Process for the selective production of a single axially asymmetric compound

Abstract

The present invention, in one of its embodiments, relates to a method for producing a compound of formula (I) or a salt thereof as defined in the specification. The production method includes a step of reacting a compound of formula (IIA) or a salt thereof with a compound of formula (IIIA) or a salt thereof, or reacting a compound of formula (IIB) or a salt thereof with a compound of formula (IIIB) or a salt thereof to obtain a compound of formula (I) or a salt thereof. In the compound of formula (I), R 4 is formula (VI) or (VII), and R 5 is preferably formula (VIII) or (IX) (each of the above formulas and R 4 , R 5 are all defined in the specification).

Description

Technical Field

[0001] The present invention relates to a method for selectively producing one of the axially asymmetric compounds in a compound having axial asymmetry, and more particularly to a method for selectively producing one of the axially asymmetric compounds or salts thereof of the compound of formula (I) having axial asymmetry or salts thereof. The present invention also relates to a method for efficiently producing a compound for use in a method for selectively producing an axially asymmetric compound, and an axially asymmetric compound obtained by the method for selectively producing an axially asymmetric compound.

Background Art

[0002] Patent Document 1 (International Publication No. 2022 / 173032) describes a compound represented by the following formula (A) or a salt thereof, and a method for producing the same, as a quinazoline compound for inducing the degradation of G12D mutant KRAS protein.

Chemical Formula

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Summary of the Invention

[0004] As described above, although Patent Document 1 describes a method for producing the compound represented by the above formula (A), since a compound having an asymmetric axis is obtained in the production process, production intermediates and target compounds can be synthesized as a mixture of stereoisomers based on this. For example, in Production Example 11 of Patent Document 1, (1S,4S)-5-{8-(benzyloxy)-7-bromo-6-cyclopropyl-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl (3.15 g) and 6-fluoro-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (1.92 g) were reacted to obtain (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl (1.42 g) as the M form and (1S,4S)-5-{8-(benzyloxy)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl (1.37 g) as the P form, and it is described that the M:P ratio in Production Example 11 was about 1:1. Even if synthesized as a mixture of stereoisomers, each stereoisomer can be isolated by performing a normal fractionation operation, for example, fractionation using ODS column chromatography or silica gel column chromatography. However, from the viewpoint of improving the yield of the target compound and reducing the fractionation step, it is more desirable to establish a method for selectively obtaining one axially chiral compound. In addition, if a single axially chiral compound represented by the formula (IIA) can be obtained, the compound of the formula (A) can be efficiently produced. Furthermore, from the perspective of cost reduction, it is desirable to establish a novel synthesis method of the compound represented by the formula (IIA) for use in the selective production method of the axisymmetric compound.

[0005] An object of the present invention is to develop a production method for selectively obtaining one of the axisymmetric compounds or a salt thereof in the synthesis of the compound represented by the above formula (A).

[0006] As a result of intensive studies, the present inventors have found a method for selectively obtaining one of the axisymmetric compounds or a salt thereof by controlling the axisymmetry using a chiral auxiliary group. In addition, in the process of developing the above method, the present inventors have also found a method for efficiently producing a compound for use in the selective production method of the axisymmetric compound, and an axisymmetric compound obtained by the selective production method of the axisymmetric compound.

[0007] In addition, the present inventors have also found a method for producing the compound represented by the following formula (#1) or a salt thereof by reacting the compound of the following formula (#2) with a diazo transfer reagent.

[0008] Although not limited thereto, the present invention includes the following aspects. [1] The compound of the following formula (I) or a salt thereof:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[10] The compound of formula (IIA) or a salt thereof is the following formula (IIA-2): [Chemical formula] is a compound represented by A compound of formula (IIIA) or a salt thereof is represented by the following formula (IIIA-1): [Chemical formula] is a compound represented by The following steps: [Chemical formula] including the step of obtaining a compound represented by formula (I-1) by [[3]].

[11] The following steps: [Chemical formula] including obtaining compound (1) or a salt thereof by [

[10] ].

[12] The following steps: [Chemical formula] including obtaining a compound of formula (IIA-2) by [

[10] ] or [

[11] ].

[13] A compound represented by any of the following or a salt thereof. [Chemical formula] [Chemical formula] [Chemical formula]

[14] including reacting a compound of formula (IIB) or a salt thereof with a compound of formula (IIIB) or a salt thereof, wherein X is Cl or Br, Y is -O- or -S-, R1 is a group selected from the group consisting of the following formulas (IV-1), (IV-2), (IV-3) and (V):

Chemical formula

Chemical formula

Chemical formula

[15] comprising reacting a compound of formula (IIB) or a salt thereof with a compound of formula (IIIB) or a salt thereof, wherein A is N, R 1 is a group selected from the group consisting of the following formulas (IV-1), (IV-2) and (V):

Chemical formula

Chemical formula

[14] , wherein the group is represented by:

[16] The compound of formula (IIB) or a salt thereof is represented by the following formula (IIB-1): [Chemical formula] and is a compound represented by: The compound of formula (IIIB) or a salt thereof is represented by the following formula (IIIB-1): [Chemical formula] and is a compound represented by: The following step: [Chemical formula] The method according to

[15] , comprising the step of obtaining a compound represented by formula (I-1) by:

[17] The method according to any one of [1] to [4] and

[14] to

[16] , produced in the presence of a palladium catalyst or a palladium catalyst precursor and a ligand.

[18] The method according to

[17] , produced in the presence of a base.

[19] The method according to

[18] , produced at 20 °C to 140 °C in a solvent inert to the reaction.

[20] The method according to [1], comprising reacting a compound of formula (IIA) or a salt thereof with a compound of formula (IIIA) or a salt thereof, R 5 is a group selected from the group consisting of the following formulas (VIII-1) and (IX-1): [Chemical formula] The above method, which is a group selected from the group consisting of.

[21] R 4 is a group selected from the group consisting of the following formulas (VI-1), (VI-2) and (VI-3): [Chemical formula] The method according to

[20] , which is a group selected from the group consisting of.

[22] R 3 is C 3-6 cycloalkyl, vinyl, or optionally substituted C 1-3 alkyl, and preferably, R 3 is C 3-6 cycloalkyl, the method according to

[20] or

[21] .

[23] X is Cl, Br, or I, and preferably, X is Cl or Br, the method according to any one of

[20] to

[22] .

[24] A is N, the method according to any one of

[20] to

[23] .

[25] R 1 is the following formula (V):

Chemical formula

[20] to

[24] .

[26] Y is a bond, and R 2 is optionally substituted heterocycloalkyl, and the heterocycloalkyl is a 4- to 7-membered saturated heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen, the method according to any one of

[20] to

[25] .

[27] R 2 is a group selected from the group consisting of the following formulas (X-1), (X-2), (X-3), (X-4), (X-5), (X-6), and (X-7):

Chemical formula

[26] , which is a protecting group for NH.

[28] R 2 is the following formula (X-1):

Chemical formula

Chemical formula

Chemical formula

[20] to

[27] .

[29] A compound of the following formula (#1) or a salt thereof:

Chemical formula

Chemical formula

[30] The method described in

[29] , excluding the method using 2-azido-1,3-dimethylimidazolium hexafluorophosphate as the diazo transfer reagent.

[31] R 11 is ethyl, isopropyl, tert-butyl, or C 3-6 cycloalkyl, R 12A and R 12B are the same or different from each other and are optionally substituted C 1-3 alkyl selected from the group consisting of H or F, OH and N(CH3)2, or R12A and R 12B together with the carbon to which they are attached form a cyclopropyl, R 13 is a group selected from the group consisting of H, halogen or the following,

Chemical formula

[29] or

[30] .

[32] R 11 is isopropyl, R 12A is H, R 12B is C optionally substituted with OH 1-3 alkyl, R 13 is the following group,

Chemical formula

[29] to

[31] .

[33] The method according to any one of

[29] to

[32] , wherein the diazo transfer reagent is perfluoroalkylsulfonyl azide.

[34] The method according to any one of

[29] to

[32] , wherein the diazo transfer reagent is nonafluorobutanesulfonyl azide.

[35] The method according to any one of

[29] to

[34] , using a base reagent.

[36] The method according to any one of

[29] to

[35] , using an additive.

[37] A method according to any one of

[29] to

[36] , using a polar solvent.

[38] A method according to any one of

[29] to

[37] , carried out at a reaction temperature of 10°C to 25°C.

[39] A method according to any one of [1] to

[28] , including as a step a method according to any one of

[29] to

[38] .

[40] The following compound or a salt thereof. [Chemical formula]

[41] The following compound or a salt thereof. [Chemical formula] [Advantages of the Invention]

[0009] According to one embodiment of the present invention, by introducing a chiral auxiliary group in the manufacturing process and controlling the axis of chirality using the chiral auxiliary group, one of the axis-asymmetric compounds or a salt thereof can be selectively obtained. Further, according to the present invention, it is also possible to efficiently produce a compound for use in a method for selectively producing an axis-asymmetric compound, and to obtain an axis-asymmetric compound by the method for selectively producing an axis-asymmetric compound.

[0010] Also, according to one embodiment of the present invention, by reacting the compound of the aforementioned formula (#2) with a diazo transfer reagent, the compound of the aforementioned formula (#1) or a salt thereof can be efficiently obtained. Detailed Description of the Invention

[0011] Hereinafter, the present invention will be described in detail.

[0012] 1. Definition As described above, in one aspect, the present invention relates to a method for selectively obtaining one axially asymmetric compound or a salt thereof. As used herein, the expression "selectively obtaining one axially asymmetric compound or a salt thereof" means that the ratio of the M-form to the P-form (M:P ratio) is not 1:1, and one axially asymmetric compound or a salt thereof is obtained at a higher ratio than the other axially asymmetric compound or a salt thereof. In one aspect, in the method of the present invention, the M-form is obtained at a higher ratio than the P-form, and the ratio (M:P ratio) is not particularly limited, but for example, it is 1.3:1 or more, 1.4:1 or more, 1.5:1 or more, 1.6:1 or more, 2:1 or more, 3:1 or more, 4:1 or more, 5:1 or more, 6:1 or more, 7:1 or more, 8:1 or more, 10:1 or more, 20:1 or more, 40:1 or more, 60:1 or more, 80:1 or more, 90:1 or more. When the M-form is obtained at a higher ratio than the P-form, the description of "1.3:1 or more" means that 1.3 units or more of the M-form are obtained with respect to 1 unit (gram amount or molar amount) of the P-form. For example, it means that 1.3 g or more of the M-form are obtained with respect to 1 g of the P-form. In the present invention, since the molecular weights of the M-form and the P-form are the same, the M:P ratio as a gram ratio coincides with the M:P ratio as a molar ratio. Also, in one aspect, in the method of the present invention, the P-form is obtained at a higher ratio than the M-form, and the ratio (M:P ratio) is not particularly limited, but for example, it is 1:1.3 or more, 1:1.4 or more, 1:1.5 or more, 1:1.6 or more, 1:2 or more, 1:5 or more. When the P-form is obtained at a higher ratio than the M-form, as described above, the description of "1:1.3 or more" means that 1.3 units or more of the P-form are obtained with respect to 1 unit of the M-form. In the method for producing an axially asymmetric compound without using a chiral auxiliary group, the target compound is obtained as a mixture of stereoisomers with an M:P ratio of about 1:1. Compared with such a method, the method of the present invention is advantageous in that it can enhance the stereoselectivity in obtaining the desired axially asymmetric compound.

[0013] In another aspect, the present invention relates to a method for producing an axially chiral compound using a chiral auxiliary group, and an axially chiral compound having a chiral auxiliary group is obtained. The inventors have also found that an axially chiral compound having a chiral auxiliary group is easier to separate and fractionate than one having no chiral auxiliary group. That is, a mixture of axially chiral compounds (M-form and P-form) having a chiral auxiliary group obtained by the production method of the present invention can be purified to a high purity of one of the axially chiral compounds by a simple operation such as recrystallization. Also, one of the axially chiral compounds can be purified to a high purity by a fractionation operation such as ordinary column chromatography. That is, the production method of the present invention can achieve both an improvement in the yield of a target compound having a predetermined stereoisomer and a reduction in steps such as separation and fractionation, and thus can contribute to a reduction in production cost.

[0014] The analysis method of the obtained axially chiral compound or a salt thereof can be carried out using known methods such as HPLC and NMR. There is no substantial difference between the M:P ratio calculated by HPLC analysis and the M:P ratio calculated by NMR analysis. In the present specification, the HPLC analysis conditions are as follows, but are not limited to these analysis conditions as long as the target compound or a salt thereof can be separated and analyzed. The HPLC analysis conditions described in Tables 2 to 3 below correspond to any of the following.

[0015] <HPLC analysis condition 1> · Column: InfinityLab Poroshell 120 EC-C8, 2.1 x 100 mm, 2.7 μm (Agilent) · Mobile phase: (A) pH 2.5 aqueous HClO4 solution; (B) iPrOH · Elution method: B) 45% (0 min) → 45% (2 min) → 90% (22 min) → 90% (25 min) · Flow rate: 0.1 mL / min · Column temperature: 40 °C · Detection wavelength: 254 nm

[0016] <HPLC analysis condition 2> · Column: CORTECS C18+, 4.6 x 150 mm, 2.7 μm (Waters) · Mobile phase: (A) 0.03% TFA in Water / MeCN (95 / 5); (B) 0.03% TFA in Water / MeCN (5 / 95) · Elution method: B) 45% (0 min) → 70% (8 min) → 70% (20 min) → 95% (21 min) → 95% (23 min) · Flow rate: 1.0 mL / min · Column temperature: 40 °C · Detection wavelength: 210 nm

[0017] <HPLC analysis conditions 3> · Column: InfinityLab Poroshell 120 EC-C8, 2.1 x 100 mm, 2.7 μm (Agilent) · Mobile phase: (A) pH 2.5 aqueous HClO4-NaClO4 buffer solution; (B) MeOH · Elution method: B) 70% (0 min) → 99% (30 min) → 99% (33 min) · Flow rate: 0.15 mL / min · Column temperature: 40 °C · Detection wavelength: 254 nm

[0018] <HPLC analysis conditions 4> · Column: Ascentis Express C18, 2.1 x 100 mm, 2.7 μm (Supelco, Sigma-Aldrich) · Mobile phase: (A) pH 2.5 aqueous HClO4 solution; (B) MeOH · Elution method: B) 95% (0 min) → 99% (15 min) → 99% (20 min) · Flow rate: 0.2 mL / min · Column temperature: 40 °C · Detection wavelength: 254 nm

[0019] <HPLC Analysis Conditions 5> · Column: YMC-Pack C4, 4.6 × 150 mm, 3 μm (YMC Co., Ltd.) · Mobile Phase: (A) pH 7, 10 mM phosphate buffer / MeCN (95 / 5); (B) MeCN · Elution Method: B) 0% (0 min) → 79% (10 min) → 79% (25 min) · Flow Rate: 1.5 mL / min · Column Temperature: 40 °C · Detection Wavelength: 220 nm

[0020] <HPLC Analysis Conditions 6> · Column: ZORBAX RRHD Eclipse Plus C18, 2.1 x 50 mm, 1.8 μm (Agilent Technologies) · Mobile Phase: (A) 0.1% formic acid aqueous solution; (B) 0.1% formic acid MeCN solution · Elution Method: B) 2% (0 min) → 100% (10 min) · Flow Rate: 1.0 mL / min · Column Temperature: 40 °C · Detection Wavelength: 254 nm (Note) 1 - 2 mg of the compound was dissolved in MeOH, an appropriate amount of 4M hydrochloric acid / ethyl acetate was added, and after shaking several times to remove the protecting group, HPLC measurement was performed.

[0021] <HPLC Analysis Conditions 7> · Column: InfinityLab Poroshell 120 EC-C8, 2.1 x 100 mm, 2.7 μm (Agilent Technologies) · Mobile Phase: (A) pH 2.5 aqueous HClO4 solution; (B) iPrOH · Elution Method: B) 50% (0 min) → 65% (15 min) → 90% (23 min) → 90% (25 min) · Flow Rate: 0.1 mL / min · Column temperature: 40 °C · Detection wavelength: 254 nm

[0022] <HPLC analysis conditions 8> · Column: YMC-Pack C4, 4.6 mm × 150 mm, 3 μm (manufactured by YMC) · Mobile phase: (A) pH 7, 10 mM aqueous K2HPO4 buffer solution / MeCN (95 / 5); (B) MeCN · Elution method: B) 0% (0 min) → 79% (10 min) → 79% (45 min) · Flow rate: 1.5 mL / min · Column temperature: 40 °C · Detection wavelength: 220 nm

[0023] <HPLC analysis conditions 9> · Column: YMC-Pack Pro C4, 2.0 x 100 mm, 3 μm (manufactured by YMC) · Mobile phase: (A) pH 7, 10 mM aqueous K2HPO4 buffer solution / MeCN (95 / 5); (B) MeCN · Elution method: B) 74% (0 min) → 74% (60 min) · Flow rate: 0.4 mL / min · Column temperature: 40 °C · Detection wavelength: 220 nm

[0024] 「C 1-15 "C alkyl" refers to a linear or branched alkyl group having 1 to 15 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, dodecyl, tridecyl, tetradecyl, pentadecyl, etc. In one embodiment, it is n-propyl, and in another embodiment, it is ethyl (hereinafter, the carbon number will be expressed in the same manner). 「C 1-6"Alkyl" refers to a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc. In one embodiment, it is isopropyl. Similarly, "C 1-3 alkyl" refers to a linear or branched alkyl group having 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl. In one embodiment, it is n-propyl, ethyl or methyl; in one embodiment, it is n-propyl; in one embodiment, it is ethyl; in one embodiment, it is methyl.

[0025] "C 3-6 cycloalkyl" refers to a cycloalkyl group having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. In one embodiment, it is cyclopropyl.

[0026] "Heterocycloalkane" is a 4- to 7-membered saturated heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, and may contain partially unsaturated bonds. Further, the sulfur atom as a ring-constituting atom of the saturated heterocyclic ring may be oxidized. In one embodiment, the "heterocycloalkane" may contain 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, and may contain 1 to 2 nitrogen atoms. In one embodiment, the "heterocycloalkane" may be a 4- to 6-membered saturated heterocyclic ring or a 5- to 6-membered saturated heterocyclic ring. One embodiment of "heterocycloalkane" is a "4- to 6-membered heterocycloalkane containing 1 to 2 nitrogen atoms", and in one embodiment, it is oxetane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, oxazolidine, imidazolidine, piperazine, morpholine, thiomorpholine, dioxothiomorpholine. In one embodiment, it is pyrrolidine.

[0027] "Heterocycloalkyl" means a 4- to 7-membered saturated heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms, and may contain a partially unsaturated bond. In one aspect, the "heterocycloalkyl" may contain 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms, and may contain 1 to 2 nitrogen atoms. In one aspect, the "heterocycloalkyl" may be a 4- to 6-membered saturated heterocyclic group, or may be a 5- to 6-membered saturated heterocyclic group. Also, the sulfur atom as a ring-constituting atom of the saturated heterocyclic group may be oxidized. Certain embodiments of "heterocycloalkyl" include oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, oxazolidinyl, imidazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl. In certain embodiments, it is tetrahydropyranyl or piperazinyl. In certain embodiments, it is tetrahydropyranyl. In certain embodiments, it is piperazinyl.

[0028] "Bridged heterocycloalkane" means a 7- to 9-membered bridged heterocyclic ring containing 1 to 2 nitrogen atoms as ring-constituting atoms. Certain embodiments of "bridged heterocycloalkane" include "7- to 9-membered bridged heterocycloalkane containing 1 to 2 nitrogen atoms", such as diazabicyclo[2.2.2]octane, diazabicyclo[3.2.1]octane, diazabicyclo[3.1.1]heptane, diazabicyclo[2.2.1]heptane, diazabicyclo[3.3.1]nonane. In certain embodiments, it is diazabicyclo[2.2.1]heptane. In certain embodiments, it is 2,5-diazabicyclo[2.2.1]heptane.

[0029] "Halogen" means F, Cl, Br, and I. Certain embodiments of halogen include F, Cl, or Br. In certain embodiments, it is F or Cl. In certain embodiments, it is F or Br. In certain embodiments, it is F. In certain embodiments, it is Cl. In certain embodiments, it is Br.

[0030] The "OH protecting group" means a substituent that protects OH from a specific chemical reaction. Certain embodiments of the OH protecting group include a tert-butyl group, a benzyl group, a p-methoxybenzyl group, a methoxymethyl group, a trimethylsilyl group, a triethylsilyl group, a tert-butyldimethylsilyl group, an acetyl group, a benzoyl group, and a triphenylmethyl group. In certain embodiments, it is a tert-butyl group.

[0031] The "NH protecting group" means a substituent that protects NH from a specific chemical reaction. Certain embodiments of the NH protecting group include a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a 9-fluorenylmethyloxycarbonyl group, an allyloxycarbonyl group, a phthaloyl group, a 2-nitrobenzenesulfonyl group, a 2-(trimethylsilyl)ethoxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, a triphenylmethyl group, and a tetrahydropyranyl group. In certain embodiments, it is a tert-butoxycarbonyl group, a triphenylmethyl group, or a tetrahydropyranyl group. In certain embodiments, it is a tert-butoxycarbonyl group. In certain embodiments, it is a 2-(trimethylsilyl)ethoxycarbonyl group. In certain embodiments, it is a triphenylmethyl group. In certain embodiments, it is a tetrahydropyranyl group.

[0032] As used herein, "optionally substituted" means unsubstituted or having 1 to 5 substituents. In certain embodiments, it means unsubstituted or having 1 to 3 substituents. When having a plurality of substituents, these substituents may be the same or different from each other.

[0033] "Optionally substituted C 1-15 alkyl", "optionally substituted C 1-6 alkyl", "optionally substituted C 1-3 alkyl", "optionally substituted C 3-6In the case of "cycloalkyl", "7- to 9-membered optionally substituted bridged heterocycloalkane containing 1 to 2 nitrogen atoms", "optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 heteroatom selected from the group consisting of oxygen, sulfur and nitrogen", "4- to 6-membered optionally substituted heterocycloalkane containing 1 to 2 nitrogen atoms", "optionally substituted heterocycloalkyl", "optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen", "optionally substituted 6-membered heteroaryl containing 1 to 3 nitrogen atoms", or "optionally substituted phenyl", acceptable substituents include, independently of each other, F, OH, OCH3, N(CH3)2, C 1-3 alkyl, C 2-3 alkenyl (ethenyl, 1-propenyl or 2-propenyl), C 2-3 alkynyl (ethynyl, 1-propynyl or 2-propynyl), hydroxymethyl, methoxymethyl, difluoroethyl, optionally substituted C 3-6 cycloalkyl, azabicyclo[3.3.0]octanyl, or an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 to 2 heteroatoms selected from oxygen, sulfur and nitrogen, and in one embodiment is OCH3.

[0034] Depending on the type of functional group, it may be effective in the manufacturing technique to replace it with an appropriate protecting group (a group that can be easily converted to the functional group) during the reaction process. Examples of such protecting groups include the protecting groups described in "Greene’s Protective Groups in Organic Synthesis", 5th Edition, John Wiley & Sons Inc., 2014, by P. G. M. Wuts and T. W. Greene, etc., and these may be appropriately selected and used according to the reaction conditions. After introducing the protecting group and carrying out the reaction, the desired compound can be obtained by removing the protecting group as necessary. In this specification, the "protecting group" is not particularly limited as long as it can achieve the aforementioned purpose. In one aspect, examples of the protecting group include a benzyl group, a p-methoxybenzyl group, a benzyloxycarbonyl group, a tert-butyl(dimethyl)silyl group, a (trimethylsilyl)ethoxymethyl group, an acetyl group, a trifluoroacetyl group, a benzoyl group, a tert-butyl group, a tert-butoxycarbonyl group, a triphenylmethyl group, a tetrahydropyranyl group, and the like.

[0035] 2. Method for controlling axial chirality using a chiral auxiliary group and selectively producing one of axial chiral compounds or salts thereof In one aspect, the present invention provides a method for selectively producing one of the axially asymmetric compounds of the compound of formula (I) having axial asymmetry or a salt thereof, or a salt thereof, which comprises reacting a compound of formula (IIA) or a salt thereof with a compound of formula (IIIA) or a salt thereof, or reacting a compound of formula (IIB) or a salt thereof with a compound of the following formula (IIIB) or a salt thereof. In one aspect, the present invention also provides a method for selectively producing one of the axially asymmetric compounds of the compound of formula (I) having axial asymmetry or a salt thereof, or a salt thereof, which comprises reacting a compound of formula (IIA) or a salt thereof with a compound of formula (IIIA) or a salt thereof. Here, * indicates an asymmetric axis.

Chemical formula

[0036] In the above method, A is N or CH. In one aspect, A is N, and in one aspect, A is CH.

[0037] In the above method, X is Cl, Br, I, a methanesulfonyloxy group, or a p-toluenesulfonyloxy group. In one aspect, X is Cl, Br, or I; in one aspect, X is Cl or Br; in one aspect, X is Cl; and in one aspect, X is Br.

[0038] In the above method, Y is a bond, -CH2-, -O-, -S-, -NR Y -, -S(=O), or -SO2-, and the above R Y is H or an optionally substituted C 1-3It is alkyl. Also, in one aspect, Y is a bond, -CH2-, -O-, -S- or -NR Y -, and said R Y is H or optionally substituted C 1-3 alkyl. Also, in one aspect, Y is -O- or -S-, in one aspect, Y is -O-, in one aspect, Y is -S-, and in one aspect Y is a bond.

[0039] In said method, R 1 is the following formula (IV) or (V).

Chemical formula

[0040] Also, in one aspect, R 1 is a group selected from the group consisting of the following formulas (IV-1), (IV-2), (IV-3) and (V). Also, in one aspect, R 1 is a group selected from the group consisting of the following formulas (IV-1), (IV-2) and (V), and in one aspect, R 1 is the following formula (IV-1). Also, in one aspect, R 1 is the following formula (V).

Chemical formula

[0041] In said R 1 , ring A is a 7- to 9-membered optionally substituted bridged heterocycloalkane containing 1 to 2 nitrogen atoms or a 4- to 6-membered optionally substituted heterocycloalkane containing 1 to 2 nitrogen atoms, Z is a bond, -CH2-, -O-, -S- or -N(R Z1 )-, R Z1 is H or optionally substituted C 1-3 alkyl, and PG 1is a protecting group for NH contained in ring A, and its type is not particularly limited. In one aspect, it is a tert-butoxycarbonyl group, benzyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl group, allyloxycarbonyl group, phthaloyl group, 2-nitrobenzenesulfonyl group, 2-(trimethylsilyl)ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group. Also, PG 2 is a protecting group for OH, and its type is not particularly limited. In one aspect, it is a tert-butyl group, benzyl group, p-methoxybenzyl group, methoxymethyl group, trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group, acetyl group, benzoyl group, triphenylmethyl group.

[0042] Also, in the above method, R 2 is optionally substituted C 1-15 alkyl or optionally substituted heterocycloalkyl. In one aspect, R 2 is optionally substituted C 1-3 alkyl. Also, in one aspect, R 2 is optionally substituted 4- to 7-membered heterocycloalkyl. Also, in one aspect, R 2 is tetrahydropyranyl, ethyl or C 1-3 alkyl optionally substituted with -OCH3. In one aspect, R 2 is tetrahydropyranyl. In one aspect, R 2 is ethyl. In one aspect, R 2 is n-propyl substituted with -OCH3.

[0043] Also, in one aspect, R 2 is optionally substituted heterocycloalkyl, and the heterocycloalkyl is a 4- to 7-membered saturated heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen. In one aspect, R 2The heterocycloalkyl is a 4- to 6-membered saturated heterocyclic group containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen. Also, in one embodiment, R 2 The heterocycloalkyl is a 4- to 6-membered saturated heterocyclic group containing 1 to 2 nitrogen atoms. The "optionally substituted heterocycloalkyl" is as defined above, and each independently is one or more selected from the group consisting of the above substituents.

[0044] In one embodiment, R 2 is a group selected from the following formulas (X-1), (X-2), (X-3), (X-4), (X-5), (X-6), and (X-7):

Chemical formula

[0045] In one embodiment, R 2 is the above formula (X-1), R 2A is H or C 1-3 alkyl, V is PG 4 or C 1-3 alkyl, PG 4 is a protecting group for NH.

[0046] In one embodiment, PG 4 which is a protecting group for NHOne or more selected from the group consisting of the functional groups exemplified by the above-mentioned "NH protecting group" can be used. In one embodiment, they are a tert-butoxycarbonyl group, a triphenylmethyl group, a tetrahydropyranyl group, and in one embodiment, a 2-(trimethylsilyl)ethoxycarbonyl group.

[0047] Also, in the above method, R 3 is halogen, C 3-6 cycloalkyl, vinyl, or optionally substituted C 1-3 alkyl. In one embodiment, R 3 is C 3-6 cycloalkyl, and in one embodiment, R 3 is cyclopropyl.

[0048] Also, in the above method, R 4 is represented by the following formula (VI) or (VII).

Chemical formula

[0049] In the above formula (VI) or (VII), R 4A is C 1-3 alkyl, and R 4B is naphthyl, phenanthrenyl, or optionally substituted phenyl.

[0050] In one embodiment, R 4 is a group selected from the group consisting of the following formulas (VI-1), (VI-2), and (VI-3). In one embodiment, R 4 is the following formula (VI-1).

Chemical formula

[0051] Also, in the above method, R 5 is represented by the following formula (VIII) or (IX).

Chemical formula

[0052] In the above formula (VIII) or (IX), PG 3 is a protecting group for NH, and its type is not particularly limited. In one aspect, it is a triphenylmethyl group or a tetrahydropyranyl group. Also, R 5A is H, methyl, F, or Cl, and R 5B is Cl, methyl, ethyl, or vinyl.

[0053] Also, in one aspect, R 5 is the following formula (VIII-1) or (IX-1). Also, in one aspect, R 5 is the following formula (VIII-1).

Chemical formula

[0054] In the above formula (VIII-1) or (IX-1), PG 3 is a protecting group for NH, and its type is not particularly limited. In one aspect, PG 3 is a triphenylmethyl group or a tetrahydropyranyl group. In one aspect, PG 3 is a triphenylmethyl group.

[0055] Also, in the above method, BLG is a boronic acid group, a boronic acid ester group, a trifluoroborate group, or a triol borate group. Also, in one aspect, BLG is a boronic acid ester group. In one aspect, BLG is a pinacol boronic acid ester group. Also, in one aspect, BLG is any of the substituents shown below,

Chemical formula

Chemical formula

[0056] In a method for selectively producing one of the axially chiral compounds of the compound of formula (I) having axial chirality or a salt thereof, or a salt thereof, which comprises reacting the compound of formula (IIA) or a salt thereof with the compound of formula (IIIA) or a salt thereof, the reaction conditions are not particularly limited. In one embodiment, the production method uses an equimolar amount or an excess amount of one of the compound of formula (IIA) or a salt thereof and the compound of formula (IIIA) or a salt thereof, and stirs these mixtures in the presence of a palladium catalyst and a ligand. In one embodiment, the production method uses an equimolar amount or an excess amount of one of the compound of formula (IIA) or a salt thereof and the compound of formula (IIIA) or a salt thereof, and stirs these mixtures in the presence of a base, a palladium catalyst and a ligand. In one embodiment, the production method uses an equimolar amount or an excess amount of one of the compound of formula (IIA) or a salt thereof and the compound of formula (IIIA) or a salt thereof, and stirs these mixtures in a solvent inert to the reaction, in the presence of a base, a palladium catalyst and a ligand, from room temperature to heating under reflux, preferably at 20°C to 140°C. In one embodiment, the production method uses an equimolar amount or an excess amount of one of the compound of formula (IIA) or a salt thereof and the compound of formula (IIIA) or a salt thereof, and stirs these mixtures in a solvent inert to the reaction, in the presence of a base, a palladium catalyst and a ligand, from room temperature to heating under reflux, preferably at 20°C to 140°C, usually for 0.1 hour to 5 days. Examples of the solvent used herein are not particularly limited, and include halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; alcohols such as MeOH, EtOH, iPrOH, tBuOH, amyl alcohol, and 2-methyl-2-butanol; DMF, DMSO, MeCN, 1,3-dimethylimidazolidin-2-one, water, and mixtures thereof. The base is not particularly limited, and examples include anhydrides or hydrates of inorganic bases such as barium hydroxide, tripotassium phosphate, sodium carbonate, potassium carbonate, and sodium hydroxide. The palladium catalyst is not particularly limited, and examples include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride·dichloromethane adduct, (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one / palladium (3:2), palladium(II) acetate, di-μ-chlorobis(2'-amino-1,1'-biphenyl-2-yl-C,N)dipalladium(II), bis(tri-tert-butylphosphine)palladium, bis(dibenzylideneacetone)palladium, and the like. The ligand is not particularly limited, and examples include SPhos, RuPhos, DPPF, and the like. In addition, in the production method, a palladium catalyst precursor can also be used instead of the palladium catalyst. The palladium catalyst precursor is not particularly limited, and examples include paradacycle catalyst precursors such as RuPhos Pd G3, SPhos Pd G3, RuPhos Pd G2, and SPhos Pd G2. In one aspect of the palladium catalyst or palladium catalyst precursor, it is palladium(II) acetate, RuPhos Pd G3, or SPhos Pd G3. In one aspect of the ligand, it is SPhos or RuPhos. In one aspect of the base, it is barium hydroxide or tripotassium phosphate. In one aspect of the solvent, it is DOX, 2-methyl-2-butanol, or water, and mixtures thereof. In one aspect of the reaction temperature, it is 50°C to 90°C. In one aspect of the reaction time, it is 1 hour to 2 days. In addition, heating the mixture by microwave irradiation may be advantageous for the smooth progress of the reaction.

[0057] The reaction conditions for reacting the compound of formula (IIB) or a salt thereof with the compound of formula (IIIB) or a salt thereof are not particularly limited, but basically, the reaction can be carried out under the same conditions as those for reacting the compound of formula (IIA) or a salt thereof with the compound of formula (IIIA) or a salt thereof. As one embodiment, the reaction conditions described in Example 23 can be used.

[0058] In one aspect of the present invention, a method for producing a compound of the following formula (I-1) is provided by reacting a compound of formula (IIA) or a salt thereof, which is a compound of the following formula (IIA-1), with a compound of formula (IIIA) or a salt thereof, which is a compound of the following formula (IIIA-1). In this specification, this reaction is described as the "sixth step".

Chemical formula

[0059] (Sixth step) As described above, this step is a method for producing a compound of formula (I-1) by reacting a compound of formula (IIA-1) with a compound of formula (IIIA-1). As long as the reaction proceeds, the reaction conditions are not particularly limited. In one aspect, they are the same as the conditions for reacting the compound of formula (IIA) or a salt thereof with the compound of formula (IIIA) or a salt thereof. Also, in one aspect, the reaction conditions described in Example 3 below can be used.

[0060] In one aspect of the present invention, a method for producing a compound of the following formula (I-1) is provided, which includes obtaining a compound of formula (1) from the following compound of formula (IIA-1) and the following compound of formula (IIIA-1) by the following sixth to eleventh steps. Also, in one aspect, the present invention is a method for producing a compound of formula (1) including the following sixth to eleventh steps from the following compound of formula (IIA-1) and the following compound of formula (IIIA-1).

Chemical formula

[0061] (Seventh Step) This step is to obtain the compound of formula (10) by subjecting the compound of formula (I-1) to deprotection by catalytic hydrogenation reaction. This reaction can be carried out by stirring the compound of formula (I-1) in an inert solvent for the reaction in the presence of a metal catalyst under a hydrogen atmosphere, from normal pressure to increased pressure, from cooling to heating, preferably at room temperature, for 1 hour to 5 days. Examples of the solvent include alcohols such as MeOH, EtOH, and iPrOH, ethyl acetate, water, etc. and mixtures thereof, but are not particularly limited. The metal catalyst is not particularly limited, but palladium catalysts such as Pd / C and palladium black are used. In addition, carrying out the reaction in the presence of an inorganic base such as sodium bicarbonate or potassium carbonate may be advantageous for the smooth progress of the reaction. Also, in one aspect, the reaction conditions described in Example 4 below can be used.

[0062] (Eighth Step) This step is to react compound (10) with compound (11) to obtain compound (12). This reaction is carried out by using the same equivalent amount of compound (10) and compound (11) or using one of them in an excess equivalent amount, and reacting these mixtures in an inert solvent for the reaction in the presence of a base, from cooling to heating under reflux, preferably at 0 °C to 80 °C, usually for 0.1 hour to 5 days. Examples of the solvent used here include ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane, DMF, DMAc, etc. and mixtures thereof, but are not particularly limited. Examples of the base are not particularly limited, but include inorganic bases such as potassium carbonate, cesium carbonate, and sodium hydride. Also, in one aspect, the reaction conditions described in Example 5 below can be used.

[0063] (Ninth Step) This step is to remove the protecting group (triphenylmethyl group) of NH of compound (12) to obtain compound (13). This reaction uses compound (12) and an acidic reagent in equimolar amounts or with one of them in excess, and the mixture of these is stirred in a solvent inert to the reaction, from cooling to under heating under reflux, preferably at room temperature, usually for 30 minutes to 1 hour. Examples of the acidic reagent used here are not particularly limited, and include 4-methylbenzene-1-sulfonic acid monohydrate and the like. Examples of the solvent include, but are not particularly limited to, alcohols such as MeOH, EtOH, and iPrOH. Also, in one embodiment, the reaction conditions described in Example 6 below can be used.

[0064] (Tenth step) This step is a step of obtaining compound (15) by a cycloaddition reaction between compound (13) and compound (14). This reaction uses compound (13) and compound (14) in equimolar amounts or with one of them in excess, and the mixture of these is stirred in a solvent inert to the reaction or without a solvent, from cooling to under heating under reflux, preferably at 0 °C to 100 °C, usually for 0.1 hour to 5 days, preferably in the presence of a copper salt, and more preferably in the presence of a copper salt and a reducing agent. Examples of the solvent used here include, but are not particularly limited to, ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane, alcohols such as MeOH, EtOH, iPrOH, and tBuOH, water, and mixtures thereof. Examples of the copper salt are not particularly limited, and include copper(I) iodide, copper(II) sulfate, copper(II) trifluoromethanesulfonate, and the like. Examples of the reducing agent are not particularly limited, and include sodium ascorbate and the like. Also, in one embodiment, the reaction conditions described in Example 11 below can be used.

[0065] (Eleventh step) This step is to obtain compound (1) by removing the NH protecting group (tert-butoxycarbonyl group) of compound (15). In this reaction, compound (15) and an acidic reagent are used in equimolar amounts or one of them is in excess, and the mixture of these is stirred in a solvent inert to the reaction, from cooling to heating under reflux, preferably at room temperature to 60 °C, usually for 30 minutes to 5 days. Examples of the acidic reagent used here are not particularly limited, and include methanesulfonic acid and the like. Examples of the solvent include alcohols such as MeOH, EtOH, iPrOH, tBuOH, water, and mixtures thereof, but are not particularly limited. Also, in one aspect, the reaction conditions described in Example 12 below can be used.

[0066] In one aspect, compound (14) to be reacted in the tenth step can be obtained from the following compound (16) and the following compound (17) by the following twelfth step to sixteenth step. [Chemical formula]

[0067] (Twelfth step) This step is to obtain compound (18) by the amidation reaction of compound (16) and compound (17). In this reaction, compound (16) and compound (17) are used in equimolar amounts or one of them is in excess, and the mixture of these is stirred in a solvent inert to the reaction in the presence of a condensing agent, from cooling to heating, preferably at -20 °C to 60 °C, usually for 0.1 hour to 5 days. Examples of the solvent include ethers such as diethyl ether, THF, DOX, 1,2-dimethoxyethane, DMF, and mixtures thereof, but are not particularly limited. Examples of the condensing agent are not particularly limited, and include HATU, EDCI, and the like. It may be preferable to use an additive (for example, 1-hydroxybenzotriazole) in the reaction. Conducting the reaction in the presence of an organic base such as TEA, DIPEA, or an inorganic base such as potassium carbonate, sodium carbonate, or potassium hydroxide may be advantageous for the smooth progress of the reaction. Also, in one aspect, the reaction conditions described in Example 8 below can be used.

[0068] (The 13th Step) This step is to obtain compound (19) by performing deprotection of compound (18) through catalytic hydrogenation reaction. The reaction conditions are the same as those in the aforementioned 7th step. Also, in one aspect, the reaction conditions described in Example 9 below can be used.

[0069] (The 14th Step) This step is to obtain compound (21) by amidation reaction of compound (19) and compound (20). The reaction conditions are the same as those in the aforementioned 12th step.

[0070] (The 15th Step) This step is to obtain compound (22) by removing the protecting group (tert-butoxycarbonyl group) of NH in compound (21). This reaction is carried out by stirring usually for 0.1 hour to 5 days under cooling to heating under reflux. Examples of the solvent used here are not particularly limited, and include alcohols such as MeOH, EtOH, iPrOH, tBuOH, ethyl acetate, and mixtures thereof, but are not particularly limited. Examples of the deprotection reagent are not particularly limited, and include acids such as hydrogen chloride (DOX solution), hydrogen chloride (ethyl acetate solution), trifluoroacetic acid, and methanesulfonic acid.

[0071] Also, in one aspect, the reaction conditions of the aforementioned 14th to 15th steps can use the reaction conditions described in Example 10 below.

[0072] (The 16th Step) This step involves obtaining compound (14) through the reaction of compound (22) with a diazo transfer reagent. This reaction is carried out by treating compound (22) with an equivalent or excess amount of a diazo transfer reagent in a solvent inert to the reaction, under cooling to heating, preferably at 0°C to 50°C, usually for 0.1 hour to 3 days. Examples of the diazo transfer reagent are not particularly limited, and include, for example, nonafluorobutanesulfonyl azides such as trifluoromethanesulfonyl azide and 1,1,2,2,3,3,4,4,4-nonafluoro-1-butanesulfonyl azide, imidazole-1-sulfonyl azide or its salts, ADMP, etc. The reaction may advantageously be carried out in the presence of an organic base such as TEA, DMAP, 2,6-lutidine, or a copper salt such as a catalytic amount of copper sulfate. Examples of the solvent include ethers such as THF, halogenated hydrocarbons such as dichloromethane, alcohols such as MeOH, MeCN, water, and mixtures thereof.

[0073] Also, in one embodiment, the reaction conditions of the aforementioned sixteenth step can use the reaction conditions described in Example 10-2 below.

[0074] In one embodiment, the compound of formula (IIA-1) to be reacted in the sixth step can be obtained from the following compound (2) through the following first to fifth steps. [Chemical formula]

[0075] (First step) This step involves chlorinating compound (2) to obtain compound (3). This reaction is carried out by using an equivalent amount or an excess amount of either compound (2) or a chlorinating reagent, and stirring the mixture in a solvent inert to the reaction or without a solvent, under heating and refluxing, preferably at 90°C to 110°C, usually for 0.1 hour to 3 days, in the presence of a base. Examples of the chlorinating reagent used here are not particularly limited, and include phosphorus oxychloride, etc. Examples of the base used here are not particularly limited, and include organic bases such as TEA and DIPEA. Examples of the solvent used here include DMF, etc., but are not particularly limited.

[0076] (Second Step) This step is to obtain compound (5) through the ipso-substitution reaction between compound (3) and compound (4). In this reaction, compound (3) and compound (4) are used in equimolar amounts or one of them is used in excess, and these mixtures are stirred in a solvent inert to the reaction or without solvent, from cooling to heating under reflux, preferably at 0 °C to 80 °C, usually for 0.1 hour to 5 days. Examples of the solvent used here are not particularly limited, and include halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane, DMF, DMAc, DMSO, ethyl acetate, MeCN, and mixtures thereof. Conducting the reaction in the presence of organic bases such as TEA, DIPEA, NMM, DABCO, and tBuOK, or inorganic bases such as sodium hydride, potassium carbonate, sodium carbonate, and cesium carbonate may be advantageous for the smooth progress of the reaction. Also, in one aspect, the reaction conditions described in International Publication No. 2022 / 173032 can be used.

[0077] (Third Step) This step is to obtain compound (7) through the ipso-substitution reaction between compound (5) and compound (6). The reaction conditions are the same as those in the aforementioned second step. Also, in one aspect, the reaction conditions described in International Publication No. 2022 / 173032 can be used.

[0078] (Fourth Step) This step is to obtain compound (8) through the ipso-substitution reaction between compound (7) and compound (9). The reaction conditions are the same as those in the aforementioned second step. Also, in one aspect, the reaction conditions described in Example 1 below can be used.

[0079] (Fifth Step) This step involves reacting compound (8) with cyclopropylboronic acid of compound (30) to obtain a compound of formula (IIA-1). The reaction is carried out using equimolar amounts of compound (8) and cyclopropylboronic acid of compound (30) or with one of them in excess. The mixture is stirred in a solvent inert to the reaction, in the presence of a base and a palladium catalyst, from room temperature to reflux under heating, preferably at 20 °C to 140 °C, usually for 0.1 hour to 5 days. Examples of the solvent used here are not particularly limited, and include MeCN, water, and mixtures thereof. Examples of the base include inorganic bases such as tripotassium phosphate, sodium carbonate, and potassium carbonate. The palladium catalyst is not particularly limited, and examples include tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride·dichloromethane adduct, etc. Conducting the reaction in the presence of a ligand such as DPPF may be advantageous for the smooth progress of the reaction. Also, heating the mixture by microwave irradiation may be advantageous for the smooth progress of the reaction. Also, in one embodiment, the reaction conditions described in Example 2 below can be used.

[0080] Also, in one embodiment, the compound of formula (I-1) described above can be obtained by the following First a Step to Fifth a Step from the compound of the following compound (2a) to obtain a compound of formula (IIA-2), and then, under the same reaction conditions as in the Sixth Step described above, it can be obtained by the Sixth a Step. [Chemical formula] [Chemical formula]

[0081] (First a Step) This step is to brominate compound (2a) to obtain compound (2b). In this reaction, compound (2a) and a brominating reagent are used in equimolar amounts or with one in excess, and these mixtures are stirred at 40 °C to 70 °C for usually 1 hour to 5 days in a solvent inert to the reaction in the presence of an acidic reagent. The brominating reagent used here is not particularly limited, and examples include 1,3-dibromo-5,5-dimethylhydantoin, NBS, etc. The acidic reagent used here is not particularly limited, and examples include methanesulfonic acid, sulfuric acid, etc. Examples of the solvent used here are not particularly limited, and include alcohols such as MeOH, EtOH, iPrOH, tBuOH, and MeCN, etc. Also, in one aspect, the reaction conditions described in Example 14 below can be used in the first a step.

[0082] (First b step) This step is to oximate compound (2b) to obtain compound (2c) and / or compound (2c’). In this reaction, compound (2b) and hydroxylamine hydrochloride are used in equimolar amounts or with one in excess, and these mixtures are stirred at room temperature to 60 °C for usually 0.5 hour to 5 days in a solvent inert to the reaction. Examples of the solvent used here are not particularly limited, and include alcohols such as MeOH, EtOH, iPrOH, tBuOH, etc. Conducting the reaction in the presence of an additive such as sodium acetate may be advantageous for the smooth progress of the reaction. Also, in one aspect, the reaction conditions described in Example 15 below can be used in the first b step.

[0083] (First c step) This step involves subjecting compound (2c) and / or compound (2c’) to ring expansion reaction conditions to obtain compound (3a). In this reaction, compound (2c) and / or compound (2c’) and a chlorinating reagent are used in equimolar amounts or with one in excess. The mixture is stirred in a solvent inert to the reaction at a temperature ranging from room temperature to 110 °C for usually 1 hour to 7 days in the presence of triphenylphosphine oxide and a base. The chlorinating reagent used here is not particularly limited, and examples include thionyl chloride, phosphorus oxychloride, triphosgene, etc. The base used here is not particularly limited, and examples include bases such as DIPEA. Examples of the solvent used here are not particularly limited, and include aromatic hydrocarbons such as benzene, toluene, xylene, etc. Also, trialkylphosphine oxide etc. can be used instead of triphenylphosphine oxide, but it is not limited thereto. Also, in one embodiment, the reaction conditions described in Example 16 below can be used in the first c step.

[0084] The second a step to the fifth a step can be carried out under the same reaction conditions as the second step to the fifth step described above, respectively. Also, the sixth a step can be carried out using the same reaction conditions as the sixth step described above. Also, in one embodiment, the compound of formula (IIA-2) can be obtained using the reaction conditions described in Examples 14 to 19 below, and then the compound of formula (I-1) can be obtained using the reaction conditions described in Example 3.

[0085] In one embodiment, compound (20) to be reacted in the fourteenth step can be obtained from the following compound (24) and the following compound (25) through the following seventeenth step to eighteenth step.

Chemical formula

[0086] (Seventeenth step) This step is to react compound (24) with compound (25) to obtain compound (26). In this reaction, compound (24) and compound (25) are used in equimolar amounts or one of them is used in excess. The mixture is stirred in a solvent inert to the reaction, in the presence of a base and a palladium catalyst, from room temperature to under reflux heating, preferably at 20 °C to 140 °C, usually for 0.1 hour to 5 days. Examples of the solvent used here are not particularly limited, and include ethers such as diethyl ether, THF, DOX, 1,2-dimethoxyethane, NMP, DMF, DMAc, DMSO, MeCN, 1,3-dimethylimidazolidin-2-one, ethyl acetate, water, and mixtures thereof. Examples of the base include bases such as tripotassium phosphate, sodium carbonate, potassium carbonate, and potassium acetate. Examples of the palladium catalyst include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride·dichloromethane adduct, (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one / palladium (3:2), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, palladium(II) acetate, etc. Also, heating the mixture by microwave irradiation may be advantageous for the smooth progress of the reaction. As references for the reaction, for example, the following can be referred to. Synthesis 2020, 52, p.2521-2527 PNAS 2016, 113, p.7124-7129

[0087] (The eighteenth step) This step is to remove the protecting group (tert-butoxycarbonyl group) of NH of compound (26) to obtain the compound of formula (20). The reaction conditions are the same as those in the fifteenth step described above.

[0088] In one aspect, the compound of formula (IIIA-1) to be reacted in the sixth step can be obtained from the following compound (27) through the following nineteenth to twenty-first steps.

Chemical formula

[0089] (Nineteenth step) This step is a step of protecting the NH of compound (27) with a triphenylmethyl group to obtain compound (28). As long as the reaction proceeds, the reaction conditions are not particularly limited. For example, the reaction can be carried out according to the method described in Production Example 245 of Patent Document 1.

[0090] (Twentieth step) This step is a step of methylating compound (28) to obtain compound (29). As long as the reaction proceeds, the reaction conditions are not particularly limited. For example, the reaction can be carried out according to the method described in Production Example 246 of Patent Document 1.

[0091] (Twenty-first step) This step is a step of substituting the Br of compound (29) with a pinacol boronic acid ester to obtain the compound of formula (IIIA-1). As long as the reaction proceeds, the reaction conditions are not particularly limited. For example, the reaction can be carried out according to the method described in Production Example 247 of Patent Document 1.

[0092] (Third-2 step to Sixth-2 step) Also, in one aspect, the present invention is a method for producing the compound of formula (I) or a salt thereof described in [1] above, which includes reacting the compound of formula (IIA) or a salt thereof with the compound of formula (IIIA) or a salt thereof. The compound of formula (I) is a compound represented by the following formula (I-2):

Chemical formula

Chemical formula

Chemical formula

[0093] Also, in one aspect, the compound of formula (IIIA) is the compound of formula (IIIA-1) described above.

[0094] As described above, the sixth-2 step is a method of reacting a compound of formula (IIA-3) with a compound of formula (IIIA) to produce a compound of formula (I-2). As long as the reaction proceeds, the reaction conditions are not particularly limited. In one aspect, they are the same as the conditions for reacting the compound of formula (IIA) or its salt with the compound of formula (IIIA) or its salt described above. Also, in one aspect, the reaction conditions described in Example 35 below can be used.

[0095] In one aspect, the compound of formula (IIA-3) to be reacted in the sixth-2 step can be obtained from the following compound (5-2) by the following steps.

Chemical formula

[0096] (Third-2 step) This step is a step of obtaining compound (7-2) from compound (5-2). The reaction conditions are the same as those in the third step described above. Also, in one aspect, the reaction conditions described in Example 36 below can be used.

[0097] (Fourth-2 step) This step is a step of obtaining compound (8-2) from compound (7-2). The reaction conditions are the same as those in the fourth step described above. Also, in one aspect, the reaction conditions described in Example 37 below can be used.

[0098] (Fifth-2 step) This step is to obtain compound (IIA - 3) from compound (8 - 2). The reaction conditions are the same as those in the aforementioned fourth step. In addition, in one embodiment, the reaction conditions described in Example 38 below can be used.

[0099] 3. Diazotransfer reaction In one aspect, the present invention provides a compound of the following formula (#1) or a salt thereof:

Chemical formula

Chemical formula

[0100] In one aspect, in the method for producing a compound of the above formula ( #1 ) or a salt thereof, R 11 is ethyl, isopropyl, tert-butyl, or C 3-6 cycloalkyl, R 12A and R 12B are the same or different from each other and are H, or C 1-3 alkyl optionally substituted with a group selected from the group consisting of F, OH, and N(CH3)2, or R 12A and R 12B together with the carbon to which they are attached form cyclopropyl, R 13 is H, halogen, or a group selected from the group consisting of the following:

Chemical formula

[0101] Also, in one aspect, in the method for producing a compound of the above formula ( #1 ) or a salt thereof, R 11 is isopropyl, R 12A is H, R 12Bis C which may be substituted with OH 1-3 alkyl, R 13 is the following group, [Chemical formula] R 13A is C 1-3 alkyl, W is phenyl.

[0102] As long as the aforementioned diazo transfer reaction proceeds, the type of diazo transfer reagent is not limited. For example, perfluoroalkylsulfonyl azide, imidazole-1-sulfonyl azide, or salts thereof can be used. The perfluoroalkylsulfonyl azide is, in one aspect, nonafluorobutanesulfonyl azide, heptafluoropropanesulfonyl azide, pentafluoroethanesulfonyl azide, trifluoromethanesulfonyl azide, and in one aspect, nonafluorobutanesulfonyl azide, and in one aspect, 1,1,2,2,3,3,4,4,4-nonafluoro-1-butanesulfonyl azide as a form of nonafluorobutanesulfonyl azide.

[0103] In one aspect, a base reagent can be used in the aforementioned diazo transfer reaction. Examples of the base reagent include inorganic bases such as potassium hydrogen carbonate and potassium carbonate. In one aspect, additives can be used as appropriate to promote the aforementioned diazo transfer reaction. Examples of the additives include metal salts such as copper salts like CuSO4 and zinc salts like ZnSO4. In one aspect, a polar solvent can be used as the solvent in the aforementioned diazo transfer reaction. Examples of the polar solvent include water, alcohols such as acetonitrile, methanol, and ethanol, polar organic solvents such as DMSO and MTBE, and mixtures thereof. In one aspect, the aforementioned diazo transfer reaction can be carried out at 10°C to 25°C. In one aspect, the aforementioned diazo transfer reaction can be carried out at 10°C to 20°C, for example, 15°C. In one aspect, the aforementioned diazo transfer reaction may be carried out in the presence of a metal catalyst or in the absence of a metal catalyst.

[0104] 4. Compound In one aspect, the present invention is a compound represented by any of the following or a salt thereof. These are compounds or salts thereof that can be obtained by the method for producing the compound of formula (I) or a salt thereof described above, or compounds or salts thereof that can be obtained in each of the aforementioned seventh to tenth steps.

Chemical formula

Chemical formula

Chemical formula

[0105] In one aspect, the present invention is the compound (3a) obtained in the aforementioned first c step or a salt thereof.

Chemical formula

[0106] Also, in one aspect, the present invention is the aforementioned compounds (7-2), (8-2), (IIA-3) and (I-2) or salts thereof.

Chemical formula

[0107] 4. Abbreviations In this specification, the following abbreviations may be used. TFA: Trifluoroacetic acid, DMF: N,N-Dimethylformamide, THF: Tetrahydrofuran, MeCN: Acetonitrile, MeOH: Methanol, EtOH: Ethanol, iPrOH: Isopropyl alcohol, tBuOH: tert-Butanol, iPr2O: Diisopropyl ether, DOX: 1,4-Dioxane, DMSO: Dimethyl sulfoxide, TEA: Triethylamine, DIPEA: N,N-Diisopropylethylamine, tBuOK: Potassium tert-butoxide, tBuONa: Sodium tert-butoxide, PdCl2(dppf)·CH2Cl2: [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride·dichloromethane adduct, Pd / C: Palladium on carbon, HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, DABCO: 1,4-Diazabicyclo[2.2.2] Octane, SPhos: dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine, RuPhos: dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine, SPhos Pd G2: chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), RuPhos Pd G2: chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), SPhos Pd G3: (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, RuPhos Pd G3: (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, DPPF: 1,1’-bis(diphenylphosphino)ferrocene), WSC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, Pd(PPh3)4: tetrakis(triphenylphosphine)palladium(0), DMAc: dimethylacetamide, NMP: N-methyl-2-pyridone, ADMP: 2-azido-1,3-dimethylimidazolinium hexafluorophosphate, DMAP: 4-dimethylaminopyridine, NMM: N-methylmorpholine, NBS: N-bromosuccinimide, MTBE: methyl t-butyl ether.

[0108] Also, in the following table, the following abbreviations may be used. Ex: Example number, Syn: Example number produced by the same method (e.g., Syn:9 indicates that it was produced by the same method as Example 9.), DATA: Physicochemical data, ESI+: m / z value in mass spectrometry (ionization method ESI, [M+H] when not otherwise specified) +)、ESI-: m / z value in mass spectrometry (ionization method ESI, [M-H] if not otherwise specified) - )、NMR: at 27 °C in DMSO-d6 1 δ value (ppm) of the peak in 1H-NMR (500 MHz), NMR (100 °C): at 100 °C in DMSO-d6 1 δ value (ppm) of the peak in 1H-NMR (500 MHz), s: singlet (spectrum), d: doublet (spectrum), dd: double doublet (spectrum), ddd: double double doublet (spectrum), t: triplet (spectrum), dt: double triplet (spectrum), q: quartet (spectrum), m: multiplet (spectrum), br: broad line (spectrum) (e.g., br s).

Example

[0109] Hereinafter, the present invention will be described in more detail with specific examples, but the present invention is not limited to the following specific examples. In this specification, unless otherwise specified, concentrations etc. are based on mass, and numerical ranges include their endpoints.

[0110] Example 1 (1S,4S)-5-{7-Bromo-8-fluoro-6-iodo-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl (54.8 g), (1S)-1-phenylethan-1-ol (12.4 g), and THF (400 mL) were added with tBuOK (11.3 g) in portions while maintaining the internal temperature at 10 °C or lower under a nitrogen atmosphere and ice cooling, and the mixture was stirred for 30 minutes under ice cooling. The reaction was stopped by adding a saturated aqueous ammonium chloride solution under ice cooling. Water and ethyl acetate were added, the organic layer and the aqueous layer were separated, the aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. After filtration and concentration under reduced pressure, hexane / iPr2O (1 / 1, 400 mL) was added to the residue to suspend it, and the solid was collected by filtration and dried under reduced pressure to obtain (1S,4S)-5-{7-bromo-6-iodo-2-[(oxan-4-yl)oxy]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl (52.3 g) as a solid.

[0111] Example 2 Under a nitrogen atmosphere, at room temperature, tert-butyl (1S,4S)-5-{7-bromo-6-iodo-2-[(oxan-4-yl)oxy]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (52.3 g) was suspended in MeCN (1000 mL), and cyclopropylboronic acid (10 g), PdCl2(dppf)·CH2Cl2 (5.6 g), tripotassium phosphate (55 g), and water (200 mL) were added at room temperature, and the mixture was stirred at 90 °C overnight. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure until the volume was reduced to about half, ethyl acetate was added, and the mixture was filtered through Celite®. Water was added to the filtrate, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution. Amino group-modified silica gel (25 g) and activated carbon (25 g) were added to the organic layer, and the mixture was stirred at room temperature for 1 hour, filtered through Celite®. The filtrate was concentrated under reduced pressure. iPrOH (250 mL) was added to the residue to form a powder, and the mixture was stirred at 90 °C for 3 hours and then gradually cooled to room temperature with stirring. The resulting powder was collected by filtration and dried under reduced pressure to obtain tert-butyl (1S,4S)-5-{7-bromo-6-cyclopropyl-2-[(oxan-4-yl)oxy]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (32.3 g) as a solid.

[0112] Example 3 At room temperature, (1S,4S)-5-{7-bromo-6-cyclopropyl-2-[(oxan-4-yl)oxy]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl (1 g), 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triphenylmethyl)-2H-indazole (1 g) were dissolved in DOX (20 mL) and water (4 mL), and palladium(II) acetate (35 mg), anhydrous barium hydroxide (775 mg), and SPhos (125 mg) were added. After stirring overnight at 50 °C under an argon atmosphere, 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triphenylmethyl)-2H-indazole (200 mg) was added at the same temperature and stirring was continued for an additional 4 hours. The reaction mixture was allowed to cool, ethyl acetate and Celite® were added, and the mixture was stirred at room temperature for 30 minutes, then filtered and the filtrate was washed with a saturated aqueous sodium chloride solution. Amino group-modified silica gel was added to the organic layer and the mixture was stirred at room temperature for 30 minutes, then filtered and concentrated. MeOH (40 mL) was added to the resulting residue to dissolve it, and the mixture was stirred at 50 °C for 1 hour and at room temperature for 2 hours. The resulting solid was collected by filtration, washed with MeOH, and dried under reduced pressure to obtain (1S,4S)-5-{7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(oxan-4-yl)oxy]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl (913 mg) as a solid.

[0113] Example 3-1 At room temperature, (1S,4S)-5-{7-bromo-6-cyclopropyl-2-[(oxan-4-yl)oxy]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl (300 mg), 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triphenylmethyl)-2H-indazole (300 mg), RuPhos Pd G3 (38 mg), RuPhos (21 mg), tripotassium phosphate (475 mg), DOX (5 mL), and water (1 mL) were mixed and stirred at 90 °C for 2 hours under an argon atmosphere. The reaction mixture was allowed to cool, water and ethyl acetate were added, and the mixture was filtered through Celite® and washed with ethyl acetate. The filtrate was separated, the aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (amino group-modified silica gel, hexane / ethyl acetate) to obtain (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(oxan-4-yl)oxy]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl (367 mg) as a foamy solid.

[0114] Example 3-2 At room temperature, (1S,4S)-5-{7-bromo-6-cyclopropyl-2-[(oxan-4-yl)oxy]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl (200 mg), 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triphenylmethyl)-2H-indazole (200 mg), RuPhos Pd G3 (25 mg), RuPhos (14 mg), barium hydroxide octahydrate (285 mg), DOX (3 mL), and water (0.6 mL) were mixed and stirred at 90 °C for 2 hours under an argon atmosphere. The reaction mixture was allowed to cool and filtered through Celite® while washing with ethyl acetate. Water was added to the filtrate and extracted twice with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (amino group-modified silica gel, hexane / ethyl acetate) to obtain (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(oxan-4-yl)oxy]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl (291 mg) as a foamy solid.

[0115] Example 3-3 At room temperature, (1S,4S)-5-{7-bromo-6-cyclopropyl-2-[(oxan-4-yl)oxy]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl (200 mg), 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triphenylmethyl)-2H-indazole (200 mg), palladium(II) acetate (7 mg), RuPhos (28 mg), barium hydroxide octahydrate (285 mg), DOX (3 mL), and water (0.6 mL) were mixed and stirred at 50 °C for 13 hours under an argon atmosphere. The reaction mixture was allowed to cool, ethyl acetate and Celite® were added, and the mixture was stirred at room temperature for 30 minutes, then filtered through Celite® and the filtrate was concentrated. The residue was purified by silica gel column chromatography (amino group-modified silica gel, hexane / ethyl acetate) to obtain (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(oxan-4-yl)oxy]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl (268 mg) as a foamy solid.

[0116] Example 3-4 At room temperature, (1S,4S)-5-{7-bromo-6-cyclopropyl-2-[(oxan-4-yl)oxy]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl (200 mg), 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triphenylmethyl)-2H-indazole (200 mg), palladium(II) acetate (7 mg), SPhos (25 mg), anhydrous barium hydroxide (155 mg), DOX (3 mL), and water (0.6 mL) were mixed and stirred at 50 °C for 14 hours under an argon atmosphere. The reaction mixture was allowed to cool, ethyl acetate and Celite® were added, and the mixture was stirred at room temperature for 30 minutes, then filtered through Celite® and the filtrate was concentrated. The residue was purified by silica gel column chromatography (amino group-modified silica gel, hexane / ethyl acetate) to obtain (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(oxan-4-yl)oxy]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl (281 mg) as a foamy solid.

[0117] Example 4 (1S,4S)-5-{(7M)-6-Cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(oxan-4-yl)oxy]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl (4.96 g), 10% Pd / C (about 50% water-containing, 1 g), sodium hydrogen carbonate (2 g), ethyl acetate (80 mL), and a mixture of MeOH (20 mL) were stirred overnight at room temperature and normal pressure under a hydrogen atmosphere. After substitution with argon, the reaction solution was filtered through Celite® and the filtrate was concentrated under reduced pressure to obtain (1S,4S)-5-{(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-hydroxy-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl (4.46 g) as a foamy solid.

[0118] Example 5 Under a nitrogen atmosphere, (1S,4S)-5-{(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-hydroxy-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl (34 g) and cesium carbonate (38 g) were suspended in DMF (200 mL), methanesulfonic acid (4-ethynylphenyl)methyl (8.2 g) was added at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added to ice water (about 1000 mL) and stirred at room temperature for 30 minutes. The resulting solid was collected by filtration and dried under reduced pressure to obtain (1S,4S)-5-{(7M)-6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl (35.5 g) as a solid.

[0119] Example 6 (1S,4S)-5-{(7M)-6-Cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl (745 mg) in MeOH (8 mL) was added 4-methylbenzene-1-sulfonic acid monohydrate (145 mg) at room temperature, and stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated. Ethyl acetate (3 mL) / hexane (3 mL) was added to the obtained solid to dissolve it, and then hexane (3 mL) was added, and stirred at 90 °C for 30 minutes and at room temperature for 1 hour. The resulting solid was collected by filtration and dried under reduced pressure to obtain (1S,4S)-5-{(7M)-6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl (408 mg) as a solid.

[0120] Example 7 Under ice-cooling, (4-ethynylphenyl)methanol (10 g) was dissolved in CH2Cl2 (100 mL), DIPEA (33 mL) and methanesulfonic anhydride (15.3 g) were added little by little, and stirred under ice-cooling for 1 hour. Methanesulfonic anhydride (3 g) was added under ice-cooling, and stirred for 30 minutes. Water and ethyl acetate / hexane (1 / 1) were added under ice-cooling, and extracted twice with ethyl acetate / hexane (1 / 1). The combined organic layers were washed with saturated aqueous ammonium chloride solution, water, and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated to obtain methanesulfonic acid (4-ethynylphenyl)methyl (16.0 g) as a solid.

[0121] Example 8 To a mixture of N-(tert-butoxycarbonyl)-L-valine (30.8 g), (4R)-4-hydroxy-L-proline benzyl ester hydrochloride (35 g), THF (200 mL), DMF (200 mL), and DIPEA (70 mL), HATU (53.9 g) was added portionwise under ice-cooling (the internal temperature was maintained at 10°C or lower). The mixture was stirred under ice-cooling for 15 minutes and at room temperature for 45 minutes. A semi-saturated aqueous sodium chloride solution (900 mL) was added at room temperature, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed successively with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to obtain N-(tert-butoxycarbonyl)-L-valyl-(4R)-4-hydroxy-L-proline benzyl ester (107 g, containing impurities) as an oil.

[0122] Example 9 To a solution of N-(tert-butoxycarbonyl)-L-valyl-(4R)-4-hydroxy-L-proline benzyl ester (107 g, containing impurities) obtained in Example 8 in MeOH (400 mL), 10% Pd / C (about 50% water-containing, 2.9 g) was added at room temperature under a nitrogen atmosphere. The atmosphere was replaced with a hydrogen atmosphere, and the mixture was stirred at room temperature overnight. Celite (registered trademark) was added to the reaction solution, and after stirring, the mixture was filtered while washing with MeOH, and the filtrate was concentrated. Ethyl acetate (200 mL) was added to the obtained residue, and the mixture was stirred at room temperature overnight. The solid was collected by filtration to obtain N-(tert-butoxycarbonyl)-L-valyl-(4R)-4-hydroxy-L-proline (32.7 g) as a solid.

[0123] Example 10 To a mixture of N-(tert-butoxycarbonyl)-L-valyl-(4R)-4-hydroxy-L-proline (13.7 g), (2R)-2-amino-2-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethan-1-ol dihydrochloride (13.3 g), DMF (110 mL), and THF (110 mL), DIPEA (28 mL) was added and the mixture was stirred. Under ice-cooling (ice / saturated aqueous sodium chloride solution), HATU (16.5 g) was added little by little (maintaining the internal temperature at 0 °C or lower). After stirring for 30 minutes under ice-cooling, semi-saturated aqueous sodium chloride solution (400 mL) and ethyl acetate (200 mL) were added and stirred, and the aqueous layer and the organic layer were separated. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed in order with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to obtain N-(tert-butoxycarbonyl)-L-valyl-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (32.6 g, containing impurities) as a foamy solid. To a solution of the obtained solid in ethyl acetate (100 mL) / MeOH (100 mL), 4M hydrogen chloride (ethyl acetate solution, 100 mL) was added little by little under ice-cooling, and the mixture was stirred at room temperature overnight. The resulting solid was collected by filtration, ethyl acetate (50 mL) / MeOH (100 mL) was added, and the mixture was stirred at room temperature for 2 hours. The solid was collected by filtration to obtain L-valyl-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide dihydrochloride (19.0 g) as a solid.

[0124] To the L-valyl-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide dihydrochloride obtained in Example 10, a diazo transfer reagent was reacted under the reaction conditions described in International Publication No. 2022 / 173032 to obtain (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide.

[0125] Example 10-2 A mixture of 1,1,2,2,3,3,4,4,4-nonafluoro-1-butanesulfonyl chloride (2.42 g), methyl-tert-butyl ether (19 mL), water (19 mL), MeCN (1 mL), sodium azide (0.61 g), sodium hydrogen carbonate (0.24 g), and tetrabutylammonium chloride (0.31 g) was stirred at 5 °C for 20 hours. Then, a 25% aqueous sodium chloride solution was added, and liquid separation was performed to obtain 1,1,2,2,3,3,4,4,4-nonafluoro-1-butanesulfonyl azide. The obtained organic layer was added to a mixture of L-valyl-(4R)-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide dihydrochloride (2.00 g), potassium hydrogen carbonate (1.93 g), DMSO (20 mL), and water (4 mL), and the mixture was stirred at 15 °C for 16 hours. To the reaction solution, a 25% aqueous sodium chloride solution and ethyl acetate were added, and liquid separation was performed. Silica gel and sodium sulfate were added to the obtained organic layer, and the mixture was stirred at room temperature for 30 minutes. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. Then, crystallization was performed from methanol and methyl-tert-butyl ether to obtain (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (1.15 g) as a solid.

[0126] Example 11 Under a nitrogen atmosphere, to a solution of tert-butyl (1S,4S)-5-{(7M)-6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (310 mg) and (4R)-1-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (200 mg) in tBuOH (0.4 mL) / THF (0.5 mL) / water (0.4 mL) were added sodium ascorbate (80 mg) and copper(I) iodide (20 mg) at room temperature, and the mixture was stirred for 4 hours. Copper(I) iodide (20 mg) was added at room temperature, and the mixture was further stirred for 15 hours. To this mixture was added an aqueous solution of disodium ethylenediaminetetraacetate (750 mg) in water (20 mL), diluted with ethyl acetate (20 mL), and stirred at room temperature for 1 hour. The mixture was extracted twice with ethyl acetate, and the combined organic layers were washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (amino group-modified silica gel, CHCl3 / MeOH) to obtain tert-butyl (1S,4S)-5-{(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-8-{[4-(1-{(2S)-1-[(2S,4R)-4-hydroxy-2-({(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}carbamoyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}-1H-1,2,3-triazol-4-yl)phenyl]methoxy}-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (452 mg) as a solid.

[0127] Example 12 In a nitrogen atmosphere, methanesulfonic acid (100 μL) was added to a solution of tert-butyl (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (200 mg) in MeOH (1 mL) at room temperature, and the mixture was stirred at 50 °C for 4 hours. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase chromatography (ODS column, 0.1% aqueous formic acid solution / 0.1% formic acid MeCN solution). The fraction containing the target product was collected, 5% aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted twice with CHCl3 / MeOH (9 / 1). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (139 mg) as a solid.

[0128] Example 14 Under an argon atmosphere, at room temperature, 6-chloro-7-fluoro-1H-indole-2,3-dione (250.8 g) and MeCN (1.25 L) were mixed and stirred, methanesulfonic acid (24.2 g) and 1,3-dibromo-5,5-dimethylhydantoin (359.3 g) were added, and the mixture was stirred at room temperature for 10 minutes. After stirring at 55 °C for 20 hours, it was cooled to 10 °C or lower, and an aqueous solution of sodium ascorbate (497.9 g) in water (2.5 L) was added. After stirring at 10 °C or lower for 1 hour, water (2.5 L) was added at room temperature and stirred for 1 hour. The precipitate was collected by filtration, washed with water, and dried under reduced pressure at 60 °C to obtain 5-bromo-6-chloro-7-fluoro-1H-indole-2,3-dione (320.4 g) as a solid.

[0129] Example 15 Under an argon atmosphere, at room temperature, 5-bromo-6-chloro-7-fluoro-1H-indole-2,3-dione (320 g), EtOH (2.24 L), and sodium acetate (141 g) were mixed and stirred for 10 minutes, then hydroxylamine hydrochloride (87.8 g) was added and the mixture was stirred at 50 °C for 2 hours. After adding water (4.16 L) at 50 °C, it was cooled to room temperature, stirred for 30 minutes, and the solid was collected by filtration. The filtrate was washed successively with EtOH / water (1 / 2) and water, and dried under reduced pressure at 60 °C to obtain 5-bromo-6-chloro-7-fluoro-3-(hydroxyimino)-1,3-dihydro-2H-indol-2-one (314 g) as a solid.

[0130] Example 16 Under a nitrogen atmosphere at room temperature, 5-bromo-6-chloro-7-fluoro-3-(hydroxyimino)-1,3-dihydro-2H-indol-2-one (1 g), toluene (10 mL), triphenylphosphine oxide (192 mg), and DIPEA (0.12 mL) were mixed and stirred. Thionyl chloride (1.24 mL) was added little by little so that the internal temperature did not exceed 50 °C, and then heated to an internal temperature of 65-75 °C and stirred for 17 hours. After adding thionyl chloride (1.24 mL) at the same temperature, it was stirred at an internal temperature of 95-105 °C for 6 days. The reaction solution was cooled to room temperature and slowly added dropwise to an aqueous solution (10 mL) of potassium hydrogen phosphate (11.9 g) cooled with ice (so that the internal temperature did not exceed 30 °C). The resulting mixture was filtered while washing with toluene, the filtrate was separated, and the organic layer was washed with an aqueous sodium hydrogen carbonate solution to obtain a toluene solution of 6-bromo-2,4,7-trichloro-8-fluoroquinazoline. To this toluene solution, DIPEA (875 μL) and tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.71 g) were added at room temperature and stirred for 2.5 hours. Water was added for separation, the organic layer was washed with water, and concentrated under reduced pressure. Ethanol was added to the residue and concentrated again under reduced pressure to azeotrope with toluene, and then ethanol (4 mL) was added to the residue to dissolve it. After stirring at 50 °C, it was cooled to room temperature, the precipitated solid was collected by filtration, and dried at 60 °C under reduced pressure to obtain tert-butyl (1S,4S)-5-(6-bromo-2,7-dichloro-8-fluoroquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.27 g) as a solid.

[0131] Example 17 At room temperature, (1S,4S)-5-(6-bromo-2,7-dichloro-8-fluoroquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl (5 g) and tetrahydro-2H-pyran-4-ol (1.24 g) were dissolved in DMF (15 mL), cesium carbonate (9.93 g) was added, and the mixture was stirred. DABCO (228 mg) was added at room temperature, and the mixture was stirred for 20 minutes and then stirred at 55 °C for 1.5 hours. After cooling to room temperature, toluene and water were added and the layers were separated, and the organic layer was washed twice with water. The organic layer was concentrated, ethanol (50 mL) and water (10 mL) were added to the residue, the precipitate was collected by filtration, washed with ethanol / water (1 / 1), and dried under reduced pressure at 60 °C to obtain (1S,4S)-5-{6-bromo-7-chloro-8-fluoro-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl (4.13 g) as a solid.

[0132] Example 18 Under a nitrogen atmosphere, at room temperature, tBuONa (620 mg) was dissolved in DMF (5 mL) and stirred. A solution of (1S)-1-phenylethan-1-ol (821 mg) and tert-butyl (1S,4S)-5-{6-bromo-7-chloro-8-fluoro-2-[(oxan-4-yl)oxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (3 g) in DMF (10 mL) was added at room temperature, and the mixture was stirred for 2 hours. Toluene (15 mL) was added. After 10 minutes, (1S)-1-phenylethan-1-ol (82.1 mg) and tBuONa (62 mg) were added, and the mixture was stirred for 45 minutes. Then, tBuONa (103 mg) was added. After stirring at room temperature for 45 minutes, toluene and water were added, and liquid separation was performed. The organic layer was washed twice with water, dried over sodium sulfate, insoluble matters were filtered off, and the mixture was concentrated under reduced pressure. EtOH was added to the residue and stirred. The precipitated solid was collected by filtration, washed with EtOH, and dried at 50 °C under reduced pressure to obtain tert-butyl (1S,4S)-5-{6-bromo-7-chloro-2-[(oxan-4-yl)oxy]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (3.07 g) as a solid.

[0133] Example 19 (1S,4S)-5-{6-Bromo-7-chloro-2-[(oxan-4-yl)oxy]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl (1 g), toluene (7 mL), water (2 mL), tripotassium phosphate (964 mg), and cyclopropylboronic acid (221 mg) were degassed under reduced pressure at room temperature. PdCl2(dppf)·CH2Cl2 (55.4 mg) was added and the mixture was degassed under reduced pressure, then stirred at 80 °C for 16 h. After cooling to room temperature, activated carbon was added to the reaction solution and stirred at room temperature for 30 min. The insoluble matter was filtered off while washing with toluene and water, and the filtrate was separated. The obtained organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain (1S,4S)-5-{7-chloro-6-cyclopropyl-2-[(oxan-4-yl)oxy]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl (0.95 g) as a solid.

[0134] Example 20 6-Fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triphenylmethyl)-2H-indazole (100 mg), (1S,4S)-5-{7-chloro-6-cyclopropyl-2-[(oxan-4-yl)oxy]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl (100 mg), barium hydroxide octahydrate (152 mg), RuPhos (4 mg), 2-methyl-2-butanol (0.8 mL), and water (0.2 mL) were mixed and degassed under reduced pressure. RuPhos Pd G3 (7 mg) was added thereto and the mixture was degassed under reduced pressure, then stirred at 65 °C for 1.5 h. After cooling to room temperature, water (0.6 mL) and activated carbon (10 mg) were added and stirred for 30 min. The insoluble matter was filtered while washing with toluene, and the filtrate was separated. The obtained organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a solid. MeOH / water (4 / 1) was added to the obtained solid, and the precipitated solid was collected by filtration and washed with MeOH / water (4 / 1) (the ratio of isomers derived from axial asymmetry was M:P = 4.5:1). The obtained solid was suspended in MeOH, collected by filtration while washing with MeOH, the obtained solid was suspended in MeOH again, collected by filtration while washing with MeOH, and dried under reduced pressure to obtain tert-butyl (1S,4S)-5-{6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(oxan-4-yl)oxy]-8-[(1S)-1-phenylethoxy]quinazolin-4-yl}-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (53.9 mg, the ratio of isomers derived from axial asymmetry was M:P = 58:1) as a solid.

[0135] Example 21 (3S)-3-[(7-bromo-6-cyclopropyl-2-[(2S)-2-methoxypropoxy]-8-[(1S)-1-(naphthalen-1-yl)ethoxy]quinazolin-4-yl)(methyl)amino]pyrrolidine-1-carboxylic acid tert-butyl (1.40 g), 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triphenylmethyl)-2H-indazole (1.50 g), SPhos (85 mg), SPhos Pd G3 (155 mg), tripotassium phosphate (1.70 g), DOX (30 mL), and water (6 mL) were mixed, and after performing degassing-argon gas substitution several times, the mixture was stirred at 80 °C for 3 hours under an argon atmosphere. Ethyl acetate was added to the cooled reaction suspension, and the mixture was filtered through Celite® while washing with ethyl acetate. The filtrate was washed with water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (3S)-3-[(6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]-8-[(1S)-1-(naphthalen-1-yl)ethoxy]quinazolin-4-yl)(methyl)amino]pyrrolidine-1-carboxylic acid tert-butyl (1.47 g) as a foamy solid.

[0136] Example 22 Under an argon atmosphere, to a solution of 7-bromo-4-tert-butoxy-6-cyclopropyl-2-(ethylsulfanyl)-8-[(1S)-1-(naphthalen-1-yl)ethoxy]quinazoline (1.5 g) in DOX (30 mL) and water (6 mL), 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triphenylmethyl)-2H-indazole (1.17 g), SPhos (81 mg), SPhos Pd G3 (153 mg), and tripotassium phosphate (1.66 g) were added, and the mixture was stirred at 80 °C for 3 hours under an argon atmosphere. After allowing to cool to room temperature, water and ethyl acetate were added to the reaction solution and separated, and the organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 4-tert-butoxy-6-cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-(naphthalen-1-yl)ethoxy]quinazoline (1.00 g) as a foamy solid.

[0137] Example 23 Under an argon atmosphere, (3S)-3-[{6-cyclopropyl-7-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-2-[(2S)-2-methoxypropoxy]-8-[(1S)-1-(naphthalen-1-yl)ethoxy]quinazolin-4-yl}(methyl)amino]pyrrolidine-1-carboxylic acid tert-butyl (1.00 g, about 83% purity), 4-bromo-6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazole (630 mg), SPhos (90.0 mg), barium hydroxide octahydrate (1.06 g), 2-methyl-2-butanol (4.15 mL), and water (4.15 mL) were mixed and degassed under reduced pressure. SPhos Pd G3 (170 mg) was added to the reaction solution, and after degassing again under reduced pressure, the mixture was stirred at 60 °C for 3 hours. It was cooled to room temperature, activated carbon (80 mg) was added, and the mixture was stirred for 68 hours. The insoluble matter was filtered using Celite (registered trademark) and washed with toluene (33 mL) and water (17 mL). The filtrate was separated, and the organic layer was washed twice with water (4.1 mL) and concentrated under reduced pressure. Toluene (4 mL) and heptane (6 mL) were added to the residue (the ratio of isomers derived from axial chirality was M:P = 8.2:1), and further amino group-modified silica gel (3.3 g), neutral silica gel (1.6 g), and heptane (40 mL) were added, and the mixture was stirred for 2 hours and 40 minutes. The mixture was filtered, washed with heptane and ethyl acetate, and the filtrate was concentrated. Methanol was added to the residue and stirred, and then concentrated. Half of the residue was purified twice by silica gel column chromatography (hexane / ethyl acetate) and purified by silica gel column chromatography (amino group-modified silica gel, hexane / ethyl acetate) to obtain (3S)-3-[{(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]-8-[(1S)-1-(naphthalen-1-yl)ethoxy]quinazolin-4-yl}(methyl)amino]pyrrolidine-1-carboxylic acid tert-butyl (105 mg) as a foamy solid. The starting materials used in Example 23 were prepared by the following method. Under an argon atmosphere, (3S)-3-[(7-chloro-6-cyclopropyl-2-[(2S)-2-methoxypropoxy]-8-[(1S)-1-(naphthalen-1-yl)ethoxy]quinazolin-4-yl)(methyl)amino]pyrrolidine-1-carboxylic acid tert-butyl (2.21 g), 5,5,5',5'-tetramethyl-2,2'-bi-1,3,2-dioxaborolane (1.51 g), potassium propionate (1.12 g), 2-(2,6-dimethoxyphenyl)-3-(diphenylphosphanyl)-1-methyl-1H-indole (0.15 g), and toluene (17.7 mL) were mixed at room temperature and degassed under reduced pressure. Di-μ-chlorobis(2'-amino-1,1'-biphenyl-2-yl-C,N)dipalladium(II) (0.05 g) was added to the reaction solution, which was then degassed under reduced pressure and stirred, followed by stirring at 70 °C for 24 hours. The reaction solution was cooled to room temperature, the insoluble matter was filtered through Celite® and washed with toluene, and then the filtrate was concentrated under reduced pressure. Methanol was added to the residue and azeotroped three times, then methanol (6 mL) was added to dissolve it, and the solution was added dropwise to water (80 mL) while washing with methanol (2 mL). The precipitated solid was collected by filtration and dried under reduced pressure to obtain (3S)-3-[(6-cyclopropyl-7-(5,5-dimethyl-1,3,2-dioxaborolane-2-yl)-2-[(2S)-2-methoxypropoxy]-8-[(1S)-1-(naphthalen-1-yl)ethoxy]quinazolin-4-yl)(methyl)amino]pyrrolidine-1-carboxylic acid tert-butyl (2.99 g, about 83% purity) as a solid.

[0138] Example 34 At room temperature, 4-tert-butoxy-7-chloro-6-cyclopropyl-2-[(2S)-2-methoxypropoxy]-8-[(1S)-1-(naphthalen-1-yl)ethoxy]quinazoline (0.7 g), DOX (5.6 mL), water (1.4 mL), 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triphenylmethyl)-2H-indazole (814 mg), barium hydroxide octahydrate (1.24 g), and SPhos (53.7 mg) were mixed and degassed under reduced pressure. Subsequently, SPhos Pd G3 (102 mg) was added, degassed under reduced pressure, and stirred at 65 °C for 6 hours. After cooling to room temperature, activated carbon (70 mg) was added and stirred for 10 minutes, then filtered and washed with toluene. The filtrate was separated, the organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated. iPrOH (14 mL) was added to the residue to dissolve it, and water (4.9 mL) was added little by little. The resulting solid was collected by filtration, washed with iPrOH / water (3 / 1), and dried under reduced pressure to obtain 4-tert-butoxy-6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]-8-[(1S)-1-(naphthalen-1-yl)ethoxy]quinazoline (0.74 g) as a solid.

[0139] Example 35 At room temperature, 4-{7-bromo-4-tert-butoxy-6-cyclopropyl-8-[(1S)-1-phenylethoxy]quinazolin-2-yl}piperazine-1-carboxylic acid 2-(trimethylsilyl)ethyl (200 mg), 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triphenylmethyl)-2H-indazole (220 mg), SPhos Pd G3 (47 mg), SPhos (25 mg), anhydrous barium hydroxide (73 mg), toluene (6 mL), and water (6 mL) were mixed. After performing degassing-argon gas substitution several times, the mixture was stirred at 60 °C for 3 hours under an argon atmosphere. The reaction mixture was allowed to cool, ethyl acetate was added, and the mixture was filtered through Celite®. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 4-{4-tert-butoxy-6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(1S)-1-phenylethoxy]quinazolin-2-yl}piperazine-1-carboxylic acid 2-(trimethylsilyl)ethyl (237 mg) as a foamy solid.

[0140] Example 36 A mixture of 7-bromo-4-tert-butoxy-2-chloro-8-fluoro-6-iodoquinazoline (21.0 g), molecular sieves 4A (21.0 g), DIPEA (10.35 mL), and THF (210 mL) was added to 2-(trimethylsilyl)ethyl piperazine-1-carboxylate (8.9 g), and the mixture was stirred at 40 °C for 12 hours. Water (400 mL) was added to the mixture, and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed twice with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. MeOH (100 mL) was added to the obtained residue to powderize it, and it was collected by filtration and dried under reduced pressure to obtain 2-(trimethylsilyl)ethyl 4-(7-bromo-4-tert-butoxy-8-fluoro-6-iodoquinazolin-2-yl)piperazine-1-carboxylate (12.2 g) as a solid.

[0141] Example 37 Under an argon gas atmosphere, to a mixture of 2-(trimethylsilyl)ethyl 4-(7-bromo-4-tert-butoxy-8-fluoro-6-iodoquinazolin-2-yl)piperazine-1-carboxylate (2.00 g), (1S)-1-phenylethan-1-ol (0.42 g), and THF (20 mL), tBuOK (0.72 g) was added while stirring at room temperature, and the mixture was stirred at room temperature for 40 minutes. Ice and a saturated aqueous ammonium chloride solution were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography (amino group-modified silica gel, hexane / ethyl acetate) to obtain 2-(trimethylsilyl)ethyl 4-{7-bromo-4-tert-butoxy-6-iodo-8-[(1S)-1-phenylethoxy]quinazolin-2-yl}piperazine-1-carboxylate (2.13 g) as a foamy solid.

[0142] Example 38 At room temperature, 2-(trimethylsilyl)ethyl 4-{7-bromo-4-tert-butoxy-6-iodo-8-[(1S)-1-phenylethoxy]quinazolin-2-yl}piperazine-1-carboxylate (2.02 g), cyclopropylboronic acid (400 mg), tripotassium phosphate (2.00 g), PdCl2(dppf)·CH2Cl2 (230 mg), MeCN (50 mL) and water (10 mL) were mixed and stirred at 90 °C for 6 hours under an argon atmosphere. The reaction mixture was allowed to cool, ethyl acetate was added, and the mixture was filtered through Celite®. Water was added to the filtrate to separate the two layers, and the organic layer was dried over anhydrous magnesium sulfate. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 2-(trimethylsilyl)ethyl 4-{7-bromo-4-tert-butoxy-6-cyclopropyl-8-[(1S)-1-phenylethoxy]quinazolin-2-yl}piperazine-1-carboxylate (1.41 g) as a foamy solid.

[0143]

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

[0144]

Table 2-1

Table 2-2

Table 2-3

Table 2-4

Table 2-5

[0145]

Table 3

[0146]

Table 4

Industrial Applicability

[0147] According to the method of the present invention, in the production of a compound of formula (I) having axial asymmetry or a salt thereof, by controlling the axial asymmetry using a chiral auxiliary group, one of the axially asymmetric compounds or a salt thereof can be selectively obtained. By using the method of the present invention, the yield can be increased compared to the conventional method, and the fractionation step can be reduced, which is very useful.

Claims

1. A compound of the following formula (I) or a salt thereof: 【Chemistry 1】 [In the formula, A is N or CH; Y is a bond, -CH 2 -, -O-, -S- or -NR Y - and R Y is H or optionally substituted C 1-3 is alkyl, R 1 is represented by the following formula (IV) or (V): 【Chemistry 2】 Ring A is an optionally substituted 7- to 9-membered bridged heterocycloalkane containing 1 to 2 nitrogen atoms or an optionally substituted 4- to 6-membered heterocycloalkane containing 1 to 2 nitrogen atoms; Z is a bond, -CH 2 -, -O-, -S- or -N(R Z1 )-and R Z1 is H or optionally substituted C 1-3 is alkyl, PG 1 is a protecting group for NH contained in ring A, PG 2 is a protecting group for OH, R 2 may be substituted C 1-15 alkyl or optionally substituted heterocycloalkyl; R 3 But halogen, C 3-6 Cycloalkyl, vinyl, or optionally substituted C 1-3 is alkyl, R 4 is represented by the following formula (VI) or (VII): 【Chemistry 3】 R 4A But, C 1-3 is alkyl, R 4B is naphthyl, phenanthrenyl, or optionally substituted phenyl; R 5 is represented by the following formula (VIII) or (IX), 【Chemistry 4】 PG ３ is a protecting group for NH, R 5A is H, methyl, F or Cl; R 5B is Cl, methyl, ethyl or vinyl; * indicates an asymmetric axis. A method for producing A step of reacting a compound of the following formula (IIA) or a salt thereof with a compound of the following formula (IIIA) or a salt thereof, or reacting a compound of the following formula (IIB) or a salt thereof with a compound of the following formula (IIIB) or a salt thereof to obtain a compound of the formula (I) or a salt thereof: 【Chemistry 5】 [In the formula, A, Y, R Y , R 1 , ring A, Z, R Z1 , P.G. 1 , P.G. 2 , R 2 , R 3 , R 4 , R 4A , R 4B , R 5 , P.G. ３ , R 5A , R 5B , and * are as defined above, X is Cl, Br, I, a methanesulfonyloxy group, or a p-toluenesulfonyloxy group; BLG is a boronic acid group, a boronic ester group, a trifluoroborate group, or a triolborate group. Including, The above-mentioned method comprises selectively producing one of the axially chiral compounds of the above formula (I) or salts thereof having axial asymmetry or a salt thereof.

2. Reacting a compound of formula (IIA) or a salt thereof with a compound of formula (IIIA) or a salt thereof, Where: X is Cl or Br; Y is -O- or -S-; R 1 The following formulas (IV-1), (IV-2), (IV-3) and (V): 【Chemistry 6】 is a group selected from the group consisting of R 2 is tetrahydropyranyl, or -OCH 3 C which may be substituted with 1-3 is alkyl, R 3 is cyclopropyl, R 4 The compound represented by the following formulas (VI-1), (VI-2) and (VI-3): 【Chemistry 7】 is a group selected from the group consisting of R 5 The following formulas (VIII-1) and (IX-1): 【Chemistry 8】 The method of claim 1 , wherein the group is selected from the group consisting of:

3. Reacting a compound of formula (IIA) or a salt thereof with a compound of formula (IIIA) or a salt thereof, Where: A is N, R 1 The following formulas (IV-1), (IV-2) and (V): 【Chemistry 9】 is a group selected from the group consisting of R 5 The compound represented by the following formula (VIII-1): 【Chemistry 10】 The method according to claim 2 , wherein the group is represented by the formula:

4. The compound of formula (IIA) or a salt thereof is represented by the following formula (IIA-1): 【Chemistry 11】 A compound represented by the formula: The compound of formula (IIIA) or a salt thereof is represented by the following formula (IIIA-1): 【Chemistry 12】 A compound represented by the formula: The process is as follows: 【Chemistry 13】 The method according to claim 3, comprising the step of obtaining a compound represented by formula (I-1) by:

5. The following steps: 【Chemistry 14】 The method according to claim 4, comprising obtaining compound (1) or a salt thereof by:

6. The following compound (16) and the following compound (17) can be produced by the following steps: 【Chemistry 15】 6. The method of claim 5, comprising obtaining compound (14) by:

7. The following compound (2) can be produced by the following process: 【Chemistry 16】 The method of claim 5, comprising obtaining the compound of formula (IIA-1) by:

8. The following compound (24) and the following compound (25) are subjected to the following steps: 【Chemistry 17】 7. The method of claim 6, comprising obtaining compound (20) by:

9. The following compound (27) can be produced by the following steps: 【Chemistry 18】 The method according to any one of claims 4 to 8, comprising obtaining the compound of formula (IIIA-1) by:

10. The compound of formula (IIA) or a salt thereof is represented by the following formula (IIA-2): 【Chemistry 19】 A compound represented by the formula: The compound of formula (IIIA) or a salt thereof is represented by the following formula (IIIA-1): 【Chemistry 20】 A compound represented by the formula: The process is as follows: 【Chemistry 21】 The method according to claim 3, comprising the step of obtaining a compound represented by formula (I-1) by:

11. The following steps: 【Chemical 22】 The method according to claim 10, comprising obtaining compound (1) or a salt thereof by:

12. The following steps: 【Chemistry 23】 The method according to claim 10 or 11, comprising obtaining the compound of formula (IIA-2) by:

13. Reacting a compound of formula (IIB) or a salt thereof with a compound of formula (IIIB) or a salt thereof, Where: X is Cl or Br; Y is -O- or -S-; R 1 The following formulas (IV-1), (IV-2), (IV-3) and (V): 【Chemistry 24】 is a group selected from the group consisting of R 2 is tetrahydropyranyl, or -OCH 3 C which may be substituted with 1-3 is alkyl, R 3 is cyclopropyl, R 4 The compound represented by the following formulas (VI-1), (VI-2) and (VI-3): 【Chemistry 25】 is a group selected from the group consisting of R 5 The following formulas (VIII-1) and (IX-1): 【Chemistry 26】 The method of claim 1 , wherein the group is selected from the group consisting of:

14. Reacting a compound of formula (IIB) or a salt thereof with a compound of formula (IIIB) or a salt thereof, Where: A is N, R 1 The following formulas (IV-1), (IV-2) and (V): 【Chemical 27】 is a group selected from the group consisting of R 5 The compound represented by the following formula (VIII-1): 【Chemistry 28】 The method according to claim 1 , wherein the group is represented by the formula:

15. Y is a bond; R 2 The method of claim 1, wherein:

16. R 2 The following formulas (X-1), (X-2), (X-3), (X-4), (X-5), (X-6) and (X-7): 【Chemical Formula 29】 is a group selected from the group consisting of R 2A is H or optionally substituted C 1-3 is alkyl, V is PG 4 or optionally substituted C 1-3 is alkyl, PG 4 The method of claim 15 , wherein is a protecting group for NH.

17. Reacting a compound of formula (IIA) or a salt thereof with a compound of formula (IIIA) or a salt thereof, The compound of formula (I) is a compound represented by the following formula (I-2): 【Chemistry 30】 The compound of formula (IIA) is represented by the following formula (IIA-3): 【Chemistry 31】 A compound represented by the formula: The process is as follows: 【Chemistry 32】 The method according to claim 1, comprising obtaining a compound represented by formula (I-2) by:

18. The method according to claim 17, comprising obtaining a compound of formula (IIA-3) by the steps of: 【Chemical 33】

19. A compound represented by any one of the following formulas or a salt thereof: 【Hua 34-1】 【Chemistry 34-2】 【Chemistry 34-3】 【Chemistry 34-4】

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