Process for preparing phthalazinone derivatives and intermediates thereof

Abstract

The present application provides methods for preparing 4-[3-{3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one or pharmaceutically acceptable salts thereof, intermediates in the preparation, methods for preparing the intermediates, and compositions and products containing the compounds produced from the methods that result in high purity and high yield.

Description

[Technical field]

[0001] [CROSS REFERENCE TO RELATED APPLICATIONS] This application claims priority to U.S. Patent Application No. 63 / 013,310, filed April 21, 2020, the contents of which are incorporated by reference in their entirety herein.

[0002] [Technical field] The present invention relates to processes for preparing phthalazinone derivatives that are poly(ADP-ribose) polymerase (PARP) inhibitors, intermediates used in these processes, processes for preparing the intermediates, and compositions and products comprising said derivatives prepared from the processes that result in high purity and high yields. [Background technology]

[0003] Patent Document 1 (U.S. Patent No. 9,682,973) discloses phthalazinone derivatives, their racemates, enantiomers or diastereomers, or pharma- ceutically acceptable salts thereof, which have anticancer activity as poly(ADP-ribose) polymerase (PARP) inhibitors.

[0004] The patent document discloses a method for preparing phthalazinone derivatives, in particular, in Examples 143 and 171, a method for preparing 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one or a pharma- ceutically acceptable salt thereof, as shown in Reaction Scheme 1 below.

[0005] [ka]

[0006] When 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one or a pharma- ceutically acceptable salt thereof is prepared according to the above-mentioned preparation method, the reaction does not go to completion at each step, resulting in a very low overall yield of the final product relative to the starting material. In addition, multiple impurities are generated, necessitating purification by column chromatography. Furthermore, since most of the intermediates prepared are present in the liquid phase, it is difficult to achieve quantitative reaction at each step, and poor quality reproducibility makes it difficult to apply to mass (e.g., large-scale and commercial) production.

[0007] In particular, in the synthesis process of 4-[3-(3-[(cyclopropylamino)methyl(azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one (Example 143, Step 2), the reaction does not go to completion even if it proceeds for more than 24 hours. Furthermore, due to the formation of multiple related substances, additional purification steps, including column chromatography, are required to obtain a substantially pure sample, which reduces the final yield. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] U.S. Patent No. 9,682,973 Summary of the Invention [Problem to be solved by the invention]

[0009] One aspect of the present invention is to provide a process for preparing 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one, or a pharma- ceutically acceptable salt thereof, in which one or more intermediates are obtained in solid phase and do not require additional purification steps due to reduced impurity formation, thereby increasing the overall yield in a manner suitable for large-scale (e.g., large-scale and commercial) production.

[0010] Another aspect is to provide one or more novel intermediates that can be used in the above preparation methods.

[0011] Another aspect is to provide a method for preparing one or more intermediates.

[0012] Compositions and products containing the compounds of Formula 1, or pharma- ceutically acceptable salts thereof, prepared from the processes of the invention are also provided.

[0013] Other objects and advantages of the present invention will become apparent from the following detailed description taken in conjunction with the accompanying drawings. Regarding the contents not described in this specification, those skilled in the art of the present invention or a similar art can fully recognize and infer them, so the description thereof will be omitted. [Means for solving the problem]

[0014] According to one aspect of the invention, there is provided a method for preparing a compound of formula 1, or a pharma- ceutically acceptable salt thereof.

[0015] [ka]

[0016] The method comprises the step (a2) of deprotecting a compound of formula 4 to prepare a compound of formula 1,

[0017] [ka]

[0018] In the formula, X 1 is an amine protecting group.

[0019] According to another aspect of the invention there is provided a process for preparing a compound of formula 4 comprising the step (a1) of reacting a compound of formula 2 with a compound of formula 3.

[0020] [ka]

[0021] In the formula, X 1 is an amine protecting group and HA is an acid that forms an acid addition salt.

[0022] [ka]

[0023] According to another aspect of the invention, a method for preparing a compound of formula 2 is provided.

[0024] [ka]

[0025] The method comprises: Amine Protecting Group X 1 into the compound of formula 6 to prepare a compound of formula 7; and Azetidine Nitrogen Protecting Group X 2 from the compound of formula 7 to prepare a compound of formula 2,

[0026] [ka]

[0027] [ka]

[0028] In the formula, X 1 is an amine protecting group, X 2 is an azetidine nitrogen protecting group, HA is an acid that forms an acid addition salt.

[0029] According to another aspect of the present invention, there is provided a compound of formula 2:

[0030] [ka]

[0031] In the formula, X 1 is an amine protecting group, HA is an acid that forms an acid addition salt.

[0032] According to another aspect of the present invention, there is provided a compound of formula 4:

[0033] [ka]

[0034] In the formula, X 1 is an amine protecting group.

[0035] According to another aspect of the present invention, there is provided a compound of formula 7:

[0036] [ka]

[0037] In the formula, X 1 is an amine protecting group, X 2 is an azetidine nitrogen protecting group. Effect of the Invention

[0038] According to one aspect of the present invention, one or more intermediates produced according to the method are obtained in solid phase, and therefore separation of the intermediates may be more convenient. In each process, the reaction producing the intermediates may be completed with minimal side reactions and low levels of impurities, and thus, column chromatography, which was previously required for separation and purification to obtain substantially pure compounds, is not required. Due to the reduced production of impurities and the ease of separation of the intermediates, the final product may be obtained in high purity and high yield. Thus, the preparation method according to one aspect of the present invention may be more economical in preparing 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one or a pharma- ceutically acceptable salt thereof with higher purity and higher yield, and therefore suitable for large-scale (e.g., large-scale and commercial) production. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0039] The present invention will now be described in further detail.

[0040] Unless otherwise specified, all terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention pertains. Furthermore, although preferred methods or embodiments are described herein, similar or equivalent methods or embodiments are also within the scope of the present invention. Furthermore, the term "comprises" is intended to have an inclusive meaning and can include additional elements other than the recited elements.

[0041] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and the like used in the specification and claims are to be understood as being modified in all instances by the term "about."

[0042] As used herein, the term "compound of formula" is not intended to be limiting to the formula. When a structure is shown, it is understood that all possible stereoisomers and tautomers thereof are included unless otherwise specified.

[0043] The term "protecting group" refers to a functional group that protects a functional group, such as an amino group, an alcohol group, etc., from unintended reactions by being attached thereto via a covalent bond and that allows the functional group to be regenerated (i.e., deprotected) after treatment of the protecting group with an appropriate reagent.

[0044] As used herein, the term "the intermediate produced according to the present method is obtained in solid phase" means that the intermediate is obtained in solid form, for example, by filtration and drying, or similar steps known in the art.

[0045] The term "ambient temperature" refers to indoor ambient temperatures ranging from about 1°C to about 30°C.

[0046] The contents of all publications cited herein as references are hereby incorporated by reference in their entireties.

[0047] Each of the descriptions and embodiments disclosed in the present invention can be applied to other descriptions and embodiments. That is, all combinations of the various elements disclosed in the present invention belong to the scope of the present invention. Furthermore, the scope of the present invention should not be limited by the specific descriptions described below.

[0048] One aspect of the invention provides a method for preparing a compound of formula 1 or a pharma- ceutically acceptable salt thereof.

[0049] [ka]

[0050] The method comprises the step (a2) of deprotecting a compound of formula 4 to prepare a compound of formula 1,

[0051] [ka]

[0052] In the formula, X 1is an amine protecting group.

[0053] A compound of formula 4 can be prepared by reacting a compound of formula 2 with a compound of formula 3, step (a1).

[0054] [ka]

[0055] In the formula, X 1 is an amine protecting group and HA is an acid that forms an acid addition salt.

[0056] [ka]

[0057] Another aspect of the invention provides a method for preparing a compound of formula 4, comprising the step (a1) of reacting a compound of formula 2 with a compound of formula 3.

[0058] [ka]

[0059] [ka]

[0060] During the ceremony, X 1 is an amine protecting group, HA is an acid that forms an acid addition salt.

[0061] HA can be any acid that forms an acid addition salt as described above.For example, the acid addition salt can be a hydrohalide.Hydrohalide includes hydrochloric acid (HCl), hydrobromic acid (HBr) or hydroiodic acid (HI), preferably hydrochloric acid (HCl).

[0062] In step (a1), the compound of formula 4 may be obtained by amide coupling of the compound of formula 2 with the compound of formula 3. In step (a2), the compound of formula 1 may be obtained by amide coupling of the compound of formula 4 with the compound of formula 3 with the protecting group X, 1 may be obtained by removing

[0063] In one embodiment, a method for preparing a compound of Formula 1, or a pharma- ceutically acceptable salt thereof, can be represented by Reaction Scheme 2 below.

[0064] [ka]

[0065] The compound of formula 3 used in step (a1) can be prepared according to any method known in the art, for example the method disclosed in WO2004 / 080976 (see section b under "Synthesis of key intermediates").

[0066] In one embodiment, the compound of formula 2 can be in the form of a hydrochloride salt, where HA is hydrochloric acid. 1 is the reaction of step (a1) 1 The amine protecting group may be any amine protecting group capable of protecting the amine group to which it is attached, including, but not limited to, fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa) or p-methoxybenzyl (PMB).

[0067] Step (a1) of preparing a compound of formula 4 can be carried out under any conditions that allow the formation of an amide bond between the azetidinium amine of a compound of formula 2 and the carboxyl group of a compound of formula 3.

[0068] In one embodiment, step (a1) can be carried out in the presence of an amide coupling reagent. The amide coupling reagent refers to a reagent that can activate the carboxyl group of a reactant to form an amide group during reaction with an amine. The amide coupling reagent includes, but is not limited to, trimethylacetyl chloride, 1,1'-carbonyldiimidazole, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC), or any combination thereof.

[0069] Step (a1) may be carried out in the presence of a base, for example, at least one base selected from the group consisting of diisopropylethylamine, triethylamine, N-methylmorpholine, and any combination thereof.

[0070] In one embodiment, step (a1) may be carried out in the presence of both at least one amide coupling reagent and at least one base.

[0071] In one embodiment, step (a1) can be carried out in the presence of both at least one amide coupling agent selected from the group consisting of trimethylacetyl chloride, 1,1'-carbonyldiimidazole, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC), and any combination thereof, and at least one base selected from the group consisting of diisopropylethylamine, triethylamine, N-methylmorpholine, and any combination thereof.

[0072] In the reaction in step (a1), a solvent that does not inhibit the reaction can be used.For example, the solvent can be selected from acetonitrile, acetone, toluene, tetrahydrofuran, dichloromethane, chloroform, N,N-dimethylformamide, and any combination thereof.In one embodiment, the solvent can be toluene.

[0073] The reaction in step (a1) can be carried out at a temperature from about -20°C to reflux temperature, in some embodiments from about -20°C to about 120°C, and in other embodiments from about -10°C to about 40°C.

[0074] In step (a1), the reaction product, the compound of formula 4, may be obtained in a solid phase, i.e., the compound of formula 4 may be obtained in a solid form by filtration and drying.

[0075] Step (a2) of preparing a compound of formula 1 comprises reacting an amine protecting group X 1 from a compound of formula 4, 1 The reaction conditions for removing the amine protecting group X 1 The number of times may vary depending on the type of

[0076] In one embodiment, step (a2) of preparing a compound of formula 1 comprises the step of: 1 When is fluorenylmethoxycarbonyl (Fmoc), the compound of formula 4 can be reacted with a non-nucleophilic base. The non-nucleophilic base is not limited to a particular type, and can be a amine protecting group X 1 The non-nucleophilic base may be any non-nucleophilic base capable of effectively removing X. For example, the non-nucleophilic base may be selected from piperidine, diisopropylethylamine, 1,8-diazabicyclo[5,4,0]undec-7-ene, and any combination thereof. In this case, the reaction solvent in step (a2) may be acetonitrile, tetrahydrofuran, N,N-dimethylformamide, or any combination thereof. For example, 1 When is fluorenylmethoxycarbonyl (Fmoc), the non-nucleophilic base and solvent can be piperidine and acetonitrile, diisopropylethylamine and tetrahydrofuran, or 8-diazabicyclo[5,4,0]undec-7-ene and N,N-dimethylformamide, respectively.

[0077] In another embodiment, in step (a2), X 1When is trifluoroacetyl (Tfa), the compound of formula 4 can be reacted with an alkali base. The alkali base is not limited to a particular type, and the amine protecting group X 1 The alkali base may be any alkali base capable of effectively separating X. For example, the alkali base may be potassium hydroxide, potassium carbonate, sodium hydroxide, sodium carbonate, or any combination thereof. In this case, the reaction solvent in step (a2) may be a solvent obtained by adding water to a C1-C4 linear alcohol, a C1-C4 branched alcohol, or any combination thereof. For example, X 1 When is trifluoroacetyl (Tfa), the alkali base and solvent can be potassium hydroxide and isopropyl alcohol / water, potassium carbonate and methanol / water, sodium hydroxide and methanol / water, or sodium carbonate and ethanol / water, respectively.

[0078] In yet another embodiment, in step (a2), X 1 When X is p-methoxybenzyl (PMB), the compound of formula 4 may be reacted with an acid. The acid is not limited to a specific type and may be any acid that can effectively remove the amine protecting group. For example, trifluoroacetic acid may be used as a reagent and a solvent. In this case, in the reaction of step (2), the ratio (w / v) of the weight of the compound of formula 4 to the volume of trifluoroacetic acid may be about 1:5 to about 1:40. For example, 1 When is p-methoxybenzyl (PMB), the ratio (w / v) of the compound of formula 4 to trifluoroacetic acid used in the reaction of step (a2) may be about 1:10.

[0079] In step (a2), the reaction product, the compound of formula 1, may be obtained in a solid phase, i.e., the compound of formula 1 may be obtained in a solid form by filtration and drying.

[0080] A pharma- ceutically acceptable salt of the compound of formula 1 can be prepared by further carrying out step (a3) ​​of reacting the compound of formula 1 with an acid to prepare an acid addition salt of the compound of formula 1. The preparation of the acid addition salt of the compound of formula 1 can be carried out by a person skilled in the art using a suitable method based on the common knowledge in the field of organic chemistry. The acid addition salt of the compound of formula 1 can be any pharma- ceutically acceptable acid addition salt, for example, an acid addition salt formed from a free acid. The free acid can be an inorganic acid or an organic acid. The inorganic acid can be hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid. The organic acid can be, but is not limited to, acetic acid, trifluoroacetic acid, oxalic acid, maleic acid, succinic acid, fumaric acid, adipic acid, L- or D-tartaric acid, DL-tartaric acid, citric acid, lactic acid, benzoic acid, mandelic acid, salicylic acid, cinnamic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, glycolic acid, pyruvic acid, glucuronic acid, glutamic acid, aspartic acid, or any combination thereof.

[0081] In one embodiment, the acid addition salt is an inorganic acid addition salt, which in one embodiment may be a hydrochloric acid addition salt. The reaction in step (a) of preparing the acid addition salt of the compound of formula 1 may be carried out in any solvent that does not inhibit the formation of the acid addition salt. For example, the solvent may be selected from alcohols, ketones, ethers, acetates, dichloromethane, chloroform, and any combination thereof, and in some embodiments, may be selected from C1-C5 alcohols, C3-C6 alcohols, C4-C8 alcohols, C5-C6 alcohols, C6-C8 alcohols, C7-C9 alcohols, C8-C10 alcohols, C9-C11 alcohols, C12-C13 alcohols, C13-C14 alcohols, C14-C15 alcohols, C15-C16 alcohols, C16-C17 alcohols, C17-C18 alcohols, C18-C19 alcohols, C20-C210 alcohols, C21-C220 alcohols, C22-C30 alcohols, C23-C310 alcohols, C24-C250 alcohols, C25-C310 alcohols, C26-C320 alcohols, C27-C330 alcohols, C28-C340 alcohols, C29-C350 alcohols, C30-C360 alcohols, C31-C370 alcohols, C32-C380 alcohols, C33-C390 alcohols, C40-C410 alcohols, C41-C420 alcohols, C42-C430 alcohols, C43-C440 alcohols, C44-C450 alcohols, C45-C460 alcohols, C45-C470 alcohols, C46-C480 alcohols, C47-C480 alcohols, C48-C490 10 Ketones, C2-C 10 It may be ether, C2-C4 alkyl acetate, dichloromethane, chloroform or any combination thereof.

[0082] The reaction in step (a3) ​​can be carried out at a temperature from about -20°C to reflux temperature, in some embodiments from about -20°C to about 50°C, and in other embodiments from about -10°C to about 30°C.

[0083] In one embodiment, the hydrochloride salt of the compound of formula 1 can be prepared by adding anhydrous or concentrated hydrochloric acid to the compound of formula 1 at a temperature ranging from about -20°C to reflux temperature together with a solvent of an alcohol, a mixture of an alcohol and a ketone, a mixture of an alcohol and dichloromethane, a mixture of an alcohol and chloroform, a mixture of an alcohol and an ether, or a mixture of an alcohol and an acetate. For example, the alcohol, ketone, ether, and acetate can be C1-C5 alcohol, C3-C6 alcohol, C4-C8 alcohol, C5-C6 alcohol, C6-C7 alcohol, C7-C8 alcohol, C8-C9 alcohol, C9-C10 alcohol, C10-C11 alcohol, C11-C12 alcohol, C12-C13 alcohol, C13-C14 alcohol, C14-C15 alcohol, C15-C16 alcohol, C16-C17 alcohol, C17-C18 alcohol, C18-C19 alcohol, C19-C20 alcohol, C20-C21 alcohol, C21-C22 alcohol, C22-C31 alcohol, C22-C42 alcohol, C23-C43 alcohol, C24-C54 alcohol, C25-C26 alcohol, C26-C27 alcohol, C27-C31 alcohol, C28-C32 alcohol, C29-C33 alcohol, C30-C34 alcohol, C31-C35 alcohol, C32-C45 alcohol, C33-C46 alcohol, C34-C47 alcohol, C35-C48 alcohol, C36-C49 alcohol, C37-C48 alcohol, C38-C49 alcohol, C39-C56 alcohol, C40-C41 alcohol, C41-C42 alcohol, C42-C43 alcohol, C43-C44 alcohol, C44-C45 alcohol, C4 10 Ketones, C2-C 10 It can be an ether and a C2-C4 alkyl acetate.

[0084] In one embodiment, the hydrochloride salt of the compound of formula 1 can be prepared by adding anhydrous or concentrated hydrochloric acid to the compound of formula 1 together with a solvent of an alcohol, a mixture of an alcohol and a ketone, a mixture of an alcohol and dichloromethane, a mixture of an alcohol and chloroform, or a mixture of an alcohol and an ether at a temperature ranging from about −20° C. to reflux temperature, and then filtering and drying the solid thus formed. For example, the alcohol, ketone, and ether can be C1-C5 alcohols, C3-C6 alcohols, C4-C8 alcohols, C5-C6 alcohols, C6-C8 alcohols, C7-C9 alcohols, C8-C10 alcohols, C9-C11 alcohols, C12-C13 alcohols, C13-C14 alcohols, C14-C15 alcohols, C15-C16 alcohols, C16-C17 alcohols, C17-C18 alcohols, C18-C19 alcohols, C19-C20 alcohols, C20-C25 alcohols, C21-C26 alcohols, C22-C30 alcohols, C23-C24 alcohols, C24-C30 alcohols, C25-C30 alcohols, C26-C40 alcohols, C27-C40 alcohols, C28-C29 alcohols, C29-C30 alcohols, C30-C40 alcohols, C30-C40 alcohols, C40-C50 alcohols, C40-C50 alcohols, C50-C60 alcohols, C40-C40 alcohols, C50-C50 alcohols, C60-C70 alcohols, C70-C40 alcohols, C40-C40 alcohols, C50-C50 alcohols, C60-C40 alcohols, C70-C40 alcohols, C80-C40 10 Ketones and C2-C 10 It may be an ether.

[0085] In step (a3), the reaction product, the acid addition salt of the compound of formula 1, may be obtained in a solid phase, i.e., the acid addition salt of the compound of formula 1 may be obtained in a solid form by filtration and drying.

[0086] In another aspect, a method for preparing a compound of formula 2 above is provided.

[0087] The method comprises: Amine Protecting Group X 1 (b1) introducing into the compound of formula 6 to prepare the compound of formula 7; and Azetidine Nitrogen Protecting Group X 2 (b2) preparing a compound of formula 2 by removing from a compound of formula 7 Including,

[0088] [ka]

[0089] [ka]

[0090] In the above formula, X 1 is an amine protecting group, and X 2 is an azetidine nitrogen protecting group.

[0091] In one embodiment, the compound of formula 2 can be an acid addition salt, where HA in formula 2 is hydrochloric acid.

[0092] Amine Protecting Group X 1 In the reaction of step (b1) in which a compound of formula 7 is prepared by introducing into a compound of formula 6, when a compound of formula 2 is prepared from a compound of formula 7, i.e., in the reaction of step (b2), an amine protecting group X 1 can protect secondary amine groups that do not belong to the nitrogen of the azetidine ring of the compound of formula 7. Thus, the amine protecting group X 1 represents the azetidine nitrogen protecting group X of the compound of formula 7. 2 In preparing the acid addition salt compound of formula 2 by the deprotection reaction of the formula (I), the protecting group can be any protecting group capable of protecting a secondary amine group not included in the azetidine ring. For example, the amine protecting group X 1 can be fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa) or p-methoxybenzyl (PMB).

[0093] In the reaction of step (b1), an amine protecting group X 1 Reagents capable of introducing the amine protecting group X into compounds of formula 6 include 1For example, the reaction in step (b1) can be carried out by reacting the compound of formula 6 with a reagent selected from fluorenylmethoxycarbonyl chloride, trifluoroacetic anhydride, 4-methoxybenzyl chloride, and any combination thereof.

[0094] The reaction of step (b1) can be carried out in the presence of a base. The base is used to convert the amine protecting group X 1 The base may be any base as long as it does not inhibit the reaction of introducing the compound of formula 6. For example, the base may be a tertiary amine. For example, the tertiary amine may be selected from diisopropylethylamine, triethylamine, N-methylmorpholine, and any combination thereof.

[0095] In one embodiment, the reaction of step (b) comprises reacting an amine protecting group X 1 For example, the reaction of step (b) can be carried out in the presence of both a reagent selected from fluorenylmethoxycarbonyl chloride, trifluoroacetic anhydride, 4-methoxybenzyl chloride, and any combination thereof, and a base selected from diisopropylethylamine, triethylamine, N-methylmorpholine, and any combination thereof.

[0096] The solvent used in the reaction of step (b) is not limited to a specific type as long as it does not inhibit the reaction. For example, the solvent can be selected from acetonitrile, toluene, tetrahydrofuran, dichloromethane, chloroform, N,N-dimethylformamide, and any combination thereof.

[0097] The reaction of step (b1) can be carried out at a temperature of from about -20°C to reflux temperature or lower, in some embodiments from about -20°C to about 120°C, and in other embodiments from about -10°C to about 80°C.

[0098] The reaction of step (b2) for preparing the compound of formula 2, which is carried out after the reaction of step (b1), is carried out by reacting the azetidine nitrogen protecting group X2 from the compound of formula 7 and replace it with hydrogen. 2 is an amine protecting group X 1 The protecting group X may be any protecting group that can be removed without removing the nitrogen atom and that can be replaced with hydrogen. For example, the azetidine nitrogen protecting group X 2 can be selected from the group consisting of butoxycarbonyl (Boc), triphenylmethyl (Trt) and tetrahydropyranyl (THP). In one embodiment, the azetidine nitrogen protecting group X 2 is butoxycarbonyl (Boc).

[0099] The hydrogen substitution process in step (b2) can be carried out at a temperature between about -20°C and reflux temperature, and in some embodiments, between about 0°C and about 90°C.

[0100] For example, the process of substitution with hydrogen in the reaction of step (b2) can be carried out by reacting a compound of formula 7 with an acid to form an azetidine nitrogen protecting group X 2 from the compound of formula 7 and replace it with hydrogen. The acid is not limited to a specific type, and the azetidine nitrogen protecting group X 2 The acid may be any acid capable of effectively removing 1,2-dichlorophenyl ether and forming an acid addition salt of formula 2. For example, the acid may be a hydrohalic acid, such as hydrochloric acid, hydrobromic acid, or hydroiodic acid. In one embodiment, the acid may be anhydrous hydrochloric acid or concentrated hydrochloric acid.

[0101] The solvent used in the hydrogen substitution process in the reaction of step (b2) can be any solvent that does not inhibit the corresponding reaction. For example, the azetidine nitrogen protecting group X 2 When is butoxycarbonyl (Boc), the solvent may be selected from acetone, ethyl acetate, C1-C4 straight chain or branched alcohols, and any combination thereof.

[0102] In one embodiment, X 2When is butoxycarbonyl (Boc), the acid and solvent used in the reaction of step (b2) can be hydrochloric acid and acetone, or hydrochloric acid and ethyl acetate, or hydrochloric acid and isopropyl alcohol, or hydrochloric acid and ethanol, or hydrochloric acid and methanol, respectively.

[0103] The acid addition salt of formula 2 can be prepared by adding an acid to a solvent in the reaction of step (b2) to give X 2 can be prepared by removing from the compound of formula 7 and replacing with hydrogen, followed by evaporation without post-treatment process, or by precipitation with the addition of a suitable solvent. The suitable solvent added to precipitate the acid addition salt can be selected from, but not limited to, ethyl acetate, acetone, n-hexane, isopropyl alcohol, and any combination thereof. Any suitable solvent can be selected by those skilled in the art in consideration of the conditions required for the solvent in the corresponding reaction.

[0104] In one embodiment, the hydrochloride salt of one of the acid addition salts of the compound of formula 2 can be prepared by adding concentrated hydrochloric acid to the compound of formula 7 in methanol, reacting, concentrating the reaction product under reduced pressure, then adding ethyl acetate and refluxing, stirring at ambient temperature, then filtering and drying.

[0105] Compounds of formula 6 can be prepared by reductive amination of compounds of formula 5, step (b0).

[0106] [ka]

[0107] In Equation 5, X 2 is an azetidine nitrogen protecting group.

[0108] In the reaction of step (b0), the reductive amination reaction of the compound of formula 5 can be carried out by a person skilled in the art based on the common knowledge known in the art. In one embodiment, in the reaction of step (b0), the compound of formula 6 can be prepared in high yield by using trifluoroethanol as a solvent, sodium borohydride, and carrying out the reductive amination without a catalyst or additive (see Synthesis 2011, No.3, p.490-496).

[0109] In one embodiment, a method for preparing a compound of Formula 1, or a pharma- ceutically acceptable salt thereof, can be represented by Reaction Scheme 3 below.

[0110] [ka]

[0111] According to an exemplary preparation method of the present invention, for example as depicted in Reaction Scheme 3, 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one or a pharma- ceutically acceptable salt thereof can be prepared in higher purity and higher yield. In one embodiment, the yield can be about 3-10 times, preferably 5-8 times, higher than that obtained by known methods, for example as disclosed in U.S. Pat. No. 9,682,973. In another embodiment, the final product obtained by the method can have a purity as determined by HPLC area percentage of at least 90%, preferably at least 95%, more preferably at least 97%, and most preferably at least 99% (including 99.5% or 99.9%).

[0112] In the method for preparing the compound of formula 1 or a pharma- ceutically acceptable salt thereof, according to one aspect of the present invention, one or more intermediates (e.g., compounds of formula 2 or 4) produced according to the method are obtained in solid phase, and therefore the separation of the intermediates may be more convenient. In each process, the reaction for producing the intermediate is completed, and the production of related substances is reduced, and therefore, column chromatography, which was previously required for separation and purification, is not required. Due to the reduced production of related substances and the ease of separation of intermediates, the final product may be obtained in high yield. Furthermore, the method may be advantageously applied to mass production, since column chromatography, which is a process that is not suitable for mass (e.g., large-scale and commercial) production, can be avoided, and the quality reproducibility may be improved.

[0113] In another aspect, a compound of formula 2 is provided:

[0114] [ka]

[0115] In formula 2, X 1 is an amine protecting group and HA is an acid that forms an acid addition salt.

[0116] Amine Protecting Group X 1 can be selected from the group consisting of, but not limited to, fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa) and p-methoxybenzyl (PMB).

[0117] The HA can be any acid that forms an acid addition salt. For example, the HA can be a hydrohalic acid. The hydrohalic acid can be hydrochloric acid, hydrobromic acid, or hydroiodic acid, for example, hydrochloric acid.

[0118] The compound of formula 2 is a novel intermediate compound in solid phase, which, as mentioned above, has not been used in the existing method for preparing the compound of formula 1 or a pharma- ceutically acceptable salt thereof. By using the compound of formula 2 as an intermediate, all products of the subsequent steps, including the intermediate, can be obtained in solid phase. Then, a method for preparing the compound of formula 1 or a pharma- ceutically acceptable salt thereof in high yield and high purity with minimal purification steps may be obtained. Thus, the compound of formula 1 or a pharma- ceutically acceptable salt thereof can be produced in large quantities (e.g., large scale and commercial) in high yield and high purity.

[0119] In one embodiment, the compound of formula 2 can be selected from the group consisting of the following compounds:

[0120] (9H-fluoren-9-yl)methyl(azetidin-3-ylmethyl)(cyclopropyl)carbamate hydrochloride of formula 2a,

[0121] [ka]

[0122] N-(azetidin-3-ylmethyl)-N'-cyclopropyl-2,2,2-trifluoroacetamide hydrochloride of formula 2b,

[0123] [ka]

[0124] N-(azetidin-3-ylmethyl)-N'-(4-methoxybenzyl)cyclopropanamine hydrochloride of formula 2c.

[0125] [ka]

[0126] In another aspect, there is provided a compound of formula 4:

[0127] [ka]

[0128] In the formula, X 1 is an amine protecting group.

[0129] Amine Protecting Group X 1 can be selected from the group consisting of, but not limited to, fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa) and p-methoxybenzyl (PMB).

[0130] The compound of formula 4 is a novel intermediate compound in solid phase, which, as mentioned above, has not been used in the existing method for preparing the compound of formula 1 or a pharma- ceutically acceptable salt thereof. Using the compound of formula 4 as an intermediate, the compound of formula 1 may be obtained in solid phase. Then, the purification step can be minimized, resulting in a method for preparing the compound of formula 1 or a pharma- ceutically acceptable salt thereof with high yield and high purity. Therefore, the compound of formula 1 or a pharma- ceutically acceptable salt thereof can be produced in large quantities (e.g., large scale and commercial) with high yield and high purity.

[0131] In one embodiment, the compound of formula 4 can be selected from the group consisting of the following compounds:

[0132] (9H-fluoren-9-yl)methylcyclopropyl([1-(2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoyl)azetidin-3-yl]methyl)carbamate of formula 4a,

[0133] [ka]

[0134] N-cyclopropyl-2,2,2-trifluoro-N'-([1-(2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoyl)azetidin-3-yl]methyl)acetamide of formula 4b,

[0135] [ka]

[0136] 4-(3-[3-([cyclopropyl(4-methoxybenzyl)amino]methyl)azetidine-1-carbonyl]-4-fluorobenzyl)phthalazin-1(2H)-one of formula 4c.

[0137] [ka]

[0138] In another aspect, a compound of formula 7 is provided:

[0139] [ka]

[0140] In the formula, X 1 is an amine protecting group, X 2 is an azetidine nitrogen protecting group.

[0141] Amine Protecting Group X 1 can be selected from the group consisting of, but not limited to, fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa) and p-methoxybenzyl (PMB).

[0142] Azetidine Nitrogen Protecting Group X 2 can be selected from the group consisting of butoxycarbonyl (Boc), triphenylmethyl (Trt) and tetrahydropyranyl (THP). In one embodiment, the azetidine nitrogen protecting group X 2can be butoxycarbonyl (Boc).

[0143] The compound of formula 7 is a novel intermediate compound, which, as discussed above, has not been used by existing methods in the preparation of the compound of formula 1 or a pharma- ceutically acceptable salt thereof.

[0144] In one embodiment, the compound of formula 7 can be selected from the group consisting of the following compounds:

[0145] tert-Butyl 3-([([(9H-fluoren-9-yl)methoxy]carbonyl)(cyclopropyl)amino]methyl)azetidine-1-carboxylate of formula 7a,

[0146] [ka]

[0147] tert-Butyl 3-[(cyclopropyl-2,2,2-trifluoroacetamido)methyl]azetidine-1-carboxylate of formula 7b,

[0148] [ka]

[0149] tert-Butyl 3-([cyclopropyl(4-methoxybenzyl)amino]methyl)azetidine-1-carboxylate of formula 7c.

[0150] [ka]

[0151] In another aspect of the present invention, the method of the present invention is used to prepare a drug substance, pharmaceutical composition, or drug product comprising a compound of formula 1 or a pharma- ceutically acceptable salt thereof. When a compound of formula 1 or a pharma- ceutically acceptable salt thereof is used as a drug substance, the intermediate compounds described herein may be present as impurities. The amount of each of the compounds of formulas 2-7, when present as an impurity, can be controlled to be present at trace levels, for example, about 1.0% or less, about 0.5% or less, about 0.2% or less, about 0.1% or less of the drug substance, or to be completely absent.

[0152] Thus, in one aspect, a substantially pure form of the compound of formula 1 prepared by the method of the present invention is provided for use as a drug substance in the preparation of a pharmaceutical composition or drug product. In one embodiment, the present invention encompasses a pharmaceutical composition comprising a substantially pure drug substance, wherein the compound of formula 1 or a pharma- ceutically acceptable salt thereof is present in the drug substance in an amount greater than about 90%, about 95%, about 97%, about 99%, about 99.5% or about 99.9%. The purity percentage can be determined using methods well known in the art. For example, the purity percentage can be determined by referring to the percentage of the measured peak area from the sum of the peak areas of all peaks under suitable chromatographic (e.g., HPLC) detection conditions.

[0153] In one aspect, the present invention therefore provides a pharmaceutical composition comprising an effective amount of a compound of formula 1 or a pharma- ceutically acceptable salt thereof as an active ingredient, said compound being prepared from the process of the present invention (e.g., one or more intermediates described herein, and Reaction Scheme 1 and Reaction Scheme 2). The pharmaceutical composition of the present invention can be administered to a patient to treat cancer, including cancers sensitive to PARP inhibitors. Such formulations can include binders, fillers, disintegrants, lubricants, colorants and preservatives, as well as other pharma- ceutically acceptable excipients.

[0154] In another non-limiting embodiment, the present invention provides a product comprising a compound of formula 1 or a pharma- ceutically acceptable salt thereof.

[0155] [ka]

[0156] The compound of formula 1 or a pharma- ceutically acceptable salt thereof can be prepared by the above-described method of the present invention, for example, as shown in Reaction Scheme 2 and Reaction Scheme 3.

[0157] The present invention will now be described in more detail with reference to the following examples, but these examples are merely illustrative and the present invention is not limited to these examples. EXAMPLES

[0158] Preparation of tert-butyl 3-[(cyclopropylamino)methyl]azetidine-1-carboxylate (Formula 6a)

[0159] [ka]

[0160] 1.0 kg of tert-butyl 3-formylazetidine-1-carboxylate was added to the reactor, and 6.5 kg of trifluoroethanol was added thereto. 0.3 kg of cyclopropylamine was added at 0°C, and stirred at ambient temperature for 1 hour, and then the reactor was cooled to 0°C. 0.2 kg of sodium borohydride was gradually added thereto, and stirred at ambient temperature for 1 hour, and then the reactor was cooled to 0°C. After 10.0 kg of water was gradually added thereto, the reaction mixture was extracted with 6.7 kg of dichloromethane, and the aqueous layer thus obtained was further extracted with 6.7 kg of dichloromethane. The organic layer was washed with 15% aqueous sodium chloride solution, treated with 0.5 kg of anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure to obtain 0.98 kg of compound 6a as a yellow oil (yield 80.1%). Compound 6a was used in the subsequent process without a separate purification process. 1H NMR(CDCl3, 400MHz)δ 3.99(t, 2H), 3.60~3.57(m, 2H), 2.90(d, 2H), 2.66~2.62(m, 1H), 2.11~2.0 6(m, 1H), 1.59(br, 1H), 1.44(s, 9H), 0.46~0.42(m, 2H), 0.32~0.28(m, 2H) EXAMPLES

[0161] tert-Butyl 3-([([(9H-fluoren-9-yl)methoxy]carbonyl)(cyclopropyl)amino]methyl)azetidine-1-carboxylate (Formula 7a:X 1 Preparation of (Fmoc)

[0162] [ka]

[0163] 4.0 kg of dichloromethane was added to the reactor, 300.0 g of tert-butyl 3-[(cyclopropylamino)methyl]azetidine-1-carboxylate prepared in Example 1 and 188.4 g of diisopropylethylamine were added thereto in sequence, and then the reactor was cooled to 0°C. 377.2 g of 9-fluorenylmethoxycarbonyl chloride was gradually added to the reactor so that the internal temperature of the reactor did not exceed 20°C, and the reaction mixture was stirred for 1 hour. 5.0 kg of water was added thereto to wash the organic layer, and the organic layer was further washed with 5.0 kg of 1N aqueous hydrochloric acid. The organic layer was further washed with 15% aqueous sodium chloride solution, treated with 250.0 g of anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to quantitatively obtain 576.7 g of compound 7a as a yellow oil. Compound 7a was used in the subsequent process without a separate purification process. 1H NMR(CDCl3, 400MHz)δ 7.72(d, 2H), 7.56(d, 2H), 7.36(t, 2H), 7.30~7.26(m, 2H), 4.52(d, 2H), 4.17(t, 1H), 3.89~3.85( m, 2H), 3.56(m, 2H), 3.30(m, 2H), 2.60(m, 1H), 2.28(m, 1H), 1.43(s, 9H), 0.61(m, 2H), 0.45(m, 2H) EXAMPLES

[0164] tert-Butyl 3-[(cyclopropyl-2,2,2-trifluoroacetamido)methyl]azetidine-1-carboxylate (Formula 7b:X 1 Preparation of Tfa

[0165] [ka]

[0166] 2.7 kg of dichloromethane was added to a reactor, and 200.0 g of tert-butyl 3-[(cyclopropylamino)methyl]azetidine-1-carboxylate prepared in Example 1 was added thereto. 107.3 g of triethylamine was added thereto, and then the reactor was cooled to 0°C. 222.7 g of anhydrous trifluoroacetic acid was gradually added to the reactor so that the internal temperature of the reactor did not exceed 20°C, and the reaction mixture was stirred for 1 hour. 2.0 kg of water was added thereto to wash the organic layer, and the organic layer was further washed with 2.0 kg of 1N aqueous hydrochloric acid. The organic layer was further washed with 7% aqueous sodium chloride solution, treated with 100.0 g of anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to quantitatively obtain 284.8 g of compound 7b as a white solid and a yellow oil. Compound 7b was used in the subsequent process without a separate purification process. 1 H NMR (CDCl3, 400MHz)δ 3.99(t, 2H), 3.60~3.57(m, 2H), 2.90(d, 2H), 2.68~2.60(m, 1H), 2.10~2.06(m, 1H), 1.44(s, 9H), 0.46- 0.41(m, 2H), 0.32~0.28(m, 2H) EXAMPLES

[0167] tert-Butyl 3-([cyclopropyl(4-methoxybenzyl)amino]methyl)azetidine-1-carboxylate (Formula 7c:X 1 Preparation of PMB

[0168] [ka]

[0169] 1.4 kg of acetonitrile was added to a reactor, 226.3 g of tert-butyl 3-[(cyclopropylamino)methyl]azetidine-1-carboxylate prepared in Example 1 and 111.3 g of triethylamine were added thereto in sequence, and then the reactor was cooled to 0° C. 156.6 g of 4-methoxybenzyl chloride was gradually added thereto and stirred overnight at ambient temperature. The reaction mixture was concentrated under reduced pressure, 2.0 kg of water and 1.8 kg of ethyl acetate (EA) were added thereto, and the organic layer was separated. The organic layer was further washed with 2.0 kg of 0.5 N aqueous hydrochloric acid solution.

[0170] The organic layer was further washed with 7% aqueous sodium chloride solution, treated with 100.0 g of anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure to obtain 285.8 g of compound 7c as a yellow oil (yield 82.5%). Compound 7c was used in the subsequent process without a separate purification process. 1 H NMR (CDCl3, 400MHz)δ 7.17~7.13(m, 2H), 6.85- 6.82(m, 2H), 3.88(t, 2H), 3.80(s, 3H), 3.65(s, 2H), 3.47~3.43(m, 2H), 2.78~2.72(m, 1H), 2.66(d, 2H), 1.72~1.67(m, 1H), 1.41(s, 9H), 0.51~0.47(m, 2H), 0.37~0.34(m, 2H) EXAMPLES

[0171] (9H-fluoren-9-yl)methyl(azetidin-3-ylmethyl)(cyclopropyl)carbamate hydrochloride (Formula 2a:X 1 Preparation of HA (=Fmoc, HA=HCl)

[0172] [ka]

[0173] 1.0L of ethanol was added to a reactor, 100.0g of tert-butyl 3-([([(9H-fluoren-9-yl)methoxy]carbonyl)(cyclopropyl)amino]methyl)azetidine-1-carboxylate prepared in Example 2 and 24.8mL of concentrated hydrochloric acid were added thereto in sequence, and then the resulting mixture was heated. The reaction was allowed to proceed at reflux temperature for 30 minutes, and then the reaction mixture was concentrated under reduced pressure. 170mL of ethyl acetate and 430mL of n-hexane were added to the residue, stirred at ambient temperature overnight, filtered, and then dried at 40°C to obtain 78.2g of compound 2a (yield 91.2%). 1 H NMR(CDCl3, 400MHz)δ 9.63(br, 1H), 9.40(br, 1H), 7.75~7.70(m, 2H), 7.60~7.55(m, 2H), 7.38(t, 2H), 7.32~7.29(m, 2H), 4.52(d, 2H), 4 .18(t, 1H), 3.99(m, 2H), 3,81(m, 2H), 3,44~3.28(m, 2H), 2.94(m, 1H), 2,27(m, 1H), 0,60~0.59(m, 2H), 0,43(m, 2H) EXAMPLES

[0174] N-(azetidin-3-ylmethyl)-N'-cyclopropyl-2,2,2-trifluoroacetamide hydrochloride (Formula 2b:X 1 Preparation of HA (=Tfa, HA=HCl)

[0175] [ka]

[0176] 650 mL of methanol was added to a reactor, 64.5 g of tert-butyl 3-[(cyclopropyl-2,2,2-trifluoroacetamido)methyl]azetidine-1-carboxylate prepared in Example 3 and 22.0 mL of concentrated hydrochloric acid were added thereto in sequence, and then the resulting mixture was heated. The reaction was allowed to proceed at reflux temperature for 1 hour, and then the reaction mixture was concentrated under reduced pressure. 50 mL of isopropyl alcohol and 600 mL of ethyl acetate were added to the residue, stirred at ambient temperature overnight, filtered, and then dried at 40° C. to obtain 44.7 g of compound 2b (86.3% yield). 1 H NMR (DMSO-d6, 400MHz)δ 9.39(br, 2H), 3.98~3.93(m, 2H), 3.77~3.72(m, 2H), 3.67(d, 2H), 3.09~3.01(m, 1H), 2.96~2.90(m, 1H), 0.88~0.86(m, 4H) EXAMPLES

[0177] N-(azetidin-3-ylmethyl)-N'-(4-methoxybenzyl)cyclopropanamine hydrochloride (Formula 2c:X 1 Preparation of HA (=PMB, HA=HCl)

[0178] [ka]

[0179] 520 mL of isopropyl alcohol was added to a reactor, 52.0 g of tert-butyl 3-([cyclopropyl(4-methoxybenzyl)amino]methyl)azetidine-1-carboxylate prepared in Example 4 and 19.0 mL of concentrated hydrochloric acid were added thereto in sequence, and then the resulting mixture was heated. The reaction was allowed to proceed at reflux temperature for 6 hours, and then the reaction mixture was concentrated under reduced pressure. 85 mL of isopropyl alcohol and 210 mL of n-hexane were added to the residue, stirred at ambient temperature overnight, filtered, and then dried under reduced pressure to give 34.0 g of compound 2c (80.1% yield). 1H NMR(CDCl3, 400MHz)δ 9.29~9.18(m, 2H), 7.54(m, 2H), 6.89~6.88(m, 2H), 4.41(m, 3H), 4.24(m, 2H), 3.92(m, 2H), 3. 77(m, 3H), 3.68(m, 2H), 2.58(m, 1H), 1.40~1.36(m, 1H), 1.00(m, 1H), 0.91(m, 1H), 0.71(m, 1H) EXAMPLES

[0180] (9H-Fluoren-9-yl)methylcyclopropyl([1-(2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoyl)azetidin-3-yl]methyl)carbamate (Formula 4a:X 1 Preparation of (Fmoc)

[0181] [ka]

[0182] 300 mL of dichloromethane was added to the reactor, and 29.8 g of 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid and 17.9 g of 1,1'-carbonyldiimidazole were added thereto in sequence. The reaction was allowed to proceed at ambient temperature for 1 hour, and then the reactor was cooled to 15°C. Then, 42.3 g of (9H-fluoren-9-yl)methyl(azetidin-3-ylmethyl)(cyclopropyl)carbamate hydrochloride prepared in Example 5 was added thereto, and 19.4 g of diisopropylamine was added thereto gradually. The reaction mixture was stirred at ambient temperature for 1 hour, and 300 mL of water was added thereto to wash the organic layer, and then the organic layer was further washed with 1N aqueous hydrochloric acid and 1N aqueous sodium carbonate. The organic layer was further washed with 5% aqueous sodium chloride, treated with 10.0 g of anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. 70 mL of ethyl acetate and 350 mL of n-hexane were added to the residue, stirred at ambient temperature overnight, filtered, and then dried at 50° C. to give 63.2 g of compound 4a (yield 91.3%). 1H NMR (DMSO-d6, 400MHz) δ 12.60(s, 1H), 8.26~8.24(m, 1H), 7.97(d, 1H), 7.90~7.78(m, 4H), 7.65~7.62(m, 2H), 7.48~7.28(m, 7H), 4.51~4.48(m, 2H), 4.32(s, 2H), 4 .26~4.23(m, 1H), 3.97~3.86(m, 2H), 3.62~3.56(m, 2H), 3.30~3.25(m , 2H), 2.24(m, 1H), 1.24~1.23(m, 1H), 0.48(m, 2H), 0.38~0.35(m, 2H) EXAMPLES

[0183] N-Cyclopropyl-2,2,2-trifluoro-N'-([1-(2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoyl)azetidin-3-yl]methyl)acetamide (Formula 4b:X 1 Preparation of Tfa

[0184] [ka]

[0185] 300 mL of dichloromethane was added to the reactor, and 29.8 g of 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid was added thereto, followed by 17.9 g of 1,1'-carbonyldiimidazole. The reaction was allowed to proceed at ambient temperature for 1 hour, the reactor was cooled to 15°C, and then 28.5 g of N-(azetidin-3-ylmethyl)-N'-cyclopropyl-2,2,2-trifluoroacetamide hydrochloride prepared in Example 6 was added thereto, followed by 19.4 g of triethylamine, which were added thereto gradually. The reaction mixture was stirred at ambient temperature for 1 hour, followed by adding 300 mL of water to wash the organic layer, and then the organic layer was further washed with 1N aqueous hydrochloric acid and 1N aqueous sodium carbonate. The organic layer was washed with 5% aqueous sodium chloride, treated with 10.0 g of anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. 400 mL of methanol was added to the residue, stirred at 0° C. for 2 hours, filtered, and then dried at 50° C. to give 44.7 g of compound 4b (yield 89.1%). 1 H NMR (DMSO-d6, 400MHz)δ 12.62(s, 1H), 8.27~8.25(m, 1H), 7.97(d, 1H), 7.90~7.86(m, 1H), 7.83~7.79(m, 1H), 7.48~7.46(m, 2H), 7.24~7.19 (m, 1H), 4.33(s, 2H), 4.14~4.02(m, 2H), 3.79~3.62(m, 4H), 3.01~2.91(m, 1H), 2.88~2.85(m, 1H), 0.87~0.68(m, 4H) EXAMPLES

[0186] 4-(3-[3-([cyclopropyl(4-methoxybenzyl)amino]methyl)azetidine-1-carbonyl]-4-fluorobenzyl)phthalazin-1(2H)-one (Formula 4c:X 1 Preparation of PMB

[0187] [ka]

[0188] 300 mL of dichloromethane was added to the reactor, and 29.8 g of 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid and 17.9 g of 1,1'-carbonyldiimidazole were added thereto in sequence. The reaction was allowed to proceed at ambient temperature for 1 hour, and then the reactor was cooled to 15°C. Then, 31.1 g of N-(azetidin-3-ylmethyl)-N'-(4-methoxybenzyl)cyclopropanamine hydrochloride prepared in Example 7 was added thereto, and 19.4 g of triethylamine was slowly added thereto.

[0189] The reaction mixture was stirred at ambient temperature for 1 hour, 300 mL of water was added thereto to wash the organic layer, and then the organic layer was washed with 1N aqueous hydrochloric acid and 1N aqueous sodium carbonate. The organic layer was washed with 5% aqueous sodium chloride, treated with 10.0 g of anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. 300 mL of toluene was added to the residue, stirred overnight at ambient temperature, filtered, and then dried at 50° C. to obtain 47.0 g of compound 4c (yield 81.2%). 1 H NMR (DMSO-d6, 400MHz)δ 12.61(s, 1H), 8.26(d, 1H), 7.98(d, 1H), 7.92~7.87(m, 1H), 7.84~7.80(m, 1H), 7.52~7 .48(m, 2H), 7.43~7.42(m, 1H), 7.26~7.12(m, 2H), 6.97(d, 2H), 4.32(m, 2H), 4.26(m, 2H) ), 4.18~4.09(m, 2H), 3.90~3.82(m, 2H), 3.77(s, 3H), 3.36(m, 1H), 3.32(m, 2H), 2.55~2 .50(m, 1H), 1.19~1.13(m, 1H), 0.86~0.85(m, 1H), 0.80~0.75(m, 1H), 0.69~0.68(m, 1H) EXAMPLES

[0190] Preparation of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one (Formula 1) (1)

[0191] [ka]

[0192] 150 mL of acetonitrile was added to a reactor, and 30.0 g of (9H-fluoren-9-yl)methylcyclopropyl([1-(2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoyl)azetidin-3-yl]methyl)carbamate prepared in Example 8 and 34.5 g of piperidine were added thereto in sequence, and stirred at ambient temperature for 1 hour. After concentrating the reaction mixture under reduced pressure, 300 mL of 2N aqueous hydrochloric acid was added to the residue, stirred for 1 hour, and then filtered through diatomaceous earth. The filtrate was then adjusted to pH 9 or higher with 1N sodium hydroxide solution, and extracted by adding 300 mL of dichloromethane.

[0193] The aqueous layer was further extracted with 300mL of dichloromethane, then the organic layer was mixed with it, washed with 5% aqueous sodium chloride solution, and then concentrated. 80mL of methanol and 40mL of dichloromethane were added to the residue, and then 150mL of acetone was slowly added to it. The resulting solid was stirred at ambient temperature overnight, filtered, and dried at 40°C to obtain 17.5g of compound 1 (yield: 90.1%). 1 H NMR (DMSO-d6, 400MHz)δ 12.62(s, 1H), 8.27~8.25(m, 1H), 7.97(d, 1H), 7.90~7.86(m, 1H), 7.84~7.79(m, 1H), 7.46~7.43(m, 2H), 7.22~7. 18(m, 1H), 4.32(s, 2H), 4.04~3.56(m, 4H), 2.73~2.63(m, 3H), 2.30(br, 1H), 2.00~1.95(m, 1H), 0.33~0.12(m, 4H) EXAMPLES

[0194] Preparation of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one (Formula 1)(2)

[0195] [ka]

[0196] 300mL of methanol was added to the reactor, 30.0g of N-cyclopropyl-2,2,2-trifluoro-N'-([1-(2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoyl)azetidin-3-yl]methyl)acetamide prepared in Example 9 was added, and then the reactor was cooled to 0°C. 60mL of 20% aqueous potassium carbonate was added slowly to the reactor so that the internal temperature of the reactor did not exceed 20°C, and the reaction mixture was stirred at ambient temperature overnight. 240mL of water and 300mL of 300mL of dichloromethane were added thereto to extract the aqueous layer, and then the aqueous layer was further extracted with 300mL of dichloromethane. The organic layer was then mixed with it, washed with 5% aqueous sodium chloride solution, and then concentrated. 100mL of methanol and 50mL of dichloromethane were added to the residue, and then 200mL of acetone was added thereto slowly. The resulting solid was stirred at ambient temperature overnight, filtered and dried at 40° C. to give 22.4 g of compound 1 (92.1% yield). 1 H NMR (DMSO-d6, 400MHz)δ 12.59(s, 1H), 8.27~8.25(m, 1H), 7.97(d, 1H), 7,91~7,87(m, 1H), 7.84~7.80(m, 1H), 7.46~7,42(m, 2H), 7,22~7, 18(m, 1H), 4,32(s, 2H), 4.04~3.55(m, 4H), 2.74~2.63(m, 3H), 2.30(br, 1H), 2.02~1.97(m, 1H), 0.34~0.14(m, 4H) EXAMPLES

[0197] Preparation of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one (Formula 1)(3)

[0198] [ka]

[0199] 100mL of trifluoroacetic acid was added to the reactor, and 10.0g of 4-(3-[3-([cyclopropyl(4-methoxybenzyl)amino]methyl)azetidine-1-carbonyl]-4-fluorobenzyl)phthalazin-1(2H)-one prepared in Example 10 was added thereto, and stirred at 60°C for 1 hour. Then, the reactor was cooled to 0°C, and 100mL of dichloromethane was added thereto, and then 100mL of water was gradually added thereto. The aqueous layer was further washed with 100mL of dichloromethane, adjusted to pH 9 or higher with 1N aqueous sodium hydroxide solution, and then extracted with 100mL of dichloromethane. The aqueous layer was further extracted with 100mL of dichloromethane, and the organic layer was mixed with it, washed with 5% aqueous sodium chloride solution, and then concentrated. 60mL of methanol and 30mL of dichloromethane were added to the residue, and 120mL of acetone was gradually added thereto. The resulting solid was stirred at ambient temperature overnight, filtered and dried at 40° C. to give 13.4 g of compound 1 (86.9% yield). 1 H NMR (DMSO-d6, 400MHz)δ 12.59(s, 1H), 8.27~8.25(m, 1H), 7.98(d, 1H), 7.91~7.87(m, 1H), 7.85~7.80(m, 1H), 7.46~7.42(m, 2H), 7.23~7. 18(m, 1H), 4.32(s, 2H), 4.04~3.55(m, 4H), 2.74~2.63(m, 3H), 2.30(br, 1H), 2.02~1.97(m, 1H), 0,34~0.14(m, 4H) EXAMPLES

[0200] Preparation of the hydrochloride salt of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one (formula 1a)(1)

[0201] [ka]

[0202] 40mL of methanol and 100mL of acetone were added to a reactor, and 10.0g of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one prepared in Example 11 was added thereto, and then the reactor was cooled to 0°C. 2.4g of concentrated hydrochloric acid was added thereto gradually over 30 minutes, stirred overnight at ambient temperature, filtered, and dried at 40°C to obtain 10.4g of compound 1a (yield 95.7% and HPLC purity 99.86% (area%)). 1 H NMR (DMSO-d6, 400MHz) δ 12.61(s, 1H), 9.37(br, 2H), 8.27~8.25(m, 1H), 7.98(d 1H), 7.93~7.88(m, 1H), 7.85~7.81(m, 1H), 7.49~7.45(m, 2H), 7.25~7.20(m, 1H), 4.33(s, 2H), 4.13~3.82(m, 4H), 3.31~3.22(m, 2H), 3.07~3.00(m, 1H), 2.65~2.60(m, 1H), 0.91~0.67(m, 4H) EXAMPLES

[0203] Preparation of the hydrochloride salt of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one (formula 1a)(2)

[0204] [ka]

[0205] 40mL of ethanol and 60mL of ethyl acetate were added to a reactor, and 10.0g of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one prepared in Example 12 was added thereto, and then the reactor was cooled to 0°C. 2.4g of concentrated hydrochloric acid was added thereto gradually over 30 minutes, stirred overnight at ambient temperature, filtered, and dried at 40°C to obtain 10.4g of compound 1a (yield 92.1% and HPLC purity 99.86% (area%)). 1 H NMR (DMSO-d6, 400MHz)δ 12,60(s, 1H), 9.19(br, 2H), 8.27~8.25(m, 1H), 7.98(d, 1H), 7.93~7.89(m, 1H), 7.85~7.81(m, 1H), 7.50~7.44(m, 2H), 7.2 5~7.20(m, 1H), 4.33(s, 2H), 4.13~3.81(m, 4H), 3.30~3.22(m, 2H), 3.05~2.98(m, 1H), 2.65~2.61(m, 1H), 0.88~0.68(m, 4H) EXAMPLES

[0206] Preparation of the hydrochloride salt of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one (formula 1a)(3)

[0207] [ka]

[0208] 50mL of ethanol and 100mL of tert-butyl methyl ether were added to a reactor, and 10.0g of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one prepared in Example 13 was added thereto, and then the reactor was cooled to 0°C. 2.4g of concentrated hydrochloric acid was added thereto gradually over 30 minutes, stirred overnight at ambient temperature, filtered, and dried at 40°C to obtain 10.6g of compound 1a (yield 97.2% and HPLC purity 99.80% (area%)). 1H NMR (DMSO-d6, 400MHz)δ 12.60(s, 1H), 9.23(br, 2H), 8.27~8.25(m, 1H), 7.98(d, 1H), 7.93~7.89(m, 1H), 7.85~7.81(m, 1H), 7.50~7.44(m, 2H), 7.2 5~7.20(m, 1H), 4.33(s, 2H), 4.13~3.81(m, 4H), 3.28~3.22(m, 2H), 3.08~2.97(m, 1H), 2.66~2.62(m, 1H), 0.89~0.68(m, 4H)

[0209] The described embodiments are to be considered in all respects only as illustrative and not restrictive. Those skilled in the art will recognize that the invention can be embodied in other specific forms without departing from its spirit or essential characteristics. The scope of the invention is therefore indicated by the appended claims rather than by the foregoing description. All changes that come within the meaning and range of equivalency of the claims are embraced within their scope.

Claims

1. A process for preparing a compound of formula 1 or a pharma- ceutically acceptable salt thereof, comprising: 【Chemistry 1】 preparing a compound of formula 4; and deprotecting said compound of formula 4; 【Chemistry 2】 In the formula, X １ is an amine protecting group selected from the group consisting of fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa) and p-methoxybenzyl (PMB), and said compound of formula 4 is prepared by reacting a compound of formula 2 with a compound of formula 3, 【Chemistry 3】 In the formula, X １ is an amine protecting group selected from the group consisting of fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa) and p-methoxybenzyl (PMB), HA is an acid that forms an acid addition salt; 【Chemistry 4】 Preparing the compound of formula 4 is carried out in the presence of at least one amide coupling reagent and at least one base; the at least one amide coupling reagent is selected from the group consisting of 1,1'-carbonyldiimidazole, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC), and any combination thereof, and the at least one base is triethylamine; method.

2. 2. The method of claim 1, wherein the HA is hydrochloric acid (HCl), hydrobromic acid (HBr) or hydroiodic acid (HI).

3. X １ 3. The method of claim 1 or 2, wherein is an amine protecting group selected from the group consisting of fluorenylmethoxycarbonyl (Fmoc), and p-methoxybenzyl (PMB).

4. reacting the compound of formula 4 with a non-nucleophilic base, １ The method of any one of claims 1 to 3, wherein is fluorenylmethoxycarbonyl (Fmoc).

5. reacting the compound of formula 4 with an alkali base, １ The method according to any one of claims 1 to 3, wherein is trifluoroacetyl (Tfa).

6. reacting the compound of formula 4 with an acid, １ The method according to any one of claims 1 to 3, wherein is p-methoxybenzyl (PMB).

7. 7. The method of any one of claims 1 to 6, further comprising reacting the compound of formula 1 with an acid to prepare a pharma- ceutically acceptable acid addition salt of the compound of formula 1.

8. 2. The method of claim 1 , The compound of formula 2 is 【Chemistry 5】 Amine Protecting Group X １ into a compound of formula 6 to prepare a compound of formula 7; and Azetidine Nitrogen Protecting Group X ２ from the compound of formula 7 to prepare 【Chemistry 6】 【Chemistry 7】 In the formula, X １ is an amine protecting group selected from the group consisting of fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa) and p-methoxybenzyl (PMB); X ２ is an azetidine nitrogen protecting group selected from the group consisting of butoxycarbonyl (Boc), triphenylmethyl (Trt) and tetrahydropyranyl (THP); HA is an acid that forms an acid addition salt; method.

9. 9. The method of claim 8, Amine Protecting Group X １ to a compound of formula 6 to prepare a compound of formula 7, 【Chemistry 8】 【Chemistry 9】 In the formula, X １ is an amine protecting group selected from the group consisting of fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa) and p-methoxybenzyl (PMB); X ２ is an azetidine nitrogen protecting group selected from the group consisting of butoxycarbonyl (Boc), triphenylmethyl (Trt) and tetrahydropyranyl (THP); method.

10. 9. The method of claim 8, wherein the HA is hydrochloric acid (HCl), hydrobromic acid (HBr) or hydroiodic acid (HI).

11. 2. The method of claim 1, wherein the compound of formula 2 is the following compound: (9H-fluoren-9-yl)methyl(azetidin-3-ylmethyl)(cyclopropyl)carbamate hydrochloride of formula 2a, 【Chemistry 10】 N-(azetidin-3-ylmethyl)-N'-cyclopropyl-2,2,2- of formula 2b Trifluoroacetamide hydrochloride, 【Chemistry 11】 and N-(azetidin-3-ylmethyl)-N'-(4-methoxybenzyl)cyclopropanamine hydrochloride of formula 2c 【Chemistry 12】 The method of claim 1, wherein the

12. 2. The method of claim 1 , wherein the compound of formula 4 is the following compound: (9H-fluoren-9-yl)methylcyclopropyl([1-(2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoyl)azetidin-3-yl]methyl)carbamate of formula 4a, 【Chemistry 13】 N-cyclopropyl-2,2,2-trifluoro-N'-([1-(2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoyl)azetidin-3-yl]methyl)acetamide of formula 4b, 【Chemistry 14】 and 4-(3-[3-([cyclopropyl(4-methoxybenzyl)amino]methyl)azetidine-1-carbonyl]-4-fluorobenzyl)phthalazin-1(2H)-one of formula 4c 【Chemistry 15】 The method of claim 1, wherein the

13. 9. The method of claim 8, wherein the compound of formula 7 is the following compound: tert-Butyl 3-([([(9H-fluoren-9-yl)methoxy]carbonyl)(cyclopropyl)amino]methyl)azetidine-1-carboxylate of formula 7a, 【Chemistry 16】 tert-Butyl 3-[(cyclopropyl-2,2,2-trifluoroacetamido)methyl]azetidine-1-carboxylate of formula 7b, 【Chemistry 17】 and tert-butyl 3-([cyclopropyl(4-methoxybenzyl)amino]methyl)azetidine-1-carboxylate of formula 7c 【Chemistry 18】 The method of claim 1, wherein the

Images