Synthesis of benzodiazepine derivatives

Abstract

The present invention relates to a process for the synthesis of benzodiazepine derivatives of general formula I:

Description

Invention Field

[0001] This invention relates to benzodiazepines. Synthesis of derivatives.

[0002] background

[0003] benzodiazepines Derivatives such as YF476 are used as antagonists of gastrin / CCK2 receptors (Semple et al., JMed Chem 1997; 40:331–341).

[0004]

[0005] Other benzodiazepines Derivatives are described in WO93 / 16999, Yano et al., Chem Pharm Bull (Tokyo) 1996;44:2309–2313, Murphy et al., Clin Pharmacol Ther 1993;54:533–39, and Kramer et al., Biol Psychiatry 1995;37:462–466.

[0006] Benzodiazepines described by Semple et al. The synthesis of derivatives involves the combination of isocyanates and amines, such as 3-[N-(tert-butoxycarbonyl)methylamino]phenyl isocyanate, and the amine, such as (R)-3-amino-1-[(tert-butylcarbonyl)-methyl]-2,3-dihydro-5-(2-pyridyl)-1H-1,4-benzodiazepine. -2-one. This isocyanate is prepared using azide chemistry, which carries an explosion risk.

[0007] Further improvements are needed in synthetic methods for the production of this type of benzodiazepine. Derivatives are needed to avoid the use of azide chemistry, which carries an explosion risk. Additionally, there remains a need for effective gastrin / cholecystokinin 2 (CCK2) receptor antagonists that can be successfully incorporated into pharmaceutical compositions to provide beneficial pharmacokinetic properties, improve bioavailability, avoid the need for food-based administration, and minimize the processing steps required for formulation. Summary of the Invention

[0008] In a first aspect, the present invention provides a method for producing compounds of general formula (I) or pharmaceutically acceptable salts thereof.

[0009]

[0010] In the formula:

[0011] R1 is:

[0012] (i)-CH2C(O)C(R2)(R3)-L-R4 or -CH2CHOHC(R2)(R3)-L-R4, where:

[0013] R2 and R3 are independently H and C. 1–3 Aliphatic group, halogen or C 1–3 A haloaliphatic group, or in which R2 and R3 together with the spacer carbon atoms they are bonded to form a C group. 3–6 Carbon ring portion;

[0014] L is a key or C 1–3 Alkylene; and

[0015] R4 is –OR5 or –SR5, where R5 is hydrogen, or optionally substituted alkyl (e.g., C10). 1-6 Alkyl group, such as methyl group, protecting group or –C(O)R6, wherein R6 is an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety;

[0016] (ii)-CH2CHOH(CH2) a R7 or -CH2C(O)(CH2) a R8, where a is 0 or 1, and R7 and R8 are selected from alkyl, cycloalkyl, and saturated heterocyclic groups optionally substituted at the heteroatom; or

[0017] (iii) Optionally substituted aliphatic moieties;

[0018] W and X are independently hydrogen, halogen, and C. 1–8 Alkyl or C 1–8 Alkoxy; rings A and B are each independently a monocyclic aryl or heteroaryl group, which is optionally substituted by one or more substituents independently selected from: halogen, hydroxyl, amino, nitro, carboxyl, carboxamido, cyano, -SO3H, and optionally substituted C. 1–8 Alkyl, C 1–8 Alkoxy, C 1–8 Alkylamino or di(C) 1–8 alkyl)amino,

[0019] Wherein, any one or more substituents on R1, ring A, or ring B can be in unprotected or protected form;

[0020] The method includes:

[0021] (a) A reaction mixture is provided by adding a compound of general formula (IA), a compound of general formula (IB), and a phosgene synthesis equivalent or phosgene to an aprotic solvent to form a compound of general formula (I).

[0022]

[0023] (b) A reaction mixture is provided by adding a compound of formula (IC), a phosgene synthesis equivalent, or phosgene to an aprotic solvent, and then a compound of formula (IB) is added to the reaction mixture to form a compound of formula (I):

[0024]

[0025] Phosgene synthetic equivalents include carbonyl diimidazole (CDI), diphosgene, triphosgene, chloroformates (e.g., 4-nitrophenyl chloroformate), or disuccinimidyl carbonate.

[0026] Phosgene synthesis equivalents or phosgene can be, for example, CDI.

[0027] In some embodiments, where any one or more substituents on R1, ring A, or ring B are in a protected form, the method includes an additional deprotection step to remove one or more protecting groups. For example, as described above, in compounds of general formula (IA), (IB), or (IC), the protecting group may be present on any one or more substituents on R1, ring A, or ring B. In these embodiments, the method may include an additional deprotection step to remove one or more protecting groups, forming a compound of general formula (I) or any embodiment of such a compound described herein. Therefore, the method may include providing a reaction mixture by adding a compound of formula (IA), a compound of formula (IB), and a phosgene synthesis equivalent or phosgene to an aprotic solvent to form a compound of formula (I), specifically by first forming a protected compound (I) and then removing one or more protecting groups using an additional deprotection step to form a compound of formula (I); or by providing a reaction mixture by adding a compound of formula (IC), a phosgene synthesis equivalent, or phosgene to an aprotic solvent, and then adding a compound of formula (IB) to the reaction mixture to form a compound of formula (I), specifically by first forming a protected compound (I) and then removing one or more protecting groups using an additional deprotection step to form a compound of formula (I).

[0028] In some embodiments, the method includes step (a), which involves providing a reaction mixture by adding a compound of formula (IA), a compound of formula (IB), and a phosgene synthesis equivalent or phosgene to an aprotic solvent to form a compound of formula (I), and maintaining the reaction mixture at a temperature not exceeding 50°C, not exceeding 40°C, or preferably not exceeding 30°C.

[0029] In the method comprising step (a), which involves providing a reaction mixture to form a compound of formula (I) by adding a compound of formula (IA), a compound of formula (IB), and a phosgene synthesis equivalent or phosgene to an aprotic solvent, the compound of formula (IA), the compound of formula (IB), and the phosgene synthesis equivalent or phosgene can be added to the solvent in any order. The addition of these compounds to provide the reaction mixture results in a reaction in the reaction mixture to form a compound of formula (I). Preferably, the compound of formula (IA) and the phosgene synthesis equivalent or phosgene are added to the solvent before the compound of formula (IB) is added. In some embodiments, during the addition of the compound of formula (IA) and the phosgene synthesis equivalent or phosgene to the solvent, the temperature of the reaction mixture is maintained at 0–10°C, preferably 0–5°C. During the subsequent addition of the compound of formula (IB), the reaction mixture is preferably maintained at a temperature not exceeding 30°C, for example, at 15–20°C.

[0030] In step (a), the aprotic solvent may be, for example, dichloromethane, acetonitrile, or toluene, preferably dichloromethane.

[0031] The method includes step (b), in which a reaction mixture is provided by adding a compound of general formula (IC) and a phosgene synthesis equivalent or phosgene to an aprotic solvent, and then adding a compound of general formula (IB) to the reaction mixture. The addition of these compounds causes a reaction in the reaction mixture to form a compound of general formula (I). Step (b) may include heating the reaction mixture to a temperature of at least 40°C, preferably at least 50°C, prior to adding the compound of general formula (IB). Alternatively, instead of heating, step (b) may include adding a non-aqueous base to the reaction prior to adding the compound of general formula (IB).

[0032] In step (b), the aprotic solvent may be, for example, dichloromethane, acetonitrile, or toluene, preferably acetonitrile.

[0033] It should be understood that the definitions of rings A and B, R1, W and X in compounds of general formulas (IA), (IB) and (IC) or in any of the embodiments described herein correspond to those substituents or their protected forms presented in general formula (I) or any of the embodiments described herein. Thus, in general formulas (IA) and (IC), ring A is a monocyclic aryl or heteroaryl group, optionally substituted by one or more substituents independently selected from: halogen, hydroxyl, amino, nitro, carboxyl, formamido, cyano, -SO3H and optionally substituted C. 1–8 Alkyl, C 1–8 Alkoxy, C 1–8 Alkylamino or di(C) 1–8Alkyl)amino, wherein any one or more substituents on ring A can be in unprotected or protected form; in general formula (IB), W and X are independently hydrogen, halogen, C 1–8 Alkyl or C 1–8 Alkoxy; ring B is a monocyclic aryl or heteroaryl group, which is optionally substituted by one or more substituents independently selected from: halogen, hydroxyl, amino, nitro, carboxyl, formamido, cyano, -SO3H and optionally substituted C. 1–8 Alkyl, C 1–8 Alkoxy, C 1–8 Alkylamino or di(C) 1–8 Alkyl)amino, wherein any one or more substituents on ring B may be in unprotected or protected form; R1 is: (i)-CH2C(O)C(R2)(R3)-L-R4 or -CH2CHOHC(R2)(R3)-L-R4, wherein: R2 and R3 are each independently H, C 1–3 Aliphatic group, halogen or C 1–3 A haloaliphatic group, or in which R2 and R3 together with the spacer carbon atoms they are bonded to form a C group. 3–6 The carbon ring moiety; L represents a bond or C. 1–3 Alkylene; R4 is –OR5 or –SR5, where R5 is hydrogen, optionally substituted alkyl (e.g., C10). 1-6 (ii) -CH2CHOH(CH2) alkyl group, such as methyl group, protecting group, or –C(O)R6, wherein R6 is an optionally substituted aliphatic, heteroaliphatic, aromatic, or heteroaromatic moiety; a R7 or -CH2C(O)(CH2) a R8, where a is 0 or 1, and R7 and R8 are selected from alkyl, cycloalkyl and saturated heterocyclic groups optionally substituted at heteroatoms; or (iii) optionally substituted aliphatic moiety, wherein any one or more substituents on R1 may be in unprotected or protected form.

[0034] Any embodiment of the method of the present invention described above can, for example, be used to produce compounds in which at least one of ring A and ring B is an unsubstituted or substituted phenyl or pyridyl group. At least one of ring A and ring B can be an unsubstituted, monosubstituted, or disubstituted phenyl group, or an unsubstituted, monosubstituted, or disubstituted 2-, 3-, or 4-pyridyl group. When ring A and / or ring B is optionally substituted with C... 1–8 Alkyl, C 1–8 Alkoxy, C 1–8 Alkylamino or di(C) 1–8 When alkyl)amino is substituted, the C 1–8 Alkyl, C 1–8 Alkoxy, C 1–8 Alkylamino or di(C) 1–8Optional substituents on the alkyl)amino group include any substituents as described herein for substituents on the aliphatic group, such as halogen, -NO2, -CN, amino, C 1–8 Alkylamino, di(C) 1–8 Alkyl)amino, -S(O)H, or -CO2H. In some embodiments, ring A is a phenyl group having a meta-substituent selected from: NHMe, NMeEt, NEt2, F, Cl, Br, OH, OCH3, NH2, NMe2, NO2, Me, (CH2). n -CO2H, CN, CH2NMe2, NHCHO and (CH2) n -SO3H, where n is 0-2; an unsubstituted phenyl group or optionally a 2-, 3-, or 4-pyridyl group having substituents selected from F, Cl, CH3, and CO2H; ring B is 2-, 3-, or 4-pyridyl or phenyl. As described above, any one or more substituents on ring A or ring B can be in unprotected or protected forms.

[0035] In any of the above embodiments, W and X can be independently H, halogen, C. 1–3 Alkyl or C 1–3 Alkyl group. Preferably, both W and X are H.

[0036] For example, any of the above embodiments can be used to produce compounds in which R1 is -CH2C(O)C(R2)(R3)-L-R4 or -CH2CHOHC(R2)(R3)-L-R4, preferably in which R1 is -CH2C(O)C(R2)(R3)-L-R4.

[0037] Alternatively, the method of the present invention described herein can be used to produce a product in which R1 is -CH2CHOH(CH2). a R7 or -CH2C(O)(CH2) a The compound R8, wherein a is 0 or 1, and R7 and R8 are independently alkyl, cycloalkyl, or saturated heterocyclic groups optionally substituted at the heteroatom. In some embodiments, R7 and R8 are selected from C10. 1-8 Alkyl, C 3-8 Cycloalkyl (which may be unsubstituted or substituted with one or more C atoms) 1-8 Alkyl substitution); and saturated heterocyclic groups of general formulas (ia) and (ib):

[0038]

[0039] Where R9 is H or C 1-3 Alkyl or C 1-3 Acyl group, b is 1 or 2. In some embodiments, R7 is C. 4-7 Straight-chain or branched alkyl groups, R8 is C1-7 (Preferred C) 4-7 Straight-chain or branched alkyl groups.

[0040] In any of the above embodiments of the invention, the compound of general formula (IA) can be a compound of general formula (II-A) as described below. In any of the above embodiments of the invention, the compound of general formula (IB) can be a compound of general formula (II-B) as described below. In any of the above embodiments of the invention, the compound of general formula (IC) can be a compound of general formula (II-C) as described below.

[0041] Compounds of general formula (I) may be compounds of general formula (II) or their pharmaceutically acceptable salts:

[0042]

[0043] Wherein, R2, R3, L, and R4 are as defined above with respect to general formula (I). In embodiments of the method of the present invention where the compound of general formula (I) is a compound of general formula (II), the compound of general formula (IA) is a compound of general formula (II-A), the compound of general formula (IB) is a compound of general formula (II-B), and the compound of general formula (IC) is a compound of general formula (II-C),

[0044]

[0045] Wherein PG is a protecting group, preferably a Boc protecting group. It should be understood that in this embodiment or any other embodiment described herein, the protected form of compound (II) is...

[0046] First, it is formed in step (a) or (b) described above, a method including the additional deprotection step described above to remove PG, forming a compound of general formula (II).

[0047] In any of the above embodiments in which R2 and R3 together with the spacer carbon atoms they are bonded to form a carbide ring moiety, the carbide ring moiety may be C 3–4 Carbon ring portion.

[0048] In any of the above embodiments, R2 and R3 can each be independently H or C. 1–2 Alkyl group, L can be a bond or C 1–3 Alkylene. In some embodiments, R2 and R3 may each be independently C2. 1–2 Alkyl group, L can be C 1–3 Alkylene. In some embodiments, R2 and R3 may each be independently H or C. 1–2Alkyl group, where L can be a C1 alkylene group (-CH2-). In some embodiments, R2 and R3 can each be independently C1 alkylene group. 1–2 Alkyl group, where L can be a C1 alkylene group (-CH2-).

[0049] In any of the above embodiments in which R1 is -CH2C(O)C(R2)(R3)-L-R4 or -CH2CHOHC(R2)(R3)-L-R4 (preferably -CH2C(O)C(R2)(R3)-L-R4), R4 may be -OR5 or –SR5, wherein R5 is hydrogen, methyl, or –C(O)R6, and wherein R6 is an optionally substituted aliphatic, heteroaliphatic, aromatic, or heteroaromatic moiety. In some embodiments, R6 is an optionally substituted aliphatic group, for example, R6 is a substituted or unsubstituted C 1–6 Aliphatic group, preferably substituted or unsubstituted C 1–3 Aliphatic group, more preferably methyl. Preferably, R4 is –OR5, and R5 is –C(O)R6.

[0050] Compounds of general formulas (I), (IB), (II), and (II-B) contain a chiral center at the position marked * and may be present in enantiomeric form. The compounds may be provided as racemic mixtures of enantiomers, non-racemic mixtures of enantiomers, or as a single enantiomer in optically pure form (e.g., the R-enantiomer marked *).

[0051]

[0052] Compounds of general formula (I) or (II) can be, for example, selected from the following:

[0053] Or its pharmaceutically acceptable salt.

[0054] In some embodiments, the compound may be selected from:

[0055] Or its pharmaceutically acceptable salt.

[0056] Compounds of formula (II) may be compounds of formula (III) or their pharmaceutically acceptable salts.

[0057]

[0058] (III)

[0059] Where R 11 Selected from

[0060]

[0061] R6 is as defined in any of the embodiments of general formula (I) or (II) above. In some embodiments, the compound is a compound of general formula (IV) or a pharmaceutically acceptable salt thereof:

[0062]

[0063] Preferably, R 11 Selected from:

[0064]

[0065] In a preferred embodiment, the compound of formula (I) or (II) is compound (TR) or a pharmaceutically acceptable salt thereof:

[0066]

[0067] The compound (TR) contains a chiral center and therefore exists as two enantiomers, denoted as (TR2) (R-enantiomer) and (TR3) (S-enantiomer).

[0068]

[0069] In the method of the present invention, (TR) may be provided as a racemic mixture of enantiomers (TR2) and (TR3), a non-racemic mixture of enantiomers (TR2) and (TR3), or as a single enantiomer (TR2 or TR3) in optically pure form. The racemic mixture of (TR2) and (TR3) is referred to herein as "(TR1)".

[0070] In a preferred embodiment, the compound of formula (I) or (II) is compound (TR-A) or a pharmaceutically acceptable salt thereof:

[0071]

[0072] It should be understood that, in this embodiment, the compound (II-B) is a compound in which -CH2C(O)C(R2)(R3)-L-R4 is -CH2C(O)C(Me)(Me)CH2-OC(O)Me. Therefore, the compound of formula (IA) can be a compound of formula (II-A) that undergoes the aforementioned additional deprotection step to remove PG, forming compound (TR-A). Compound (TR-A) can be provided as a racemic mixture (TR1-A) of enantiomers (TR2-A)(R-enantiomer) and (TR3-A)(S-enantiomer), a non-racemic mixture of enantiomers (TR2-A) and (TR3-A), or as a single enantiomer (TR2-A or TR3-A) in optical purity.

[0073]

[0074] In another embodiment, the compound of formula (I) or (II) can be YF476 or a pharmaceutically acceptable salt thereof:

[0075]

[0076] In embodiments of the method of the present invention, the method can be used to produce compounds of the general formula (TR2-A):

[0077]

[0078] The method includes:

[0079] A reaction mixture is provided by adding a compound of general formula (II-A), a compound of general formula (II-Ba), and a phosgene synthesis equivalent or phosgene to an aprotic solvent to form a compound of general formula (TR2-A), the formation of which is achieved by first forming a compound of general formula (TR2-A-PG).

[0080]

[0081] Wherein PG is a protecting group, optionally a Boc protecting group;

[0082]

[0083] Deprotection of compounds of general formula (TR2-A-PG) yields compounds of general formula (TR2-A).

[0084] The acetyl group of a compound of general formula (TR2-A) can be removed to form a compound of general formula (TR2).

[0085] Deprotection of the Boc protecting group can be carried out under conditions known to those skilled in the art, such as by exposure to strong acids, such as TFA or HCl.

[0086] In an embodiment of the method of the present invention, the method can be used to produce compounds of the general formula (TR2):

[0087]

[0088] The method includes:

[0089] A reaction mixture is provided by adding a compound of general formula (II-A), a compound of general formula (II-Bb), and a phosgene synthesis equivalent or phosgene to an aprotic solvent to form a compound of general formula (TR2), the formation of which is achieved by first forming a compound of general formula (TR2-PG).

[0090]

[0091] Wherein PG is a protecting group, optionally a Boc protecting group;

[0092] Deprotection of compounds of general formula (TR2-PG) yields compounds of general formula (TR2).

[0093] In a second aspect, the present invention provides compounds obtained by means of the method according to the first aspect of the present invention.

[0094] Thirdly, the present invention provides compounds of general formula (II-C):

[0095]

[0096] PG is a protecting group, preferably a Boc protecting group.

[0097] An alternative method for producing compounds of general formula (I) or pharmaceutically acceptable salts thereof includes providing a reaction mixture to form a compound of general formula (I) by adding a compound of general formula (VA), one or more reagents capable of rearranging general formula (VA) to form an isocyanate intermediate of general formula (VB), and a compound of general formula (IB) to a non-aqueous solvent.

[0098]

[0099] The reaction that forms the intermediate (VB) can be carried out via an N-bromo derivative (V-Bi).

[0100]

[0101] In this embodiment, one or more reagents capable of rearranging compounds of general formula (VA) to form isocyanate intermediates of general formula (VB) include brominating agents, such as N-bromosuccinimide, and bases, such as DBU (1,8-diazabicyclo[5.4.0]undecene). The non-aqueous solvent can be an aprotic solvent, such as toluene. Intermediates (VB) and (V-Bi) are formed and reacted in situ with compounds of general formula (IB).

[0102] In the above methods, the ring A of compounds of general formula (IB) and general formula (I), as well as compounds of general formula (VA), (VB) and (V-Bi), is as defined in any embodiment of the first aspect of the present invention above.

[0103] 2-(2-Aminobenzoyl)pyridine can be used to prepare compounds of general formula (II-B) or embodiments of the compounds described herein. 2-(2-Aminobenzoyl)pyridine can be prepared by a method comprising the following steps: reacting morpholine with isatoic anhydride to form N-(2-aminobenzoyl)morpholine, and reacting N-(2-aminobenzoyl)morpholine with 2-lithium pyridine to form 2-(2-aminobenzoyl)pyridine. 2-Lithium pyridine can be prepared by reacting 2-bromopyridine with n-butyllithium. This process can be carried out in an aprotic solvent such as toluene. Invention Details

[0105] The meanings of the terms used in this application will be explained below, and the invention will be described in detail.

[0106] As used herein, the term "aliphatic" refers to a substituted or unsubstituted straight-chain, branched, or cyclic hydrocarbon that is fully saturated or contains one or more non-aromatic unsaturated units. Aliphatic groups include substituted or unsubstituted straight-chain, branched, or cyclic alkyl, alkenyl, ynyl, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl. In various embodiments, the aliphatic group has 1 to 12, 1 to 8, 1 to 6, or 1 to 3 carbons. For example, C 1–3 Aliphatic groups include straight-chain and branched C 1–3 Alkyl, alkenyl, and alkynyl groups, as well as cyclopropyl groups. The term "heteroaliphatic" refers to an aliphatic group in which one or more carbon atoms are replaced by heteroatoms. The term "heteroatom" refers to nitrogen (N), oxygen (O), or sulfur (S).

[0107] The term "alkylene" refers to a divalent alkyl group. "alkylene" is methylene or polymethylene, i.e., -(CH2). n - where n is a positive integer. Alkylenes can be substituted or unsubstituted. A substituted alkylene is an alkylene in which one or more methylene hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups. The alkylene chain may also be substituted at one or more positions by an aliphatic group or a substituted aliphatic group.

[0108] The term "carbocyclic moiety" refers to a cyclic aliphatic group and includes, for example, a cycloalkyl moiety.

[0109] The term "aryl" refers to a C-type compound containing one to three rings. 6–14 (Preferred C) 6–10Aromatic hydrocarbons, each of which is optionally substituted. Aryl groups include, but are not limited to, phenyl, naphthyl, and anthracene. In some embodiments, two adjacent substituents on the aromatic ring, together with spacer ring atoms, form an optionally substituted fused 5- to 6-membered aromatic or 4- to 8-membered non-aromatic ring having 0 to 3 cyclic heteroatoms selected from N, O, and S. Thus, the term "aryl" as used herein includes a group in which the aromatic ring is fused with one or more heteroaromatic, alicyclic, or heterocyclic rings, wherein the connecting group or junction is on the aromatic ring.

[0110] The terms "heteroaryl" and "heteroaryl-" refer to an aromatic group having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms, and having one to four heteroatoms as ring atoms in addition to carbon atoms. The term "heteroatom" refers to N, O, or S. In some embodiments, two adjacent substituents on the heteroaryl group, together with the spacer ring atom, form an optionally substituted fused 5- to 6-membered aromatic ring or a 4- to 8-membered non-aromatic ring having 0 to 3 cyclic heteroatoms selected from N, O, and S. Therefore, as used herein, the terms "heteroaryl" and "heteroaryl-" also include groups in which the heteroaryl ring is fused with one or more aromatic rings, alicyclic rings, or heterocycles, wherein the connecting group or connection point is on the heteroaryl ring.

[0111] The term "halogen" as used in this article refers to fluorine, chlorine, bromine, or iodine.

[0112] As used in this article, "halogenated aliphatic" refers to the aliphatic portion that has been replaced by one or more halogen moieties as defined above.

[0113] As used herein, “alkoxy” refers to the -O-alkyl moiety. As defined herein, and therefore, it may be optionally substituted as defined herein for optional substituents of the aliphatic moiety.

[0114] As used herein, “formamide group” refers to the -C(O)NR2 moiety, wherein each R is independently an H or an aliphatic group, preferably H.

[0115] As used herein, the term "including" means "including but not limited to".

[0116] As used herein, the term "substituted" means that a hydrogen group in a specific moiety is replaced by a specified substituent group, provided that the substitution produces a stable or chemically viable compound. The phrase "one or more substituents" as used herein means that the number of substituents is equal to one to the maximum possible number of substituents, based on the number of bonding sites. Unless otherwise stated, when multiple substituents are present, the substituents may be the same or different.

[0117] The aryl or heteroaryl group may be optionally substituted. Suitable substituents on the unsaturated carbon atom of the aryl or heteroaryl group include: halogen, -NO2, -CN, -R', -C(R')=C(R')2, -C≡C-R', -OR', -SR', -S(O)R', -SO2R', -SO3R', -SO2N(R')2, -N(R')2, -NR'C(O)R', -NR'C(O)N(R')2, -NR'CO2R', -NR'SO2R', -NR' SO2N(R')2, -OC(O)R', -O-CO2R', -OC(O)N(R'), -C(O)R', -CO2R', -C(O)N(R')2, -P(O)(R')2, -P(O)(OR')2, -OP(O)-OR', wherein R' is independently hydrogen or an optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, or R' appearing twice together with their spacer atoms to form optionally substituted 5-7 membered aromatic rings, heteroaromatic rings, alicyclic rings or heterocyclic rings.

[0118] Aliphatic or heteroaliphatic groups (including carbocyclic or heterocyclic groups) may be "optionally substituted". Unless otherwise defined, suitable substituents on the saturated carbon of the optionally substituted aliphatic or heteroaliphatic group are selected from the substituents listed above for the unsaturated carbon of aryl or heteroaryl groups, and said suitable substituents also include: =O, =S, =C(R”)2, where R” is hydrogen or an optionally substituted C 1–6 Aliphatic groups.

[0119] In addition to the substituents defined above, optional substituents on the nitrogen atom of a non-aromatic heterocycle include, and are generally selected from, R', -N(R')2, -C(O)R', -C(O)OR', -S(O)2R', and -S(O)2N(R')2, where each R' is as defined above. The cyclic nitrogen atom of a heteroaryl or non-aromatic heterocycle may also be oxidized to form the corresponding N-hydroxyl or N-oxide compound.

[0120] As used herein, the “protected form” of a compound refers to a compound in which the functional moiety is protected by a protecting group. The functional moiety to be protected can be a hydroxyl, carboxyl, amino, or alkylamino moiety. Therefore, the protected form used herein can contain a protected hydroxyl, a protected carboxyl, or a protected amino or alkylamino moiety. Protection involves temporarily blocking the moiety, allowing the reaction to selectively proceed at another reaction site in the polyfunctional compound. The protected amino or alkylamino group may be protected by a protecting group selected from the following protecting groups, including but not limited to: urethane (including methyl urethane, ethyl urethane, and substituted ethyl urethane (e.g., Troc), benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (BOC), 9-fluorenylmethoxycarbonyl (Fmoc)), p-methoxybenzyloxycarbonyl (Moz or MeOZ), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), succinoyl (Suc), methoxysuccinoyl (MeOSuc), formyl, urethane protecting groups, toluenesulfonyl (Ts), and other sulfonamides (e.g., Nosyl and Nps). For example, in some embodiments, certain exemplary oxygen protecting groups are used, as detailed herein. The protected hydroxyl or carboxyl group can be protected by an oxygen protecting group selected from the following protecting groups, including but not limited to acetyl (Ac), benzoyl (Bz), benzyl (Bn), neopentanoyl (Piv), methyl ethers, substituted methyl ethers (e.g., MOM (methoxymethyl ether), β-methoxyethoxymethyl ether (MEM), MTM (methyl thiomethyl ether), BOM (benzyloxymethyl ether), p-methoxybenzyl (PMB), PMBM (p-methoxybenzyloxymethyl ether)), substituted ethyl ethers, ethoxyethyl ethers, substituted benzyl ethers, methoxytriphenylmethyl (MMT), tetrahydropyranyl (THP), and triphenylmethyl (Tr). Silyl ethers (e.g., TMS (trimethylsilyl ether), TES (triethylsilyl ether), TIPS (triisopropylsilyl ether), TBDMS (tert-butyl dimethylsilyl ether), tribenzyl silyl ether, TBDPS (tert-butyl diphenylsilyl ether, TOM (triisopropylsiloxymethyl)), esters (e.g., formate esters, acetate esters (Ac), benzoate esters (Bz), trifluoroacetate esters, dichloroacetate esters), carbonates, cyclic acetals, and ketals. It should be understood that the present invention is not intended to be limited to these protecting groups; rather, various other equivalent protecting groups can be readily identified using the above criteria and used in the present invention.In addition, the various protecting groups are described in the third edition of "Protective Groups in Organic Synthesis", Greene, TW, and Wuts, PG, Eds., John Wiley & Sons, New York: 1999, the entire contents of which are incorporated herein by reference.

[0121] According to standard terminology in this field, "aprotic solvent" as used herein refers to a solvent that cannot be used as a proton donor. Aprotic solvents include, but are not limited to, dichloromethane, tetrahydrofuran, ethyl acetate, acetonitrile, dimethylformamide, dimethyl sulfoxide, acetone, hexane, pentane, benzene, toluene, 1,4-dioxane, diethyl ether, and chloroform.

[0122] As used in this document, a "proton solvent" is a solvent that can be used as a proton donor, according to standard terminology in the art. Generally, such a solvent has an unstable hydrogen atom that bonds to oxygen or nitrogen. Proton solvents include, but are not limited to, water, alcohols (e.g., methanol, ethanol, isopropanol), acetic acid, formic acid, hydrogen fluoride, and ammonia.

[0123] The “phosgene synthesis equivalent” used in the method of the present invention can be, for example, carbonyl diimidazole, diphosgene, triphosgene, chloroformate (e.g., 4-nitrophenyl chloroformate) or disuccinimidyl carbonate (DSC).

[0124] Chloroformates are compounds of the general formula ClC(O)OR. R can be, for example, optionally substituted aliphatic, heteroaliphatic, aryl, or heteroaryl.

[0125] The compounds of general formulas (I) and (II) described herein can be used as CCK2 / gastrin receptor antagonists for the prevention and / or treatment of diseases related to the CCK2 / gastrin receptor, diseases caused by or related to hypergastrinemia, or diseases related to gastric acid. Such diseases include those related to CCK2 receptor-carrying cells or those involving the loss or dysfunction of the physiological function of gastrin. Therefore, examples of treatable and / or preventable diseases include, but are not limited to, any one or more of the following: gastric and duodenal ulcers, nonsteroidal anti-inflammatory drug (NSAID)-induced gastric ulcers, dyspepsia, gastroesophageal reflux disease (GORD), Barrett's esophagus, Zollinger-Ellison syndrome (ZES), hypergastrinemia induced by proton pump inhibitors (PPIs) or other acid inhibitors (including withdrawal effects) and conditions caused by hypergastrinemia (e.g., bone loss, impaired bone quality, and fractures), gastritis (including Helicobacter pylori-induced gastritis and complications of autoimmune chronic atrophic gastritis, such as gastric carcinoids and enterochromaffin (ECL) cell hyperplasia), neuroendocrine tumors (not limited to gastric carcinoids), parietal cell hyperplasia, gastric basal gland polyps, gastric cancer, colorectal cancer, medullary thyroid carcinoma, pancreatic cancer, and small cell lung cancer. The compounds may also be used to prevent and / or treat diseases caused by dysfunction of physiological functions controlled by central or peripheral CCK2 receptors, such as anxiety, nociception, pain, drug addiction, analgesia dependence, and analgesia withdrawal.

[0126] The compounds of general formulas (I) and (IB) described herein and their embodiments have at least one chiral carbon atom and may have more than one chiral carbon atom. This invention includes any enantiomeric forms and mixtures thereof at any level of optical purity, including racemic and non-racemic mixtures. Therefore, all stereoisomeric forms of the compounds disclosed herein form part of this invention. The enantiomers of the optically pure forms described herein have an enantiomer excess (ee) of at least 90%, preferably at least 95%, more preferably at least 98%, and even more preferably at least 99%. ee can be evaluated, for example, by chiral HPLC.

[0127] The compounds disclosed herein can exist in both non-solventized and solvated forms (e.g., solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc.), and it is intended that the invention encompass both solvated and non-solventized forms. The compounds described herein, their enantiomers, and mixtures thereof can be provided as free compounds or as suitable salts or hydrates thereof. Salts should preferably be pharmaceutically acceptable salts, and salts and hydrates can be prepared by conventional methods, such as contacting the compounds of the invention with an acid or base whose counterions do not interfere with the intended use of the compounds. Examples of pharmaceutically acceptable salts include hydrohalides, inorganic acid salts, organic carboxylates, organic sulfonates, amino acid salts, quaternary ammonium salts, alkali metal salts, alkaline earth metal salts, etc. Basic compounds can form non-toxic acid addition salts with various inorganic and organic acids, i.e., salts containing pharmacologically acceptable anions, including but not limited to malates, oxalates, chlorides, bromides, iodides, nitrates, sulfates, bisulfates, phosphates, acid phosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, oleates, tannates, pantothenates, hydrogen tartrates, ascorbic acid salts, succinates, maleates, gentianates, fumarates, gluconates, glucaronates, glycosides, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, toluenesulfonates, and bis(hydroxynaphthyl)ate. Acidic compounds can form salts with various pharmacologically acceptable cations, including alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds containing basic or acidic moieties can also form pharmacologically acceptable salts with various amino acids. Example

[0128] abbreviation

[0129] DCM dichloromethane

[0130] DIPEA N,N'-Diisopropylethylamine

[0131] DMF N,N'-dimethylformamide

[0132] DMS dimethyl sulfate

[0133] GC gas chromatography

[0134] HPLC (High Performance Liquid Chromatography)

[0135] MeI methyl iodine

[0136] MTBE (methyl tert-butyl ether)

[0137] THF Tetrahydrofuran

[0138] TLC (Thin Layer Chromatography)

[0139] UV ultraviolet rays

[0140] Gas chromatography was performed on a Shimadzu GC2014. HPLC was performed on an Agilent / HP1100 reverse-phase HPLC system. NMR spectra were recorded on a 400 MHz Bruker Avance 111 spectrometer with QNP (1H / 13C / 19F / 31P / refrigerator) or a 500 MHz dual (1H / 13C) Bruker Avance 111HD spectrometer. Elemental analysis (CHN) was performed on an Exeter Analytical CE-440 elemental analyzer. XPRD spectra were obtained on a Panalytical X'pert Pro diffractometer.

[0141] The following embodiments of the invention are provided to aid in understanding the invention, but should not be considered as limiting the scope of the invention. Unless otherwise stated, reagents may be commercially available or prepared according to methods described in the literature.

[0142] Reference example – using azide chemistry methods

[0143] The method of this invention avoids the need for azide chemistry, which carries an explosion risk. For reference only, reaction schemes illustrating the azide chemistry avoided by using the method of this invention are given below in Parts A and B.

[0144]

[0145] Part A

[0146]

[0147] Part B

[0148] If desired, the racemic mixture (TR1) can be separated by chiral HPLC chromatography, for example, with a column of Chiralcel OD 250 mm × 20 mm, 5 μm; mode of supercritical fluid (SFC); eluent of 40% methanol, without modifier; flow rate of 50 mL / min; and run time of 4 min.

[0149] Example 1: Synthesis of (TR2) and (TR2-A) from tert-butyl (3-aminophenyl)methylaminocarbamate (N4)

[0150] (TR2) and (TR2-A) were synthesized according to Scheme 1 below. It should be understood that this scheme can generally be applied to the synthesis of compounds of general formula (I) by appropriately changing the starting materials N4 and 14-A.

[0151]

[0152] Option 1

[0153] Compound 14-A was synthesized according to the following scheme 2:

[0154]

[0155] Option 2

[0156] Compound 11 was synthesized according to the following scheme 3:

[0157]

[0158] Option 3

[0159] Compound N4 was synthesized according to the following scheme 4:

[0160]

[0161] Option 4

[0162] Scheme 4 illustrates the synthesis of N4 via N2 and N3. While exemplary reagents are shown in Scheme 4, it should be understood that these reagents are subject to change. For example, the Boc in N2-N4 can be replaced with an alternative amino protecting group, such as Fmoc, Cbz, or Ac. For example, 3-nitroaniline can be converted to N2 using an organic base other than triethylamine, such as DIPEA. Methylation of N2 to N3 preferably involves the use of a base (e.g., KO). t The solvent used in this step can be an aprotic solvent, preferably a polar aprotic solvent (e.g., DMF or THF). The reduction of N3 to N4 can be carried out with an iron metal or by hydrogenation over a catalyst such as palladium / carbon or Raney nickel.

[0163] 4-Hydroxy-3,3-dimethyl-2-butanone (1)

[0164] Paraformaldehyde (465 g, 15.48 mol) and 3-methyl-2-butanone (1111 g, 12.90 mol) were added to trifluoroacetic acid (6.0 L), and the mixture was slowly heated to 90 °C in an oil bath over 1 hour. The paraformaldehyde dissolved completely at approximately 50 °C. The oil bath was cooled to 75 °C (dry ice was added to the oil). Once the temperature of the contents of the flask had decreased to 85 °C, another feed of paraformaldehyde (465 g, 15.48 mol) and 3-methyl-2-butanone (1111 g, 12.90 mol) was added. The mixture was slowly exothermic to approximately 92 °C (the oil bath remained at 75 °C). Once the temperature of the contents of the flask had decreased to 85 °C, a final feed of paraformaldehyde (465 g, 15.48 mol) and 3-methyl-2-butanone (1111 g, 12.90 mol) was added. After the exothermic reaction was complete, the mixture was stirred at 90°C for another 8 hours, then cooled to room temperature overnight. GC (a small sample was added to water and the pH was adjusted to 14 with sodium hydroxide before extraction to DCM) showed approximately 2% 3-methyl-2-butanone and 86% product. The product solution was poured into a stirred mixture of ice (16 kg; from the ultracold chamber of the freezer) and solid sodium hydroxide (3 kg). Another feed of sodium hydroxide (approximately 260 g) was added to adjust the pH to just 14. GC indicated that hydrolysis was complete. The aqueous solution was saturated with sodium chloride (approximately 3 kg) and then immediately extracted with DCM (3 × 8 L). The combined DCM layers were washed with saturated brine (3 L) and then dried with anhydrous sodium sulfate. The solution was evaporated under vacuum to give a light brown liquid (approximately 3.7 kg). The crude product was distilled through a 20 cm Vigreux column (approximately 95 °C / 45 mmHg) (the fore-end was removed, and some residue remained after distillation) to obtain a nearly colorless product (2.85 kg, 63% yield, GC purity = 98%).

[0165] 1-Bromo-4-hydroxy-3,3-dimethyl-2-butanone (2)

[0166] Compound 1 (2566 g, 22.09 mol) was dissolved in methanol (13 L) and stirred at 20 °C. The reaction flask was covered to protect from light. Bromine (200 g, 1.25 mol) was added over 15 minutes. After a brief induction period, the reaction decolorized and underwent slight exothermic reaction. Once the mixture was decolorized, it was cooled to 0–5 °C. Bromine (3300 g, 20.65 mol) was slowly added over 2 hours while maintaining the temperature at 0–5 °C (now decolorizing rapidly). GC showed approximately 94% product and <1% starting material. Several small back peaks were observed by GC. The mixture was immediately poured into a saturated brine solution (20 L) and ice (4 kg), and then extracted with DCM (4 × 8 L). The combined DCM extracts were washed with saturated brine (2 × 5 L) and dried over anhydrous sodium sulfate. The solution was evaporated under vacuum at 40 °C to give a pale yellow / brown liquid (4191 g, 97% yield, GC purity 91%).

[0167] 1-Bromo-4-(tert-butyl-dimethyl-silyloxy)-3,3-dimethyl-2-butanone (3)

[0168] Imidazole (645 g, 9.47 mol) was added to DCM (8.5 L) and cooled to -15 to -20 °C under a nitrogen atmosphere. Compound 2 (1650 g, 8.46 mol) was added at -15 to -20 °C to give a clear solution. Tert-butyl-dimethylsilyl chloride (1365 g, 9.06 mol) was slowly added while maintaining the temperature at -15 to -20 °C. The mixture was stirred at this temperature for another 3 hours. GC showed 78% product, less than 1% of the starting material, and 14% residual tert-butyl-dimethylsilyl chloride. The reaction mixture was poured into cold water (7.5 L). The aqueous layer was removed and extracted again with DCM (2 L). The combined DCM layers were washed with water (2 × 2 L), followed by washing with saturated brine (2 × 3 L), and then dried over anhydrous sodium sulfate. The solution was evaporated under vacuum at 40°C to obtain a yellow oily substance (2559 g, 97% yield, GC purity approximately 75%).

[0169] 1 H NMR (400MHz, CDCl3) δ4.24 (s, 2H); 3.55 (s, 2H); 1.17 (s, 6H); 0.86 (s, 9H); 0.02 (s, 6H).

[0170] 2-(2-Aminobenzoyl)pyridine (4)

[0171] 2-Bromopyridine (1075 g, 6.80 mol) in toluene (4.2 L) was cooled to <-65 °C with stirring under a nitrogen atmosphere. Butyllithium (1.6 M, in hexane; 4160 mL, 6.66 mol) was added over 1 hour while maintaining the temperature <-60 °C. The mixture was stirred at <-60 °C for 30 minutes, and then the presence of 2-bromopyridine was detected by GC. A solution of 2-aminobenzonitrile (350 g, 2.96 mol) in toluene (2.3 L) was slowly added over 30 minutes (a slight warming may be necessary to dissolve it) while maintaining the temperature <-60 °C. The mixture was slowly warmed to room temperature with stirring overnight. The mixture was carefully poured into a cold hydrochloric acid solution (1.96 L 32% hydrochloric acid, 3 L water, and 2 kg ice) with stirring. The mixture was stirred for another 1 hour, and then separated into layers. Remove the bottom aqueous layer and extract the upper organic layer with hydrochloric acid solution (350 mL 32% hydrochloric acid and 3 L water). Add ice (4 kg) to the combined acidic aqueous layer, then adjust to pH 10 with 35% ammonia solution (approximately 6.5 L). Add more ice as needed to reach a final temperature of 0–5 °C. Stir the slurry at 0–5 °C for another 30 minutes. Filter the slurry and wash with water until ammonia-free. Dry the product in a circulating air oven at 50 °C (until constant weight) to give a yellow / orange solid (558 g, yield 95%, GC purity 87%).

[0172] 2-(benzotriazol-1-yl)-2-(benzyloxycarbonylamino)-acetic acid (8)

[0173] A mixture of vigorously stirred benzotriazole (512 g, 4.30 mol), benzyl carbamate (650 g, 4.30 mol), and glyoxylic acid monohydrate (396 g, 4.30 mol) in toluene (12 L) was heated to reflux and dehydrated using a Dean and Stark apparatus. The heating rate was adjusted to maintain a foaming-free state. Evaporation was stopped after approximately 150 mL of water had been collected. A solid was simultaneously formed in the stirred mixture. The mixture was reheated under reflux for 1 hour, followed by slow cooling overnight. The solid was filtered off and pulled down hard for 30 minutes, then washed with MTBE (2 × 1 L). The product was air-dried at 40 °C (until constant weight) to give a nearly white solid (1330 g, 95% yield, TLC single point).

[0174] Benzyl-(benzotriazol-1-yl-[2-(pyridin-2-carbonyl)-phenylcarbamoyl]-methyl)-carbamate (9)

[0175] A mixture of crude compound 4 (2000 g, 10.09 mol) and compound 8 (3620 g, 11.09 mol) in a 36 L DCM was cooled to 0–5 °C in a 60 L reaction vessel. 4-Dimethylaminopyridine (148 g, 1.21 mol) was added in a single batch. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2417 g, 12.61 mol) was added in small portions over 30 minutes while maintaining the temperature at 0–5 °C. The mixture was stirred at 0–5 °C for 1 hour to obtain a clear, dark brown solution. TLC (elution buffer: hexane solution of 50% ethyl acetate) showed that all of compound 4 (Rf = 0.7 yellow point) had been consumed, forming compound 9 (Rf = 0.35). A saturated sodium bicarbonate solution (20 L) was added and the mixture was stirred for 5 minutes. The aqueous layer was removed, and the organic layer was dried with anhydrous sodium sulfate, followed by vacuum evaporation to give a thick oil (approximately 7150 g, 140% crude yield).

[0176] (2-oxo-5-pyridin-2-yl-2,3-dihydro-1H-benzo[e][1,4]diaza) 3-yl)-carbamate benzyl ester (10)

[0177] Crude compound 9 (approximately 7.15 kg) was dissolved in methanol (10 L) and stirred at room temperature. A methanol solution saturated with ammonia (10 L) was added all at once. The mixture was stirred at room temperature for 1 hour. TLC (eluent: 50% ethyl acetate in hexane) showed that compound 9 (Rf = 0.35) had eliminated benzotriazole (Rf = 0.5), giving an uncyclic intermediate (Rf = 0.1). The mixture was first heated to approximately 30 °C and then stirred overnight while cooling to room temperature. A solid formed in the stirred mixture. TLC (eluent: 50% ethyl acetate in hexane) showed that the uncyclic intermediate (Rf = 0.1) cyclized, forming compound 10 (Rf = 0.15). The slurry was filtered, and the filter cake was washed with cold methanol (1 L), then with ethyl acetate (3 L), and finally with hexane (2 L). The filtrate was vaporized to approximately half its original volume and then allowed to stand for two days. The second product (if formed) is filtered off and washed with cold methanol, ethyl acetate, and hexane. The combined superior products are air-dried in a circulating air chamber at 40–50 °C to give a grayish-white solid (1785 g). If desired, the material is slurried in two volumes of DCM, filtered, and then dried to improve purity.

[0178] Using the above method, 27.6 kg (92% HPLC purity) of crude compound 10 was obtained from 114.4 kg of crude compound 9. DCM slurry reduced the yield to 25.9 kg (98% HPLC purity; 42% yield for the two steps starting from compound 4).

[0179] 1H NMR (400MHz, CDCl3) δ8.67 (1H, s), 8.61 (1H, d, J = 4.1Hz), 8.10 (1H, d, J = 7.5Hz), 7.84 (1H, dt J=1.4,7.5Hz),7.50-7.28(8H,m),7.20(1H,t,J=7.5Hz),6.99(1H,d,J=7.5Hz),6.65(1H,d,J=8.2Hz),5.37(1H,d,J=8.2Hz),5.15(2H,d,J=2.7Hz).

[0180] (1-[4-(tert-butyl-dimethyl-silyloxy)-3,3-dimethyl-2-oxo-butyl]-2-oxo-5-pyridin-2-yl-2,3-dihydro-1H-benzo[e][1,4]diaza) 3-yl)-Benzyl carbamate (11)

[0181] Compound 10 (1040 g, 2.69 mol) was slurried in tetrahydrofuran (10.4 L) at 0–5 °C under a nitrogen atmosphere. The addition of potassium tert-butoxide (423 g, 3.77 mol) in single parts produced an exothermic reaction at 10 °C. A nearly clear solution briefly formed, followed by the formation of another solid. The mixture was cooled again to 0–5 °C. Crude compound 3 (2080 g, 6.72 mol crude product with 5.04 mol active content) was slowly added over 30 minutes while maintaining the temperature at 0–-5 °C. Stirring was continued for 30 minutes. The mixture was then heated to 20–25 °C and stirred for another hour. TLC (elution: hexane solution of 50% ethyl acetate) showed that compound 12 had formed (Rf = 0.55), but some of compound 10 remained (Rf = 0.15). A silyl byproduct spot was also observed (Rf = 0.8). Add another batch of potassium tert-butoxide (78 g, 0.70 mol) in a single batch and stir the mixture for 20 minutes. Random TLC analysis showed that all of compound 10 had been consumed. If TLC showed some residual compound 10, add an additional crude compound 3 (200 g, 0.65 mol) and stir for 10 minutes. Add an additional potassium tert-butoxide (78 g, 0.70 mol) and stir for 20 minutes. The reaction should now proceed to completion, but this step can be repeated until compound 10 is consumed. Stir the mixture for another hour and then let it stand overnight at room temperature. Pour the reaction mixture into a 5% saline solution (20 L) and extract with ethyl acetate (10 L, then 5 L). Wash the combined organic extracts with a 5% saline solution (5 L) and then dry with anhydrous sodium sulfate. Evaporate the solution under vacuum to give a viscous oil (sometimes containing some crystals). Slowly pour the oil into hexane (15 L) and wait for solids to form. Stir the resulting slurry for 2 hours to form a fine slurry. The mixture was filtered and washed with hexane (2 × 3 L). The filter cake was air-dried in a circulating air chamber at 20–30 °C to give a brown solid (1291 g, 78% yield, 97.6% HPLC purity).

[0182] 1H NMR (400MHz, CDCl3) δ8.63 (1H, d, J = 4.8Hz), 8.15 (1H, d, J = 8.2Hz), 7.81 (1H, t, J = 7.5H z),7.47(1H,t,J=7.5Hz),7.42–7.28(6H,m),7.23(1H,t,J=7.5Hz),7.10(1H,d,J=8.2 Hz),6.73(1H,d,J=8.2Hz),5.49(1H,d,J=8.2Hz),5.20-5.10(3H,m),4.45(1H,d,J=17 .7Hz),3.67(2H,s),1.24(3H,s),1.19(3H,s),0.90(9H,s),0.08(3H,s),0.05(3H,s).

[0183] (3-Nitrophenyl)-tert-butyl carbamate (N2)

[0184] At room temperature, triethylamine (915 g, 9.04 mol) and 4-(dimethylamino)pyridine (30 g, 0.25 mol) were added to a tetrahydrofuran (6.1 L) solution of 3-nitroaniline (833 g, 6.03 mol). The mixture was heated to reflux, and then external heating was stopped. A tetrahydrofuran (2.2 L) solution of di-tert-butyl dicarbonate (1448 g, 6.63 mol) was added at a rate maintained at reflux. The mixture was then heated under reflux for another 2 hours using external heating. TLC (eluent: hexane solution of 33% ethyl acetate) showed that all 3-nitroaniline (Rf = 0.6) had been consumed, forming compound N2 (Rf = 0.85). The mixture was cooled to room temperature overnight. The solvent was evaporated under vacuum, and the residue dissolved in DCM (15 L). The mixture was washed with water (2 × 8 L) and dried with anhydrous sodium sulfate. The DCM solution was passed through a silica gel stopper (1 kg) and washed with more DCM (5 L) to remove residual 4-(dimethylamino)-pyridine. The solution was evaporated under vacuum to give a thick slurry. Hexane (4 L) was added, and the mixture was cooled overnight. The mixture was filtered and washed with hexane (3 L). The filter cake was dried overnight in a circulating air cabinet to give a brown solid (1205 g, 84% yield, single-point TLC).

[0185] tert-butyl methyl-(3-nitrophenyl)-carbamate (N3)

[0186] A solution of tert-butyl-(3-nitrophenyl)-carbamate (904 g, 3.79 mol) in tetrahydrofuran (11.25 L) was cooled to 0–5 °C under a nitrogen atmosphere. Potassium tert-butoxide (555 g, 4.95 mol) was added in small portions over 1 hour while maintaining the temperature <10 °C. The mixture was then stirred at approximately 10 °C for 90 minutes and then recooled to 0–5 °C. Dimethyl sulfate compound (622 g, 4.93 mol) was slowly added over 1 hour while maintaining the temperature <10 °C. The mixture was warmed to room temperature and stirred overnight. TLC (elution buffer: hexane solution of 10% ethyl acetate) showed that all N2 (Rf = 0.35) had been consumed, forming N3 (Rf = 0.45). The mixture was carefully poured into a dilute ammonia solution (3 L 33% w / w ammonia solution and 10 L water) and stirred for 1 hour. The mixture was extracted with DCM (3 × 5 L). The combined organic extracts were washed successively with water (5 L) and brine (5 L), and then dried over anhydrous sodium sulfate. The mixture was then evaporated under vacuum to give a red / brown oil (943 g, 98% yield, 98.5% GC purity).

[0187] 1 H NMR (400MHz, CDCl3) δ8.14 (1H,t,J=2.1Hz), 7.98 (1H,dd,J=8.1,2.0Hz), 7.61 (1H,d,J=8.1Hz), 7.47 (1H,t,J=8.1Hz), 3.31 (3H,s), 1.46 (9H,s).

[0188] (3-Aminophenyl)-methyl-tert-butyl carbamate (N4)

[0189] Triethylamine (30 mL) was added to a methanol (2.5 L) solution of methyl-(3-nitrophenyl)-tert-butyl carbamate (500 g, 1.98 mol). Palladium / carbon (5% w / w; Johnson Matthey 87L paste, 50% water; 50 g) was carefully added under a nitrogen atmosphere, and the mixture was hydrogenated using a Parr shaker at 50 psi hydrogen pressure. Hydrogen was rapidly absorbed, and the mixture was exothermally heated from 20 °C to 75 °C. After the exothermic reaction ceased, hydrogenation was continued for 1 hour. TLC (eluent: 89% chloroform, 10% methanol, and 1% ammonia solution) showed that N3 (Rf = 0.75) had been consumed, forming N4 (Rf = 0.55). The mixture was carefully filtered through a diatomaceous earth bed on a GF-F fiber mat. The filtrate was evaporated to dryness under vacuum. The resulting solid residue was stirred into a slurry in hexane (1000 mL) for 1 hour. The mixture was filtered and washed with hexane (500 L). The product was dried in a vacuum oven at 40 °C to give a brownish-yellow solid (429 g, 97% yield). 98.6% GC purity, melting range = 100–102 °C. (The hydrogenation was also carried out at atmospheric pressure).

[0190] 1 H NMR (400MHz, CDCl3) δ7.09 (1H, t, J = 7.9 Hz), 6.65–6.56 (2H, m), 6.5 (1H, dd, J = 8.1, 2.0 Hz), 3.65 (2H, br s), 3.22 (3H, s), 1.45 (9H, s).

[0191] 3-Amino-1-(4-acetoxy-3,3-dimethyl-2-oxo-butyl)-5-pyridin-2-yl-1,3-dihydrobenzo[e][1,4]diaza -2-keto(13-A)

[0192] A 45% w / v solution of hydrogen bromide in acetic acid (2080 mL, 11.6 mol) was diluted with more acetic acid (11 L) and stirred at room temperature. Compound 11 (2230 g, 3.63 mol) was added in one go (exothermic at 4 °C). The mixture was heated to 35–40 °C and held for 2 hours. TLC (a small sample was neutralized with saturated sodium bicarbonate and extracted with dichloromethane, eluted with a 5% methanol solution in dichloromethane) showed that all of compound 11 (Rf = 0.95) had been consumed, with only a small amount of the Cbz-protected intermediate (Rf = 0.45) remaining. The mixture was evaporated under vacuum (75 °C / <100 mbar) to remove most of the acetic acid. The thick residue was dissolved in cold water (20 L) at <10 °C and washed with dichloromethane (2 x 8 L) to remove benzyl bromide and silyl byproducts. Each dichloromethane wash was back-extracted with water (3 L). Fresh dichloromethane (10 L) was added to an aqueous solution. Solid sodium bicarbonate was added to the stirred mixture until bubbling ceased and the pH reached 8. The dichloromethane layer was removed, and the aqueous layer was extracted with more dichloromethane (5 L). The combined dichloromethane layers were dried over anhydrous sodium sulfate and evaporated under vacuum to give a thick oil. Ethyl acetate (5 L) was added to this oil while it was still in a rotating rotary evaporator flask. The oil dissolved and crystallized into a solid. The slurry was cooled to room temperature and filtered. The filter cake was thoroughly washed with cold ethyl acetate. The mother liquor was evaporated to produce another batch of product. This product was dried at 35 °C in a circulating air chamber to give a grayish-white powder (1250 g, 84% yield, 98.6% HPLC purity).

[0193] 1 H NMR (400MHz, CDCl3) δ8.62(1H,d,J=3.9Hz),8.17(1H,d,7.8Hz),7.81(1H,dt,J=2.0,7.8Hz),7.49(1H,dt,J=2.0,7.8Hz),7.42–7.33(2H,m),7. 23(1H,dt,J=1.0,7.8Hz),7.09(1H,d,J=8.3Hz),5.10(1H,d,J=18.0Hz),4.67(1H,s),4.43(1H,d,J=18.0Hz),4.18(2H,q,J=10Hz),3.65(2H,br s),2.47(1H,br s),2.08(3H,s),1.32(3H,s),1.28(3H,s).

[0194] (R)-3-amino-1-(4-acetoxy-3,3-dimethyl-2-oxo-butyl)-5-pyridin-2-yl-1,3-dihydrobenzo[e][1,4]diaza -2-keto(R)-mandelate (14-AR-mandelate)

[0195] Small-scale – Compound 13-A (28 g, 68.7 mmol) was slurried in acetonitrile (178 mL) at 20 °C. R-mandelic acid (6.27 g, 41.1 mmol) was added, and the mixture was stirred until a clear solution was formed. Diethyl ether (59 mL) was added, and the mixture was then slowly cooled to -5 °C. The mixture was filtered and washed with ice-cold acetonitrile solution of 30% ether (40 mL). The product was dried under vacuum at 40 °C to give a nearly white solid (20.3 g, 43% ee R-isomer as indicated by chiral HPLC). The crude product was dissolved in acetonitrile (89 mL) at about 45 °C, and then slowly cooled to 20 °C and allowed to stand for 2 hours. Fibrous crystals slowly formed. The mixture was filtered and washed with cold (-18 °C) acetonitrile (20 mL), followed by washing with diethyl ether (40 mL). The product was dried under vacuum at 35 °C to give a white solid (8.2 g, 21% yield, 98.8% ee R-isomer as indicated by chiral HPLC).

[0196] Large-scale reaction – Compound 13-A (1266 g, 3.10 mol) was slurried in acetonitrile (8050 mL) at 20 °C. Approximately half of the solid appeared to dissolve. R-mandelic acid (283 g, 1.86 mol, 0.6 molar equivalent) was added to the stirred mixture. The remaining solid was added slowly, forming a clear yellow solution. Ether (2660 mL) was added. The solution remained clear at 20 °C. The mixture was slowly cooled to -5 °C over 30 minutes. As the temperature decreased below 5 °C, the previously prepared R-mandelic acid salt was added to the solution as seed crystals. A very thick suspension (almost solidified) was formed, which was slowly thinned while stirring for another 2 hours. The mixture was filtered (slowly) and washed with a cold (-18 °C) solution of 50% acetonitrile in ether (1.5 L), followed by washing with ether only (2.5 L). The product was dried overnight at 35°C in a circulating air chamber to give a nearly white solid (1022 g, slightly damp). The solid may be slightly sticky if any acetonitrile remains during air drying. Chiral HPLC showed that the salt consisted of about 69% R-isomer and 32% S-isomer. The crude product (1022 g) was dissolved in acetonitrile (4.1 L) at about 45°C. Heating was continued until just dissolved, then immediately allowed to cool naturally with only occasional stirring. Prolonged heating or overheating appeared to cause product decomposition. Once the temperature dropped below 35°C, the previously prepared compound 14-A R-mandelate (>99% ee as shown by chiral HPLC) was added to the solution as a seed crystal. The mixture was slowly cooled to about 20°C over 4 hours with occasional stirring. The thick mixture was filtered and washed with cold (about -10°C) acetonitrile (1 L), followed by washing with diethyl ether (2 L). The product was dried overnight in a circulating air chamber at 35°C to give a white crystalline solid (461 g, 99.5% ee R-isomer as determined by chiral HPLC, 26.5% yield).

[0197] Adding the compound 14-AR-mandelate prepared in the above steps as a seed crystal can accelerate crystallization, but it is not necessary.

[0198] (R)-3-amino-1-(4-acetoxy-3,3-dimethyl-2-oxo-butyl)-5-pyridin-2-yl-1,3-dihydrobenzo[e][1,4]diaza -2-keto(14-A)

[0199] Compound 14-A R-mandelate (4474 g, 7.98 mol) was dissolved in a mixture of saturated sodium bicarbonate (25 L) and dichloromethane (25 L) under stirring for 10 minutes. The aqueous layer was removed and back-extracted with dichloromethane (5 L). The combined dichloromethane layers were washed with more saturated sodium bicarbonate solution (10 L). The fresh aqueous layer was back-extracted again with dichloromethane (5 L). The combined dichloromethane extracts were dried over anhydrous sodium sulfate. The free base solution was evaporated to a volume of 15 L. The solution was considered to contain 3260 g (7.98 mol) of compound 14-A. This solution was used directly in the next step. HPLC purity: 99.6%, eeR-isomer chiral HPLC purity: 99.3%.

[0200] 1 H NMR (400MHz, CDCl3) δ8.62(1H,d,J=4.1Hz),8.17(1H,d,J=7.5Hz),7.82(1H,dt,J=1.3,8.1Hz),7.50(1H,dt,J=2.0,7.8Hz),7.42–7.33(2H,m ),7.23(1H,t,J=6.8Hz),7.09(1H,d,J=8.2Hz),5.10(1H,d,J=18.0Hz),4.67(1H,s),4.43(1H,d,J=18.0Hz),4.18(2H,q,J=10Hz),2.48(1H,br s),2.08(3H,s),1.56(2H,br s), 1.32(3H,s), 1.28(3H,s).

[0201] (R)-1-[1-(4-acetoxy-3,3-dimethyl-2-oxo-butyl)-2-oxo-5-pyridin-2-yl-2,3-dihydro-1H-benzo[e][1,4]diaza] [-3-yl]-3-(3-tert-butoxycarbonyl-methylamino-phenyl)-urea(18-A)

[0202] A slurry of 1,1'-carbonyldiimidazole (421 g, 2.60 mol) in DCM (3260 mL) was cooled to 0–5 °C under a nitrogen atmosphere. A solution of compound N4 (577 g, 2.60 mol) in DCM (1630 mL) was slowly added over 30 minutes while maintaining the temperature at 0–5 °C. During the addition, the 1,1'-carbonyldiimidazole slowly dissolved, forming a light orange solution. This solution was stirred at 0–5 °C for another 1 hour, then the temperature was raised to 15–20 °C and stirred for another hour. A solution of 21.73% w / v compound 14A (3751 mL, containing 815 g, 2.00 mol) in DCM was slowly added over 30 minutes while maintaining the temperature at 15–20 °C. The mixture was then stirred at this temperature for another 2 hours. TLC (small sample quenched in saturated sodium bicarbonate solution, eluent: ethyl acetate) showed that all of compound 14A (Rf = 0.1) had been consumed, forming compound 18A (Rf = 0.35). The mixture was washed with saturated sodium bicarbonate solution (2 × 6 L). Each wash was back-extracted with DCM (2 L). The combined DCM layers were dried over anhydrous sodium sulfate and evaporated under vacuum to give a thick oil (2020 g, still slightly wetted by solvent). Ethyl acetate (5 L) was added, and evaporation continued to remove residual DCM from the mixture. The volume of the mixture was made up to 7.25 L with ethyl acetate (crude concentration approximately 25% w / v). HPLC purity was 85.8%, with two earlier eluting fractions (6.9% and 0.8%) and two later eluting fractions (3.9% and 0.6%).

[0203] Purification of compound 18-A

[0204] A 3 kg silica gel wet-packed column was prepared using 79% ethyl acetate, 20% hexane, and 1% triethylamine (triethylamine was used only during column packing). Approximately 1000 mL of a solution of compound 18A (containing approximately 250 g of crude product) was diluted to 2000 mL with ethyl acetate, followed by slow addition of 500 mL of hexane while stirring. This clear solution was loaded onto the column. The column was eluted with a solution of 20% hexane in ethyl acetate (approximately 35 L required) until minor polar impurities were removed, followed by elution with ethyl acetate (approximately 35 L required) until compound 18A was removed. A well-prepared fraction was evaporated under vacuum to remove the solvent. Evaporation was stopped while the product oil remained mobile, resulting in a thick tar / glassy residue. The HPLC purity was 96.8%.

[0205] 1H NMR (400MHz, CDCl3) δ8.61 (1H, d, J = 4.1Hz), 8.15 (1H, d, J = 7.5Hz), 7.79 (1H, dt, J = 2.0, 7.5Hz), 7.51 (1H, t, J = 7.9Hz), 7.42–7.30(3H,m),7.26(1H,t,J=7.5Hz),7.19(1H,t,J=8.1Hz),7.13–7.05(2H,m),6.93(1H,d,J=7.5Hz),6.86(1H,br s), 6.75 (1H, d, J = 8.1Hz), 5.70 (1H, d, J = 7.5Hz), 5.03 (1H, d, J = 18.4Hz), 4.52 (1H, d, J = 18.4Hz) ,4.16(2H,q,J=11.0,6.0Hz),3.21(3H,s),2.07(3H,s),1.45(9H,s),1.29(3H,s),1.26(3H,s).

[0206] (R)-1-[1-(4-acetoxy-3,3-dimethyl-2-oxo-butyl)-2-oxo-5-pyridin-2-yl-2,3-dihydro-1H-benzo[e][1,4]diaza] [-3-yl]-3-(3-methylamino-phenyl)-urea (TR2-A)

[0207] Compound 18-A (1046 g) was dissolved in acetic acid (11 L) saturated with hydrogen chloride (approximately 1.5 mol) to give a pale orange solution. The mixture was exothermic, rising from 15 °C to 23 °C. The mixture was stirred at room temperature for 3 hours. TLC (a small sample was neutralized with sodium bicarbonate and extracted with DCM; eluent: ethyl acetate) showed that all 18-A (Rf = 0.35) had been converted to TR2-A (Rf = 0.20). Nitrogen was purged through the solution for 1 hour to reduce the hydrogen chloride content. Most of the acetic acid was removed under vacuum (65 °C / <60 mmHg) to give a thick amber oil. The product was dissolved in DCM (10 L) and poured into a stirred saturated solution of sodium bicarbonate (15 L). More solid sodium bicarbonate was added until bubbling stopped and the pH = 8. (Do not use a base stronger than bicarbonate. Even carbonates will remove the acetate groups). The DCM layer was removed, and the aqueous layer was re-extracted with DCM (2 × 2 L). The combined DCM extract was dried over anhydrous sodium sulfate and filtered through a diatomaceous earth bed. The DCM solution was evaporated under vacuum to give foamed-up oil. Ethyl acetate (5.5 L) was added to the material while it was still in a rotating rotary evaporator flask with the vacuum closed. The oil dissolved and slowly formed a solid. The mixture was cooled to room temperature and allowed to stand overnight. The mixture was filtered and washed with ethyl acetate (4 L). The filter cake was pulled off and dried overnight in a vacuum oven at 35 °C. The solid was crushed and sieved, and then dried under vacuum at 35 °C for 2 days (no weight change between the second and third days of drying) to give a grayish-white powder (740 g). TR2-A can be recrystallized from ethyl acetate if desired.

[0208] Using the above method, approximately 5234 g of compound 18-A was used to prepare 3711 g (84% yield, 98.2% HPLC purity, 99.9% ee R-isomer chiral HPLC purity) of compound TR2-A.

[0209] 1H NMR (500MHz, CDCl3) δ8.60 (1H, d, J = 4.9Hz), 8.15 (1H, d, J = 7.9Hz), 7.77 (1H, dt, J = 1.8, 7.9Hz), 7.49 (1H, dt, J = 1.8,7.9Hz),7.38(1H,dd,J=1.8,7.9Hz),7.33(1H,ddd,J=1.2,4.9,7.3Hz),7.25(with CHCl3 peak,t,J=7.3Hz),7.10 (1H,d,J=7.3Hz),7.03–6.93(3H,m),6.75(1H,t,J=2.1Hz),6.52(1H,dd,J=1.8,7.3Hz),6.28(1H,dd,J=1.8,7. 9Hz), 5.72 (1H, d, J = 7.9Hz), 4.96 (1H, d, J = 18.0Hz), 4.50 (1H, d, J = 18.0Hz), 4.14 (2H, q, J = 10.6Hz), 3.73 (1H, br s),2.77(3H,s),2.05(3H,s),1.26(3H,s),1.23(3H,s).

[0210] (R)-1-[1-(4-hydroxy-3,3-dimethyl-2-oxo-butyl)-2-oxo-5-pyridin-2-yl-2,3-dihydro-1H-benzo[e][1,4]diaza] [-3-yl]-3-(3-methylamino-phenyl)-urea (TR2)

[0211] Compound 18-A was dissolved in acetic acid saturated with hydrogen chloride at approximately 20°C and stirred for about 3 hours. Most of the acetic acid in the mixture was removed under reduced pressure, and the residue was then dissolved in water. The mixture was neutralized with sodium bicarbonate and then extracted with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and then evaporated under reduced pressure to give a glassy oil TR2-A, which was used directly in the next step.

[0212] Dissolve TR2-A in methanol. Add an aqueous solution of potassium carbonate and stir the mixture at approximately 20°C for about 2 hours. Remove most of the methanol from the mixture under reduced pressure, and then dissolve the residue in water.

[0213] The mixture was extracted with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and then evaporated under reduced pressure to give a yellow, glassy oil. The yellow oil was purified by rapid column chromatography through silica gel with gradient elution (1-3% methanol in dichloromethane solution). The well fraction was evaporated under vacuum to give TR2 as a pale yellow, glassy solid.

[0214] 1¹H NMR (400MHz, CD₃Cl₃) δ 8.60 (¹H, d, J = 4.0 Hz); 8.12 (¹H, d, J = 11.2 Hz); 7.78 (¹H, dt, J = 8.0 and 2.4 Hz); 7.52 (¹H, dt, J = 7.2 and 2.0 Hz); 7.39–7.32 (²H, m); 7.28–7.23 (¹H, m); 7.20 (¹H… 7.04 (1H,t,J=8.0Hz); 6.94–6.85 (2H,m) 6.76 (1H,t,J=2.0Hz); 6.55, 6.30 (2H,2×dd,J=8.0,2.0Hz and 8.4,3.2Hz); 5.70 (1H,d,J=7.8Hz); 4.91, 4.49 (2H,AB system,J AB =22.0Hz); (2H, AB system, J AB =14.0Hz); 3.16 (1H,br s); 2.78 (3H, s); 1.20, 1.19 (6H, 2×s).

[0215] The precise mass spectrum obtained by positive ion electrospray mass spectrometry is M+H = 515.2418 m / z (for composition C). 28 H 31 Theoretical value of N6O4: 515.2407 m / z.

[0216] Example 2: Synthesis of (TR2-A) from (3-hydroxycarbamoylphenyl)methylcarbamate tert-butyl (N1)

[0217] Compound (TR2-A) was synthesized according to scheme 5 below.

[0218]

[0219] Option 5

[0220] Compound N1 was synthesized according to scheme 6 below.

[0221]

[0222] Option 6

[0223] Scheme 6 illustrates the synthesis of N1 via 15 and 16. While exemplary reagents are shown in Scheme 6, it should be understood that these reagents are modifiable. For example, the Boc in 15-N1 can be replaced with an alternative amino protecting group, such as Fmoc, Cbz, or Ac. For example, methyl 3-aminobenzoate can be converted to 15 using an organic base other than DIPEA, such as triethylamine. Methylation of 15 to 16 preferably involves the use of a base (e.g., KO). tThe solvent used in this step can be an aprotic solvent, preferably a polar aprotic solvent (e.g., DMF or THF). The conversion from 16 to N1 can be carried out using a hydroxylamine salt (e.g., HCl or sulfate) or a hydroxylamine solution, a base (e.g., KOH), and a protic solvent (e.g., methanol).

[0224] Methyl 3-(tert-butoxycarbonylamino)benzoate (15)

[0225] Acetonitrile (6.5 L), methyl-3-aminobenzoate (848 g, 5.6 mol), N,N-diisopropylethylamine (1.44 kg, 11.2 mol, 2.0 equivalent), and di-tert-butyl dicarbonate (2.0 kg, 9.16 mol, 1.63 equivalent) were added to a 20.0 L three-necked round-bottom flask equipped with a top stirrer, thermometer, nitrogen bubbler, and reflux condenser. A nitrogen atmosphere was established, and stirring was initiated. The contents of the flask were heated at 70 °C for 3 days, after which TLC (eluent: 1:1 hexane / ethyl acetate) showed no residue of the raw material. Heating was then stopped, and the contents of the flask were cooled to ~50 °C and transferred to a 20 L rotary evaporator. The solvent was removed under reduced pressure, and the resulting beige / orange residue was ground with hexane (4.0 L) for 1 hour, followed by filtration of the resulting solid. The recovered solids were re-slurryed overnight in hexane (4.0 L), filtered, washed with hexane (2 × 0.5 L) over a funnel, and drained. Wet yield = 1213 g. The solids were dried in a vacuum chamber at 40 °C (48 h) to constant weight. Dry yield = 1185 g, 84.2%. This material was used directly for the next stage.

[0226] 1 H NMR (400MHz, CDCl3) δ12.10(1H,br s),7.99(1H,s),7.91(1H,d,J=7.5Hz),7.55-7.50(1H,m),7.43(1H,t,J=7.5Hz),3.31(3H,s),1.47(9H,s)ppm.

[0227] methyl 3-(tert-butoxycarbonylmethylamino)benzoate (16)

[0228] A 13.4 L solution of compound 15 (1075 g, 4.28 mol) in DMF was dissolved in a 20 L flange flask equipped with a top stirrer, thermometer, and 500 mL PE dropping funnel. Stirring was initiated, and the contents of the flask were cooled to 0–10 °C in an ice / water / salt bath. Sodium hydride (60% oil dispersion) (256 g, 6.42 mol, 1.5 equivalents) was added in portions over 20 minutes, maintaining the internal temperature <10 °C. Once complete, the reaction mixture was warmed to ambient temperature and stirred for 1 hour, then recooled to 0–10 °C. Dimethyl sulfate (863 g, 6.84 mol, 1.6 equivalents) was added over 30 minutes, and then the cooling bath was removed, and the contents of the flask were warmed to ambient temperature. After this, TLC (eluent: 9:1 hexane / ethyl acetate + ninhydrin) showed the desired product (3) with no starting material residue. The reaction mixture was then carefully stopped with 6M ammonia solution (18.0 L [12.0 L water + 6.0 L 0.880 ammonia]), and the resulting mixture was stirred for 1 hour. DCM (10.0 L) was then added, and stirring was continued for another 30 minutes. The biphase layers were separated, and the upper aqueous layer was back-extracted with DCM (5.0 L). The combined organic layers were back-washed with water (5.0 L) and a 5% w / w brine solution (5.0 L). The organic layers were concentrated to ~2.5 kg on a rotary evaporator and then washed with water (2 × 10.0 L). The concentrate was then stripped again under high vacuum (~50 mbar) to give a brownish-red oily substance. The total yield of compound 16 was 1270 g, 112%. Residual mineral oil from sodium hydride (e.g., ...) was found in the product. 1 (As shown by H NMR), however, since this residue poses no risk to the process, no further purification of the material is necessary, and the material can be used directly for the next stage. The NMR spectroscopy conforms to the desired structure.

[0229] 1 H NMR (400MHz, CDCl3) δ7.90(1H,s),7.82(1H,d,J=8.0Hz),7.48-7.35(2H,m),3.90(3H,s),3.27(3H,s),1.44(9H,s)ppm.

[0230] tert-Butyl-(3-hydroxycarbamoylphenyl)methylcarbamate (N1)

[0231] Methanol (3.7 L) and hydroxylamine hydrochloride (644 g, 9.27 mol, 2.0 equivalent) were added to a 20 L flange flask equipped with a top stirrer, thermometer, and reflux condenser. Stirring was initiated, and the contents were heated to near reflux to dissolve the solids. The reaction mixture was then cooled to ~40 °C, and a pre-prepared solution of potassium hydroxide (779 g, 13.89 mol, 3.0 equivalent) dissolved in methanol (2.5 L) was added in one go. The contents were then cooled to room temperature, and compound 16 (1229 g, 4.63 mol, 1.0 equivalent) was added in one go, with stirring continued for 2 h. After this, TLC (eluent: 9:1 DCM / methanol) showed residual feedstock, so the reaction mixture was heated to 35–40 °C and held for another 2 h. TLC showed no feedstock residue, and after cooling to room temperature, the reaction mixture was neutralized by adding acetic acid (612 g, 10.19 mol, 2.2 equivalent). The mixture was then poured into water (20.0 L) and extracted with ethyl acetate (3 × 8.0 L). The combined organic layers were backwashed with 25% w / w brine (2 × 5.0 L), dried with sodium sulfate, filtered, and the filtrate was stripped on a rotary evaporator to obtain a thick paste. Hexane (2.5 L) was added to the warm paste, and then the mixture was cooled to room temperature. The resulting slurry was filtered, washed with hexane (2 × 0.5 L) on a funnel, and drained. The solid was air-dried in a vacuum oven [without heating] until constant weight. Total yield = 847 g, 69%. NMR conformed to the desired structure.

[0232] 1 H NMR (400MHz, CDCl3) δ8.98 (1H, br s), 7.66 (1H, s), 7.48 (1H, d, J = 7.5Hz), 7.42-7.30 (2H, m), 3.25 (3H, s), 1.47 (9H, s) ppm.

[0233] (R)-1-[1-(4-acetoxy-3,3-dimethyl-2-oxo-butyl)-2-oxo-5-pyridin-2-yl-2,3-dihydro-1H-benzo[e][1,4]diaza] [-3-yl]-3-(3-tert-butoxycarbonyl-methylamino-phenyl)-urea(18-A)

[0234] Compound N1 (8.50 g, 31.92 mmol, 1.3 molar equivalents) was slurried in acetonitrile at room temperature. Carbonyl diimidazole (5.20 g, 32.07 mmol, 1.3 molar equivalents) was added in a single addition (no exothermic reaction observed), yielding a clear solution. The solution was stirred at room temperature for 30 min, then heated to 60 °C and held for 1 h, followed by recooling to room temperature. TLC showed that all N1 had been consumed. Compound 14-A (10.0 g, 24.48 mmol) was added, and the mixture was stirred at room temperature for 2 h. TLC showed that almost all of 14-A had been consumed, forming a new, purer product. Most of the acetonitrile was removed under vacuum at 35 °C, yielding a thick oil (no change observed on TLC). The remaining oil was dissolved in dichloromethane (200 mL) and washed with a saturated sodium bicarbonate solution (2 × 150 mL). The solution was dried over anhydrous sodium sulfate and stripped to give a pink, bubbly oil (27.3 g). HPLC showed that the product was 45.4% compound 18-A containing 31.3% major impurities.

[0235] TR2-A was prepared from crude compound 18-A (obtained via the Lossen method).

[0236] Crude compound 18-A (25 g) was dissolved in acetic acid saturated with hydrogen chloride (250 mL) and stirred overnight at room temperature. TLC showed the reaction was complete by comparison with a previously prepared reference sample. Most of the acetic acid was removed under vacuum at 50 °C, yielding a viscous oil. The oil was dissolved in water (250 mL) and neutralized by adding solid sodium bicarbonate while stirring. The mixture was extracted with dichloromethane (2 × 250 mL), and the combined extracts were dried over anhydrous sodium sulfate, followed by solvent evaporation under vacuum to give foam / glass (18.1 g). TLC showed complete conversion. HPLC showed the product to be 40.9% TR2-A and 32.3% impurities. After rapid chromatographic processing, HPLC showed 69.0% TR2-A and 20.9% impurities.

[0237] Example 3: Another synthesis of 2-(2-aminobenzoyl)pyridine (4)

[0238]

[0239] A 10 L solution of morpholine (855 g, 9.81 mol) in toluene was stirred at 90 °C while indocyanine anhydride (1600 g, 9.81 mol) was added in 25 g portions over 2.5 hours. Carbon dioxide was rapidly released during the addition. The resulting mixture (hereinafter referred to as the morpholine solution) was stirred at 90 °C for another hour and then cooled to room temperature.

[0240] In a separate container, a solution of 2-bromopyridine (3580 g, 22.66 mol) in toluene (12 L) was cooled to <-60 °C under a nitrogen atmosphere. Over 2 hours, 14.10 L (22.56 mol) of n-butyllithium (1.6 M, in hexane) was slowly added while maintaining the temperature <-60 °C. The mixture was then stirred at <-60 °C for another 30 minutes. Over 4 hours, the previously prepared morpholine solution was slowly added while maintaining the temperature <-60 °C. The mixture was then slowly warmed to room temperature while stirring overnight.

[0241] The reaction mixture was added to a stirred mixture of hydrochloric acid (32%) (6.5 L), ice (6 kg), and water (6 L). The aqueous layer was removed and the mixture was filtered. More ice (8 kg) was added, followed by slow addition of ammonium hydroxide (33%) (approximately 3.0 L) until pH = 9. The resulting solid was filtered and washed with water. The filter cake was dried to give 2-(2-aminobenzoyl)pyridine (compound 4) (1630 g) as a yellow / brown solid in a crude yield of 80%.

[0242] Example 4: Solubility Study

[0243] Solubility studies confirmed that (TR1) and (TR2-A) are more soluble in aqueous solutions than YF476; (TR2-A) is more soluble in aqueous solutions than (TR1).

[0244] Weigh 2.5 mg of the test compound (n = 1) into a clear glass vial and add 0.5 mL of Britton-Robinson's buffer (pH 2.01, 3.06, 4.06, 5.08, 5.99, 6.98, and 8.16). Stir the solution overnight at ambient temperature using a vial roller system, then filter (0.45 μm pore size; unsaturated). Take two aliquots (50 μL) from the filtrate, dilute with 1 volume of 0.1 N hydrochloric acid and methanol (1:1 v / v), and analyze by HPLC-UV. Prepare a standard at 10 mg / mL (n = 1) in DMSO, then dilute 10-fold in 0.1 N hydrochloric acid and methanol (1:1 v / v) to obtain a 1 mg / mL solution. Quantify the concentration of the test compound in the filtrate relative to the concentrated standard.

[0245] Analysis was performed using a gradient HPLC-UV system with a total cycle time of 6 minutes. UV detection between 220 nm and 300 nm was performed using a photodiode array detector. The overall response was monitored.

[0246]

[0247] The solubility advantage of (TR1) and (TR2-A) over YF476 is particularly significant at pH 4–6, a pH range in which most drug absorption occurs in the small intestine (duodenum to terminal jejunum or midiliac crest). This improved solubility suggests that (TR1), (TR2), (TR3), and (TR2-A) may have higher bioavailability than YF476 and are therefore better drug candidates.

[0248] The values ​​in the table above are for crystal YF476 and (TR2-A) as well as amorphous (TR1).

[0249] The crystalline (TR2-A) and amorphous (TR2-A) forms have almost identical solubility profiles, and therefore likely possess comparable oral bioavailability. This is surprising because the crystalline YF476 has poor bioavailability and must be converted to an amorphous form (spray-dried dispersion) to improve solubility and oral bioavailability. However, this is not necessary for (TR2-A).

[0250]

[0251] Example 5: Morphological Study

[0252] Compared to YF476, studies show that (TR1) and the pure enantiomers (TR2) and (TR3) are more likely to be in an amorphous state than in a crystalline state.

[0253] Initial attempts to crystallize (TR2) and (TR3) failed, indicating a preference for their amorphous form. Indeed, XRPD analysis of (TR2) confirmed its amorphous state. This implies an advantage over YF476 in formulating suitable pharmaceutical compositions. YF476 is crystalline, resulting in poor solubility and bioavailability. Amorphous YF476 can be used to improve bioavailability, but requires stabilization, which can be achieved as a solid dispersion on hydroxypropyl methylcellulose via spray drying. Formulations favoring the amorphous form of (TR) (racemic, non-racemic, or diastereomeric pure forms) avoid the need for this stabilization treatment.

[0254] Example 6: CCK receptor antagonism

[0255] Compare (TR2) and (TR3) with YF476 and YM022 in CCK1 and CCK2 receptor function tests according to the following test criteria.

[0256]

[0257] HTRF: Homogeneous time-resolved fluorescence

[0258] cAMP: Cyclic adenosine monophosphate

[0259] CHO: Chinese hamster ovary

[0260] The test results are shown in the table below:

[0261] #imgpt58#

[0262] (TR2) and (TR3) are potent CCK2 receptor antagonists and less potent CCK1 receptor antagonists. In CCK2 assays, (TR2) is comparable to YF476 and YM022: its potency is only about 5 times weaker than both YF476 and YM022; although its affinity for the CCK2 receptor is about 5 times weaker than that of YF476, it is twice that of YM022. Furthermore, (TR2) exhibits 30% higher selectivity for the CCK2 receptor relative to the CCK1 receptor than YF476. Antagonist potency is expressed as IC50. 50 This refers to the antagonist concentration that results in half-maximal inhibition of the response to the control agonist. The affinity of the antagonist for the receptor is expressed as K. B This refers to the antagonist concentration that accounts for 50% of the receptor at equilibrium.

[0263] Example 7: Receptor Binding Screening

[0264] The potential of (TR2) and (TR3) to bind to other cellular and nuclear receptors was tested in a group of 80 receptors. The assay used reflectively labeled receptor ligands (agonists or antagonists, depending on the receptor), and the ability of compounds to inhibit ligand binding was measured by scintillation counting. No significant receptor binding was found (except for CCK2 and CCK1).

[0265] Example 8: Preclinical Study: In Vitro Cell Proliferation

[0266] In the sulforhodamine-B (SRB) proliferation assay, using the human gastrin / CCK2 receptor gene (AGS) GR The potency of (TR2) and (TR3) was tested in stable metastatic human gastric adenocarcinoma cell lines. SRB is a protein-binding fluorescent dye, so cells with high protein synthesis rates (proliferating cells) will show high levels of fluorescence in the SRB assay. Gastrin fragment G17 against AGS GRThe cells exhibited an antiproliferative effect. Therefore, when treated with G17, the cells showed lower levels of fluorescence in the SRB assay. (TR2) and (TR3) were compared with the positive controls YF476 and YM022. (TR2), YF476, and YM022 all completely inhibited the antiproliferative effect of G17 (10 nM) at a concentration of 100 nM. (TR3) showed the same effect at a concentration of 500 nM. None of the compounds tested affected AGS in the absence of G17. GR Cell proliferation.

[0267] Example 9: Preclinical study: Rats with gastric fistula

[0268] The effects of subcutaneous injections of YF476, (TR2), and (TR3) on pentagastrin-stimulated gastric acid secretion were tested in conscious rats with chronic gastric fistula. All treatments dose-dependently inhibited the acid secretion response. The effects of YF476, (TR2), and (TR3) on gastric acid secretion were also investigated. 50 The values ​​were 0.012, 0.03, and 0.3 μmol / kg, respectively.

[0269] Example 10: Pharmacokinetics in Healthy Subjects

[0270] In the initial study, healthy volunteers received a single oral dose of 100 mg of the active pharmaceutical ingredient (API) (TR2) in the capsule. Plasma concentrations were measured. The area under the plasma concentration curve for (TR2) after a single oral dose of 100 mg of the active pharmaceutical ingredient (AUC = 439.1) was approximately twice that observed for a similar formulation of YF476 after a single oral dose of 100 mg (AUC = 198.5). Therefore, higher bioavailability of (TR2) was observed compared to YF476.

[0271] In further clinical studies, healthy volunteers (n=8) received single oral doses of 5, 15, 50, and 100 mg as the active pharmaceutical ingredient (API) in the capsule (TR2). Plasma concentrations were measured. The area under the plasma concentration curve (AUC) after a single oral dose of 100 mg API (TR2) was also measured. 0–24h (ng.h / mL) = 241.5) is the area under the plasma concentration curve (AUC) observed for a single oral dose of 100 mg of a similar formulation of YF476. 0–24h (81.3; n=10) is approximately three times that of (TR2). Therefore, in healthy subjects, (TR2) was observed to have better oral bioavailability than YF476.

[0272] Healthy volunteers (n=8) received single oral doses of 5, 15, 25, and 50 mg as (TR2-A) of the API in capsule form (TR2-A (crystals) in hard gelatin capsules, without excipients, and without API processing). Plasma concentrations of (TR2) and (TR2-A) were measured. The area under the curve (AUC) of plasma concentration of (TR2) after a single oral dose of 50 mg (TR2-A) API was calculated. 0–24h =212.5) and the area under the plasma concentration curve (AUC) observed for a single oral dose of 100 mg of a similar formulation of (TR2). 0–24h =241.5) are roughly the same. Therefore, in healthy subjects, (TR2-A) was observed to have better oral bioavailability than (TR2). Moreover, (TR2-A) had a lower plasma concentration (AUC). 0–24h <10) indicates that (TR2-A) is a prodrug of (TR2).

[0273] Example 11: Clinical Study: Pharmacodynamic Effects in Healthy Subjects

[0274] Pentagastrin induces gastric acid secretion, thereby increasing H2O. + Concentration. In the initial study in healthy volunteers, it was observed that single oral doses of 5, 25, and 100 mg (TR2) combined with pentagastrin infusion resulted in H+ concentrations in gastric aspirate similar to those induced by intravenous pentagastrin infusion, as with corresponding doses of YF476 and pentagastrin infusion. + Increased concentration leads to dose-dependent inhibition. Therefore, in healthy subjects, the potency of (TR2) as a CCK2 receptor antagonist is similar to that of YF476.

[0275] In further clinical studies, in healthy volunteers, single oral doses of 5, 15, 50, and 100 mg (TR2) or 5, 15, 25, and 50 mg (TR2-A) were administered in combination with pentagastrin infusion (intravenous infusion, dose 0.6 μg / kg / h, 2 hours). It was observed that (TR2) and (TR2-A) resulted in similar levels of H+ in gastric aspirate induced by intravenous pentagastrin infusion as administration of YF476 and pentagastrin infusion. + Dose-dependent inhibition by increased concentration. 100 mg (TR2) and 50 mg (TR2-A) resulted in similar inhibition of H+ in gastric aspirate induced by intravenous pentagastrin as administration of 100 mg YF476. +Increased concentration inhibition. Therefore, in healthy subjects, the potency of (TR2) as a CCK2 receptor antagonist was similar to that of the corresponding YF476, while the potency of (TR2-A) was higher than that of both (TR2) and YF476. The observed results showed that (TR2) inhibited the action of pentagastrin in a dose-dependent manner, and that the dose of (TR2-A) required for complete inhibition was lower than that of (TR2).

[0276] Embodiments of the present invention have been described by way of examples, which should be considered exemplary rather than limiting. It should be understood that changes in form and detail may be made without departing from the true scope of the invention, as defined by the appended claims.

Claims

1. A method for preparing general formula ( I Methods involving compounds or pharmaceutically acceptable salts thereof: ( I ) In the formula: R1 is: (i) -CH2C(O)C(R2)(R3)-L-R4, where: R2 and R3 are each independently H or C. 1–3 Aliphatic groups; L is a key or C 1–3 Alkylene; and R4 is –OR5, where R5 is hydrogen, C 1-6 Alkyl or –C(O)R6, where R6 is C 1–6 aliphatic group; or (ii) -CH2C(O)(CH2) a R8, where a is 0 and R8 is an alkyl group; Both W and X are hydrogen; and Ring A is a phenyl group with a meta-substituent selected from NHMe, NMeEt, NEt2, F, Cl, Br, OH, OCH3, NH2, NMe2, NO2, Me, and (CH2). n -CO2H, CN, CH2NMe2, NHCHO and (CH2) n -SO3H, where n is 0-2; ring B is 2-, 3-, or 4-pyridyl. in, R1, any one or more substituents on ring A or ring B can be in unprotected or protected form; The method includes: By using the general formula ( IC Compounds of phosgene, phosgene synthesis equivalents, or phosgene are added to an aprotic solvent to provide the reaction mixture, and then the general formula ( IB A compound of formula (I) is added to the reaction mixture to form a compound of general formula (I): ( IC ) ( IB )； Phosgene synthetic equivalents include carbonyl diimidazole (CDI), diphosgene, triphosgene, chloroformate, or disuccinimidyl carbonate.

2. A method for preparing general formula ( II Methods involving compounds or pharmaceutically acceptable salts thereof: ( II ) In the formula: R2 and R3 are each independently C 1–2 alkyl; L is -CH2-; and R4 is –OR5, where R5 is hydrogen, C 1-6 Alkyl or –C(O)R6, where R6 is C 1-6 Aliphatic groups; in, general formula( II The -NHMe portion of the ) can be in a protected form; The method includes: By using the general formula ( II-A Compounds of the general formula ( II-B Compounds of the general formula ( ) and phosgene synthesis equivalents or phosgene are added to an aprotic solvent to provide the reaction mixture to form phosgene. II ) compounds ( II-A ) ( II-B )； Among them, the phosgene synthesis equivalents are carbonyl diimidazole (CDI), diphosgene, triphosgene, chloroformate, or disuccinimidyl carbonate; PG is a protecting group; and Optionally, the method includes an additional deprotection step to remove the protecting group; The general formula ( II The compound of formula () is TR2 )or( TR2-A Compounds of or pharmaceutically acceptable salts thereof: ( TR2 )( TR2-A )。 3. A method for preparing a compound of general formula (I) or a pharmaceutically acceptable salt thereof: ( I ) In the formula: R1 is -CH2C(O)(CH2) a R8, where a is 0, and R8 is C. 4-7 alkyl; Both W and X are hydrogen; and Ring A is a phenyl group having a meta-substituent selected from NHMe, NMeEt, NEt2, NH2, and NMe2; ring B is a 2-, 3-, or 4-pyridyl group. in, R1, any one or more substituents on ring A or ring B can be in unprotected or protected form; The method includes: By using the general formula ( IA Compounds of the general formula ( IB Compounds of the general formula ( ) and phosgene synthesis equivalents or phosgene are added to an aprotic solvent to provide the reaction mixture to form phosgene. I ) compounds ( IA ) ( IB )； The reaction is carried out at a temperature not exceeding 30°C and in the absence of alkali. Phosgene synthetic equivalents include carbonyl diimidazole (CDI), diphosgene, triphosgene, chloroformate, or disuccinimidyl carbonate.

4. The method according to any one of claims 1-3, characterized in that, The phosgene synthetic equivalent or phosgene is carbonyl diimidazole.

5. The method as described in claim 1 or 3, characterized in that, In cases where any one or more substituents on R1, ring A, or ring B are in a protected form, the method includes an additional deprotection step to remove one or more protecting groups.

6. The method as described in claim 2, characterized in that, The method includes an additional deprotection step to remove the protecting group.

7. The method as described in claim 2, characterized in that, general formula( II-A Compounds of phosgene and phosgene synthetic equivalents or phosgene in the addition of general formula ( II-B The compound is added to the solvent beforehand.

8. The method as described in claim 3, characterized in that, general formula( IA Compounds of phosgene and phosgene synthetic equivalents or phosgene in the addition of general formula ( IB The compound is added to the solvent beforehand.

9. The method according to any one of claims 1-3, characterized in that, The aprotic solvent is ethyl acetate, dichloromethane, acetonitrile, or toluene.

10. The method as described in claim 1, characterized in that, R5 is a methyl group.

11. The method as described in claim 1, characterized in that, R1 is -CH2C(O)C(R2)(R3)-L-R4.

12. The method as described in claim 1, characterized in that, The general formula ( I Compounds of the same type or pharmaceutically acceptable salt thereof are of the general formula ( ). II Compounds of or pharmaceutically acceptable salts thereof: ( II ) Wherein R2, R3, L and R4 are as defined in claim 1, the general formula ( IB Compounds of the general formula () II-B Compounds of the general formula ( IC Compounds of the general formula () II-C ) compounds, ( II-B ) ( II-C ) PG is a protecting group.

13. The method of claim 2 or 12, wherein, PG is a Boc protecting group.

14. The method as described in claim 1, characterized in that, R2 and R3 are each independently C 1–2 Alkyl group, where L is -CH2-.

15. The method as described in claim 1, characterized in that, R1 is –CH2C(O)C(R2)(R3)-L-R4, R4 is -OR5, R5 is hydrogen, methyl, or –C(O)R6, and R6 is C. 1–6 Aliphatic groups.

16. The method as described in claim 1, characterized in that, R4 is –OR5, and R5 is –C(O)R6.

17. The method as described in claim 1, characterized in that, The general formula ( I The compounds or pharmaceutically acceptable salts thereof are selected from the following compounds: ; ; ; ; ; ; ; ;and ; Or its pharmaceutically acceptable salt.

18. The method as described in claim 17, characterized in that, The compound is selected from: ; ; ; ; ; ; ; ;and ; Or its pharmaceutically acceptable salt.

19. The method as described in claim 1, characterized in that, The general formula ( I Compounds of the same type or pharmaceutically acceptable salt thereof are of the general formula ( ). III Compounds of or pharmaceutically acceptable salts thereof: ( III ) Where R 11 Selected from: ; ; ; ; and ; Where R6 is C 1-6 Aliphatic groups.

20. The method as described in claim 19, characterized in that, The compound is of the general formula ( IV Compounds of or pharmaceutically acceptable salts thereof: ( IV ) 。 21. The method as described in claim 1, characterized in that, The general formula ( I )or( II The compound or its pharmaceutically acceptable salt is a compound ( TR )or( TR-A Or pharmaceutically acceptable salts: , ( TR )( TR-A ) 。 22. The method as described in claim 21, characterized in that, The compound is a compound ( TR2 )or( TR2-A Or pharmaceutically acceptable salts: ( TR2 )( TR2-A )。 23. The method as described in claim 1 or 3, characterized in that, The general formula ( I The compound or a pharmaceutically acceptable salt thereof is YF476 or a pharmaceutically acceptable salt thereof: YF476.

24. The method of claim 2, used for producing general formula ( TR2-A Compounds of: ( TR2-A ) in, The method includes: (a) A reaction mixture is provided by adding a compound of general formula (II-A), a compound of general formula (II-Ba), and a phosgene synthesis equivalent or phosgene to an aprotic solvent to form a compound of general formula (II-A). TR2-A-PG ) compounds, ( II-A ) ( II-Ba) ( TR2-A-PG ) Where PG is a protecting group; and (b) For the general formula ( TR2-A-PG The compound is deprotected to form the general formula ( ) TR2-A ) compounds.

25. The method of claim 24, wherein, PG is a Boc protecting group.

26. A general formula ( II-C Compounds of: ( II-C ) PG is a protecting group.

27. The compound of claim 26, characterized in that, PG is a Boc protecting group.

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