Antibody drug conjugates

Abstract

Disclosed is an antibody drug conjugate represented by Formula (I): # imgabs0 # (wherein Ab is an antibody, X is a group represented by Formula (X-1), Formula (X-2) or Formula (X-3): # imgabs1 # imgabs2 # (wherein # imgabs3 # on the left side represents a binding site with NH and # imgabs4 # on the right side represents a binding site with D), D is a group represented by Formula (D-1) # imgabs5 # or Formula (D-2): # imgabs6 # (wherein # imgabs7 # represents a binding site with X), and n is in the range of about 1 to about 8).

Description

Technical Field

[0001] The present invention relates to an antibody-drug conjugate. Background Art

[0002] Cancer is one of the leading causes of illness and death worldwide, with approximately 14 million new cases and 8.2 million cancer-related deaths in 2012. The most common causes of cancer death are lung cancer (1.59 million deaths), liver cancer (745,000 deaths), stomach cancer (723,000 deaths), colorectal cancer (694,000 deaths), breast cancer (521,000 deaths), and esophageal cancer (400,000 deaths). It is predicted that the number of cancer cases will increase by approximately 70% in the next 20 years, with approximately 22 million new cancer cases each year (NPL 1). Among the many types of cancer, pancreatic cancer has few treatment options, and its 5-year survival rate is very low at 10% even in medically developed countries, so it has a very high unmet medical need. Unlike other types of cancer, deaths caused by pancreatic cancer are expected to continue to increase in the future.

[0003] Protein degraders are artificial chimeric molecules that can induce the degradation of specific proteins in a proteasome-dependent manner within cells and have attracted attention as a new form of molecular targeted drugs. BRD2 / 4 (bromodomain-containing protein 2 / 4) is a protein that recognizes acetylated histones and mobilizes transcription factors to affect gene transcription. BRD2 / 4 inhibition is known to produce anti-tumor activity. Some degraders that degrade BRD2 / 4 have been reported previously (NPL 2 and PTL 1). However, due to their strong toxicity, they have not yet been used clinically. Most protein degraders have problems due to their physical properties as drugs, which poses another obstacle to their clinical application.

[0004] CEACAM6 (carcinoembryonic antigen-related cell adhesion molecule 6) is a membrane protein reported to be highly expressed in a variety of cancers, including pancreatic cancer. However, CEACAM6 is also expressed in a few important normal cells, and the clinical application of antibody-drug conjugates using small molecule drugs targeting it has not yet been developed.

[0005] Reference List

[0006] Patent Literature

[0007] [PTL 1] International Patent Publication No. WO 2020 / 086858

[0008] Non-patent literature

[0009] [NPL 1] World Cancer Report 2014

[0010] [NPL 2] Thomas et al. "Antibody Conjugation of a Chimeric BET Degrader Enables in vivo Activity" ChemMedChem [Medicinal Chemistry] 2020, 15, 17-25 Summary of the invention

[0011] Technical issues

[0012] The object of the present invention is to provide an antibody-drug conjugate that is effective against cancer.

[0013] Solution to the problem

[0014] The present inventors have conducted extensive studies to solve the above problems and have found that the antibody-drug conjugate represented by formula (I) has antitumor activity against various cancers including pancreatic cancer, thereby completing the present invention.

[0015] Therefore, the present invention relates to the following [1] to

[35] .

[0016] [1] An antibody-drug conjugate, the antibody-drug conjugate is represented by formula (I):

[0017]

[0018] (in

[0019] Ab is antibody,

[0020] X is a group represented by formula (X-1), formula (X-2) or formula (X-3):

[0021]

[0022] (The left

[0023]

[0024] Indicates the binding site with NH and the right side

[0025]

[0026] represents the binding site with D),

[0027] D is a group represented by formula (D-1) or formula (D-2):

[0028]

[0029] (in

[0030]

[0031] represents the binding site with X), and

[0032] n is in the range of about 1 to about 8).

[0033] [2] The antibody-drug conjugate of [1], wherein the antibody is an anti-CEACAM6 antibody, an anti-folate receptor α antibody, an anti-mesothelin antibody, an anti-HER2 antibody, an anti-FLT3 antibody, an anti-DLL3 antibody, an anti-CLDN6 antibody, an anti-EGFR antibody, an anti-fibronectin 4 antibody, an anti-CA9 antibody, an anti-CLDN3 / 4 antibody or an anti-TROP2 antibody.

[0034] [3] The antibody-drug conjugate of [1] or [2], wherein the antibody is an anti-CEACAM6 antibody, D is a group represented by formula (D-1), and X is a group represented by formula (X-1) or formula (X-3).

[0035] [4] The antibody-drug conjugate of [2] or [3], wherein the anti-CEACAM6 antibody comprises:

[0036] The heavy chain comprises:

[0037] (a) a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 18;

[0038] (b) a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 19; and

[0039] (c) a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 20; and

[0040] Light chain, which includes:

[0041] (d) a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21;

[0042] (e) a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO:21-1; and

[0043] (f) a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO:22.

[0044] [5] A pharmaceutical composition comprising the antibody-drug conjugate according to any one of [1] to [4] above.

[0045] [6] The pharmaceutical composition according to [5] above, which is used for treating cancer.

[0046] [7] A method for treating cancer, comprising administering the antibody-drug conjugate according to any one of [1] to [4] above to a patient in need thereof.

[0047] [8] Use of the antibody-drug conjugate according to any one of [1] to [4] above in the preparation of an anticancer agent.

[0048] [9] The antibody-drug conjugate according to any one of [1] to [4] above, which is used for treating cancer.

[0049]

[10] A compound represented by formula (D'):

[0050]

[0051] (in

[0052] Het is a group selected from the group consisting of:

[0053]

[0054] (in

[0055]

[0056] represents the binding site),

[0057] R 1 is hydroxy, amino or optionally substituted C 1-6 Alkylcarbamoyloxy,

[0058] R 2 C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or C 3-6 Cycloalkoxy,

[0059] R 3 C 1-6 Alkyl or C 6-10 Aryl, and

[0060] R A is a group represented by formula (a) or formula (b):

[0061]

[0062] (in

[0063]

[0064] represents the binding site),

[0065] or a pharmacologically acceptable salt thereof.

[0066]

[11] A compound represented by formula (D'-1) or formula (D'-2):

[0067] or a pharmacologically acceptable salt thereof.

[0068]

[12] A compound represented by formula (M):

[0069]

[0070] in

[0071] Het is a group selected from the group consisting of:

[0072]

[0073] (in

[0074]

[0075] represents the binding site),

[0076] R 1 is hydroxy, amino or optionally substituted C 1-6 Alkylcarbamoyloxy,

[0077] R 2 C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or C 3-6 Cycloalkoxy,

[0078] R 3 C 1-6 Alkyl or C 6-10 Aryl, and

[0079] R 4 It is an amino group or a group represented by the following formula:

[0080]

[0081] (in

[0082] R 5 is ethynyl, piperidinyl, piperazinyl, piperidinyloxy or piperazinylmethyl, the piperidinyl, piperazinyl, piperidinyloxy and piperazinylmethyl being optionally substituted with one or more groups selected from the group consisting of methyl, ethynyl, hydroxyl, amino and propynylamino),

[0083] or a pharmacologically acceptable salt thereof.

[0084]

[13] An anti-CEACAM6 antibody, comprising:

[0085] The heavy chain comprises:

[0086] (a) a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 18;

[0087] (b) a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 19; and

[0088] (c) a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 20; and

[0089] Light chain, which includes:

[0090] (d) a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21;

[0091] (e) a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO:21-1; and

[0092] (f) a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO:22.

[0093]

[14] The anti-CEACAM6 antibody of

[13] , wherein the heavy chain comprises a variable region comprising the amino acid sequence set forth in SEQ ID NO:6, and the light chain comprises a variable region comprising the amino acid sequence set forth in SEQ ID NO:7.

[0094]

[15] The anti-CEACAM6 antibody of

[13] or

[14] , wherein the constant region of the heavy chain and the constant region of the light chain comprise an amino acid sequence derived from a human antibody.

[0095]

[16] The anti-CEACAM6 antibody of

[15] , wherein the constant region of the heavy chain comprises human IgG1 and human IgG2.

[0096]

[17] The anti-CEACAM6 antibody as described in

[16] , wherein the constant region of human IgG1 and human IgG2 comprises the amino acid sequence listed in SEQ ID NO:10.

[0097]

[18] The anti-CEACAM6 antibody according to any one of

[15] to

[17] , wherein the constant region of the light chain includes a constant region of human Igλ.

[0098]

[19] The anti-CEACAM6 antibody of

[18] , wherein the human Igλ comprises the amino acid sequence as listed in SEQ ID NO:11.

[0099]

[20] An anti-CEACAM6 antibody, comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence set forth in SEQ ID NO:14, and the light chain comprises the light chain comprising the amino acid sequence set forth in SEQ ID NO:15.

[0100]

[21] An antibody-drug conjugate, the antibody-drug conjugate is represented by formula (I):

[0101]

[0102] (in

[0103] Ab is anti-CEACAM6 antibody,

[0104] X is a group represented by formula (X-1), formula (X-2) or formula (X-3):

[0105]

[0106] (The left

[0107]

[0108] Indicates the binding site with NH and the right side

[0109]

[0110] represents the binding site with D),

[0111] D is a group represented by formula (D-1) or formula (D-2):

[0112] (in

[0113]

[0114] represents the binding site with X), and

[0115] n is in the range of about 1 to about 8).

[0116]

[22] An antibody-drug conjugate, the antibody-drug conjugate is represented by formula (I):

[0117] (in

[0118] Ab is anti-folate receptor α antibody,

[0119] X is a group represented by formula (X-1), formula (X-2) or formula (X-3):

[0120]

[0121] (The left

[0122]

[0123] Indicates the binding site with NH and the right side

[0124]

[0125] represents the binding site with D),

[0126] D is a group represented by formula (D-1) or formula (D-2):

[0127]

[0128] (in

[0129]

[0130] represents the binding site with X), and

[0131] n is in the range of about 1 to about 8).

[0132]

[23] An antibody-drug conjugate, the antibody-drug conjugate is represented by formula (I):

[0133] (in

[0134] Ab is anti-mesothelin antibody,

[0135] X is a group represented by formula (X-1), formula (X-2) or formula (X-3):

[0136]

[0137] (The left

[0138]

[0139] Indicates the binding site with NH and the right side

[0140] represents the binding site with D),

[0141] D is a group represented by formula (D-1) or formula (D-2):

[0142]

[0143] (in

[0144]

[0145] represents the binding site with X), and

[0146] n is in the range of about 1 to about 8).

[0147]

[24] An antibody-drug conjugate, the antibody-drug conjugate is represented by formula (I):

[0148]

[0149] (in

[0150] Ab is an anti-HER2 antibody, an anti-FLT3 antibody, an anti-DLL3 antibody, an anti-CLDN6 antibody, an anti-EGFR antibody, an anti-adhesion protein 4 antibody, an anti-CA9 antibody, an anti-CLDN3 / 4 antibody or an anti-TROP2 antibody,

[0151] X is a group represented by formula (X-1), formula (X-2) or formula (X-3):

[0152]

[0153] (The left

[0154]

[0155] Indicates the binding site with NH and the right side

[0156]

[0157] represents the binding site with D),

[0158] D is a group represented by formula (D-1) or formula (D-2):

[0159]

[0160] (in

[0161]

[0162] represents the binding site with X), and

[0163] n is in the range of about 1 to about 8).

[0164]

[25] A pharmaceutical composition, which is administered in combination with a PD-1 antagonist and comprises an antibody drug conjugate represented by formula (I):

[0165]

[0166] (in

[0167] Ab is anti-CEACAM6 antibody,

[0168] X is a group represented by formula (X-1), formula (X-2) or formula (X-3):

[0169]

[0170] (The left

[0171]

[0172] Indicates the binding site with NH and the right side

[0173]

[0174] represents the binding site with D),

[0175] D is a group represented by formula (D-1) or formula (D-2):

[0176]

[0177] (in

[0178]

[0179] represents the binding site with X), and

[0180] n is in the range of about 1 to about 8).

[0181]

[26] A pharmaceutical composition comprising a PD-1 antagonist, which is administered in combination with an antibody drug conjugate represented by the formula:

[0182]

[0183] (in

[0184] Ab is anti-CEACAM6 antibody,

[0185] X is a group represented by formula (X-1), formula (X-2) or formula (X-3):

[0186]

[0187] (The left

[0188]

[0189] Indicates the binding site with NH and the right side

[0190]

[0191] represents the binding site with D),

[0192] D is a group represented by formula (D-1) or formula (D-2):

[0193]

[0194] (in

[0195]

[0196] represents the binding site with X), and

[0197] n is in the range of about 1 to about 8).

[0198]

[27] A pharmaceutical composition, which is administered in combination with a PD-1 antagonist and comprises an antibody drug conjugate represented by formula (I):

[0199]

[0200] (in

[0201] Ab is an anti-folate receptor α antibody, an anti-mesothelin antibody, an anti-HER2 antibody, an anti-FLT3 antibody, an anti-DLL3 antibody, an anti-CLDN6 antibody, an anti-EGFR antibody, an anti-adhesion protein 4 antibody, an anti-CA9 antibody, an anti-CLDN3 / 4 antibody or an anti-TROP2 antibody,

[0202] X is a group represented by formula (X-1), formula (X-2) or formula (X-3):

[0203]

[0204] (The left

[0205]

[0206] Indicates the binding site with NH and the right side

[0207]

[0208] represents the binding site with D),

[0209] D is a group represented by formula (D-1) or formula (D-2):

[0210]

[0211] (in

[0212]

[0213] represents the binding site with X), and

[0214] n is in the range of about 1 to about 8).

[0215]

[28] A pharmaceutical composition comprising a PD-1 antagonist, which is administered in combination with an antibody drug conjugate represented by formula (I):

[0216]

[0217] (in

[0218] Ab is an anti-folate receptor α antibody, an anti-mesothelin antibody, an anti-HER2 antibody, an anti-FLT3 antibody, an anti-DLL3 antibody, an anti-CLDN6 antibody, an anti-EGFR antibody, an anti-adhesion protein 4 antibody, an anti-CA9 antibody, an anti-CLDN3 / 4 antibody or an anti-TROP2 antibody,

[0219] X is a group represented by formula (X-1), formula (X-2) or formula (X-3):

[0220]

[0221] (The left

[0222]

[0223] Indicates the binding site with NH and the right side

[0224]

[0225] represents the binding site with D),

[0226] D is a group represented by formula (D-1) or formula (D-2):

[0227]

[0228] (in

[0229]

[0230] represents the binding site with X), and

[0231] n is in the range of about 1 to about 8).

[0232]

[29] The pharmaceutical composition of any one of

[25] to

[28] , wherein the PD-1 antagonist is an anti-PD-1 antibody.

[0233]

[30] The pharmaceutical composition of

[29] , wherein the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, sintilimab, toripalimab, spartalizumab, tislelizumab, dotalimab, carrelizumab, genolizumab, lodapolimab, retifanlimab, balstilimab, serplulimab, budigalimab, and serotonin. ab), Prolgolimab, Sasanlimab, Cetrelimab, Zimberelimab, Penpulimab, AMP-514, STI-A1110, ENUM388D4, ENUM244C8, GLS010, CS1003, BAT-1306, AK103, BI754091, LZM009, CMAB819, Sym021, SSI-361, JY034, HX008, ISU106, and CX-188.

[0234]

[31] The pharmaceutical composition of

[30] , wherein the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, cemiplizumab, sintilimab and toripalimab.

[0235]

[32] A method for treating a tumor, comprising administering an antibody-drug conjugate represented by formula (I) and a PD-1 antagonist to a patient in need thereof:

[0236]

[0237] (in

[0238] Ab is an anti-CEACAM6 antibody, an anti-folate receptor α antibody, an anti-mesothelin antibody, an anti-HER2 antibody, an anti-FLT3 antibody, an anti-DLL3 antibody, an anti-CLDN6 antibody, an anti-EGFR antibody, an anti-adhesion protein 4 antibody, an anti-CA9 antibody, an anti-CLDN3 / 4 antibody or an anti-TROP2 antibody,

[0239] X is a group represented by formula (X-1), formula (X-2) or formula (X-3):

[0240]

[0241] (The left

[0242]

[0243] Indicates the binding site with NH and the right side

[0244]

[0245] represents the binding site with D),

[0246] D is a group represented by formula (D-1) or formula (D-2):

[0247]

[0248] (in

[0249]

[0250] represents the binding site with X), and

[0251] n is in the range of about 1 to about 8).

[0252]

[33] The method of

[32] , wherein the PD-1 antagonist is an anti-PD-1 antibody.

[0253]

[34] The method of

[33] , wherein the anti-PD-1 antibody is selected from the group consisting of: nivolumab, pembrolizumab, cemiplizumab, sintilimab, toripalizumab, spartalizumab, tislelizumab, dotalimumab, carrelizumab, genoluzumab, lodalizumab, rivalizumab, batilizumab, srulimab, buglilimab, prolgolimab, sasanlimab, cefotaxime trelimab, sepalizumab, penpulimab, AMP-514, STI-A1110, ENUM388D4, ENUM244C8, GLS010, CS1003, BAT-1306, AK103, BI754091, LZM009, CMAB819, Sym021, SSI-361, JY034, HX008, ISU106, and CX-188.

[0254]

[35] The method of

[34] , wherein the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, cemiplizumab, sintilimab and toripalimab.

[0255] Advantageous Effects of the Invention

[0256] According to the present invention, an antibody-drug conjugate effective against cancer can be provided. The antibody-drug conjugate of the present invention has the potential to be used as an anticancer agent. BRIEF DESCRIPTION OF THE DRAWINGS

[0257] Figure 14 is a graph showing the change in tumor volume in mice subcutaneously transplanted with the human pancreatic cancer cell line AsPC-1 in Example 401 after injection of the antibody drug conjugate.

[0258] Figure 2 4 is a graph showing the change in tumor volume in mice subcutaneously transplanted with the human pancreatic cancer cell line AsPC-1 after injection of the antibody drug conjugate in Example 402.

[0259] Figure 3 403 is a graph showing the change in tumor volume after the antibody drug conjugate was injected into the mouse subcutaneously transplanted with the human uterine cancer cell line HEC-251 in Example 403.

[0260] Figure 4 4 is a graph showing the change in tumor volume after the antibody drug conjugate was injected into the mouse subcutaneously transplanted with the human lung cancer cell line NCI-H226 in Example 404.

[0261] Figure 5 405 is a graph showing the change in tumor volume after the mouse subcutaneously transplanted with the human gastric cancer cell line NCI-N87 was injected with the antibody drug conjugate.

[0262] Figure 6 is a graph showing the change in tumor volume after the antibody drug conjugate was injected into mice subcutaneously transplanted with the human bladder cancer cell line HT-1376 in Example 406.

[0263] Figure 7 4 is a graph showing the change in tumor volume in mice subcutaneously transplanted with the human pancreatic cancer cell line HPAF-II after injection of the antibody drug conjugate in Example 407.

[0264] Figure 8 4 is a graph showing the change in tumor volume after the antibody drug conjugate was injected into mice subcutaneously transplanted with the human ovarian cancer cell line COV644 in Example 408.

[0265] Fig. 9 The graph shows the change in tumor volume after the antibody drug conjugate was injected into the mouse subcutaneously transplanted with the human pancreatic cancer cell line HPAF-II in Example 409.

[0266] Fig.10 4 is a graph showing the change in tumor volume after the antibody drug conjugate was injected into the mouse subcutaneously transplanted with the human pancreatic cancer cell line HPAF-II in Example 410.

[0267] Fig.11 is a graph showing the changes in mean tumor volume of each group after the start of administration of the antibody drug conjugate and / or mouse PD-1 antibody in Example 502. DETAILED DESCRIPTION

[0268] The present invention will now be explained in detail.

[0269] As used herein, “C 1-6 "Alkyl" means a straight or branched chain saturated aliphatic hydrocarbon group having 1 to 6 carbon atoms. 1-6 Examples of the alkyl group include methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 1-butyl, 2-butyl, 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl and 3-hexyl, preferably methyl, ethyl and 1-propyl.

[0270] As used herein, “C 2-6 "Alkynyl" means a straight or branched unsaturated aliphatic hydrocarbon group of 2 to 6 carbon atoms having one or more carbon-carbon triple bonds. 2-6 Examples of the alkynyl group include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 3-butynyl, 1-pentynyl and 1-hexynyl, preferably ethynyl.

[0271] As used herein, “C 3-6 "Cycloalkyl" means an aliphatic saturated hydrocarbon ring group having 3 to 6 carbon atoms. 3-6 Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, preferably cyclopropyl.

[0272] As used herein, “C 6-10 "Aryl" refers to an aromatic cyclic hydrocarbon group having 6 to 10 carbon atoms. 6-10 Examples of the aryl group include phenyl, 1-naphthyl and 2-naphthyl, preferably phenyl.

[0273] As used herein, “C 1-6 "Alkoxy" means the above-mentioned "C 1-6 Alkyl". 1-6 Examples of alkoxy groups include methoxy, ethoxy, 1-propoxy, 2-propoxy, 2-methyl-1-propoxy, 2-methyl-2-propoxy, 1-butoxy, 2-butoxy, 1-pentoxy, 2-pentoxy, 3-pentoxy, 1-hexyloxy, 2-hexyloxy and 3-hexyloxy, preferably methoxy, ethoxy and 1-propoxy.

[0274] As used herein, “C 3-6 "Cycloalkoxy" means the above-mentioned "C 3-6 Cycloalkyl". 3-6 Examples of cycloalkoxy include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy, preferably cyclopropyloxy.

[0275] As used herein, “C 1-6"Alkylcarbamoyloxy" means the above-mentioned "C 1-6 Alkyl". 1-6 Examples of the alkylcarbamoyloxy group include a methylcarbamoyloxy group and an ethylcarbamoyloxy group.

[0276] As used herein, "pharmacologically acceptable salt" refers to, for example, a salt of an inorganic acid, a salt of an organic acid, or a salt of an acidic amino acid.

[0277] Preferred examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid.

[0278] Preferred examples of the salt of the organic acid include salts of acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid and p-toluenesulfonic acid.

[0279] Preferred examples of the salt of the acidic amino acid include salts of aspartic acid and glutamic acid.

[0280] [Drug moiety in antibody drug conjugates]

[0281] The drug moiety in the antibody drug conjugate of this embodiment is a group represented by formula (D-1) or formula (D-2):

[0282]

[0283] (in

[0284]

[0285] indicates the binding site with the linker).

[0286] [Drug Release from Antibody Drug Conjugates]

[0287] The drug released from the antibody drug conjugate of one embodiment is a compound represented by formula (D'):

[0288]

[0289] (wherein these symbols have the same definitions as in

[10] above),

[0290] or a pharmaceutically acceptable salt thereof.

[0291] The drug released from the antibody drug conjugate of one embodiment is a compound represented by formula (D'-1) or formula (D'-2) or a pharmaceutically acceptable salt thereof.

[0292]

[0293] In addition, the partial structure of the drug released from the antibody drug conjugate of one embodiment may be a compound represented by formula (M):

[0294]

[0295] (wherein these symbols have the same definitions as in

[12] above),

[0296] or a pharmacologically acceptable salt thereof.

[0297] [Linkers for Antibody Drug Conjugates]

[0298] The linker in the antibody drug conjugate of this embodiment is stable outside the cell so as to be fully effective in treatment. According to one embodiment, because the linker is stable outside the cell, the antibody drug conjugate maintains the antibody portion bound to the drug portion through the linker when it exists under extracellular conditions (e.g., before transport or delivery to the cell).

[0299] The linker can be "cleavable" or "non-cleavable". Cleavable linkers are designed to release the drug when exposed to specific environmental factors, such as when internalized into target cells. Non-cleavable linkers are generally dependent on the antibody portion itself. According to one embodiment, the linker is a cleavable linker and can be any linker that includes a cleavable portion. As used herein, the term "cleavable portion" refers to any chemical bond that can be cleaved. Suitable cleavable chemical bonds are known in the art and include, but are not limited to, acid-labile bonds, protease / peptidase-labile bonds, photolabile bonds, disulfide bonds, and esterase-labile bonds.

[0300] According to one embodiment, the linker can be cut by a cleavage agent (e.g., an enzyme) in the intracellular environment (e.g., in a lysosome). The linker can be, but is not limited to, a peptide linker that is cut by an intracellular peptidase or protease (e.g., in a lysosome). According to one embodiment, the linker is a cleavable peptide linker. As used herein, the term "cleavable peptide linker" refers to any linker containing a cleavable peptide portion. The term "cleavable peptide portion" refers to any chemically bonded cross-linked amino acids (natural or synthetic amino acid derivatives) that can be cut by an active substance in the intracellular environment. For example, the linker can be cut by a cathepsin (e.g., cathepsin B) or a cysteine ​​protease (e.g., asparagine endopeptidase).

[0301] According to one embodiment, the joint is combined with the antibody part through the chemically active groups of one or more amino acid residues of the antibody part. For example, the joint can be combined with the antibody part (for example, at the N-terminal or C-terminal, with the ε amino group of one or more lysine residues, with the free carboxyl group of one or more glutamic acid or aspartic acid residues, or with the sulfhydryl of one or more cysteine ​​residues) via free amino groups, imino groups, hydroxyl groups, thiol groups or carboxyl groups. The binding site of the joint can be a natural residue in the amino acid sequence of the antibody part, or can be introduced into the antibody part by DNA recombination technology (for example, by introducing cysteine ​​residues into the amino acid sequence) or by using protein biochemistry (for example, by reduction, pH adjustment or hydrolysis).

[0302] According to one embodiment, the linker may further include at least one spacer unit that connects the antibody portion to the drug portion. According to one embodiment, the spacer unit connects a cleavage site (e.g., a cleavable peptide portion) within the linker to the antibody portion, and according to one embodiment, the linker includes one or more polyethylene glycol (PEG) moieties.

[0303] According to one embodiment, the linker is a group represented by the following formula (X-1'), formula (X-2') or formula (X-3'):

[0304]

[0305] [Antibody portion of antibody drug conjugate]

[0306] The antibody portion of the antibody drug conjugate of this embodiment can be an anti-CEACAM6 antibody, an anti-folate receptor α antibody, an anti-mesothelin antibody, an anti-HER2 antibody, an anti-FLT3 antibody, an anti-DLL3 antibody, an anti-CLDN6 antibody, an anti-EGFR antibody, an anti-adhesion protein 4 antibody, an anti-CA9 antibody, an anti-CLDN3 / 4 antibody, or an anti-TROP2 antibody. The antibody can be a monoclonal antibody (mAb) or an antigen-binding fragment thereof. The monoclonal antibody can be a human antibody, a humanized antibody, or a chimeric antibody, and can also include a human constant region. The human constant region can be selected from the group consisting of IgG1, IgG2, IgG3, and IgG4 constant regions. The antigen-binding fragment is selected from Fab, Fab'-SH, F(ab') 2, scFv and Fv fragments. The antibody portion of the antibody drug conjugate of the present embodiment can be any category such as IgG, IgA or IgM (or their subclasses), not limited to any specific category. According to the category of the antibody amino acid sequence based on the heavy chain (H chain) constant region, immunoglobulins are classified into different categories. 5 main immunoglobulin classes: IgA, IgD, IgE, IgG and IgM, which are further subdivided into the following subclasses (isotypes): IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2. The corresponding heavy chain constant regions of specific classes of immunoglobulins are respectively referred to as α, δ, ε, γ and μ. Antibody light chains (also referred to as L chains) have λ chain and κ chain types.

[0307] The antibody portion of the antibody drug conjugate of this embodiment can be an IgG antibody, such as an IgG1 antibody or an IgG2 antibody. The antibody portion of the antibody drug conjugate of this embodiment can be a monomer, a dimer or a multimer.

[0308] The variable region of the antibody disclosed herein can be the variable region of the antibody light chain and / or the variable region of the antibody heavy chain, and the constant region of the antibody can be the constant region of the antibody light chain and / or the constant region of the antibody heavy chain. The variable regions of the heavy chain and the light chain are each connected by three CDRs (also called complementary determining regions) to form four framework regions (FRs). The CDRs in each chain are tightly bound by the FRs and contribute to the formation of the antigen binding site of the antibody together with the CDRs in the other chain. The techniques for determining CDRs are not limited, and examples include (1) methods based on sequence variability between different types (e.g., Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed., 1991, National Institutes of Health, Bethesda MD); and (2) methods based on crystallographic studies of antigen-antibody complexes (Al-lazikani et al., 1997 J. Molec. Biol. 273:927-948). These methods can also be used in combination with other methods.

[0309] As used herein, "monoclonal antibody" may also refer to an antibody obtained from a substantially homogeneous antibody population. In other words, the individual antibodies in the population are identical, except for some natural mutants that may exist. Monoclonal antibodies are highly specific for a single antigenic site. In contrast to typical polyclonal antibodies that have different antigens or different epitopes as targets, monoclonal antibodies target only a single epitope of an antigen. The modified term "monoclonal" indicates the characteristic of an antibody obtained from a substantially homogeneous antibody population, and should not be construed as limiting the need to produce antibodies by a specific method.

[0310] The antibody part in the antibody drug conjugate of the present embodiment can be a mouse antibody, a chimeric antibody, a humanized antibody or a fully human antibody. A chimeric antibody can be an antibody having a non-human (e.g., mouse or rat) antibody variable region fused to a human antibody constant region, for example, an antibody having a variable region derived from a non-human antibody and a constant region derived from a human antibody. A humanized antibody can be an antibody having a complementary determining region (CDR) (also referred to as a hypervariable region) of a non-human antibody imported into a human antibody, for example, having a CDR derived from a non-human antibody and other antibody regions derived from a human antibody. However, the boundary between a chimeric antibody and a humanized antibody does not necessarily have to be clear, and an antibody can also be defined as an antibody that can be referred to as both a chimeric antibody and a humanized antibody. In a chimeric antibody or a humanized antibody, the entirety of the antibody region (FR or constant region) derived from a human antibody does not necessarily have to be composed entirely of amino acids from a human antibody, and as long as it can be used normally in a human subject, one or more amino acids from a non-human antibody can also be included. An embodiment of a humanized antibody is an antibody in which the CDR is derived from a rodent antibody and the remaining antibody region is derived from a human antibody. A more specific embodiment of a humanized antibody is an antibody in which CDR is derived from a mouse antibody and the remaining antibody region is derived from a human antibody. For such an embodiment, the CDR may include one or more amino acids derived from a non-rodent antibody or one or more amino acids derived from a non-mouse antibody, and the non-CDR antibody region may include one or more amino acids derived from a non-human antibody. The qualifier "or more" may be 2 to 20, 2 to 15 or 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3 or 2, or it may be within 10%, within 9%, within 8%, within 7%, within 6%, within 5%, within 4%, within 3%, within 2% or within 1% of the number of amino acids in the amino acid sequence, but is not limited thereto. Humanization of antibodies can be performed by CDR grafting (Kontermann and Dubel, Antibody Engineering, Springer Lab Manual (2001) and Tsurushita et al., Methods 36:69-83 (2005)), or by methods known in the art (e.g., Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-327 (1988) or Verhoeyen et al., Science 239:1534-1536 (1988)), or by replacing CDR sequences with the corresponding sequences of a human antibody.

[0311] The above-mentioned chimeric antibodies or humanized antibodies are appropriately modified (e.g., antibody modification or partial substitution, addition and / or deletion in the antibody amino acid sequence) while maintaining the antibody function (or having additional or improved antibody function through modification) and are also included in the scope of the antibodies disclosed herein. More specifically, antibodies with an amino acid sequence of a changed constant region to modify the antibody effector function are also included in the scope of the disclosure, for example, in order to reduce antibody-dependent cell-mediated toxicity (ADCC) activity and / or antibody-dependent cellular phagocytosis (ADCP) activity, based on the Eu numbering of human IgG2 antibodies, antibodies with alanine (Ala) substituted for valine (Val) at position 234 and alanine (Ala) substituted for glycine (Gly) at position 237 are also included in the scope of the disclosure. The scope of the disclosure also includes dual-specific antibodies, which have antibody binding sites that bind to different antigens (Kontermann (2012), mAbs 4, 182-97), as well as antibody binding sites having CDR sequences of antibodies disclosed herein.

[0312] The antibody portion of the antibody drug conjugate of this embodiment can also be modified as needed. The modification of the antibody can be a modification that changes the following: (a) the three-dimensional structure of the amino acid sequence in the modified region, such as its sheet or helical conformation; (b) the charge or hydrophobic state of the molecule at the target site; or (c) the maintenance of the side chain volume, or a modification in which such a change cannot be clearly observed. The modification of the antibody disclosed herein can be achieved by, for example, substitution, deletion, or addition of the constituent amino acid residues.

[0313] The term "amino acid" as used herein includes not only natural amino acids, such as serine (Ser), asparagine (Asn), valine (Val), leucine (Leu), isoleucine (Ile), alanine (Ala), tyrosine (Tyr), glycine (Gly), lysine (Lys), arginine (Arg), histidine (His), aspartic acid (Asp), glutamic acid (Glu), glutamine (Gln), threonine (Thr), cysteine ​​(Cys), methionine (Met), phenylalanine (Phe), tryptophan (Trp) and proline (Pro) in its broadest sense, but also non-natural amino acids, such as amino acid variants and derivatives. Those skilled in the art will consider that the amino acids referred to throughout this article include L-amino acids in its broadest sense; D-amino acids; chemically modified amino acids, such as amino acid variants and amino acid derivatives; amino acids that do not become constituent materials of biological proteins, such as norleucine, β-alanine and ornithine; and chemically synthesized compounds having amino acid properties well known to those skilled in the art. Examples of unnatural amino acids include α-methyl amino acids (such as α-methylalanine), D-amino acids (such as D-aspartic acid and D-glutamate), histidine-like amino acids (such as 2-amino-histidine, β-hydroxy-histidine, homohistidine, α-fluoromethyl-histidine and α-methyl-histidine), amino acids with extra methylene groups in their side chains (“homo” amino acids), and amino acids with carboxylic acid functional groups in their side chains replaced by sulfonic acid groups (such as cysteine).

[0314] Naturally occurring amino acid residues can be divided into the following groups based on general side chain properties:

[0315] (1) Hydrophobicity: Met, Ala, Val, Leu, Ile;

[0316] (2) Neutral hydrophilicity: Asn, Gln, Cys, Ser, Thr;

[0317] (3) Acidic: Asp, Glu;

[0318] (4) Basic: His, Lys, Arg;

[0319] (5) Residues that affect chain orientation: Gly, Pro; and

[0320] (6) Aromatic: Trp, Tyr, Phe.

[0321] Non-conservative substitutions of the amino acid sequence constituting the antibody can be made by replacing an amino acid belonging to one of these groups with an amino acid belonging to another group. For more conservative substitutions, amino acids belonging to one of these groups can be replaced with other amino acids belonging to the same group. Deletions or substitutions in the amino acid sequence can also be appropriately performed.

[0322] The modification of the amino acids constituting the antibody is a post-translational modification, such as glycosylation, acetylation or phosphorylation based on sugar. Antibodies can be glycosylated at the conserved position of their constant region. The glycosylation of the antibody will generally be N-linked or O-linked. N-linked is the connection of the sugar moiety to the side chain of the asparagine residue. The tripeptide sequences asparaginyl-X-serine, asparaginyl-X-threonine and asparaginyl-X-cysteine ​​(wherein X is any amino acid except proline) are recognition sequences for enzymatic addition of the sugar moiety to the asparaginyl side chain. All of these tripeptide sequences are present in the antibody, so potential glycosylation sites will be generated. O-linked glycosylation can be the connection of N-acetylgalactosamine, galactose or xylose to hydroxyamino acids (such as serine or threonine), or optionally to 5-hydroxyproline or 5-hydroxylysine. The conditions for glycosylation (in the case of glycosylation by biological methods, for example, the type and pH of the host cell and cell culture medium) can be appropriately selected by those skilled in the art according to the purpose.

[0323] The antibodies disclosed herein may also be modified by other modification methods based on technical knowledge known to those skilled in the art, either alone or in combination. The antibodies disclosed herein may also be produced by methods known to those skilled in the art. For example, a nucleic acid encoding an antibody disclosed herein may be integrated into an expression vector, the expression vector may be introduced into a host cell, and the antibody may be produced by culturing the host cell.

[0324] As used herein, the abbreviation "CEACAM6" refers to "carcinoembryonic antigen-related cell adhesion molecule 6", also known as "CD66c" (differentiation antigen group 66c), non-specific cross-reactive antigen, NCA or NCA-50 / 90. As used herein, "CEACAM6" may be understood to refer to human, mouse, rat or monkey CEACAM6. Human, mouse, rat and monkey CEACAM6 can be obtained from public databases where sequence information is registered, such as Genbank provided by the American Center for Biotechnology Information, and the sequence information of the CEACAM6 gene can also be cloned from RNA extracted from the target animal species using primers designed based on the nucleotide sequence information of CEACAM6 of closely related animal species. CEACAM6 is a glycosylphosphatidylinositol (GPI)-bound cell surface protein that is involved in cell-cell adhesion. CEACAM6 is highly expressed on the surface of a variety of tumor cells, including colon cancer, pancreatic cancer, breast cancer and lung cancer cells.

[0325] According to one embodiment, the anti-CEACAM6 antibody of the present disclosure comprises the following CDRs:

[0326] (a) a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 18;

[0327] (b) a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 19; and

[0328] (c) a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 20; and

[0329] (d) a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 21;

[0330] (e) a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO:21-1; and

[0331] (f) a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO:22.

[0332] According to one embodiment, the anti-CEACAM6 antibody is a humanized antibody, a fully human antibody or a chimeric antibody, and according to a more specific embodiment, is particularly a chimeric antibody. According to a more specific embodiment, the anti-CEACAM6 antibody is a chimeric antibody of IgG1 and IgG2m that has no affinity for FcgR and disulfide bond isomers.

[0333] According to one embodiment, the anti-CEACAM6 antibody comprises a heavy chain and a light chain, the variable region of the heavy chain comprises an amino acid sequence as set forth in SEQ ID NO: 6, and the variable region of the light chain comprises an amino acid sequence as set forth in SEQ ID NO: 7. According to this embodiment, the heavy chain variable region and / or the light chain variable region may comprise an amino acid sequence having one or more amino acids substituted, added and / or deleted in the amino acid sequence as set forth in SEQ ID NO: 6 and / or the amino acid sequence as set forth in SEQ ID NO: 7. As long as the binding affinity to CEACAM6 is maintained and the cleavage of CEACAM6 is promoted, the qualifier "or more" is not limited, and may be 2 to 15, 2 to 10, 9, 8, 7, 6, 5, 4, 3 or 2, or it is within 10% of the number of amino acids in the amino acid sequence, for example within 9%, within 8%, within 7%, within 6%, within 5%, within 4%, within 3%, within 2% or within 1%.

[0334] According to one embodiment, the heavy chain of the anti-CEACAM6 antibody comprises a portion of human IgG1 and a portion of human IgG2 constant region. According to a specific embodiment, the anti-CEACAM6 antibody comprises an amino acid sequence as set forth in SEQ ID NO: 10, which has a CH1 portion and a hinge portion as human IgG1, and a CH2 portion and a CH3 portion as a human IgG2 constant region containing V234A and G237A.

[0335] According to one embodiment, the light chain of the anti-CEACAM6 antibody comprises a partial constant region of human Igλ. According to a specific embodiment, the constant region of human Igλ comprises the amino acid sequence as set forth in SEQ ID NO:11.

[0336] According to one embodiment, the anti-CEACAM6 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:6 and a light chain comprising the amino acid sequence set forth in SEQ ID NO:7.

[0337] The antibody portion of the antibody drug conjugate of this embodiment can be an anti-folate receptor alpha antibody, and according to one embodiment, it can be farletuzumab. Farletuzumab is a humanized IgG1 monoclonal antibody against a folate receptor, folate receptor alpha (FRA), which can be produced, for example, by the method described in U.S. Pat. No. 4,805,848.

[0338] According to one embodiment, the anti-folate receptor alpha antibody of the present disclosure comprises the following CDRs:

[0339] (g) a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 28;

[0340] (h) a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 29; and

[0341] (i) a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 30; and

[0342] (j) a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO:31;

[0343] (k) a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO:31-1; and

[0344] (l) a light chain CDR3 comprising the amino acid sequence as set forth in SEQ ID NO:32.

[0345] According to a specific embodiment, the anti-folate receptor alpha antibody comprises a heavy chain and a light chain, the variable region of the heavy chain comprises the amino acid sequence as set forth in SEQ ID NO: 33, and the variable region of the light chain comprises the amino acid sequence as set forth in SEQ ID NO: 34. According to this embodiment, the heavy chain variable region and / or the light chain variable region may comprise an amino acid sequence having one or more amino acids substituted, added and / or deleted in the amino acid sequence as set forth in SEQ ID NO: 33 and / or the amino acid sequence as set forth in SEQ ID NO: 34. As long as the binding affinity to folate receptor α is maintained and the cleavage of folate receptor α is promoted, the qualifier "or more" is not limited, and it can be 2 to 15, 2 to 10, 9, 8, 7, 6, 5, 4, 3 or 2, or it is within 10% of the number of amino acids in the amino acid sequence, for example within 9%, within 8%, within 7%, within 6%, within 5%, within 4%, within 3%, within 2% or within 1%.

[0346] According to one embodiment, the anti-folate receptor alpha antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:35 and a light chain comprising the amino acid sequence set forth in SEQ ID NO:36.

[0347] The antibody portion of the antibody drug conjugate of this embodiment can be an anti-mesothelin antibody. The anti-mesothelin antibody can be produced by the method described in International Patent Publication No. 2021 / 0900062.

[0348] According to one embodiment, the anti-mesothelin antibody of the present disclosure comprises the following CDRs:

[0349] (g) a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 38;

[0350] (h) a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 39; and

[0351] (i) a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO:40; and

[0352] (j) a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO:41;

[0353] (k) a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO:41-1; and

[0354] (l) a light chain CDR3 comprising the amino acid sequence as set forth in SEQ ID NO:42.

[0355] According to one embodiment, the anti-mesothelin antibody comprises a heavy chain and a light chain, the variable region of the heavy chain comprises an amino acid sequence as set forth in SEQ ID NO: 43, and the variable region of the light chain comprises an amino acid sequence as set forth in SEQ ID NO: 44. According to this embodiment, the heavy chain variable region and / or the light chain variable region may comprise an amino acid sequence having one or more amino acids substituted, added and / or deleted in the amino acid sequence as set forth in SEQ ID NO: 43 and / or the amino acid sequence as set forth in SEQ ID NO: 44. As long as the binding affinity to mesothelin is maintained and the cleavage of mesothelin is promoted, the qualifier "or more" is not limited, and it may be 2 to 15, 2 to 10, 9, 8, 7, 6, 5, 4, 3 or 2, or it is within 10% of the number of amino acids in the amino acid sequence, for example, within 9%, within 8%, within 7%, within 6%, within 5%, within 4%, within 3%, within 2% or within 1%.

[0356] According to one embodiment, the anti-mesothelin antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:45 and a light chain comprising the amino acid sequence set forth in SEQ ID NO:46.

[0357] An example of an anti-HER2 antibody is trastuzumab.

[0358] According to one embodiment, the anti-FLT3 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:48 and a light chain comprising the amino acid sequence set forth in SEQ ID NO:49.

[0359] According to one embodiment, the anti-DLL3 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:50 and a light chain comprising the amino acid sequence set forth in SEQ ID NO:51.

[0360] According to one embodiment, the anti-CLDN6 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:52 and a light chain comprising the amino acid sequence set forth in SEQ ID NO:53.

[0361] According to one embodiment, the anti-EGFR antibody may be, for example, cetuximab.

[0362] According to one embodiment, the anti-fibronectin 4 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:54 and a light chain comprising the amino acid sequence set forth in SEQ ID NO:55.

[0363] According to one embodiment, the anti-TROP2 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:56 and a light chain comprising the amino acid sequence set forth in SEQ ID NO:57.

[0364] According to one embodiment, the anti-CA9 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:58 and a light chain comprising the amino acid sequence set forth in SEQ ID NO:59.

[0365] According to one embodiment, the anti-CLDN3 / 4 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:60 and a light chain comprising the amino acid sequence set forth in SEQ ID NO:61.

[0366] [Antibody Drug Conjugates]

[0367] The antibody drug conjugate of this embodiment is represented by formula (I):

[0368]

[0369] (wherein these symbols are as defined in [1] above).

[0370] The antibody drug conjugate of the present embodiment can be administered by injection (intravenous injection, arterial injection or local injection), or by nasal, percutaneous or pulmonary route, or by eye drops, and for example, the injection can be intravenous injection, subcutaneous injection, intradermal injection or intraarterial injection, or local injection to target cells or organs. The dosage form of the antibody drug conjugate for parenteral administration can be an injection, a drop, an eye drop, an ointment, a suppository, a suspension, a plaster, a lotion, an aerosol or a plaster, or according to one embodiment, it is an injection or a drop. The antibody drug conjugate of the present embodiment can be formulated, for example, by the method described in the 17th edition of the Japanese Pharmacopoeia (JP), the United States Pharmacopoeia (USP) or the European Pharmacopoeia (EP).

[0371] The type of cancer treated by the pharmaceutical composition of this embodiment is not particularly limited, and may be pancreatic cancer, breast cancer, gastric cancer, non-small cell lung cancer, bladder cancer, endometrial cancer, hepatocellular carcinoma, bile duct cancer, melanoma, esophageal cancer, colorectal cancer, renal cell carcinoma, head and neck cancer, pleural mesothelioma or Hodgkin's lymphoma. According to one embodiment, the cancer treated is pancreatic cancer.

[0372] [Drug-to-Antibody Ratio (DAR) of Antibody Drug Conjugates]

[0373] The drug-antibody ratio (DAR) of the antibody drug conjugate is represented by "n", which is the average number of drug moieties per antibody moiety (i.e., average DAR or average "n"), which can be calculated by methods known in the art, such as mass spectrometry (including reverse phase LC-MS) or hydrophobic interaction chromatography (HIC). According to a specific embodiment, the drug-antibody ratio is determined by hydrophobic interaction chromatography (HIC). According to another specific embodiment, the drug-antibody ratio is determined by reverse phase liquid chromatography-mass spectrometry (LC-MS) and capillary-SDS gel electrophoresis (c-SDS).

[0374] According to another specific embodiment, the drug-antibody ratio may be in the range of 1 to 8 / antibody moiety. According to another specific embodiment, "n" is an integer from 1 to 8. According to another specific embodiment, "n" is in the range of about 1 to 8, about 1 to 7, about 1 to 6, about 1 to 5, about 1 to 4, about 1 to 3 or about 1 to 2. According to another specific embodiment, "n" is in the range of about 2 to 8, about 2 to 7, about 2 to 6, about 2 to 5, about 2 to 4 or about 2 to 3. According to another specific embodiment, "n" is an integer from about 3 to 4. According to another specific embodiment, "n" is about 1, about 2, about 3, about 4, about 5 or about 6, preferably about 3 or about 4.

[0375] The drug to antibody ratio (DAR) of an antibody drug conjugate may be limited by the number of binding sites on the antibody moiety. As used herein, when referring to the drug to antibody ratio, the term "about" means + / - 10%.

[0376] A specific embodiment of the present disclosure provides a pharmaceutical composition comprising the antibody drug conjugate of this embodiment and a pharmaceutically acceptable diluent, carrier and / or additive.

[0377] Another embodiment includes the use of the antibody drug conjugate of this embodiment for the treatment and diagnosis of cancer management. Yet another embodiment includes a method for managing cancer expressing an antigen (e.g., CEACAM6) that is targeted by the antibody portion of the antibody drug conjugate of this embodiment. Yet another embodiment provides a method of killing tumor cells or cancer cells or inhibiting their growth by administering a therapeutically effective amount and / or regimen of any of the antibody drug conjugates of this embodiment.

[0378] According to a specific embodiment of the present disclosure, the antibody drug conjugate of this embodiment is administered in combination with a PD-1 antagonist.

[0379] The PD-1 antagonists disclosed herein may include any compound or biological molecule that blocks the binding of PD-L1 expressed in cancer cells to PD-1 expressed in immune cells (T cells, B cells, or natural killer T (NKT) cells), or blocks the binding of PD-L2 expressed in cancer cells to PD-1 expressed in immune cells. The PD-1 antagonist blocks the binding of human PD-L1 to human PD-1, and according to one embodiment, it blocks the binding of both human PD-L1 and PD-L2 to human PD-1. The amino acid sequence of human PD-1 can be confirmed by NCBI Locus No.: NP_005009. The amino acid sequences of human PD-L1 and PD-L2 can be confirmed by NCBI Locus No.: NP_054862 and NP_079515, respectively.

[0380] The PD-1 antagonists disclosed herein may also include a monoclonal antibody (mAb) or an antigen-binding fragment thereof that specifically binds to PD-1 or PD-L1, or specifically binds to human PD-1 or human PD-L1. mAbs may be human antibodies, humanized antibodies, or chimeric antibodies, and may also include a human constant region. The human constant region is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4 constant regions, and according to one embodiment, the human constant region is an IgG1 or IgG4 constant region. The antigen-binding fragment may be selected from Fab, Fab'-SH, F(ab') 2 , scFv and Fv fragments.

[0381] An example of a PD-1 antagonist is an anti-PD-1 antibody, and according to one embodiment, it is an anti-human PD-1 antibody, and according to a more specific embodiment, it is an anti-human PD-1 monoclonal antibody (anti-human PD-1 mAb). Examples of mAbs that bind to human PD-1 are U.S. Pat. No. 7488802, U.S. Pat. No. 7521051, U.S. Pat. No. 8008449, U.S. Pat. No. 8354509, U.S. Pat. No. 8168757, International Patent Publication No. WO 2004 / 004771, International Patent Publication No. WO 2004 / 072286, International Patent Publication No. WO 2004 / 056875, and U.S. Patent Application Publication No. 2011 / 0271358. When the PD-1 antagonist is an anti-human PD-1 monoclonal antibody, “anti-human PD-1 monoclonal antibody” includes nivolumab, pembrolizumab, cemiprilimab, sintilimab and toripalimab. When the PD-1 antagonist is an anti-PD-1 antibody, “anti-PD-1 antibody” further includes spartalizumab, tislelizumab, dotalimumab, carrelizumab, genoluzumab, lodalimab, rivulimab, batilizumab, srulimab, brigalimab, prolgolimab, sasanlimab, cetrelimab, sepalizumab, penpulimab, AMP-514, STI-A1110, ENUM388D4, ENUM244C8, GLS010, CS1003, BAT-1306, AK103, BI754091, LZM009, CMAB819, Sym021, SSI-361, JY034, HX008, ISU106 and CX-188.

[0382] Another example of a PD-1 antagonist is an anti-PD-L1 antibody, and according to one embodiment, it is an anti-human PD-L1 antibody, and according to a more specific embodiment, it is an anti-human PD-L1 monoclonal antibody (anti-human PD-L1mAb). When the PD-1 antagonist is an anti-PD-L1 antibody, "anti-PD-L1 antibody" includes Atezolizumab, Avelumab, Durvalumab, Manelimab, Pacmilimab, Envafolimab, Cosibelimab, BMS-936559, STI-1014, KN035, LY33,00054, HLX20, SHR-1316, CS1001, MSB2311, BGB-A333 and KL-A16.

[0383] The PD-1 antagonist of the present disclosure can be administered by injection (intravenous, arterial or local injection), or orally, nasally, percutaneously or by pulmonary route, or by eye drops, and for example, the injection can be intravenous, subcutaneous, intradermal or intraarterial, or local injection to target cells or organs. The dosage form of the preparation containing the PD-1 antagonist for oral administration can be, for example, tablets, powders, granules, syrups, capsules or oral liquids. The dosage form of the preparation containing the PD-1 antagonist for parenteral administration can be an injection, a drop, an eye drop, an ointment, a suppository, a suspension, a plaster, a lotion, an aerosol or a plaster, or according to one embodiment, it can be an injection or a drop. The PD-1 antagonist of the present disclosure can be prepared by the method described in, for example, the 17th edition of the Japanese Pharmacopoeia (JP), the United States Pharmacopoeia (USP) or the European Pharmacopoeia (EP).

[0384] When the PD-1 antagonist is an anti-PD-1 antibody, the anti-PD-1 antibody may be provided as a liquid medicine, or may be prepared as a liquid solution of a lyophilized powder in sterile water for injection prior to use.

[0385] When anti-human PD-1 mAb as a PD-1 antagonist is administered to a patient as a single agent, the dosage will vary significantly depending on the type of disease being treated, as well as the patient's age, sex, weight and degree of symptoms. Anti-human PD-1 mAb is administered at a dose of 1, 2, 3, 5 or 10 mg / kg (body weight) at about 14 days (±2 days), about 21 days (±2 days) or about 30 days (±2 days).

[0386] The administration form of the antibody drug conjugate and the PD-1 antagonist of the present embodiment is not particularly limited, as long as the antibody drug conjugate and the PD-1 antagonist shown in formula (I) are administered in combination. For example, the antibody drug conjugate and the PD-1 antagonist shown in formula (I) can be administered to the patient simultaneously, separately, continuously or at different times. The term "simultaneously" means that each component is administered in the same time period or strictly at the same time, or via the same administration route. The term also means that the two components are administered without significant intervals, so that they can play an additive effect, preferably a synergistic effect. The term "separate" means that each component is administered at different intervals or frequencies, or by different administration routes. The term "continuously" means that each component is administered in any order during a fixed time period by the same or different administration routes. The term "at different times" means that each component is administered by the same or different administration routes, and is administered at different intervals for each component. When the PD-1 antagonist is administered during one cycle of administration of the antibody drug conjugate represented by formula (I), or during repeated cycles, the two are judged to be administered in combination.

[0387] The manner of combining the antibody drug conjugate represented by formula (I) and the PD-1 antagonist is not particularly limited, and any method known to those skilled in the art may be used.

[0388] Examples

[0389] The compounds of the present invention can be produced by the methods described in the following Production Examples and Examples. However, these specific examples are merely illustrative and are not intended to limit the compounds of the present invention in any way.

[0390] Unless otherwise specified, the purification silica gel used in the silica gel column chromatography of the Examples and the Examples was YMC GEL SILICA (YMC Co., Ltd., catalog code: SL06I52W), Silica Gel 60 (Kanto Chemicals), Silica Gel Spheres (Fuji Silysia Chemical Ltd., catalog code: PSQ60B), Silica Gel 60 (Merck KGaA, catalog code: 1.07734), CHROMATOREX BW (Fuji Silysia Chemical Co., Ltd., catalog code: BW-300), Hi-Flash Column (Yamazen Corporation)), or Presep Silica Gel (Wako), and the purification silica gel used for NH silica gel column chromatography was NH Siliga Gel (Fuji Silysia Chemical Co., Ltd., catalog code: NH-DM2035), Hi-Flash Column Amino (Yamazen) or Presep NH2 HC (Photosynthetic Pure Chemical Industries, Ltd.), the silica gel used for purification by ODS silica gel column chromatography is Hi-Flash Column ODS (Yamazen). In addition, the TLC plate used for purification by silica gel thin layer chromatography is TLC Silica gel 60F 254 (Merck KGaA, catalog code: 1.05715 or 1.05744), and the PLC plate for purification used in NH silica gel thin layer chromatography was CHROMATOREX NH-PLC05 plate (Fuji Silicon Chemical Co., Ltd., catalog code: NH-PLC05). The solid phase extraction column used was Presep (Wako Pure Chemical Industries, Ltd., diatomaceous earth, granular).

[0391] Unless otherwise stated, the microwave reactor used in the Production Examples and Examples was an Initiator+Eight (Biotage).

[0392] Unless otherwise stated, an automated fractionation LC system (Waters MassLynx MS, fractionation system) was used for the generation and fractionation purification of the examples. The column used was an Xbridge Prep C18 5 μm OBD (19 mm×100 mm) from Waters.

[0393] Unless otherwise stated, supercritical fluid chromatography (SFC) (Prep100 SFC system of Waters) was used to generate chiral separations in the examples and the examples. The columns used were CHIRALPAK (registered trademark) IB (2 cm × 25 cm), CHIRALPAK (registered trademark) IF (3 cm × 25 cm), CHIRALPAK (registered trademark) IG (2 cm × 25 cm) of Daicel Corp.

[0394] Varian Mercury 400, Varian Mercury Plus 400, JEOL 400 (JMTC-400 / 54 / SS, ECZ400S), JEOL 500 (JMTC-500 / 54 / JJ, ECZ500RS) or Avance Neo 700 MHz (Bruker) were used for proton NMR spectroscopy analysis. Chemical shifts for proton NMR spectra are reported in delta units (ppm) relative to tetramethylsilane, and coupling constants are reported in Hertz (Hz). The abbreviations for splitting patterns are as follows. s: singlet, d: doublet, dd: doublet of doublets, t: triplet, dt: doublet of triplets, q: quartet, quin: quintet, spt: septet, m: multiplet, brs: broad singlet, brd: broad doublet, brdd: broad doublet of doublets, brt: broad triplet. In the present specification, b or br may be used as a broad single peak.

[0395] Mass spectrometry was performed using a Waters UPLC TM The ionization method used was electrospray ionization (ESI).

[0396] In the Production Examples and Examples, commercial products were used as appropriate compounds.

[0397] The abbreviations used have the following meanings.

[0398] n-Heptane: normal heptane

[0399] CDCl 3 : Deuterated chloroform

[0400] DABCO: 1,4-diazabicyclo[2.2.2]octane

[0401] DHP: 3,4-dihydro-2H-pyran

[0402] DIBAL-H: Diisobutylaluminum hydride

[0403] DMF: N,N-dimethylformamide

[0404] DMSO: dimethyl sulfoxide

[0405] DMSO-d 6 : Deuterated dimethyl sulfoximine

[0406] HATU: N,N,N',N'-Tetramethyl-O-(7-azobenzotriazol-1-yl)uronium hexafluorophosphate

[0407] LHMDS: Lithium Hexamethyldisilazide

[0408] NMP: N-methyl-2-pyrrolidone

[0409] TBME: tert-butyl methyl ether

[0410] TFA: trifluoroacetic acid

[0411] THF: Tetrahydrofuran

[0412] [Example 1]

[0413] N-(6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(2-hydroxy-1-phenyl-1-(4-(trifluoromethyl)phenoxy)ethyl)quinazolin-2-yl)methanesulfonamide

[0414]

[0415] To a solution of 5-(2-chloro-4-(1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)-1-(4-(trifluoromethyl)phenoxy)ethyl)quinazolin-6-yl)1,3-dimethylpyridin-2(1H)-one (15.0 mg, 0.023 mmol) obtained in Example 1-4 in 1,4-dioxane (1 mL) at room temperature were added methanesulfonamide (4.39 mg, 0.046 mmol), cesium carbonate (18.8 mg, 0.058 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthine (4.01 mg, 6.92 μmol) and tris(dibenzylideneacetone)dipalladium(0) (6.34 mg, 6.92 μmol), and the mixture was stirred at 100° C. for 3 hours. The reaction mixture was returned to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (ethyl acetate: methanol = 19: 1) to obtain a crude product. To the solution of the obtained crude product in methanol (1mL) was added p-toluenesulfonic acid monohydrate (8.78mg, 0.046mmol) at room temperature, and the mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and after stirring for 10 minutes, the mixture was concentrated under reduced pressure. Dichloromethane was added to the obtained residue, and after the mixture was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (ethyl acetate: methanol = 19: 1) to obtain the title compound (2.0mg).

[0416] ESI-MS (m / z): 625.33 [M+H] + .

[0417] [Generation Example 1-1]

[0418] 2-phenyl-2-(4-(trifluoromethyl)phenoxy)acetic acid

[0419]

[0420] At room temperature, potassium carbonate (639 mg, 4.63 mmol) was added to a solution of 4-hydroxybenzotrifluoride (500 mg, 3.08 mmol) and ethyl α-chlorophenylacetate (613 mg, 3.08 mmol) in DMF (10 mL), and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine. After the organic layer was dried over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane to n-heptane: ethyl acetate = 7:3) to obtain the title compound (864 mg).

[0421] ESI-MS (m / z): 325.08 [M+H] + .

[0422] [Generation Example 1-2]

[0423] 2-(2-Chloro-6-iodoquinazolin-4-yl)-2-phenyl-2-(4-(trifluoromethyl)phenoxy)acetic acid

[0424]

[0425] At -78 ° C, to a solution of ethyl 2-phenyl-2-(4-(trifluoromethyl)phenoxy)acetate (864 mg, 2.66 mmol) and 2,4-dichloro-6-iodoquinazoline (866 mg, 2.66 mmol) of 1-1 in THF (20 mL) was added dropwise LHMDS (1M THF solution, 4.00 mL, 4.00 mmol), and the mixture was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with brine. After the organic layer was dried over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane to n-heptane: ethyl acetate = 7:3) to give the title compound (1.28 g).

[0426] ESI-MS (m / z): 613.19 [M+H] + .

[0427] [Generation Examples 1-3]

[0428] 2-Chloro-6-iodo-4-(1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)-1-(4-(trifluoromethyl)phenoxy)ethyl)quinazoline

[0429]

[0430] Under nitrogen atmosphere, DIBAL-H (1M toluene solution, 6.27mL, 6.27mmol) was added dropwise to a solution of 2-(2-chloro-6-iodoquinazoline-4-yl)-2-phenyl-2-(4-(trifluoromethyl)phenoxy)ethyl acetate (1.28g, 2.09mmol) of Example 1-2 in toluene (20mL) at -78°C, and the mixture was stirred at room temperature for 2 hours. Saturated Rochelle salt aqueous solution and ethyl acetate were added and stirred. After the reaction mixture was oil-water partitioned, the organic layer was washed with brine and dried over magnesium sulfate. After filtering the organic layer, the filtrate was concentrated under reduced pressure to obtain a crude product. At room temperature, DHP (879mg, 10.4mmol) and p-toluenesulfonic acid monohydrate (199mg, 1.04mmol) were added to a solution of the resulting crude product in dichloromethane (20mL), and the mixture was stirred at room temperature for 3 days. The reaction mixture was purified by silica gel column chromatography (n-heptane to n-heptane:ethyl acetate=7:3) to give the title compound (677 mg).

[0431] ESI-MS (m / z): 655.32 [M+H] + .

[0432] [Generation Examples 1-4]

[0433] 5-(2-Chloro-4-(1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)-1-(4-(trifluoromethyl)phenoxy)ethyl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[0434]

[0435] At room temperature, ethanol (1 mL), sodium carbonate (2M aqueous solution, 2.00 mL, 4.00 mmol) and tetrakis(triphenylphosphine)palladium(0) (26.5 mg, 0.023 mmol) were added to a solution of 2-chloro-6-iodo-4-(1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)-1-(4-(trifluoromethyl)phenoxy)ethyl)quinazoline (300 mg, 0.458 mmol) and 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (137 mg, 0.550 mmol) produced in toluene (4 mL), and the mixture was stirred at 70° C. for 12 hours. The reaction mixture was returned to room temperature, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with brine. After the organic layer was dried over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=1:1 to ethyl acetate) to give the title compound (153 mg).

[0436] ESI-MS (m / z): 650.39 [M+H] + .

[0437] [Example 2]

[0438] 5-(2-amino-4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[0439]

[0440] To a solution of 5-(2-amino-4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (10 mg, 0.19 mmol) producing Example 2-5 in methanol (0.384 mL) at room temperature was added p-toluenesulfonic acid monohydrate (5.42 mg, 0.28 mmol), and the mixture was stirred for 1 hour. Dichloromethane and aqueous sodium bicarbonate solution were added to the reaction mixture, and extraction was performed with dichloromethane. The organic layer was dried over sodium sulfate, and after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel thin layer chromatography (ethyl acetate) to give the title compound (3.3 mg).

[0441] 1 H-NMR spectrum (400 MHz, CDCl 3 )δ(ppm):0.17-0.32(1H,m),0.32-0.43(1H,m),0.44-0.58(1H,m),0.64-0.79( 1H,m),2.16(3H,s),2.93-3.05(1H,m),3.27-3.38(1H,m),3.54(3H,s),4.36-4 .50(1H,m),4.54-4.62(1H,m),5.21(2H,s),6.89-6.94(1H,m),7.10-7.13(1H, m),7.26-7.38(5H,m),7.53-7.58(1H,m),7.58-7.62(1H,m),7.85-7.88(1H,m).

[0442] [Generation Example 2-1]

[0443] Ethyl 2-cyclopropyloxy-2-phenylacetate

[0444]

[0445] To a solution of cyclopropanol (3.36 g, 57.8 mmol) and rhodium acetate (II) dimer (320 mg, 0.723 mmol) in dichloromethane (20 mL) was added dropwise a solution of ethyl 2-diazo-2-phenylacetate (5.50 g, 28.9 mmol) in dichloromethane (10 mL), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane to n-heptane: ethyl acetate = 4: 1) to give the title compound (5.83 g).

[0446] 1 H-NMR spectrum (500 MHz, CDCl 3 )δ(ppm):0.43-0.56(2H,m),0.64-0.78(2H,m),1.19-1.24(3H,m),3.38-3.45 (1H,m),4.10-4.26(2H,m),4.94(1H,s),7.29-7.38(3H,m),7.42-7.47(2H,m).

[0447] [Generation Example 2-2]

[0448] Ethyl 2-(2-chloro-6-iodoquinazolin-4-yl)-2-cyclopropyloxy-2-phenylacetate

[0449]

[0450] Under nitrogen atmosphere, at -78 ° C, LHMDS (1.09M THF solution, 3.30mL, 3.60mmol) was added dropwise to a solution of ethyl 2-cyclopropyloxy-2-phenylacetate (661mg, 3.00mmol) and 2,4-dichloro-6-iodoquinazoline (1.17g, 3.60mmol) produced in Example 2-1 in THF (10mL), and the mixture was stirred at -78 ° C for 10 minutes. The reaction mixture was then stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with brine. After the organic layer was dried over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (n-heptane to n-heptane: ethyl acetate = 7: 3) to obtain the title compound (1.35g).

[0451] ESI-MS (m / z): 509.25 [M+H] + .

[0452] [Generation Example 2-3]

[0453] 2-Chloro-4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-6-iodoquinazoline

[0454]

[0455] At -78 ° C, DIBAL-H (1M toluene solution, 5.84 mL, 5.84 mmol) was added dropwise to a solution of ethyl 2-(2-chloro-6-iodoquinazolin-4-yl)-2-cyclopropyloxy-2-phenylacetate (1.35 g, 2.65 mmol) of Example 2-2 in toluene (15 mL), and the mixture was stirred at 0 ° C for 1 hour. Saturated Rochelle salt aqueous solution and ethyl acetate were added, and after stirring for 3 hours, the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After filtering the organic layer, the filtrate was concentrated under reduced pressure to obtain a crude product. DHP (720 μL, 7.96 mmol) and (1S)-(+)-10-camphorsulfonic acid (123 mg, 0.531 mmol) were added to a solution of the obtained crude product in dichloromethane (10 mL) at room temperature, and the mixture was stirred at room temperature for 1.5 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture to terminate the reaction, and extraction was performed with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=95:5 to 7:3) to obtain the title compound (1.67 g).

[0456] ESI-MS (m / z): 551.25 [M+H] + .

[0457] [Generation Example 2-4]

[0458] 5-(2-chloro-4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[0459]

[0460] To a solution of 2-chloro-4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-6-iodoquinazoline (846 mg, 1.54 mmol) and 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (421 mg, 1.69 mmol) produced in toluene (5 mL) at room temperature, ethanol (1.25 mL), sodium carbonate (2M aqueous solution, 2.50 mL, 5.00 mmol) and tetrakis(triphenylphosphine)palladium(0) (177 mg, 0.154 mmol) were added, and the mixture was stirred at 70° C. for 18 hours. The reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=1:1 to ethyl acetate) to give the title compound (659 mg).

[0461] ESI-MS (m / z): 546.38 [M+H] +

[0462] [Generation Example 2-5]

[0463] 5-(2-amino-4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[0464]

[0465] At room temperature, 28% aqueous ammonia solution (0.5 mL) was added to a solution of 5-(2-chloro-4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (50 mg, 0.092 mmol) in NMP (0.5 mL) producing Example 2-4, and the mixture was stirred in a sealed tube at 90° C. for 21 hours. The reaction mixture was returned to room temperature, water was added, and extracted with ethyl acetate. After washing the organic layer with brine, it was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 1: 1 to ethyl acetate) to give the title compound (23.0 mg).

[0466] ESI-MS (m / z): 527.82 [M+H] + .

[0467] [Example 3]

[0468] 5-(4-(1-cyclopropyl-3-hydroxy-2-phenylpropane-2-yl)-2-((dimethyl(oxo)-16-thiolidene)amino)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[0469]

[0470] To a solution of 5-(2-chloro-4-(1-cyclopropyl-2-phenyl-3-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (20 mg, 0.037 mmol) obtained in Example 3-4 in 1,4-dioxane (1 mL) at room temperature were added dimethylsulfoximine (6.85 mg, 0.074 mmol), cesium carbonate (29.9 mg, 0.092 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthine (6.38 mg, 0.011 mmol) and tris(dibenzylideneacetone)dipalladium(0) (10.1 mg, 0.011 mmol), and the mixture was stirred at 100° C. for 3 hours. The reaction mixture was returned to room temperature, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After filtering the organic layer, the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 1: 1 to ethyl acetate to ethyl acetate: methanol = 7: 3) to obtain a crude product. To the solution of the obtained crude product in methanol (1mL) was added p-toluenesulfonic acid monohydrate (3.50mg, 0.018mmol) at room temperature, and the mixture was stirred at room temperature for 12 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and after stirring for 15 minutes, the mixture was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (ethyl acetate to ethyl acetate: methanol = 7: 3) to obtain the title compound (4.38mg).

[0471] ESI-MS (m / z): 517.34 [M+H] + .

[0472] [Generation Example 3-1]

[0473] Ethyl 3-cyclopropyl-2-phenylpropionate

[0474]

[0475] At 0 ° C, 50% to 72% sodium hydride oil (440 mg) was added to a solution of (bromomethyl)cyclopropane (1.07 mL, 11.0 mmol) and ethyl 2-phenylacetate (1.64 g, 9.99 mmol) in DMF (39 mL), and the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane: ethyl acetate = 97: 3 to 9: 1) to obtain the title compound (1.37 g).

[0476] 1 H-NMR spectrum (400 MHz, CDCl 3 )δ(ppm):-0.04-0.15(2H,m),0.28-0.47(2H,m),0.53-0.70(1H,m),1.16-1.24(3H,m),1.6 6-1.80(1H,m),1.83-1.95(1H,m),3.53-3.70(1H,m),4.01-4.23(2H,m),7.22-7.40(5H,m).

[0477] [Generation Example 3-2]

[0478] 2-(2-Chloro-6-iodoquinazolin-4-yl)-3-cyclopropyl-2-phenylpropionic acid ethyl ester

[0479]

[0480] At -78 ° C, 2,4-dichloro-6-iodoquinazoline (744 mg, 2.29 mmol) solution in THF (18 mL) was added to produce Example 3-1 3-cyclopropyl-2-phenylpropionic acid ethyl ester (500 mg, 2.29 mmol). LHMDS (1M THF solution, 3.44 mL, 3.44 mmol) was added dropwise to the reaction mixture, and then stirred at -78 ° C for 10 minutes. The reaction mixture was gradually heated and then stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the resulting mixture was stirred for 5 minutes, followed by addition of ethyl acetate and water. After oil-water distribution, the water layer was extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane: ethyl acetate = 20: 1 to 4: 1) to obtain the title compound (892 mg).

[0481] 1 H-NMR spectrum (400 MHz, CDCl 3)δ(ppm):-0.24--0.06(2H,m),0.22-0.36(2H,m),0.83-0.95(1H,m),0.99-1.12(3H,m),2.41-2.56(1H,m),2.5 6-2.68(1H,m),3.99-4.27(2H,m),7.13-7.39(3H,m),7.42-7.60(2H,m),7.60-7.69(1H,m),7.89-8.03(2H,m).

[0482] [Generate Example 3-3]

[0483] 2-Chloro-4-(1-cyclopropyl-2-phenyl-3-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)-6-iodoquinazoline

[0484]

[0485] At -78°C, DIBAL-H (1M THF solution, 5.28 ml, 5.28 mmol) was added to a solution of ethyl 2-(2-chloro-6-iodoquinazolin-4-yl)-3-cyclopropyl-2-phenylpropanoate (892 mg, 1.76 mmol) of Example 3-2 in toluene (12 mL). The mixture was warmed to 0°C and stirred for 10 minutes. A saturated Rochelle salt solution was added and the mixture was stirred. Ethyl acetate and water were added, and after oil-water distribution, the organic layer was dried over sodium sulfate, filtered, and then the filtrate was concentrated under reduced pressure to obtain a reaction intermediate. DHP (740 mg, 8.80 mmol) and (1S)-(+)-10-camphorsulfonic acid (82.0 mg, 0.352 mmol) were added to a solution of the obtained reaction intermediate in dichloromethane (17.6 mL) at room temperature, and the mixture was stirred at room temperature for 10 minutes. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane: ethyl acetate = 19: 1 to 4: 1) to give the title compound (714 mg).

[0486] 1 H-NMR spectrum (400 MHz, CDCl 3)δ(ppm):-0.51--0.36(2H,m),-0.04-0.17(4H,m),0.22-0.44(4H,m),1.00-1.50(6H,m),1.70-1.92(3H,m),2.1 3-2.30(2H,m),2.55-2.67(2H,m),2.71-2.82(1H,m),3.12-3.21(1H,m),3.32-3.45(2H,m),3.47-3.56(1H,m),3. 83-3.91 (1H, m), 4.08-4.13 (1H, m), 4.25-4.33 (2H, m), 4.47-4.53 (1H, m), 4.66-4.71 (1H, m), 4.81-4.86 (1H, m), 4.91-4.96 (1H, m), 7.13-7.19 (4H, m), 7.26-7.33 (6H, m), 7.56-7.64 (2H, m), 7.79-7.86 (2H, m), 7.87-7.92 (2H, m). (diastereomeric mixture)

[0487] [Generate Example 3-4]

[0488] 5-(2-chloro-4-(1-cyclopropyl-2-phenyl-3-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[0489]

[0490] At room temperature, sodium carbonate (0.5M aqueous solution, 3.64mL, 1.82mmol) and tetrakis(triphenylphosphine)palladium(0) (84.0mg, 0.073mmol) were added to a solution of 2-chloro-4-(1-cyclopropyl-2-phenyl-3-((tetrahydro-2H-pyran-2-yl)oxy)propane-2-yl)-6-iodoquinazoline (400mg, 0.729mmol) and 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (218mg, 0.875mmol) produced in toluene (7.2mL) and ethanol (1.8mL), and the mixture was stirred at 80°C for 16 hours under a nitrogen atmosphere. The reaction mixture was then stirred at 90°C for 6 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=3:7 to 1:9) to give the title compound (200 mg).

[0491] 1H-NMR spectrum (400 MHz, CDCl 3 )δ(ppm):-0.54--0.44(2H,m),0.01-0.14(4H,m),0.28-0.48(4H,m),1.00-1.50(10H,m),2.15(6H,s),2. 17-2.32(4H,m),2.65-2.75(2H,m),2.75-2.86(1H,m),3.10-3.21(1H,m),3.28-3.42(2H,m),3.53(6H,s), 4.14-4.21 (1H, m), 4.30-4.34 (1H, m), 4.34-4.39 (1H, m), 4.49-4.59 (1H, m), 4.65-4.72 (1H, m), 4.80-4.91 (1H, m), 6.77-6.83 (2H, m), 6.90-6.98 (2H, m), 7.28-7.45 (12H, m), 7.72-7.78 (2H, m), 7.88-7.95 (2H, m). (diastereomeric mixture)

[0492] [Example 4]

[0493] N-(6-(5-methoxy-1-methyl-6-oxo-1,6-dihydroxypyridin-3-yl)-4-(2-(pyridin-2-yl)propan-2-yl)quinazolin-2-yl)methanesulfonamide

[0494]

[0495] Under nitrogen atmosphere, at -78 ° C, to a solution of 5-(2-chloro-4-(1-(pyridin-2-yl)ethyl)quinazoline-6-yl)-3-methoxy-1-methylpyridin-2(1H)-one (27 mg, 0.066 mmol) and iodomethane (28.3 mg, 0.199 mmol) in THF (1 mL) was added potassium tert-butoxide (14.9 mg, 0.133 mmol), and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After filtering the organic layer, the filtrate was concentrated under reduced pressure. At room temperature, methanesulfonamide (5.88 mg, 0.062 mmol), cesium carbonate (25.2 mg, 0.077 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthine (5.36 mg, 9.3 μmol) and tris(dibenzylideneacetone)dipalladium (0) (8.49 mg, 9.3 μmol) were added to a solution of a portion of the obtained reaction intermediate (13.0 mg, 0.031 mmol) in 1,4-dioxane (1 mL), and the mixture was stirred at 100 ° C for 12 hours. The reaction mixture was returned to room temperature, saturated aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After filtering the organic layer, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-heptane: ethyl acetate = 1: 1 to ethyl acetate to methanol: ethyl acetate = 3: 7) to obtain the title compound (2.00 mg).

[0496] ESI-MS (m / z): 480.21 [M+H] + .

[0497] [Generation Example 4-1]

[0498] 4-Methoxybenzyl 2-(pyridin-2-yl) propionate

[0499]

[0500] 4-methoxybenzyl chloride (1.51 g, 9.63 mmol) was added to a solution of 2-(pyridin-2-yl) propionate (970 mg, 6.42 mmol) and potassium carbonate (2.66 g, 19.3 mmol) in DMF (30 mL), and the mixture was stirred at 80 ° C for 2 days. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with brine. After the organic layer was dried over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane to n-heptane: ethyl acetate = 7: 3) to obtain the title compound (1.60 g).

[0501] ESI-MS (m / z): 272.04 [M+H] + .

[0502] [Generation Example 4-2]

[0503] 4-Methoxybenzyl 2-(2-chloro-6-iodoquinazolin-4-yl)-2-(pyridin-2-yl) propanoate

[0504]

[0505] Under nitrogen atmosphere, at -78 ° C, LHMDS (1M THF solution, 4.87 mL, 4.87 mmol) was added dropwise to a solution of 4-methoxybenzyl 2-(pyridin-2-yl) propionate (1.60 g, 3.24 mmol) and 2,4-dichloro-6-iodoquinazoline (1.58 g, 4.87 mmol) produced in Example 4-1 in THF (30 mL), and the mixture was stirred at room temperature for 3 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with brine. After the organic layer was dried over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane to n-heptane: ethyl acetate = 4: 1) to obtain the title compound (710 mg).

[0506] 1 H-NMR spectrum (500 MHz, CDCl 3 )δ(ppm):2.18(3H,s),3.78(3H,s),5.01(1H,d,J=10.0Hz),5.21(1H,d,J=10.0Hz),6.73-6.78(2H,m),7.01-7.06(2H, m),7.17-7.21(1H,m),7.49-7.53(1H,m),7.59-7.64(1H,m),7.64-7.70(2H,m),7.88-7.93(1H,m),8.38-8.43(1H,m).

[0507] [Generation Example 4-3]

[0508] 2-Chloro-6-iodo-4-(1-(pyridin-2-yl)ethyl)quinazoline

[0509]

[0510] At room temperature, hydrochloric acid (4M ethyl acetate solution, 10.0mL, 40.0mmol) was added to 4-methoxybenzyl 2-(2-chloro-6-iodoquinazoline-4-yl)-2-(pyridin-2-yl) propanoate (710.0mg, 1.27mmol) producing Example 4-2, and the mixture was stirred for 12 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane to n-heptane: ethyl acetate = 7:3) to obtain the title compound (263mg).

[0511] ESI-MS (m / z): 396.03 [M+H] + .

[0512] [Generate Example 4-4]

[0513] 5-Bromo-3-methoxy-1-methylpyridin-2(1H)-one

[0514]

[0515] To a solution of 5-bromo-2,3-dimethoxypyridine (207 mg, 949 μmol) in acetonitrile (1 mL) was added iodomethane (18 μL, 285 μmol) at room temperature, and the mixture was stirred at 150° C. for 24 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane: ethyl acetate = 1:1 to ethyl acetate) to give the title compound (155 mg).

[0516] 1 H-NMR spectrum (500 MHz, CDCl 3 )δ (ppm): 3.55 (3H, s), 3.82 (3H, s), 6.65 (1H, d, J = 2.4Hz), 7.05 (1H, d, J = 2.4Hz).

[0517] [Generation Example 4-5]

[0518] 3-Methoxy-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one

[0519]

[0520] 1,1'-bis(diphenylphosphino)ferrocene(II)palladium dichloride and dichloromethane (29 mg, 36 μmol) were added to a solution of 5-bromo-3-methoxy-1-methylpyridin-2(1H)-one (155 mg, 0.711 mmol) of Example 4-4 produced in 1,4-dioxane (10 mL), bis-pinacol borate (361 mg, 1.42 mmol) and potassium acetate (140 mg, 1.42 mmol), and the mixture was stirred at 100 ° C for 24 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane: ethyl acetate = 1: 1 to ethyl acetate) to give the title compound (54 mg).

[0521] 1 H-NMR spectrum (400 MHz, CDCl 3 )δ(ppm):1.28(12H,s),3.60(3H,s),3.85(3H,s),6.87(1H,d,J=1.56Hz),7.42(1H,d,J=1.56Hz).

[0522] [Generate Examples 4-6]

[0523] 5-(2-Chloro-4-(1-(pyridin-2-yl)ethyl)quinazolin-6-yl)-3-methoxy-1-methylpyridin-2(1H)-one

[0524]

[0525] At room temperature, ethanol (0.2 mL), sodium carbonate (2M aqueous solution, 0.40 mL, 0.80 mmol) and tetrakis (triphenylphosphine) palladium (0) (7.30 mg, 6.32 μmol) were added to a solution of 2-chloro-6-iodo-4-(1-(pyridin-2-yl)ethyl)quinazoline (50.0 mg, 0.126 mmol) and 3-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (40.2 mg, 0.152 mmol) produced in toluene (0.8 mL), and the mixture was stirred at 70 ° C for 12 hours. The reaction mixture was returned to room temperature, water was added, and extracted with ethyl acetate. The organic layer was washed with brine. After the organic layer was dried over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=1:1 to ethyl acetate) to give the title compound (27.0 mg).

[0526] ESI-MS (m / z): 407.16 [M+H] + .

[0527] [Example 5]

[0528] N-(4-(1-cyclopropyl-3-hydroxy-2-(pyridin-2-yl)propan-2-yl)-6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)methanesulfonamide

[0529]

[0530] To a solution of 5-(2-chloro-4-(1-cyclopropyl-2-(pyridin-2-yl)-3-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (15.0 mg, 0.028 mmol) obtained in Example 5-4 in 1,4-dioxane (1 mL) were added methanesulfonamide (5.24 mg, 0.055 mmol), cesium carbonate (22.4 mg, 0.069 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthine (4.78 mg, 8.26 μmol) and tris(dibenzylideneacetone)dipalladium(0) (7.56 mg, 8.26 μmol) at room temperature, and the mixture was stirred at 100° C. for 12 hours. The reaction mixture is returned to room temperature, followed by addition of saturated aqueous citric acid solution, and the mixture is then extracted with ethyl acetate. The organic layer is washed with brine and dried over magnesium sulfate. After filtering the organic layer, the filtrate is concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (n-heptane: ethyl acetate = 1: 1 to ethyl acetate to ethyl acetate: methanol = 7: 3) to obtain a reaction intermediate. At room temperature, p-toluenesulfonic acid monohydrate (2.62 mg, 14 μmol) is added to the solution of the obtained reaction intermediate in methanol (1 mL), and the mixture is stirred at room temperature for 12 hours. The reaction mixture is then concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (ethyl acetate to ethyl acetate: methanol = 7: 3) to obtain the title compound (6.52 mg).

[0531] ESI-MS (m / z): 520.32 [M+H] + .

[0532] [Generation Example 5-1]

[0533] Ethyl 3-cyclopropyl-2-(pyridin-2-yl)propanoate

[0534]

[0535] Under nitrogen atmosphere, at 0 ℃, 50% to 72% sodium hydride oil (581mg) was added to a solution of ethyl 2-pyridyl acetate (2.00g, 12.1mmol) in DMF (25mL), and the mixture was stirred at room temperature for 15 minutes. Cyclopropyl methyl bromide (1.72g, 12.7mmol) was added and the mixture was stirred for 30 minutes. Water was added to the reaction mixture, then diluted with brine and extracted with ethyl acetate. The organic layer was washed with brine, dried with magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (n-heptane to n-heptane: ethyl acetate = 7:3) to obtain the title compound (2.39g).

[0536] ESI-MS (m / z): 219.93 [M+H] + .

[0537] [Generation Example 5-2]

[0538] Ethyl 2-(2-chloro-6-iodoquinazolin-4-yl)-3-cyclopropyl-2-(pyridin-2-yl)propanoate

[0539]

[0540] Under nitrogen atmosphere, at -78 ° C, LHMDS (1.09M THF solution, 12.0 mL, 13.1 mmol) was added dropwise to a solution of 3-cyclopropyl-2-(pyridin-2-yl)propionic acid ethyl ester (2.39 g, 10.9 mmol) and 2,4-dichloro-6-iodoquinazoline (3.90 g, 12.0 mmol) produced in Example 5-1 in THF (20 mL), and after stirring for 10 minutes, the mixture was stirred at room temperature for 3 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with brine. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (n-heptane to n-heptane: ethyl acetate = 7: 3) to obtain the title compound (6.5 g).

[0541] ESI-MS (m / z): 508.29 [M+H] + .

[0542] [Generation Example 5-3]

[0543] 2-(2-Chloro-6-iodoquinazolin-4-yl)-3-cyclopropyl-2-(pyridin-2-yl)propan-1-ol

[0544]

[0545] At -78 ° C, DIBAL-H (1M toluene solution, 22.0 ml, 22.0 mmol) was added to a solution of 2-(2-chloro-6-iodoquinazoline-4-yl)-3-cyclopropyl-2-(pyridin-2-yl) propionic acid ethyl ester (5.59 g, 11.0 mmol) in toluene (20 mL) and THF (2 mL) to produce Example 5-2. After stirring for 10 minutes, the mixture was warmed to 0 ° C and stirred for 10 minutes. A saturated Rochelle salt solution was added and the mixture was stirred at room temperature overnight. After oil-water distribution, the organic layer was washed twice with brine, then dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 9: 1 to ethyl acetate) to obtain the title compound (2.2 g).

[0546] ESI-MS (m / z): 466.18 [M+H] + .

[0547] [Generation Example 5-4]

[0548] 5-(2-chloro-4-(1-cyclopropyl-2-(pyridin-2-yl)-3-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[0549]

[0550] To the 2-(2-chloro-6-iodoquinazoline-4-yl)-3-cyclopropyl-2-(pyridin-2-yl)propan-1-ol (2.2g, 4.72mmol) and DHP (1.59g, 18.9mmol) solution of producing Example 5-3 in dichloromethane (30mL), (1S)-(+)-10-camphorsulfonic acid (1.21g, 5.20mmol) was added, and the mixture was stirred at room temperature overnight. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and extracted with ethyl acetate. After washing the organic layer with salt water, it was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. To a solution of the obtained crude product and 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (1.23 g, 4.94 mmol) in toluene (15 mL) at room temperature, ethanol (3 mL), sodium carbonate (2M aqueous solution, 7.5 mL, 15 mmol) and tetrakis(triphenylphosphine)palladium(0) (272 mg, 0.235 mmol) were added, and the mixture was stirred at 70° C. for 18 hours under a nitrogen atmosphere. The reaction mixture was filtered with ethyl acetate, the filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=1:1 to ethyl acetate to ethyl acetate:methanol=9:1) to obtain the title compound (1.25 g).

[0551] ESI-MS (m / z): 545.45 [M+H] + .

[0552] [Example 6]

[0553] 5-(2-((dimethyl(oxo)-16-thiolidene)amino)-4-(1-hydroxy-2-phenyl-3-(tetrahydro-2H-pyran-4-yl)propan-2-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[0554]

[0555] By the same method as Example 3, the title compound (7.40 mg) was obtained from 5-(2-chloro-4-(2-phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)-3-(tetrahydro-2H-pyran-4-yl)propan-2-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (18.0 mg, 0.031 mmol) producing Example 6-3.

[0556] ESI-MS (m / z): 561.35 [M+H] + .

[0557] [Generation Example 6-1]

[0558] Ethyl 2-(2-chloro-6-iodoquinazolin-4-yl)-2-phenyl-3-(tetrahydro-2H-pyran-4-yl)propanoate

[0559]

[0560] Under a nitrogen atmosphere, at 0 ° C, 50% to 72% sodium hydride oil (219 mg) was added to a solution of 4-(iodomethyl)tetrahydro-2H-pyran (757 mg, 3.35 mmol) and ethyl phenylacetate (500 mg, 3.05 mmol) in DMF (10 mL), and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine. After the organic layer was dried over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. Under a nitrogen atmosphere, LHMDS (1M THF solution, 4.57 mL, 4.57 mmol) was added dropwise to the resulting crude product and 2,4-dichloro-6-iodoquinazoline (989 mg, 3.05 mmol) solution in THF (20 mL) at -78 ° C, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine. The organic layer was dried over magnesium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane to n-heptane:ethyl acetate=9:1) to obtain the title compound (506 mg).

[0561] ESI-MS (m / z): 551.28 [M+H] + .

[0562] [Generation Example 6-2]

[0563] 2-Chloro-6-iodo-4-(2-phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)-3-(tetrahydro-2H-pyran-4-yl)propan-2-yl)quinazoline

[0564]

[0565] Under nitrogen atmosphere, DIBAL-H (1M toluene solution, 2.76 mL, 2.76 mmol) was added dropwise to a solution of ethyl 2-(2-chloro-6-iodoquinazolin-4-yl)-2-phenyl-3-(tetrahydro-2H-pyran-4-yl)propanoate (506 mg, 0.919 mmol) of Example 6-1 in toluene (10 mL) at -78°C, and the mixture was stirred at 0°C for 2 hours. Saturated Rochelle salt aqueous solution and ethyl acetate were added to the reaction mixture, and stirring was continued. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with brine and then dried over magnesium sulfate. After filtering the organic layer, the filtrate was concentrated under reduced pressure to obtain a crude product. DHP (386 mg, 4.59 mmol) and p-toluenesulfonic acid monohydrate (87.0 mg, 0.459 mmol) were added to a solution of the resulting crude product in dichloromethane (10 mL) at room temperature, and the mixture was stirred at room temperature for 12 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine. After the organic layer was dried over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane to n-heptane: ethyl acetate = 7: 3) to obtain the title compound (477 mg).

[0566] ESI-MS (m / z): 593.28 [M+H] + .

[0567] [Generation Example 6-3]

[0568] 5-(2-Chloro-4-(2-phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)-3-(tetrahydro-2H-pyran-4-yl)propan-2-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[0569]

[0570] To a solution of 2-chloro-6-iodo-4-(2-phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)-3-(tetrahydro-2H-pyran-4-yl)propane-2-yl)quinazoline (150 mg, 0.253 mmol) and 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (118 mg, 0.304 mmol) in toluene (2 mL), ethanol (0.5 mL), sodium carbonate (2M aqueous solution, 1.00 mL, 2.00 mmol) and tetrakis(triphenylphosphine)palladium(0) (14.6 mg, 0.013 mmol) were added, and the mixture was stirred at 70° C. for 12 hours. The reaction mixture was returned to room temperature, water was added, and extracted with ethyl acetate. The organic layer was washed with brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=1:1 to ethyl acetate to ethyl acetate:methanol=9:1) to obtain the title compound (37.0 mg).

[0571] ESI-MS (m / z): 588.41 [M+H] + .

[0572] [Example 7]

[0573] 5-(2-((dimethyl(oxo)-16-thiolidene)amino)-4-(1-hydroxy-4-methyl-2-phenylpentane-2-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[0574]

[0575] By the same method as Example 3, the title compound (4.56 mg) was obtained from 5-(2-chloro-4-(4-methyl-2-phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)pentan-2-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (15.0 mg, 0.027 mmol) producing Example 7-3.

[0576] ESI-MS (m / z): 519.42 [M+H] + .

[0577] [Generation Example 7-1]

[0578] 2-(2-Chloro-6-iodoquinazolin-4-yl)-4-methyl-2-phenylpentanoic acid ethyl ester

[0579]

[0580] By the same method as in Production Example 6-1, the title compound (740 mg) was obtained from 1-iodo-2-methylpropane (616 mg, 3.35 mmol) and ethyl phenylacetate (500 mg, 3.05 mmol).

[0581] ESI-MS (m / z): 509.18 [M+H] + .

[0582] [Generation Example 7-2]

[0583] 2-Chloro-6-iodo-4-(4-methyl-2-phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)pentan-2-yl)quinazoline

[0584]

[0585] Under nitrogen atmosphere, at -78 ° C, DIBAL-H (1M toluene solution, 4.36 mL, 4.36 mmol) was added dropwise to a solution of 2-(2-chloro-6-iodoquinazoline-4-yl)-4-methyl-2-phenylpentanoic acid ethyl ester (740 mg, 1.45 mmol) produced in toluene (10 mL) and the mixture was stirred at 0 ° C for 2 hours. Saturated Rochelle salt aqueous solution and ethyl acetate were added and stirred. The organic layer was washed with brine and dried over magnesium sulfate. After filtering the organic layer, the filtrate was concentrated under reduced pressure to obtain a crude product. At room temperature, DHP (612 mg, 7.27 mmol) and p-toluenesulfonic acid monohydrate (138 mg, 0.727 mmol) were added to a solution of the obtained crude product in dichloromethane (10 mL), and the mixture was stirred at room temperature for 12 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine. The organic layer was dried over magnesium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane to n-heptane:ethyl acetate=7:3) to obtain the title compound (704 mg).

[0586] ESI-MS (m / z): 551.21 [M+H] + .

[0587] [Generation Example 7-3]

[0588] 5-(2-chloro-4-(4-methyl-2-phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)pentan-2-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[0589]

[0590] At room temperature, ethanol (0.5 mL), sodium carbonate (2M aqueous solution, 1.00 mL, 2.00 mmol) and tetrakis (triphenylphosphine) palladium (0) (15.7 mg, 0.014 mmol) were added to a solution of 2-chloro-6-iodo-4-(4-methyl-2-phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)pentane-2-yl)quinazoline (150 mg, 0.272 mmol) and 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (127 mg, 0.327 mmol) produced in toluene (2 mL), and the mixture was stirred at 70° C. for 12 hours. The reaction mixture was returned to room temperature, water was added, and extracted with ethyl acetate. The organic layer was washed with brine. After the organic layer was dried over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=1:1 to ethyl acetate to ethyl acetate:methanol=9:1) to give the title compound (81.0 mg).

[0591] ESI-MS (m / z): 546.38 [M+H] + .

[0592] [Example 8]

[0593] N-(4-(1-cyclobutyl-3-hydroxy-2-phenylpropan-2-yl)-6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)methanesulfonamide

[0594]

[0595] By the same method as Example 1, the title compound (12.2 mg) was obtained from 5-(2-chloro-4-(1-cyclobutyl-2-phenyl-3-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)quinazolin-6-yl)-1,3-dimethoxypyridin-2(1H)-one (15.0 mg, 0.027 mmol) producing Example 8-3.

[0596] ESI-MS (m / z): 533.35 [M+H] + .

[0597] [Generation Example 8-1]

[0598] Ethyl 2-(2-chloro-6-iodoquinazolin-4-yl)-3-cyclobutyl-2-phenylpropanoate

[0599]

[0600] Under a nitrogen atmosphere, at 0 ° C, 50% to 72% sodium hydride oil (219 mg) was added to a solution of (bromomethyl)cyclobutane (454 mg, 3.05 mmol) and ethyl phenylacetate (500 mg, 3.05 mmol) in DMF (20 mL), and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine. After the organic layer was dried over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. Under a nitrogen atmosphere, LHMDS (1M THF solution, 4.57 mL, 4.57 mmol) was added dropwise to the obtained crude product and 2,4-dichloro-6-iodoquinazoline (989 mg, 3.05 mmol) solution in THF (20 mL) at -78 ° C, and the mixture was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with brine. After the organic layer was dried over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane to n-heptane:ethyl acetate=9:1) to give the title compound (1.13 g).

[0601] ESI-MS (m / z): 521.17 [M+H] + .

[0602] [Generation Example 8-2]

[0603] 2-Chloro-4-(1-cyclobutyl-2-phenyl-3-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)-6-iodoquinazoline

[0604]

[0605] The title compound (565 mg) was obtained from ethyl 2-(2-chloro-6-iodoquinazolin-4-yl)-3-cyclobutyl-2-phenylpropanoate (1.13 g, 2.17 mmol) of Production Example 8-1 by the same method as Production Example 1-3.

[0606] ESI-MS (m / z): 563.208 [M+H] + .

[0607] [Generation Example 8-3]

[0608] 5-(2-chloro-4-(1-cyclobutyl-2-phenyl-3-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[0609]

[0610] By the same method as in Production Example 1-4, the title compound (125 mg) was obtained from 2-chloro-4-(1-cyclobutyl-2-phenyl-3-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)-6-iodoquinazoline (150 mg, 0.266 mmol) of Production Example 8-2.

[0611] ESI-MS (m / z): 558.10 [M+H] + .

[0612] [Example 9]

[0613] 5-(1-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)-3-((dimethyl(oxo)-16-thiocyanate)amino)isoquinolin-7-yl)-1,3-dimethylpyridin-2(1H)-one

[0614]

[0615] To a solution of 5-(3-chloro-1-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)isoquinolin-7-yl)-1,3-dimethylpyridin-2(1H)-one (32.0 mg, 0.059 mmol) produced in Example 9-3 in 1,4-dioxane (1 mL) at room temperature were added dimethylsulfoximine (10.9 mg, 0.117 mmol), cesium carbonate (47.8 mg, 0.147 mmol), BRETTPHOS (9.45 mg, 0.018 mmol) and tris(dibenzylideneacetone)dipalladium(0) (16.1 mg, 0.018 mmol), and the mixture was stirred at 90° C. for 13 hours. The reaction mixture was returned to room temperature. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with brine. After the organic layer was dried over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 1: 1 to ethyl acetate) to obtain a crude product. To the solution of the obtained crude product in methanol (1 mL) at room temperature, p-toluenesulfonic acid monohydrate (5.58 mg, 0.029 mmol) was added, and the mixture was stirred at room temperature for 12 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and after stirring for 15 minutes, the mixture was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate to ethyl acetate: methanol = 9: 1) to obtain the title compound (8.99 mg).

[0616] ESI-MS (m / z): 518.45 [M+H] + .

[0617] [Generation Example 9-1]

[0618] Ethyl 2-(7-bromo-3-chloroisoquinolin-1-yl)-2-cyclopropyloxy-2-phenylacetate

[0619]

[0620] Under nitrogen atmosphere, bis(tri-tert-butylphosphine)palladium(0) (46.1 mg, 0.090 mmol) was added to a solution of ethyl 2-cyclopropyloxy-2-phenylacetate (477 mg, 2.17 mmol) and 7-bromo-1,3-dichloroisoquinoline (500 mg, 1.81 mmol) in THF (20 mL) producing Example 2-1. LHMDS (1M THF solution, 4.15 mL, 4.15 mmol) was added dropwise at -78°C, and the mixture was stirred at room temperature for 3 days. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and extracted with ethyl acetate. After drying the organic layer with magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane to n-heptane: ethyl acetate = 9:1) to obtain the title compound (568 mg).

[0621] ESI-MS (m / z): 460.16 [M+H] + .

[0622] [Generation Example 9-2]

[0623] 7-Bromo-3-chloro-1-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)isoquinoline

[0624]

[0625] By the same method as in Production Example 3-3, the title compound (352 mg) was obtained from ethyl 2-(7-bromo-3-chloroisoquinolin-1-yl)-2-cyclopropyloxy-2-phenylacetate (568 mg, 1.23 mmol) of Production Example 9-1.

[0626] ESI-MS (m / z): 502.16 [M+H] + .

[0627] [Generation Example 9-3]

[0628] 5-(3-Chloro-1-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)isoquinolin-7-yl)-1,3-dimethylpyridin-2(1H)-one

[0629]

[0630] The title compound (32.0 mg) was obtained from 7-bromo-3-chloro-1-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)isoquinoline (30.0 mg, 0.060 mmol) of Production Example 9-2 by the same method as Production Example 1-4.

[0631] ESI-MS (m / z): 545.45 [M+H] + .

[0632] [Example 10]

[0633] N-(4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)-6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)-3-hydroxyazetidine-1-carboxamide

[0634]

[0635] At room temperature, 3-hydroxyazetidine hydrochloride (6.10 mg, 0.056 mmol) and triethylamine (14.1 mg, 0.139 mmol) were added to a solution of phenyl (4- (1-cyclopropyloxy-1-phenyl-2- ((tetrahydro-2H-pyran-2-yl) oxy) ethyl) -6- (1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl) quinazoline-2-yl) carbamate (30.0 mg, 0.046 mmol) produced in DMF (2 mL) Example 10-1, and the mixture was stirred for 12 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine. After the organic layer was dried over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure to give a crude product. At room temperature, p-toluenesulfonic acid monohydrate (4.41 mg, 0.023 mmol) was added to the solution of the obtained crude product in methanol (2 mL), and the mixture was stirred at room temperature for 3 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and after stirring for 30 minutes, the mixture was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 1: 1 to ethyl acetate to ethyl acetate: methanol = 4: 1) to obtain the title compound (10.7 mg).

[0636] ESI-MS (m / z): 542.41 [M+H] + .

[0637] [Generation Example 10-1]

[0638] Phenyl (4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)carbamate

[0639]

[0640] At room temperature, to a solution of 5-(2-chloro-4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (100.0 mg, 0.183 mmol) in NMP (2 mL) producing Example 2-4 was added aqueous ammonia (28% to 30% aqueous solution, 1.00 mL), and the mixture was stirred in a sealed tube at 90° C. for 6 hours. The reaction mixture was returned to room temperature, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with water and brine. After the organic layer was dried over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. At room temperature, pyridine (29.0 mg, 0.366 mmol) and phenyl chloroformate (43.0 mg, 0.275 mmol) were added to a solution of the resulting crude product in THF (5 mL), and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (92.0 mg).

[0641] ESI-MS (m / z): 647.59 [M+H] + .

[0642] [Example 11]

[0643] 7-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(1-hydroxy-2-(pyridin-2-yl)pentan-2-yl)isoquinolin-3(2H)-one

[0644]

[0645] To a solution of 5-(3-chloro-1-(2-(pyridin-2-yl)-1-((tetrahydro-2H-pyran-2-yl)oxy)pentane-2-yl)isoquinolin-7-yl)-1,3-dimethylpyridin-2(1H)-one (20.0 mg, 0.038 mmol) produced in 1,4-dioxane (1 mL) at room temperature were added water (0.5 mL), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (1.60 mg, 3.76 μmol) and tris(dibenzylideneacetone)dipalladium(0) (1.72 mg, 1.88 μmol), and the mixture was stirred at 100° C. for 3 hours. The reaction mixture was returned to room temperature. The reaction mixture was purified by silica gel column chromatography (n-heptane:ethyl acetate=1:1 to ethyl acetate) to give a crude product. At room temperature, p-toluenesulfonic acid monohydrate (3.57 mg, 0.019 mmol) was added to the solution of the obtained crude product in methanol (1 mL), and the mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and after stirring for 30 minutes, the mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate to ethyl acetate: methanol = 4: 1) to obtain the title compound (4.20 mg).

[0646] ESI-MS (m / z): 430.35 [M+H] + .

[0647] [Generation Example 11-1]

[0648] Ethyl 2-(7-bromo-3-chloroisoquinolin-1-yl)-2-(pyridin-2-yl)pentanoate

[0649]

[0650] At 0°C, 50% to 72% sodium hydride oil (327 mg) was added to a solution of ethyl 2-pyridyl acetate (750 mg, 4.54 mmol) and 1-iodopropane (772 mg, 4.54 mmol) in DMF (20 mL), and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine. After the organic layer was dried over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. Bis(tri-tert-butylphosphine)palladium(0) (116 mg, 0.227 mmol) was added to the resulting crude product and a solution of 7-bromo-1,3-dichloroisoquinoline (1.26 g, 4.54 mmol) in toluene (40 mL). LHMDS (1M THF solution, 6.81 mL, 6.81 mmol) was added dropwise at -78°C and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine. The organic layer was dried over magnesium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane to n-heptane:ethyl acetate=4:1) to obtain the title compound (1.01 g).

[0651] ESI-MS (m / z): 449.19 [M+H] + .

[0652] [Generation Example 11-2]

[0653] 2-(7-Bromo-3-chloroisoquinolin-1-yl)-2-(pyridin-2-yl)pentan-1-ol

[0654]

[0655] Under nitrogen atmosphere, at -78 ° C, DIBAL-H (1M toluene solution, 6.77 mL, 6.77 mmol) was added dropwise to a solution of 2-(7-bromo-3-chloroisoquinoline-1-yl)-2-(pyridin-2-yl) ethyl pentanoate (1.01 g, 2.26 mmol) in toluene (20 mL) producing Example 11-1, and the mixture was stirred at 0 ° C for 3 hours. Saturated Rochelle salt aqueous solution and ethyl acetate were added to the reaction mixture and stirred for 3 hours. The reaction mixture was subjected to oil-water distribution, and the organic layer was washed with brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane: ethyl acetate = 9: 1 to 1: 1) to give the title compound (385 mg).

[0656] ESI-MS (m / z): 407.12 [M+H] + .

[0657] [Generation Example 11-3]

[0658] 5-(3-chloro-1-(2-(pyridin-2-yl)-1-((tetrahydro-2H-pyran-2-yl)oxy)pentan-2-yl)isoquinolin-7-yl)-1,3-dimethylpyridin-2(1H)-one

[0659]

[0660] At room temperature, DHP (399 mg, 4.75 mmol) and p-toluenesulfonic acid monohydrate (90.0 mg, 0.474 mmol) were added to a solution of 2-(7-bromo-3-chloroisoquinoline-1-yl)-2-(pyridin-2-yl)pentane-1-ol (385 mg, 0.949 mmol) of Example 11-2 in dichloromethane (10 mL), and the mixture was stirred at room temperature for 12 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with brine. After the organic layer was dried over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. At room temperature, ethanol (1 mL), sodium carbonate (2M aqueous solution, 2 mL, 4.00 mmol) and tetrakis (triphenylphosphine) palladium (0) (54.8 mg, 0.047 mmol) were added to the obtained crude product and 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine-2 (1H) -one (284 mg, 1.14 mmol) solution in toluene (4 mL), and the mixture was stirred at 70 ° C for 3 days. The reaction mixture was returned to room temperature, water was added, and extracted with ethyl acetate. The organic layer was washed with brine. After the organic layer was dried over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane: ethyl acetate = 1: 1 to ethyl acetate) to obtain the title compound (302 mg).

[0661] ESI-MS (m / z): 532.48 [M+H] + .

[0662] [Example 12]

[0663] 5-(2-amino-4-(4-ethoxy-1-hydroxy-2-(pyridin-2-yl)butan-2-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[0664]

[0665] At room temperature, ammonia (28% to 30% aqueous solution, 0.500 mL) was added to a solution of 5-(2-chloro-4-(4-ethoxy-2-(pyridin-2-yl)-1-((tetrahydro-2H-pyran-2-yl)oxy)butane-2-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (20.0 mg, 0.036 mmol) in NMP (1 mL) producing Example 12-3, and the mixture was stirred in a sealed tube at 90° C. for 12 hours. The reaction mixture was returned to room temperature, water was added, and extracted with ethyl acetate. The organic layer was washed with brine. After the organic layer was dried over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. At room temperature, p-toluenesulfonic acid monohydrate (3.38 mg, 0.018 mmol) was added to the resulting crude product solution in methanol (1 mL), and the mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and after stirring for 30 minutes, the mixture was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=1:1 to ethyl acetate) to give the title compound (6.55 mg).

[0666] 1 H-NMR spectrum (500 MHz, CDCl 3 )δ(ppm):1.02(3H,t,J=6.9Hz),2.14(3H,s),2.84(2H,t,J=6.9Hz),3.25-3.34(2H ,m),3.35-3.41(1H,m),3.53(3H,s),3.59-3.58-3.65(1H,m),4.19-4.24(2H,m),4. 43-4.49(1H,m),5.23(2H,brs),6.88-6.94(2H,m),7.02-7.05(1H,m),7.12-7.14( 1H,m),7.22-7.26(1H,m),7.52-7.58(2H,m),7.59-7.63(1H,m),8.63-8.69(1H,m).

[0667] ESI-MS (m / z): 460.34 [M+H] + .

[0668] [Generation Example 12-1]

[0669] 2-(2-Chloro-6-iodoquinazolin-4-yl)-4-ethoxy-2-(pyridin-2-yl)butanoic acid ethyl ester

[0670]

[0671] Under a nitrogen atmosphere, at 0 ° C, 50% to 72% sodium hydride oil (218 mg) was added to a solution of ethyl 2-pyridyl acetate (500 mg, 3.03 mmol) and 2-bromoethyl ether (486 mg, 3.18 mmol) in DMF (10 mL), and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine. After the organic layer was dried over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. Under a nitrogen atmosphere, LHMDS (1M THF solution, 4.54 mL, 4.54 mmol) was added dropwise to the obtained crude product and 2,4-dichloro-6-iodoquinazoline (885 mg, 2.72 mmol) solution in THF (20 mL) at -78 ° C, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine. After the organic layer was dried over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane to n-heptane:ethyl acetate=4:1) to give the title compound (406 mg).

[0672] ESI-MS (m / z): 526.19 [M+H] + .

[0673] [Generation Example 12-2]

[0674] 2-Chloro-4-(4-ethoxy-2-(pyridin-2-yl)-1-((tetrahydro-2H-pyran-2-yl)oxy)butan-2-yl)-6-iodoquinazoline

[0675]

[0676] In a nitrogen atmosphere, at -78°C, DIBAL-H (1M toluene solution, 2.32 mL, 2.32 mmol) was added dropwise to a solution of 2-(2-chloro-6-iodoquinazoline-4-yl)-4-ethoxy-2-(pyridin-2-yl)butyric acid ethyl ester (406 mg, 0.772 mmol) produced in toluene (10 mL) and the mixture was stirred at 0°C for 30 minutes. A saturated Rochelle salt aqueous solution and ethyl acetate were added and stirred. The reaction mixture was subjected to oil-water distribution, and the organic layer was washed with brine. After the organic layer was dried over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. At room temperature, DHP (325 mg, 3.86 mmol) and p-toluenesulfonic acid monohydrate (73.4 mg, 0.386 mmol) were added to the resulting crude product solution in dichloromethane (10 mL), and the mixture was stirred at room temperature for 6 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine. After the organic layer was dried over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane to n-heptane: ethyl acetate = 4: 1) to obtain the title compound (261 mg).

[0677] ESI-MS (m / z): 568.29 [M+H] + .

[0678] [Generation Example 12-3]

[0679] 5-(2-chloro-4-(4-ethoxy-2-(pyridin-2-yl)-1-((tetrahydro-2H-pyran-2-yl)oxy)butan-2-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[0680]

[0681] At room temperature, ethanol (1 mL), sodium carbonate (2M aqueous solution, 2 mL, 4.00 mmol) and tetrakis (triphenylphosphine) palladium (0) (26.6 mg, 0.023 mmol) were added to a solution of 2-chloro-4-(4-ethoxy-2-(pyridin-2-yl)-1-((tetrahydro-2H-pyran-2-yl)oxy)butane-2-yl)-6-iodoquinazoline (261 mg, 0.460 mmol) and 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (137 mg, 0.552 mmol) in toluene (4 mL) and the mixture was stirred at 70 ° C for 6 hours. The reaction mixture was returned to room temperature, water was added, and extracted with ethyl acetate. The organic layer was washed with brine. After the organic layer was dried over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=1:1 to ethyl acetate) to give the title compound (213 mg).

[0682] ESI-MS (m / z): 563.39 [M+H] + .

[0683] [Example 13]

[0684] 5-(4-(1-cyclobutyloxy-2-hydroxy-1-phenylethyl)-2-((dimethyl(oxo)-16-thiolidene)amino)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[0685]

[0686] At room temperature, to a solution of 5-(2-chloro-4-(1-cyclobutoxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (20.0 mg, 0.036 mmol) produced in 1,4-dioxane (1 mL) were added dimethylsulfoximine (4.99 mg, 0.054 mmol), cesium carbonate (29.1 mg, 0.089 mmol), BRETTPHOS (5.75 mg, 0.011 mmol) and tris(dibenzylideneacetone)dipalladium(0) (9.81 mg, 0.011 mmol), and the mixture was stirred at 90° C. for 13 hours. The reaction mixture was then returned to room temperature. Purification by NH silica gel column chromatography (n-heptane:ethyl acetate=1:1 to ethyl acetate) gave a crude product. At room temperature, p-toluenesulfonic acid monohydrate (3.40 mg, 0.018 mmol) was added to the obtained crude product solution in methanol (1 mL), and the mixture was stirred at room temperature for 12 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and after stirring for 15 minutes, the mixture was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (ethyl acetate to ethyl acetate: methanol = 9: 1) to obtain a racemic mixture of the title compound. Then purified by SFC (IB, carbon dioxide: methanol = 75: 25) to obtain the pre-isomer (5.03 mg) of the title compound.

[0687] 1 H-NMR spectrum (500 MHz, CDCl 3 )δ(ppm):1.15-1.27(1H,m),1.46-1.56(2H,m),1.71-1.87(1H,m),2.14-2.24(4H,m),2.25-2 .34(1H,m),3.51(3H,s),3.51(3H,s),3.54(3H,s),3.56-3.62(1H,m),3.98-4.04(1H,m),4.1 8-4.22(1H,m),4.33-4.36(1H,m),6.98-7.02(1H,m),7.17-7.18(1H,m),7.21-7.25(1H,m),7 .27-7.30(2H,m),7.37-7.41(2H,m),7.61-7.64(1H,m),7.69-7.73(1H,m),7.99-8.02(1H,m).

[0688] ESI-MS (m / z): 533.35 [M+H] + .

[0689] [Generation Example 13-1]

[0690] Ethyl 2-cyclobutyloxy-2-phenylacetate

[0691]

[0692] At room temperature, cyclobutanol (500mg, 6.94mmol) and rhodium acetate (II) dimer (64.0mg, 0.145mmol) solution in dichloromethane (5mL) were added dropwise to 2-diazo-2-phenylacetate (1.10g, 5.78mmol) solution, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane to n-heptane: ethyl acetate = 7:3) to obtain the title compound (1.19g).

[0693] ESI-MS (m / z): 235.05 [M+H] + .

[0694] [Generation Example 13-2]

[0695] Ethyl 2-(2-chloro-6-iodoquinazolin-4-yl)-2-cyclobutoxy-2-phenylacetate

[0696]

[0697] Under nitrogen atmosphere, at -78 ° C, LHMDS (1M THF solution, 2.31 mL, 2.31 mmol) was added dropwise to a solution of ethyl 2-cyclobutoxy-2-phenylacetate (397 mg, 1.69 mmol) and 2,4-dichloro-6-iodoquinazoline (500 mg, 1.54 mmol) produced in THF (10 mL) and the mixture was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine. After the organic layer was dried over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane to n-heptane: ethyl acetate = 9: 1) to obtain the title compound (679 mg).

[0698] ESI-MS (m / z): 523.18 [M+H] + .

[0699] [Generation Example 13-3]

[0700] 2-Chloro-4-(1-cyclobutyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-6-iodoquinazoline

[0701]

[0702] Under nitrogen atmosphere, at -78 ° C, DIBAL-H (1M toluene solution, 3.90 mL, 3.90 mmol) was added dropwise to a solution of 2-(2-chloro-6-iodoquinazoline-4-yl)-2-cyclobutoxy-2-phenylethyl acetate (679 mg, 1.30 mmol) in toluene (15 mL) producing Example 13-2, and the mixture was stirred at 0 ° C for 30 minutes. Saturated Rochelle salt aqueous solution and ethyl acetate were added and stirred. The reaction mixture was subjected to oil-water distribution. The organic layer was washed with brine and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. At room temperature, DHP (546 mg, 6.49 mmol) and (1S)-(+)-10-camphorsulfonic acid (151 mg, 0.649 mmol) were added to the resulting crude product solution in dichloromethane (10 mL), and the mixture was stirred at room temperature for 12 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane to n-heptane:ethyl acetate=4:1) to give the title compound (430 mg).

[0703] ESI-MS (m / z): 565.21 [M+H] + .

[0704] [Generation Example 13-4]

[0705] 5-(2-chloro-4-(1-cyclobutyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[0706]

[0707] At room temperature, ethanol (1 mL), sodium carbonate (2M aqueous solution, 2.00 mL, 4.00 mmol) and tetrakis (triphenylphosphine) palladium (0) (44.0 mg, 0.038 mmol) were added to a solution of 2-chloro-4-(1-cyclobutoxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-6-iodoquinazoline (430 mg, 0.761 mmol) and 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (228 mg, 0.914 mmol) produced in toluene (4 mL), and the mixture was stirred at 70 ° C for 12 hours. The reaction mixture was returned to room temperature, water was added, and extracted with ethyl acetate. The organic layer was washed with brine. After the organic layer was dried over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=1:1 to ethyl acetate) to give the title compound (244 mg).

[0708] ESI-MS (m / z): 560.42 [M+H] + .

[0709] [Generation Example 14]

[0710] 7-(4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)-2-((1-methylpiperidin-4-yl)oxy)quinazolin-6-yl)-5-methyl-3,5-dihydrofuran[3,4-c]pyridin-4(1H)-one

[0711]

[0712] 1,1'-bis(diphenylphosphino)ferrocene(II)palladium dichloride and dichloromethane (50.3 mg, 69 μmol) were added to a solution of 7-bromo-5-methyl-3,5-dihydrofurano[3,4-c]pyridin-4(1H)-one (316 mg, 1.37 mmol), bis-pinacol borate (523 mg, 2.06 mmol) and potassium acetate (404 mg, 4.12 mmol) in DMSO (10 mL), and the mixture was stirred at 80° C. for 3 hours. Water was added to the reaction mixture, and extracted 7 times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and then the filtrate was concentrated under reduced pressure to obtain a crude product (381 mg).

[0713] At room temperature, ethanol (0.25 mL), sodium carbonate (2M aqueous solution, 0.500 mL, 1.00 mmol) and tetrakis(triphenylphosphine)palladium(0) (2.75 mg, 0.0024 mmol) were added to a portion of the obtained crude product (19.8 mg) and a solution of 4-(1-cyclopropyloxy-1-phenyl-2((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-6-iodo-2-((1-methylpiperidin-4-yl)oxy)quinazoline (30.0 mg, 0.048 mmol) in toluene (1 mL), and the mixture was stirred at 80° C. for 12 hours. The reaction mixture was returned to room temperature, water was added, and extracted with ethyl acetate. The organic layer was washed with brine. After the organic layer was dried over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 1: 1 to ethyl acetate) to give a crude product. At room temperature, p-toluenesulfonic acid monohydrate (4.53 mg, 0.024 mmol) was added to the obtained crude product solution in methanol (1 mL), and the mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and after stirring for 30 minutes, the mixture was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 1: 1 to ethyl acetate to ethyl acetate: methanol = 4: 1) to obtain a racemic mixture of the title compound. Then SFC (IG, carbon dioxide: methanol = 70: 30) was used for purification to obtain the pre-isomer (9.46 mg) of the title compound.

[0714] ESI-MS (m / z): 569.54 [M+H] + .

[0715] [Generation Example 14-1]

[0716] 4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-6-iodo-2-((1-methylpiperidin-4-yl)oxy)quinazoline

[0717]

[0718] Under nitrogen atmosphere, at 0 ° C, 2-chloro-4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-6-iodoquinazoline (30.0 mg, 0.054 mmol) and 4-hydroxy-1-methylpiperidine (9.41 mg, 0.082 mmol) solution of Example 2-3 in THF (1 mL) was added 50% to 72% sodium hydride oil (3.92 mg), and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine and dried with magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 7: 3 to ethyl acetate) to obtain the title compound (30.0 mg).

[0719] ESI-MS (m / z): 630.34 [M+H] + .

[0720] [Generation Example 14-2]

[0721] 3-Amino-4-chloro-1-methylpyridin-2(1H)-one

[0722]

[0723] Potassium carbonate (4.75 g, 34.4 mmol) was added to a solution of 4-chloro-3-nitro-2-pyridone (3.00 g, 17.2 mmol) and iodomethane (3.66 g, 25.8 mmol) in DMF (50 mL), and the mixture was stirred at 70 ° C for 2 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After filtering the organic layer, the filtrate was concentrated under reduced pressure to obtain a crude product. Tin dichloride dihydrate (8.26 g, 36.3 mmol) was added to the resulting crude product solution in ethyl acetate (100 mL), and the mixture was stirred at room temperature for 3 hours. After the reaction mixture was cooled to 0 ° C, potassium carbonate aqueous solution was added to adjust the pH to about 10. The reaction mixture was extracted 3 times with ethyl acetate, and the organic layer was dried over sodium sulfate. After filtering the organic layer, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=7:3 to ethyl acetate) to give the title compound (1.7 g).

[0724] 1 H-NMR spectrum (500 MHz, CDCl 3 )δ (ppm): 3.53 (3H, s), 4.48 (2H, brs), 6.16 (1H, d, J = 7.3Hz), 6.63 (1H, d, J = 7.3Hz).

[0725] [Generation Example 14-3]

[0726] 3,4-Dichloro-1-methylpyridin-2(1H)-one

[0727]

[0728] At 0 ° C, a solution of sodium nitrite (3.70 g, 53.6 mmol) in water (15 mL) was added dropwise to a mixture of 3-amino-4-chloro-1-methylpyridine-2 (1H) -one (1.70 g, 10.7 mmol) and concentrated hydrochloric acid (30 mL) producing Example 14-2 over at least 2 minutes, and the mixture was stirred for 2 minutes. At 0 ° C, copper chloride (10.6 g, 107 mmol) was added in batches, and the mixture was stirred for 5 minutes and further stirred at room temperature for 30 minutes. 5N sodium hydroxide aqueous solution was added to the reaction mixture, and then extracted with ethyl acetate 3 times. The organic layer was washed with brine and dried over magnesium sulfate. After filtering the organic layer, the filtrate was concentrated under reduced pressure to obtain the title compound (1.27 g).

[0729] ESI-MS (m / z): 177.81 [M+H] + .

[0730] [Generation Example 14-4]

[0731] 5-Methyl-3,5-dihydrofuro[3,4-c]pyridin-4(1H)-one

[0732]

[0733] To a solution of 3,4-dichloro-1-methylpyridin-2(1H)-one (700 mg, 3.93 mmol) obtained in Example 14-3 in 1,4-dioxane (20 mL) was added tris(dibenzylideneacetone)dipalladium(0) (360 mg, 0.393 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (412 mg, 0.865 mmol) and (oxybis(methylene))bis(tributyltinane) (2.58 g, 4.13 mmol), and the mixture was stirred at 95° C. for 12 hours. The reaction mixture was directly purified by silica gel column chromatography (n-heptane:ethyl acetate=1:1 to ethyl acetate to ethyl acetate:methanol=10:1) to give the title compound (339 mg).

[0734] ESI-MS (m / z): 151.83 [M+H] + .

[0735] [Generation Example 14-5]

[0736] 7-Bromo-5-methyl-3,5-dihydrofuro[3,4-c]pyridin-4(1H)-one

[0737]

[0738] N-bromosuccinimide (419 mg, 2.36 mmol) was added to a solution of 5-methyl-3,5-dihydrofuran [3,4-c] pyridine-4 (1H) -one (339 mg, 2.24 mmol) in chloroform (15 mL) producing Example 14-4, and the mixture was stirred at 0 ° C for 3 hours. Water was added to the reaction mixture, and then extracted with dichloromethane. The organic layer was dried over sodium sulfate. After filtering the organic layer, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-heptane: ethyl acetate = 1: 1 to 1: 4) to give the title compound (316 mg).

[0739] ESI-MS (m / z): 229.85 [M+H] + .

[0740] [Example 15]

[0741] 5-(2-amino-4-(1-cyclopropyloxy-2-hydroxy-1-(thien-2-yl)ethyl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[0742]

[0743] Using the same method as that used to produce Example 2-5 and Example 2, the title compound (7 mg) was obtained from 5-(2-chloro-4-(1-cyclopropyloxy-2-((tetrahydro-2H-pyran-2-yl)oxy)-1-(thiophen-2-yl)ethyl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (10 mg) used to produce Example 15-4.

[0744] ESI-MS (m / z): 449.38 [M+H] + .

[0745] [Generation Example 15-1]

[0746] Ethyl 2-cyclopropyloxy-2-(thiophen-2-yl)acetate

[0747]

[0748] Using the same method as in Production Example 2-1, the title compound (320 mg) was obtained from ethyl 2-diazo-2-(thiophen-2-yl)acetate (830 mg).

[0749] 1H-NMR spectrum (400 MHz, CDCl 3 )δ(ppm):0.47-0.60(2H,m),0.67-0.82(2H,m),1.24-1.37(4H,m),3.44-3.56(1H ,m),4.20-4.36(2H,m),6.95-7.04(1H,m),7.11-7.19(1H,m),7.29-7.37(1H,m).

[0750] [Generation Example 15-2]

[0751] Ethyl 2-(2-chloro-6-iodoquinazolin-4-yl)-2-cyclopropyloxy-2-(thiophen-2-yl)acetate

[0752]

[0753] The title compound (740 mg) was obtained from ethyl 2-cyclopropoxy-2-(thiophen-2-yl)acetate (320 mg) of Production Example 15-1 using the same method as in Production Example 2-2.

[0754] 1 H-NMR spectrum (400 MHz, CDCl 3 )δ(ppm):0.20-0.42(2H,m),0.44-0.61(2H,m),1.20(3H,t),3.49-3.64(1H,m),4.20-4.36(2H,m),6.97-7 .06(1H,m),7.25-7.27(m,1H),7.38-7.48(1H,m),7.63-7.76(1H,m),8.00-8.16(1H,m),8.78-8.87(1H,m).

[0755] [Generation Example 15-3]

[0756] 2-Chloro-4-(1-cyclopropyloxy-2-((tetrahydro-2H-pyran-2-yl)oxy)-1-(thien-2-yl)ethyl)-6-iodoquinazoline

[0757]

[0758] Using the same method as in Production Example 2-3, the title compound (791 mg) was obtained from ethyl 2-(2-chloro-6-iodoquinazolin-4-yl)-2-cyclopropyloxy-2-(thiophen-2-yl)acetate (981 mg) of Production Example 15-2.

[0759] ESI-MS (m / z): 557.00 [M+H] + .

[0760] [Generation Example 15-4]

[0761] 5-(2-chloro-4-(1-cyclopropyloxy-2-((tetrahydro-2H-pyran-2-yl)oxy)-1-(thien-2-yl)ethyl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[0762]

[0763] Using the same method as Production Example 2-4, the title compound (290 mg) was obtained from 2-chloro-4-(1-cyclopropyloxy-2-((tetrahydro-2H-pyran-2-yl)oxy)-1-(thien-2-yl)ethyl)-6-iodoquinazoline (370 mg) of Production Example 15-3.

[0764] 1 H-NMR spectrum (400 MHz, CDCl 3 )δ(ppm):0.20-1.04(4H,m),1.25-1.75(6H,m),2.23(3H,s),3.05-3.95(6H,m),4.40-5.10(3H,m),6.55-6 .69(1H,m),6.78-6.94(1H,m),7.21-7.32(2H,m),7.34-7.44(1H,m),7.78-8.01(2H,m),8.46-8.61(1H,m).

[0765] [Example 16]

[0766] 7-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(1-ethoxy-2-hydroxy-1-phenylethyl)isoquinoline-3-carboxamide

[0767]

[0768] A racemic mixture of the title compound was obtained from 7-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(1-ethoxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)isoquinoline-3-carboxamide (48 mg, 0.089 mmol) produced in Example 16-6 using the same method as in Example 2. The obtained racemic mixture was purified by SFC (IG, carbon dioxide:methanol=8:2) to obtain the proisomer of the title compound (21.2 mg).

[0769] ESI-MS (m / z): 458.30 [M+H] + .

[0770] [Generation Example 16-1]

[0771] 2-Ethoxy-2-phenylacetic acid ethyl ester

[0772]

[0773] Using the same method as in Production Example 2-1, the title compound (2.34 g) was obtained from ethyl 2-diazo-2-phenylacetate (2.30 g, 12.1 mmol).

[0774] 1 H-NMR spectrum (400 MHz, CDCl 3 )δ(ppm):1.14-1.34(6H,m),3.45-3.66(2H,m),4.06-4.25(2H,m),4.85(1H,s),7.28-7.56(5H,m).

[0775] [Generation Example 16-2]

[0776] 7-Bromo-1,3-dichloroisoquinoline

[0777]

[0778] To a solution of 7-bromo-1-chloroisoquinoline (5.00 g, 20.6 mmol) in dichloromethane (100 mL) was added meta-chloroperbenzoic acid (9.24 g, 41.2 mmol), and the mixture was stirred at room temperature for 2 days. Dichloromethane and 1N aqueous sodium hydroxide solution were added to the reaction mixture, and after stirring for 2 hours, oil-water distribution was performed, and the organic layer was washed with brine. After the organic layer was dried over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. Phosphorus oxychloride (40.0 mL, 429 mmol) was added to the obtained crude product, and the mixture was stirred at 120 ° C for 12 hours. The reaction mixture was concentrated under reduced pressure, and then toluene was added to the obtained residue, and the mixture was concentrated again under reduced pressure. The residue was dissolved in dichloromethane, saturated sodium bicarbonate aqueous solution was added, and oil-water distribution was performed. The aqueous layer was extracted with dichloromethane. The organic layer was washed with brine. After the organic layer was dried over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=19:1 to 9:1) to give the title compound (2.05 g).

[0779] ESI-MS (m / z): 277.84 [M+H] + .

[0780] [Generation Example 16-3]

[0781] Ethyl 2-(7-bromo-3-chloroisoquinolin-1-yl)-2-ethoxy-2-phenylacetate

[0782]

[0783] Under a nitrogen atmosphere, at 0°C, to a solution of ethyl 2-ethoxy-2-phenylacetate (564 mg, 2.71 mmol) of Example 16-1 and 7-bromo-1,3-dichloroisoquinoline (500 mg, 1.80 mmol) and bis(tri-tert-butylphosphine)palladium(0) (27.7 mg, 0.054 mmol) in toluene (10 mL) was added LHMDS (1M THF solution, 5.42 mL, 5.42 mmol), and the mixture was stirred at room temperature for 14 hours. Ethyl acetate and water were added to the reaction mixture for oil-water distribution. The organic layer was washed with brine. After the organic layer was dried over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane to n-heptane: ethyl acetate = 4:1) to give the title compound (538 mg).

[0784] ESI-MS (m / z): 448.13 [M+H] + .

[0785] [Generation Example 16-4]

[0786] 7-Bromo-3-chloro-1-(1-ethoxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)isoquinoline

[0787]

[0788] Using the same procedure as in Production Example 2-3, the title compound (588 mg) was obtained from ethyl 2-(7-bromo-3-chloroisoquinolin-1-yl)-2-ethoxy-2-phenylacetate (538 mg, 1.20 mmol) of Production Example 16-3.

[0789] ESI-MS (m / z): 490.20 [M+H] + .

[0790] [Generation Example 16-5]

[0791] 5-(3-Chloro-1-(1-ethoxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)isoquinolin-7-yl)-1,3-dimethylpyridin-2(1H)-one

[0792]

[0793] Using the same method as in Production Example 2-4, the title compound (382 mg) was obtained from 7-bromo-3-chloro-1-(1-ethoxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)isoquinoline (588 mg, 1.20 mmol) of Production Example 16-4.

[0794] ESI-MS (m / z): 533.35 [M+H] + .

[0795] [Generation Example 16-6]

[0796] 7-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-(1-ethoxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)isoquinoline-3-carboxamide

[0797]

[0798] To a solution of 5-(3-chloro-1-(1-ethoxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)isoquinolin-7-yl)-1,3-dimethylpyridin-2(1H)-one (73.0 mg, 0.137 mmol) and zinc cyanide (32.2 mg, 0.274 mmol) produced in Example 16-5 in DMF (1 mL) was added tetrakis(triphenylphosphine)palladium(0) (158 mg, 0.137 mmol), and the mixture was stirred at 140° C. for 5 hours under a nitrogen atmosphere. The reaction mixture was filtered and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate to ethyl acetate: methanol = 9: 1) to give a crude product. To the resulting crude product solution in THF (1mL), lithium hydroxide peroxide is added, and the mixture is stirred at room temperature for 1 hour, wherein the lithium hydroxide peroxide is prepared by adding 30% aqueous hydrogen peroxide solution (0.093mL, 0.822mmol) to a solution of lithium hydroxide (11.8mg, 0.493mmol) in water (0.30mL). Saturated aqueous sodium sulfite solution is added to the reaction mixture, and extracted with ethyl acetate. The organic layer is washed with brine. The organic layer is dried over sodium sulfate and filtered. The filtrate is concentrated under reduced pressure, and the residue is purified by NH silica gel column chromatography (ethyl acetate to ethyl acetate: methanol = 9: 1) to obtain the title compound (48mg).

[0799] ESI-MS (m / z): 542.44 [M+H] + .

[0800] [Example 17]

[0801] 6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-ethyl-4-(2-hydroxy-1-methoxy-1-phenylethyl)quinazolin-2(1H)-one

[0802]

[0803] At room temperature, p-toluenesulfonic acid monohydrate (381 mg, 2.00 mmol) was added to a solution of 6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-ethyl-4-(1-methoxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)quinazoline-2(1H)-one (530 mg, 1.00 mmol) in methanol (10 mL) producing Example 17-5, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with brine. After the organic layer was dried over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate to ethyl acetate: methanol = 9: 1) to obtain a racemic mixture of the title compound. The resulting racemic mixture was purified by SFC (IF, carbon dioxide: methanol = 70: 30) to obtain the title compound (124 mg).

[0804] 1 H-NMR spectrum (500 MHz, CDCl 3 )δ(ppm):1.40-1.45(3H,m),3.11(1H,brs),3.46(3H,s),3.52(3H,s),4.23-4.35(3H,m),4.41-4.47(1H,m),5.26(3H,s), 6.89(1H,brs),7.06(1H,brs),7.23-7.28(1H,m),7.31-7.35(3H,m),7.45-7.50(2H,m),7.60-7.65(1H,m),8.10(1H,brs).

[0805] ESI-MS (m / z): 446.34 [M+H] + .

[0806] [Generation Example 17-1]

[0807] 2-Methoxy-2-phenylacetic acid ethyl ester

[0808]

[0809] At room temperature, sulfuric acid (0.193 mL, 3.61 mmol) was added dropwise to a solution of DL-α-methoxyphenylacetic acid (3.00 g, 18.1 mmol) in ethanol (30 mL), and the mixture was stirred at 80 ° C for 4 hours. At room temperature, sodium carbonate (1.00 g, 11.9 mmol) was added to the reaction mixture and stirred for 1 hour. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate and filtered through silica gel. The filtrate was concentrated under reduced pressure to obtain the title compound (2.73 g).

[0810] 1 H-NMR spectrum (400 MHz, CDCl 3 )δ(ppm):1.17-1.24(3H,m),3.40(3H,s),4.10-4.25(2H,m),4.74(1H,s),7.30-7.38(3H,m),7.40-7.46(2H,m).

[0811] [Generation Example 17-2]

[0812] Ethyl 2-(2-chloro-6-iodoquinazolin-4-yl)-2-methoxy-2-phenylacetate

[0813]

[0814] Under nitrogen atmosphere, at -78 ° C, LHMDS (1.09M THF solution, 7.09mL, 7.72mmol) was added dropwise to a solution of 2-methoxy-2-phenylethyl acetate (1.00g, 5.15mmol) and 2,4-dichloro-6-iodoquinazoline (2.34g, 7.21mmol) produced in THF (15mL) at -78 ° C. The reaction mixture was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (n-heptane to n-heptane: ethyl acetate = 7: 3) to obtain the title compound (2.52g).

[0815] ESI-MS (m / z): 483.18 [M+H] + .

[0816] [Generation Example 17-3]

[0817] 2-Chloro-6-iodo-4-(1-methoxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)quinazoline

[0818]

[0819] At -78 ° C, DIBAL-H (1M toluene solution, 12.0 mL, 12.0 mmol) was added dropwise to a solution of ethyl 2-(2-chloro-6-iodoquinazolin-4-yl)-2-methoxy-2-phenylacetate (2.52 g, 5.22 mmol) in dichloromethane (20 mL) producing Example 17-2, and the mixture was stirred at 0 ° C for 1 hour. After adding a saturated Rochelle salt aqueous solution and ethyl acetate to the reaction mixture and stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After filtering the organic layer, the filtrate was concentrated under reduced pressure to obtain a crude product. At room temperature, DHP (1.42 mL, 15.7 mmol) and (1S)-(+)-10-camphorsulfonic acid (243 mg, 1.04 mmol) were added to the resulting crude product solution in dichloromethane (20 mL), and the mixture was stirred at room temperature for 1 hour. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by NH silica gel column chromatography (n-heptane to n-heptane:ethyl acetate=1:1) to give the title compound (3.00 g).

[0820] ESI-MS (m / z): 525.24 [M+H] + .

[0821] [Generation Example 17-4]

[0822] 5-(2-Chloro-4-(1-methoxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[0823]

[0824] To a solution of 2-chloro-6-iodo-4-(1-methoxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)quinazoline (3.00 g, 5.72 mmol) and 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (1.50 g, 6.00 mmol) produced in toluene (20 mL) at room temperature, ethanol (5 mL), sodium carbonate (2M aqueous solution, 10 mL, 20.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (661 mg, 0.572 mmol) were added, and the mixture was stirred at 70° C. for 18 hours. The reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=1:1 to ethyl acetate) to give the title compound (3.11 g).

[0825] ESI-MS (m / z): 520.42 [M+H] + .

[0826] [Generation Example 17-5]

[0827] 6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-1-ethyl-4-(1-methoxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)quinazolin-2(1H)-one

[0828]

[0829] Potassium carbonate (0.532 g, 3.85 mmol) and DABCO (0.108 g, 0.961 mmol) were added to a solution of 5-(2-chloro-4-(1-methoxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (1.00 g, 1.92 mmol) produced in 1,4-dioxane (6 mL) and water (2 mL) at room temperature, and the mixture was stirred at 80° C. for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with brine. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a crude product. Potassium carbonate (0.797 g, 5.77 mmol) and ethyl iodide (461 μL, 5.77 mmol) were added to the resulting crude product solution in DMF (7.5 mL), and the mixture was stirred at room temperature for 20 hours. Brine and ethyl acetate were added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate = 1: 1 to ethyl acetate to ethyl acetate: methanol = 9: 1) to obtain the title compound (0.530 g).

[0830] ESI-MS (m / z): 530.48 [M+H] + .

[0831] [Example 18]

[0832] N-((4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)-6-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)methyl)methanesulfonamide

[0833]

[0834] At room temperature, 4-dimethylaminopyridine (5.29 mg, 0.043 mmol) and methanesulfonyl chloride (3.35 μL, 0.043 mmol) were added to a solution of 5-(2-(aminomethyl)-4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (19.5 mg, 0.036 mmol) producing Example 18-2 in dichloromethane (1 mL), and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with brine. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. To the resulting crude product solution in methanol (1.0 mL) was added p-toluenesulfonic acid monohydrate (13.7 mg, 0.072 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by NH silica gel column chromatography (ethyl acetate to ethyl acetate: methanol = 9: 1) to obtain the title compound (7.1 mg).

[0835] 1 H-NMR spectrum (400 MHz, CDCl 3 )δ(ppm):0.17-0.30(2H,m),0.48-0.55(1H,m),0.72-0.79(1H,m),2.18(3H,s),2. 78(1H,brs),3.09(3H,s),3.23-3.27(1H,m),3.56(3H,s),4.53-4.60(1H,m),4.64- 4.70(1H,m),4.81-4.84(2H,m),5.80-5.86(1H,m),7.00-7.02(1H,m),7.13-7.16( 1H,m),7.27-7.34(5H,m),7.80-7.85(1H,m),7.94-7.98(1H,m),8.07-8.10(1H,m).

[0836] ESI-MS (m / z): 535.35 [M+H] + .

[0837] [Generation Example 18-1]

[0838] 4-(1-Cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-6-iodoquinazoline-2-carbonitrile

[0839]

[0840] At room temperature, sodium cyanide (101 mg, 2.07 mmol) and DABCO (232 mg, 2.07 mmol) were added to a solution of 2-chloro-4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-6-iodoquinazoline (950 mg, 1.73 mmol) of Example 2-3 in dimethylsulfoximine (7 mL), and the mixture was stirred at room temperature for 32 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane to heptane: ethyl acetate = 1: 1) to give the title compound (496 mg).

[0841] ESI-MS (m / z): 542.26 [M+H] + .

[0842] [Generation Example 18-2]

[0843] 5-(2-(Aminomethyl)-4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[0844]

[0845] At -78 ° C, to a solution of 4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-6-iodoquinazoline-2-carbonitrile (100 mg, 0.185 mmol) produced in toluene (1 mL) was added dropwise DIBAL-H (1M toluene solution, 0.406 mL, 0.406 mmol), and the mixture was stirred at 0 ° C for 15 minutes. After adding saturated Rochelle salt aqueous solution and ethyl acetate to the reaction mixture and stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. To the obtained crude product and 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (69.0 mg, 0.277 mmol) solution in toluene (1 mL) was added ethanol (0.25 mL), sodium carbonate (2M aqueous solution, 0.5 mL, 1.00 mmol) and tetrakis(triphenylphosphine)palladium(0) (21.3 mg, 0.018 mmol) at room temperature, and the mixture was stirred at 70°C for 18 hours. The reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate to ethyl acetate: methanol = 9: 1) to obtain the title compound (59.7 mg).

[0846] ESI-MS (m / z): 541.23 [M+H] + .

[0847] [Example 19]

[0848] 5-(2-((dimethyl(oxo)-16-thiolidene)amino)-4-(2-hydroxy-1-isopropoxy-1-phenylethyl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[0849]

[0850] To a solution of 5-(2-((dimethyl(oxo)-16-sulfanylidene)amino)-4-(1-isopropoxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (32 mg) producing Example 19-5 in methanol (2 mL) at 0°C, p-toluenesulfonic acid (20 mg) was added, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and extraction was performed with dichloromethane. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain a racemic mixture of the title compound. The resulting racemic mixture was purified by SFC (IG, carbon dioxide: methanol = 80: 20) to obtain the proisomer (6.63 mg) of the title compound.

[0851] 1 H-NMR spectrum (400 MHz, CDCl 3 )δ(ppm):0.58-0.69(3H,m),1.30-1.37(3H,m),2.16(3H,s),3.52(6H,s),3.53 (3H,s),3.65-3.78(1H,m),3.99-4.15(1H,m),4.24-4.35(1H,m),4.36-4.51(1 H,m),6.85-6.99(1H,m),7.06-7.15(1H,m),7.06-7.15(1H,m),7.23-7.32(3H, m),7.36-7.38(2H,m),7.56-7.67(1H,m),7.67-7.76(1H,m),7.84-7.96(1H,m)

[0852] [Generation Example 19-1]

[0853] 2-Isopropoxy-2-phenylacetic acid ethyl ester

[0854]

[0855] At room temperature, to a solution of propane-2-ol (1.58 g, 26.3 mmol) and rhodium acetate (II) dimer (58 mg, 0.131 mmol) in dichloromethane (10 mL), a solution of ethyl 2-diazo-2-phenylacetate (1.00 g, 5.26 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane: ethyl acetate = 99: 1 to n-heptane: ethyl acetate = 4: 1) to obtain the title compound (1.00 g).

[0856] 1 H-NMR spectrum (400 MHz, CDCl 3 )δ(ppm):0.86-0.88(3H,m),1.18-1.25(6H,m),3.62-3.73(1H,m),4.10 -4.24(2H,m),4.91-4.99(1H,m),7.30-7.36(3H,m),7.44-7.46(2H,m).

[0857] [Generate Example 19-2]

[0858] 2-(2-Chloro-6-iodoquinazolin-4-yl)-2-isopropoxy-2-phenylacetic acid ethyl ester

[0859]

[0860] At -78 ° C, to the 2-isopropoxy-2-phenylacetate (1.23 g, 5.54 mmol) and 2,4-dichloro-6-iodoquinazoline (1.2 g, 3.69 mmol) solution of Example 19-1 in THF (20 mL), LHMDS (1M THF solution, 3.69 mL, 3.69 mmol) was added dropwise, and the mixture was stirred at room temperature for 1.5 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with brine. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane: ethyl acetate = 99: 1 to n-heptane: ethyl acetate = 4: 1) to obtain the title compound (1.15 g).

[0861] ESI-MS (m / z): 511.24 [M+H] + .

[0862] [Generation Example 19-3]

[0863] 2-Chloro-6-iodo-4-(1-isopropoxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)quinazoline

[0864]

[0865] At -78 ° C, DIBAL-H (1M toluene solution, 7.88 mL, 7.88 mmol) was added dropwise to a solution of ethyl 2-(2-chloro-6-iodoquinazoline-4-yl)-2-isopropoxy-2-phenylacetate (1.15 g, 2.25 mmol) in toluene (20 mL) producing Example 19-2, and the mixture was stirred at 0 ° C for 30 minutes. Saturated Rochelle salt aqueous solution and ethyl acetate were added and stirred. After the reaction mixture was partitioned into oil and water, the organic layer was dried over sodium sulfate. After filtering the organic layer, the filtrate was concentrated under reduced pressure to obtain a crude product. At room temperature, DHP (758 mg, 9.01 mmol) and p-toluenesulfonic acid monohydrate (86 mg, 0.45 mmol) were added to the resulting crude product solution in dichloromethane (20 mL), and the mixture was stirred at room temperature for 4 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=99:1 to n-heptane:ethyl acetate=7:3) to give the title compound (980 mg).

[0866] ESI-MS (m / z): 553.26 [M+H] + .

[0867] [Generate Example 19-4]

[0868] 5-(2-Chloro-4-(1-isopropoxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[0869]

[0870] At room temperature, ethanol (3mL), sodium carbonate (2M aqueous solution, 1.77mL, 3.54mmol) and tetrakis (triphenylphosphine) palladium (0) (205mg, 0.177mmol) were added to a solution of 2-chloro-6-iodo-4-(1-isopropoxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)quinazoline (980mg, 1.77mmol) and 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (486mg, 1.95mmol) produced in toluene (12mL), and the mixture was stirred at 70°C for 12 hours. The reaction mixture was returned to room temperature, water was added, and extracted with ethyl acetate. The organic layer was washed with brine. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=9:1 to n-heptane:ethyl acetate=35:65) to give the title compound (706 mg).

[0871] ESI-MS (m / z): 548.40 [M+H] + .

[0872] [Generate Example 19-5]

[0873] 5-(2-((dimethyl(oxo)-16-thiolidene)amino)4-(1-isopropoxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[0874]

[0875] To a solution of 5-(2-chloro-4-(1-isopropoxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (80.0 mg, 0.146 mmol) obtained in Example 19-4 in 1,4-dioxane (2 mL) at room temperature were added dimethylsulfoximine (20.4 mg, 0.219 mmol), cesium carbonate (95.0 mg, 0.292 mmol), BRETTPHOS (15.7 mg, 0.029 mmol) and tris(dibenzylideneacetone)palladium (13.4 mg, 0.015 mmol), and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was returned to room temperature, and after filtering the insoluble matter, the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=1:9 to ethyl acetate to ethyl acetate:methanol=95:5) to give the title compound (32 mg).

[0876] ESI-MS (m / z): 605.45 [M+H] + .

[0877] [Example 20]

[0878] 5-(2-amino-4-(1-cyclopropyl-3-hydroxy-2-(pyridin-3-yl)propan-2-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[0879]

[0880] At 0°C, 2M hydrochloric acid (ethanol solution, 1 mL) was added to a solution of 5-(2-amino-4-(1-cyclopropyl-2-(pyridin-3-yl)-3-((tetrahydro-2H-pyran-2-yl)oxy)propane-2-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (25 mg, 47 μmol) in ethanol (2 mL) producing Example 20-3, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and extraction was performed with dichloromethane. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate to ethyl acetate: methanol = 85: 15) to give the title compound (16 mg).

[0881] 1 H-NMR spectrum (400 MHz, CDCl 3 )δ(ppm):-0.49-0.47(1H,m),-0.01-0.08(2H,m),0.34-0.40(1H,m),0.46-0.55(1H,m),2.13(3H,s),2.33 (1H,dd,J=6.8,13.6Hz),2.47(1H,dd,J=5.8,13.6Hz),3.51(3H,s),3.91(1H,d,J=11.5Hz),4.67(1H,d,J=1 1.5Hz),5.28(2H,s),6.77(1H,d,J=2.9Hz),6.89-6.90(1H,m),7.05(1H,brs),7.30(1H,dd,J=4.9,8.0Hz) ,7.54(1H,dt,J=1.8,1.8,8.0Hz),7.59(2H,d,J=1.0Hz),8.53(1H,d,J=2.0Hz),8.59(1H,dd,J=1.5,4.9Hz)

[0882] ESI-MS (m / z): 442.36 [M+H] + .

[0883] [Generation Example 20-1]

[0884] Ethyl 2-(2-chloro-6-iodoquinazolin-4-yl)-3-cyclopropyl-2-(pyridin-3-yl)propanoate

[0885]

[0886] At 0 ° C, to a solution of ethyl 2-(pyridin-3-yl)acetate (1.00 g, 6.05 mmol) and (bromomethyl)cyclopropane (899 mg, 6.66 mmol) in DMF (10 mL), a solution of potassium tert-butoxide (1.02 g, 9.08 mmol) in DMF (10 mL) was added dropwise, and the mixture was stirred at 0 ° C for 30 minutes. Water was added to the reaction mixture, extracted with ethyl acetate, the organic layer was dried over sodium sulfate, and filtered. Concentrated under reduced pressure, the residue was purified by silica gel column chromatography (n-heptane: ethyl acetate = 9: 1 to 2: 1) to give a crude product (760 mg). At -78 ° C, LHMDS (1M THF solution, 3.00 mL, 3.00 mmol) was added dropwise to the obtained crude product (506 mg) and 2,4-dichloro-6-iodoquinazoline (750 mg, 2.31 mmol) solution in THF (15 mL), and the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with brine. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane: ethyl acetate = 95: 5 to 4: 1) to obtain the title compound (1.08 g).

[0887] 1 H-NMR spectrum (400 MHz, CDCl 3 )δ(ppm):-0.20--0.13(2H,m),-0.27-0.38(2H,m)0.20-0.40(3H,s),0.45-0.50(1H,m)1.14-1.18(3H,m),1.97(1H,dd,J=6.8,14. 2Hz),2.10(1H,dd,J=5.8,14.2Hz),4.05-4.16(2H,m),7.18-7.25(1H,m),7.63-7.65(1H,m),7.94-8.01(2H,m),8.42-8.55(3H,m)

[0888] [Generation Example 20-2]

[0889] 2-Chloro-4-(1-cyclopropyl-2-(pyridin-3-yl)-3-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)-6-iodoquinazoline

[0890]

[0891] At -78 ° C, to the 2- (2-chloro-6-iodoquinazoline-4-yl) -3-cyclopropyl-2- (pyridin-3-yl) propionic acid ethyl ester (720 mg, 1.42 mmol) solution of Example 20-1 in toluene (10 mL), DIBAL-H (1M toluene solution, 4.96 mL, 4.96 mmol) was added dropwise, and the mixture was stirred at 0 ° C for 30 minutes. Saturated Rochelle salt aqueous solution and ethyl acetate were added to the reaction mixture and stirred. After the reaction mixture was distributed in oil and water, the organic layer was dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane: ethyl acetate = 3: 1 to 1: 4) to obtain a crude product. At room temperature, DHP (716mg, 8.51mmol) and p-toluenesulfonic acid monohydrate (135mg, 0.709mmol) were added to the obtained crude product solution in dichloromethane (6mL), and the mixture was stirred at room temperature for 4 hours. Saturated sodium bicarbonate aqueous solution and dichloromethane were added and the mixture was stirred. After the reaction mixture was distributed to oil and water, the organic layer was dried over sodium sulfate. After filtering the organic layer, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane: ethyl acetate = 4: 1 to 1: 2) to obtain the title compound (600mg).

[0892] ESI-MS (m / z): 550.25 [M+H] + .

[0893] [Generation Example 20-3]

[0894] 5-(2-chloro-4-(1-cyclopropyl-2-(pyridin-3-yl)-3-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[0895]

[0896] To a solution of 2-chloro-4-(1-cyclopropyl-2-(pyridin-3-yl)-3-((tetrahydro-2H-pyran-2-yl)oxy)propane-2-yl)-6-iodoquinazoline (70.0 mg, 0.127 mmol) and 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (34.9 mg, 0.140 mmol) produced in toluene (2.0 mL) at room temperature, ethanol (0.5 mL), sodium carbonate (2M aqueous solution, 0.127 mL, 0.225 mmol) and tetrakis(triphenylphosphine)palladium(0) (14.7 mg, 0.013 mmol) were added, and the mixture was stirred at 75° C. for 3 hours under a nitrogen atmosphere. The reaction mixture was returned to room temperature, water was added, and extraction was performed with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=3:2 to ethyl acetate) to give the title compound (40.5 mg).

[0897] ESI-MS (m / z): 545.38 [M+H] + .

[0898] [Generation Example 20-4]

[0899] 5-(2-amino-4-(1-cyclopropyl-2-(pyridin-3-yl)-3-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[0900]

[0901] At room temperature, to a solution of 5-(2-chloro-4-(1-cyclopropyl-2-(pyridin-3-yl)-3-((tetrahydro-2H-pyran-2-yl)oxy)propane-2-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (40.5 mg, 0.074 mmol) in NMP (0.7 mL) producing Example 20-3 was added 28% aqueous ammonia solution (0.5 mL, 7.48 mmol), and the mixture was stirred in a sealed tube at 90 ° C for 8 hours. The reaction mixture was returned to room temperature, water was added, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 2: 3 to ethyl acetate to methanol: ethyl acetate = 5: 95) to give the title compound (24.5 mg).

[0902] ESI-MS (m / z): 526.44 [M+H] + .

[0903] [Example 21]

[0904] 5-(2-(((dimethyl(oxo)-16-thiophene)amino)-4-(1-(3-fluoro-4-methoxyphenyl)-3-hydroxy-2-(pyridin-2-yl)propan-2-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[0905]

[0906] To a solution of 5-(2-((dimethyl(oxo)-16-sulfanylidene)amino)-4-(1-(3-fluoro-4-methoxyphenyl)-2-(pyridin-2-yl)-3-((tetrahydro-2H-pyran-2-yl)oxy)propane-2-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (30 mg, 44 μmol) in ethanol (2 mL) at 0°C was added 2M hydrochloric acid (ethanol solution, 1 mL), and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and extraction was performed with dichloromethane. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate to ethyl acetate: methanol = 9: 1) to give the title compound (15 mg).

[0907] 1 H-NMR spectrum (400 MHz, CDCl 3 )δ(ppm):2.17(3H,s),3.02(3H,s),3.28(3H,s),3.55(3H,s),3.72(3H,s),3.80-3.92(4H,m ),4.67(1H,dd,J=2.0,8.8Hz),6.21-6.23(1H,m),6.41(1H,dd,J=2.2,12.5Hz),6.54(1H,t,J =8.8Hz),6.92-6.98(3H,m),7.10(1H,d,J=1.9Hz),7.31(1H,ddd,J=1.0,4.9,7.3Hz),7.55( 1H,dt,J=1.9,7.8,7.8Hz),7.66(1H,dd,J=1.9,8.8Hz),7.77-7.86(1H,m),8.79-8.80(1H,m)

[0908] ESI-MS (m / z): 602.42 [M+H] + .

[0909] [Generation Example 21-1]

[0910] Ethyl 3-(3-fluoro-4-methoxyphenyl)-2-(pyridin-2-yl)propanoate

[0911]

[0912] At 0°C, 50% to 72% sodium hydride oil (127 mg) was added to a solution of 2-(pyridin-2-yl)ethyl acetate (500 mg, 3.03 mmol) in DMF (10 mL), and the mixture was stirred at 0°C for 10 minutes. A solution of 4-(chloromethyl)-2-fluoro-1-methoxybenzene (528 mg, 3.03 mmol) in DMF (2 mL) was added dropwise to the reaction mixture, followed by stirring at room temperature for 4 hours. At 0°C, water was added to the reaction mixture, extracted with ethyl acetate, the organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane: ethyl acetate = 7: 3 to 35: 65) to give the title compound (649 mg).

[0913] ESI-MS (m / z): 304.13 [M+H] + .

[0914] [Generation Example 21-2]

[0915] 2-Chloro-4-(1-(3-fluoro-4-methoxyphenyl)-2-(pyridin-2-yl)-3-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)-6-iodoquinazoline

[0916]

[0917] Under nitrogen atmosphere, at -78 ° C, to the 3- (3-fluoro-4-methoxyphenyl) -2- (pyridin-2-yl) propionic acid ethyl ester (652 mg, 2.15 mmol) and 2,4-dichloro-6-iodoquinazoline (698 mg, 2.15 mmol) solution of Example 21-1 in THF (20 mL) was added dropwise LHMDS (1M THF solution, 3.22 mL, 3.22 mmol), and the mixture was stirred at room temperature for 3 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with brine. After the organic layer was dried over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane to n-heptane: ethyl acetate = 4: 1) to obtain a crude product. At -78 ° C, DIBAL-H (1M toluene solution, 4.04 mL, 4.04 mmol) was added dropwise to the obtained crude product solution in toluene (20 mL), and the mixture was stirred at 0 ° C for 6 hours. Saturated Rochelle salt aqueous solution and ethyl acetate were added and stirred. The reaction mixture was subjected to oil-water distribution, and the organic layer was dried with magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane to n-heptane: ethyl acetate = 1: 1) to obtain a crude product. At room temperature, DHP (318 mg, 3.78 mmol) and p-toluenesulfonic acid monohydrate (72 mg, 0.378 mmol) were added to the obtained crude product solution in dichloromethane (10 mL), and the mixture was stirred at room temperature for 12 hours. Saturated sodium bicarbonate aqueous solution and dichloromethane were added to the reaction mixture, followed by stirring. After the reaction mixture was oil-water distributed, the organic layer was dried with sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane to n-heptane:ethyl acetate=7:3) to give the title compound (480 mg).

[0918] ESI-MS (m / z): 634.27 [M+H] +

[0919] [Generation Example 21-3]

[0920] 5-(2-(((dimethyl(oxo)-16-thiophene)amino)-4-(1-(3-fluoro-4-methoxyphenyl)-2-(pyridin-2-yl)-3-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[0921]

[0922] At room temperature, ethanol (1.0 mL), sodium carbonate (2M aqueous solution, 2.0 mL, 4.0 mmol) and tetrakis (triphenylphosphine) palladium (0) (16.4 mg, 0.014 mmol) were added to a solution of 2-chloro-4-(1-(3-fluoro-4-methoxyphenyl)-2-(pyridin-2-yl)-3-((tetrahydro-2H-pyran-2-yl)oxy)propane-2-yl)-6-iodoquinazoline (180 mg, 0.284 mmol) and 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (85 mg, 0.341 mmol) produced in toluene (4.0 mL), and the mixture was stirred at 70° C. for 12 hours. The reaction mixture was returned to room temperature, water was added, and extraction was performed with ethyl acetate. After the organic layer was dried over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate to methanol: ethyl acetate = 1: 4) to obtain a crude product (141 mg). At room temperature, dimethyl sulfoximine (8.53 mg, 0.092 mmol), sodium tert-butoxide (13.5 mg, 0.141 mmol), BRETTPHOS (7.56 mg, 0.014 mmol) and tris (dibenzylideneacetone) dipalladium (0) (6.45 mg, 0.0070 mmol) were added to a portion of the obtained crude product (44.3 mg) solution in 1,4-dioxane (2 mL), and the mixture was stirred at 80 ° C for 1 hour. The reaction mixture was returned to room temperature, diluted with ethyl acetate, and filtered with diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 3: 1 to ethyl acetate to n-methanol: ethyl acetate = 5: 95) to obtain the title compound (30 mg).

[0923] ESI-MS (m / z): 686.54 [M+H] + .

[0924] [Example 22]

[0925] 5-(2-((dimethyl(oxo)-16-thiolidene)amino)-4-(1-hydroxy-4-methoxy-2-phenylbutan-2-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[0926]

[0927] To a solution of 5-(2-(((dimethyl(oxo)-16-sulfanylidene)amino)-4-(4-methoxy-2-phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)butan-2-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (27 mg, 0.045 mmol) producing Example 22-4 in ethanol (1 mL) was added 2M hydrochloric acid (ethanol solution, 0.5 mL) at 0°C, and the mixture was stirred at room temperature for 1.5 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and extraction was performed with dichloromethane. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate to ethyl acetate:methanol=9:1) to give the title compound (13 mg).

[0928] 1 H-NMR spectrum (400 MHz, CDCl 3 )δ(ppm):2.13(3H,s),2.72-2.81(2H,m),3.02-3.08(1H,m),3.10(3H,s),3.46-3.57(11H,m),4.16(1H,d,J=11.6Hz),4.26(1H,d,J=11.6 Hz),6.77(1H,d,J=2.4Hz),6.91-6.92(1H,m),7.21(1H,d,J=2.0Hz),7.26-7.38(5H,m),7.60(1H,dd,J=2.0,8.8Hz),7.74(1H,d,J=8.8Hz)

[0929] ESI-MS (m / z): 521.32 [M+H] + .

[0930] [Generation Example 22-1]

[0931] 2-(2-Chloro-6-iodoquinazolin-4-yl)-4-methoxy-2-phenylbutyric acid ethyl ester

[0932]

[0933] At 0°C, 50% to 72% sodium hydride oil (1.29 g) was added to a solution of ethyl phenylacetate (4.00 g, 24.4 mmol) in DMF (100 mL), and the mixture was stirred at 0°C for 30 minutes. 2-Bromoethyl methyl ether (2.55 mL, 26.8 mmol) was added dropwise to the reaction mixture and stirred at 0°C for 2 hours. An aqueous solution of ammonium chloride was added to the reaction mixture at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and filtered to obtain a crude product (5.41 g). LHMDS (1M THF solution, 9.69 mL, 9.69 mmol) was added dropwise to a solution of the obtained crude product (1.58 g) and 2,4-dichloro-6-iodoquinazoline (2.1 g, 6.46 mmol) in THF (50 mL) at -78°C, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with brine. The organic layer was dried over magnesium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane to n-heptane:ethyl acetate=4:1) to obtain the title compound (3.3 g).

[0934] 1 H-NMR spectrum (500 MHz, CDCl 3 )δ(ppm):1.11(3H,t,J=7.1Hz),2.79-2.87(1H,m),2.93-3.01(1H,m),3.15(3H,s),3.27-3.35(1H,m),3.45-3 .52(1H,m),4.15(2H,q,J=7.1Hz),7.25-7.35(3H,m),7.39-7.44(2H,m),7.65(1H,d,8.8Hz),7.92-7.98(2H,m)

[0935] [Generation Example 22-2]

[0936] 2-Chloro-6-iodo-4-(4-methoxy-2-phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)butan-2-yl)quinazoline

[0937]

[0938] Under nitrogen atmosphere, at -78 ° C, to toluene (20mL) in the production example 22-1 of 2- (2-chloro-6-iodoquinazoline-4-yl) -4-methoxy-2-phenylbutyric acid ethyl ester (1.80g, 3.52mmol) solution, DIBAL-H (1M toluene solution, 10.6mL, 10.6mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. Saturated Rochelle salt solution was added to the reaction mixture and stirred overnight. The reaction mixture was subjected to oil-water distribution, and the organic layer was dried with magnesium sulfate. After filtering the organic layer, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-heptane: ethyl acetate = 97: 3 to 3: 1) to obtain a crude product (1.30g). At room temperature, DHP (633 μL, 7.00 mmol) and p-toluenesulfonic acid monohydrate (665 mg, 3.50 mmol) were added to a solution of a portion (1.09 g) of the obtained crude product in THF (20 mL), and the mixture was stirred at 50° C. for 3 hours. DHP (633 μL, 7.00 mmol) and p-toluenesulfonic acid monohydrate (665 mg, 3.50 mmol) were further added, and the mixture was stirred at 50° C. for 6.5 hours, and DHP (2.00 mL, 22.1 mmol) was further added and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was returned to room temperature, saturated sodium bicarbonate aqueous solution was added, and extraction was performed with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=95:5 to 1:1) and then by silica gel column chromatography (n-heptane:ethyl acetate=97:3 to 7:3) to give the title compound (646 mg).

[0939] ESI-MS (m / z): 553.14 [M+H] + .

[0940] [Generation Example 22-3]

[0941] 5-(2-chloro-4-(4-methoxy-2-phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)butan-2-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[0942]

[0943] At room temperature, ethanol (2mL), sodium carbonate (2M aqueous solution, 0.904mL, 1.81mmol) and tetrakis (triphenylphosphine) palladium (0) (105mg, 0.09mmol) were added to a solution of 2-chloro-6-iodo-4-(4-methoxy-2-phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)butane-2-yl)quinazoline (500mg, 0.904mmol) and 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (293mg, 1.18mmol) in toluene (8mL) and the mixture was stirred at 80°C for 5 hours. The reaction mixture was returned to room temperature, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with brine. After the organic layer was dried over magnesium sulfate, it was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=3:2 to ethyl acetate) to give the title compound (299 mg).

[0944] ESI-MS (m / z): 548.35 [M+H] + .

[0945] [Generation Example 22-4]

[0946] 5-(2-((dimethyl(oxo)-16-sulfanylidene)amino)-4-(4-methoxy-2-phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)butan-2-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[0947]

[0948] To a solution of 5-(2-chloro-4-(4-methoxy-2-phenyl-1-((tetrahydro-2H-pyran-2-yl)oxy)butan-2-yl)quinazolin-6-yl)-1,3-dimethylcyclopyridin-2(1H)-one (50.0 mg, 0.091 mmol) producing Example 22-3 in 1,4-dioxane (2 mL) at room temperature were added dimethylsulfoximine (12.8 mg, 0.137 mmol), sodium tert-butoxide (17.5 mg, 0.182 mmol), BRETTPHOS (9.8 mg, 0.018 mmol) and tris(dibenzylideneacetone)palladium (8.35 mg, 9.12 μmol), and the mixture was stirred at 90° C. for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=1:1 to ethyl acetate to methanol:ethyl acetate=5:95) to give the title compound (27.3 mg).

[0949] ESI-MS (m / z): 605.42 [M+H] + .

[0950] [Example 23]

[0951] 5-(2-((dimethyl(oxo)-16-thiolidene)amino)-4-(1-hydroxy-2,3-diphenylpropane-2-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[0952]

[0953] To a solution of 5-(2-((dimethyl(oxo)-16-sulfanylidene)amino)-4-(1,2-diphenyl-3-((tetrahydro-2H-pyran-2-yl)oxy)propane-2-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (18 mg, 29 μmol) in ethanol (1 mL) at 0°C was added 2M hydrochloric acid (ethanol solution, 1 mL), and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and extraction was performed with dichloromethane. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel thin layer chromatography (dichloromethane: methanol = 95: 5) to give the title compound (4.6 mg).

[0954] 1 H-NMR spectrum (400 MHz, CDCl 3 )δ(ppm):2.15(3H,s),2.73(3H,s),3.16(3H,s),3.27-3.31(1H,m),3.52(3H,d,J=2.0Hz),3.69-3.83(3H,m),4.63-4.68(1H,m),6.5 1-6.53(2H,m),6.76-6.77(1H,m),6.96-7.05(4H,m),7.33-7.46(6H,m),7.66(1H,dt,J=1.5,1.58.8Hz),7.79(1H,dd,J=2.0,8.8Hz)

[0955] ESI-MS (m / z): 553.36 [M+H] + .

[0956] [Generation Example 23-1]

[0957] Ethyl 2,3-diphenylpropionate

[0958]

[0959] To a solution of 2,3-diphenylpropionic acid (8.00 g, 35.4 mmol) in ethanol (80 mL) was added sulfuric acid (800 μL, 15.0 mmol) and the mixture was stirred at 80° C. for 36 hours. Aqueous sodium bicarbonate solution was added to the reaction mixture at 0° C. and the mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (9.5 g).

[0960] ESI-MS (m / z): 255.06 [M+H] +

[0961] [Generation Example 23-2]

[0962] Ethyl 2-(2-chloro-6-iodoquinazolin-4-yl)-2,3-diphenylpropionate

[0963]

[0964] At -78 ° C, LHMDS (1M THF solution, 53.1 mL, 53.1 mmol) was added dropwise to a solution of ethyl 2,3-diphenylpropionate (9.0 g, 35.4 mmol) and 2,4-dichloro-6-iodoquinazoline (11.5 g, 35.4 mmol) produced in THF (300 mL) and the mixture was stirred at room temperature for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the obtained solid was filtered. The obtained residue was purified by silica gel column chromatography (n-heptane: ethyl acetate = 97: 3 to 4: 1) and combined with the obtained solid to obtain the title compound (16.3 g).

[0965] ESI-MS (m / z): 543.27 [M+H] +

[0966] [Generation Example 23-3]

[0967] 2-Chloro-4-(1,2-diphenyl-3-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)-6-iodoquinazoline

[0968]

[0969] At -78 ° C, DIBAL-H (1M toluene solution, 90 mL, 90 mmol) was added dropwise to a solution of 2-(2-chloro-6-iodoquinazoline-4-yl)-2,3-diphenylpropionic acid ethyl ester (16.3 g, 30.0 mmol) in toluene (400 mL) producing Example 23-2, and the mixture was stirred at 0 ° C for 30 minutes. Saturated Rochelle salt aqueous solution and ethyl acetate were added and stirred. After the reaction mixture was partitioned into oil and water, the organic layer was dried over sodium sulfate. After filtering the organic layer, the filtrate was concentrated under reduced pressure to obtain a crude product. At room temperature, DHP (5.05 g, 60.1 mmol) and p-toluenesulfonic acid monohydrate (1.14 g, 60.1 mmol) were added to the resulting crude product solution in dichloromethane (400 mL), and the mixture was stirred at room temperature for 3 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture for oil-water distribution. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=20:1 to 4:1) to give the title compound (14.8 g).

[0970] ESI-MS (m / z): 585.30 [M+H] + .

[0971] [Generation Example 23-4]

[0972] 5-(2-Chloro-4-(1,2-diphenyl-3-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[0973]

[0974] At room temperature, ethanol (80 mL), sodium carbonate (3.99 g, 37.6 mmol), water (40 mL) and tetrakis (triphenylphosphine) palladium (0) (1.09 g, 0.94 mmol) were added to a solution of 2-chloro-4-(1,2-diphenyl-3-((tetrahydro-2H-pyran-2-yl)oxy)propane-2-yl)-6-iodoquinazole (11.0 g, 18.8 mmol) and 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (5.62 g, 22.6 mmol) produced in toluene (160 mL), and the mixture was stirred at 80 ° C for 8 hours. The reaction mixture was returned to room temperature, water was added, and extracted with ethyl acetate. The organic layer was washed with brine. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=7:3 to ethyl acetate) to give the title compound (9.9 g).

[0975] ESI-MS (m / z): 580.47 [M+H] + .

[0976] [Generation Example 23-5]

[0977] 5-(2-((dimethyl(oxo)-16-sulfanylidene)amino)-4-(1,2-diphenyl-3-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[0978]

[0979] To a solution of 5-(2-chloro-4-(1,2-diphenyl-3-((tetrahydro-2H-pyran-2-yl)oxy)propane-2-yl)quinazolin-6-yl)-1,3-dimethylcyclopyridin-2(1H)-one (40.0 mg, 0.069 mmol) producing Example 23-4 in 1,4-dioxane (2 mL) at room temperature were added dimethylsulfoximine (8.35 mg, 0.09 mmol), sodium tert-butoxide (13.3 mg, 0.138 mmol), BRETTPHOS (7.4 mg, 0.014 mmol) and tris(dibenzylideneacetone)palladium (6.3 mg, 0.0069 mmol), and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=3:1 to methanol:ethyl acetate=1:9) to give the title compound (18.2 mg).

[0980] ESI-MS (m / z): 637.46 [M+H] + .

[0981] [Example 24]

[0982] 5-(2-amino-4-(1-hydroxy-3-phenyl-2-(pyrimidin-2-yl)propan-2-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[0983]

[0984] To a solution of 5-(2-chloro-4-(1-phenyl-2-(pyrimidin-2-yl)-3-((tetrahydro-2H-pyran-2-yl)oxy)propane-2-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (10 mg, 0.017 mmol) producing Example 24-5 in NMP (1000 μL) was added 28% aqueous ammonia solution (322 μL), and the mixture was heated in a sealed tube at 110° C. for 20 hours. Water was added at room temperature, and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (1000 μL), p-toluenesulfonic acid monohydrate (10 mg, 0.053 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and then extracted 3 times with ethyl acetate. The organic layer was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=3:2 to ethyl acetate) to give the title compound (1.1 mg).

[0985] 1 H-NMR spectrum (500 MHz, CDCl 3 )δ(ppm):2.15(3H,s),3.55(3H,m),3.97(2H,s),4.22-4.31(1H,m),4.46-4.54(1H,m),5.03-5.13(2 H,m),6.65-6.73(2H,m),6.80-6.85(1H,m),6.93-7.08(6H,m),7.54-7.61(2H,m),8.71-8.79(2H,m).

[0986] ESI-MS (m / z): 479.38 [M+H] + .

[0987] [Generation Example 24-1]

[0988] Ethyl 3-phenyl-2-(pyrimidin-2-yl)propanoate

[0989]

[0990] Under ice bath cooling, 50% to 72% sodium hydride oil (0.281 g) was added to a solution of ethyl 2-pyrimidine acetate (1.07 g, 6.43 mmol) in DMF (15 mL). After 10 minutes, benzyl bromide (1.00 g, 5.85 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane: ethyl acetate = 9: 1 to 7: 3) to obtain the title compound (900 mg).

[0991] ESI-MS (m / z): 257.24 [M+H] + .

[0992] [Generation Example 24-2]

[0993] Ethyl 2-(2-chloro-6-iodoquinazolin-4-yl)-3-phenyl-2-(pyrimidin-2-yl)propanoate

[0994]

[0995] At -78 ° C, 2,4-dichloro-6-iodoquinazoline (1000 mg, 3.08 mmol) in THF (30 mL) and 3-phenyl-2-(pyrimidin-2-yl) propionic acid ethyl ester (868 mg, 3.39 mmol) solution produced in Example 24-1 were dripped with bis(trimethylsilyl) lithium amide (1.17 M, 5.78 mL, 6.76 mmol). After stirring at -78 ° C for 10 minutes, the mixture was stirred at room temperature for 3 hours. Saturated ammonium chloride was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product (1.6 g) of the title compound.

[0996] ESI-MS (m / z): 545.22 [M+H] + .

[0997] [Generation Example 24-3]

[0998] 2-(2-Chloro-6-iodoquinazolin-4-yl)-3-phenyl-2-(pyrimidin-2-yl)propan-1-ol

[0999]

[1000] At -78 ° C, to the crude product (1.6 g) solution of 2-(2-chloro-6-iodoquinazoline-4-yl)-3-phenyl-2-(pyrimidin-2-yl)propionic acid ethyl ester of Example 24-2 in toluene (50 ml), DIBAL-H (1M toluene solution, 14.69 mL, 14.69 mmol) was added dropwise, and then the temperature was raised to 0 ° C, and the mixture was stirred for 10 minutes. A saturated Rochelle salt solution was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane: ethyl acetate = 1: 1) to obtain the title compound (140 mg).

[1001] 1 H-NMR spectrum (400 MHz, CDCl 3 )δ(ppm):4.08-4.23(4H,m),4.32-4.37(1H,m),6.93-7.07(6H,m),7.11-7.17(2H,m),7.1 7-7.22(1H,m),7.59(1H,d,J=8.56Hz),7.68(1H,d,J=1.83Hz),7.89(1H,m),8.66(2H,m).

[1002] ESI-MS (m / z): 503.23 [M+H] + .

[1003] [Generation Example 24-4]

[1004] 2-Chloro-6-iodo-4-(1-phenyl-2-(pyrimidin-2-yl)-3-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)quinazoline

[1005]

[1006] To a solution of 2-(2-chloro-6-iodoquinazoline-4-yl)-3-phenyl-2-(pyrimidin-2-yl)propane-1-ol (140 mg, 0.278 mmol) of Example 24-3 in dichloromethane (3.00 mL), DHP (50.9 μL, 0.557 mmol) and p-toluenesulfonic acid monohydrate (5.3 mg, 0.028 mmol) were added and the mixture was stirred. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, which was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane: ethyl acetate = 3: 1) to give the title compound (80 mg).

[1007] ESI-MS (m / z): 587.26 [M+H] + .

[1008] [Generation Example 24-5]

[1009] 5-(2-Chloro-4-(1-phenyl-2-(pyrimidin-2-yl)-3-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[1010]

[1011] 2-Chloro-6-iodo-4-(1-phenyl-2-(pyrimidin-2-yl)-3-((tetrahydro-2H-pyran-2-yl)oxy)propane-2-yl)quinazoline (40 mg, 0.068 mmol) and 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (20.38 mg, 0.082 mmol) producing Example 24-4 were dissolved in toluene (3000 μL), ethanol (500 μL) and water (100 μL), followed by the addition of sodium carbonate (14.45 mg, 0.136 mmol) and tetrakistriphenylphosphine palladium (0) (3.94 mg, 3.41 μmol). Under a nitrogen atmosphere, the reaction mixture was stirred at 80° C. for 18 hours, and then water was added at room temperature. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane: ethyl acetate = 7: 3 to 0: 1) to give the title compound (35 mg).

[1012] ESI-MS (m / z): 582.45 [M+H] + .

[1013] [Example 25]

[1014] 5-(2-amino-4-(1-cyclopropyl-3-hydroxy-2-(pyridin-3-yl)propan-2-yl)quinazolin-6-yl)-4-methoxy-1-methylpyridin-2(1H)-one

[1015]

[1016] To a mixed solution of formate (25.0 mg) of 5-(2-amino-4-(1-cyclopropyl-2-(pyridin-3-yl)-3-((tetrahydro-2H-pyran-2-yl)oxy)propane-2-yl)quinazolin-6-yl)-4-methoxy-1-methylpyridin-2(1H)-one produced in Example 25-2 in dichloromethane (0.3 mL) and methanol (0.3 mL), trifluoroacetic acid (0.3 mL) was added, and the mixture was stirred at room temperature for 1 hour. At 0°C, triethylamine (0.55 mL) was added to the reaction mixture, and the reaction mixture was sorted and purified (distilled water containing 0.3% ammonia: acetonitrile containing 0.3% ammonia = 4:1 to 3:2) to obtain the title compound (6.1 mg).

[1017] ESI-MS (m / z): 458.34 [M+H] + .

[1018] [Generation Example 25-1]

[1019] 5-(2-chloro-4-(1-cyclopropyl-2-(pyridin-3-yl)-3-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)quinazolin-6-yl)-4-methoxy-1-methylpyridin-2(1H)-one

[1020]

[1021] At room temperature, ethanol (8 mL), sodium carbonate (2M aqueous solution, 4 mL, 8 mmol), tetrakis (triphenylphosphine) palladium (0) (820 mg, 0.709 mmol) were added to a solution of 2-chloro-4-(1-cyclopropyl-2-(pyridin-3-yl)-3-((tetrahydro-2H-pyran-2-yl)oxy)propane-2-yl)-6-iodoquinazoline (1.95 g, 3.55 mmol) and 4-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (1.41 g, 5.32 mmol) produced in toluene (16 mL), and the mixture was stirred at 75 ° C for 4 hours. The reaction mixture was returned to room temperature, water was added, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane to n-heptane:ethyl acetate=1:1 to ethyl acetate) to give the title compound (1.33 g).

[1022] ESI-MS (m / z): 561.70 [M+H] + .

[1023] [Generation Example 25-2]

[1024] 5-(2-amino-4-(1-cyclopropyl-2-(pyridin-3-yl)-3-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-yl)quinazolin-6-yl)-4-methoxy-1-methylpyridin-2(1H)-one

[1025]

[1026] To a solution of 5-(2-chloro-4-(1-cyclopropyl-2-(pyridin-3-yl)-3-((tetrahydro-2H-pyran-2-yl)oxy)propane-2-yl)quinazolin-6-yl)-4-methoxy-1-methylpyridin-2(1H)-one (50.0 mg, 0.089 mmol) in NMP (0.5 mL) at room temperature, 28% aqueous ammonia solution (500 μL, 6.47 mmol) was added, and the mixture was stirred at 100° C. for 3 hours in a sealed tube using a microwave reactor. The reaction mixture was purified by ODS silica gel column chromatography (distilled water containing 0.3% formic acid: acetonitrile containing 0.3% formic acid = 9:1 to 0:10) to give the formate salt (25.0 mg) of the title compound.

[1027] ESI-MS (m / z): 543.36 [M+H] + .

[1028] [Example 26]

[1029] 4-(4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)-2-(4-ethynylpiperidin-1-yl)quinazolin-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[1030]

[1031] To a solution of 4-(4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-2-(4-ethynylpiperidin-1-yl)quinazolin-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (30 mg, 0.047 mmol) producing Example 26-3 in dichloromethane (1 mL) was added trifluoroacetic acid (0.5 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and extraction was performed with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=7:3 to ethyl acetate to methanol:ethyl acetate=15:85) to give the title compound (21 mg).

[1032] ESI-MS (m / z): 560.39 [M+H] + .

[1033] [Generation Example 26-1]

[1034] 4-(2-chloro-4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)quinazolin-6-yl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[1035]

[1036] To a solution of 2-chloro-4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-6-iodoquinazoline (2.90 g, 5.27 mmol) obtained in Example 2-3 in 1,4-dioxane (24 mL) and water (6 mL) was added sodium carbonate (1.12 g, 10.5 mmol), followed by 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (2.71 g, 6.32 mmol) and tetrakis(triphenylphosphine)palladium(0) (608 mg, 0.526 mmol) at room temperature, and the mixture was stirred at 80° C. for 22 hours under a nitrogen atmosphere. The reaction mixture was returned to room temperature and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=1:1 to n-heptane:ethyl acetate=1:3) to give the title compound (3.08 g).

[1037] ESI-MS (m / z): 726.33 [M+H] + .

[1038] [Generation Example 26-2]

[1039] 4-(4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-2-(4-ethynylpiperidin-1-yl)quinazolin-6-yl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[1040]

[1041] At room temperature, 4-ethynylpiperidine hydrochloride (201 mg, 1.38 mmol) and N,N-diisopropylethylamine (482 μL, 2.76 mmol) were added to a solution of 4-(2-chloro-4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)quinazolin-6-yl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (500 mg, 0.689 mmol) in DMF (5 mL) producing Example 26-1, and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was returned to room temperature, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=1:1) to give the title compound (550 mg).

[1042] ESI-MS (m / z): 798.22 [M+H] + .

[1043] [Generation Example 26-3]

[1044] 4-(4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-2-(4-ethynylpiperidin-1-yl)quinazolin-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[1045]

[1046] At room temperature, 1M aqueous sodium hydroxide solution (1.88 mL, 1.88 mmol) was added to a solution of 4-(4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-2-(4-ethynylpiperidin-1-yl)quinazolin-6-yl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (300 mg, 0.376 mmol) producing Example 26-2 in ethanol (15 mL), and the mixture was stirred at 50° C. for 1 hour and 30 minutes. The reaction mixture was allowed to reach room temperature and then concentrated under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (240 mg).

[1047] ESI-MS (m / z): 644.31 [M+H] + .

[1048] [Example 27]

[1049] 4-(2-(4-amino-4-methyl-[1,4'-bipiperidinyl]-1'-yl)-4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)quinazolin-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[1050]

[1051] At room temperature, to a solution of (1'-(4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-6-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)quinazoline-2-yl)-4-methyl-[1,4'-bipiperidine]-4-yl)carbamic acid tert-butyl ester (106 mg, 0.127 mmol) producing Example 27-5 in dichloromethane (3 mL) was added TFA (3 mL), and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was then concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the residue, and extraction was performed with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by ODS column chromatography (water containing 0.1% formic acid: acetonitrile containing 0.1% formic acid = 95:5 to 1:1) to give the formate salt of the title compound (55 mg).

[1052] ESI-MS (m / z): 648.39 [M+H] + .

[1053] [Generation Example 27-1]

[1054] Benzyl 4-((tert-Butoxycarbonyl)amino)-4-methyl-[1,4'-bipiperidinyl]-1'-carboxylate

[1055]

[1056] At room temperature, 1-(benzyloxycarbonyl)-4-piperidone (700mg, 3.00mmol) was added to a solution of (4-methylpiperidin-4-yl) tert-butyl carbamate (1286mg, 6.00mmol) and acetic acid (172μL, 3.00mmol) in dichloromethane (10mL), and the mixture was stirred at room temperature for 5 minutes. Then sodium triacetoxyborohydride (>80wt%, 827mg) was added and the mixture was stirred at room temperature for 19 hours and 25 minutes. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate=6:4 to ethyl acetate) to obtain the title compound (941mg).

[1057] ESI-MS (m / z): 432.41 [M+H] + .

[1058] [Generation Example 27-2]

[1059] tert-Butyl (4-methyl-[1,4'-bipiperidinyl]-4-yl)carbamate

[1060]

[1061] At room temperature, 10% palladium-carbon (50% water, 138 mg) was added to a solution of 4-((tert-butoxycarbonyl)amino)-4-methyl-[1,4'-bipiperidine]-1'-benzyl carboxylate (279 mg, 0.646 mmol) in methanol (10 mL) producing Example 27-1, and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours and 25 minutes at normal pressure. After the reaction mixture was replaced under a nitrogen atmosphere, it was filtered with diatomaceous earth and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the title compound (192 mg).

[1062] ESI-MS (m / z): 298.30 [M+H] + .

[1063] [Generation Example 27-3]

[1064] tert-Butyl (1'-(4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-6-iodoquinazolin-2-yl)-4-methyl-[1,4'-bipiperidinyl]-4-yl)carbamate

[1065]

[1066] At room temperature, to a solution of 2-chloro-4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-6-iodoquinazoline (100 mg, 0.182 mmol) in DMF (2 mL) producing Example 2-3, (4-methyl-[1,4'-bipiperidinyl]-4-yl)carbamic acid tert-butyl ester (64.8 mg, 0.218 mmol) and N,N-diisopropylethylamine (63 μL, 0.36 mmol) producing Example 27-2 were added, and the mixture was stirred at 80 ° C for 1 hour and 30 minutes. After the reaction mixture reached room temperature, water was added to terminate the reaction and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 8: 2 to ethyl acetate) to obtain the title compound (132 mg).

[1067] ESI-MS (m / z): 812.34 [M+H] + .

[1068] [Generation Example 27-4]

[1069] tert-Butyl (1'-(4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-6-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)quinazolin-2-yl)-4-methyl-[1,4'-bipiperidinyl]-4-yl)carbamate

[1070]

[1071] To a solution of tert-butyl (1'-(4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-6-iodoquinazolin-2-yl)-4-methyl-[1,4'-bipiperidinyl]-4-yl)carbamate (131 mg, 0.161 mmol) obtained in Example 27-3 in 1,4-dioxane (4 mL) and water (1 mL) was added 6-methyl-4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (83 mg, 0.19 mmol), tetrakis(triphenylphosphine)palladium(0) (18.7 mg, 16 μmol) and cesium carbonate (79 mg, 0.24 mmol), and the mixture was stirred at 80 ° C for 1 hour and 10 minutes under a nitrogen atmosphere. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 8: 2 to ethyl acetate to ethyl acetate: methanol = 9: 1) to give the title compound (150 mg).

[1072] ESI-MS (m / z): 986.51 [M+H] + .

[1073] [Generation Example 27-5]

[1074] tert-Butyl (1'-(4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-6-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)quinazolin-2-yl)-4-methyl-[1,4'-bipiperidinyl]-4-yl)carbamate

[1075]

[1076] At room temperature, to a solution of (1'-(4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-6-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)quinazolin-2-yl)-4-methyl-[1,4'-bipiperidin]-4-yl)carbamic acid tert-butyl ester (149 mg, 0.151 mmol) producing Example 27-4 in THF (4 mL) and methanol (2 mL) was added 1M aqueous sodium hydroxide solution (1.51 mL, 1.51 mmol), and the mixture was stirred at 80°C for 1 hour. After the reaction mixture reached room temperature, brine was added and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=1:1 to ethyl acetate to ethyl acetate:methanol=8:2) to give the title compound (107 mg).

[1077] ESI-MS (m / z): 832.46 [M+H] + .

[1078] [Example 28]

[1079] 4-(4-(2-amino-1-cyclopropyloxy-1-phenylethyl)-2-(4-(((2S,5R)-2,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)quinazolin-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[1080]

[1081] To a solution of tert-butyl formate (2R,5S)-4-((1-(4-(2-amino-1-cyclopropyloxy-1-phenylethyl)-6-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)quinazolin-2-yl)piperidin-4-yl)methyl)-2,5-dimethylpiperazine-1-carboxylate (30 mg) producing Example 28-6 in dichloromethane (0.5 mL) was added TFA (0.5 mL) at room temperature, and the mixture was stirred at room temperature for 90 minutes. The reaction mixture was then concentrated under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the residue, and extraction was performed with chloroform / isopropanol (4:1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel thin layer chromatography (chloroform: methanol = 30: 1) to give the title compound (21 mg).

[1082] ESI-MS (m / z): 661.43 [M+H] + .

[1083] [Generation Example 28-1]

[1084] tert-Butyl (2R,5S)-4-((1-((Benzyloxy)carbonyl)piperidin-4-yl)methyl)-2,5-dimethylpiperazine-1-carboxylate

[1085]

[1086] At room temperature, 4-formyl-N-CBZ-piperidine (3.00 g, 12.1 mmol) was added to a solution of (2R, 5S)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (3.90 g, 18.2 mmol) in dichloromethane (90 mL) and acetic acid (69 μL, 1.21 mmol), and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (>80wt%, 7.71 g) was then added, and the mixture was stirred at room temperature for 12 hours and 20 minutes. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and chloroform was used for extraction. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 4: 1 to 1: 1) to obtain the title compound (5.12 g).

[1087] ESI-MS (m / z): 446.37 [M+H] + .

[1088] [Generation Example 28-2]

[1089] tert-Butyl (2R,5S)-2,5-dimethyl-4-(piperidin-4-ylmethyl)piperazine-1-carboxylate

[1090]

[1091] To a solution of tert-butyl (2R,5S)-4-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl-2,5-dimethylpiperazine-1-carboxylate (5.12 g, 11.5 mmol) produced in Example 28-1 in THF (100 mL) was added 10% palladium-carbon (50% water, 9.78 g) at room temperature, and the mixture was stirred under a hydrogen atmosphere at room temperature at normal pressure for 18 hours. After replacing the reaction mixture under a nitrogen atmosphere, it was filtered with celite and washed with methanol. The filtrate was concentrated under reduced pressure to give a crude product of the title compound (3.02 g).

[1092] [Generation Example 28-3]

[1093] tert-Butyl (2R,5S)-4-((1-(4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-6-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)quinazolin-2-yl)piperidin-4-yl)methyl)-2,5-dimethylpiperazine-1-carboxylate

[1094]

[1095] To a solution of 4-(2-chloro-4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)quinazolin-6-yl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (585 mg, 0.807 mmol) and (2R,5S)-2,5-dimethyl-4-(piperidin-4-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester (352 mg) produced in DMF (5 mL) was added N,N-diisopropylethylamine (352 μL, 2.02 mmol), and the mixture was stirred at 80° C. overnight. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=1:3 to ethyl acetate) to give the title compound (565 mg).

[1096] ESI-MS (m / z): 1000.73 [M+H] +

[1097] [Generation Example 28-4]

[1098] tert-Butyl (2R,5S)-4-((1-(4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)-6-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)quinazolin-2-yl)piperidin-4-yl)methyl)-2,5-dimethylpiperazine-1-carboxylate

[1099]

[1100] At room temperature, to a solution of (2R,5S)-4-((1-(4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-6-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)quinazolin-2-yl)piperidin-4-yl)methyl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (785 mg, 0.785 mmol) producing Example 28-3 in methanol (9 mL) was added p-toluenesulfonic acid monohydrate (373 mg, 1.96 mmol), and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=1:1 to ethyl acetate) to give the title compound (678 mg).

[1101] ESI-MS (m / z): 917.83 [M+H] +

[1102] [Generation Example 28-5]

[1103] tert-Butyl (2R,5S)-4-((1-(4-(2-amino-1-cyclopropyloxy-1-phenylethyl)-6-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)quinazolin-2-yl)piperidin-4-yl)methyl)-2,5-dimethylpiperazine-1-carboxylate

[1104]

[1105] At room temperature, triethylamine (68 μL, 0.491 mmol) and methanesulfonyl chloride (25 μL, 0.327 mmol) were added to a solution of (2R, 5S)-4-((1-(4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)-6-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)quinazolin-2-yl)piperidin-4-yl)methyl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (150 mg, 0.164 mmol) in dichloromethane (1.5 mL) producing Example 28-4, and the mixture was stirred for 10 minutes under ice bath cooling and at room temperature for 20 minutes. Water was added to the reaction mixture, and extraction was performed with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. To the residue solution in NMP (2 mL) was added 28% aqueous ammonia (1 mL) at room temperature, and the mixture was reacted at 130° C. for 45 minutes using a microwave reactor. The reaction mixture was purified by ODS silica gel column chromatography (acetonitrile (containing 0.1% formic acid): water (containing 0.1% formic acid) = 1:9 to 1:0) to give the formate salt of the title compound (124 mg).

[1106] ESI-MS (m / z): 915.67 [M+H] + .

[1107] [Generation Example 28-6]

[1108] tert-Butyl (2R,5S)-4-((1-(4-(2-amino-1-cyclopropyloxy-1-phenylethyl)-6-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)quinazolin-2-yl)piperidin-4-yl)methyl)-2,5-dimethylpiperazine-1-carboxylate

[1109]

[1110] To a solution of (2R, 5S)-4-((1-(4-(2-amino-1-cyclopropyloxy-1-phenylethyl)-6-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)quinazolin-2-yl)piperidin-4-yl)methyl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (104 mg, 0.114 mmol) in THF (0.5 mL) / methanol (1 mL) was added 2M aqueous sodium hydroxide solution (0.5 mL, 1.00 mmol), and the mixture was stirred at 60 ° C for 2 hours. The reaction mixture was returned to room temperature, diluted with water, and the resulting solid was filtered. The solid was washed with TBME and dried to give a crude purified product (74 mg) of the title compound.

[1111] ESI-MS (m / z): 761.58 [M+H] + .

[1112] [Example 29]

[1113] 4-(4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)-2-(4-methyl-4-(prop-2-yn-1-ylamino)-[1,4'-bipiperidinyl]-1'-yl)quinazolin-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[1114]

[1115] 1M aqueous sodium hydroxide solution (2.71 mL, 2.71 mmol) was added to a solution of 4-(4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)-2-(4-methyl-4-(prop-2-yn-1-ylamino)-[1,4'-bipiperidine]-1'-yl)quinazoline-6-yl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (569 mg, 0.677 mmol) producing Example 29-5 in ethanol (13.8 mL), and the mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with 5 mL of water and extracted twice with 10% methanol / chloroform solution (50 mL). The combined organic layers were washed with brine (10 mL) and then dried over sodium sulfate. The organic layer was filtered and then concentrated under reduced pressure. Since a solid was obtained by adding ethyl acetate (5 mL) to the residue, filtration was performed. The obtained solid was further washed with ethyl acetate (10 mL) to obtain the title compound (360 mg), and 5 mg of it was purified by NH silica gel thin layer chromatography (methanol:ethyl acetate=9:1) to obtain the title compound (4.3 mg).

[1116] ESI-MS (m / z): 686.41 [M+H] + .

[1117] [Generation Example 29-1]

[1118] 2-(2-Chloro-6-iodoquinazolin-4-yl)-2-cyclopropyloxy-2-phenylethane-1-ol

[1119]

[1120] To a solution of 2-chloro-4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-6-iodoquinazoline (1 g, 2 mmol) produced in dichloromethane (7 mL) was added TFA (3 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and purified by NH silica gel column chromatography (n-heptane:ethyl acetate=9:1 to 7:3) to give the title compound (630 mg).

[1121] ESI-MS (m / z): 467.05 [M+H] + .

[1122] [Generation Example 29-2]

[1123] 4-(2-Chloro-4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)quinazolin-6-yl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[1124]

[1125] At room temperature, ethanol (1.80 mL), sodium carbonate (2M aqueous solution, 3.54 mL, 7.07 mmol) and tetrakis (triphenylphosphine) palladium (0) (149 mg, 0.129 mmol) were added to a solution of 2-(2-chloro-6-iodoquinazolin-4-yl)-2-cyclopropyloxy-2-phenylethane-1-ol (600 mg, 1.29 mmol) and 6-methyl-4-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (578 mg, 1.35 mmol) produced in toluene (7.12 mL), and the mixture was stirred at 70 ° C for 40 hours. Water and ethyl acetate were added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=3:1 to ethyl acetate to ethyl acetate:methanol=9:1) to give the title compound (700 mg).

[1126] ESI-MS (m / z): 641.23 [M+H] + .

[1127] [Generation Example 29-3]

[1128] 4-Methyl-N-(prop-2-yn-1-yl)piperidin-4-amine

[1129]

[1130] To a solution of tert-butyl 4-methyl-4-(prop-2-yn-1-ylamino)piperidine-1-carboxylate (10.0 g, 39.6 mmol) in dichloromethane (25 mL) was added trifluoroacetic acid (25 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by ODS silica gel column chromatography (0.1% formic acid in water) to give the formate salt of the title compound (9.80 g).

[1131] ESI-MS (m / z): 153.05 [M+H] + .

[1132] [Generation Example 29-4]

[1133] 4-Methyl-4-(prop-2-yn-1-ylamino)-[1,4'-bipiperidinyl]-1'-carboxylic acid tert-butyl ester

[1134]

[1135] N, N-diisopropylethylamine (15 mL) was added to a solution of 4-methyl-N-(prop-2-yn-1-yl)piperidin-4-amine formate (4.2 g, 17 mmol) obtained in Example 29-3 in tetrahydrofuran (30 mL) and dichloromethane (30 mL), and the mixture was stirred at room temperature for 5 minutes. BOC-4-piperidone (5.14 g, 25.8 mmol) was added to the reaction mixture and stirred at room temperature for 1 hour. After the reaction mixture was cooled to 0 ° C, sodium triacetoxyborohydride (> 80wt%, 9.11 g) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, and ethyl acetate and 1N hydrochloric acid were added. The water layer was separated and washed with ethyl acetate, thereby removing unreacted ketone and its reduced body. The water layer was neutralized with a saturated sodium bicarbonate aqueous solution and extracted 3 times with a chloroform: isopropanol = 4: 1 solution. The organic layer was washed with brine and dried over magnesium sulfate. After the organic layer was filtered and concentrated under reduced pressure, the residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=75:25 to 0:100) to give the title compound (4.23 g).

[1136] ESI-MS (m / z): 336.32 [M+H] + .

[1137] [Generation Example 29-5]

[1138] 4-(4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)-2-(4-methyl-4-(prop-2-yn-1-ylamino)-[1,4'-bipiperidinyl]-1'-yl)quinazolin-6-yl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[1139]

[1140] To a solution of tert-butyl 4-methyl-4-(prop-2-yn-1-ylamino)-[1,4'-bipiperidine]-1'-carboxylate (610 mg, 90% purity, 1.64 mmol) obtained in Example 29-4 in dichloromethane (3.44 mL) was added TFA (3.37 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure (toluene was added for azeotropic distillation) to give a crude product. DMF (9.47 mL), N,N-diisopropylethylamine (2.86 mL) and 4-(2-chloro-4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)quinazolin-6-yl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (700 mg, 1.09 mmol, azeotropic distillation with toluene before use) were added to the obtained crude product. The mixture was stirred at 85°C for 1 hour, then N,N-diisopropylethylamine (0.95 mL) was added and the mixture was stirred for 3 hours. After the mixture was cooled to room temperature, it was concentrated to 1 / 4 capacity under reduced pressure, and ethyl acetate and sodium bicarbonate aqueous solution were added. After separation of the organic layer, the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=1:1 to ethyl acetate to ethyl acetate:methanol=7:3) and further purified by silica gel column chromatography (ethyl acetate to ethyl acetate:methanol=1:1) to obtain the title compound (569 mg).

[1141] ESI-MS (m / z): 840.42 [M+H] + .

[1142] [Example 30]

[1143] 4-[4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl-2-{4-ethynyl-4-hydroxy-[1,4'-bipiperidinyl]-1'-yl}quinazolin-6-yl]-6-methyl-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one

[1144]

[1145] To a solution of 4-{4-[1-cyclopropyloxy-2-(oxane-2-yloxy)-1-phenylethyl]-2-{4-ethynyl-4-hydroxy-[1,4'-bipiperidin]-1'-yl}quinazoline-6-yl}-6-methyl-1H, 6H, 7H-pyrrolo[2,3-c]pyridin-7-one (5.2 mg, 7.0 μmol) in dichloromethane (225 μL) was added TFA (268 μL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was then concentrated under reduced pressure. The resulting residue was purified by ODS silica gel column chromatography (acetonitrile (containing 0.1% formic acid): water (containing 0.1% formic acid) = 2:98 to 70:30). The compound obtained by concentration under reduced pressure was dissolved in dichloromethane and washed with saturated sodium bicarbonate aqueous solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (3.02 mg).

[1146] ESI-MS (m / z): 659.39 [M+H] + .

[1147] [Generation Example 30-1]

[1148] 4-Ethynyl-4-hydroxy-[1,4'-bipiperidinyl]-1'-carboxylic acid tert-butyl ester

[1149]

[1150] TFA (10.2 mL) was added to a solution of N-BOC-4-ethynylpiperidin-4-ol (600 mg, 2.66 mmol) in dichloromethane (10.3 mL), and the mixture was stirred at room temperature for 1 hour, and then concentrated under reduced pressure. Tetrahydrofuran (21.8 mL) and N-BOC-4-piperidone (796 mg, 4.0 mmol) and sodium triacetoxyborohydride (>80 wt%, 2.82 g) were added to the resulting residue, and the mixture was stirred at room temperature for 14 hours. Saturated aqueous sodium bicarbonate solution was added, and the mixture was stirred at room temperature for 30 minutes for neutralization, and then extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The organic layer was filtered and then concentrated under reduced pressure. The residue was purified by ODS silica gel column chromatography (acetonitrile (containing 0.1% formic acid): water (containing 0.1% formic acid) = 2:98 to 100:0) to obtain the formate (344 mg) of the title compound.

[1151] ESI-MS (m / z): 309.67 [M+H] + .

[1152] [Generation Example 30-2]

[1153] 4-{4-[1-cyclopropyloxy-2-(oxan-2-yloxy)-1-phenylethyl]-2-{4-ethynyl-4-hydroxy-[1,4'-bipiperidinyl]-1'-yl}quinazolin-6-yl}-6-methyl-1H,6H,7H-pyrrolo[2,3-c]pyridin-7-one

[1154]

[1155] TFA (4.25 mL) was added to a solution of tert-butyl formate (221 mg) of 4-ethynyl-4-hydroxy-[1,4'-bipiperidine]-1'-carboxylate of Example 30-1 in dichloromethane (14.2 mL), and the mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The residue was dissolved in toluene (3 mL), concentrated under reduced pressure, and the operation was repeated 3 times. The residue was dissolved in dimethylformamide (14.9 ml). Diisopropylethylamine (1.93 mL, 11.0 mmol) and 4-(2-chloro-4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)quinazolin-6-yl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (400 mg, 0.552 mmol) producing Example 26-1 were added, and the mixture was stirred at 50 ° C for 4 hours. The reaction mixture was concentrated under reduced pressure. To a solution of the residue in tetrahydrofuran (9.04 mL) and methanol (8.93 mL) was added 2M aqueous sodium hydroxide solution (2.21 mL, 4.41 mmol), and the mixture was stirred at 70 ° C for 50 minutes. Ethyl acetate and brine were added to the reaction mixture for oil-water distribution. The organic layer was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by ODS silica gel column chromatography (acetonitrile (containing 0.1% formic acid):water (containing 0.1% formic acid)=0:100 to 70:30) to give the formate salt of the title compound (170 mg).

[1156] ESI-MS (m / z): 743.57 [M+H] + .

[1157] [Example 31]

[1158] 4-(4-(2-amino-1-cyclopropyloxy-1-phenylethyl)-2-(4-((2S,5R)-2,5-dimethylpiperazin-1-yl)piperidin-1-yl)quinazolin-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[1159]

[1160] To a solution of (2R, 5S)-4-(1-(4-(2-amino-1-cyclopropyloxy-1-phenylethyl)-6-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)quinazolin-2-yl)piperidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (115 mg, 0.154 mmol) producing Example 31-5 in dichloromethane (1 mL) was added TFA (1 mL), and the mixture was stirred at room temperature for 1 hour. After the reaction mixture was concentrated under reduced pressure, the residue was purified by ODS silica gel column chromatography (acetonitrile (containing 0.1% formic acid): water (containing 0.1% formic acid) = 5:95 to 3:7) to obtain the formate of the title compound. The formate of the title compound was neutralized by NH silica gel column chromatography, and the filtrate was concentrated to obtain the title compound (41 mg).

[1161] ESI-MS (m / z): 647.38 [M+H] + .

[1162] [Example 31-1]

[1163] tert-Butyl (2R,5S)-4-(1-((Benzyloxy)carbonyl)piperidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate

[1164]

[1165] At room temperature, 1-(benzyloxycarbonyl)-4-piperidone (3.50 g, 15.0 mmol) was added to a solution of (2R, 5S)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (4.82 g, 22.5 mmol) in dichloromethane (100 mL) and acetic acid (86 μL, 1.50 mmol), and the mixture was stirred at room temperature for 10 minutes. Sodium triacetoxyborohydride (>80wt%, 9.54 g) was then added and the mixture was stirred at room temperature for 99 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 4: 1 to 1: 1) to obtain the title compound (4.29 g).

[1166] ESI-MS (m / z): 432.79 [M+H] + .

[1167] [Generation Example 31-2]

[1168] tert-Butyl (2R,5S)-2,5-dimethyl-4-(piperidin-4-yl)piperazine-1-carboxylate

[1169]

[1170] At room temperature, 10% palladium-carbon (50% water, 8.46 g) was added to a solution of (2R, 5S)-4-(1-((benzyloxy)carbonyl)piperidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (4.29 g, 9.94 mmol) of producing Example 31-1 in THF (25 mL) and ethyl acetate (25 mL), and the mixture was stirred at room temperature under a hydrogen atmosphere for 22 hours and 35 minutes at normal pressure. After the reaction mixture was replaced under a nitrogen atmosphere, it was filtered with diatomaceous earth and washed with methanol. The filtrate was concentrated under reduced pressure to give the title compound (2.81 g).

[1171] ESI-MS (m / z): 298.22 [M+H] + .

[1172] [Generation Example 31-3]

[1173] (2R,5S)-tert-butyl 4-(1-(4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)-6-iodoquinazolin-2-yl)piperidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate

[1174]

[1175] To a solution of 2-chloro-4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-6-iodoquinazoline (4.6 g, 8.4 mmol) of Example 2-3 and (2R, 5S)-2,5-dimethyl-4-(piperidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (2.86 g, 9.60 mmol) of Example 31-2 in DMF (30 mL) was added N,N-diisopropylethylamine (3.65 mL, 20.9 mmol), and the mixture was stirred at 80 ° C overnight. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with water and brine. After the organic layer was dried over anhydrous magnesium sulfate, it was filtered and the filtrate was concentrated under reduced pressure to give a crude product. To the obtained crude product solution in methanol (30mL) and dichloromethane (5mL), p-toluenesulfonic acid monohydrate (3.97g, 20.9mmol) was added, and the mixture was stirred at room temperature for 4 hours. N, N-diisopropylethylamine (7.29mL, 41.8mmol) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 50:50 to 25:75) to obtain the title compound (6.1g).

[1176] ESI-MS (m / z): 728.91 [M+H] +

[1177] [Generation Example 31-4]

[1178] tert-Butyl (2R,5S)-4-(1-(4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)-6-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)quinazolin-2-yl)piperidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate

[1179]

[1180] To a solution of (2R,5S)-tert-butyl 4-(1-(4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)-6-iodoquinazolin-2-yl)piperidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate (1.00 g, 1.37 mmol) obtained in Example 31-3 in 1,4-dioxane (11 mL) and water (2.75 mL) was added sodium carbonate (291 mg, 2.75 mmol). , 6-methyl-4-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (706mg, 1.65mmol) and tetrakis(triphenylphosphine)palladium(0) (159mg, 0.137mmol), and the mixture was stirred at 80°C for 20 hours and 30 minutes under a nitrogen atmosphere. The reaction mixture was returned to room temperature, diluted with ethyl acetate, and then filtered with diatomaceous earth. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 1: 1 to 1: 4) to obtain the title compound (983mg).

[1181] ESI-MS (m / z): 902.97 [M+H] + .

[1182] [Generation Example 31-5]

[1183] tert-Butyl (2R,5S)-4-(1-(4-(2-amino-1-cyclopropyloxy-1-phenylethyl)-6-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)quinazolin-2-yl)piperidin-4-yl)-2,5-dimethylpiperazine-1-carboxylate

[1184]

[1185] At room temperature, triethylamine (93 μL, 0.665 mmol) and methanesulfonyl chloride (34 μL, 0.443 mmol) were added to a solution of (2R, 5S)-4-(1-(4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)-6-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)quinazolin-2-yl)piperidin-4-yl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (200 mg, 0.222 mmol) in dichloromethane (1.5 mL) producing Example 31-4, and the mixture was stirred for 10 minutes under ice-bath cooling and at room temperature for 10 minutes. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and extraction was performed with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. At room temperature, 28% ammonia (1.5 mL) was added to the NMP (3 mL) solution of the residue, and a microwave reactor was used to react at 130 ° C for 40 minutes. The reaction mixture was extracted with dichloromethane, the organic layer was washed with water, and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 2M sodium hydroxide aqueous solution (500 μL, 1.00 mmol) was added to the residue solution in THF (0.5 mL) and methanol (1 mL), and the mixture was stirred at 50 ° C for 3 hours. The reaction mixture was returned to room temperature, water was added, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (chloroform: methanol = 100: 0 to 97: 3) to obtain the title compound (115 mg).

[1186] ESI-MS (m / z): 747.30 [M+H] + .

[1187] [Example 32]

[1188] 5-(4-(4-(Hydroxymethyl)heptan-4-yl)-2-(4-(piperazin-1-ylmethyl)piperidin-1-yl)quinazolin-6-yl)-4-methoxy-1-methylpyridin-2(1H)-one

[1189]

[1190] At room temperature, to a solution of tert-butyl 4-((1-(6-(4-methoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)heptane-4-yl)quinazolin-2-yl)piperidin-4-yl)methyl)piperazine-1-carboxylate (84 mg, 0.110 mmol) in dichloromethane (1 mL) was added TFA (0.5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by ODS silica gel column chromatography (0.1% formic acid aqueous solution: 0.1% formic acid acetonitrile solution = 95:5 to 30:70) to give the formate salt of the title compound (41.2 mg).

[1191] ESI-MS (m / z): 577.52 [M+H] + .

[1192] [Generation Example 32-1]

[1193] Ethyl 2-(2-chloro-6-iodoquinazolin-4-yl)-2-propylpentanoate

[1194]

[1195] At -78 ° C, lithium diisopropylamide (1.09M solution in THF, 14.68 mL, 16.00 mmol) was added dropwise to a solution of ethyl 2-propylpentanoate (2.76 g, 16.0 mmol) in THF (20 mL), and the mixture was stirred at -78 ° C for 10 minutes. Then, a solution of 2,4-dichloro-6-iodoquinazoline (4.00 g, 12.3 mmol) in THF (20 mL) was added at -78 ° C, the temperature was slowly raised, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The solid was washed with diethyl ether: n-heptane = 1: 1 to obtain part of the title compound. The filtrate was concentrated under reduced pressure, and the solid was washed with diethyl ether: n-heptane = 1: 1 to obtain part of the title compound. The filtrates were purified by silica gel column chromatography (n-heptane to n-heptane:ethyl acetate=99:1 to 9:1) and the combined residues gave the title compound (3.40 g).

[1196] ESI-MS (m / z): 461.18 [M+H] + .

[1197] [Generation Example 32-2]

[1198] 2-Chloro-6-iodo-4-(4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)heptane-4-yl)quinazoline

[1199]

[1200] At -78 ° C, DIBAL-H (1M toluene solution, 8.68 mL, 8.68 mmol) was added dropwise to a solution of 2-(2-chloro-6-iodoquinazoline-4-yl)-2-propylpentanoic acid ethyl ester (1.60 g, 3.47 mmol) produced in toluene (150 mL), and the mixture was stirred at 0 ° C for 2 hours. Saturated Rochelle salt aqueous solution and ethyl acetate were added to the reaction mixture and stirring was continued. After the reaction mixture was oil-water partitioned, the organic layer was washed with brine and dried over sodium sulfate. After filtering the organic layer, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane: ethyl acetate = 99: 1 to 7: 3) to obtain a crude product. At 0 ° C, DHP (380 mg, 4.51 mmol) and p-toluenesulfonic acid monohydrate (132 mg, 0.695 mmol) were added to the resulting crude product solution in dichloromethane (5 mL), and the mixture was stirred at room temperature for 4 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane: ethyl acetate = 99: 1 to 7: 3) to give the title compound (430 mg).

[1201] ESI-MS (m / z): 503.22 [M+H] +

[1202] [Generation Example 32-3]

[1203] tert-Butyl 4-((6-iodo-4-(4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)heptane-4-yl)quinazolin-2-yl)piperidin-4-yl)methyl-)piperazine-1-carboxylate

[1204]

[1205] At room temperature, 4-(piperidin-4-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester (54.1 mg, 0.191 mmol) and N,N-diisopropylethylamine (100 μL, 0.573 mmol) were added to a solution of 2-chloro-6-iodo-4-(4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)heptane-4-yl)quinazoline (80 mg, 0.16 mmol) in DMF (2 mL) producing Example 32-2, and the mixture was stirred at 80° C. for 3 hours. Water was added to the reaction mixture, and extraction was performed with dichloromethane. After the organic layer was dried over anhydrous sodium sulfate, it was filtered and the filtrate was concentrated under reduced pressure to obtain the title compound (112 mg).

[1206] ESI-MS (m / z): 750.50 [M+H] + .

[1207] [Generation Example 32-4]

[1208] tert-Butyl 4-((1-(6-(4-methoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)heptane-4-yl)quinazolin-2-yl)piperidin-4-yl)methyl)piperazine-1-carboxylate

[1209]

[1210] To a solution of tert-butyl 4-((1-6-iodo-4-(4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)heptane-4-yl)quinazolin-2-yl)piperidin-4-methyl)piperazine-1-carboxylate (112 mg, 0.149 mmol) obtained in Example 32-3 in toluene (2 mL), ethanol (0.5 mL) and 2M aqueous sodium carbonate solution (0.5 mL) at room temperature, 4-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (55.4 mg, 0.209 mmol) and tetrakis(triphenylphosphine)palladium(0) (17.26 mg, 0.015 mmol) were added, and the mixture was stirred at 90° C. for 3 hours under a nitrogen atmosphere. The reaction mixture was returned to room temperature and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=7:3 to ethyl acetate) to obtain the title compound (84 mg).

[1211] ESI-MS (m / z): 761.68 [M+H] + .

[1212] [Example 33]

[1213] 5-(2-(4-amino-4-methyl-[1,4'-bipiperidinyl]-1'-yl)-4-(1-cyclopropyloxy-2-hydroxy-1-(naphthalen-1-yl)ethyl)quinazolin-6-yl)-4-methoxy-1-methylpyridin-2(1H)-one

[1214]

[1215] To a solution of (1'-(4-(1-cyclopropyloxy-2-hydroxy-1-(naphthalen-1-yl)ethyl)-6-(4-methoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)-4-methyl-[1,4'-bipiperidine]-4-yl)carbamic acid tert-butyl ester (31.4 mg, 0.0400 mmol) producing Example 33-5 in dichloromethane (1.5 mL) was added TFA (0.5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure. The residue was purified by ODS silica gel column chromatography (acetonitrile (containing 0.1% formic acid): water (containing 0.1% formic acid) = 5:95 to 1:0 to methanol = 100%) to give the formate salt (22.9 mg) of the title compound.

[1216] ESI-MS (m / z): 689.36 [M+H] + .

[1217] [Generation Example 33-1]

[1218] 2-Cyclopropyloxy-2-(naphthalen-1-yl)acetic acid methyl ester

[1219]

[1220] At 0 ° C, (diazomethyl) trimethylsilane (8.06 mL, 16.1 mmol) was added to a solution of 1-naphthylacetic acid (1.50 g, 8.06 mmol) in methanol (20 mL), and the mixture was stirred at room temperature for 1 hour. Acetic acid (3 mL) was added to the reaction mixture and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane: ethyl acetate = 1: 0 to 1: 1) to obtain a crude product. At 0 ° C, DBU (1.80 mL, 12.1 mmol) was added to a solution of the obtained crude product and 4-acetylaminobenzenesulfonyl azide (2.32 g, 9.67 mmol) in acetonitrile (15 mL), and the mixture was stirred at room temperature for 3 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and extracted with ethyl acetate. After washing the organic layer with brine, the organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane: ethyl acetate = 1: 0 to 1: 1) to obtain a crude product. At room temperature, diacetoxyrhodium (0.0890 g, 0.201 mmol) was added to the obtained crude product and cyclopropanol (0.936 ml, 16.1 mmol) solution in dichloromethane (15 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was purified by silica gel column chromatography (n-heptane: ethyl acetate = 1: 0 to 7: 3) to obtain the title compound (1.37 g).

[1221] 1H-NMR spectrum (400MHz, CDCl3) δ (ppm): 0.42-0.53(2H,m),0.67-0.79(2H,m),3.39-3.51(1H,m),3.67(3H,s),5.57 -5.60(1H,m),7.43-7.57(3H,m),7.63(1H,dd,J=7.3,0.98Hz),7.85(2H,t,J=7.8Hz),8.27(1H,t,J=7.8Hz).

[1222] [Generation Example 33-2]

[1223] 2-(2-Chloro-6-iodoquinazolin-4-yl)-2-cyclopropyloxy-2-(naphthalen-1-yl)acetic acid methyl ester

[1224]

[1225] At -78 ° C, to the 2-cyclopropyloxy-2-(naphthalene-1-yl)acetic acid methyl ester (1.40 g, 5.46 mmol) solution of Example 33-1 in THF (15 mL), diisopropylamide lithium (1.43 M THF solution, 7.64 mL, 10.9 mmol) was added dropwise, and 2,4-dichloro-6-iodoquinazoline (1.95 g, 6.01 mmol) solution in THF (15 mL) was added at -78 ° C, the temperature was slowly raised, and the mixture was stirred at room temperature for 40 minutes. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and extracted with ethyl acetate. After washing the organic layer with water and brine, the organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane: ethyl acetate = 1: 0 to 1: 1) to obtain the title compound (1.43 g).

[1226] ESI-MS (m / z): 545.15 [M+H] + .

[1227] [Generation Example 33-3]

[1228] 2-(2-Chloro-6-iodoquinazolin-4-yl)-2-cyclopropyloxy-2-(naphthalen-1-yl)ethan-1-ol

[1229]

[1230] At -78 ° C, to the 2- (2-chloro-6-iodoquinazoline-4-yl) -2-cyclopropyloxy -2- (naphthalene-1-yl) methyl acetate (250mg, 0.459mmol) solution of Example 33-2 in toluene (5mL) was added dropwise DIBAL-H (1M toluene solution, 1.38ml, 1.38mmol), and the mixture was stirred for 10 minutes. The reaction mixture was warmed to 0 ° C and stirred for 30 minutes. A saturated Rochelle salt aqueous solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane: ethyl acetate = 1: 0 to 1: 1) to obtain the title compound (69.8mg).

[1231] ESI-MS (m / z): 516.68 [M+H] + .

[1232] [Generation Example 33-4]

[1233] 5-(2-Chloro-4-(1-cyclopropyloxy-2-hydroxy-1-(naphthalen-1-yl)ethyl)quinazolin-6-yl)-4-methoxy-1-methylpyridin-2(1H)-one

[1234]

[1235] To a solution of 2-(2-chloro-6-iodoquinazolin-4-yl)-2-cyclopropyloxy-2-(naphthalen-1-yl)ethane-1-ol (69.8 mg, 0.135 mmol) for producing Example 33-3 in 1,4-dioxane (5 mL) and water (0.5 mL) at room temperature, 4-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (53.7 mg, 0.203 mmol), cesium carbonate (66.0 mg, 0.203 mmol) and tetrakis(triphenylphosphine)palladium(0) (31.2 mg, 0.0270 mmol) were added, and the mixture was stirred at 80° C. for 3 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=1:0 to 1:1) to give the title compound (49.6 mg).

[1236] ESI-MS (m / z): 528.23 [M+H] + .

[1237] [Generation Example 33-5]

[1238] tert-Butyl (1'-(4-(1-cyclopropyloxy-2-hydroxy-1-(naphthalen-1-yl)ethyl)-6-(4-methoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)-4-methyl-[1,4'-bipiperidinyl]-4-yl)carbamate

[1239]

[1240] At room temperature, to a solution of 5-(2-chloro-4-(1-cyclopropyloxy-2-hydroxy-1-(naphthalene-1-yl)ethyl)quinazolin-6-yl)-4-methoxy-1-methylpyridin-2(1H)-one (49.6 mg, 0.0940 mmol) in DMF (3 mL) producing Example 33-4, (4-methyl-[1,4'-bipiperidinyl]-4-yl)carbamic acid tert-butyl ester (30.7 mg, 0.103 mmol) and N,N-diisopropylethylamine (49 μL, 0.28 mmol) producing Example 27-2 were added, and the mixture was stirred at 80° C. for 2 hours and 30 minutes. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. After washing the organic layer with brine, the organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=1:0 to 1:1) to give the title compound (31.2 mg).

[1241] ESI-MS (m / z): 789.43 [M+H] + .

[1242] [Example 34]

[1243] 2-Cyclopropyloxy-2-(2-(4-(((2S,5R)-2,5-dimethylpiperazin-1-yl)methyl)piperidin-1-yl)-6-(4-methoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-4-yl)-2-phenylethylmethyl(2-(methylamino)ethyl)carbamate

[1244]

[1245] To a solution of (2R, 5S)-4-((1-(4-(1-cyclopropyloxy-2-((methyl(2-(methylamino)ethyl)carbamoyl)oxy)-1-phenylethyl)-6-(4-methoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)piperidin-4-yl)methyl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (120 mg, 0.138 mmol) producing Example 34-3 in dichloromethane (2 mL) was added TFA (2 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added to the residue, and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=9:1 to chloroform:methanol=99:1 to 9:1) to give the title compound (91 mg).

[1246] ESI-MS (m / z): 767.31 [M+H] + .

[1247] [Generation Example 34-1]

[1248] 5-(2-chloro-4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)quinazolin-6-yl)-4-methoxy-1-methylpyridin-2(1H)-one

[1249]

[1250] At room temperature, 4-methoxy-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (825mg, 2.18mmol), sodium carbonate (385mg, 3.63mmol) and tetrakis(triphenylphosphine)palladium(0) (210mg, 0.182mmol) were added to a solution of 2-chloro-4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-6-iodoquinazoline (1.00g, 1.82mmol) of Example 2-3 in 1,4-dioxane (7.3mL) and water (1.82mL), and the mixture was stirred at 80°C for 24 hours under a nitrogen atmosphere. The reaction mixture was returned to room temperature and diluted with ethyl acetate. The diluted reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=1:3 to ethyl acetate to ethyl acetate:methanol=9:1) to give the title compound (292 mg).

[1251] ESI-MS (m / z): 562.31 [M+H] +

[1252] [Generation Example 34-2]

[1253] tert-Butyl (2R,5S)-4-((1-(4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)-6-(4-methoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)piperidin-4-yl)methyl)-2,5-dimethylpiperazine-1-carboxylate

[1254]

[1255] To a solution of 5-(2-chloro-4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)quinazolin-6-yl)-4-methoxy-1-methylpyridin-2(1H)-one (290 mg, 0.516 mmol) producing Example 34-1 and (2R,5S)-2,5-dimethyl-4-(piperidin-4-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester (225 mg, 0.722 mmol) producing Example 28-2 in DMF (2 mL) was added N,N-diisopropylethylamine (270 μL, 1.55 mmol), and the mixture was stirred at 80° C. for 8 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. At room temperature, p-toluenesulfonic acid monohydrate (294 mg, 1.55 mmol) was added to the residue solution in methanol (3 mL), and the mixture was stirred at room temperature for 2 hours. Triethylamine (431 μL, 3.10 mmol) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 1: 4 to ethyl acetate to ethyl acetate: methanol = 9: 1) to obtain the title compound (326 mg).

[1256] ESI-MS (m / z): 754.07 [M+H] +

[1257] [Generation Example 34-3]

[1258] tert-Butyl (2R,5S)-4-((1-(4-(1-cyclopropyloxy-2-((methyl(2-(methylamino)ethyl)carbamoyl)oxy)-1-phenylethyl)-6-(4-methoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)piperidin-4-yl)methyl)-2,5-dimethylpiperazine-1-carboxylate

[1259]

[1260] Under ice-bath cooling, triphosgene (35.5 mg, 0.12 mmol) was added to a solution of (2R, 5S)-4-((1-(4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)-6-(4-methoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2-yl)piperidin-4-yl)methyl)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (150 mg, 0.199 mmol) and 4-dimethylaminopyridine (73 mg, 0.60 mmol) in dichloromethane (3 mL), and the mixture was further stirred for 5 minutes, and then stirred for another 10 minutes at room temperature. After the reaction mixture was cooled in an ice bath again, N, N'-dimethylethylenediamine (214 μL, 1.99 mmol) was added, and the mixture was stirred directly for 10 minutes, and then further stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=99:1 to 9:1) to give the title compound (143 mg).

[1261] ESI-MS (m / z): 867.19 [M+H] +

[1262] [Example 35]

[1263] 4-(4-(2-Hydroxy-1,1-diphenylethyl)-2-(4-(piperidin-4-yloxy)piperidin-1-yl)quinazolin-6-yl)-6-methylfuro[2,3-c]pyridin-7(6H)-one

[1264]

[1265] At room temperature, 4-(2-chloro-4-(1,1-diphenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)quinazolin-6-yl)-6-methylfuro[2,3-c]pyridin-7(6H)-one (30 mg, 0.051 mmol) solution of Example 35-3 in DMF (1 mL) was added tert-butyl 4-(piperidin-4-yloxy)piperidine-1-carboxylate (18.73 mg, 0.066 mmol) and N,N-diisopropylethylamine (100 μL, 0.573 mmol), and the mixture was stirred at 80° C. for 2 hours. Water was added to the reaction mixture, and the resulting solid was washed with water to give a crude product. TFA (0.5 mL) was added to a solution of the crude product in dichloromethane (1 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by ODS silica gel column chromatography (0.1% formic acid aqueous solution:0.1% formic acid acetonitrile solution=95:5 to 30:70) to give the formate salt of the title compound (13.0 mg).

[1266] ESI-MS (m / z): 656.45 [M+H] + .

[1267] [Generation Example 35-1]

[1268] 2-(2-Chloro-6-iodoquinazolin-4-yl)-2-diphenylacetic acid methyl ester

[1269]

[1270] At -78 ° C, LHMDS (1.43M THF solution, 8.11 mL, 11.6 mmol) was added dropwise to a solution of 2,4-dichloro-6-iodoquinazoline (2.90 g, 8.93 mmol) and diphenylacetic acid methyl ester (2.12 g, 9.37 mmol) in THF (50 mL), and the mixture was stirred at 0 ° C for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting solid was washed with TBME to obtain the title compound (3.68 g).

[1271] ESI-MS (m / z): 515.04 [M+H] + .

[1272] [Generation Example 35-2]

[1273] 2-Chloro-4-(1,1-diphenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-6-iodoquinazoline

[1274]

[1275] At -78 ° C, DIBAL-H (1M toluene solution, 72.9 mL, 72.9 mmol) was added dropwise to a solution of 2-(2-chloro-6-iodoquinazolin-4-yl)-2,2-diphenylacetic acid methyl ester (15 g, 29 mmol) in toluene (300 mL) producing Example 35-1, and the mixture was stirred for 30 minutes and then stirred at 0 ° C for 4 hours. Saturated Rochelle salt aqueous solution and ethyl acetate were added to the reaction mixture and stirring was continued for 4 hours. After the reaction mixture was oil-water partitioned, the organic layer was washed with brine and dried over magnesium sulfate. After filtering the organic layer, the filtrate was concentrated under reduced pressure to obtain a crude product. At 0 ° C, DHP (10.7 mL, 117 mmol) and p-toluenesulfonic acid monohydrate (1.11 g, 5.83 mmol) were added to the resulting crude product solution in dichloromethane (300 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture, and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting solid was washed with heptane:TBME=1:1 to obtain part of the title compound. The filtrate was purified by silica gel column chromatography (n-heptane:ethyl acetate=99:1 to 7:3) and combined to obtain the title compound (7.76 g).

[1276] ESI-MS (m / z): 571.14 [M+H] +

[1277] [Generation Example 35-3]

[1278] 4-(2-Chloro-4-(1,1-diphenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)quinazolin-6-yl)-6-methylfuro[2,3-c]pyridin-7(6H)-one

[1279]

[1280] At room temperature, 2M aqueous sodium carbonate solution (1 mL), 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) furano[2,3-c]pyridine-7(6H)-one (212 mg, 0.771 mmol) and tetrakis(triphenylphosphine)palladium(0) (81 mg, 0.070 mmol) were added to a solution of 2-chloro-4-(1,1-diphenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-6-iodoquinazoline (400 mg, 0.701 mmol) of Example 35-2 in toluene (1 mL) and ethanol (4 mL), and the mixture was stirred at 80° C. for 4 hours under a nitrogen atmosphere. The reaction mixture was returned to room temperature, water was added, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=7:3 to ethyl acetate) to give the title compound (177 mg).

[1281] ESI-MS (m / z): 592.24 [M+H] + .

[1282] [Example 36]

[1283] (S)-5-(2-amino-4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one

[1284]

[1285] A solution of 5-(2-amino-4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (120 mg, 0.271 mmol) of Example 2 in methanol (about 30 mg / mL) was separated by SFC (IG, carbon dioxide:methanol=75:25) to give the former isomer (S)-5-(2-amino-4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)quinazolin-6-yl)-1,3-dimethylpyridin-2(1H)-one (48.3 mg).

[1286] 1 H-NMR spectrum (400 MHz, CDCl 3)δ(ppm):0.20-0.28(1H,m),0.32-0.39(1H,m),0.47-0.54(1H,m),0.69-0.76( 1H,m),2.16(3H,s),2.99-3.06(1H,m),3.29-3.34(1H,m),3.53(3H,s),4.42-4 .45(1H,m),4.59-4.63(1H,m),5.29(2H,s),6.91-6.92(1H,m),7.11-7.12(1H, m),7.26-7.36(5H,m),7.54-7.58(1H,m),7.59-7.61(1H,m),7.86-7.86(1H,m).

[1287] [Pharmacological test examples]

[1288] 1. BRD4 Binding Inhibition Assay

[1289] This assay measures the binding inhibitory activity of the test substance to the bromodomain of the BRD4 protein.

[1290] BRD4 binding inhibition activity was measured using BRD4 (BD1 + BD2) TR-FRET Assay Kit (BPS Bioscience Inc., catalog number 32612) according to the instructions attached. 8 μL of Tb-labeled donor / dye-labeled acceptor solution diluted to 160 times with 1×BRD TR-FRET assay buffer 1 was added to a flat-bottom 384-well white plate (Griner 781080), 5 μL of BET bromodomain ligand diluted to 40 times with 1×BRDTR-FRET assay buffer 1 was added to the test substance measurement well and the positive control well, and 5 μL of non-acetylated ligand 1 diluted to 40 times with 1×BRDTR-FRET assay buffer 1 was added to the negative control well. 2 μL of the test substance diluted with 1×BRD TR-FRET Assay Buffer 1 was added to the test substance measurement well, 2 μL of the dimethyl sulfoxide solution diluted 100 times with 1×BRD TR-FRET Assay Buffer 1 was added to the positive control well and the negative control well, and 5 μL of the BRD4 (BD1+BD2) protein solution prepared with 1×BRD TR-FRET Assay Buffer 1 to 3.6 ng / μL was added, and the mixture was reacted at room temperature for 2 hours. TM(Perkin Elmer) The fluorescence intensity at 620 nm and 665 nm was measured when each well was irradiated with an excitation light of 340 nm. The ratio of the fluorescence intensity at 655 nm to the fluorescence intensity at 620 nm of each well was recorded as the TR-FRET ratio, and the value of the negative control well was subtracted, and the value of the positive control well was set as 100% to obtain the TR-FRET ratio in the presence of the test substance. The concentration of the test substance required to inhibit 50% of the BRD4 binding activity (IC 50 ), and are shown in Table 1.

[1291] [Table 1]

[1292]

[1293]

[1294] [Example 101]

[1295] (S)-1-(5-(3-((1'-(4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)-6-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)quinazolin-2-yl)-4-methyl-[1,4'-bipiperidinyl]-4-yl)amino)prop-1-yn-1-yl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1296]

[1297] To the (S)-4-(4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)-2-(4-methyl-4-(prop-2-yn-1-ylamino)-[1,4'-bipiperidinyl]-1'-yl)quinazolin-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (250 mg, 364 μmol) of Production Example 101-9 in DMF (5.65 mL) was added a 5% ethanol; 01-10 1- (5-iodo-2-methoxyphenyl) dihydropyrimidine-2,4 (1H, 3H) -dione (252mg, 729μmol) and CuI (34.7mg, 182μmol) solution was added N, N-diisopropylethylamine (637μL, 3.65mmol) and tetrakis (triphenylphosphine) palladium (0) (211mg, 182μmol), and the mixture was stirred at 50 ° C for 1 hour under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was purified by ODS silica gel chromatography (0.1% formic acid aqueous solution: 0.1% formic acid acetonitrile solution = 9: 1 to 7: 3) to obtain a crude product. Then, the crude product was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 1: 1 to ethyl acetate to ethyl acetate: methanol = 7: 3) to obtain the title compound (193mg).

[1298] ESI-MS (m / z): 904.69 [M+H] + .

[1299] [Generation Instance 101-1]

[1300] Ethyl 2-cyclopropyloxy-2-phenylacetate

[1301]

[1302] To a solution of cyclopropanol (3.36 g, 57.8 mmol) and rhodium acetate (II) dimer (320 mg, 723 μmol) in dichloromethane (20 mL), a solution of ethyl 2-diazo-2-phenylacetate (5.50 g, 28.9 mmol) was added dropwise, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-heptane to n-heptane: ethyl acetate = 4: 1) to obtain the title compound (5.83 g).

[1303] 1 H-NMR spectrum (500 MHz, CDCl 3)δ(ppm):0.43-0.56(2H,m),0.64-0.78(2H,m),1.19-1.24(3H,m),3.38-3.45 (1H,m),4.10-4.26(2H,m),4.94(1H,s),7.29-7.38(3H,m),7.42-7.47(2H,m).

[1304] [Generation Instance 101-2]

[1305] Ethyl 2-(2-chloro-6-iodoquinazolin-4-yl)-2-cyclopropyloxy-2-phenylacetate

[1306]

[1307] Under nitrogen atmosphere, at -78 ° C, LHMDS (1.09M THF solution, 3.30mL, 3.60mmol) was added dropwise to a solution of ethyl 2-cyclopropyloxy-2-phenylacetate (661mg, 3.00mmol) and 2,4-dichloro-6-iodoquinazoline (1.17g, 3.60mmol) produced in THF (10mL) and the mixture was stirred at -78 ° C for 10 minutes. The reaction mixture was then stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (n-heptane to n-heptane: ethyl acetate = 7: 3) to obtain the title compound (1.35g).

[1308] ESI-MS (m / z): 509.25 [M+H] + .

[1309] [Generation Instance 101-3]

[1310] (R)-2-(2-chloro-6-iodoquinazolin-4-yl)-2-cyclopropyloxy-2-phenylacetic acid ethyl ester

[1311] (S)-2-(2-Chloro-6-iodoquinazolin-4-yl)-2-cyclopropyloxy-2-phenylacetic acid ethyl ester

[1312]

[1313] The ethyl 2-(2-chloro-6-iodoquinazolin-4-yl)-2-cyclopropyloxy-2-phenylacetate (100 g, 197 mmol) produced in Example 101-2 was separated by supercritical fluid chromatography (SFC) (Waters SFC 350, Whelk-O1 (250*50 mm), carbon dioxide: isopropanol = 70:30) to obtain the R-type title compound (48.0 g, 94 mmol, 100% ee) and the S-type title compound (48.0 g, 94 mmol, 99% ee). The absolute stereo configuration was determined by X-ray crystallographic analysis of the compound produced in Example 101-9.

[1314] (R)-isomer, ESI-MS (m / z): 509.14 [M+H] + .

[1315] (S)-isomer, ESI-MS (m / z): 509.14 [M+H] + .

[1316] In addition, the X-ray crystallography of the compound of Production Example 101-9 described above is used as Reference Example 1.

[1317] [Reference Example 1]

[1318] Methanol (2 mL) was added to (S)-4-(4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)-2-(4-methyl-4-(prop-2-yn-1-ylamino)-[1,4'-bipiperidine]-1'-yl)quinazoline-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (1.30 mg) producing Example 101-9. After the mixture was filtered, a 400 μL portion thereof was placed in a vial, the vial was placed in a container filled with 2 mL of 1-propanol, the container was covered, and it was allowed to stand at room temperature (vapor diffusion method with 1-propanol as a poor solvent). After 3 days, a single crystal was obtained in the vial. The single crystal was analyzed by X-ray diffraction. The crystallographic data and structural analysis data are shown in Table 2, and the atomic coordinate data are shown in Table 3. The absolute stereostructure of the compound was determined in this way.

[1319] [Table 2]

[1320]

[1321] [Table 3]

[1322]

[1323]

[1324]

[1325]

[1326]

[1327]

[1328]

[1329] [Generation Example 101-4]

[1330] (S)-2-(2-Chloro-6-iodoquinazolin-4-yl)-2-cyclopropyloxy-2-phenylethane-1-ol

[1331]

[1332] At -78 ° C, DIBAL-H (1.0M toluene solution, 47.2 mL) was added dropwise to a solution of (S) 2-(2-chloro-6-iodoquinazoline-4-yl)-2-cyclopropyloxy-2-phenylethyl acetate (10 g, 19.7 mmol) in toluene (147 mL) for 20 minutes. The reaction mixture was warmed to 0 ° C, stirred for 10 minutes, and then a saturated Rochelle salt aqueous solution (100 mL) and ethyl acetate (100 mL) were added, and the mixture was stirred at room temperature for 2 hours. After separation of the organic layer, the aqueous layer was extracted with ethyl acetate (100 mL). The organic layer was washed with brine (100 mL) and then dried over sodium sulfate. After filtering the organic layer, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane: ethyl acetate = 9: 1 to 7: 3) to obtain a crude product (8.8 g) of the title compound.

[1333] ESI-MS (m / z): 467.09 [M+H] + .

[1334] [Generation Example 101-5]

[1335] (S)-4-(2-chloro-4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)quinazolin-6-yl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[1336]

[1337] At room temperature, ethanol (18.0 mL), sodium carbonate (2M aqueous solution, 35.3 mL, 70.5 mmol) and tetrakis (triphenylphosphine) palladium (0) (1.48 g, 1.28 mmol) were added to a solution of the crude product (6.30 g) of (S)-2-(2-chloro-6-iodoquinazolin-4-yl)-2-cyclopropyloxy-2-phenylethane-1-ol of Example 101-4 and 6-methyl-4-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one in toluene (71 mL) and stirred at 70° C. for 24 hours. Water and ethyl acetate were added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=3:1 to ethyl acetate to ethyl acetate:methanol=9:1) to give a crude product of the title compound (6.76 g).

[1338] ESI-MS (m / z): 641.23 [M+H] + .

[1339] [Generation Example 101-6]

[1340] 4-Methyl-N-(prop-2-yn-1-yl)piperidin-4-amine

[1341]

[1342] To a solution of tert-butyl 4-methyl-4-(prop-2-yn-1-ylamino)piperidine-1-carboxylate (10.0 g, 39.6 mmol) in dichloromethane (25 mL) was added TFA (25 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by ODS silica gel column chromatography (0.1% formic acid aqueous solution: 0.1% formic acid acetonitrile solution = 1:0) to give the formate salt of the title compound (9.80 g).

[1343] ESI-MS (m / z): 153.05 [M+H] + .

[1344] [Generation Example 101-7]

[1345] 4-Methyl-4-(prop-2-yn-1-ylamino)-[1,4'-bipiperidinyl]-1'-carboxylic acid tert-butyl ester

[1346]

[1347] N, N-diisopropylethylamine (15 mL) was added to a formate solution (4.2 g) of 4-methyl-N-(prop-2-yn-1-yl)piperidin-4-amine obtained in Example 101-6 in THF (30 mL) and dichloromethane (30 mL), and the mixture was stirred at room temperature for 5 minutes. BOC-4-piperidone (5.14 g, 25.8 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. After the reaction mixture was cooled to 0 ° C, sodium triacetoxyborohydride (> 80wt%, 9.11 g) was added, and the mixture was stirred at room temperature overnight. Water, ethyl acetate and 1N hydrochloric acid were added to the reaction mixture. The water layer was separated and washed with ethyl acetate to remove unreacted ketone and its reduced body. The water layer was neutralized with a saturated sodium bicarbonate aqueous solution and extracted 3 times with a chloroform: isopropanol = 4: 1 solution. The organic layer was washed with brine and dried over magnesium sulfate. The organic layer was filtered and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=75:25 to 0:100) to give the title compound (4.2 g).

[1348] ESI-MS (m / z): 336.32 [M+H] + .

[1349] [Generation Example 101-8]

[1350] (S)-4-(4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)-2-(4-methyl-4-(prop-2-yn-1-ylamino)-[1,4'-bipiperidinyl]-1'-yl)quinazolin-6-yl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[1351]

[1352] To a solution of tert-butyl 4-methyl-4-(prop-2-yn-1-ylamino)-[1,4'-bipiperidine]-1'-carboxylate (1.56 g, 4.65 mmol) producing Example 101-7 in dichloromethane (9.78 mL) was added TFA (9.56 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and azeotropically distilled with toluene to obtain an intermediate. N, N-diisopropylethylamine (8.10 mL) and a crude product of (S)-4-(2-chloro-4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)quinazolin-6-yl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (2.21 g, azeotropically distilled with toluene before use) were added to the resulting intermediate solution in DMF (26.9 mL). The reaction mixture was stirred at 85° C. for 1 hour, then N, N-diisopropylethylamine (1.62 mL) was added and the mixture was stirred at 85° C. for 2 hours. N, N-diisopropylethylamine (1.08 mL) was further added and the mixture was stirred at 85° C. for 1 hour. The reaction mixture was cooled to room temperature and then concentrated to 1 / 4 capacity under reduced pressure, and ethyl acetate (50 mL) and aqueous sodium bicarbonate solution (30 mL) were added. After separation of the organic layer, the aqueous layer was extracted twice with ethyl acetate (50 mL). The combined organic layer was dried over sodium sulfate, filtered, and then the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate = 1: 1 to ethyl acetate to ethyl acetate: methanol = 7: 3) to obtain the title compound (1.91 g).

[1353] ESI-MS (m / z): 840.42 [M+H] + .

[1354] [Generation Example 101-9]

[1355] (S)-4-(4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)-2-(4-methyl-4-(prop-2-yn-1-ylamino)-[1,4'-bipiperidinyl]-1'-yl)quinazolin-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[1356]

[1357] To a solution of (S)-4-(4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)-2-(4-methyl-4-(prop-2-yn-1-ylamino)-[1,4'-bipiperidine]-1'-yl)quinazolin-6-yl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (1.85 g, 2.20 mmol) in ethanol (44.9 mL) was added an aqueous sodium hydroxide solution (1 M, 8.81 mL, 8.81 mmol), and the mixture was stirred at room temperature for 18 hours. After dilution with 10 mL of water, extraction was performed with chloroform. The organic layer was washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate (10 mL) was added to the residue, and the precipitated solid was filtered out. The obtained solid was further washed with ethyl acetate (10 mL) to give the title compound (1.25 g).

[1358] ESI-MS (m / z): 686.58 [M+H] + .

[1359] [Generation Example 101-10]

[1360] 1-(5-iodo-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1361]

[1362] Acrylic acid (10.3 mL, 151 mmol) and acetic acid (20 mL) were added to 5-iodo-2-methoxyaniline (15 g, 60 mmol), and the mixture was stirred at 110 ° C for 3 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, urea (14.5 g, 241 mmol) and acetic acid (20 mL) were added, and the mixture was stirred at 110 ° C for 21.5 hours under a nitrogen atmosphere. The reaction mixture was poured into crushed ice, and the mixture was stirred at room temperature for 1 hour. After the reaction mixture was ultrasonically treated for 30 minutes, the precipitated solid was filtered out and washed with water. A mixed solvent of diethyl ether and ethyl acetate (6: 1, 400 mL) was added to the obtained solid, and ultrasonic treatment was performed for 20 minutes. The precipitated solid was filtered and washed with diethyl ether to obtain the title compound (12 g).

[1363] ESI-MS (m / z): 347.05 [M+H] + .

[1364] [Example 102]

[1365] (S)-1-(5-((1'-4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)-6-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)quinazolin-2-yl)-4-hydroxy-[1,4'-bipiperidinyl]-4-yl)ethynyl)-2-methoxyphenyl)dihydropyrimidine-2,4-(1H,3H)-dione

[1366]

[1367] Under nitrogen atmosphere, to a solution of 1-(5-iodo-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (24 mg, 0.69 mmol) and CuI (3.3 mg, 17 μmol) from Example 101-10 in DMF (0.69 mL) were added N,N-diisopropylethylamine (0.17 mL, 34 μmol), tetrakis(triphenylphosphine)palladium(0) (20 mg, 1 7 μmol) and (S)-4-(4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)-2-(4-ethynyl-4-hydroxy-[1,4'-bipiperidinyl]-1'-yl)quinazolin-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (23 mg, 34 μmol) producing Example 102-7 were added, and the mixture was stirred at 50° C. for 1 hour. Tetrakis(triphenylphosphine)palladium(0) (20 mg, 17 μmol) and CuI (3.3 mg, 17 μmol) were added to the reaction mixture, which was then stirred at 50° C. for 1 hour. After the reaction mixture was cooled to room temperature, it was purified by ODS silica gel chromatography (0.1% formic acid aqueous solution: 0.1% formic acid acetonitrile solution = 19:1 to 0:1) to obtain the title compound (22.4 mg).

[1368] ESI-MS (m / z): 877.30 [M+H] + .

[1369] [Generation Instance 102-1]

[1370] 2-Chloro-4-((1S)-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-6-iodoquinazoline

[1371]

[1372] Using the same method as that of Production Example 104-3, the title compound (150 mg) was obtained from (S)-ethyl 2-(2-chloro-6-iodoquinazolin-4-yl)-2-cyclopropyloxy-2-phenylacetate (155 mg, 305 μmol) of Production Example 101-3.

[1373] ESI-MS (m / z): 551.17 [M+H] + .

[1374] [Generation Instance 102-2]

[1375] 4-(2-Chloro-4-((1S)-1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)quinazolin-6-yl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[1376]

[1377] Using the same method as that of Production Example 101-5, the title compound (35 mg) was obtained from 2-chloro-4-((1S)-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-6-iodoquinazoline (30 mg, 54 μmol) of Production Example 102-1.

[1378] ESI-MS (m / z): 725.38 [M+H] + .

[1379] [Generation Instance 102-3]

[1380] tert-Butyl 4-hydroxy-4-((triethylsilyl)ethynyl)piperidine-1-carboxylate

[1381]

[1382] At -78 ° C, to a solution of trimethylsilyl acetylene (2.71 g, 27.6 mmol) in THF (50 mL) was added n-butyl lithium (2.6 M, 10.6 mL, 27.6 mmol), and the mixture was stirred for 50 minutes. Boc-4-piperidone (5.00 g, 25.1 mmol) was added to the reaction mixture and stirred at room temperature for 3 hours and 10 minutes. Saturated aqueous ammonium chloride solution was added to the reaction mixture and extracted 3 times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane: ethyl acetate = 1: 4) to obtain the title compound (6.17 g).

[1383] 1 H-NMR spectrum (400 MHz, CDCl 3)δ(ppm):0.16(9H,s),1.45(9H,s),1.60-1.73(2H,m),1.82-1.93(2H,m),2.01(1H,s),3.17-3.27(2H,m),3.70-3.90(2H,m).

[1384] [Generation Instance 102-4]

[1385] tert-Butyl 4-ethynyl-4-hydroxypiperidine-1-carboxylate

[1386]

[1387] At 0°C, tetrabutylammonium fluoride (1M, 22.8 mL, 22.8 mmol) was added to a solution of tert-butyl 4-hydroxy-4-((triethylsilyl)ethynyl)piperidine-1-carboxylate (6.17 g, 20.7 mmol) in THF (100 mL) producing Example 102-3, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture and extracted 3 times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane: ethyl acetate = 1: 4) to give the title compound (4.43 g).

[1388] 1 H-NMR spectrum (400 MHz, CDCl 3 )δ(ppm):1.44(9H,s),1.65-1.75(2H,m),1.84-1.95(2H,m),2.04(1H,s),2.52(1H,s),3.22-3.29(2H,m),3.65-3.89(2H,m).

[1389] [Generation Example 102-5]

[1390] 4-Ethynyl-4-hydroxy-[1,4'-bipiperidinyl]-1'-carboxylic acid tert-butyl ester

[1391]

[1392] TFA (0.2 mL) was added to a solution of tert-butyl 4-ethynyl-4-hydroxypiperidine-1-carboxylate (300 mg, 1.33 mmol) of Example 102-4 in dichloromethane (5.1 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and azeotropically distilled with toluene. N, N-diisopropylethylamine (233 μL, 1.33 mmol) and BOC-4-piperidone (398 mg, 2.00 mmol) and sodium triacetoxyborohydride (>80 wt%, 847 mg) were added to the residue solution in THF (10.9 mL), and the mixture was stirred at room temperature for 1 day. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture and extracted 3 times with dichloromethane. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=1:0 to 0:1) to give a crude product of the title compound (530 mg).

[1393] ESI-MS (m / z): 309.26 [M+H] + .

[1394] [Generation Example 102-6]

[1395] (S)-4-(4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)-2-(4-ethynyl-4-hydroxy-[1,4'-bipiperidinyl]-1'-yl)quinazolin-6-yl)-6-methyl-1-toluenesulfonyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[1396]

[1397] To the 4-ethynyl-4-hydroxy-[1,4'-bipiperidine]-1'-tert-butyl carboxylate (80mg, 0.26mmol) solution of producing Example 102-5 in dichloromethane (1mL), TFA (0.2mL) was added, and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was concentrated under reduced pressure and azeotropically distilled with toluene to obtain a crude product. In addition, to the 4-(2-chloro-4-((1S)-1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)quinazoline-6-yl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridine-7-one (170mg, 234μmol) solution of producing Example 102-2 in dichloromethane (1mL), TFA (0.2mL) was added, and the mixture was stirred at room temperature for 20 minutes. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture and extracted 3 times with dichloromethane. After washing the organic layer with brine, it was dried over anhydrous magnesium sulfate. The organic layer was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product. N, N-diisopropylethylamine (409 μL, 2.34 mmol) was added to two groups of crude product solutions in DMF (2 mL), and the mixture was stirred at 70 ° C for 4 hours. The reaction mixture was purified by NH silica gel column chromatography (ethyl acetate to ethyl acetate: methanol = 1: 0 to 1: 1), followed by ODS silica gel chromatography (0.1% formic acid aqueous solution: 0.1% formic acid acetonitrile solution = 4: 1 to 0: 1) to obtain the title compound (90.3 mg).

[1398] ESI-MS (m / z): 813.72 [M+H] + .

[1399] [Generation Example 102-7]

[1400] (S)-4-(4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)-2-(4-ethynyl-4-hydroxy-[1,4'-bipiperidinyl]-1'-yl)quinazolin-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[1401]

[1402] To a solution of (S)-4-(4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)-2-(4-ethynyl-4-hydroxy-[1,4'-bipiperidine]-1'-yl)quinazolin-6-yl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (90.4 mg, 111 μmol) in methanol (1.1 mL) and THF (1.1 mL) was added an aqueous sodium hydroxide solution (2M, 445 μL, 0.89 mmol), and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and extraction was performed with dichloromethane. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: methanol = 1:0 to 1:1) to give the title compound (67.7 mg).

[1403] ESI-MS (m / z): 659.35 [M+H]

[1404] [Example 103]

[1405] (S)-1-(3-(4-((1-(4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)-6-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)quinazolin-2-yl)azetidin-3-yl)oxy)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1406]

[1407] To a solution of (S)-4-(4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)-2-(3-(piperidin-4-yloxy)azetidin-1-yl)quinazolin-6-yl)6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (17.5 mg, 29.0 μmol) from Example 103-5 and 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoic acid (8.78 mg, 37.0 μmol) from Example 103-6 in DMF (1000 μL) were added N,N-diisopropylethylamine (10.1 μL, 58.0 μmol) and HATU (21.9 mg, 58.0 μmol), and the mixture was stirred at room temperature for 3 hours and 30 minutes. The reaction mixture was purified by ODS silica gel chromatography (0.1% formic acid aqueous solution: 0.1% formic acid acetonitrile solution = 19: 1 to 9: 11) to give a crude product. The obtained crude product was purified by NH silica gel thin layer chromatography (ethyl acetate: methanol = 9: 1) to give the title compound (10.5 mg).

[1408] ESI-MS (m / z): 823.31 [M+H] + .

[1409] [Generation Instance 103-1]

[1410] Tert-butyl 3-(pyridin-4-yloxy)azetidine-1-carboxylate

[1411]

[1412] To N-Boc-3-hydroxyazetidine (1138mg, 6.57mmol), 4-hydroxypyridine (500mg, 5.26mmol) and triphenylphosphine (1793mg, 6.84mmol) solution in THF (15mL), diisopropyl azodicarboxylate (2.2M, 3.11mL, 6.84mmol) is added, and the mixture is stirred at 55 ° C for 9 hours. The reaction mixture is returned to room temperature, water is then added, and extracted with ethyl acetate. After the organic layer is washed with brine, it is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (n-heptane: ethyl acetate=1:1 to ethyl acetate) to obtain the title compound (525mg).

[1413] 1 H NMR (400 MHz, CDCl 3 ): δ=1.44(9H,s),3.93-4.08(2H,m),4.27-4.42(2H,m),4.89-4.97(1H,m),6.64-6.68(2H,m),8.44-8.48(2H,m).

[1414] [Generation Instance 103-2]

[1415] Benzyl 4-(azetidin-3-yloxy)piperidine-1-carboxylate

[1416]

[1417] To 3- (pyridine -4- yloxy) azetidine -1- tert-butyl formate (678mg, 2.71mmol) solution of producing Example 103-1 in acetic acid (15mL) was added platinum oxide (IV) (338mg, 1.49mmol), and the mixture was stirred for 15 hours at 70 ° C under a hydrogen atmosphere. The reaction mixture was returned to room temperature and filtered with diatomaceous earth under a nitrogen atmosphere. The filtrate was concentrated under reduced pressure, and 3 toluene azeotropic distillations were performed to obtain a crude product of 3- (piperidin -4- yloxy) azetidine -1- tert-butyl formate. Triethylamine (7.55mL, 54.1mmol) and benzyl chloroformate (464μL, 3.25mmol) were added to the resulting crude product solution in THF (30mL), and the mixture was stirred for 5 hours. Water was added to the reaction mixture and extracted with ethyl acetate. After the organic layer was washed with brine, it was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane: ethyl acetate = 0: 1 to 1: 0) to obtain a reaction intermediate. TFA (4 mL) was added to the obtained reaction intermediate solution in dichloromethane (15 mL) and the mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure and azeotropically distilled with toluene twice. Saturated sodium bicarbonate aqueous solution was added to the obtained residue and extracted 3 times with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (153 mg).

[1418] 1 H NMR (400 MHz, CDCl 3 ): δ=1.40-1.85(4H,m),3.10-3.24(2H,m),3.41-3.52(1H,m),3.56-3.72(4 H,m),3.76-3.92(2H,m),4.35-4.45(1H,m),5.11(2H,s),7.28-7.40(5H,m).

[1419] [Generation Instance 103-3]

[1420] 4-((1-(4-((1S)-1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-6-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)quinazolin-2-yl)azetidin-3-yl)oxy)piperidin-1-carboxylate benzyl ester

[1421]

[1422] To a solution of 4-(2-chloro-4-((1S)-1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)quinazolin-6-yl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (200 mg, 276 μmol) produced in Example 102-2 and benzyl 4-(azetidin-3-yloxy)piperidine-1-carboxylate (96.0 mg, 331 μmol) produced in Example 103-2 in DMF (2000 μL) was added N,N-diisopropylethylamine (96 μL, 0.55 mol), and the mixture was stirred at 80°C for 5 hours and 30 minutes. After the reaction mixture was allowed to reach room temperature, it was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (n-heptane:ethyl acetate=1:1 to ethyl acetate) to give the title compound (232 mg).

[1423] ESI-MS (m / z): 979.26 [M+H] + .

[1424] [Generation Instance 103-4]

[1425] 4-(4-((1S)-1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-2-(3-(piperidin-4-yloxy)azetidin-1-yl)quinazolin-6-yl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[1426]

[1427] 10% palladium-carbon (50% water, 90 mg) was added to a mixed solution of 4-((1-(4-((1S)-1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-6-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)quinazolin-2-yl)azetidin-3-yl)oxy)piperidine-1-carboxylic acid benzyl ester (139 mg, 142 μmol) in ethanol (3000 μL) and THF (1000 μL), and the mixture was stirred for 4 hours at room temperature under a hydrogen atmosphere at normal pressure. The reaction mixture was filtered through celite under a nitrogen atmosphere, and the filtrate was concentrated under reduced pressure to give the title compound (112 mg).

[1428] ESI-MS (m / z): 845.50 [M+H] + .

[1429] [Generation Example 103-5]

[1430] (S)-4-(4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)-2-(3-(piperidin-4-yloxy)azetidin-1-yl)quinazolin-6-yl)-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

[1431]

[1432] 1N aqueous sodium hydroxide solution (665 μL, 665 μmol) was added to a solution of 4-(4-((1S)-1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-2-(3-(piperidin-4-yloxy)azetidin-1-yl)quinazoline-6-yl)-6-methyl-1-tosyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (112 mg, 133 μmol) producing Example 103-4 in ethanol (4000 μL), and the mixture was stirred at 50°C for 1 hour. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with dichloromethane. After the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. TFA (1025 μL) was added to the residue solution in dichloromethane (5000 μL), and the mixture was stirred for 2 hours and 40 minutes. 1N aqueous sodium hydroxide solution was added to the reaction mixture and extracted 3 times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate: methanol = 1: 0 to 9: 1) to obtain the title compound (34.5 mg).

[1433] ESI-MS (m / z): 607.25 [M+H] + .

[1434] [Generation Instance 103-6]

[1435] 3-(2,4-Dioxotetrahydropyrimidin-1(2H)-yl)benzoic acid

[1436]

[1437] Using the same method as Example 101-10, the title compound (1.95 g) was obtained from 3-aminobenzoic acid (3.00 g, 21.9 mmol).

[1438] ESI-MS (m / z): 235.093 [M+H] + .

[1439] [Example 104]

[1440] N-(1'-(4-(1-cyclopropyloxy-2-hydroxy-1-phenylethyl)-6-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)quinazolin-2-yl)-4-methyl-[1,4'-bipiperidinyl]-4-yl)-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzamide

[1441]

[1442] At room temperature, to a solution of (1'-(4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-6-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)quinazolin-2-yl)-4-methyl-[1,4'-bipiperidinyl]-4-yl)carbamic acid tert-butyl ester (36 mg, 43 μmol) producing Example 104-6 in dichloromethane (1 mL) was added TFA (1 mL), and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was then concentrated under reduced pressure. At room temperature, N,N-diisopropylethylamine (151 μL, 865 μmol), 3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-4-methoxybenzoic acid (13 mg, 48 μmol) and HATU (20 mg, 52 μmol) were added to the residue solution in DMF (1 mL), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel thin layer chromatography (ethyl acetate: methanol = 10: 1, then ethyl acetate: methanol = 10: 3 for 4 times) to obtain the title compound (22 mg).

[1443] ESI-MS (m / z): 894.63 [M+H] + .

[1444] [Generation Instance 104-1]

[1445] Benzyl 4-((tert-Butoxycarbonyl)amino)-4-methyl-[1,4'-bipiperidinyl]-1'-carboxylate

[1446]

[1447] At room temperature, 1-(benzyloxycarbonyl)-4-piperidone (700mg, 3.00mmol) was added to a solution of (4-methylpiperidin-4-yl) tert-butyl carbamate (1286mg, 6.00mmol) and acetic acid (172μL, 3.00mmol) in dichloromethane (10mL), and the mixture was stirred at room temperature for 5 minutes. Then sodium triacetoxyborohydride (>80wt%, 827mg) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 19 hours and 25 minutes. Water was added to the reaction mixture at room temperature, and extracted with ethyl acetate. The organic layer was washed with salt water, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (n-heptane: ethyl acetate=6:4 to ethyl acetate) to obtain the title compound (941mg).

[1448] ESI-MS (m / z): 432.41 [M+H] + .

[1449] [Generation Instance 104-2]

[1450] tert-Butyl (4-methyl-[1,4'-bipiperidinyl]-4-yl)carbamate

[1451]

[1452] At room temperature, 10% palladium-carbon (50% water, 138 mg) was added to a solution of 4-((tert-butoxycarbonyl)amino)-4-methyl-[1,4'-bipiperidine]-1'-benzyl carboxylate (279 mg, 646 μmol) of Example 104-1 in methanol (10 mL), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours and 25 minutes at normal pressure. After the reaction mixture was replaced under a nitrogen atmosphere, it was filtered with diatomaceous earth and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the title compound (192 mg).

[1453] ESI-MS (m / z): 298.30 [M+H] + .

[1454] [Generation Instance 104-3]

[1455] 2-Chloro-4-(1-cyclopropyloxy-1-phenyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl-6-iodoquinazoline

[1456]

[1457] At -78 ° C, DIBAL-H (1.0M toluene solution, 4.67 mL, 4.67 mmol) was added to a...

Claims

1. An antibody-drug conjugate, which is represented by formula (I): (in Ab is antibody, X is a group represented by formula (X-1), formula (X-2) or formula (X-3): (The left Indicates the binding site with NH and the right side represents the binding site with D), D is a group represented by formula (D-1) or formula (D-2): (in represents the binding site with X), and n is in the range of about 1 to about 8).

2. The antibody drug conjugate of claim 1, wherein the antibody is an anti-CEACAM6 antibody, an anti-folate receptor α antibody, an anti-mesothelin antibody, an anti-HER2 antibody, an anti-FLT3 antibody, an anti-DLL3 antibody, an anti-CLDN6 antibody, an anti-EGFR antibody, an anti-fibronectin 4 antibody, an anti-CA9 antibody or an anti-TROP2 antibody.

3. A compound represented by formula (D'): (in Het is a group selected from the group consisting of: (in represents the binding site), R1 is hydroxy, amino or optionally substituted C 1-6 Alkylcarbamoyloxy, R2 is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or C 3-6 Cycloalkoxy, R3 is C 1-6 Alkyl or C 6-10 Aryl, and R A is a group represented by formula (a) or formula (b): (in represents the binding site), or a pharmacologically acceptable salt thereof.

4. A compound represented by formula (D'-1) or formula (D'-2): or a pharmacologically acceptable salt thereof.

5. A compound represented by formula (M): (in Het is a group selected from the group consisting of: (in represents the binding site), R1 is hydroxy, amino or optionally substituted C 1-6 Alkylcarbamoyloxy, R2 is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy or C 3-6 Cycloalkoxy, R3 is C 1-6 Alkyl or C 6-10 Aryl, and R4 is an amino group or a group represented by the following formula: (in R5 is ethynyl, piperidinyl, piperazinyl, piperidinyloxy or piperazinylmethyl, and the piperidinyl, piperidinyl, piperazinyl, piperidinyloxy and piperazinylmethyl are optionally substituted with one or more groups selected from the group consisting of methyl, ethynyl, hydroxyl, amino and propynylamino), or a pharmacologically acceptable salt thereof.

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