Selective production of single axially chiral compound

Abstract

As one embodiment, the present invention 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 for 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), it is preferable that R4 is formula (VI) or (VII) and R5 is formula (VIII) or (IX) (each of the above formulas and R4 and R5 are defined in the specification).

Description

Selective production of single axially chiral compounds

[0001] The present invention relates to a method for selectively producing one axially chiral compound among compounds having axial chirality. More specifically, the present invention relates to a method for selectively producing one axially chiral compound among compounds of formula (I) having axial chirality or salts thereof. The present invention also relates to a method for efficiently producing a compound to be used in the selective method for producing an axially chiral compound, and an axially chiral compound obtained by the selective method for producing an axially chiral compound.

[0002] Patent Document 1 (WO 2022 / 173032) describes a compound represented by the following formula (A) or a salt thereof as a quinazoline compound for inducing the degradation of G12D mutant KRAS protein, as well as methods for producing the compound or a salt thereof: (For the definition of each group in the formula, see Patent Document 1.)

[0003] International Publication No. 2022 / 173032

[0004] As mentioned above, Patent Document 1 describes a method for producing the compound represented by the above formula (A). However, since a compound having an asymmetric axis is obtained in the production process, a production intermediate or a target compound can be synthesized as a mixture of stereoisomers based on the compound. For example, in Production Example 11 of Patent Document 1, tert-butyl (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-carboxylate (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) are used. tert-butyl (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-carboxylate (1.42 g) as the M form and tert-butyl (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-carboxylate (1.37 g) as the P form It has been described that the compound represented by formula (IIA) can be obtained from the axially chiral compound (IIA), and the M:P ratio in Example 11 was approximately 1:1. Even if the compound is synthesized as a mixture of stereoisomers, each stereoisomer can be isolated by conventional fractionation procedures, such as 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 of the axially chiral compounds. Furthermore, if a single axially chiral compound represented by formula (IIA) is obtained, compound (A) can be efficiently produced. Furthermore, from the viewpoint of cost reduction, it is desirable to establish a new synthetic method for compound represented by formula (IIA) for use in the selective production of axially chiral compounds.

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

[0006] The present inventors have, through extensive research, discovered a method for selectively obtaining one axially chiral compound or a salt thereof by controlling axial asymmetry using a chiral auxiliary. In the course of developing the above method, the present inventors have also discovered a method for efficiently producing a compound to be used in a selective method for producing an axially chiral compound, and an axially chiral compound obtained by the selective method for producing an axially chiral compound.

[0007] The present inventors have also discovered a method for producing a compound of formula (#1) described below or a salt thereof by reacting a compound of formula (#2) described below with a diazo transfer reagent.

[0008] Although not limited thereto, the present invention includes the following aspects: [1] A compound of the following formula (I) or a salt thereof: wherein A is N or CH, and Y is a bond, —CH—, —O—, —S—, or —NR Y - and R Y is H or optionally substituted C 1-3 is alkyl, and R 1 is the following formula (IV) or (V), Ring A is a 7- to 9-membered bridged heterocycloalkane containing 1 to 2 nitrogen atoms which may be substituted or a 4- to 6-membered heterocycloalkane containing 1 to 2 nitrogen atoms which may be substituted, and Z is a bond, —CH—, —O—, —S—, or —N(R Z1 )- and R Z1 is H or optionally substituted C 1-3 alkyl, PG 1 is a protecting group for NH contained in ring A, and PG 2 is a protecting group for OH, and R 2 may be substituted C 1-15 alkyl or optionally substituted heterocycloalkyl, R 3 But halogen, C 3-6cycloalkyl, vinyl, or optionally substituted C 1-3 is alkyl, and R 4 is the following formula (VI) or (VII), R 4A But C 1-3 is alkyl, and R 4B is naphthyl, phenanthrenyl, or optionally substituted phenyl, and R 5 is represented by the following formula (VIII) or (IX), PG ３ is a protecting group for NH, and R 5A is H, methyl, F or Cl, R 5B is Cl, methyl, ethyl or vinyl, and * indicates an asymmetric axis, comprising the steps 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: [In the formula, A, Y, R Y , R 1 , rings 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 5Band * are as defined above, X is Cl, Br, I, a methanesulfonyloxy group or a p-toluenesulfonyloxy group, and BLG is a boronic acid group, a boronic ester group, a trifluoroborate group or a triolborate group, wherein the axially asymmetric compound or salt thereof of the compound of formula (I) having axial asymmetry is selectively produced. [2] The method comprises reacting a compound of formula (IIA) or a salt thereof with a compound of formula (IIIA) or a salt thereof, wherein X is Cl or Br, Y is -O- or -S-, and R 1 The following formulas (IV-1), (IV-2), (IV-3) and (V): and R is a group selected from the group consisting of 2 C optionally substituted with tetrahydropyranyl or -OCH 1-3 is alkyl, and R 3 is cyclopropyl, and R 4 is represented by the following formulas (VI-1), (VI-2) and (VI-3): and R is a group selected from the group consisting of 5 The following formulas (VIII-1) and (IX-1): [3] The method according to [1], which comprises reacting a compound of formula (IIA) or a salt thereof with a compound of formula (IIIA) or a salt thereof, wherein A is N, and R 1 The following formulas (IV-1), (IV-2) and (V): and R is a group selected from the group consisting of 5 is represented by the following formula (VIII-1): [4] The method according to [2], wherein the compound of formula (IIA) or a salt thereof is a group represented by the following formula (IIA-1): The compound of formula (IIIA) or a salt thereof is a compound represented by the following formula (IIIA-1): and a compound represented by the formula (I) above, which is obtained by the following steps: [5] The method according to [3], comprising a step of obtaining a compound represented by formula (I-1) by the following steps: [6] The method according to [4], comprising obtaining compound (1) or a salt thereof by the following steps from compound (16) and compound (17): [7] The method according to [5], comprising obtaining the compound (14) by the following steps from the following compound (2): [8] The method according to [5], comprising obtaining a compound of formula (IIA-1) by the following steps from the following compound (24) and the following compound (25): [9] The method according to [6], comprising obtaining the compound (20) by the following steps from the following compound (27):

[10] The method according to any one of [4] to [8], wherein the compound of formula (IIA) or a salt thereof is a compound of the following formula (IIA-2): The compound of formula (IIIA) or a salt thereof is a compound represented by the following formula (IIIA-1): and a compound represented by the formula (I) above, which is obtained by the following steps:

[11] The method according to [3], comprising a step of obtaining a compound represented by formula (I-1) by the following steps:

[12] The method according to

[10] , comprising obtaining compound (1) or a salt thereof by the following steps:

[13] A compound represented by any one of the following formulas or a salt thereof:

[14] A method of 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-, and R 1 The following formulas (IV-1), (IV-2), (IV-3) and (V): and R is a group selected from the group consisting of 2C optionally substituted with tetrahydropyranyl or -OCH 1-3 is alkyl, and R 3 is cyclopropyl, and R 4 is represented by the following formulas (VI-1), (VI-2) and (VI-3): and R is a group selected from the group consisting of 5 The following formulas (VIII-1) and (IX-1):

[15] The method according to [1], which comprises reacting a compound of formula (IIB) or a salt thereof with a compound of formula (IIIB) or a salt thereof, wherein A is N, and R 1 The following formulas (IV-1), (IV-2) and (V): and R is a group selected from the group consisting of 5 is represented by the following formula (VIII-1):

[16] The method according to

[14] , wherein the compound of formula (IIB) or a salt thereof is a group represented by the following formula (IIB-1): The compound of formula (IIIB) or a salt thereof is a compound represented by the following formula (IIIB-1): and a compound represented by the formula (I) above, which is obtained by the following steps:

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

[14] to

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

[18] The method according to

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

[19] The method according to

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

[20] The method according to [1], wherein the compound is produced in a solvent inert to the reaction at 20°C to 140°C.

[21] The method according to [1], wherein the compound is produced in a solvent inert to the reaction at 20°C to 140°C.

[22] The method according to [1], wherein the compound is produced in a solvent inert to the reaction at 20°C to 140°C.

[23] The method according to [1], wherein the compound is produced in a solvent inert to the reaction at 20°C to 140°C.

[24] The method according to [1], wherein the compound is produced in a solvent inert to the reaction at 20°C to 140°C.

[25] The method according to [1], wherein the compound is produced in a solvent inert to the reaction at 20°C to 140°C.

[26] The method according to [1], wherein the compound is produced in a solvent inert to the reaction at 20°C to 140°C.

[27] The method according to [1], wherein the compound is produced in a solvent inert to the reaction at 20°C to 140°C. 5 The following formulas (VIII-1) and (IX-1):

[21] R 4 is represented by the following formulas (VI-1), (VI-2) and (VI-3):

[22] The method according to

[20] , wherein R is a group selected from the group consisting of 3 But C 3-6 cycloalkyl, vinyl, or optionally substituted C 1-3 alkyl, preferably R 3 C 3-6

[23] The method according to any one of

[20] to

[22] , wherein X is Cl, Br or I, preferably X is Cl or Br.

[24] The method according to any one of

[20] to

[23] , wherein A is N.

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

[26] The method according to any one of

[20] to

[24] , wherein Y is a bond, and R 2

[27] The method according to any one of

[20] to

[25] , wherein R is an 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. 2 are represented by the following formulae (X-1), (X-2), (X-3), (X-4), (X-5), (X-6) and (X-7): and R is a group selected from the group consisting of 2A is H or optionally substituted C 1-3 alkyl, and V is PG 4 or optionally substituted C 1-3 alkyl, PG 4

[28] The method according to

[26] , wherein R is a protecting group for NH. 2 is the following formula (X-1), R 2A But H or C 1-3 alkyl, and V is PG 4 or C 1-3 alkyl, PG 4 is a protecting group for NH, and R 3 is cyclopropyl, and R 4 is the following formula (VI-1): R 5 is the following formula (VIII-1): The method according to any one of

[20] to

[27] .

[29] A compound represented by the following formula (#1) or a salt thereof: [In the formula, R 11 may be substituted C 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl or an optionally substituted 4- to 6-membered saturated heterocyclic group containing one heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen; R 12A and R 12B are the same or different and represent H or optionally substituted C 1-6 alkyl or R 12A and R 12B may be substituted together with the carbon to which they are attached. 3-6 cycloalkyl or forms an optionally substituted 4- to 6-membered saturated heterocyclic ring containing one heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen, R 13 H; halogen; C 1-3 Alkyl; -SO2CH3; C 3-6 cycloalkyl; an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen; an optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen; or a 6-membered heteroaryl containing 1 to 3 nitrogen atoms, and W is an optionally substituted phenyl or an optionally substituted 6-membered heteroaryl containing 1 to 3 nitrogen atoms.], comprising the steps of reacting a compound of the following formula (#2) with a diazo transfer reagent to obtain a compound of the above formula (#1) or a salt thereof: [In the formula, R 11 , R 12A , R 12B , R 13and W is as defined above.

[30] The method according to

[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 is cycloalkyl, and R 12A and R 12B are the same or different and may be substituted with H or a group selected from the group consisting of F, OH, and N(CH3)2; 1-3 alkyl or R 12A and R 12B together with the carbon to which they are attached to form a cyclopropyl, and R 13 is H, halogen or a group selected from the group consisting of: R 13A , R 13B are the same or different and may be substituted with H or OH; 1-3 The method according to

[29] or

[30] , wherein R is alkyl and W is phenyl.

[32] 11 is isopropyl, and R 12A is H and R 12B C optionally substituted with OH 1-3 is alkyl, and R 13 is the group R 13A But C 1-3The method according to any one of

[29] to

[31] , wherein W is alkyl, and W is phenyl.

[33] The method according to any one of

[29] to

[32] , wherein the diazo transfer reagent is a 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] , wherein a basic reagent is used.

[36] The method according to any one of

[29] to

[35] , wherein an additive is used.

[37] The method according to any one of

[29] to

[36] , wherein a polar solvent is used.

[38] The method according to any one of

[29] to

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

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

[28] , comprising the method according to any one of

[29] to

[38] as a step.

[40] The following compound or a salt thereof:

[41] The following compound or a salt thereof:

[0009] According to one embodiment of the present invention, a chiral auxiliary is introduced in a production process, and the chiral axis is controlled using the chiral auxiliary, thereby making it possible to selectively obtain one axially chiral compound or a salt thereof. Furthermore, according to the present invention, it is possible to efficiently produce a compound to be used in a selective method for producing an axially chiral compound, and it is also possible to obtain an axially chiral compound by a selective method for producing an axially chiral compound.

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

[0011] The present invention will be described in detail below.

[0012] 1. Definitions As described above, one aspect of the present invention relates to a method for selectively obtaining one axially chiral compound or a salt thereof. In this specification, the expression "selectively obtaining one axially chiral compound or a salt thereof" means that the ratio of the M isomer to the P isomer (M:P ratio) is not 1:1, but rather that one axially chiral compound or a salt thereof is obtained in a higher proportion than the other axially chiral compound or a salt thereof. In one aspect, the method of the present invention provides a higher proportion of the M isomer than the P isomer, and the ratio (M:P ratio) is not particularly limited, and may be, for example, 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, or 90:1 or more. When the M isomer is obtained in a higher proportion than the P isomer, the expression "1.3:1 or more" means that 1.3 units or more of the M isomer are obtained per 1 unit (gram or molar amount) of the P isomer. For example, this means that 1.3 g or more of the M isomer is obtained per 1 g of the P isomer. In the present invention, since the molecular weights of the M and P isomers are the same, the M:P ratio in terms of gram ratio is the same as the M:P ratio in terms of molar ratio. In one embodiment, the P isomer is obtained in a higher proportion than the M isomer by the method of the present invention. The ratio (M:P ratio) is not particularly limited, but is, for example, 1:1.3 or more, 1:1.4 or more, 1:1.5 or more, 1:1.6 or more, 1:2 or more, or 1:5 or more. When the P isomer is obtained in a higher proportion than the M isomer, as described above, the expression "1:1.3 or more" means that 1.3 units or more of the P isomer are obtained per 1 unit of the M isomer. In addition, in a method for producing an axially asymmetric compound that does not use a chiral auxiliary, the target compound is obtained as a mixture of stereoisomers with an M:P ratio of about 1: 1. Compared to such methods, the method of the present invention is advantageous in that it can enhance the stereoselectivity when obtaining the desired axially asymmetric compound.

[0013] In one aspect, the present invention relates to a method for producing an axially chiral compound using a chiral auxiliary, which produces an axially chiral compound having a chiral auxiliary. The inventors have also found that axially chiral compounds having a chiral auxiliary are easier to separate and fractionate than compounds not having a chiral auxiliary. That is, from a mixture of axially chiral compounds (M and P isomers) having a chiral auxiliary obtained by the production method of the present invention, one of the axially chiral compounds can be purified to high purity by a simple procedure such as recrystallization. Furthermore, one of the axially chiral compounds can also be purified to high purity by a fractionation procedure such as conventional column chromatography. That is, the production method of the present invention can simultaneously improve the yield of a target compound having a desired stereoisomerism and reduce steps such as separation and fractionation, thereby contributing to reduced production costs.

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

[0015] <HPLC analysis conditions 1> ・Column: InfinityLab Poroshell 120 EC-C8, 2.1 x 100 mm, 2.7 μm (Agilent) ・Mobile phase: (A) pH 2.5 aqueous HClO4solution; (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℃ ・Detection wavelength: 254 nm

[0016] <HPLC analysis conditions 2> ・Kurora: 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) ・Dissolution method: B) 45% (0 min)→70% (8 min)→70% (20 min)→95% (21 min)→95% (23 min) ・Flow rate: 1.0 mL / min ・Current temperature: 40℃ ・Output wavelength: 210 nm

[0017] <HPLC Analysis Conditions 3> ・Cell: 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 ・Cell temperature: 40°C ・Detection wavelength: 254 nm

[0018] <HPLC Analysis Conditions 4> ・Cell: 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 ・Cell temperature: 40°C ・Detection wavelength: 254 nm

[0019] <HPLC Analysis Conditions 5> ・Cell: YMC-Pack C4, 4.6 × 150 mm, 3 μm (YMC) ・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 ・Cell temperature: 40°C ・Detection wavelength: 220 nm

[0020] <HPLC analysis condition 6> Column: ZORBAX RRHD Eclipse Plus C18, 2.1 x 50 mm, 1.8 μm (Agilent) 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 to 2 mg of compound was dissolved in MeOH, an appropriate amount of 4 M hydrochloric acid / ethyl acetate was added, and the mixture was shaken several times to remove the protecting groups, followed by HPLC measurement.

[0021] <HPLC analysis conditions 7> ・Column: InfinityLab Poroshell 120 EC-C8, 2.1 x 100 mm, 2.7 μm (Agilent) ・Mobile phase: (A) pH 2.5 aqueous HClO4solution; (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℃ ・Detection wavelength: 254 nm

[0022] <HPLC analysis conditions 8> ・Column: YMC-Pack C4, 4.6 mm × 150 mm, 3 μm (YMC) ・Mobile phase: (A) pH7, 10 mM aqueous K2HPO4buffer 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℃ ・Detection wavelength: 220 nm

[0023] <HPLC analysis conditions 9> ・Column: YMC-Pack Pro C4, 2.0 x 100 mm, 3μm (YMC) ・Mobile phase: (A) pH7, 10 mM aqueous K2HPO4buffer solution / MeCN (95 / 5); (B) MeCN ・Elution method: B) 74% (0 min)→74% (60 min) ・Flow rate: 0.4 mL / min ・Column temperature: 40℃ ・Detection wavelength: 220 nm

[0024] "C 1-15 The term "alkyl" refers to a straight-chain or branched alkyl 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., and in one embodiment is n-propyl, and in another embodiment is ethyl (hereinafter, the number of carbon atoms will be expressed in the same manner). 1-6 The term "alkyl" refers to a straight-chain or branched alkyl 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., and in one embodiment is isopropyl. 1-3 The term "alkyl" refers to a straight-chain or branched alkyl having 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, or isopropyl, and in one embodiment, n-propyl, ethyl, or methyl, in one embodiment, n-propyl, in one embodiment, ethyl, or in one embodiment, methyl.

[0025] "C 3-6 The term "cycloalkyl" refers to cycloalkyl having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and in one embodiment, cyclopropyl.

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

[0027] "Heterocycloalkyl" refers to 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 embodiment, the "heterocycloalkyl" may contain 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms, or may contain 1 to 2 nitrogen atoms. In another embodiment, the "heterocycloalkyl" may be a 4- to 6-membered saturated heterocyclic group, or may be a 5- to 6-membered saturated heterocyclic group. In addition, 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, and dioxothiomorpholinyl; certain embodiments include tetrahydropyranyl and piperazinyl; certain embodiments include tetrahydropyranyl, and certain embodiments include piperazinyl.

[0028] A "bridged heterocycloalkane" is a 7- to 9-membered bridged heterocycle containing 1 or 2 nitrogen atoms as ring-constituting atoms. One embodiment of the "bridged heterocycloalkane" is a "7- to 9-membered bridged heterocycloalkane containing 1 or 2 nitrogen atoms", and examples thereof include diazabicyclo[2.2.2]octane, diazabicyclo[3.2.1]octane, diazabicyclo[3.1.1]heptane, diazabicyclo[2.2.1]heptane, and diazabicyclo[3.3.1]nonane. One embodiment is diazabicyclo[2.2.1]heptane, and one embodiment is 2,5-diazabicyclo[2.2.1]heptane.

[0029] "Halogen" means F, Cl, Br, and I. In one embodiment, halogen is F, Cl, or Br, in another embodiment, F or Cl, in another embodiment, F or Br, in one embodiment, F, in one embodiment, Cl, or in one embodiment, Br.

[0030] The term "OH-protecting group" refers to a substituent that protects OH from a specific chemical reaction. Some 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, and another embodiment is a tert-butyl group.

[0031] The term "NH-protecting group" refers to a substituent that protects NH from a specific chemical reaction. Some 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. Some embodiments include a tert-butoxycarbonyl group, a triphenylmethyl group, and a tetrahydropyranyl group. Some embodiments include a tert-butoxycarbonyl group, a 2-(trimethylsilyl)ethoxycarbonyl group, a triphenylmethyl group, and a tetrahydropyranyl group.

[0032] In this specification, "optionally substituted" means unsubstituted or having 1 to 5 substituents. In one embodiment, it means unsubstituted or having 1 to 3 substituents. When multiple substituents are present, the 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 3-6Some embodiments of the permissible substituents in "optionally substituted cycloalkyl," "optionally substituted 7- to 9-membered bridged heterocycloalkane containing 1 to 2 nitrogen atoms," "optionally substituted 4- to 6-membered saturated heterocyclic group containing one heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen," "optionally substituted 4- to 6-membered 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" each independently include F, OH, OCH3, N(CH3), 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 It is 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 terms of production technology to replace it with an appropriate protecting group (a group that can be easily converted into the functional group) during the reaction process. Examples of such protecting groups include those described in "Greene's Protective Groups in Organic Synthesis," 5th Edition, by P.G.M. Wuts and T.W. Greene, John Wiley & Sons Inc., 2014. These protecting groups may be appropriately selected depending on 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. The term "protecting group" used herein is not particularly limited as long as it achieves the aforementioned objective. In one embodiment, protecting groups include benzyl, p-methoxybenzyl, benzyloxycarbonyl, tert-butyl(dimethyl)silyl, (trimethylsilyl)ethoxymethyl, acetyl, trifluoroacetyl, benzoyl, tert-butyl, tert-butoxycarbonyl, triphenylmethyl, and tetrahydropyranyl.

[0035] 2. Method for selectively producing one axially chiral compound or a salt thereof by controlling axial chirality using a chiral auxiliary In one aspect, the present invention is a method for selectively producing one axially chiral compound of the compound of formula (I) having axial chirality or a salt thereof, which comprises a step of reacting a compound of formula (IIA) or a salt thereof with a compound of formula (IIIA) or a salt thereof, or a step of reacting a compound of formula (IIB) or a salt thereof with a compound of formula (IIIB) or a salt thereof. In another aspect, the present invention is a method for selectively producing one axially chiral compound of the compound of formula (I) having axial chirality or a salt thereof, which comprises a step of 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.

[0036] In the above method, A is N or CH. Also, 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. Also, in one embodiment, X is Cl, Br, or I, in another embodiment, X is Cl or Br, in one embodiment, X is Cl, and in one embodiment, X is Br.

[0038] In the method, Y is a bond, —CH—, —O—, —S—, or —NR Y -, -S(=O) or -SO2-, and R Y is H or optionally substituted C 1-3 In one embodiment, Y is a bond, —CH—, —O—, —S—, or —NR Y wherein R Y is H or optionally substituted C 1-3 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 the method, R 1 is represented by the following formula (IV) or (V).

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

[0041] R 1 In the formula (I), 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, and Z is a bond, —CH—, —O—, —S—, or —N(R Z1 )- and R Z1is H or optionally substituted C 1-3 alkyl, PG 1 is a protecting group for NH contained in ring A, and the type thereof is not particularly limited, but in one embodiment, it is 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, or a 2,2,2-trichloroethoxycarbonyl group. 2 is a protecting group for OH, and the type thereof is not particularly limited, but in one embodiment is 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, or a triphenylmethyl group.

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

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

[0044] In one aspect, R 2 are represented by the following formulae (X-1), (X-2), (X-3), (X-4), (X-5), (X-6) and (X-7): where R is a group selected from the group consisting of 2A is H or optionally substituted C 1-3 alkyl, and V is PG 4 or optionally substituted C 1-3 alkyl, PG 4 is a protecting group for NH.

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

[0046] In one embodiment, the NH protecting group PG 4 can be one or more selected from the group consisting of the functional groups listed above in the "NH-protecting group", and in one embodiment is a tert-butoxycarbonyl group, a triphenylmethyl group, or a tetrahydropyranyl group, and in another embodiment is a 2-(trimethylsilyl)ethoxycarbonyl group.

[0047] In the above method, R 3 is a halogen, C 3-6 cycloalkyl, vinyl, or optionally substituted C 1-3 In one embodiment, R3 is C 3-6 cycloalkyl, and in one aspect, R 3 is cyclopropyl.

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

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

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

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

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

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

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

[0055] In the method, BLG is a boronic acid group, a boronic ester group, a trifluoroborate group, or a triolborate group. In one embodiment, BLG is a boronic ester group, and in another embodiment, BLG is a boronic acid pinacol ester group. In another embodiment, BLG is any of the following substituents: In one embodiment, BLG is any of the substituents shown below.

[0056] In the method for selectively producing an axially chiral compound of the compound of formula (I) or a salt thereof having axial asymmetry, which comprises the step of reacting a compound of formula (IIA) or a salt thereof with a compound of formula (IIIA) or a salt thereof, the reaction conditions are not particularly limited. In one embodiment, the production method uses equivalent amounts of a compound of formula (IIA) or a salt thereof and a compound of formula (IIIA) or a salt thereof, or an excess equivalent of either, and stirs the mixture in the presence of a palladium catalyst and a ligand. In another embodiment, the production method uses equivalent amounts of a compound of formula (IIA) or a salt thereof and a compound of formula (IIIA) or a salt thereof, or an excess equivalent of either, and stirs the mixture in the presence of a base, a palladium catalyst, and a ligand. In one embodiment, the production method uses equivalent amounts of a compound of formula (IIA) or a salt thereof and a compound of formula (IIIA) or a salt thereof, or an excess equivalent of either, and stirs a mixture thereof in a solvent inert to the reaction in the presence of a base, a palladium catalyst, and a ligand, at room temperature to reflux, preferably at 20° C. to 140° C. In one embodiment, the production method uses equivalent amounts of a compound of formula (IIA) or a salt thereof and a compound of formula (IIIA) or a salt thereof, or an excess equivalent of either, and stirs a mixture thereof in a solvent inert to the reaction in the presence of a base, a palladium catalyst, and a ligand, at room temperature to reflux, preferably at 20° C. to 140° C., usually for 0.1 hours to 5 days. Examples of solvents used herein include, but are not limited to, 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. Examples of bases include, but are not limited to, anhydrous or hydrated inorganic bases such as barium hydroxide, tripotassium phosphate, sodium carbonate, potassium carbonate, and sodium hydroxide.Examples of palladium catalysts include, but are not limited to, 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, and bis(dibenzylideneacetone)palladium. Examples of ligands include, but are not limited to, SPhos, RuPhos, and DPPF. In addition, a palladium catalyst precursor can be used in place of the palladium catalyst in this production method. Examples of palladium catalyst precursors include, but are not limited to, palladacycle catalyst precursors such as RuPhos Pd G3, SPhos Pd G3, RuPhos Pd G2, and SPhos Pd G2. An embodiment of the palladium catalyst or palladium catalyst precursor is palladium(II) acetate, RuPhos Pd G3, or SPhos Pd G3. An embodiment of the ligand is SPhos or RuPhos. An embodiment of the base is barium hydroxide or tripotassium phosphate. An embodiment of the solvent is DOX, 2-methyl-2-butanol, water, or a mixture thereof. An embodiment of the reaction temperature is 50°C to 90°C. An embodiment of the reaction time is 1 hour to 2 days. Heating the mixture by microwave irradiation may be advantageous for smooth reaction progression.

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

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

[0059] (Step 6) 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). The reaction conditions are not particularly limited as long as the reaction proceeds, but in one embodiment, the reaction conditions are the same as those for reacting a compound of formula (IIA) or a salt thereof with a compound of formula (IIIA) or a salt thereof. In another embodiment, the reaction conditions described in Example 3 below can be used.

[0060] In one aspect, the present invention is a method for producing a compound of formula (I-1) below, which comprises obtaining a compound of formula (1) from a compound of formula (IIA-1) below and a compound of formula (IIIA-1) below through the sixth to eleventh steps below. In another aspect, the present invention is a method for producing a compound of formula (1) from a compound of formula (IIA-1) below and a compound of formula (IIIA-1) below, which comprises the sixth to eleventh steps below.

[0061] (Step 7) This step involves catalytic hydrogenation of the compound of formula (I-1) to deprotect it, thereby obtaining a compound of formula (10). This reaction can be carried out by stirring the compound of formula (I-1) under a hydrogen atmosphere at atmospheric to elevated pressure in a reaction-inert solvent in the presence of a metal catalyst, with cooling to heating, preferably at room temperature, for 1 hour to 5 days. Examples of suitable solvents include, but are not limited to, alcohols such as MeOH, EtOH, and iPrOH, ethyl acetate, water, and mixtures thereof. Examples of suitable metal catalysts include, but are not limited to, palladium catalysts such as Pd / C and palladium black. Carrying out the reaction in the presence of an inorganic base such as sodium bicarbonate or potassium carbonate can be advantageous for smooth reaction progression. In one embodiment, the reaction conditions described in Example 4 below can be used.

[0062] (Step 8) This step involves reacting compound (10) with compound (11) to obtain compound (12). This reaction is carried out by using equal equivalents of compound (10) and compound (11) or an excess equivalent of either compound (10) or compound (11). The reaction is carried out in the presence of a base in a reaction-inert solvent, under cooling to reflux, preferably at 0°C to 80°C, for typically 0.1 hours to 5 days. Examples of solvents used here include, but are not limited to, ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane, DMF, DMAc, and mixtures thereof. Examples of bases include, but are not limited to, inorganic bases such as potassium carbonate, cesium carbonate, and sodium hydride. In one embodiment, the reaction conditions described in Example 5 below can be used.

[0063] (Step 9) This step involves removing the NH protecting group (triphenylmethyl group) of compound (12) to obtain compound (13). This reaction involves using equal equivalents of compound (12) and an acidic reagent, or an excess equivalent of either, and stirring the mixture in a reaction-inert solvent under cooling to reflux, preferably at room temperature, typically for 30 minutes to 1 hour. Examples of the acidic reagent used here include, but are not limited to, 4-methylbenzene-1-sulfonic acid monohydrate. Examples of solvents include, but are not limited to, alcohols such as MeOH, EtOH, and iPrOH. In one embodiment, the reaction conditions described in Example 6 below can be used.

[0064] (Step 10) This step involves the cycloaddition reaction of compound (13) with compound (14) to obtain compound (15). This reaction involves using equal equivalents of compound (13) and compound (14), or an excess equivalent of either compound (13) or compound (14). The resulting mixture is stirred, preferably in the presence of a copper salt, more preferably in the presence of a copper salt and a reducing agent, in a reaction-inert solvent or without a solvent, under cooling to reflux, preferably at 0°C to 100°C, typically for 0.1 hours to 5 days. Examples of solvents used here include, but are not 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 copper salts include, but are not limited to, copper(I) iodide, copper(II) sulfate, and copper(II) trifluoromethanesulfonate. Examples of reducing agents include, but are not limited to, sodium ascorbate. In one embodiment, the reaction conditions described in Example 11 below can be used.

[0065] (Step 11) This step involves removing the NH protecting group (tert-butoxycarbonyl group) of compound (15) to obtain compound (1). This reaction involves using equal equivalents of compound (15) and an acidic reagent, or an excess equivalent of either, and stirring the mixture in a reaction-inert solvent under cooling to reflux, preferably at room temperature to 60°C, typically for 30 minutes to 5 days. Examples of the acidic reagent used here include, but are not limited to, methanesulfonic acid. Examples of solvents include, but are not limited to, alcohols such as MeOH, EtOH, iPrOH, and tBuOH, water, and mixtures thereof. In one embodiment, the reaction conditions described in Example 12 below can be used.

[0066] In one embodiment, 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 to sixteenth steps.

[0067] (Step 12) This step involves the amidation reaction of compound (16) with compound (17) to obtain compound (18). This reaction involves using equal amounts of compound (16) and compound (17) or an excess of either compound. A mixture of these compounds is stirred in the presence of a condensing agent in a reaction-inert solvent under cooling to heating, preferably at −20°C to 60°C, typically for 0.1 hours to 5 days. Examples of solvents include, but are not limited to, ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane, DMF, and mixtures thereof. Examples of condensing agents include, but are not limited to, HATU and EDCI. The use of an additive (e.g., 1-hydroxybenzotriazole) may be preferable for the reaction. Carrying out the reaction in the presence of an organic base such as TEA or DIPEA, or an inorganic base such as potassium carbonate, sodium carbonate, or potassium hydroxide, may be advantageous for smooth reaction progression. In one embodiment, the reaction conditions described in Example 8 below may be used.

[0068] (Step 13) This step is a step of obtaining compound (19) by deprotecting compound (18) by catalytic hydrogenation. The reaction conditions are the same as those in the above-mentioned Step 7. In one embodiment, the reaction conditions described in Example 9 below can be used.

[0069] (Step 14) This step is a step of obtaining compound (21) by amidation reaction of compound (19) and compound (20). The reaction conditions are the same as those in the above-mentioned step 12.

[0070] (Step 15) This step involves removing the NH protecting group (tert-butoxycarbonyl group) of compound (21) to obtain compound (22). This reaction is carried out under cooling or reflux with stirring, usually for 0.1 hours to 5 days. Examples of solvents used here include, but are not limited to, alcohols such as MeOH, EtOH, iPrOH, and tBuOH, ethyl acetate, and mixtures thereof. Examples of deprotecting reagents include, but are not limited to, hydrogen chloride (DOX solution), hydrogen chloride (ethyl acetate solution), and acids such as trifluoroacetic acid and methanesulfonic acid.

[0071] In one embodiment, the reaction conditions for the fourteenth and fifteenth steps can be the same as those described in Example 10 below.

[0072] (Step 16) This step involves reacting compound (22) with a diazo transfer reagent to obtain compound (14). In this reaction, compound (22) is treated with an equivalent or excess amount of diazo transfer reagent in a reaction-inert solvent under cooling to heating, preferably at 0°C to 50°C, typically for 0.1 hours to 3 days. Examples of diazo transfer reagents include, but are not limited to, trifluoromethanesulfonyl azide, nonafluorobutanesulfonyl azides such as 1,1,2,2,3,3,4,4,4-nonafluoro-1-butanesulfonyl azide, imidazole-1-sulfonyl azide or its salt, ADMP, etc. It may be advantageous to carry out the reaction in the presence of an organic base such as TEA, DMAP, or 2,6-lutidine, or a catalytic amount of a copper salt such as copper sulfate. Examples of solvents include ethers such as THF, halogenated hydrocarbons such as dichloromethane, alcohols such as MeOH, MeCN, water, and mixtures thereof.

[0073] In one embodiment, the reaction conditions for the sixteenth step can be the same as those described in Example 10-2 below.

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

[0075] (Step 1) This step involves chlorinating compound (2) to obtain compound (3). This reaction involves using equal equivalents of compound (2) and a chlorinating reagent, or an excess equivalent of either, and stirring a mixture of these in the presence of a base, in a reaction-inert solvent or without a solvent, under reflux, preferably at 90°C to 110°C, for typically 0.1 hours to 3 days. Examples of the chlorinating reagent used here include, but are not limited to, phosphorus oxychloride. Examples of the base used here include, but are not limited to, organic bases such as TEA and DIPEA. Examples of the solvent used here include, but are not limited to, DMF.

[0076] (Step 2) This step involves the ipso substitution reaction of compound (3) with compound (4) to obtain compound (5). This reaction involves using equal equivalents of compound (3) and compound (4), or an excess equivalent of either compound (3) or compound (4). The mixture is stirred in a reaction-inert solvent, or without solvent, under cooling to reflux, preferably at 0°C to 80°C, for typically 0.1 hours to 5 days. Examples of solvents that can be used include, but are not limited to, 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. It may be advantageous to carry out the reaction in the presence of an organic base such as TEA, DIPEA, NMM, DABCO, or tBuOK, or an inorganic base such as sodium hydride, potassium carbonate, sodium carbonate, or cesium carbonate, in order to ensure smooth reaction progress. In one aspect, the reaction conditions described in International Publication No. 2022 / 173032 can be used.

[0077] (Third step) This step is a step of obtaining compound (7) by ipso substitution reaction between compound (5) and compound (6). The reaction conditions are the same as those of the second step described above. In one embodiment, the reaction conditions described in WO 2022 / 173032 can be used.

[0078] (Step 4) This step is a step of obtaining compound (8) by ipso substitution reaction between compound (7) and compound (9). The reaction conditions are the same as those of Step 2 described above. In one embodiment, the reaction conditions described in Example 1 below can be used.

[0079] (Step 5) This step involves reacting compound (8) with cyclopropylboronic acid compound (30) to obtain a compound of formula (IIA-1). The reaction involves using equal equivalents of compound (8) and cyclopropylboronic acid compound (30), or an excess equivalent of either compound. The mixture is stirred in a reaction-inert solvent in the presence of a base and a palladium catalyst at room temperature or reflux, preferably at 20°C to 140°C, typically for 0.1 hours to 5 days. Examples of solvents used here include, but are not limited to, MeCN, water, and mixtures thereof. Examples of bases include inorganic bases such as tripotassium phosphate, sodium carbonate, and potassium carbonate. Examples of palladium catalysts include, but are not limited to, tetrakis(triphenylphosphine)palladium and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane adduct. Carrying out the reaction in the presence of a ligand such as DPPF may be advantageous for smooth reaction progression. In addition, it may be advantageous to heat the mixture by microwave irradiation in order to smoothly proceed with the reaction. In one embodiment, the reaction conditions described in Example 2 below can be used.

[0080] In one embodiment, the compound of formula (I-1) can be obtained by obtaining a compound of formula (IIA-2) from compound (2a) through the following steps 1a to 5a, and then performing step 6a under the same reaction conditions as in step 6.

[0081] (Step 1a) This step involves brominating compound (2a) to obtain compound (2b). This reaction involves using equal equivalents of compound (2a) and a brominating reagent, or an excess equivalent of either, and stirring the mixture in the presence of an acidic reagent in a reaction-inert solvent at 40°C to 70°C for typically 1 hour to 5 days. Examples of the brominating reagent used here include, but are not limited to, 1,3-dibromo-5,5-dimethylhydantoin and NBS. Examples of the acidic reagent used here include, but are not limited to, methanesulfonic acid and sulfuric acid. Examples of the solvent used here include, but are not limited to, alcohols such as MeOH, EtOH, iPrOH, and tBuOH, as well as MeCN. In one embodiment, the reaction conditions described in Example 14 below can be used in Step 1a.

[0082] (Step 1b) This step involves oximating compound (2b) to obtain compound (2c) and / or compound (2c'). This reaction involves using equal equivalents of compound (2b) and hydroxylamine hydrochloride, or an excess equivalent of either, and stirring the mixture in a reaction-inert solvent at room temperature to 60°C for typically 0.5 hours to 5 days. Examples of solvents that can be used include, but are not limited to, alcohols such as MeOH, EtOH, iPrOH, and tBuOH. Carrying out the reaction in the presence of an additive such as sodium acetate can be advantageous in some cases for smooth reaction progression. In one embodiment, the reaction conditions described in Example 15 below can be used in Step 1b.

[0083] (Step 1c) This step involves subjecting compound (2c) and / or compound (2c') to ring expansion reaction conditions to obtain compound (3a). This reaction involves using equal equivalents of compound (2c) and / or compound (2c') and a chlorinating reagent, or an excess equivalent of either, and stirring the resulting mixture in the presence of triphenylphosphine oxide and a base in a reaction-inert solvent at room temperature to 110°C for typically 1 hour to 7 days. Examples of the chlorinating reagent used herein include, but are not limited to, thionyl chloride, phosphorus oxychloride, triphosgene, etc. Examples of the base used herein include, but are not limited to, DIPEA, etc. Examples of the solvent used herein include, but are not limited to, aromatic hydrocarbons such as benzene, toluene, and xylene. Furthermore, trialkylphosphine oxide, etc., can be used in place of triphenylphosphine oxide, but are not limited thereto. In one embodiment, the reaction conditions described in Example 16 below can be used in Step 1c.

[0084] Steps 2a to 5a can be carried out under the same reaction conditions as those for Steps 2 to 5 described above, respectively. Step 6a can be carried out under the same reaction conditions as those for Step 6 described above. In one embodiment, the compound of formula (IIA-2) can be obtained under the reaction conditions described in Examples 14 to 19 below, and then the compound of formula (I-1) can be obtained under 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) by the following seventeenth and eighteenth steps.

[0086] (Step 17) This step involves reacting compound (24) with compound (25) to obtain compound (26). This reaction involves using equal equivalents of compound (24) and compound (25), or an excess equivalent of either compound, and stirring the mixture in a reaction-inert solvent in the presence of a base and a palladium catalyst at room temperature to reflux, preferably at 20°C to 140°C, for typically 0.1 hours to 5 days. Examples of solvents used here include, but are not limited to, ethers such as diethyl ether, THF, DOX, and 1,2-dimethoxyethane; NMP, DMF, DMAc, DMSO, MeCN, 1,3-dimethylimidazolidin-2-one, ethyl acetate, water, and mixtures thereof. Examples of bases include tripotassium phosphate, sodium carbonate, potassium carbonate, and potassium acetate. Palladium catalysts 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, and palladium(II) acetate. Microwave heating of the mixture can sometimes be advantageous for smooth reaction progression. For references on the reaction, see, for example, the following: Synthesis 2020, 52, p.2521-2527 PNAS 2016, 113, p.7124-7129

[0087] (Step 18) This step is a step of removing the NH protecting group (tert-butoxycarbonyl group) of compound (26) to obtain a compound of formula (20). The reaction conditions are the same as those in the above-mentioned Step 15.

[0088] In one embodiment, the compound of formula (IIIA-1) to be reacted in the sixth step can be obtained from the following compound (27) by the following 19th to 21st steps.

[0089] (Step 19) This step is a step in which the NH of compound (27) is protected with a triphenylmethyl group to obtain compound (28). The reaction conditions are not particularly limited as long as the reaction proceeds, but the reaction can be carried out, for example, according to the method described in Production Example 245 of Patent Document 1.

[0090] (Step 20) This step is a step of methylating compound (28) to obtain compound (29). The reaction conditions are not particularly limited as long as the reaction proceeds, but the reaction can be carried out, for example, according to the method described in Production Example 246 of Patent Document 1.

[0091] (Step 21) This step is a step of substituting Br of compound (29) with pinacol boronate to obtain a compound of formula (IIIA-1). The reaction conditions are not particularly limited as long as the reaction proceeds, but the reaction can be carried out, for example, according to the method described in Production Example 247 of Patent Document 1.

[0092] (Step 3-2 to Step 6-2) In one aspect, the present invention provides a method for producing a compound of formula (I) or a salt thereof according to the above item [1], which comprises reacting a compound of formula (IIA) or a salt thereof with a compound of formula (IIIA) or a salt thereof, wherein the compound of formula (I) is a compound represented by the following formula (I-2): The compound of formula (IIA) is represented by the following formula (IIA-3): and a compound represented by the formula (I) above, which is obtained by the following steps: The method includes a step of obtaining a compound represented by formula (I-2) by the following procedure.

[0093] In one embodiment, the compound of formula (IIIA) is the compound of formula (IIIA-1) described above.

[0094] As described above, Step 6-2 is a method of producing a compound of formula (I-2) by reacting a compound of formula (IIA-3) with a compound of formula (IIIA). The reaction conditions are not particularly limited as long as the reaction proceeds, and in one embodiment, the reaction conditions are the same as those for reacting a compound of formula (IIA) or a salt thereof with a compound of formula (IIIA) or a salt thereof. In another embodiment, the reaction conditions described in Example 35 below can be used.

[0095] In one embodiment, 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:

[0096] (Step 3-2) This step is a step of obtaining compound (7-2) from compound (5-2). The reaction conditions are the same as those in the above-mentioned Step 3. In one embodiment, the reaction conditions described in Example 36 below can be used.

[0097] (Step 4-2) This step is a step of obtaining compound (8-2) from compound (7-2). The reaction conditions are the same as those in the above-mentioned Step 4. In one embodiment, the reaction conditions described in Example 37 below can be used.

[0098] (Step 5-2) This step is a step of obtaining compound (IIA-3) from compound (8-2). The reaction conditions are the same as those in the above-mentioned Step 4. In one embodiment, the reaction conditions described in Example 38 below can be used.

[0099] 3. Diazo Transfer Reaction In one aspect, the present invention provides a compound of the following formula (#1) or a salt thereof: [In the formula, R 11 may be substituted C 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl or an optionally substituted 4- to 6-membered saturated heterocyclic group containing one heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen; R 12A and R 12B are the same or different and represent H or optionally substituted C 1-6 alkyl or R 12Aand R 12B may be substituted together with the carbon to which they are attached. 3-6 cycloalkyl or forms an optionally substituted 4- to 6-membered saturated heterocyclic ring containing one heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen, R 13 H; halogen; C 1-3 Alkyl; -SO2CH3; C 3-6 cycloalkyl; an optionally substituted 4- to 6-membered saturated heterocyclic group containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen; an optionally substituted 5-membered heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen; or a 6-membered heteroaryl containing 1 to 3 nitrogen atoms, and W is an optionally substituted phenyl or an optionally substituted 6-membered heteroaryl containing 1 to 3 nitrogen atoms.], comprising the steps of reacting a compound of the following formula (#2) with a diazo transfer reagent to obtain a compound of the above formula (#1) or a salt thereof: [In the formula, R 11 , R 12A , R 12B , R 13 and W is as defined above.

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

[0101] In one embodiment, in the method for producing the compound of formula (#1) or a salt thereof, R 11 is isopropyl, and R 12A is H and R 12B C optionally substituted with OH 1-3 is alkyl, and R 13 is the group R 13A But C 1-3 alkyl and W is phenyl.

[0102] The type of diazo transfer reagent is not limited as long as the diazo transfer reaction proceeds, but for example, perfluoroalkylsulfonyl azide, imidazole-1-sulfonyl azide, or a salt thereof can be used. In one embodiment, the perfluoroalkylsulfonyl azide is nonafluorobutanesulfonyl azide, heptafluoropropanesulfonyl azide, pentafluoroethanesulfonyl azide, trifluoromethanesulfonyl azide, nonafluorobutanesulfonyl azide, or 1,1,2,2,3,3,4,4,4-nonafluoro-1-butanesulfonyl azide, which is one form of nonafluorobutanesulfonyl azide.

[0103] In one embodiment, a basic reagent may be used in the diazo transfer reaction. Examples of the basic reagent include inorganic bases such as potassium bicarbonate and potassium carbonate. In one embodiment, an additive may be used in the diazo transfer reaction to facilitate the reaction. Examples of the additive include metal salts such as copper salts (e.g., CuSO4) and zinc salts (e.g., ZnSO4). In one embodiment, a polar solvent may be used as the solvent in the diazo transfer reaction. Examples of polar solvents include water, acetonitrile, alcohols (e.g., methanol and ethanol), polar organic solvents (e.g., DMSO and MTBE), and mixtures thereof. In one embodiment, the diazo transfer reaction may be performed at 10°C to 25°C. In one embodiment, the diazo transfer reaction may be performed at 10°C to 20°C, e.g., 15°C. In one embodiment, the diazo transfer reaction may be performed in the presence or absence of a metal catalyst.

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

[0105] In one aspect, the present invention relates to compound (3a) or a salt thereof obtained in the aforementioned step 1c.

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

[0107] 4. Abbreviations The following abbreviations may be used in this specification: TFA: trifluoroacetic acid, DMF: N,N-dimethylformamide, THF: tetrahydrofuran, MeCN: acetonitrile, MeOH: methanol, EtOH: ethanol, iPrOH: isopropyl alcohol, tBuOH: tert-butanol, iPrO: diisopropyl ether, DOX: 1,4-dioxane, DMSO: dimethyl sulfoxide, TEA: triethylamine, DIPEA: N,N-diisopropylethylamine, tBuOK: potassium tetrabromide rt-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) methanesulfonic acid, RuPhos Pd G3: (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonic acid, 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] In the tables below, the following abbreviations may be used: Ex: Example number; Syn: Example number produced by the same method (for example, 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] unless otherwise specified). + ), ESI-: m / z value in mass spectrometry (ionization method ESI, [M−H] unless otherwise specified)- ), NMR: DMSO-d6 at 27 °C 1 δ value (ppm) of peak in H-NMR (500 MHz), NMR (100 °C): in DMSO-d6 at 100 °C 1 δ value (ppm) of peak in H-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).

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

[0110] Example 1: To a mixture of tert-butyl (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-carboxylate (54.8 g), (1S)-1-phenylethan-1-ol (12.4 g), and THF (400 mL), tBuOK (11.3 g) was added in several portions under a nitrogen atmosphere and ice-cooled while maintaining the internal temperature below 10°C, and the mixture was stirred for 30 minutes under ice-cooling. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution under ice-cooling. Water and ethyl acetate were added, and the organic and aqueous layers were separated. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. After filtration and concentration under reduced pressure, the residue was suspended in hexane / iPrO (1 / 1, 400 mL), and the solid was collected by filtration and dried under reduced pressure to give 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) as a solid.

[0111] Example 2: Under a nitrogen atmosphere, 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) at room temperature, and cyclopropylboronic acid (10 g), PdCl(dppf)·CHCl (5.6 g), potassium phosphate tripotassium (55 g), and water (200 mL) were added at room temperature. The mixture was stirred at 90°C overnight. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to approximately half its volume. Ethyl acetate was added and the mixture was filtered through Celite®. Water was added to the filtrate, which was then extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride. Amino-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. The mixture was then filtered through Celite®, and the filtrate was concentrated under reduced pressure. The residue was powdered with iPrOH (250 mL), 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 give 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: (1S,4S)-tert-butyl 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 (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) at room temperature, 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 stirred for an additional 4 hours. The reaction mixture was allowed to cool, and ethyl acetate and Celite® were added. The mixture was stirred at room temperature for 30 minutes, filtered, and the filtrate was washed with saturated aqueous sodium chloride. Amino-modified silica gel was added to the organic layer and stirred at room temperature for 30 minutes, then filtered and concentrated. The resulting residue was dissolved in MeOH (40 mL) and 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 give tert-butyl (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-carboxylate (913 mg) as a solid.

[0113] Example 3-1: 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 (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 at room temperature and stirred at 90°C for 2 hours under an argon atmosphere. The reaction mixture was allowed to cool, and water and ethyl acetate were added. 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-modified silica gel, hexane / ethyl acetate) to give 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 (367 mg) as a foamy solid.

[0114] Example 3-2: (1S,4S)-tert-butyl 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 (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 at room temperature and stirred at 90°C for 2 hours under an argon atmosphere. The reaction mixture was allowed to cool and filtered through Celite®, washing with ethyl acetate. The filtrate was added with water and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (amino-modified silica gel, hexane / ethyl acetate) to give 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 (291 mg) as a foamy solid.

[0115] Example 3-3: 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 (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 at room temperature 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. The mixture was 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 give 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 (268 mg) as a foamy solid.

[0116] Example 3-4 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 (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 at room temperature 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. The mixture was 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 give 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 (281 mg) as a foamy solid.

[0117] Example 4 A mixture of tert-butyl (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-carboxylate (4.96 g), 10% Pd / C (about 50% water content, 1 g), sodium bicarbonate (2 g), ethyl acetate (80 mL), and MeOH (20 mL) was stirred under a hydrogen atmosphere at room temperature and pressure overnight. After purging with argon, the reaction mixture was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure to give tert-butyl (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-carboxylate (4.46 g) as a foamy solid.

[0118] Example 5: Under a nitrogen atmosphere, tert-butyl (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-carboxylate (34 g) and cesium carbonate (38 g) were suspended in DMF (200 mL), and (4-ethynylphenyl)methyl methanesulfonate (8.2 g) was added at room temperature and stirred at room temperature for 2 hours. The reaction mixture was added to ice water (approximately 1000 mL) and stirred at room temperature for 30 minutes. The resulting solid was collected by filtration and dried under reduced pressure to give tert-butyl (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-carboxylate (35.5 g) as a solid.

[0119] Example 6: To a solution of tert-butyl (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-carboxylate (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 bicarbonate was added to the reaction mixture, which was then extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated. The resulting solid was dissolved in ethyl acetate (3 mL) / hexane (3 mL), followed by stirring at 90°C for 30 minutes and then at room temperature for 1 hour. The resulting solid was collected by filtration and dried under reduced pressure to give 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 (408 mg) as a solid.

[0120] Example 7: (4-ethynylphenyl)methanol (10 g) was dissolved in CHCl (100 mL) under ice-cooling, and DIPEA (33 mL) and methanesulfonic anhydride (15.3 g) were added portionwise. The mixture was stirred under ice-cooling for 1 hour. Methanesulfonic anhydride (3 g) was added under ice-cooling, and the mixture was stirred for 30 minutes. Water and ethyl acetate / hexane (1 / 1) were added under ice-cooling, and the mixture was extracted twice with ethyl acetate / hexane (1 / 1). The combined organic layer was washed with saturated aqueous ammonium chloride, water, and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated to give (4-ethynylphenyl)methyl methanesulfonate (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) was added HATU (53.9 g) portionwise under ice-cooling (the internal temperature was maintained below 10°C). The mixture was stirred for 15 minutes under ice-cooling and then for 45 minutes at room temperature. 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 layer was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, followed by drying over anhydrous magnesium sulfate. Insoluble materials were removed by filtration, and the mixture was concentrated under reduced pressure to give 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 (approximately 50% water content, 2.9 g) was added at room temperature under a nitrogen atmosphere. The atmosphere was replaced with hydrogen and the mixture was stirred overnight at room temperature. Celite® was added to the reaction mixture, which was then stirred and filtered while washing with MeOH. The filtrate was concentrated. Ethyl acetate (200 mL) was added to the resulting residue, and the mixture was stirred overnight at room temperature. The solid was collected by filtration to give 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 stirred. HATU (16.5 g) was added portionwise under ice cooling (ice / saturated aqueous sodium chloride solution) while maintaining the internal temperature below 0°C. After stirring for 30 minutes under ice cooling, half-saturated aqueous sodium chloride solution (400 mL) and ethyl acetate (200 mL) were added and stirred, and the aqueous and organic layers were separated. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed sequentially with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. The insoluble material was removed by filtration, and the mixture was concentrated under reduced pressure to give 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 resulting solid in ethyl acetate (100 mL) / MeOH (100 mL), 4 M hydrogen chloride (in ethyl acetate, 100 mL) was added portionwise under ice cooling, and the mixture was stirred overnight at room temperature. The resulting solid was collected by filtration, and ethyl acetate (50 mL) / MeOH (100 mL) was added, followed by stirring 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] 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 was reacted with a diazo transfer reagent under the reaction conditions described in WO 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 bicarbonate (0.24 g), and tetrabutylammonium chloride (0.31 g) was stirred at 5°C for 20 hours, and then a 25% aqueous sodium chloride solution was added, followed by separation of the layers, 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 bicarbonate (1.93 g), DMSO (20 mL), and water (4 mL), and the mixture was stirred at 15°C for 16 hours. 25% aqueous sodium chloride and ethyl acetate were added to the reaction mixture, and the layers were separated. 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 removed by filtration, and the filtrate was concentrated under reduced pressure. The filtrate was then crystallized from methanol and methyl tert-butyl ether to give (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, 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) was added with sodium ascorbate (80 mL) at room temperature. A solution of 100 mg of ethylenediaminetetraacetic acid (750 mg) in water (20 mL) was added, 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 layer was washed with water and saturated aqueous sodium chloride, 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 give 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) was obtained as a solid.

[0127] Example 12 Under a nitrogen atmosphere, 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 (200 mg) was dissolved in MeOH (1 Methanesulfonic acid (100 μL) was added to the 2 mL solution at room temperature and 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% formic acid in water / 0.1% formic acid in MeCN). Fractions containing the target compound were pooled, 5% aqueous sodium bicarbonate 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 give (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, 6-chloro-7-fluoro-1H-indole-2,3-dione (250.8 g) and MeCN (1.25 L) were mixed and stirred at room temperature. Methanesulfonic acid (24.2 g) and 1,3-dibromo-5,5-dimethylhydantoin (359.3 g) were added and stirred at room temperature for 10 minutes. After stirring at 55°C for 20 hours, the mixture was cooled to below 10°C, and a solution of sodium ascorbate (497.9 g) in water (2.5 L) was added. After stirring at below 10°C 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, 5-bromo-6-chloro-7-fluoro-1H-indole-2,3-dione (320 g), EtOH (2.24 L), and sodium acetate (141 g) were mixed at room temperature and stirred for 10 minutes. Hydroxylamine hydrochloride (87.8 g) was added and the mixture was stirred at 50°C for 2 hours. Water (4.16 L) was added at 50°C, cooled to room temperature, stirred for 30 minutes, and the solid was collected by filtration. The residue was washed successively with EtOH / water (1 / 2) and water and dried under reduced pressure at 60°C to give 5-bromo-6-chloro-7-fluoro-3-(hydroxyimino)-1,3-dihydro-2H-indol-2-one (314 g) as a solid.

[0130] Example 16: 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 under a nitrogen atmosphere at room temperature. Thionyl chloride (1.24 mL) was added portionwise so that the internal temperature did not exceed 50°C. The mixture was then heated to an internal temperature of 65-75°C and stirred for 17 hours. Thionyl chloride (1.24 mL) was added at the same temperature, and the mixture was stirred at an internal temperature of 95-105°C for 6 days. The reaction mixture was cooled to room temperature and added portionwise dropwise to an ice-cooled solution of dipotassium hydrogen phosphate (11.9 g) in water (10 mL) so that the internal temperature did not exceed 30°C. The resulting mixture was filtered, washing with toluene. The filtrate was separated, and the organic layer was washed with aqueous sodium bicarbonate to give 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, and the organic layer was washed with water and concentrated under reduced pressure. EtOH was added to the residue, and the mixture was concentrated again under reduced pressure to azeotrope the toluene. EtOH (4 mL) was then added to dissolve the residue. After stirring at 50°C, the mixture was cooled to room temperature, and the precipitated solid was collected by filtration and dried under reduced pressure at 60°C to give 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: (1S,4S)-tert-butyl 5-(6-bromo-2,7-dichloro-8-fluoroquinazolin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (5 g) and tetrahydro-2H-pyran-4-ol (1.24 g) were dissolved in DMF (15 mL) at room temperature, and cesium carbonate (9.93 g) was added and stirred. DABCO (228 mg) was added at room temperature and stirred for 20 minutes, followed by stirring at 55°C for 1.5 hours. The mixture was cooled to room temperature, and toluene and water were added, followed by separation. The organic layer was washed twice with water. The organic layer was concentrated, and EtOH (50 mL) and water (10 mL) were added to the residue. The precipitate was collected by filtration, washed with EtOH / water (1 / 1), and dried at 60°C under reduced pressure to give 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 (4.13 g) as a solid.

[0132] Example 18: Under a nitrogen atmosphere, tBuONa (620 mg) was dissolved in DMF (5 mL) and stirred at room temperature. 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 and stirred for 2 hours. Toluene (15 mL) was added, and after 10 minutes, (1S)-1-phenylethan-1-ol (82.1 mg) and tBuONa (62 mg) were added. The mixture was stirred for 45 minutes at room temperature, followed by the addition of tBuONa (103 mg). After stirring for 45 minutes at room temperature, toluene and water were added and the mixture was separated. The organic layer was washed twice with water, dried over sodium sulfate, filtered to remove insoluble material, and concentrated under reduced pressure. The residue was stirred with EtOH, and the precipitated solid was collected by filtration, washed with EtOH, and dried under reduced pressure at 50 °C to give 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: A mixture of 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 (1 g), toluene (7 mL), water (2 mL), tripotassium phosphate (964 mg), and cyclopropylboronic acid (221 mg) was degassed under reduced pressure at room temperature. PdCl2(dppf)·CHCl2 (55.4 mg) was added, the mixture was degassed under reduced pressure, and the mixture was stirred at 80°C for 16 hours. After cooling to room temperature, activated carbon was added to the reaction mixture and the mixture was stirred at room temperature for 30 minutes. Insoluble matter was removed by filtration while washing with toluene and water, and the filtrate was separated. The resulting organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl (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-carboxylate (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), tert-butyl (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-carboxylate (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, degassed under reduced pressure, and the mixture was stirred at 65°C for 1.5 hours. After cooling to room temperature, water (0.6 mL) and activated carbon (10 mg) were added and stirred for 30 minutes. The insoluble matter was filtered while washing with toluene, and the filtrate was separated. The resulting 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 resulting 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 resulting solid was suspended in MeOH, filtered while washing with MeOH, and the resulting solid was suspended again in MeOH, filtered while washing with MeOH, and dried under reduced pressure to give 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, ratio of isomers due to axial asymmetry M:P = 58:1) as a solid.

[0135] Example 21 tert-Butyl (3S)-3-[{7-bromo-6-cyclopropyl-2-[(2S)-2-methoxypropoxy]-8-[(1S)-1-(naphthalen-1-yl)ethoxy]quinazolin-4-yl}(methyl)amino]pyrrolidine-1-carboxylate (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, degassed, and purged with argon gas several times, and then stirred under an argon atmosphere at 80° C. for 3 hours. 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 saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give tert-butyl (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-carboxylate (1.47 g) as a foamy solid.

[0136] Example 22: Under an argon atmosphere, 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) was mixed with 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) at room temperature, and the mixture was stirred at 80° C. for 3 hours under an argon atmosphere. After cooling to room temperature, water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (hexane / ethyl acetate) to give 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, tert-butyl (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-carboxylate (1.00 g, approximately 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 mixture, which was then degassed again under reduced pressure and stirred at 60°C for 3 hours. The mixture was cooled to room temperature, activated carbon (80 mg) was added, and the mixture was stirred for 68 hours. The insoluble matter was filtered through Celite® 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. The residue (the ratio of isomers due to axial asymmetry was 8.2:1) was added to toluene (4 mL) and heptane (6 mL), followed by amino-modified silica gel (3.3 g), neutral silica gel (1.6 g), and heptane (40 mL). The mixture was then stirred for 2 hours and 40 minutes. The mixture was filtered, washed with heptane and ethyl acetate, and the filtrate was concentrated. The residue was added with MeOH and stirred, then concentrated. Half of the residue was purified twice by silica gel column chromatography (hexane / ethyl acetate), and then 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-carboxylate tert-butyl ester (105 mg) as a foamy solid. The starting material used in Example 23 was prepared by the following method.Under an argon atmosphere, tert-butyl (3S)-3-[{7-chloro-6-cyclopropyl-2-[(2S)-2-methoxypropoxy]-8-[(1S)-1-(naphthalen-1-yl)ethoxy]quinazolin-4-yl}(methyl)amino]pyrrolidine-1-carboxylate (2.21 g), 5,5,5',5'-tetramethyl-2,2'-bi-1,3,2-dioxaborinane (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 mixture, which was then degassed under reduced pressure and stirred at 70 °C for 24 hours. The reaction mixture was cooled to room temperature, and insoluble matter was filtered through Celite (registered trademark) and washed with toluene. The filtrate was concentrated under reduced pressure. The residue was azeotroped three times with MeOH, then dissolved in MeOH (6 mL), and added dropwise to water (80 mL) while washing with MeOH (2 mL). The precipitated solid was collected by filtration and dried under reduced pressure to give tert-butyl (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-carboxylate (2.99 g, ca. 83% purity) as a solid.

[0138] Example 34: 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 at room temperature and degassed under reduced pressure. SPhos Pd G3 (102 mg) was then added, degassed under reduced pressure, and stirred at 65°C for 6 hours. The mixture was cooled to room temperature, activated carbon (70 mg) was added, and stirred for 10 minutes. The mixture was then filtered and washed with toluene. The filtrate was separated, and the organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in iPrOH (14 mL), and water (4.9 mL) was added portionwise. The resulting solid was collected by filtration, washed with iPrOH / water (3 / 1), and dried under reduced pressure to give 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: 2-(trimethylsilyl)ethyl 4-{7-bromo-4-tert-butoxy-6-cyclopropyl-8-[(1S)-1-phenylethoxy]quinazolin-2-yl}piperazine-1-carboxylate (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 at room temperature, degassed, and purged with argon gas several times, followed by stirring at 60°C under an argon atmosphere for 3 hours. 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 layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 2-(trimethylsilyl)ethyl 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-carboxylate (237 mg) as a foamy solid.

[0140] Example 36: 2-(trimethylsilyl)ethyl piperazine-1-carboxylate (8.9 g) was added to 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), 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 layer was washed twice with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was triturated with MeOH (100 mL), filtered, and dried under reduced pressure to give 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 atmosphere, tBuOK (0.72 g) was added 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) with stirring at room temperature, and the mixture was stirred at room temperature for 40 minutes. Ice and saturated aqueous ammonium chloride were added to the reaction mixture, which was then extracted twice with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium chloride 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 give 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: 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), PdCl(dppf)·CHCl (230 mg), MeCN (50 mL), and water (10 mL) were mixed at room temperature 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. Insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 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]

[0144]

[0145]

[0146]

[0147] According to the method of the present invention, in the production of a compound of formula (I) or a salt thereof having axial chirality, one of the axially asymmetric compounds or a salt thereof can be selectively obtained by controlling the axial chirality using a chiral auxiliary. The method of the present invention is very useful because it can increase the yield compared to conventional methods and reduce the fractionation step.

Claims

1. A compound of the following formula (I) or a salt thereof: wherein A is N or CH, and Y is a bond, -CH2-, -O-, -S- or -NR Y - and R Y is H or optionally substituted C 1-3 alkyl, R 1 is represented by the following formula (IV) or (V): 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, and Z is a bond, -CH2-, -O-, -S- or -N(R Z1 )- and R Z1 is H or optionally substituted C 1-3 alkyl, PG 1 is a protecting group for NH contained in ring A, and 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 alkyl, R 4 is represented by the following formula (VI) or (VII): R 4A But, C 1-3 alkyl, R 4B is naphthyl, phenanthrenyl, or optionally substituted phenyl; R 5 is represented by the following formula (VIII) or (IX), PG ３ is a protecting group for NH, and R 5A is H, methyl, F or Cl, R 5B is Cl, methyl, ethyl or vinyl, and * indicates an asymmetric axis, comprising the steps 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: [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, and BLG is a boronic acid group, a boronic ester group, a trifluoroborate group or a triolborate group, wherein the above-mentioned method comprises selectively producing one of the axially chiral compounds of the above-mentioned 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, wherein X is Cl or Br, Y is -O- or -S-, and R 1 The following formulas (IV-1), (IV-2), (IV-3) and (V): R is a group selected from the group consisting of 2 is optionally substituted with tetrahydropyranyl or -OCH 1-3 alkyl, R 3 is cyclopropyl, R 4 The compound represented by the following formulas (VI-1), (VI-2) and (VI-3): R is a group selected from the group consisting of 5 The following formulas (VIII-1) and (IX-1): 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, wherein A is N and R 1 The following formulas (IV-1), (IV-2) and (V): R is a group selected from the group consisting of 5 The compound represented by the following formula (VIII-1): 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): The compound of formula (IIIA) or a salt thereof is represented by the following formula (IIIA-1): The compound represented by the formula (I) is obtained by the following process: The method according to claim 3, comprising the step of obtaining a compound represented by formula (I-1) by:

5. The following process: The method according to claim 4, comprising obtaining compound (1) or a salt thereof by:

6. Compound (16) and compound (17) are synthesized by the following steps:

6. The method of claim 5, comprising obtaining compound (14) by:

7. A process for producing a compound (2) according to the following method: The method of claim 5, comprising obtaining the compound of formula (IIA-1) by:

8. Compound (24) and compound (25) are synthesized by the following steps:

7. The method of claim 6, comprising obtaining compound (20) by:

9. A compound (27) according to the following steps: 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): The compound of formula (IIIA) or a salt thereof is represented by the following formula (IIIA-1): The compound represented by the formula (I) is obtained by the following process: The method according to claim 3, comprising the step of obtaining a compound represented by formula (I-1) by:

11. The following process: The method according to claim 10, comprising obtaining compound (1) or a salt thereof by:

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

13. A compound represented by any one of the following formulae or a salt thereof:

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