Methods and intermediates for producing diazaspirolactam compounds

Abstract

The invention relates to a method for preparing a diazaspirolactam compound and an intermediate used in the method.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority and / or the benefit of U.S. Provisional Application No. 62 / 865,840, filed on June 24, 2019, the entirety of which is hereby incorporated by reference and serves as the basis for this application to claim priority and / or the benefit. Technical Field

[0003] The subject matter described herein relates to processes for producing diazaspirolactam compounds and intermediates used in said processes. Background Art

[0004] N-methyl-D-aspartate receptors (NMDA receptors) are believed to play a major role in synaptic plasticity, which is the basis of many higher cognitive functions, such as memory acquisition, memory retention and learning, and in certain cognitive pathways and pain perception. NMDA receptors also appear to be involved in a wide range of central nervous system disorders. Therefore, NMDA receptor modulators may provide pharmaceutical benefits.

[0005] US 9,512,134, which is incorporated herein by reference in its entirety, discloses NMDA receptor modulators useful in treating, for example, depression.There remains a need for economical and simple methods for preparing the diazaspirolactam compounds described herein. Summary of the invention

[0006] The following aspects and embodiments thereof described and illustrated below are intended to be exemplary and illustrative, not limiting in scope.

[0007] In one aspect, a method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof is provided. The method comprises contacting a compound of formula II and a coupling agent in an organic solvent to obtain a compound of formula I or a pharmaceutically acceptable salt thereof:

[0008]

[0009] in:

[0010] R b Selected from H, halogen, cyano and C 1 -C 6 alkyl;

[0011] R 1 H or C 1 -C 6 alkyl;

[0012] R 2 H or C 1 -C 6 alkyl;

[0013] R 3 Selected from C 1 -C 6 Alkyl and C(O)OR 8 ;

[0014] R 8 Selected from C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl and -CH 2 -C 3 -C 10 Cycloalkyl, wherein C 3 -C 10 Cycloalkyl is optionally selected from C 1 -C 3 One, two or three groups are substituted in the alkyl group;

[0015] R 4 and R 5 Independently selected from H, C 1 -C 6 Alkyl, X and -C 1 -C 6 Alkylene-X, wherein X is selected from:

[0016] (i)C 3 -C 6 Cycloalkyl;

[0017] (ii) a heteroaryl group comprising 5 to 6 ring atoms, wherein one, two or three of the ring atoms are independently selected from N, NH, N(C 1 -C 3 alkyl), O and S;

[0018] (iii) a heterocyclic group comprising 3 to 6 ring atoms, wherein 1, 2 or 3 of the ring atoms are independently selected from N, NH, N(C 1 -C 3 alkyl), O and S; and

[0019] (iv) phenyl;

[0020] Among them C 3 -C 6 Cycloalkyl, heterocyclyl, heteroaryl and phenyl are each optionally independently selected from halogen, cyano, C 1 -C 6 Alkyl, hydroxyl and C1 -C 6 One, two or three substituents are substituted on the alkoxy group;

[0021] or R 4 and R 5 and the nitrogen to which they are attached together form a heterocyclic group comprising 4 to 6 ring atoms; wherein the heterocyclic group comprises no more than two ring heteroatoms (including R 4 and R 5 The second ring heteroatom, when present, is independently selected from -N-C 1 -C 6 alkyl, O and S; and wherein the heterocyclic group is optionally independently selected from halogen, cyano, C 1 -C 6 Alkyl and C 1 -C 6 One, two or three substituents are substituted on the alkoxy group;

[0022] R 6 Selected from -OH, C 1 -C 6 Alkoxy, -OC(O)–C 1 -C 6 Alkyl and -OC(O)phenyl; and

[0023] R 7 H or C 1 -C 6 alkyl.

[0024] In another aspect, a compound is provided for use in a method for preparing a diazaspirolactam compound of formula I. The compound is a compound of formula II:

[0025]

[0026] Where R b , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 Same as described with respect to Formula I and Formula II.

[0027] In another aspect, a compound is provided for use in a method for preparing a diazaspirolactam compound of formula I. The compound is a compound of formula III:

[0028]

[0029] Where R b , R 1 , R2 , R 4 , R 5 , R 6 and R 7 Same as described with respect to Formula I and Formula II.

[0030] In another aspect, another compound is provided for use in the method for preparing a diazaspirolactam compound of formula I. The compound is a compound of formula IV:

[0031]

[0032] Where R 9 -CCl 3 ; and R b , R 1 , R 2 , R 4 , R 5 , R 6 and R 7 Same as described with respect to Formula I and Formula II.

[0033] In another aspect, another compound is provided for use in the method for preparing a diazaspirolactam compound of formula I. The compound is a compound of formula V or VI:

[0034]

[0035] Where R b , R 1 , R 2 , R 4 , R 5 and R 7 As described for Formula I and Formula II, R 9 Same as described for Formula IV, and R 6 Selected from C 1 -C 6 Alkoxy, -OC(O)–C 1 -C 6 Alkyl and –OC(O)phenyl.

[0036] In another aspect, a method for preparing (S)-2-((2S,3R)-1-amino-3-hydroxy-1-oxobutane-2-yl)-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylic acid tert-butyl ester ("Compound A") is provided. The method comprises contacting Compound B and a coupling agent in an organic solvent to obtain Compound A:

[0037]

[0038] Some non-limiting exemplary embodiments are listed below.

[0039] Exemplary embodiment 1: A method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof, comprising contacting a compound of formula II with a coupling agent in an organic solvent to obtain a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the coupling agent comprises an art-recognized reagent for coupling an amine and a carboxylic acid to form an amide bond:

[0040]

[0041] in:

[0042] R b Selected from H, halogen, cyano and C 1 -C 6 alkyl;

[0043] R 1 H or C 1 -C 6 alkyl;

[0044] R 2 H or C 1 -C 6 alkyl;

[0045] R 3 Selected from C 1 -C 6 Alkyl and C(O)OR 8 ;

[0046] R 8 Selected from C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl and -CH 2 -C 3 -C 10 Cycloalkyl, wherein C 3 -C 10 Cycloalkyl is optionally selected from C 1 -C 3 One, two or three groups are substituted in the alkyl group;

[0047] R 4 and R 5 Independently selected from H, C 1 -C 6 Alkyl, X and -C 1 -C 6 Alkylene-X, wherein X is selected from:

[0048] (i)C 3 -C 6 Cycloalkyl;

[0049] (ii) a heteroaryl group comprising 5 to 6 ring atoms, wherein one, two or three of the ring atoms are independently selected from N, NH, N(C 1 -C 3 alkyl), O and S;

[0050] (iii) a heterocyclic group comprising 3 to 6 ring atoms, wherein 1, 2 or 3 of the ring atoms are independently selected from N, NH, N(C 1 -C 3 alkyl), O and S; and

[0051] (iv) phenyl;

[0052] Among them C 3 -C 6 Cycloalkyl, heterocyclyl, heteroaryl and phenyl are each optionally independently selected from halogen, cyano, C 1 -C 6 Alkyl, hydroxyl and C 1 -C 6 One, two or three substituents are substituted on the alkoxy group;

[0053] or R 4 and R 5 and the nitrogen to which they are attached together form a heterocyclic group comprising 4 to 6 ring atoms; wherein the heterocyclic group comprises no more than two ring heteroatoms (including R 4 and R 5 The second ring heteroatom, when present, is independently selected from -N-C 1 -C 6 alkyl, O and S; and wherein the heterocyclic group is optionally independently selected from halogen, cyano, C 1 -C 6 Alkyl and C 1 -C 6 One, two or three substituents are substituted on the alkoxy group;

[0054] R 6 Selected from -OH, C 1 -C 6 Alkoxy, -OC(O)–C 1 -C 6 Alkyl and -OC(O)phenyl; and

[0055] R 7 H or C 1 -C 6 alkyl.

[0056] Exemplary embodiment 2: The method according to exemplary embodiment 1, wherein the coupling agent comprises a carbodiimide, optionally together with 1-hydroxybenzotriazole (HOBt).

[0057] Exemplary embodiment 3: The method according to exemplary embodiment 2, wherein the coupling agent comprises a carbodiimide, and the carbodiimide is selected from dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) and ethyl-(N',N'-dimethylamino)propylcarbodiimide hydrochloride (EDC).

[0058] Exemplary embodiment 4: The method according to exemplary embodiment 1, wherein the coupling agent comprises (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-azabenzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (PyAOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP), bis (2-oxo-3-oxazolidinyl) phosphinyl chloride (BOP-Cl), O-(benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-azabenzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (PyAOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP), bis (2-oxo-3-oxazolidinyl) phosphinyl chloride (BOP-Cl), O-(benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (PyBOP), N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TATU), O-(6-chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate ( Uronium hexafluorophosphate (HCTU), O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbonium hexafluorophosphate (COMU), O-(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU), O-(5-norbornene-2,3-dicarboximido)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TNTU) , O-(1,2-dihydro-2-oxo-1-pyridinyl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TPTU), N,N,N',N'-tetramethyl-O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)uranium tetrafluoroborate (TDBTU), N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH), 3-(diethylphosphoryloxy)-1,2,3-benzotriazine-4(3H)-one (DEPBT) and carbonyldiimidazole (CDI).

[0059] Exemplary embodiment 5: The method according to exemplary embodiment 1, wherein the coupling agent comprises a di-C halophosphate 1 -C 6 Alkyl esters, dialkylphosphinyl halides or propanephosphoric anhydride.

[0060] Exemplary embodiment 6: The method according to exemplary embodiment 1, wherein the coupling agent comprises diethyl chlorophosphate.

[0061] Exemplary embodiment 7: The method according to any one of exemplary embodiments 1 to 6, wherein the coupling agent is used together with an organic base.

[0062] Exemplary embodiment 8: The method according to exemplary embodiment 7, wherein the organic base comprises an amine.

[0063] Exemplary embodiment 9: The method according to exemplary embodiment 8, wherein the organic base comprises triethylamine, N,N-diisopropylethylamine (DIPEA) or 4-dimethylaminopyridine (DMAP).

[0064] Exemplary embodiment 10: The method according to any one of exemplary embodiments 1 to 9, wherein the method is carried out in an organic solvent, the organic solvent comprising dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), acetonitrile (MeCN), dichloromethane (DCM), tetrahydrofuran (THF) or 2-methyltetrahydrofuran (2-MeTHF).

[0065] Exemplary embodiment 11: The method according to exemplary embodiment 10, wherein the organic solvent comprises THF.

[0066] Exemplary embodiment 12: The method according to any one of exemplary embodiments 1 to 11, further comprising contacting the compound of formula IV with a base in a solvent to obtain a compound of formula III, wherein the compound of formula III is subsequently contacted with an alkylating agent or a carbamate-forming agent to obtain a compound of formula II, wherein R b , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 Same as described in Exemplary Embodiment 1, and R 9 -CCl 3 :

[0067]

[0068] Exemplary embodiment 13: The method according to exemplary embodiment 12, wherein the base comprises an amine.

[0069] Exemplary embodiment 14: The method according to exemplary embodiment 13, wherein the base comprises an amine selected from triethylamine and DIPEA.

[0070] Exemplary embodiment 15: The method according to any one of exemplary embodiments 12 to 14, wherein the solvent is an aqueous solvent.

[0071] Exemplary embodiment 16: The method according to any one of exemplary embodiments 12 to 15, wherein the aqueous solvent comprises a mixture of water and acetonitrile, a mixture of water and THF, a mixture of water and 2-MeTHF, a mixture of water and methanol, a mixture of water and ethanol, a mixture of water and isopropanol, a mixture of water and DMF, or a mixture of water and DMSO.

[0072] Exemplary embodiment 17: The method according to any one of exemplary embodiments 12 to 16, wherein the alkylating agent is C 1 -C 6 The alkyl halide and the carbamate forming agent is di-R 8 -dicarbonate, where R 8 As defined in exemplary embodiment 1.

[0073] Exemplary embodiment 18: The method according to any one of exemplary embodiments 1 to 17, further comprising contacting the compound of formula VII with an amine of formula VIII to obtain a condensation product of formula V or VI, which is then contacted with a reducing agent to obtain a compound of formula IV, wherein R b , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 As defined in Exemplary Embodiment 1, R 9 As defined in exemplary embodiment 12

[0074]

[0075] Exemplary embodiment 19: The method according to exemplary embodiment 18, wherein the solvent used for the condensation reaction comprises dichloromethane, dimethylformamide, tetrahydrofuran or acetonitrile.

[0076] Exemplary embodiment 20: The method according to exemplary embodiment 18, wherein the solvent used for the condensation reaction comprises toluene.

[0077] Exemplary embodiment 21: The method according to any one of exemplary embodiments 18 to 20, wherein the compound of formula V or VI is not isolated prior to contacting the compound of formula V or VI with the reducing agent.

[0078] Exemplary Embodiment 22: The method according to any one of Exemplary Embodiments 18 to 21, wherein the reducing agent comprises a borohydride.

[0079] Exemplary embodiment 23: The method according to exemplary embodiment 22, wherein the reducing agent comprises a compound selected from the group consisting of sodium borohydride, lithium borohydride, calcium borohydride, magnesium borohydride, sodium triacetoxyborohydride (NaBH(OAc) 3 ), NBu 4 BH 4 、NaCNBH 3 and NMe 4 BH(OAc) 3 borohydride in.

[0080] Exemplary embodiment 24: The method according to exemplary embodiment 23, wherein the reducing agent comprises sodium triacetoxyborohydride (NaBH(OAc) 3 ).

[0081] Exemplary embodiment 25: The method according to any one of exemplary embodiments 1 to 24, further comprising contacting the compound of formula IX with a base known in the art in a solvent to deprotonate the alpha carbon adjacent to the carbonyl group (CO), followed by adding R 2 COOR to obtain a compound of formula VII, wherein R is methyl or ethyl, R b , R 1 and R 2 As defined in Exemplary Embodiment 1, and R 9 As defined in Exemplary Embodiment 12:

[0082]

[0083] Exemplary embodiment 26: The method according to exemplary embodiment 25, wherein the deprotonation is performed at a temperature below 0°C.

[0084] Exemplary embodiment 27: The method according to exemplary embodiment 26, wherein the deprotonation is performed at a temperature of -80 to -20°C.

[0085] Exemplary embodiment 28: The method according to any one of exemplary embodiments 25 to 27, wherein the base comprises lithium diisopropylamide.

[0086] Exemplary embodiment 29: The method according to any one of exemplary embodiments 25 to 28, wherein the solvent comprises toluene optionally mixed with methyl tert-butyl ether (MTBE), THF optionally mixed with toluene or MTBE, or 2-MeTHF optionally mixed with toluene or MTBE.

[0087] Exemplary embodiment 30: The method according to any one of exemplary embodiments 25 to 29, wherein R 2 C(O)OR is added to the deprotonated Formula IX.

[0088] Exemplary embodiment 31: The method according to exemplary embodiment 30, wherein R 2 C(O)OR is added to the deprotonated Formula IX.

[0089] Exemplary embodiment 32: The method according to exemplary embodiment 31, wherein R 2 C(O)OR is added to the deprotonated Formula IX.

[0090] Exemplary embodiment 33: The method according to any one of exemplary embodiments 1 to 32 further comprises reacting a compound of formula X with an aldehyde R 9 CHO or a hydrate thereof to obtain a compound of formula IX, wherein R b and R 1 As defined in Exemplary Embodiment 1 and R 9 As defined in Exemplary Embodiment 12:

[0091]

[0092] Exemplary embodiment 34: The method according to exemplary embodiment 33, wherein the solvent used to obtain the compound of Formula IX comprises THF, acetonitrile or toluene.

[0093] Exemplary embodiment 35: The method according to any one of exemplary embodiments 1 to 34, wherein:

[0094] R b Selected from H, halogen, cyano and C 1 -C 6 alkyl;

[0095] R 1 H or C 1 -C 6 alkyl;

[0096] R 2 H or C 1 -C 6alkyl;

[0097] R 3 Selected from C 1 -C 6 Alkyl and C(O)OR 8 ;

[0098] R 8 Selected from C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl and -CH 2 -C 3 -C 10 Cycloalkyl, wherein C 3 -C 10 Cycloalkyl is optionally selected from C 1 -C 3 One, two or three groups are substituted in the alkyl group;

[0099] R 4 and R 5 Independently selected from H and C 1 -C 6 Alkyl; or R 4 and R 5 and the nitrogen to which they are attached together form a heterocyclic group comprising 4 to 6 ring atoms; wherein the heterocyclic group comprises no more than two ring heteroatoms (including R 4 and R 5 The second ring heteroatom, when present, is independently selected from NC 1 -C 6 alkyl, O and S; and wherein the heterocyclic group is optionally independently selected from halogen, cyano, C 1 -C 6 Alkyl and C 1 -C 6 One, two or three substituents are substituted on the alkoxy group;

[0100] R 6 Selected from -OH, C 1 -C 6 Alkoxy, -OC(O)–C 1 -C 6 Alkyl and -OC(O)phenyl;

[0101] R 7 H or C 1 -C6 alkyl; and

[0102] R 9 Selected from CCl 3 .

[0103] Exemplary embodiment 36: The method according to exemplary embodiment 35, wherein R 1 and R 2 For H.

[0104] Exemplary embodiment 37: The method according to exemplary embodiment 35, wherein R 1 , R 2 , R 4 and R 5 Each of them is H.

[0105] Exemplary embodiment 38: The method according to any one of exemplary embodiments 35 to 37, wherein R 6 For OH.

[0106] Exemplary embodiment 39: The method according to any one of exemplary embodiments 35 to 38, wherein R 7 C 1 -C 6 alkyl.

[0107] Exemplary embodiment 40: The method according to exemplary embodiment 39, wherein R 7 It is methyl.

[0108] Exemplary embodiment 41: The method according to any one of exemplary embodiments 35 to 40, wherein R 3 OC(O)R 8 .

[0109] Exemplary embodiment 42: The method according to exemplary embodiment 41, wherein R 8 C 1 -C 6 alkyl.

[0110] Exemplary embodiment 43: The method according to exemplary embodiment 42, wherein R 8 It is tert-butyl.

[0111] Exemplary embodiment 44: A method for preparing (S)-2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylic acid tert-butyl ester ("Compound A"), comprising contacting Compound B and a coupling agent in an organic solvent to obtain Compound A, wherein the coupling agent comprises an art-recognized reagent for coupling an amine and a carboxylic acid to form an amide bond:

[0112]

[0113] and wherein compound B is prepared by reacting compound C with di-tert-butyl dicarbonate (BOC 2 O) Contact to obtain:

[0114]

[0115] Exemplary embodiment 45: The method according to exemplary embodiment 44, wherein the coupling agent comprises a carbodiimide, optionally together with 1-hydroxybenzotriazole (HOBt).

[0116] Exemplary embodiment 46: A method according to exemplary embodiment 45, wherein the coupling agent comprises a carbodiimide, and the carbodiimide is selected from dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) and ethyl-(N',N'-dimethylamino)propylcarbodiimide hydrochloride (EDC).

[0117] Exemplary embodiment 47: A method according to exemplary embodiment 44, wherein the coupling agent comprises (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP), bis(2-oxo-3-oxazolidinyl)phosphinyl chloride (BOP-Cl), O-(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TATU), O-(6-chlorobenzotriazol-1-yl)-N,N,N',N'- Tetramethyluronium hexafluorophosphate (HCTU), O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbonium hexafluorophosphate (COMU), O-(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU), O-(5-norbornene-2,3-dicarboximido)-N,N,N',N'-tetramethyluronium tetrafluoroborate ( TNTU), O-(1,2-dihydro-2-oxo-1-pyridinyl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TPTU), N,N,N',N'-tetramethyl-O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)uranium tetrafluoroborate (TDBTU), N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH), 3-(diethylphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT), or carbonyldiimidazole (CDI).

[0118] Exemplary embodiment 48: The method according to exemplary embodiment 44, wherein the coupling agent comprises a di-C halophosphate 1 -C 6 Alkyl esters, dialkylphosphinyl halides or propanephosphoric anhydride.

[0119] Exemplary embodiment 49: The method according to exemplary embodiment 48, wherein the coupling agent comprises diethyl chlorophosphate.

[0120] Exemplary embodiment 50: The method according to any one of exemplary embodiments 44 to 49, wherein the coupling agent is used together with an organic base.

[0121] Exemplary embodiment 51: The method according to exemplary embodiment 50, wherein the organic base comprises an amine.

[0122] Exemplary embodiment 52: The method according to exemplary embodiment 51, wherein the organic base comprises triethylamine, N,N-diisopropylethylamine (DIPEA) or 4-dimethylaminopyridine (DMAP).

[0123] Exemplary embodiment 53: The method according to exemplary embodiment 52, wherein the organic base comprises triethylamine.

[0124] Exemplary embodiment 54: A method according to any one of exemplary embodiments 44 to 53, wherein the organic solvent used to prepare compound A comprises dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), acetonitrile (MeCN), dichloromethane (DCM), tetrahydrofuran (THF) or 2-methyltetrahydrofuran (2-MeTHF).

[0125] Exemplary embodiment 55: The method of exemplary embodiment 54, wherein the solvent comprises THF.

[0126] Exemplary embodiment 56: The method according to any one of exemplary embodiments 44 to 55, wherein the solvent used to prepare compound B comprises acetonitrile, methanol, ethanol, isopropanol, MTBE, toluene, acetone, CH 2 Cl 2 , THF, 2-MeTHF, water and mixtures thereof.

[0127] Exemplary embodiment 57: The method according to any one of exemplary embodiments 44 to 56, further comprising contacting compound D with a base in a solvent to obtain compound C:

[0128]

[0129] Exemplary embodiment 58: The method according to exemplary embodiment 57, wherein the base comprises an amine.

[0130] Exemplary embodiment 59: The method according to exemplary embodiment 58, wherein the base comprises triethylamine or DIPEA.

[0131] Exemplary embodiment 60: The method according to any one of exemplary embodiments 56 to 59, wherein the solvent is an aqueous solvent.

[0132] Exemplary embodiment 61: A method according to exemplary embodiment 60, wherein the aqueous solvent comprises a mixture of water and acetonitrile, a mixture of water and THF, a mixture of water and 2-MeTHF, a mixture of water and methanol, a mixture of water and ethanol, a mixture of water and isopropanol, a mixture of water and DMF, or a mixture of water and DMSO.

[0133] Exemplary embodiment 62: The method according to any one of exemplary embodiments 44 to 61, further comprising condensing compound F with compound G to obtain compound E, which is subsequently contacted with a reducing agent to obtain compound D:

[0134]

[0135] Exemplary embodiment 63: The method according to exemplary embodiment 62, wherein the solvent used for the condensation reaction comprises dichloromethane.

[0136] Exemplary embodiment 64: The method according to exemplary embodiment 62, wherein the solvent used for the condensation reaction comprises toluene.

[0137] Exemplary Embodiment 65: The method according to any one of Exemplary Embodiments 62 to 64, wherein the reducing agent comprises a borohydride.

[0138] Exemplary embodiment 66: The method according to any one of exemplary embodiments 65, wherein the reducing agent comprises a compound selected from the group consisting of sodium borohydride, lithium borohydride, calcium borohydride, magnesium borohydride, sodium triacetoxyborohydride (NaBH(OAc) 3 ), NBu 4 BH 4 、NaCNBH 3 and NMe 4 BH(OAc) 3 borohydride in.

[0139] Exemplary embodiment 67: The method according to any one of exemplary embodiments 62 to 66, wherein compound E is not isolated before contacting it with the reducing agent.

[0140] Exemplary embodiment 68: The method according to any one of exemplary embodiments 44 to 67, further comprising contacting compound H with a base known in the art in a solvent to deprotonate the alpha carbon next to the carbonyl group (CO), which is then contacted with HCOOR, wherein R is methyl or ethyl, to obtain compound F:

[0141]

[0142] Exemplary embodiment 69: The method according to exemplary embodiment 68, wherein the deprotonation is performed at a temperature below 0°C.

[0143] Exemplary embodiment 70: The method according to exemplary embodiment 69, wherein the deprotonation is performed at a temperature of -80 to -20°C.

[0144] Exemplary embodiment 71: The method according to exemplary embodiment 70, wherein the deprotonation is performed at a temperature of about -45°C.

[0145] Exemplary embodiment 72: The method according to any one of exemplary embodiments 68 to 71, wherein the base comprises lithium diisopropylamide.

[0146] Exemplary embodiment 73: The method according to any one of exemplary embodiments 68 to 72, wherein the solvent comprises methyl tert-butyl ether (MTBE), toluene optionally mixed with MTBE, THF optionally mixed with toluene, THF optionally mixed with MTBE, 2-MeTHF optionally mixed with toluene, or 2-MeTHF optionally mixed with MTBE.

[0147] Exemplary embodiment 74: The method according to any one of exemplary embodiments 68 to 73, wherein HC(O)OR is added to the deprotonated compound H at a temperature below 0°C.

[0148] Exemplary embodiment 75: The method according to exemplary embodiment 74, wherein HC(O)OR is added to the deprotonated compound H at a temperature of -80 to -20°C.

[0149] Exemplary embodiment 76: The method according to exemplary embodiment 75, wherein HC(O)OR is added to the deprotonated compound H at a temperature of about -60°C.

[0150] Exemplary embodiment 77: The method according to any one of exemplary embodiments 44 to 76, further comprising contacting D-proline with chloral to obtain compound H:

[0151]

[0152] Exemplary embodiment 78: The method according to exemplary embodiment 77, wherein the solvent used to obtain compound H comprises THF, 2-MeTHF, acetonitrile, toluene, dichloromethane, chloroform or MTBE.

[0153] Exemplary embodiment 79: The method according to exemplary embodiment 78, wherein the solvent used to obtain compound H comprises acetonitrile.

[0154] Exemplary embodiment 80: A compound of formula II:

[0155]

[0156] in:

[0157] R b Selected from H, halogen, cyano and C 1 -C 6 alkyl;

[0158] R 1 H or C 1 -C 6 alkyl;

[0159] R 2 H or C 1 -C 6 alkyl;

[0160] R 3 Selected from C 1 -C 6 Alkyl and C(O)OR 8 ;

[0161] R 8 Selected from C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl and -CH 2 -C 3 -C 10 Cycloalkyl, wherein C 3 -C 10 Cycloalkyl is optionally selected from C 1 -C 3 One, two or three groups are substituted in the alkyl group;

[0162] R 4 and R 5 Independently selected from H, C 1 -C 6 Alkyl, X and -C 1 -C 6 Alkylene-X, wherein X is selected from

[0163] (i)C 3 -C 6 Cycloalkyl;

[0164] (ii) a heteroaryl group comprising 5 to 6 ring atoms, wherein one, two or three of the ring atoms are independently selected from N, NH, N(C 1 -C 3 alkyl), O and S;

[0165] (iii) a heterocyclic group comprising 3 to 6 ring atoms, wherein 1, 2 or 3 of the ring atoms are independently selected from N, NH, N(C 1 -C 3 alkyl), O and S; and

[0166] (iv) phenyl;

[0167] Among them C 3 -C 6 Cycloalkyl, heterocyclyl, heteroaryl and phenyl are each optionally independently selected from halogen, cyano, C 1 -C 6 Alkyl, hydroxyl and C 1 -C 6 One, two or three substituents are substituted on the alkoxy group;

[0168] or R 4 and R 5 and the nitrogen to which they are attached together form a heterocyclic group comprising 4 to 6 ring atoms; wherein the heterocyclic group comprises no more than two ring heteroatoms (including R 4 and R 5 The second ring heteroatom, when present, is independently selected from -N-C 1 -C 6 alkyl, O and S; and wherein the heterocyclic group is optionally independently selected from halogen, cyano, C 1 -C 6 Alkyl and C 1 -C 6 One, two or three substituents are substituted on the alkoxy group;

[0169] R 6 Selected from -OH, C 1 -C 6 Alkoxy, -OC(O)–C 1 -C 6 Alkyl and -OC(O)phenyl; and

[0170] R 7 H or C 1 -C 6 alkyl.

[0171] Exemplary embodiment 81: The compound according to exemplary embodiment 80, wherein the compound of formula II is a compound of formula IIa:

[0172]

[0173] Exemplary embodiment 82: The compound according to exemplary embodiment 81, wherein the compound of formula IIa is a compound of formula IIb:

[0174]

[0175] Exemplary embodiment 83: The compound according to exemplary embodiment 82, wherein the compound of formula IIb is a compound of formula IIc:

[0176]

[0177] Exemplary embodiment 84: A compound according to any one of exemplary embodiments 80 to 83, wherein:

[0178] R b Selected from H, halogen, cyano and C 1 -C 6 alkyl;

[0179] R 1 H or C 1 -C 6 alkyl;

[0180] R 2 H or C 1 -C 6 alkyl;

[0181] R 3 Selected from C 1 -C 6 Alkyl and C(O)OR 8 ;

[0182] R 8 Selected from C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl and -CH 2 -C 3 -C 10 Cycloalkyl, wherein C 3 -C 10 Cycloalkyl is optionally selected from C 1 -C 3 One, two or three groups are substituted in the alkyl group;

[0183] R 4 and R 5 Independently selected from H and C 1 -C 6 Alkyl; or R 4 and R 5 and the nitrogen to which they are attached together form a heterocyclic group comprising 4 to 6 ring atoms; wherein the heterocyclic group comprises no more than two ring heteroatoms (including R 4 and R 5 The second ring heteroatom, when present, is independently selected from NC 1 -C 6 alkyl, O and S; and wherein the heterocyclic group is optionally independently selected from halogen, cyano, C 1 -C 6 Alkyl and C 1 -C 6 One, two or three substituents are substituted on the alkoxy group;

[0184] R 6 Selected from -OH, C 1 -C 6 Alkoxy, -OC(O)–C 1 -C 6 Alkyl and -OC(O)phenyl; and

[0185] R 7 H or C 1 -C 6 alkyl.

[0186] Exemplary embodiment 85: The compound according to exemplary embodiment 84, wherein R 1 and R 2 For H.

[0187] Exemplary embodiment 86: The compound according to exemplary embodiment 84, wherein R 1 , R 2 , R 4 and R 5 Each of them is H.

[0188] Exemplary embodiment 87: A compound according to any one of exemplary embodiments 84 to 86, wherein R 6 For OH.

[0189] Exemplary embodiment 88: A compound according to any one of exemplary embodiments 84 to 87, wherein R 7 C 1 -C 6 alkyl.

[0190] Exemplary embodiment 89: The compound according to exemplary embodiment 88, wherein R 7 It is methyl.

[0191] Exemplary embodiment 90: A compound according to any one of exemplary embodiments 84 to 89, wherein R 3 OC(O)R 8 , R 8 C 1 -C 6 alkyl.

[0192] Exemplary embodiment 91: The compound according to exemplary embodiment 90, wherein R 8 It is tert-butyl.

[0193] Exemplary embodiment 92: The compound according to exemplary embodiment 80, wherein the compound of formula II is selected from the following compounds:

[0194]

[0195] Exemplary embodiment 93: The compound according to exemplary embodiment 92, wherein the compound of formula II is compound B.

[0196] Exemplary embodiment 94: A compound of formula III:

[0197]

[0198] in:

[0199] R b Selected from H, halogen, cyano and C 1 -C 6 alkyl;

[0200] R 1 H or C 1 -C 6 alkyl;

[0201] R 2 H or C 1 -C 6 alkyl;

[0202] R 8 Selected from C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10Cycloalkyl and -CH 2 -C 3 -C 10 Cycloalkyl, wherein C 3 -C 10 Cycloalkyl is optionally selected from C 1 -C 3 One, two or three groups are substituted in the alkyl group;

[0203] R 4 and R 5 Independently selected from H, C 1 -C 6 Alkyl, X and -C 1 -C 6 Alkylene-X, wherein X is selected from

[0204] (i)C 3 -C 6 Cycloalkyl;

[0205] (ii) a heteroaryl group comprising 5 to 6 ring atoms, wherein one, two or three of the ring atoms are independently selected from N, NH, N(C 1 -C 3 alkyl), O and S;

[0206] (iii) a heterocyclic group comprising 3 to 6 ring atoms, wherein 1, 2 or 3 of the ring atoms are independently selected from N, NH, N(C 1 -C 3 alkyl), O and S; and

[0207] (iv) phenyl;

[0208] Among them C 3 -C 6 Cycloalkyl, heterocyclyl, heteroaryl and phenyl are each optionally independently selected from halogen, cyano, C 1 -C 6 Alkyl, hydroxyl and C 1 -C 6 One, two or three substituents are substituted on the alkoxy group;

[0209] or R 4 and R 5 and the nitrogen to which they are attached together form a heterocyclic group comprising 4 to 6 ring atoms; wherein the heterocyclic group comprises no more than two ring heteroatoms (including R 4 and R 5 The second ring heteroatom, when present, is independently selected from -N-C 1 -C 6 alkyl, O and S; and wherein the heterocyclic group is optionally independently selected from halogen, cyano, C 1 -C6 Alkyl and C 1 -C 6 One, two or three substituents are substituted on the alkoxy group;

[0210] R 6 Selected from -OH, C 1 -C 6 Alkoxy, -OC(O)–C 1 -C 6 Alkyl and -OC(O)phenyl; and

[0211] R 7 H or C 1 -C 6 alkyl.

[0212] Exemplary embodiment 95: The compound according to exemplary embodiment 94, wherein the compound of formula III is a compound of formula IIIa:

[0213]

[0214] Exemplary embodiment 96: The compound according to exemplary embodiment 95, wherein the compound of formula IIIa is a compound of formula IIIb:

[0215]

[0216] Exemplary embodiment 97: The compound according to exemplary embodiment 96, wherein the compound of formula IIIb is a compound of formula IIIc:

[0217]

[0218] Exemplary embodiment 98: A compound according to any one of exemplary embodiments 94 to 97, wherein:

[0219] R b Selected from H, halogen, cyano and C 1 -C 6 alkyl;

[0220] R 1 H or C 1 -C 6 alkyl;

[0221] R 2 H or C 1 -C 6 alkyl;

[0222] R 8 Selected from C 1 -C 6 Alkyl, C 1 -C6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl and -CH 2 -C 3 -C 10 Cycloalkyl, wherein C 3 -C 10 Cycloalkyl is optionally selected from C 1 -C 3 One, two or three groups are substituted in the alkyl group;

[0223] R 4 and R 5 Independently selected from H and C 1 -C 6 Alkyl; or R 4 and R 5 and the nitrogen to which they are attached together form a heterocyclic group comprising 4 to 6 ring atoms; wherein the heterocyclic group comprises no more than two ring heteroatoms (including R 4 and R 5 The second ring heteroatom, when present, is independently selected from NC 1 -C 6 alkyl, O and S; and wherein the heterocyclic group is optionally independently selected from halogen, cyano, C 1 -C 6 Alkyl and C 1 -C 6 One, two or three substituents are substituted on the alkoxy group;

[0224] R 6 Selected from -OH, C 1 -C 6 Alkoxy, -OC(O)–C 1 -C 6 Alkyl and -OC(O)phenyl; and

[0225] R 7 H or C 1 -C 6 alkyl.

[0226] Exemplary embodiment 99: The compound according to exemplary embodiment 98, wherein R 1 and R 2 For H.

[0227] Exemplary embodiment 100: A compound according to exemplary embodiment 98, wherein R 1 , R 2 , R4 and R 5 Each of them is H.

[0228] Exemplary embodiment 101: A compound according to any one of exemplary embodiments 98 to 100, wherein R 6 For OH.

[0229] Exemplary embodiment 102: A compound according to any one of exemplary embodiments 98 to 101, wherein R 7 C 1 -C 6 alkyl.

[0230] Exemplary embodiment 103: The compound according to exemplary embodiment 102, wherein R 7 It is methyl.

[0231] Exemplary embodiment 104: A compound according to any one of exemplary embodiments 98 to 103, wherein R 3 OC(O)R 8 , R 8 C 1 -C 6 alkyl.

[0232] Exemplary embodiment 105: The compound according to exemplary embodiment 104, wherein R 8 It is tert-butyl.

[0233] Exemplary embodiment 106: The compound according to exemplary embodiment 94, wherein the compound of formula III is selected from the following compounds:

[0234]

[0235] Exemplary embodiment 107: The compound according to exemplary embodiment 106, wherein the compound of formula II is compound C.

[0236] Exemplary embodiment 108: A compound of formula IV:

[0237]

[0238] in:

[0239] R b Selected from H, halogen, cyano and C 1 -C 6 alkyl;

[0240] R 1 H or C 1 -C 6 alkyl;

[0241] R 2 H or C 1 -C 6 alkyl;

[0242] R 4 and R 5 Independently selected from H, C 1 -C 6 Alkyl, X and -C 1 -C 6 Alkylene-X, wherein X is selected from:

[0243] (i)C 3 -C 6 Cycloalkyl;

[0244] (ii) a heteroaryl group comprising 5 to 6 ring atoms, wherein one, two or three of the ring atoms are independently selected from N, NH, N(C 1 -C 3 alkyl), O and S;

[0245] (iii) a heterocyclic group comprising 3 to 6 ring atoms, wherein 1, 2 or 3 of the ring atoms are independently selected from N, NH, N(C 1 -C 3 alkyl), O and S; and

[0246] (iv) phenyl;

[0247] Among them C 3 -C 6 Cycloalkyl, heterocyclyl, heteroaryl and phenyl are each optionally independently selected from halogen, cyano, C 1 -C 6 Alkyl, hydroxyl and C 1 -C 6 One, two or three substituents are substituted on the alkoxy group;

[0248] or R 4 and R 5 and the nitrogen to which they are attached together form a heterocyclic group comprising 4 to 6 ring atoms; wherein the heterocyclic group comprises no more than two ring heteroatoms (including R 4 and R 5 The second ring heteroatom, when present, is independently selected from -N-C 1 -C 6 alkyl, O and S; and wherein the heterocyclic group is optionally independently selected from halogen, cyano, C 1 -C 6 Alkyl and C 1 -C 6 One, two or three substituents are substituted on the alkoxy group;

[0249] R 6 Selected from -OH, C 1 -C 6 Alkoxy, -OC(O)–C 1 -C 6 Alkyl and -OC(O)phenyl; and

[0250] R 7 H or C 1 -C 6 alkyl; and

[0251] R 9 -CCl 3 .

[0252] Exemplary embodiment 109: The compound according to exemplary embodiment 108, wherein the compound of formula IV is a compound of formula IVa:

[0253]

[0254] Exemplary embodiment 110: The compound according to exemplary embodiment 109, wherein the compound of formula IVa is a compound of formula IVb:

[0255]

[0256] Exemplary embodiment 111: The compound according to exemplary embodiment 110, wherein the compound of formula IVb is a compound of formula IVc:

[0257]

[0258] Exemplary embodiment 112: The compound according to exemplary embodiment 111, wherein the compound of formula IVc is a compound of formula IVd:

[0259]

[0260] Exemplary embodiment 113: A compound according to any one of exemplary embodiments 108 to 112, wherein

[0261] R b Selected from H, halogen, cyano and C 1 -C 6 alkyl;

[0262] R 1 H or C 1 -C 6 alkyl;

[0263] R 2 H or C 1 -C6 alkyl;

[0264] R 4 and R 5 Independently selected from H and C 1 -C 6 Alkyl; or R 4 and R 5 and the nitrogen to which they are attached together form a heterocyclic group comprising 4 to 6 ring atoms; wherein the heterocyclic group comprises no more than two ring heteroatoms (including R 4 and R 5 The second ring heteroatom, when present, is independently selected from NC 1 -C 6 alkyl, O and S; and wherein the heterocyclic group is optionally independently selected from halogen, cyano, C 1 -C 6 Alkyl and C 1 -C 6 One, two or three substituents are substituted on the alkoxy group;

[0265] R 6 Selected from -OH, C 1 -C 6 Alkoxy, -OC(O)–C 1 -C 6 Alkyl and -OC(O)phenyl;

[0266] R 7 H or C 1 -C 6 alkyl; and

[0267] R 9 -CCl 3 .

[0268] Exemplary embodiment 114: The compound according to exemplary embodiment 113, wherein R 1 and R 2 For H.

[0269] Exemplary embodiment 115: A compound according to exemplary embodiment 113 or 114, wherein R 9 CCl 3 .

[0270] Exemplary embodiment 116: A compound according to any one of exemplary embodiments 113 to 115, wherein R 1 , R 2 , R 4 and R 5 Each of them is H.

[0271] Exemplary embodiment 117: A compound according to any one of exemplary embodiments 113 to 116, wherein R 6 For OH.

[0272] Exemplary embodiment 118: A compound according to any one of exemplary embodiments 113 to 117, wherein R 7 C 1 -C 6 alkyl.

[0273] Exemplary embodiment 119: The compound according to exemplary embodiment 118, wherein R 7 It is methyl.

[0274] Exemplary embodiment 120: The compound according to exemplary embodiment 108, wherein the compound of formula IV is selected from the following compounds:

[0275]

[0276] Exemplary embodiment 121: The compound according to exemplary embodiment 120, wherein the compound of formula IV is compound D.

[0277] Exemplary embodiment 122: A compound of formula V or VI:

[0278]

[0279] in:

[0280] R b Selected from H, halogen, cyano and C 1 -C 6 alkyl;

[0281] R 1 H or C 1 -C 6 alkyl;

[0282] R 2 H or C 1 -C 6 alkyl;

[0283] R 4 and R 5 Independently selected from H, C 1 -C 6 Alkyl, X and -C 1 -C 6 Alkylene-X, wherein X is selected from:

[0284] (i)C 3 -C 6 Cycloalkyl;

[0285] (ii) a heteroaryl group comprising 5 to 6 ring atoms, wherein one, two or three of the ring atoms are independently selected from N, NH, N(C 1 -C 3 alkyl), O and S;

[0286] (iii) a heterocyclic group comprising 3 to 6 ring atoms, wherein 1, 2 or 3 of the ring atoms are independently selected from N, NH, N(C 1 -C 3 alkyl), O and S; and

[0287] (iv) phenyl;

[0288] Among them C 3 -C 6 Cycloalkyl, heterocyclyl, heteroaryl and phenyl are each optionally independently selected from halogen, cyano, C 1 -C 6 Alkyl, hydroxyl and C 1 -C 6 One, two or three substituents are substituted on the alkoxy group;

[0289] or R 4 and R 5 and the nitrogen to which they are attached together form a heterocyclic group comprising 4 to 6 ring atoms; wherein the heterocyclic group comprises no more than two ring heteroatoms (including R 4 and R 5 The second ring heteroatom, when present, is independently selected from N-C 1 -C 6 alkyl, O and S; and wherein the heterocyclic group is optionally independently selected from halogen, cyano, C 1 -C 6 Alkyl and C 1 -C 6 One, two or three substituents are substituted on the alkoxy group;

[0290] R 6 Selected from C 1 -C 6 Alkoxy, -OC(O)–C 1 -C 6 Alkyl and -OC(O)phenyl;

[0291] R 7 H or C 1 -C 6 alkyl; and

[0292] R 9 -CCl 3 .

[0293] Exemplary embodiment 123: The compound according to exemplary embodiment 122, wherein the compound of formula V and the compound of formula VI are respectively a compound of formula Va and a compound of formula VIa:

[0294]

[0295] Exemplary embodiment 124: The compound according to exemplary embodiment 123, wherein the compound of formula Va and the compound of formula VIa are respectively a compound of formula Vb and a compound of formula VIb:

[0296]

[0297] Exemplary embodiment 125: The compound according to exemplary embodiment 124, wherein the compound of formula Vb and the compound of formula VIb are respectively the compound of formula Vc and the compound of formula VIc:

[0298]

[0299] Exemplary embodiment 126: The compound according to exemplary embodiment 125, wherein the compound of formula Vc and the compound of formula VIc are respectively the compound of formula Vd and the compound of formula VId:

[0300]

[0301] Exemplary embodiment 127: A compound according to any one of exemplary embodiments 122 to 126, wherein

[0302] R b Selected from H, halogen, cyano and C 1 -C 6 alkyl;

[0303] R 1 H or C 1 -C 6 alkyl;

[0304] R 2 H or C 1 -C 6 alkyl;

[0305] R 4 and R 5 Independently selected from H and C 1 -C 6 Alkyl; or R 4 and R 5 and the nitrogen to which they are attached together form a heterocyclic group comprising 4 to 6 ring atoms; wherein the heterocyclic group comprises no more than two ring heteroatoms (including R4 and R 5 The second ring heteroatom, when present, is independently selected from NC 1 -C 6 alkyl, O and S; and wherein the heterocyclic group is optionally independently selected from halogen, cyano, C 1 -C 6 Alkyl and C 1 -C 6 One, two or three substituents are substituted on the alkoxy group;

[0306] R 6 Selected from C 1 -C 6 Alkoxy, -OC(O)–C 1 -C 6 Alkyl and -OC(O)phenyl;

[0307] R 7 H or C 1 -C 6 alkyl; and

[0308] R 9 -CCl 3 .

[0309] Exemplary embodiment 128: The compound according to exemplary embodiment 127, wherein R 1 and R 2 For H.

[0310] Exemplary embodiment 129: The compound according to exemplary embodiment 127 or 128, wherein R 9 CCl 3 .

[0311] Exemplary embodiment 130: A compound according to any one of exemplary embodiments 127 to 129, wherein R 1 , R 2 , R 4 and R 5 Each of them is H.

[0312] Exemplary embodiment 131: A compound according to any one of exemplary embodiments 127 to 130, wherein R 7 C 1 -C 6 alkyl.

[0313] Exemplary embodiment 132: A compound according to exemplary embodiment 131, wherein R 7 It is methyl.

[0314] Exemplary embodiment 133: The compound according to exemplary embodiment 122, wherein the compound of formula V is selected from the following compounds:

[0315]

[0316] Exemplary embodiment 134: The compound according to exemplary embodiment 133, wherein the compound of formula V is compound E.

[0317] Additional embodiments of each aspect will be apparent from the following description, examples, and claims. It will be understood from the foregoing and following description that each feature described herein, and each combination of two or more such features, is included within the scope of the present disclosure, provided that the features included in such combinations are not mutually inconsistent. In addition, any feature or combination of features may be specifically excluded from any embodiment of the invention. Additional aspects and advantages of the invention are set forth in the following description and claims, particularly when considered in conjunction with the accompanying examples. Specific implementation plan

[0318] I. Definitions

[0319] Various aspects will now be described more fully below. However, these aspects may be embodied in many different forms and should not be construed as limited to the embodiments described herein; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey its scope to those skilled in the art.

[0320] As used herein, the term "alkenyl" refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-6 or 3-4 carbon atoms, respectively referred to herein as C 2 -C 6 Alkenyl and C 3 -C 4 Alkenyl. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, and the like.

[0321] As used herein, the term "alkyl" refers to a saturated straight or branched chain hydrocarbon, such as a straight or branched chain group of 1 to 6, 1 to 4, or 1 to 3 carbon atoms, respectively referred to herein as C 1 -C 6 Alkyl, C 1 -C 4 Alkyl and C 1 -C 3Alkyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 3-methyl-2-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, and the like.

[0322] As used herein, the term "alkoxy" refers to a straight or branched chain alkyl group attached to an oxygen (alkyl-O-). Exemplary alkoxy groups include, but are not limited to, alkoxy groups of 1-6 or 2-6 carbon atoms, referred to herein as C 1 -C 6 Alkoxy and C 2 -C 6 Alkoxy. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.

[0323] As used herein, the term "alkylene" refers to a divalent saturated straight or branched chain hydrocarbon, such as a straight or branched chain group of 1 to 6, 1 to 4, or 1 to 3 carbon atoms, respectively referred to herein as C 1 -C 6 Alkylene, C 1 -C 4 Alkylene and C 1 -C 3 Alkylene. Exemplary alkylene groups include, but are not limited to, methylene (—CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -) and isopropylidene (-CH 2 CH(CH 3 )).

[0324] As used herein, the term "alkynyl" refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2-6 or 3-6 carbon atoms, referred to herein as C 2 -C 6 Alkynyl and C 3 -C 6 Alkynyl. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, and the like.

[0325] As used herein, the term "cycloalkyl" refers to a monocyclic saturated or partially unsaturated (non-aromatic) hydrocarbon group, for example, of 3-6 or 4-6 carbon atoms, referred to herein as, for example, "C 3 -C 6 Cycloalkyl" or "C 4 -C 6 "Cycloalkyl" and is derived from cycloalkane. Exemplary cycloalkyls include, but are not limited to, cyclohexane, cyclohexene, cyclopentane, cyclobutane, cyclopropane, or cyclopentane.

[0326] As used herein, the term "haloalkyl" refers to a saturated straight or branched chain alkyl group in which one or more hydrogen atoms of the alkyl group are replaced by one or more independently selected halogens. The term "haloalkyl" includes alkyl groups in which all hydrogen atoms of the alkyl group are replaced by independently selected halogens (sometimes referred to as "perhalo" alkyl groups). Exemplary haloalkyl groups include, but are not limited to, CH 2 F, CH 2 CH 2 Cl, CF 3 , CHFCH 2 Cl.

[0327] As used herein, the term "heteroaryl" refers to a monocyclic aromatic 4-6 membered ring system containing one or more heteroatoms (e.g., one to three heteroatoms such as nitrogen, oxygen and sulfur). Where possible, the heteroaryl ring may be attached to adjacent groups via carbon or nitrogen. Examples of heteroaryl rings include, but are not limited to, furan, thiophene, pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine and pyrimidine.

[0328] As used herein, the term "heterocyclyl" or "heterocyclic group" refers to a saturated or partially unsaturated (but non-aromatic) 4- to 7-membered ring structure, the ring structure of which includes one to three heteroatoms, such as nitrogen, oxygen and sulfur. The heterocycle may be fused to one or more phenyl, partially unsaturated or saturated rings. Examples of heterocyclyls include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine and piperazine.

[0329] As used herein, "isolated" means that the compound is substantially free of solvent and / or impurities.

[0330] In particular, with respect to intermediates (i.e., compounds other than compounds of Formula I or Compound A), "isolated" means substantially free of related impurities (e.g., impurities containing a substructure of the isolated intermediate having a molecular mass of at least 50% of the molecular mass of the intermediate), without considering solvents or non-related impurities such as inorganic substances, wherein "substantially free of related impurities" means that the related impurities are less than 20% of the weight of the intermediate in total. Therefore, in some embodiments, when the intermediate enters the next step, the solvent content of the isolated intermediate may exceed 50 wt%. Similarly, in some embodiments, when the intermediate enters the next step, the inorganic content of the isolated intermediate may also exceed 50 wt%.

[0331] Similarly, for the compound of formula I (e.g., compound A), "isolated" means substantially free of all relevant and irrelevant impurities, solvents and inorganics, wherein "substantially free of all relevant and irrelevant impurities, solvents and inorganics" means that the relevant impurities are less than 3wt% of the total weight of the obtained mass (including the target compound, solvent, etc.), the irrelevant impurities are less than 3wt% of the total weight of the obtained mass (including the target compound, solvent, etc.), the solvent (except water) is less than 5% of the total weight of the obtained mass (including the target compound, solvent, etc.), and the inorganics are less than 3wt% of the total weight of the obtained mass (including the target compound, solvent, etc.). Therefore, in some embodiments, water is usually present in the isolated compound of formula I (e.g., compound A) with up to 5wt%. Similarly, in some embodiments, the solvent in the isolated compound A is less than 0.5wt%. In some embodiments, the absolute purity based on water and solvent correction is usually higher than 98wt% in the isolated compound of formula I (e.g., compound A).

[0332] As used herein, the term "hydrate" in reference to an aldehyde (eg, "the aldehyde or a hydrate thereof") refers to the hydrated form of the aldehyde:

[0333]

[0334] In particular, in some embodiments, when an aldehyde is contacted with another compound (e.g., in a chemical reaction), the aldehyde may initially be in the form of a hydrate, which may, for example, have better handling properties than the aldehyde form (e.g., chloral hydrate, Cl 3 CH(OH) 2 , can be compared to the chloral itself Cl 3CHO is easier to handle because chloral hydrate is crystalline and not susceptible to possible polymerization reactions that chloral may undergo). Thus, even if the species in the chemical reaction that reacts with the compound it comes into contact with is an aldehyde, the original reagent used in the reaction may be in the hydrate form of the aldehyde, which may be in equilibrium with the aldehyde form (and the equilibrium may be shifted toward the aldehyde by removing water, for example, using molecular sieves, co-distillation with acetonitrile or other solvents, and / or other water removal methods that would be recognizable to the skilled artisan).

[0335] As used herein, the term "contacting" refers to bringing two or more substances (e.g., compounds) into close proximity so that the molecules of the two substances can react chemically. In some embodiments, the two substances are contacted when the two substances are dissolved in a solvent. In some embodiments, the first substance is contacted with the second substance by dissolving and / or suspending the first substance in a solvent (e.g., a liquid solvent), and i) adding the second substance (e.g., pure or in a solvent such as a liquid solvent) to a solution or suspension of the first substance, or ii) adding a solution or suspension of the first substance to the second substance (which itself can be dissolved and / or suspended in a solvent), thereby allowing the molecules of the two substances to react.

[0336] Compounds of the present disclosure may contain one or more chiral centers and / or double bonds and may therefore exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers. When used herein, the term "stereoisomer" consists of all geometric isomers, enantiomers or diastereomers. These compounds may be represented by the symbol "R" or "S", depending on the configuration of the substituents around the chiral carbon atom. The present invention encompasses various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. A mixture of enantiomers or diastereomers may be represented in the nomenclature as "(.+-.)", or "+ / -" or "±", but the skilled person will recognize that the structure may implicitly represent a chiral center.

[0337] Individual enantiomers and diastereomers of the compounds of the present disclosure may be synthesized from commercially available starting materials containing asymmetric or stereogenic centers, or by preparing a racemic mixture followed by resolution methods well known to those of ordinary skill in the art. Examples of such resolution methods include: (1) attaching the enantiomeric mixture to a chiral auxiliary, separating the resulting diastereomeric mixture by recrystallization or chromatography, and releasing the optically pure product from the auxiliary, (2) forming salts using an optically active resolving agent, (3) directly separating the optical enantiomer mixture on a chiral liquid chromatography column, or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. The racemic mixture may also be resolved into its component enantiomers by well-known methods, such as chiral gas chromatography or crystallization of the compound in a chiral solvent. Stereoselective synthesis is a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereogenic center or during the conversion of an existing stereogenic center, and is well known in the art. Stereoselective synthesis includes both enantioselective and diastereoselective transformations. See, for example, Carreira and Kvaemo, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

[0338] Where a range of values ​​is provided, every intervening value between the upper and lower limits of that range and any other specified value or intervening value in the stated range is intended to be encompassed in the present disclosure. For example, if a range is specified as 1 μm to 8 μm, it is intended to also explicitly disclose 2 μm, 3 μm, 4 μm, 5 μm, 6 μm and 7 μm as well as ranges of values ​​greater than or equal to 1 μm and ranges of values ​​less than or equal to 8 μm. Similarly, if a range such as C is specified, 1 -C 6 alkyl, it is intended to also explicitly disclose C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl and C 6 alkyl.

[0339] Unless the context clearly dictates otherwise, the singular forms "a," "an," and "the" include plural referents. Thus, for example, reference to "a liposome" includes a single liposome as well as two or more of the same or different liposomes, reference to "an excipient" includes a single excipient as well as two or more of the same or different excipients, etc.

[0340] The closed terms "consisting essentially of" or "consisting of" are within the scope of the open terms "comprising," "containing," or "including."

[0341] II. Methods

[0342] A. Preparation of Compounds of Formula I

[0343] In one aspect, a method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof is provided. The method comprises contacting a compound of formula II with a coupling agent in an organic solvent to obtain a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the coupling agent comprises an art-recognized reagent for coupling an amine and a carboxylic acid to form an amide bond:

[0344]

[0345] in:

[0346] R b Selected from H, halogen, cyano and C 1 -C 6 alkyl;

[0347] R 1 H or C 1 -C 6 alkyl;

[0348] R 2 H or C 1 -C 6 alkyl;

[0349] R 3 Selected from C 1 -C 6 Alkyl and C(O)OR 8 ;

[0350] R 8 Selected from C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl and -CH 2 -C 3 -C 10 Cycloalkyl, wherein C 3 -C 10 Cycloalkyl is optionally selected from C 1 -C3 One, two or three groups are substituted in the alkyl group;

[0351] R 4 and R 5 Independently selected from H, C 1 -C 6 Alkyl, X and -C 1 -C 6 Alkylene-X, wherein X is selected from:

[0352] (i)C 3 -C 6 Cycloalkyl;

[0353] (ii) a heteroaryl group comprising 5 to 6 ring atoms, wherein one, two or three of the ring atoms are independently selected from N, NH, N(C 1 -C 3 alkyl), O and S;

[0354] (iii) a heterocyclic group comprising 3 to 6 ring atoms, wherein 1, 2 or 3 of the ring atoms are independently selected from N, NH, N(C 1 -C 3 alkyl), O and S; and

[0355] (iv) phenyl;

[0356] Among them C 3 -C 6 Cycloalkyl, heterocyclyl, heteroaryl and phenyl are each optionally independently selected from halogen, cyano, C 1 -C 6 Alkyl, hydroxyl and C 1 -C 6 One, two or three substituents are substituted on the alkoxy group;

[0357] or R 4 and R 5 and the nitrogen to which they are attached together form a heterocyclic group comprising 4 to 6 ring atoms; wherein the heterocyclic group comprises no more than two ring heteroatoms (including R 4 and R 5 The second ring heteroatom, when present, is independently selected from N-C 1 -C 6 alkyl, O and S; and wherein the heterocyclic group is optionally independently selected from halogen, cyano, C 1 -C 6 Alkyl and C 1 -C 6 One, two or three substituents are substituted on the alkoxy group;

[0358] R 6 Selected from -OH, C1 -C 6 Alkoxy, -OC(O)–C 1 -C 6 Alkyl and -OC(O)phenyl; and

[0359] R 7 H or C 1 -C 6 alkyl.

[0360] In some embodiments, the coupling agent comprises a carbodiimide, optionally with 1-hydroxybenzotriazole (HOBt). In some embodiments, the coupling agent comprises a carbodiimide selected from dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), and ethyl-(N',N'-dimethylamino)propylcarbodiimide hydrochloride (EDC).

[0361] In some embodiments, the coupling agent comprises (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP), bis(2-oxo-3-oxazolidinyl)phosphinyl chloride (BOP-Cl), O-(benzotriazol-1-yl)-N,N,N',N '-Tetramethyluronium hexafluorophosphate (HBTU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TATU), O-(6-chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ( HCTU), O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbonium hexafluorophosphate (COMU), O-(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU), O-(5-norbornene-2,3-dicarboximido)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TNTU), O-(1,2-dihydro-2-oxo-1-pyridinium-N,N,N',N'-tetramethyluronium tetrafluoroborate (TPTU), N,N,N',N'-tetramethyl-O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)uranium tetrafluoroborate (TDBTU), N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH), 3-(diethylphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT), or carbonyldiimidazole (CDI).

[0362] In some embodiments, the coupling agent is a di-C halophosphate 1 -C 6 Alkyl esters (e.g., di-C 1 -C 6 alkyl esters), dialkylphosphinic halides or propanephosphoric anhydride (e.g. ). In some embodiments, the coupling agent comprises diethyl chlorophosphate.

[0363] In some embodiments, the coupling agent is used with an organic base. In some embodiments, the organic base comprises an amine. In some embodiments, the organic base comprises triethylamine, N,N-diisopropylethylamine (DIPEA) or 4-dimethylaminopyridine (DMAP). In some embodiments, the organic base comprises triethylamine.

[0364] In some embodiments, the method is carried out in an organic solvent, the organic solvent comprising dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), acetonitrile (MeCN), dichloromethane (DCM), tetrahydrofuran (THF) or 2-methyltetrahydrofuran (2-MeTHF). In some embodiments, the solvent comprises THF.

[0365] In some embodiments, the method further comprises contacting the compound of formula IV with a base in a solvent to obtain a compound of formula III, wherein the compound of formula III is subsequently subjected to an alkylating agent (e.g., an alkyl halide) or a carbamate-forming agent (e.g., a di-R 8 Dicarbonates, such as BOC 2 O) to obtain a compound of formula II, wherein R b , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 Same as above, and R 9 -CCl 3 :

[0366]

[0367] In some embodiments, the base comprises an amine. In some embodiments, the base comprises an amine selected from triethylamine or DIPEA.

[0368] In some embodiments, the solvent is an aqueous solvent. In some embodiments, the aqueous solvent is a mixture of water and acetonitrile or a mixture of water and THF (or with 2-MeTHF). In other embodiments, the aqueous solvent is a mixture of water and methanol, a mixture of water and ethanol, a mixture of water and isopropanol, a mixture of water and DMF, or a mixture of water and DMSO.

[0369] In some embodiments, the method further comprises contacting the compound of formula VII with an amine of formula VIII to obtain a condensation product of formula V or VI, which is then contacted with a reducing compound to obtain a compound of formula IV, wherein R b , R 1 , R 2 , R 3, R 4 , R 5 , R 6 , R 7 and R 9 Same as above:

[0370]

[0371] In some embodiments, the solvent for the condensation reaction comprises dichloromethane. In some embodiments, the solvent for the condensation reaction comprises toluene. In some embodiments, the solvent comprises DMF. In some embodiments, the solvent comprises THF. In some embodiments, the solvent comprises 2-MeTHF. In some embodiments, the solvent comprises DMF. In some embodiments, the solvent comprises acetonitrile.

[0372] In some embodiments, the reducing agent comprises a borohydride. In some embodiments, the reducing agent comprises a borohydride selected from the group consisting of sodium borohydride, lithium borohydride, calcium borohydride, magnesium borohydride, sodium triacetoxyborohydride (NaBH(OAc) 3 ), NBu 4 BH 4 、NaCNBH 3 and NMe 4 BH(OAc) 3 In some embodiments, the reducing agent comprises sodium triacetoxyborohydride (NaBH(OAc) 3 ).

[0373] In some embodiments, the compound of Formula V or VI is not isolated prior to contacting the compound of Formula V or VI with the reducing agent.

[0374] In some embodiments, the method further comprises contacting the compound of Formula IX with a base known in the art (e.g., lithium diisopropylamide (LDA), potassium tert-butoxide (KOtBu), and other bases that can be recognized by a skilled artisan after reading this disclosure) in a solvent to deprotonate the alpha carbon adjacent to the carbonyl group (CO), to which R is then added. 2 C(O)OR (R is methyl, ethyl, phenyl, -CH 2 CF 3 or -CH 2 CN) to obtain the compound of formula VII:

[0375]

[0376] In some embodiments, the deprotonation is performed at a temperature below 0°C, such as at a temperature between -80 and -20°C.

[0377] In some embodiments, the base comprises lithium diisopropylamide. In some embodiments, the base is potassium tert-butoxide.

[0378] In some embodiments, the solvent comprises toluene and optionally added methyl tert-butyl ether (MTBE). In some embodiments, the solvent is MTBE. In some embodiments, the solvent comprises THF optionally mixed with toluene or MTBE. In some embodiments, the solvent comprises 2-MeTHF optionally mixed with toluene or MTBE.

[0379] In some embodiments, R 2 C(O)OR is added to the deprotonated Formula IX at a temperature below 0°C, for example at a temperature between -80 and -20°C, for example about -60°C.

[0380] In some embodiments, the method further comprises reacting a compound of formula X with an aldehyde R 9 CHO or its hydrate to obtain a compound of formula IX:

[0381]

[0382] In some embodiments, the solvent used to obtain the compound of Formula IX includes THF, 2-MeTHF, acetonitrile, toluene, dichloromethane, chloroform, or MTBE.

[0383] In some embodiments, the compound of Formula I is a compound of Formula Ia:

[0384]

[0385] In some embodiments, the compound of Formula Ia is a compound of Formula Ib:

[0386]

[0387] In some embodiments, the compound of Formula Ib is a compound of Formula Ic:

[0388]

[0389] In some embodiments, the compound of Formula II is a compound of Formula IIa:

[0390]

[0391] In some embodiments, the compound of Formula IIa is a compound of Formula IIb:

[0392]

[0393] In some embodiments, the compound of Formula IIa is a compound of Formula IIc:

[0394]

[0395] In some embodiments, the compound of Formula III is a compound of Formula IIIa:

[0396]

[0397] In some embodiments, the compound of Formula IIIa is a compound of Formula IIIb:

[0398]

[0399] In some embodiments, the compound of Formula IIIa is a compound of Formula IIIc:

[0400]

[0401] In some embodiments, the compound of Formula IV is a compound of Formula IVa:

[0402]

[0403] In some embodiments, the compound of Formula IVa is a compound of Formula IVb:

[0404]

[0405] In some embodiments, the compound of Formula IVb is a compound of Formula IVc:

[0406]

[0407] In some embodiments, the compound of Formula IVb is a compound of Formula IVd:

[0408]

[0409] In some embodiments, the compound of Formula V and the compound of Formula VI are the compound of Formula Va and the compound of Formula VIa, respectively:

[0410]

[0411] In some embodiments, the compound of formula Va and the compound of formula VIa are the compound of formula Vb and the compound of formula VIb, respectively:

[0412]

[0413] In some embodiments, the compound of formula Vb and the compound of formula VIb are the compound of formula Vc and the compound of formula VIc, respectively:

[0414]

[0415] In some embodiments, the compound of formula Vc and the compound of formula VIc are the compound of formula Vd and the compound of formula VId, respectively:

[0416]

[0417] In some embodiments, the compound of Formula VII is a compound of Formula Vila:

[0418]

[0419] In some embodiments, the compound of Formula VIIa is a compound of Formula VIIb:

[0420]

[0421] In some embodiments, the compound of Formula VIII is a compound of Formula VIIIa:

[0422]

[0423] In some embodiments, the compound of Formula VIIIa is a compound of Formula VIIIb:

[0424]

[0425] In some embodiments, the compound of Formula IX is a compound of Formula IXa:

[0426]

[0427] In some embodiments, the compound of Formula IXa is a compound of Formula IXb:

[0428]

[0429]

[0430] In some embodiments, the compound of Formula X is a compound of Formula Xa:

[0431]

[0432] In some embodiments, in each of Formulae I through X (including their formulae where chiral center(s) are defined), where applicable,

[0433] R b Selected from H, halogen, cyano and C 1 -C 6 alkyl;

[0434] R1 H or C 1 -C 6 alkyl;

[0435] R 2 H or C 1 -C 6 alkyl;

[0436] R 3 Selected from C 1 -C 6 Alkyl and C(O)OR 8 ;

[0437] R 8 Selected from C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl and -CH 2 -C 3 -C 10 Cycloalkyl, wherein C 3 -C 10 Cycloalkyl is optionally selected from C 1 -C 3 One, two or three groups are substituted in the alkyl group;

[0438] R 4 and R 5 Independently selected from H and C 1 -C 6 Alkyl; or R 4 and R 5 and the nitrogen to which they are attached together form a heterocyclic group comprising 4 to 6 ring atoms; wherein the heterocyclic group comprises no more than two ring heteroatoms (including R 4 and R 5 The second ring heteroatom, when present, is independently selected from NC 1 -C 6 alkyl, O and S; and wherein the heterocyclic group is optionally independently selected from halogen, cyano, C 1 -C 6 Alkyl and C 1 -C 6 One, two or three substituents are substituted on the alkoxy group;

[0439] R 6 Selected from -OH, C 1 -C 6Alkoxy, -OC(O)–C 1 -C 6 Alkyl and -OC(O)phenyl;

[0440] R 7 H or C 1 -C 6 alkyl; and

[0441] R 9 Selected from CCl 3 .

[0442] In some embodiments, in each of Formulae I through X (including their formulae where chiral center(s) are defined), where applicable, R 1 and R 2 For H.

[0443] In some embodiments, in each of Formulae I through X (including their formulae where chiral center(s) are defined), where applicable, R 1 , R 2 , R 4 and R 5 Each of them is H.

[0444] In some embodiments, in each of Formulas I through VIII, including those wherein chiral center(s) are defined, R 6 For OH.

[0445] In some embodiments, in each of Formulas I through VIII, including those wherein chiral center(s) are defined, R 7 C 1 -C 6 An alkyl group, such as a methyl group.

[0446] In some embodiments, in each of Formulae I to II (including their formulae where chiral center(s) are defined), R 3 OC(O)R 8 , where R 8 C 1 -C 6 Alkyl, for example tert-butyl.

[0447] In some embodiments, the compound of Formula II is selected from the following compounds:

[0448]

[0449] In some embodiments, the compound of Formula III is selected from the following compounds:

[0450]

[0451] In some embodiments, the compound of Formula IV is selected from the following compounds:

[0452]

[0453] In some embodiments, the compound of Formula V is selected from the following compounds:

[0454]

[0455] B. Preparation of Compound A

[0456] In another aspect, a method for preparing (S)-2-((2S,3R)-1-amino-3-hydroxy-1-oxobutane-2-yl)-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylic acid tert-butyl ester ("Compound A") is provided. The method comprises contacting Compound B with a coupling agent in an organic solvent to obtain Compound A, wherein the coupling agent comprises an art-recognized reagent for coupling an amine and a carboxylic acid to form an amide bond:

[0457]

[0458] and wherein the compound B is prepared by reacting the compound C with di-tert-butyl dicarbonate (BOC 2 O) Contact to obtain:

[0459]

[0460] In some embodiments, the coupling agent comprises a carbodiimide, optionally with 1-hydroxybenzotriazole (HOBt). In some embodiments, the coupling agent comprises a carbodiimide selected from dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), and ethyl-(N',N'-dimethylamino)propylcarbodiimide hydrochloride (EDC).

[0461] In some embodiments, the coupling agent comprises (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP), bis(2-oxo-3-oxazolidinyl)phosphinyl chloride (BOP-Cl), O-(benzotriazol-1-yl)-N,N,N',N '-Tetramethyluronium hexafluorophosphate (HBTU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TATU), O-(6-chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ( HCTU), O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU), (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbonium hexafluorophosphate (COMU), O-(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU), O-(5-norbornene-2,3-dicarboximido)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TNTU), O-(1,2-dihydro-2-oxo-1-pyridinium-N,N,N',N'-tetramethyluronium tetrafluoroborate (TPTU), N,N,N',N'-tetramethyl-O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)uranium tetrafluoroborate (TDBTU), N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH), 3-(diethylphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT), or carbonyldiimidazole (CDI).

[0462] In some embodiments, the coupling agent is a di-C halophosphate 1 -C 6 Alkyl esters (e.g., di-C 1 -C 6 alkyl esters), dialkylphosphinic halides or propanephosphoric anhydride (e.g. ). In some embodiments, the coupling agent comprises diethyl chlorophosphate.

[0463] In some embodiments, the coupling agent is used with an organic base. In some embodiments, the organic base comprises an amine. In some embodiments, the organic base comprises triethylamine, N,N-diisopropylethylamine (DIPEA) or 4-dimethylaminopyridine (DMAP). In some embodiments, the organic base comprises triethylamine.

[0464] In some embodiments, the method is carried out in an organic solvent, the organic solvent includes dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), acetonitrile (MeCN), dichloromethane (DCM), tetrahydrofuran (THF) or 2-methyltetrahydrofuran (2-MeTHF). In some embodiments, the solvent comprises THF.

[0465] In some embodiments, the solvent used to prepare Compound B comprises acetonitrile, methanol, ethanol, isopropanol, MTBE, toluene, acetone, CH 2 Cl 2 , THF, 2-MeTHF, water and mixtures thereof. In some embodiments, an amine, such as triethylamine, is present in the reaction to prepare compound B.

[0466] In some embodiments, the method further comprises contacting compound D with a base in a solvent to obtain compound C:

[0467]

[0468] In some embodiments, the base comprises an amine. In some embodiments, the base comprises an amine selected from triethylamine and DIPEA.

[0469] In some embodiments, the solvent is an aqueous solvent. In some embodiments, the aqueous solvent is a mixture of water and acetonitrile or a mixture of water and THF (or with 2-MeTHF). In other embodiments, the aqueous solvent is a mixture of water and methanol, a mixture of water and ethanol, a mixture of water and isopropanol, a mixture of water and DMF, or a mixture of water and DMSO.

[0470] In some embodiments, the method further comprises contacting compound F with compound G to obtain a condensation product, compound E, which is subsequently contacted with a reducing compound to obtain compound D:

[0471]

[0472] In some embodiments, the solvent for the condensation reaction comprises dichloromethane. In some embodiments, the solvent for the condensation reaction comprises toluene. In some embodiments, the solvent comprises DMF. In some embodiments, the solvent comprises THF. In some embodiments, the solvent comprises 2-MeTHF. In some embodiments, the solvent comprises DMF. In some embodiments, the solvent comprises acetonitrile.

[0473] In some embodiments, the reducing agent comprises a borohydride. In some embodiments, the reducing agent comprises a borohydride selected from the group consisting of sodium borohydride, lithium borohydride, calcium borohydride, magnesium borohydride, sodium triacetoxyborohydride (NaBH(OAc) 3 ), NBu 4 BH 4 、NaCNBH 3 and NMe 4 BH(OAc) 3 borohydride in.

[0474] In some embodiments, Compound E is not isolated prior to contacting Compound E with a reducing agent.

[0475] In some embodiments, the method further comprises contacting compound H with a base known in the art in a solvent to deprotonate the alpha carbon adjacent to the carbonyl group (CO), followed by addition of HC(O)OR (R is methyl, ethyl, phenyl, -CH 2 CF 3 or -CH 2 CN) to obtain compound F:

[0476]

[0477] In some embodiments, the deprotonation is performed at a temperature below 0°C, such as at a temperature between -80 and -20°C, such as about -45°C.

[0478] In some embodiments, the base comprises lithium diisopropylamide. In some embodiments, the base is potassium tert-butoxide.

[0479] In some embodiments, the solvent comprises toluene and optionally added methyl tert-butyl ether (MTBE). In some embodiments, the solvent is MTBE. In some embodiments, the solvent comprises THF optionally mixed with toluene or MTBE. In some embodiments, the solvent comprises 2-MeTHF optionally mixed with toluene or MTBE.

[0480] In some embodiments, HC(O)OR is added to the deprotonated compound H at a temperature below 0°C (eg, at a temperature between -80 and -20°C, such as about -60°C).

[0481] In some embodiments, the method further comprises contacting D-proline with chloral to obtain compound H:

[0482]

[0483] In some embodiments, the solvent used to obtain Compound H comprises THF, 2-MeTHF, acetonitrile, toluene, dichloromethane, chloroform, or MTBE. In some embodiments, the solvent used to obtain Compound H comprises acetonitrile.

[0484] III. Intermediates

[0485] A. Compounds of Formula II

[0486] In one aspect, a compound is provided for use in a method for preparing a diazaspirolactam compound of formula I. The compound is a compound of formula II:

[0487]

[0488] in:

[0489] R b Selected from H, halogen, cyano and C 1 -C 6 alkyl;

[0490] R 1 H or C 1 -C 6 alkyl;

[0491] R 2 H or C 1 -C 6 alkyl;

[0492] R 3 Selected from C 1 -C 6 Alkyl and C(O)OR 8 ;

[0493] R 8 Selected from C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl and -CH 2 -C 3 -C 10 Cycloalkyl, wherein C 3 -C10 Cycloalkyl is optionally selected from C 1 -C 3 One, two or three groups are substituted in the alkyl group;

[0494] R 4 and R 5 Independently selected from H, C 1 -C 6 Alkyl, X and -C 1 -C 6 Alkylene-X, wherein X is selected from:

[0495] (i)C 3 -C 6 Cycloalkyl;

[0496] (ii) a heteroaryl group comprising 5 to 6 ring atoms, wherein one, two or three of the ring atoms are independently selected from N, NH, N(C 1 -C 3 alkyl), O and S;

[0497] (iii) a heterocyclic group comprising 3 to 6 ring atoms, wherein 1, 2 or 3 of the ring atoms are independently selected from N, NH, N(C 1 -C 3 alkyl), O and S; and

[0498] (iv) phenyl;

[0499] Among them C 3 -C 6 Cycloalkyl, heterocyclyl, heteroaryl and phenyl are each optionally independently selected from halogen, cyano, C 1 -C 6 Alkyl, hydroxyl and C 1 -C 6 One, two or three substituents are substituted on the alkoxy group;

[0500] or R 4 and R 5 and the nitrogen to which they are attached together form a heterocyclic group comprising 4 to 6 ring atoms; wherein the heterocyclic group comprises no more than two ring heteroatoms (including R 4 and R 5 The second ring heteroatom, when present, is independently selected from -N-C 1 -C 6 alkyl, O and S; and wherein the heterocyclic group is optionally independently selected from halogen, cyano, C 1 -C 6 Alkyl and C 1 -C 6 One, two or three substituents are substituted on the alkoxy group;

[0501] R 6 Selected from -OH, C 1 -C 6 Alkoxy, -OC(O)–C 1 -C 6 Alkyl and -OC(O)phenyl; and

[0502] R 7 H or C 1 -C 6 alkyl.

[0503] In some embodiments, the compound of Formula II is a compound of Formula IIa:

[0504]

[0505] In some embodiments, the compound of Formula IIa is a compound of Formula IIb:

[0506]

[0507] In some embodiments, the compound of Formula IIb is a compound of Formula IIc:

[0508]

[0509] In some embodiments, in each of Formula II, IIa, IIb, and IIc:

[0510] R b Selected from H, halogen, cyano and C 1 -C 6 alkyl;

[0511] R 1 H or C 1 -C 6 alkyl;

[0512] R 2 H or C 1 -C 6 alkyl;

[0513] R 3 Selected from C 1 -C 6 Alkyl and C(O)OR 8 ;

[0514] R 8 Selected from C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 2 -C 6 Alkenyl, C2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl and -CH 2 -C 3 -C 10 Cycloalkyl, wherein C 3 -C 10 Cycloalkyl is optionally selected from C 1 -C 3 One, two or three groups are substituted in the alkyl group;

[0515] R 4 and R 5 Independently selected from H and C 1 -C 6 Alkyl; or R 4 and R 5 and the nitrogen to which they are attached together form a heterocyclic group comprising 4 to 6 ring atoms; wherein the heterocyclic group comprises no more than two ring heteroatoms (including R 4 and R 5 The second ring heteroatom, when present, is independently selected from NC 1 -C 6 alkyl, O and S; and wherein the heterocyclic group is optionally independently selected from halogen, cyano, C 1 -C 6 Alkyl and C 1 -C 6 One, two or three substituents are substituted on the alkoxy group;

[0516] R 6 Selected from -OH, C 1 -C 6 Alkoxy, -OC(O)–C 1 -C 6 Alkyl and -OC(O)phenyl; and

[0517] R 7 H or C 1 -C 6 alkyl.

[0518] In some embodiments, in each of Formula II, IIa, IIb, and IIc, R 1 and R 2 For H.

[0519] In some embodiments, in each of Formula II, IIa, IIb, and IIc, R 1 , R 2 , R 4 and R 5 Each of them is H.

[0520] In some embodiments, in each of Formula II, IIa, IIb, and IIc, R 6 For OH.

[0521] In some embodiments, in each of Formula II, IIa, IIb, and IIc, R 7 C 1 -C 6 An alkyl group, such as a methyl group.

[0522] In some embodiments, in each of Formula II, IIa, IIb, and IIc, R 3 OC(O)R 8 , where R 8 C 1 -C 6 Alkyl, for example tert-butyl.

[0523] In one embodiment, the compound of formula II is selected from the following compounds:

[0524]

[0525] B. Compounds of Formula III

[0526] In another aspect, provided is a compound of formula III:

[0527]

[0528] in:

[0529] R b Selected from H, halogen, cyano and C 1 -C 6 alkyl;

[0530] R 1 H or C 1 -C 6 alkyl;

[0531] R 2 H or C 1 -C 6 alkyl;

[0532] R 8 Selected from C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl and -CH2 -C 3 -C 10 Cycloalkyl, wherein C 3 -C 10 Cycloalkyl is optionally selected from C 1 -C 3 One, two or three groups are substituted in the alkyl group;

[0533] R 4 and R 5 Independently selected from H, C 1 -C 6 Alkyl, X and -C 1 -C 6 Alkylene-X, wherein X is selected from:

[0534] (i)C 3 -C 6 Cycloalkyl;

[0535] (ii) a heteroaryl group comprising 5 to 6 ring atoms, wherein one, two or three of the ring atoms are independently selected from N, NH, N(C 1 -C 3 alkyl), O and S;

[0536] (iii) a heterocyclic group comprising 3 to 6 ring atoms, wherein 1, 2 or 3 of the ring atoms are independently selected from N, NH, N(C 1 -C 3 alkyl), O and S; and

[0537] (iv) phenyl;

[0538] Among them C 3 -C 6 Cycloalkyl, heterocyclyl, heteroaryl and phenyl are each optionally independently selected from halogen, cyano, C 1 -C 6 Alkyl, hydroxyl and C 1 -C 6 One, two or three substituents are substituted on the alkoxy group;

[0539] or R 4 and R 5 and the nitrogen to which they are attached together form a heterocyclic group comprising 4 to 6 ring atoms; wherein the heterocyclic group comprises no more than two ring heteroatoms (including R 4 and R 5 The second ring heteroatom, when present, is independently selected from N-C 1 -C 6 alkyl, O and S; and wherein the heterocyclic group is optionally independently selected from halogen, cyano, C 1 -C6 Alkyl and C 1 -C 6 One, two or three substituents are substituted on the alkoxy group;

[0540] R 6 Selected from -OH, C 1 -C 6 Alkoxy, -OC(O)–C 1 -C 6 Alkyl and -OC(O)phenyl; and

[0541] R 7 H or C 1 -C 6 alkyl.

[0542] In some embodiments, the compound of Formula III is a compound of Formula IIIa:

[0543]

[0544]

[0545] In some embodiments, the compound of Formula IIIa is a compound of Formula IIIb:

[0546]

[0547] In some embodiments, the compound of Formula IIIb is a compound of Formula IIIc:

[0548]

[0549] In some embodiments, in each of Formula II, IIa, IIb, and IIc:

[0550] R b Selected from H, halogen, cyano and C 1 -C 6 alkyl;

[0551] R 1 H or C 1 -C 6 alkyl;

[0552] R 2 H or C 1 -C 6 alkyl;

[0553] R 8 Selected from C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 2 -C6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl and -CH 2 -C 3 -C 10 Cycloalkyl, wherein C 3 -C 10 Cycloalkyl is optionally selected from C 1 -C 3 One, two or three groups are substituted in the alkyl group;

[0554] R 4 and R 5 Independently selected from H and C 1 -C 6 Alkyl; or R 4 and R 5 and the nitrogen to which they are attached together form a heterocyclic group comprising 4 to 6 ring atoms; wherein the heterocyclic group comprises no more than two ring heteroatoms (including R 4 and R 5 The second ring heteroatom, when present, is independently selected from NC 1 -C 6 alkyl, O and S; and wherein the heterocyclic group is optionally independently selected from halogen, cyano, C 1 -C 6 Alkyl and C 1 -C 6 One, two or three substituents are substituted on the alkoxy group;

[0555] R 6 Selected from -OH, C 1 -C 6 Alkoxy, -OC(O)–C 1 -C 6 Alkyl and -OC(O)phenyl; and

[0556] R 7 H or C 1 -C 6 alkyl.

[0557] In some embodiments, in each of Formula III, IIIa, IIIb, and IIIc, R 1 and R 2 For H.

[0558] In some embodiments, in each of Formula III, IIIa, IIIb, and IIIc, R 1 , R 2 , R 4 and R 5Each of them is H.

[0559] In some embodiments, in each of Formula III, IIIa, IIIb, and IIIc, R 6 For OH.

[0560] In some embodiments, in each of Formula III, IIIa, IIIb, and IIIc, R 7 C 1 -C 6 An alkyl group, such as a methyl group.

[0561] In some embodiments, the compound of Formula III is selected from the following compounds:

[0562]

[0563] C. Compounds of Formula IV

[0564] In another aspect, provided is a compound of formula IV:

[0565]

[0566] in:

[0567] R b Selected from H, halogen, cyano and C 1 -C 6 alkyl;

[0568] R 1 H or C 1 -C 6 alkyl;

[0569] R 2 H or C 1 -C 6 alkyl;

[0570] R 4 and R 5 Independently selected from H, C 1 -C 6 Alkyl, X and -C 1 -C 6 Alkylene-X, wherein X is selected from

[0571] (i)C 3 -C 6 Cycloalkyl;

[0572] (ii) a heteroaryl group comprising 5 to 6 ring atoms, wherein one, two or three of the ring atoms are independently selected from N, NH, N(C 1 -C 3 alkyl), O and S;

[0573] (iii) a heterocyclic group comprising 3 to 6 ring atoms, wherein 1, 2 or 3 of the ring atoms are independently selected from N, NH, N(C 1 -C 3 alkyl), O and S; and

[0574] (iv) phenyl;

[0575] Among them C 3 -C 6 Cycloalkyl, heterocyclyl, heteroaryl and phenyl are each optionally independently selected from halogen, cyano, C 1 -C 6 Alkyl, hydroxyl and C 1 -C 6 One, two or three substituents are substituted on the alkoxy group;

[0576] or R 4 and R 5 and the nitrogen to which they are attached together form a heterocyclic group comprising 4 to 6 ring atoms; wherein the heterocyclic group comprises no more than two ring heteroatoms (including R 4 and R 5 The second ring heteroatom, when present, is independently selected from N-C 1 -C 6 alkyl, O and S; and wherein the heterocyclic group is optionally independently selected from halogen, cyano, C 1 -C 6 Alkyl and C 1 -C 6 One, two or three substituents are substituted on the alkoxy group;

[0577] R 6 Selected from -OH, C 1 -C 6 Alkoxy, -OC(O)–C 1 -C 6 Alkyl and -OC(O)phenyl; and

[0578] R 7 H or C 1 -C 6 alkyl; and

[0579] R 9 -CCl 3 .

[0580] In some embodiments, the compound of Formula IV is a compound of Formula IVa:

[0581]

[0582] In some embodiments, the compound of Formula IVa is a compound of Formula IVb:

[0583]

[0584] In some embodiments, the compound of Formula IVb is a compound of Formula IVc:

[0585]

[0586] In some embodiments, the compound of Formula IVc is a compound of Formula IVd:

[0587]

[0588] In some embodiments, in each of Formulas IV, IVa, IVb, IVc, and IVd:

[0589] R b Selected from H, halogen, cyano and C 1 -C 6 alkyl;

[0590] R 1 H or C 1 -C 6 alkyl;

[0591] R 2 H or C 1 -C 6 alkyl;

[0592] R 4 and R 5 Independently selected from H and C 1 -C 6 Alkyl; or R 4 and R 5 and the nitrogen to which they are attached together form a heterocyclic group comprising 4 to 6 ring atoms; wherein the heterocyclic group comprises no more than two ring heteroatoms (including R 4 and R 5 The second ring heteroatom, when present, is independently selected from NC 1 -C 6 alkyl, O and S; and wherein the heterocyclic group is optionally independently selected from halogen, cyano, C 1 -C 6 Alkyl and C 1 -C 6 One, two or three substituents are substituted on the alkoxy group;

[0593] R 6 Selected from -OH, C 1 -C 6 Alkoxy, -OC(O)–C1 -C 6 Alkyl and -OC(O)phenyl;

[0594] R 7 H or C 1 -C 6 alkyl; and

[0595] R 9 -CCl 3 .

[0596] In some embodiments, in each of Formulas IV, IVa, IVb, IVc, and IVd, R 1 and R 2 For H.

[0597] In some embodiments, in each of Formulas IV, IVa, IVb, IVc, and IVd, R 9 CCl 3 .

[0598] In some embodiments, in each of Formulas IV, IVa, IVb, IVc, and IVd, R 1 , R 2 , R 4 and R 5 Each of them is H.

[0599] In some embodiments, in each of Formulas IV, IVa, IVb, IVc, and IVd, R 6 For OH.

[0600] In some embodiments, in each of Formulas IV, IVa, IVb, IVc, and IVd, R 7 C 1 -C 6 An alkyl group, such as a methyl group.

[0601] In some embodiments, the compound of Formula IV is selected from the following compounds:

[0602]

[0603] D. Compounds of Formula V and Formula VI

[0604] In another aspect, provided are compounds of Formula V or VI:

[0605]

[0606] in:

[0607] R b Selected from H, halogen, cyano and C 1 -C6 alkyl;

[0608] R 1 H or C 1 -C 6 alkyl;

[0609] R 2 H or C 1 -C 6 alkyl;

[0610] R 4 and R 5 Independently selected from H, C 1 -C 6 Alkyl, X and -C 1 -C 6 Alkylene-X, wherein X is selected from:

[0611] (i)C 3 -C 6 Cycloalkyl;

[0612] (ii) a heteroaryl group comprising 5 to 6 ring atoms, wherein one, two or three of the ring atoms are independently selected from N, NH, N(C 1 -C 3 alkyl), O and S;

[0613] (iii) a heterocyclic group comprising 3 to 6 ring atoms, wherein 1, 2 or 3 of the ring atoms are independently selected from N, NH, N(C 1 -C 3 alkyl), O and S; and

[0614] (iv) phenyl;

[0615] Among them C 3 -C 6 Cycloalkyl, heterocyclyl, heteroaryl and phenyl are each optionally independently selected from halogen, cyano, C 1 -C 6 Alkyl, hydroxyl and C 1 -C 6 One, two or three substituents are substituted on the alkoxy group;

[0616] or R 4 and R 5 and the nitrogen to which they are attached together form a heterocyclic group comprising 4 to 6 ring atoms; wherein the heterocyclic group comprises no more than two ring heteroatoms (including R 4 and R 5 The second ring heteroatom, when present, is independently selected from N-C 1 -C 6alkyl, O and S; and wherein the heterocyclic group is optionally independently selected from halogen, cyano, C 1 -C 6 Alkyl and C 1 -C 6 One, two or three substituents are substituted on the alkoxy group;

[0617] R 6 Selected from C 1 -C 6 Alkoxy, -OC(O)–C 1 -C 6 Alkyl and -OC(O)phenyl;

[0618] R 7 H or C 1 -C 6 alkyl; and

[0619] R 9 -CCl 3 .

[0620] In some embodiments, the compound of Formula V and the compound of Formula VI are the compound of Formula Va and the compound of Formula VIa, respectively:

[0621]

[0622] In some embodiments, the compound of formula Va and the compound of formula VIa are the compound of formula Vb and the compound of formula VIb, respectively:

[0623]

[0624] In some embodiments, the compound of formula Vb and the compound of formula VIb are the compound of formula Vc and the compound of formula VIc, respectively:

[0625]

[0626] In some embodiments, the compound of formula Vc and the compound of formula VIc are the compound of formula Vd and the compound of formula VId, respectively:

[0627]

[0628] In some embodiments, in each of Formulas V, Va, Vb, Vc, Vd, VI, VIa, VIb, VIc, and VId:

[0629] R b Selected from H, halogen, cyano and C 1 -C 6 alkyl;

[0630] R1 H or C 1 -C 6 alkyl;

[0631] R 2 H or C 1 -C 6 alkyl;

[0632] R 4 and R 5 Independently selected from H and C 1 -C 6 Alkyl; or R 4 and R 5 and the nitrogen to which they are attached together form a heterocyclic group comprising 4 to 6 ring atoms; wherein the heterocyclic group comprises no more than two ring heteroatoms (including R 4 and R 5 The second ring heteroatom, when present, is independently selected from NC 1 -C 6 alkyl, O and S; and wherein the heterocyclic group is optionally independently selected from halogen, cyano, C 1 -C 6 Alkyl and C 1 -C 6 One, two or three substituents are substituted on the alkoxy group;

[0633] R 6 Selected from C 1 -C 6 Alkoxy, -OC(O)–C 1 -C 6 Alkyl and -OC(O)phenyl;

[0634] R 7 H or C 1 -C 6 alkyl; and

[0635] R 9 -CCl 3 .

[0636] In some embodiments, in each of Formulas V, Va, Vb, Vc, Vd, VI, VIa, VIb, VIc, and VId, R 1 and R 2 For H.

[0637] In some embodiments, in each of Formulas V, Va, Vb, Vc, Vd, VI, VIa, VIb, VIc, VId, and IVd, R 9 CCl 3 .

[0638] In some embodiments, in each of Formulas V, Va, Vb, Vc, Vd, VI, VIa, VIb, VIc, and VId, R 1 , R 2 , R 4 and R 5 Each of them is H.

[0639] In some embodiments, in each of Formulas V, Va, Vb, Vc, Vd, VI, VIa, VIb, VIc, and VId, R 6 For OH.

[0640] In some embodiments, in each of Formulas V, Va, Vb, Vc, Vd, VI, VIa, VIb, VIc, and VId, R 7 C 1 -C 6 An alkyl group, such as a methyl group.

[0641] In some embodiments, the compound of Formula V is selected from the following compounds:

[0642]

[0643] IV. Embodiment

[0644] The following examples are illustrative in nature and are not intended to be limiting in any way.

[0645] Example 1

[0646] Preparation of compounds of formula I

[0647] Compounds of formula I can be prepared by the following general scheme:

[0648]

[0649] The compound of formula IX is prepared by reacting proline or a derivative thereof (formula X) with an aldehyde R 9 CHO or its hydrate is prepared by deprotonating the compound of formula IX with a base such as lithium diisopropylamide or a similar base and then reacting with R 2 C(O)OR treatment provides a compound of formula VII. The compound of formula VII is condensed with a compound of formula VIII to obtain a compound of formula V (when R in formula VIII is 6 is OH) or a compound of formula VI (when R in formula VIII is 6is not OH). Subjecting the compound of formula V or VI to a reducing agent (e.g., a borohydride type reducing agent) yields a compound of formula IV. The 5-membered ring is opened by treating the compound of formula IV with an alkaline agent (e.g., an organic amine) and provides a compound of formula III. Protecting the nitrogen on the five-membered ring with a dicarbonate or an alkylating agent provides a compound of formula II. The compound of formula II is cyclized in the presence of a coupling agent to provide a compound of formula I.

[0650] Other reaction conditions, such as reaction temperature, solvent, and specific reagents used to carry out the reactions can be determined by the skilled artisan.

[0651] Individual enantiomers and diastereomers of compounds of the above formula may be synthesized from commercially available starting materials that contain asymmetric or stereogenic centers or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art.

[0652] Example 2

[0653] Preparation of (S)-tert-butyl 2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate ("Compound A")

[0654] Compound A was prepared by the following scheme:

[0655]

[0656] Step 1: Synthesis of Compound H

[0657] The nitrogen-purged reactor was charged with acetonitrile, D-proline (69.0 kg), molecular sieves and chloral hydrate (106 kg). The mixture was heated at 50 ° C for 5.3 hours. Proton NMR showed complete conversion. The reaction mixture was filtered through a diatomaceous earth pad wet with acetonitrile and rinsed with acetonitrile. The filtrate was concentrated to a total volume of 100 L under vacuum at less than 45 ° C. n-Butanol (140 L) was added, and the mixture was concentrated under vacuum at less than 45 ° C for 3.5 hours until no further distillate was observed. The mixture was kept at 20 ° C overnight, then cooled to 0-5 ° C and stirred. The precipitate was collected by filter press and then washed with n-butanol. The resulting solid was dried under vacuum at 45 ° C to provide compound H (108.7 kg, 74.2% yield). 1 H-NMR (DMSO-d 6)δ1.1-1.4(m,1H),1.4-1.7(m,1H),1.7-2.0(m,1H),2.1-2.5(m,1H),3.2-3.4(m,1H),3.5-3.8(m,1H),4.1-4.4(m,1H),5.8(s,1H). MS(ESI)m / z(M-H+2H 2 O) - 277.94.

[0658] Step 2: Synthesis of Compound F

[0659] A nitrogen-purged reactor was charged with toluene, MTBE and compound H (1 equivalent). The resulting solution was cooled to -55 to -45°C. A solution of lithium diisopropylamide (LDA) in THF / n-heptane / ethylbenzene (26.8%, 1.1 equivalent) was added over 1.3 hours at -50 to -44°C. The resulting solution was stirred at -45±5°C for 37 minutes and then cooled to -75 to -65°C. A solution of methyl formate (2 equivalents) in MTBE was added over 45 minutes at below -60°C and then rinsed with MTBE. The mixture was stirred at -70 to -60°C for 44 minutes. The second reactor was purged with nitrogen and charged with deionized water and citric acid monohydrate. The resulting solution was cooled to 0 to 5°C and the contents of the first reactor were added over 53 minutes at below 10°C and rinsed with MTBE. The mixture was warmed to 11°C and the phases were separated. The aqueous layer was extracted with MTBE and then discarded. The main organic layer was then washed with an aqueous solution of sodium chloride (57%) (1.8 volumes), followed by MTBE washes. The combined organics were concentrated under vacuum at less than 50°C. Toluene (2x) was added and the mixture was concentrated after each addition until the total volume was 47 L. The mixture was cooled to 35°C and diluted with dichloromethane to give Compound F as a crude solution in 65.1% yield. Crystallization of a sample of crude Compound F from MTBE / hexane provided an analytical sample: 1 H-NMR (DMSO-d 6 )δ1.7-1.8(m,1H),1.8-1.9(m,1H),2.2-2.3(m,2H),3.3-3.4(m,1H),3.5-3.6(m,1H),5.9(s,1H),9.5(s,1H). MS(ESI)m / z(M+H) + 272.0.

[0660] Step 3: Synthesis of Compound D

[0661] A nitrogen-purged reactor was charged with a crude compound F solution, dichloromethane and compound G (1.2 equivalents). The resulting suspension was heated to 30-35°C for 6 hours and then stirred overnight at 20-25°C to give compound E. An analytical sample of compound E was isolated by silica gel column chromatography (dichloromethane / ethyl acetate eluent) followed by crystallization from ethyl acetate / hexane. 1 H-NMR (DMSO-d 6 )δ1.2(d,3H,J=8Hz),1.8-1.9(m,2H),2.0-2.1(m,1H),2.2-2.3(m,1H),3.1-3.2(m,1H), 3.2-3.3(m,1H),3.6-3.8(m,2H),4.7(d,2H,J=15Hz),5.5(s,1H),7.2(s,1H),7.5(s,1H). MS(ESI)m / z(M+H) + 372.0.

[0662] The crude Compound E mixture was cooled to 20°C and sodium triacetoxyborohydride (3.0 equiv.) was added at 20-29°C over 1.5 hours and the mixture was then stirred at 30-35°C for 5 hours. Water was added at 15-20°C over 49 minutes and gas was generated. The medium was stirred and the phases were separated. The aqueous layer was extracted twice with dichloromethane (2x). The combined organics were washed with saturated aqueous sodium bicarbonate. The dichloromethane extract contained pure Compound D in 78.9% yield as determined by HPLC. Analytical sample of crystallized Compound D from toluene / hexane and water. 1 H-NMR (DMSO-d 6 )δ1.1(d,3H,J=8Hz),1.8-1.9(m,2H),2.0-2.1(m,2H),2.7-2.8(m,2H),3.1-3.2(m,1H), 3.3-3.4(m,1H),3.6-3.7(m,1H),4.7(d,2H,J=6Hz),5.6(s,1H),7.0(s,1H),7.1(s,1H). MS(ESI)m / z(M+H) + 374.1.

[0663] Step 4: Synthesis of Compound C

[0664] The crude solution of compound D is concentrated to a total volume of 110L under vacuum at less than 45°C. Acetonitrile is added and the mixture is concentrated to a total volume of 110L. Acetonitrile, water and triethylamine (6 equivalents) are added, and the mixture is heated to 45°C and then stirred. The mixture is concentrated to a total volume of less than 110L under vacuum at less than 50°C. Acetonitrile is added, followed by isopropanol. The mixture is cooled to 15-20°C, MTBE is added within 1 hour at 15-20°C, and the resulting slurry is stirred at 15-20°C, and the product is collected by filtration. The crude solid is slurried in methanol and stirred at 60-65°C, and the suspension is then slowly cooled to 20-25°C. The product is collected by filtration and washed with methanol, and the solid is dried under vacuum at 50°C to obtain compound C, 72.4% yield. 1 H-NMR (MeOH-d 4 )δ1.23(3H,d,J=6.4Hz);1.9-2.1(m,3H),2.2-2.3(m,1H),2.9(d,1H,J=13Hz),3.0(d,1H,J=6Hz),3.1(d,1H,J=13Hz),3.2-3.3(m,1H),3.4-3.5(m,1H),3.8(quintet,1H,J=6Hz). MS(ESI)m / z(M+H) + 246.2.

[0665] Step 5: Synthesis of Compound B

[0666] A nitrogen-purged reactor was charged with acetone, water and compound C (1 equivalent) in sequence. Triethylamine (6 equivalents) was added to the medium within 20 minutes at less than 30°C and rinsed with acetone. A solution of di-tert-butyl dicarbonate (1.3 equivalents) was added to the mixture at less than 30°C and rinsed with acetone (13L). The mixture was stirred at 20-30°C. An acetone solution of di-tert-butyl dicarbonate (0.5 equivalent) was added to the mixture. An acetone solution of di-tert-butyl dicarbonate (0.5 equivalent) was added. The mixture was concentrated to a total volume of 65L at atmospheric pressure. Acetone was added, followed by tetrahydrofuran, and the mixture was concentrated to a total volume of 65L. The resulting suspension was cooled to 0-5°C, and the precipitate was then collected by filtration, washed with THF, and dried under vacuum at 45°C to obtain compound B in 90.5% yield. 1 H-NMR (DMSO-d 6)δ1.1(d,3H,J=6Hz),1.3(s,5H),1.4(s,4H),1.7-1.8(m,2H),1.9-2.0(m,1H),2.2-2.4(m,1H ),2.5-3.1(m,3H),3.2-3.5(m,3H),3.6-3.7(m,1H),7.2(d,1H,J=16Hz),7.4,(d,1H,J=16Hz). MS(ESI)m / z(M+H) + 346.3.

[0667] Step 6: Synthesis of Compound A

[0668] THF and compound B (1 equivalent) were charged into a nitrogen-purged reactor. Triethylamine (1.8 equivalents) was added at 20-25°C and rinsed with THF. A THF solution of diethyl chlorophosphate (1.8 equivalents) was added at 20-33°C. After stirring at 25-33°C, an aqueous solution of sodium chloride was added at 25-30°C, and the phases were separated. The aqueous layer was extracted twice with ethyl acetate. The combined organics were concentrated to a total volume of 65 to 70L under vacuum at less than 60°C. Ethyl acetate was added, and the mixture was concentrated to a total volume of 65 to 70L. Ethyl acetate was added to the mixture, followed by an aqueous solution of sodium chloride (60L). Phosphoric acid was then added to adjust the pH to 2.0. The mixture was stirred at 20-25°C, the phases were separated and the aqueous phase was discarded. The organic layer was washed with a mixture of sodium chloride and aqueous ammonia, and the washings were stripped with ethyl acetate. The combined organics were mixed with activated carbon, stirred overnight, then filtered through ethyl acetate wet celite and rinsed with ethyl acetate. The filtrate was concentrated under vacuum to a total volume of 100 L at less than 60 °C. Ethyl acetate was added and the mixture was concentrated to 100 L after each addition. Ethyl acetate was added and the mixture was cooled to 20-25 °C. The mixture was heated to 45-55 °C and the residual solids were removed by filtration, washed with ethyl acetate and discarded.

[0669] The filtrate was concentrated under vacuum at less than 60° C. to a total volume of 105 L. The mixture was heated to 65-70° C. and then cooled to 25° C. Diisopropyl ether was added and the mixture was stirred at 20-25° C. The precipitate was collected by filtration, washed with diisopropyl ether, and then dried at 50° C. to give Compound A in the form of a white crystalline powder in 67.2% yield. 1 H-NMR (DMSO-d 6)δ1.1(m,3H),1.3(s,4H),1.4(s,5H),1.7-1.9(m,2H),2.0-2.3(m,2H),3.1-3.5(m,3H),3.5-4.0(m,3H),4.9(m,1H),7.1-7.6(m,2H). MS(ESI)m / z(M+Na) + 350.2.

[0670] Throughout this specification, publications such as U.S. and foreign patent applications, journal articles, book chapters, etc. are cited. Unless otherwise indicated, all such publications are expressly incorporated by reference in their entirety, including the Supplementary / Supporting Information sections disclosed with the corresponding references, for all purposes.

[0671] Although many exemplary aspects and embodiments have been discussed above, those skilled in the art will recognize certain modifications, permutations, additions and sub-combinations thereof. Therefore, the following appended claims and claims introduced below are intended to be interpreted as including all such modifications, permutations, additions and sub-combinations within their true spirit and scope.

Claims

1. A method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof, comprising contacting a compound of formula II with a coupling agent in an organic solvent to obtain a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the coupling agent is used to couple an amine and a carboxylic acid to form an amide bond: in: R b is H; R1 is H or C1-C6 alkyl; R2 is H or C1-C6 alkyl; R3 is selected from C1-C6 alkyl and -C(O)OR8; R8 is selected from C1-C6 alkyl and C1-C6 haloalkyl; R4 and R5 are independently selected from H and C1-C6 alkyl; R6 is selected from -OH, C1-C6 alkoxy, -OC(O)-C1-C6 alkyl and -OC(O)phenyl; and R7 is H or C1-C6 alkyl.

2. The method according to claim 1, wherein the coupling agent is a carbodiimide, optionally together with 1-hydroxybenzotriazole (HOBt), wherein the carbodiimide is selected from dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) and ethyl-(N',N'-dimethylamino)propylcarbodiimide hydrochloride (EDC).

3. The method according to claim 1, wherein the coupling agent is selected from di-C1-C6 alkyl halophosphate, dialkyl phosphine halide or propane phosphoric anhydride.

4. The method according to claim 1, wherein the coupling agent is diethyl chlorophosphate.

5. The method according to claim 1, wherein the coupling agent is used with an amine, wherein the amine is selected from triethylamine, N,N-diisopropylethylamine (DIPEA) or 4-dimethylaminopyridine (DMAP).

6. The method according to claim 1, wherein the method is carried out in an organic solvent selected from dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), acetonitrile (MeCN), dichloromethane (DCM), tetrahydrofuran (THF) and 2-methyltetrahydrofuran (2-MeTHF). The method according to claim 6 , wherein the organic solvent is THF.

8. The method according to claim 1, further comprising contacting a compound of formula IV with a base in a solvent to obtain a compound of formula III, wherein the compound of formula III is subsequently contacted with an alkylating agent or a carbamate-forming agent to obtain a compound of formula II, wherein R b , R1, R2, R3, R4, R5, R6 and R7 are the same as those described in claim 1, and R9 is -CCl3:

9. The process according to claim 8, wherein the base is an amine, wherein the amine is selected from triethylamine and DIPEA.

10. The method according to claim 8, wherein the solvent is an aqueous solvent selected from the group consisting of a mixture of water and acetonitrile, a mixture of water and THF, a mixture of water and 2-MeTHF, a mixture of water and methanol, a mixture of water and ethanol, a mixture of water and isopropanol, a mixture of water and DMF, and a mixture of water and DMSO.

11. The method according to claim 8, wherein the alkylating agent is a C1-C6 alkyl halide and the carbamating agent is a di-R8-dicarbonate, wherein R8 is as defined in claim 1.

12. The method of claim 8, further comprising contacting the compound of formula VII with an amine of formula VIII to obtain a condensation product of formula V or VI, which is then contacted with a reducing agent to obtain a compound of formula IV, wherein R b , R1, R2, R4, R5, R6 and R7 are as defined in claim 1, and R9 is as defined in claim 8 13. The method according to claim 12, wherein the solvent used for the condensation reaction is selected from dichloromethane, dimethylformamide, tetrahydrofuran and acetonitrile.

14. The method according to claim 12, wherein the solvent used for the condensation reaction is toluene.

15. The method of claim 12, wherein the compound of formula V or VI is not isolated prior to contacting the compound of formula V or VI with the reducing agent.

16. The method of claim 12, wherein the reducing agent is a borohydride.

17. The method of claim 12, wherein the reducing agent is a borohydride selected from the group consisting of sodium borohydride, lithium borohydride, calcium borohydride, magnesium borohydride, sodium triacetoxyborohydride (NaBH(OAc)3), NBu4BH4, NaCNBH3, and NMe4BH(OAc)3.

18. The method of claim 12, wherein the reducing agent is sodium triacetoxyborohydride (NaBH(OAc)3).

19. The method according to claim 12, further comprising contacting the compound of formula IX with a base in a solvent to deprotonate the alpha carbon next to the carbonyl group, followed by adding R2COOR thereto to obtain a compound of formula VII, wherein R is methyl or ethyl, R b , R1 and R2 are as defined in claim 1, and R9 is as defined in claim 8:

20. The process of claim 19, wherein the deprotonation is performed at a temperature below 0°C.

21. The method of claim 20, wherein the deprotonation is performed at a temperature of -80 to -20°C.

22. The method of claim 19, wherein the base is lithium diisopropylamide.

23. The method of claim 19, wherein the solvent is selected from toluene optionally mixed with methyl tert-butyl ether (MTBE), THF optionally mixed with toluene or MTBE, and 2-MeTHF optionally mixed with toluene or MTBE.

24. The process of claim 19, wherein R2C(O)OR is added to the deprotonated Formula IX at a temperature below 0°C.

25. The process of claim 24, wherein R2C(O)OR is added to the deprotonated Formula IX at a temperature of -80 to -20°C.

26. The method of claim 25, wherein R2C(O)OR is added to the deprotonated Formula IX at a temperature of about -60°C.

27. The method of claim 19, further comprising contacting the compound of formula X with an aldehyde R9CHO or a hydrate thereof to obtain a compound of formula IX, wherein R b and R1 as defined in claim 1 and R9 as defined in claim 8:

28. The process according to claim 27, wherein the solvent used to obtain the compound of formula IX is selected from THF, acetonitrile and toluene.

29. The method of claim 1, wherein: R b is H; R1 is H or C1-C6 alkyl; R2 is H or C1-C6 alkyl; R3 is selected from C1-C6 alkyl and -C(O)OR8; R8 is selected from C1-C6 alkyl; R4 and R5 are independently selected from H and C1-C6 alkyl; R6 is selected from -OH, C1-C6 alkoxy, -OC(O)-C1-C6 alkyl and -OC(O)phenyl; and R7 is H or C1-C6 alkyl.

30. The method of claim 29, wherein R1 and R2 are H.

31. The method of claim 29, wherein each of R1, R2, R4 and R5 is H.

32. The method of claim 29, wherein R6 is -OH.

33. The method of claim 29, wherein R7 is C1-C6 alkyl.

34. The method of claim 33, wherein R7 is methyl.

35. The method of claim 29, wherein R3 is -C(O)OR8.

36. The method of claim 35, wherein R8 is C1-C4 alkyl.

37. The method of claim 36, wherein R8 is tert-butyl.

38. A method for preparing (S)-tert-butyl 2-((2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl)-1-oxo-2,5-diazaspiro[3.4]octane-5-carboxylate ("Compound A"), comprising contacting Compound B and a coupling agent in an organic solvent to obtain Compound A, wherein the coupling agent is used to couple an amine and a carboxylic acid to form an amide bond: And wherein the compound B is obtained by contacting the compound C with di-tert-butyl dicarbonate (BOC2O) in an organic solvent:

39. The method of claim 38, wherein the coupling agent is a carbodiimide, optionally together with 1-hydroxybenzotriazole (HOBt), wherein the carbodiimide is selected from dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) and ethyl-(N',N'-dimethylamino)propylcarbodiimide hydrochloride (EDC).

40. The method of claim 38, wherein the coupling agent is selected from di-C1-C6 alkyl halophosphates, dialkylphosphinyl halides, or propanephosphoric anhydride.

41. The method of claim 40, wherein the coupling agent is diethyl chlorophosphate.

42. The method of claim 38, wherein the coupling agent is used with an amine selected from the group consisting of triethylamine, N,N-diisopropylethylamine (DIPEA) and 4-dimethylaminopyridine (DMAP).

43. The method of claim 42, wherein the organic base is triethylamine.

44. The method of claim 38, wherein the organic solvent used to prepare compound A is selected from dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), acetonitrile (MeCN), dichloromethane (DCM), tetrahydrofuran (THF) and 2-methyltetrahydrofuran (2-MeTHF).

45. The method of claim 44, wherein the solvent is THF.

46. ​​The method of claim 38, wherein the solvent used to prepare compound B is selected from acetonitrile, methanol, ethanol, isopropanol, MTBE, toluene, acetone, CH2Cl2, THF, 2-MeTHF, water, and mixtures thereof.

47. The method according to claim 38, further comprising contacting compound D with a base in a solvent to obtain compound C:

48. The method of claim 47, wherein the base is an amine selected from triethylamine and DIPEA.

49. The method of claim 47, wherein the solvent is an aqueous solvent selected from the group consisting of a mixture of water and acetonitrile, a mixture of water and THF, a mixture of water and 2-MeTHF, a mixture of water and methanol, a mixture of water and ethanol, a mixture of water and isopropanol, a mixture of water and DMF, and a mixture of water and DMSO.

50. The method of claim 47, further comprising condensing compound F with compound G to obtain compound E, which is subsequently contacted with a reducing agent to obtain compound D:

51. The method of claim 50, wherein the solvent used in the condensation reaction is dichloromethane.

52. The method of claim 50, wherein the solvent used in the condensation reaction is toluene.

53. The method of claim 50, wherein the reducing agent is a borohydride.

54. The method of claim 53, wherein the reducing agent is a borohydride selected from the group consisting of sodium borohydride, lithium borohydride, calcium borohydride, magnesium borohydride, sodium triacetoxyborohydride (NaBH(OAc)3), NBu4BH4, NaCNBH3, and NMe4BH(OAc).

55. The method of claim 50, wherein compound E is not isolated prior to contacting compound E with the reducing agent.

56. The method of claim 50, further comprising contacting compound H with a base in a solvent to deprotonate the carbon alpha to the carbonyl group, which is then contacted with HCOOR, wherein R is methyl or ethyl, to obtain compound F:

57. The method of claim 56, wherein the deprotonation is performed at a temperature below 0°C.

58. The method of claim 57, wherein the deprotonation is performed at a temperature of -80 to -20°C.

59. The method of claim 58, wherein the deprotonation is performed at a temperature of about -45°C.

60. The method of claim 56, wherein the base is lithium diisopropylamide.

61. The method of claim 56, wherein the solvent is selected from methyl tert-butyl ether (MTBE), toluene optionally mixed with MTBE, THF optionally mixed with toluene, THF optionally mixed with MTBE, 2-MeTHF optionally mixed with toluene, and 2-MeTHF optionally mixed with MTBE.

62. The process of claim 56, wherein HC(O)OR is added to the deprotonated compound H at a temperature below 0°C.

63. The process according to claim 62, wherein HC(O)OR is added to the deprotonated compound H at a temperature of -80 to -20°C.

64. The method of claim 63, wherein HC(O)OR is added to the deprotonated compound H at a temperature of about -60°C.

65. The method of claim 56, further comprising contacting D-proline with chloral to obtain compound H:

66. The method of claim 65, wherein the solvent used to obtain Compound H is selected from THF, 2-MeTHF, acetonitrile, toluene, dichloromethane, chloroform and MTBE.

67. The method of claim 66, wherein the solvent used to obtain Compound H is acetonitrile.

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