane (DCM), dichloromethane / dimethyl Dimethylformamide mixture, acetonitrile (ACN), acetonitrile / dimethylformamide and dimethyl sulfoxide (DMSO).

3. The method according to claim 3.

5. The polar aprotic solvent in step (a) is dimethylformamide (DMF), The method according to claim 4.

6. The base in step (b) is N,N-diisopropylethylamine ( ｉ P ２ N.E.T.), Triethylamine (TEA), 4-methylmorpholine (NMM), imidazole, pyridinium 2. The method of claim 1, wherein the aryl group is selected from the group consisting of aryl amines, ...

7. The base in the step (b) is N,N-diisopropylethylamine ( ｉ P ２ N.E.T.

7. The method of claim 6, wherein

8. The organic solvent in step (b) is CH ２ C ２ , THF, diethyl ether, MeOH, The method of claim 7, wherein the solvent is selected from the group consisting of EtOH, acetone, and acetonitrile. 。

9. The organic solvent in step (b) is CH ２ C ２ The method according to claim 8, wherein

10. The second deprotecting agent in step (c) is trifluoroacetic acid (TFA), acetic acid, trifluoroacetic acid, Dichloromethane, hexafluoroisopropanol, dichloromethane, and and combinations thereof.

11. The second deprotecting agent in step (c) is trifluoroacetic acid (TFA), or a mixture of acetic acid and trifluoroacetic acid.

11. The method of claim 10, wherein the solvent is a mixture of ethyl alcohol and ethyl alcohol.

12. The organic solvent in step (c) is CH ２ C ２ , THF, diethyl ether, MeOH, The method according to claim 11, wherein the solvent is selected from the group consisting of EtOH, acetone, and acetonitrile. Law.

13. The organic solvent in step (c) is CH ２ C ２ The method of claim 12, wherein

14. The polar aprotic solvent in step (d) is dimethylformamide (DMF), N-methyl NMP, dichloromethane (DCM), dichloromethane / dimethyl Dimethylformamide mixture, acetonitrile (ACN), acetonitrile / dimethylformamide and dimethyl sulfoxide (DMSO).

1. The method according to claim 1.

15. The polar aprotic solvent in step (d) is dimethylformamide (DMF). The method according to claim 14.

16. The base in step (d) is N,N-diisopropylethylamine ( ｉ P ２ N.E.T.), Triethylamine (TEA), 4-methylmorpholine (NMM), imidazole, pyridinium 16. The method of claim 15, wherein the aryl group is selected from the group consisting of arylsulfate, arylamine, arylsulfuric acid ...

17. The base in step (d) is N,N-diisopropylethylamine ( ｉ P ２ NET) The method of claim 16 .

18. The coupling agent in step (d) is benzotriazol-1-yl-oxytripyro Lysinophosphonium hexafluorophosphate (PyBOP), 1-[bis(dimethyl Amino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-o oxide hexafluorophosphate (HATU), 2-(1H-benzotriazole-1 -yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU ), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluron 1,2-Dimethoxy-4,6-dimethoxy-2-methyl-2,4-diphenyl-2,5-diphenyl-2,6 ... ,3,5-triazine (CDMT), N-[(5-chloro-3-oxide-1H-benzo Triazol-1-yl)-4-morpholinylmethylene]-N-methylmethanaminium Hexafluorophosphate (HDMC), 1-cyano-2-ethoxy-2-oxoethyl (lidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphine dimethylamino(triazolo[4,5-b]pyridin-3-yl ester (COMU) dimethylazanium; tetrafluoroborate (TATU), N, N,N',N'-tetramethyl-S-(1-oxide-2-pyridyl)thiouronium tetrachloride tetrafluoroborate (TOTT), N-ethoxycarbonyl-2-ethoxy-1,2- Dihydroquinoline (EEDQ), 1-propanephosphonic anhydride (T3P), and 4-( 4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholinium 18. The method of claim 17, wherein the aryl group is selected from the group consisting of aryl methyl ether (DMTMM), ... and aryl methyl ether (DMTMM).

19. The coupling agent in step (d) is benzotriazol-1-yl-oxytripyro The compound according to claim 18, which is lysinophosphonium hexafluorophosphate (PyBOP). Method of posting.

20. The first deprotecting agent in step (e) is piperidine, morpholine, 1,8-diazabicin 5.4.0]undec-7-ene (DBU), diethylamine (DEA), dicyclo Hexamine, 4-methylpiperidine (4MP), tris(2-aminoethyl)amine, 2. The method of claim 1, wherein the amino acid sequence is selected from the group consisting of lysine and collidine.

21. 21. The method of claim 20, wherein the first deprotecting agent in step (e) is piperidine.

22. The polar aprotic solvent in step (e) is dimethylformamide (DMF), N-methyl NMP, dichloromethane (DCM), dichloromethane / dimethyl Dimethylformamide mixture, acetonitrile (ACN), acetonitrile / dimethylformamide and dimethyl sulfoxide (DMSO).

22. The method according to claim 21.

23. The polar aprotic solvent in step (e) is dimethylformamide (DMF), 23. The method according to claim 22.

24. The polar aprotic solvent in step (f) is dimethylformamide (DMF), N-methyl NMP, dichloromethane (DCM), dichloromethane / dimethyl Dimethylformamide mixture, acetonitrile (ACN), acetonitrile / dimethylformamide and dimethyl sulfoxide (DMSO).

1. The method according to claim 1.

25. The polar aprotic solvent in step (f) is dimethylformamide (DMF). The method according to claim 24.

26. The base in step (f) is N,N-diisopropylethylamine ( ｉ P ２ N.E.T.), Triethylamine (TEA), 4-methylmorpholine (NMM), imidazole, pyridinium 26. The method of claim 25, wherein the aryl ester is selected from the group consisting of aryl esters, ...

27. The base in step (f) is N,N-diisopropylethylamine ( ｉ P ２ NET) The method of claim 26 .

28. The coupling agent in step (f) is benzotriazol-1-yl-oxytripyro Lysinophosphonium hexafluorophosphate (PyBOP), 1-[bis(dimethyl Amino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-o oxide hexafluorophosphate (HATU), 2-(1H-benzotriazole-1 -yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU ), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluron 1,2-Dimethoxy-4,6-dimethoxy-2-methyl-2,4-diphenyl-2,5-diphenyl-2,6 ... ,3,5-triazine (CDMT), N-[(5-chloro-3-oxide-1H-benzo Triazol-1-yl)-4-morpholinylmethylene]-N-methylmethanaminium Hexafluorophosphate (HDMC), 1-cyano-2-ethoxy-2-oxoethyl (lidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphine dimethylamino(triazolo[4,5-b]pyridin-3-yl ester (COMU) dimethylazanium; tetrafluoroborate (TATU), N, N,N',N'-tetramethyl-S-(1-oxide-2-pyridyl)thiouronium tetrachloride tetrafluoroborate (TOTT), N-ethoxycarbonyl-2-ethoxy-1,2- Dihydroquinoline (EEDQ), 1-propanephosphonic anhydride (T3P), and 4-( 4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholinium 28. The method of claim 27, wherein the aryl group is selected from the group consisting of aryl methyl ether, ...

29. The coupling agent in step (f) is benzotriazol-1-yl-oxytripyro 29. The compound according to claim 28, which is lysinophosphonium hexafluorophosphate (PyBOP). Method of posting.

30. The first deprotecting agent in step (g) is piperidine, morpholine, 1,8-diazabicin 5.4.0]undec-7-ene (DBU), diethylamine (DEA), dicyclo Hexamine, 4-methylpiperidine (4MP), tris(2-aminoethyl)amine, 2. The method of claim 1, wherein the amino acid sequence is selected from the group consisting of lysine and collidine.

31. 31. The method of claim 30, wherein the first deprotecting agent in step (g) is piperidine.

32. The polar aprotic solvent in step (g) is dimethylformamide (DMF), N-methyl NMP, dichloromethane (DCM), dichloromethane / dimethyl Dimethylformamide mixture, acetonitrile (ACN), acetonitrile / dimethylformamide and dimethyl sulfoxide (DMSO).

31. The method according to claim 31.

33. The polar aprotic solvent in step (g) is dimethylformamide (DMF), The method according to claim 32.

34. The polar aprotic solvent in step (h) is dimethylformamide (DMF), N-methyl NMP, dichloromethane (DCM), dichloromethane / dimethyl Dimethylformamide mixture, acetonitrile (ACN), acetonitrile / dimethylformamide and dimethyl sulfoxide (DMSO).

1. The method according to claim 1.

35. The polar aprotic solvent in step (h) is dimethylformamide (DMF). The method according to claim 34.

36. The base in step (h) is N,N-diisopropylethylamine ( ｉ P ２ N.E.T.), Triethylamine (TEA), 4-methylmorpholine (NMM), imidazole, pyridinium 36. The method of claim 35, wherein the aryl group is selected from the group consisting of arylsuccinic acid, ...

37. The base in step (h) is N,N-diisopropylethylamine ( ｉ P ２ NET) The method of claim 36 .

38. The coupling agent in step (h) is benzotriazol-1-yl-oxytripyro Lysinophosphonium hexafluorophosphate (PyBOP), 1-[bis(dimethyl Amino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-o oxide hexafluorophosphate (HATU), 2-(1H-benzotriazole-1 -yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU ), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluron 1,2-Dimethoxy-4,6-dimethoxy-2-methyl-2,4-diphenyl-2,5-diphenyl-2,6 ... ,3,5-triazine (CDMT), N-[(5-chloro-3-oxide-1H-benzo Triazol-1-yl)-4-morpholinylmethylene]-N-methylmethanaminium Hexafluorophosphate (HDMC), 1-cyano-2-ethoxy-2-oxoethyl (lidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphine dimethylamino(triazolo[4,5-b]pyridin-3-yl ester (COMU) dimethylazanium; tetrafluoroborate (TATU), N, N,N',N'-tetramethyl-S-(1-oxide-2-pyridyl)thiouronium tetrachloride tetrafluoroborate (TOTT), N-ethoxycarbonyl-2-ethoxy-1,2- Dihydroquinoline (EEDQ), 1-propanephosphonic anhydride (T3P), and 4-( 4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholinium 38. The method of claim 37, wherein the aryl group is selected from the group consisting of aryl methyl ether, ...

39. The coupling agent in step (h) is benzotriazol-1-yl-oxytripyro 39. The compound according to claim 38, which is lysinophosphonium hexafluorophosphate (PyBOP). Method of posting.

40. The third deprotecting agent in step (i) is trifluoroacetic acid (TFA), hydrofluoric acid (H F), triflic acid (TfOH), trifluoroacetic acid (TFA) / water / triisopropyl trifluoroacetic acid (TFA) / dichloromethane (DCM) mixture; Ethyl saline (TES), indole, phenol / anisole mixture, and thioanisole.

2. The method of claim 1, wherein the compound is selected from the group consisting of:

41. The third deprotecting agent of step (i) is trifluoroacetic acid (TFA) / water / triisopropyl 41. The method of claim 40, which is a pyrsilane mixture.

42. The cleavage reagent in step (i) is trifluoroacetic acid (TFA) or trifluoroacetic acid (T 42. The method of claim 41 , wherein the mixture is a mixture of FA) / water / triisopropylsilane.

43. The organic solvent in step (i) is CH ２ C ２ , THF, diethyl ether, MeOH, The method of claim 42, wherein the solvent is selected from the group consisting of EtOH, acetone, and acetonitrile. Law.

44. The cleavage reagent in step (i) is trifluoroacetic acid (TFA) / water / triisopropyl silyl 44. The method of claim 43, which is a run mixture.

45. The organic solvent in step (i) is CH ２ C ２ 45. The method of claim 44, wherein:

46. P.G. １ 9-fluorenylmethyl-carbonyl (Fmoc) or t-butylcarbonyl 2. The method of claim 1 , wherein the aryl group is (Boc).

47. P.G. １ is 9-fluorenylmethyl-carbonyl (Fmoc), How to.

48. P.G. ２ is monomethoxytrityl (MMt) or 4-methyltrityl (Mtt); The method of claim 1.

49. P.G. ２ The method of claim 47, wherein is 4-methyltrityl (Mtt).

50. L.G. 【Chemistry 13】 (In the formula, ＊ represents a point of attachment to the remainder of the compound. Law.

51. R １ The method of claim 1 , wherein is t-butyl.

52. Formula C 【Chemistry 14】 (In the formula, PG ２ is an amine protecting group, and each R １ is C １ ~C ４ Alkyl or cyclohexyl It is Sil.) Resin-based compound.

53. Formula C' 【Chemistry 15】 (In the formula, each R １ is C １ ~C ４ alkyl or cyclohexyl) Resin-based compound.

54. Formula D 【Chemistry 16】 (In the formula, PG １ is an amine protecting group, and each R １ is C １ ~C ４ Alkyl or cyclohexyl It is Sil.) Resin-based compound.

55. Formula D' 【Chemistry 17】 (In the formula, each R １ is C １ ~C ４ alkyl or cyclohexyl) Resin-based compound.

56. Formula E 【Chemistry 18】 (In the formula, PG １ is an amine protecting group, and each R １ is C １ ~C ４ Alkyl or cyclohexyl It is Sil.) Resin-based compound.

57. Formula E' 【Chemistry 19】 (In the formula, each R １ is C １ ~C ４ alkyl or cyclohexyl) Resin-based compound.

58. Formula F 【Chemistry 20】 (Each R １ is C １ ~C ４ alkyl or cyclohexyl) Resin-based compound.

59. P.G. １ 9-fluorenylmethyl-carbonyl (Fmoc) or t-butylcarbonyl 57. The resin-based compound according to claim 54 or 56, wherein the compound is (Boc).

60. P.G. １ is 9-fluorenylmethyl-carbonyl (Fmoc), claims 54 and 56 59. A resin-based compound according to any one of claims 1 to 59.

61. P.G. ２ is monomethoxytrityl (MMt) or 4-methyltrityl (Mtt); The resin-based compound according to claim 52.

62. P.G. ２ The resin-based compound according to claim 52 or 61, wherein is 4-methyltrityl (Mtt). Compound.

63. R １ 63. The resinous compound of any one of clauses 52 to 62, wherein is t-butyl.

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