CN118829640A

CN118829640A - Heterocyclic compounds for inducing G12D mutant KRAS protein degradation

Info

Publication number: CN118829640A
Application number: CN202380025718.3A
Authority: CN
Inventors: 吉成友博; 川口贤一; 河南英次; 石冈裕贵; 渡边英之; 今泉智祯; 滨口寿雄; 高桥史江; 森川贵裕; 仓本和幸; 长岛建之; 稻村耕平
Original assignee: Astellas Pharma Inc
Current assignee: Astellas Pharma Inc
Priority date: 2022-03-11
Filing date: 2023-03-10
Publication date: 2024-10-22

Abstract

The present invention provides a compound useful as an active ingredient of a pharmaceutical composition for the treatment of pancreatic cancer. The present inventors have studied on compounds useful as active ingredients of pharmaceutical compositions for the treatment of pancreatic cancer, and have found that heterocyclic compounds represented by the formula (I) and the formula (IA) have excellent G12D mutant KRAS proteolytic activity and G12D mutant KRAS inhibitory activity, and are useful as pancreatic cancer therapeutic agents, thereby completing the present invention. The heterocyclic compound or salt thereof of the present invention is useful as a therapeutic agent for pancreatic cancer.

Description

Heterocyclic compounds for inducing G12D mutant KRAS protein degradation

Technical Field

The present invention relates to a pharmaceutical composition and a heterocyclic compound which has an excellent effect of inducing the proteolytic degradation of G12D mutant KRAS and is useful as a G12D mutant KRAS inhibitor, and for example, is expected to be useful as an active ingredient of a pharmaceutical composition for the treatment of pancreatic cancer.

Background

Pancreatic Cancer, which is mainly pancreatic ductal adenocarcinoma, is a Cancer with a survival rate of 10% or less (CA Cancer j.clin.,2016,66, p.7-30) for 5 years and a very poor prognosis, and it is reported that about 46 ten thousand cases are newly increased every year worldwide (CA Cancer j.clin.,2018,68, p.394-424). The most effective therapy in the treatment of pancreatic cancer is surgery, but most of them have been shifted due to early finding difficulty, and most of them cannot be expected to have therapeutic effects by the surgical treatment. Chemotherapy and radiotherapy are used without surgical treatment, but survival rate is not ideal. Currently, FOLFIRINOX therapy (multi-drug combination therapy with the addition of levofolinate on the basis of 3 chemotherapeutics, 5-FU, irinotecan and oxaliplatin) is used as a standard therapy for pancreatic cancer, but due to its strong toxicity, patients prescribed are limited to ECOG physical states (ECOG Performance Status) of 1 or less, and careful patient selection is required (j.clin.oncol., 2018,36, p.2545-2556). As a molecular targeted therapeutic, although the combination therapy of erlotinib, an Epidermal Growth Factor Receptor (EGFR) inhibitor, with gemcitabine has been approved, the total lifetime is prolonged by about 2 weeks as compared with gemcitabine alone, and a satisfactory therapeutic effect is not obtained, and there is still a need for a highly effective therapeutic (j.clin.oncol., 2007,25, p.1960-1966).

RAS proteins are low molecular Guanosine Triphosphate (GTP) binding proteins of about 21kDa consisting of 188-189 amino acids, and there are 4 major proteins (KRAS (KRAS 4A and KRAS 4B), NRAS, HRAS) produced by 3 genes of KRAS gene, NRAS gene, HRAS gene. RAS proteins exist as active GTP-bound and as inactive GDP-bound. The RAS protein is activated by exchanging Guanosine Diphosphate (GDP) with GTP by ligand stimulation of cell membrane receptors such as EGFR. Active RAS binds to up to 20 effector proteins such as RAF, PI3K, RALGDS, etc. to activate downstream signaling cascades. On the other hand, active RAS converts GTP into GDP by endogenous GTP hydrolysis (GTPase) activity, thereby becoming inactive. The GTPase activity may be enhanced by GTPase Activating Proteins (GAPs). Therefore, RAS plays an important role in the growth, proliferation, angiogenesis and other processes of cells by taking on the important "molecular switch" function in the intracellular signaling pathway such as EGFR (Nature Rev.Cancer,2011,11,p.761-774、Nature Rev.Drug Discov.,2014,13,p.828-851、Nature Rev.Drug Discov.,2016,15,p.771-785).

When an amino acid substitution occurs due to mutation of the RAS gene, the function of the RAS as GTPase is reduced, and the response to GAP is reduced, thereby forming a continuous activation state, and a signal is continuously transmitted downstream. This excessive signal leads to canceration and hyperproliferation of tumors. Pancreatic ductal adenocarcinoma is said to occur as a result of pancreatic intraepithelial neoplasia/PANCREATIC INTRAEPITHELIAL neoplasia (PanIN) undergoing a stage of less dysplasia to a stage of greater, early stage PanIN having seen KRAS gene mutations. Thereafter, the oncogenes INK4A, p and SMAD4 were abnormal and malignant (Nature Rev. Cancer,2010,10, p. 683-695). Furthermore, mutations are seen in the KRAS gene in 90% or more of pancreatic ductal adenocarcinomas, with most of the point mutations at codon 12 of KRAS exon 2 (CANCER CELL 2017,32, p.185-203). Thus, KRAS plays an important role in the cancerous and progressive processes of pancreatic cancer.

As KRAS gene mutations, KRAS G12C mutations, KRAS G12D mutations, etc. are known, but G12C mutations KRAS are highly frequent in non-small cell lung cancer, but are only a few percent in pancreatic cancer (CANCER CELL 2014,25, p.272-281), therapeutic agents against other KRAS mutations are desirable. The G12D mutation KRAS was reported to be seen in about 34% of pancreatic cancers, with the highest proportion among KRAS mutations (nat. Rev. Cancer,2018,18, p. 767-777).

Patent documents 1,2 and 3 disclose RAS inhibitors, and patent documents 2 and 3 disclose compounds represented by the following formulas (a) and (B), respectively (reference is made to the publication for the meaning of symbols in the formulas). Patent documents 1,2 and 3 describe that it is useful for cancers in which there is a mutation at KRAS codon 12, including G12D mutation, but do not describe the effect on G12D mutated KRAS cancers.

In addition, patent documents 9, 10 and 11 disclose KRAS G12D inhibitors.

In recent years, as a technique for inducing target protein degradation, bifunctional compounds, collectively referred to as PROTAC (PROteolysis-TARGETING CHIMERA, protein degradation targeting chimera), SNIPER (SPECIFIC AND Nongenetic IAP-DEPENDENT PROTEIN ERASER, specific and non-genetic IAP-dependent protein eraser), and the like, have been found and expected as one of novel drug development modes (drug. The bifunctional compound promotes complex formation of the target protein and the E3 ligase in the cell, inducing target protein breakdown by utilizing the ubiquitin-proteasome system. Ubiquitin-proteasome systems are one of the proteolytic mechanisms within cells. The protein called E3 ligase recognizes and ubiquitinates the protein that should be decomposed, thereby advancing the decomposition in the proteasome.

More than 600E 3 ligases exist in organisms and can be broadly divided into 4 types, HECT-domain E3s, U-box E3s, monomeric RING E3s and multi-subunit E3 s. Currently, E3 ligases used as bifunctional decomposition inducers such as PROTAC, SNIPER are limited, and representative examples thereof include Von Hippel-Lindau (VHL), celebron (CRBN), apoptosis inhibitor protein (IAP), and mouse double-micro homolog 2 (mouse double minute homolog, MDM 2). In particular, patent document 4 reports VHL, and patent document 5 reports CRBN.

The bifunctional compound is a compound in which a ligand of a target protein and a ligand of E3 ligase are linked by a linker, and a bifunctional compound that breaks down KRAS protein has been reported previously (non-patent document 1, non-patent document 2, patent document 6, patent document 7, patent document 8, patent document 12, and patent document 13). Further, patent document 14 and patent document 15 report bifunctional compounds that reduce the level of G12D mutant KRAS protein, and patent document 16 reports quinazoline compounds for inducing the decomposition of G12D mutant KRAS protein. However, there is no report that suggests that a bifunctional compound breaks down a G12D mutant KRAS protein, except for patent documents 14 to 16.

Prior art literature

Patent literature

Patent document 1: international publication No. 2016/049565

Patent document 2: international publication No. 2016/049568

Patent document 3: international publication No. 2017/172979

Patent document 4: international publication No. 2013/106643

Patent document 5: international publication No. 2015/160845

Patent document 6: U.S. patent application publication No. 2018/0015087

Patent document 7: international publication No. 2019/195609

Patent document 8: international publication No. 2020/018788

Patent document 9: international publication No. 2021/04671

Patent document 10: international publication No. 2021/106231

Patent document 11: international publication No. 2021/107160

Patent document 12: international publication No. 2021/051034

Patent document 13: international publication No. 2021/207172

Patent document 14: international publication No. 2022/148421

Patent document 15: international publication No. 2022/148422

Patent document 16: international publication No. 2022/173032

Non-patent literature

Non-patent document 1: cell chem. Biol 2020,27, p19-31

Non-patent document 2: ACS cent.sci.,2020,6, p1367-1375

Disclosure of Invention

Problems to be solved by the invention

Provided is a heterocyclic compound which has excellent action of inducing G12D mutant KRAS protein degradation, is useful as a G12D mutant KRAS inhibitor, and is expected to be useful as an active ingredient of a pharmaceutical composition for the treatment of pancreatic cancer, particularly G12D mutant KRAS positive pancreatic cancer.

Means for solving the problems

As a result of intensive studies on compounds useful as active ingredients of pharmaceutical compositions for the treatment of pancreatic cancer, the present inventors have found that a heterocyclic compound of the formula (I) and the formula (IA), in particular, a bifunctional compound of the formula (I) and the formula (IA) characterized by linking a substituent at the 8-position of the heterocyclic compound selected from the group consisting of quinazoline and quinoline to a ligand of E3 ligase or linking a substituent at the 8-position of the heterocyclic compound selected from the group consisting of quinazoline and quinoline to a ligand of E3 ligase with a linker has excellent G12D mutant KRAS proteolytic induction effect and G12D mutant KRAS inhibitory activity, and have completed the present invention.

That is, the present invention relates to a compound of formula (I) or a salt thereof, and a pharmaceutical composition containing a compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients.

(In the formula (I),

A is CR ^A or N, and the total number of the components is N,

R ^A is H or C _1-3 alkyl,

R ¹ is a naphthyl group which may be substituted by OH or a group selected from the group consisting of the following formula (II), formula (III) and formula (IV),

R ^1a、R^1b are identical or different from each other and are H, methyl, F or Cl,

R ^1c is F, cl, methyl or ethyl,

R ² is H, halogen, optionally substituted C _1-3 alkyl, cyclopropyl or vinyl,

R ³ is-P-Q or V,

P is-CH ₂ -, -O-or-N (R ^P) -,

R ^P is H or C _1-3 alkyl which can be substituted,

Q is the following formula (V) or formula (VI),

V is the following formula (VII),

R ^Q, which are identical or different from each other, are OH or C _1-3 alkyl, and R ^Q is bonded only to carbon atoms as constituent atoms of rings selected from the group consisting of an azetidine ring represented by formula (V), a pyrrolidine ring represented by formula (VI) and a piperazine ring represented by formula (VII),

M is a number from 0 to 2,

R ⁴ is an optionally substituted C _1-6 alkyl group, an optionally substituted 4-to 6-membered saturated heterocyclic group containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, an optionally substituted 5-membered heteroaryl group containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen or an optionally substituted 6-membered heteroaryl group containing 1 to 3 nitrogen atoms,

R ⁵ is C _1-6 alkyl which may be substituted, C _3-6 cycloalkyl which may be substituted or a 4-to 6-membered saturated heterocyclic group which may be substituted and contains 1 hetero atom selected from the group consisting of oxygen, sulfur and nitrogen,

R ^6a、R^6b, identical or different from one another, is H or C _1-6 -alkyl which may be substituted, or R ^6a、R^6b together with the carbon to which they are bonded may form C _3-6 -cycloalkyl which may be substituted or a 4-to 6-membered saturated heterocyclic group which may be substituted and contains 1 heteroatom selected from the group consisting of oxygen, sulfur and nitrogen,

R ⁷ is H, halogen, C _1-3 alkyl, -SO ₂CH₃、C_3-6 cycloalkyl, an optionally substituted 4-to 6-membered saturated heterocyclic group containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, an optionally substituted 5-membered heteroaryl group containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen or a 6-membered heteroaryl group containing 1 to 3 nitrogen atoms,

W is optionally substituted phenylene or optionally substituted 6-membered heteroarene diyl having 1 to 3 nitrogen atoms,

X is a bond, -CH ₂ -, -O-, -S-, or-NR ^4x -,

R ^4x is H or C _1-3 alkyl,

Y is phenylene or pyridyldiyl, which phenylene may be substituted by F,

L is- (L ¹-L²-L³-L⁴) -,

L ¹、L²、L³、L⁴, which are identical or different from one another, are selected from the group consisting of bond, -O-, -NR ^L1 -, pyrrolidinediyl which may be substituted, piperidinyl which may be substituted, piperazinediyl which may be substituted, C _1-3 alkylene which may be substituted and C=O,

R ^L1 is H or C _1-3 alkyl,

Z is NH or a 5-membered heteroarene diyl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulphur and nitrogen,

Or Y-L-Z is the following formula (VIII). )

The present invention also relates to a compound of formula (IA) or a salt thereof, and a pharmaceutical composition containing a compound of formula (IA) or a salt thereof and one or more pharmaceutically acceptable excipients.

(In the formula (I),

A is CR ^A or N, and the total number of the components is N,

R ^A is H or C _1-3 alkyl,

E is CH or N, and the R is H,

G is CR ² or N, and the total number of the components is N,

R ^1c is F, cl, methyl or ethyl,

R ² is H, halogen, optionally substituted C _1-3 alkyl, cyclopropyl or vinyl,

R ³ is-P-Q or V,

P is-CH ₂ -, -O-or-N (R ^P) -,

R ^P is H or C _1-3 alkyl which can be substituted,

Q is the following formula (V) or formula (VI),

V is the following formula (VII),

In addition, (i) when A is CR ^A, or (ii) when A is N and E or G is N,

V may be a saturated or unsaturated 7-to 8-membered bridged heterocyclic group other than the formula (VII),

M is a number from 0 to 2,

L ^Y is-O- (optionally substituted C _1-3 alkylene) -, S- (C _1-3 alkylene which may be substituted) -, -SO ₂ - (optionally substituted C _1-3 alkylene) -, -NR ^Y - (optionally substituted C _1-3 alkylene) -, and- (C _1-3 alkylene which may be substituted) -O-, C _1-3 alkylene which may be substituted) -S-, C _1-3 alkylene which may be substituted) -SO ₂ -, C _1-3 alkylene which may be substituted) -NR ^Y -,

R ^Y is H or C _1-3 alkyl,

R ^P1 is OH or F, and the total number of the components is H,

R ^P2a is H or F,

R ^P2b is H, and the hydrogen atom,

X is a bond, -CH ₂ -, -O-, -S-, or-NR ^4x -,

R ^4x is H or C _1-3 alkyl,

Y is phenylene or pyridyldiyl, which phenylene may be substituted by F,

L is- (L ¹-L²-L³-L⁴) -,

R ^L1 is H or C _1-3 alkyl,

Or Y-L-Z is the following formula (VIII). )

The compound of formula (IA) includes a compound of formula (I).

Unless otherwise specified, the same symbols in a given chemical formula in the present specification are used in other chemical formulas, and the same symbols are used in the same meaning.

In addition, the present invention relates to pharmaceutical compositions comprising a compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients; as one embodiment, a pharmaceutical composition for pancreatic cancer treatment; as one mode, a pharmaceutical composition for the treatment of G12D mutant KRAS positive pancreatic cancer; as one embodiment, a pharmaceutical composition for the treatment of metastatic pancreatic cancer; as one mode, a pharmaceutical composition for the treatment of locally advanced pancreatic cancer; as one mode, a pharmaceutical composition for the treatment of recurrent or refractory pancreatic cancer; a pharmaceutical composition for treating pancreatic cancer in an untreated and/or treatment-history patient as one mode; as one mode, a pharmaceutical composition for the treatment of metastatic G12D mutant KRAS positive pancreatic cancer; as one mode, a pharmaceutical composition for the treatment of locally progressive G12D mutant KRAS positive pancreatic cancer; as one mode, a pharmaceutical composition for the treatment of recurrent or refractory G12D mutant KRAS positive pancreatic cancer; pharmaceutical compositions for the treatment of G12D mutant KRAS positive pancreatic cancer in untreated and/or treatment-history patients as one mode. The pharmaceutical composition comprises pancreatic cancer containing a compound of formula (I) or a salt thereof, and a therapeutic agent for G12D mutant KRAS-positive pancreatic cancer as one embodiment.

In addition, the present invention relates to the use of a compound of formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for the treatment of pancreatic cancer, G12D mutant KRAS positive pancreatic cancer as one mode, metastatic pancreatic cancer as one mode, locally advanced pancreatic cancer as one mode, recurrent or refractory pancreatic cancer as one mode, pancreatic cancer of an untreated and/or treated patient as one mode, metastatic G12D mutant KRAS positive pancreatic cancer as one mode, locally advanced G12D mutant KRAS positive pancreatic cancer as one mode, recurrent or refractory G12D mutant KRAS positive pancreatic cancer as one mode, G12D mutant KRAS positive pancreatic cancer as one mode of untreated and/or treated patient; use of a compound of formula (I) or a salt thereof for the treatment of pancreatic cancer, G12D mutant KRAS positive pancreatic cancer as one mode; a compound of formula (I) or a salt thereof for use in the treatment of pancreatic cancer, G12D mutant KRAS positive pancreatic cancer as one mode; and a method of treating pancreatic cancer, G12D mutant KRAS positive pancreatic cancer as one mode, comprising the step of administering to a subject an effective amount of a compound of formula (I) or a salt thereof.

In addition, the present invention relates to a compound of formula (I) or a salt thereof as a G12D mutant KRAS proteolytic inducer and/or a G12D mutant KRAS inhibitor, a G12D mutant KRAS proteolytic inducer and/or a G12D mutant KRAS inhibitor containing a compound of formula (I) or a salt thereof.

By "subject" is meant a person or other animal in need of such treatment, as one means, a person in need of such prevention or treatment.

In addition, the present invention relates to pharmaceutical compositions comprising a compound of formula (IA) or a salt thereof and one or more pharmaceutically acceptable excipients; as one embodiment, a pharmaceutical composition for pancreatic cancer treatment; as one mode, a pharmaceutical composition for the treatment of G12D mutant KRAS positive pancreatic cancer; as one embodiment, a pharmaceutical composition for the treatment of metastatic pancreatic cancer; as one mode, a pharmaceutical composition for the treatment of locally advanced pancreatic cancer; as one mode, a pharmaceutical composition for the treatment of recurrent or refractory pancreatic cancer; a pharmaceutical composition for treating pancreatic cancer in an untreated and/or treatment-history patient as one mode; as one mode, a pharmaceutical composition for the treatment of metastatic G12D mutant KRAS positive pancreatic cancer; as one mode, a pharmaceutical composition for the treatment of locally progressive G12D mutant KRAS positive pancreatic cancer; as one mode, a pharmaceutical composition for the treatment of recurrent or refractory G12D mutant KRAS positive pancreatic cancer; pharmaceutical compositions for the treatment of G12D mutant KRAS positive pancreatic cancer in untreated and/or treatment-history patients as one mode. The pharmaceutical composition comprises a pancreatic cancer comprising a compound of formula (IA) or a salt thereof, and a therapeutic agent for G12D mutant KRAS-positive pancreatic cancer as one embodiment.

In addition, the present invention relates to the use of a compound of formula (IA) or a salt thereof for the manufacture of a pharmaceutical composition for the treatment of pancreatic cancer, G12D mutant KRAS positive pancreatic cancer as one mode, metastatic pancreatic cancer as one mode, locally advanced pancreatic cancer as one mode, recurrent or refractory pancreatic cancer as one mode, pancreatic cancer of an untreated and/or treated patient as one mode, metastatic G12D mutant KRAS positive pancreatic cancer as one mode, locally advanced G12D mutant KRAS positive pancreatic cancer as one mode, recurrent or refractory G12D mutant KRAS positive pancreatic cancer as one mode, G12D mutant KRAS positive pancreatic cancer of an untreated and/or treated patient as one mode; use of a compound of formula (IA) or a salt thereof for the treatment of pancreatic cancer, G12D mutant KRAS positive pancreatic cancer as one mode; a compound of formula (IA) or a salt thereof for use in the treatment of pancreatic cancer, G12D mutant KRAS positive pancreatic cancer as one mode; and a method of treating pancreatic cancer, G12D mutant KRAS positive pancreatic cancer as one mode, comprising the step of administering to a subject an effective amount of a compound of formula (IA) or a salt thereof.

In addition, the present invention relates to a compound of formula (IA) or a salt thereof as a G12D mutant KRAS proteolytic inducer and/or a G12D mutant KRAS inhibitor, a G12D mutant KRAS proteolytic inducer and/or a G12D mutant KRAS inhibitor containing a compound of formula (IA) or a salt thereof.

Effects of the invention

The compound of formula (I) or (IA) or a salt thereof has an effect of inducing the proteolytic decomposition of G12D mutant KRAS and G12D mutant KRAS inhibitory activity, and can be used as a therapeutic agent for pancreatic cancer, particularly G12D mutant KRAS positive pancreatic cancer.

Detailed Description

The present invention will be described in detail below.

In the present specification, "may be substituted" means unsubstituted or having 1 to 5 substituents. As one mode, it means unsubstituted or having 1 to 3 substituents. When 2 or more substituents are present, these substituents may be the same or different from each other.

"C _1-12 alkyl" means a straight or branched alkyl group having 1 to 12 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, dodecyl, etc. (hereinafter, the same applies to carbon numbers). As one embodiment, ethyl or dodecyl.

Similarly, "C _1-6 alkyl" refers to straight or branched alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl, as one mode, methyl, ethyl, n-propyl, isopropyl or sec-butyl, as one mode, methyl, ethyl, isopropyl or tert-butyl, as one mode, methyl, ethyl, n-propyl, isopropyl, n-butyl.

Similarly, "C _1-3 alkyl" refers to a straight or branched alkyl group having 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, or isopropyl, as one embodiment, methyl or ethyl, as one embodiment, n-propyl or isopropyl, as one embodiment, methyl or isopropyl, as one embodiment, ethyl or isopropyl, as one embodiment, methyl, as one embodiment, ethyl, as one embodiment, isopropyl, as one embodiment, n-propyl.

"C _3-6 cycloalkyl" means cycloalkyl having 3 to 6 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. In one embodiment, the catalyst is a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, in one embodiment, a cyclobutyl group or a cyclopentyl group, in one embodiment, a cyclopentyl group or a cyclohexyl group, in one embodiment, a cyclopropyl group, in one embodiment, a cyclobutyl group, in one embodiment, a cyclopentyl group, in one embodiment, a cyclohexyl group.

The "C _1-3 alkylene" refers to a divalent group obtained by removing a hydrogen atom from a C _1-3 alkyl group, and is a linear or branched C _1-3 alkylene group, for example, methylene, ethylene, trimethylene, methyl methylene, 1-dimethylmethylene, or the like. As one embodiment, the C _1-3 alkylene group is a straight-chain or branched-chain alkylene group, as one embodiment, a methylene group, an ethylene group, or a trimethylene group, as one embodiment, a methylene group or an ethylene group, as one embodiment, a methylene group, as one embodiment, an ethylene group.

"Saturated heterocyclic group" means a saturated hydrocarbon ring group containing a heteroatom selected from the group consisting of oxygen, sulfur and nitrogen as a ring constituting atom. In addition, a sulfur atom as a ring constituent atom of the saturated heterocyclic group may be oxidized.

Thus, the "4-to 6-membered saturated heterocyclic group" means a 4-to 6-membered saturated heterocyclic group containing a heteroatom selected from the group consisting of oxygen, sulfur and nitrogen as a ring constituting atom. One embodiment of the "4-to 6-membered saturated heterocyclic group" is a 4-to 6-membered saturated heterocyclic group containing 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring constituting atoms. As one mode of a 4-to 6-membered saturated heterocyclic group containing 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring constituent atoms, a 4-to 6-membered saturated heterocyclic group containing 1 hetero atom selected from the group consisting of oxygen, sulfur and nitrogen as ring constituent atoms, a 5-to 6-membered saturated heterocyclic group containing 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring constituent atoms, a 4-membered saturated heterocyclic group containing 1 hetero atom selected from the group consisting of oxygen, sulfur and nitrogen as ring constituent atoms, a 5-membered saturated heterocyclic group containing 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring constituent atoms, a 6-membered saturated heterocyclic group containing 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring constituent atoms, a oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, pyrrolidinyl, and the like,An oxazolyl, imidazolyl, piperazinyl, morpholinyl, thiomorpholinyl, or dioxothiomorpholinyl group as one mode, an oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or dioxothiomorpholinyl group as one mode, an oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, or morpholinyl group as one mode, an oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, or piperidinyl group as one mode, an oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl as one mode, an pyrrolidinyl or piperidinyl group as one mode, an oxetanyl as one mode, a tetrahydrofuranyl as one mode, a tetrahydropyranyl as one mode, a pyrrolidinyl as one mode, a piperidinyl as one mode, a morpholinyl as one mode, a tetrahydropyranyl as one mode, a pyrrolidinyl as one mode, an oxetanyl as one mode, a tetrahydropyranyl as one modeAn oxazolidinyl group.

"Heteroaryl" refers to an unsaturated heterocyclic group containing a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as a ring constituting atom.

Thus, "5-membered heteroaryl" refers to an unsaturated heterocyclic group containing 1 to 4 5-membered rings containing heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen as ring constituting atoms.

As one embodiment of the "5-membered heteroaryl group", there is an unsaturated heterocyclic group having a 5-membered ring containing 1 to 3 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring constituting atoms, and as one embodiment, there is a pyrazolyl group, an imidazolyl group, a triazolyl group, a tetrazolyl group,Azolyl, isoOxazolyl, thiazolyl, isothiazolyl, and the like,Diazolyl or thiadiazolyl, as one mode, pyrazolyl, imidazolyl, triazolyl,An oxazolyl group or a thiazolyl group, as one mode, is pyrazolyl imidazolyl group,An oxazolyl or thiazolyl group, as one mode, a pyrazolyl, imidazolyl, triazolyl or isoxazolyl groupAzolyl, as one embodiment, is pyrazolyl,An oxazolyl or thiazolyl group, as one mode, a pyrazolyl, triazolyl or isoxazolyl groupOxazolyl, as one embodiment, pyrazolyl or thiazolyl, as one embodiment, pyrazolyl or triazolyl, as one embodiment, pyrazolyl, as one embodiment, imidazolyl, as one embodiment, isThe oxazolyl group is, as an embodiment, a thiazolyl group, and as an embodiment, a triazolyl group. The term "5-membered heteroarenediyl" refers to a divalent group formed by removing any 1 hydrogen from "5-membered heteroaryl".

"6-Membered heteroaryl" means a 6-membered ring unsaturated heterocyclic group containing 1 to 3 nitrogen atoms as ring constituting atoms. One embodiment of the "6-membered heteroaryl group" is a pyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group or a triazinyl group, one embodiment is a pyridyl group or a pyridazinyl group, one embodiment is a pyridyl group or a pyrimidinyl group, one embodiment is a pyridyl group, one embodiment is a pyrimidinyl group. The "6-membered heteroarenediyl" refers to a divalent group formed by removing any 1 hydrogen from the "6-membered heteroaryl".

"Halogen" means F, cl, br and I. One embodiment of "halogen" is F, cl or Br, one embodiment is F or Cl, one embodiment is F or Br, one embodiment is F, one embodiment is Cl, and one embodiment is Br.

"Saturated or unsaturated 7-to 8-membered bridged heterocyclic group" means a saturated 7-to 8-membered bridged heterocyclic group containing 1 to 2 nitrogen atoms as ring constituting atoms or a 7-to 8-membered bridged heterocyclic group having an unsaturated bond containing 1 to 2 nitrogen atoms. In one embodiment, the heterocyclic group is a saturated 7-to 8-membered heterocyclic group containing 2 nitrogen atoms, and in one embodiment, the heterocyclic group is a saturated 7-to 8-membered heterocyclic group containing 2 nitrogen atoms and having 1 of the 2 nitrogen atoms bonded to 1 hydrogen atom. For example diazabicyclo [2.2.2] octyl, diazabicyclo [3.2.1] octyl diazabicyclo [3.2.1] octenyl diazabicyclo [3.1.1] heptyl, diazabicyclo [2.2.1] heptyl, and diazabicyclo [2.2.1] heptenyl. As one mode, diazabicyclo [2.2.2] octyl, diazabicyclo [3.2.1] oct-6-enyl, diazabicyclo [3.2.1] oct-2-enyl, diazabicyclo [3.1.1] heptyl, diazabicyclo [2.2.1] hept-5-enyl, as one mode, diazabicyclo [2.2.2] octyl, diazabicyclo [3.2.1] octyl, diazabicyclo [3.1.1] heptyl or diazabicyclo [2.2.1] heptyl, as one mode, 2, 5-diazabicyclo [2.2.2] octyl, 3, 8-diazabicyclo [3.2.1] octyl, 3, 6-diazabicyclo [3.1.1] heptyl or 2, 5-diazabicyclo [ 2.1.1 ] heptyl, as one mode, 2, 2.1-bicycloheptyl, as one mode, 2, 5-diazabicyclo [ 2.1.1 ] heptyl, as one mode, 2-5-diazabicyclo [ 2.2.1.1 ] heptyl.

As an acceptable substituent in the "optionally substituted C _1-6 alkyl" and "optionally substituted C _1-3 alkyl" are mentioned F, OH, OCH ₃、N(CH₃)₂, optionally substituted C _3-6 cycloalkyl, azabicyclo [3.3.0] octyl or a 4-to 6-membered saturated heterocyclic group which may be substituted and contains 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen. As one mode, F, OH, OCH ₃、N(CH₃)₂, hydroxymethyl, methoxymethyl, difluoroethyl, optionally substituted cyclopropyl, tetrahydrofuranyl, optionally substituted tetrahydropyranyl, morpholinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl or azabicyclo [3.3.0] octyl, as one mode, F, OH, OCH ₃、N(CH₃)₂, Hydroxymethyl, methoxymethyl, optionally substituted cyclopropyl, tetrahydrofuranyl, optionally substituted tetrahydropyranyl, optionally substituted pyrrolidinyl, as one form F, OH, OCH ₃、N(CH₃)₂, hydroxymethyl, methoxymethyl, cyclopropyl, (hydroxymethyl) cyclopropyl, (methoxymethyl) cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, (hydroxymethyl) tetrahydropyranyl, (methoxymethyl) tetrahydropyranyl, pyrrolidinyl or methylpyrrolidinyl, as one form F, F, OH, OCH ₃, (methoxymethyl) cyclopropyl, tetrahydrofuranyl or methylpyrrolidinyl, F, OH or cyclopropyl as one mode, F, OH or OCH ₃ as one mode, OH or OCH ₃ as one mode, As one embodiment, F or OCH ₃, as one embodiment, OH, as one embodiment, F, as one embodiment, OCH ₃.

As one mode of acceptable substituents in "5-membered heteroaryl group which may be substituted", "6-membered heteroarenediyl group which may be substituted", "C _3-6 cycloalkyl group which may be substituted", "pyrazolyl group which may be substituted", "pyridinyl group which may be substituted", "pyrimidinyl group which may be substituted", "phenyl group which may be substituted" and "cyclopropyl group which may be substituted", C _1-3 alkyl group which may be substituted by a group selected from the group consisting of OH and OCH ₃, -SO ₂CH₃, halogen, OH, OCH ₃ or C _3-6 cycloalkyl group. As one embodiment, C _1-3 alkyl which may be substituted with a group selected from the group consisting of OH and OCH ₃, as one embodiment, C _1-3 alkyl which may be substituted with OH, as one embodiment, C _1-3 alkyl which may be substituted with OCH ₃, as one embodiment, C _1-3 alkyl or halogen, as one embodiment, methyl, ethyl, methoxymethyl or F, as one embodiment, methyl, ethyl or F.

As one mode of acceptable substituents in the "4-to 6-membered saturated heterocyclic group which may be substituted", "pyrrolidinyl group which may be substituted", "piperidinyl group which may be substituted", "oxetanyl group which may be substituted", "tetrahydrofuranyl group which may be substituted", and "tetrahydropyranyl group which may be substituted", there is C _1-3 alkyl group which may be substituted with a group selected from the group consisting of F, OH and OCH ₃, F. OH, OCH ₃, oxo or oxetanyl. F, OH or OCH ₃, OH or methyl, and C _1-3 alkyl which may be substituted by a group selected from the group consisting of F, OH and OCH ₃, F, Oxo or oxetanyl, as one form of C _1-3 alkyl or oxo which may be substituted with a group selected from the group consisting of F, OH and OCH ₃, as one form of C _1-3 alkyl which may be substituted with a group selected from the group consisting of F, OH and OCH ₃, As one embodiment, a C _1-3 alkyl group which may be substituted by F, as one embodiment, a C _1-3 alkyl group which may be substituted by OH, as one embodiment, a C _1-3 alkyl group which may be substituted by OCH ₃, as one embodiment, C _1-3 alkyl.

As one mode of acceptable substituents in "pyrrolidinediyl which may be substituted", "piperidediyl which may be substituted", "piperazinediyl which may be substituted", "C _1-3 alkylene which may be substituted", no F, OH, OCH ₃ or C _1-3 alkyl which may be substituted. As one embodiment, F, OH, OCH ₃, methyl, ethyl, hydroxymethyl or methoxymethyl, as one embodiment, F, OH, OCH ₃ or methyl.

As one mode of the "C _1-3 alkyl group which may be substituted by F", a methyl group which may be substituted by F or an ethyl group which may be substituted by F is mentioned. Examples are methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl. In one embodiment, the solvent is a methyl group, an ethyl group, a monofluoromethyl group, a difluoromethyl group or a difluoroethyl group, in one embodiment, a monofluoromethyl group or a difluoroethyl group, in one embodiment, a difluoromethyl group or a difluoroethyl group, in one embodiment, a monofluoromethyl group, in one embodiment, a difluoromethyl group, in one embodiment, a difluoroethyl group, in one embodiment, a2, 2-difluoroethyl group.

As one mode of the "C _1-3 alkyl group which may be substituted with OH", a methyl group which may be substituted with 1 OH or an ethyl group which may be substituted with 1 to 2 OH is mentioned. For example, methyl, ethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1, 2-dihydroxyethyl. As one embodiment, methyl, ethyl or hydroxymethyl is used, as one embodiment, methyl or hydroxymethyl is used, as one embodiment, hydroxymethyl or hydroxyethyl is used, as one embodiment, hydroxymethyl is used, as one embodiment, hydroxyethyl is used.

As one mode of "C _1-3 alkyl group which may be substituted by OCH ₃", there is methyl group which may be substituted by 1 OCH ₃ or ethyl group which may be substituted by 1 to 2 OCH ₃. For example, methyl, ethyl, methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 1, 2-dimethoxyethyl. In one embodiment, the catalyst is methoxymethyl or methoxyethyl, in one embodiment, methoxymethyl, and in one embodiment, methoxyethyl.

As one mode of "C _1-3 alkyl group which may be substituted with N (CH ₃)₂), methyl group which may be substituted with 1N (CH ₃)₂) or ethyl group which may be substituted with 1N (CH ₃)₂), methyl group, ethyl group, dimethylaminomethyl group or dimethylaminoethyl group, methyl group or dimethylaminomethyl group, and dimethylaminoethyl group, respectively.

As one embodiment of the "phenylene group which may be substituted with F", a phenylene group which may be substituted with 1 to 2F is used. In one embodiment, the phenylene group may be substituted with 1F, the phenylene group or the fluorophenylene group, in one embodiment, the phenylene group, in one embodiment, the 2-fluoro-1, 4-phenylene group, and in one embodiment, the 3-fluoro-1, 4-phenylene group.

"G12D mutation" means a mutation in the wild-type protein from glycine to aspartic acid at an amino acid residue corresponding to codon 12.

"G12D mutant KRAS" means KRAS having the "G12D mutation" described above.

"Pancreatic cancer" refers to a malignancy that forms in the pancreas. For example, pancreatic ductal carcinoma and pancreatic ductal adenocarcinoma, as one embodiment, pancreatic ductal carcinoma and, as one embodiment, pancreatic ductal adenocarcinoma. Furthermore, as one embodiment, metastatic pancreatic cancer, locally advanced pancreatic cancer, recurrent or refractory pancreatic cancer, and untreated and/or treatment-history pancreatic cancer are all other embodiments.

"G12D mutant KRAS positive pancreatic cancer" refers to G12D mutant KRAS positive pancreatic cancer. For example, pancreatic cancer in which KRAS G12D mutation has occurred is pancreatic cancer in which G12D mutation has a high KRAS positive rate. As one mode, G12D mutant KRAS positive pancreatic ductal carcinoma, and as one mode, G12D mutant KRAS positive pancreatic ductal adenocarcinoma.

One embodiment of the compound of formula (I) or a salt thereof in the present invention is shown below.

(1-1)

A compound or salt thereof wherein a is CR ^A or N, R ^A is H or C _1-3 alkyl.

(1-2)

A is a compound or salt thereof wherein CR ^A、R^A is H or C _1-3 alkyl.

(1-3)

A is a compound of N or a salt thereof.

(1-4)

A is CH or N or a salt thereof.

(1-5)

A compound or salt thereof wherein a is CR ^A or N, R ^A is C _1-3 alkyl.

(1-6)

A is CH or a salt thereof.

(2-1)

A compound wherein R ^1c is F, cl, methyl or ethyl, or a salt thereof.

(2-2)

R ¹ is a naphthyl group which may be substituted by OH or a group selected from the group consisting of the following formula (II) and formula (III),

A compound wherein R ^1c is F, cl, methyl or ethyl, or a salt thereof.

(2-3)

R ¹ is a group of formula (IIa) or formula (IIIa),

R ^1a、R^1b are identical or different from each other and are H, methyl, F or Cl compounds or salts thereof.

(2-4)

R ¹ is of formula (IIa) or formula (IIIa),

R ^1a、R^1b are identical or different from each other, are H or F compounds or salts thereof.

(2-5)

A compound of formula (IIa) or formula (IIIa) wherein R ¹ is formula (IIa), R ^1a is F, and R ^1b is H, or a salt thereof.

(2-6)

R ¹ is a compound of the following formula (IIb) or a salt thereof.

(3-1)

A compound in which R ² is H, halogen, C _1-3 alkyl which may be substituted, cyclopropyl or vinyl, or a salt thereof.

(3-2)

R ² is halogen, C _1-3 alkyl, cyclopropyl or vinyl, and the C _1-3 alkyl may be substituted with a group selected from the group consisting of OH and OCH ₃, or a salt thereof.

(3-3)

A compound wherein R ² is halogen, C _1-3 alkyl, cyclopropyl or vinyl, or a salt thereof.

(3-4)

A compound wherein R ² is cyclopropyl or a salt thereof.

(4-1)

R ³ is-P-Q or V,

P is-CH ₂ -, -O-or-N (R ^P) -,

R ^P is H or C _1-3 alkyl which can be substituted,

Q is the following formula (V) or formula (VI),

V is the following formula (VII),

A compound wherein m is 0 to 2 or a salt thereof.

(4-2)

R³：

(I) When A is CR ^A, it is-P-Q,

P is-O-,

(Ii) A is-P-Q or V when A is N,

P is-O-or-N (R ^P) -,

R ^P is H or C _1-3 alkyl,

In either case of (i) and (ii) above, Q is a compound of the following formula (V) or formula (VI),

V is the following formula (VII),

R ^Q is the same or different from each other and is OH or methyl, R ^Q is bonded only to a carbon atom as a constituent atom of a ring selected from the group consisting of an azetidine ring represented by formula (V), a pyrrolidine ring represented by formula (VI) and a piperazine ring represented by formula (VII),

A compound wherein m is 0 to 2 or a salt thereof.

(4-3)

R³：

(I) When A is CH, it is-P-Q,

P is-O-,

(Ii) A is-P-Q or V when A is N,

P is-O-or-N (R ^P) -,

R ^P is H or C _1-3 alkyl,

V is the following formula (VII),

A compound wherein m is 0 to 2 or a salt thereof.

(4-4)

R ³ is-P-Q,

P is-O-or-N (R ^P) -,

R ^P is H or C _1-3 alkyl,

Q is the following formula (V) or formula (VI),

R ^Q are the same or different from each other and are OH or methyl, and R ^Q is bonded only to a carbon atom as a constituent atom of a ring selected from the group consisting of an azetidine ring represented by formula (V) and a pyrrolidine ring represented by formula (VI),

A compound wherein m is 0 to 2 or a salt thereof.

(4-5)

R ³ is-P-Q,

P is-O-,

Q is the following formula (V) or formula (VI),

A compound wherein m is 0 to 2 or a salt thereof.

(4-6)

R ³ is-P-Q,

P is-O-,

Q is the following formula (V) or formula (VI),

A compound wherein m is 0 to 1 or a salt thereof.

(4-7)

R ³ is V, and the R is H,

V is the following formula (VII),

R ^Q which are identical or different from each other are OH or methyl, R ^Q is bonded only to a carbon atom as a ring constituting atom of the piperazine ring represented by formula (VII),

A compound wherein m is 0 to 2 or a salt thereof.

(4-8)

R ³ is V, and the R is H,

V is the following formula (VII),

A compound wherein m is 0 to 1 or a salt thereof.

(4-9)

R ³ is-P-Q,

P is-O-or-N (R ^P) -,

R ^P is H or C _1-3 alkyl,

Q is the following formula (V) or formula (VI),

A compound wherein m is 0 or 1, or a salt thereof.

(4-10)

R ³ is-P-Q,

P is-N (R ^P) -,

R ^P is H or C _1-3 alkyl,

Q is the following formula (V) or formula (VI),

A compound wherein m is 0 or 1, or a salt thereof.

(4-11)

R ³ is-P-Q,

P is-N (R ^P) -,

R ^P is H or C _1-3 alkyl,

Q is the following formula (VI),

A compound wherein m is 0 or a salt thereof.

(4-12)

R ³ is-P-Q,

P is-N (R ^P) -,

R ^P is methyl or ethyl, and the amino group is a methyl or ethyl,

Q is (VI),

A compound wherein m is 0 or a salt thereof.

(5-1)

R ⁴ is C _1-6 alkyl which can be substituted, 4-to 6-membered saturated heterocyclic group which can be substituted and contains 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen, 5-membered heteroaryl which can be substituted and contains 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen, or 6-membered heteroaryl which can be substituted and contains 1 to 3 nitrogen atoms, or a salt thereof.

(5-2)

A compound in which R ⁴ is C _1-6 alkyl group which may be substituted, oxetanyl group which may be substituted, tetrahydrofuranyl group which may be substituted, tetrahydropyranyl group which may be substituted, pyrazolyl group which may be substituted, pyridinyl group which may be substituted, pyrimidinyl group which may be substituted, pyrrolidinyl group which may be substituted or piperidinyl group which may be substituted, or a salt thereof.

(5-3)

R ⁴ is C _1-6 alkyl which can be substituted, 4-to 6-membered saturated heterocyclic group which can be substituted containing 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen, pyrazolyl which can be substituted, pyridyl which can be substituted or pyrimidinyl which can be substituted, or a salt thereof.

(5-4)

R ⁴ is a compound which may be substituted with a group selected from the group consisting of F, OH, OCH ₃、CF₃、CHF₂, cyclopropyl which may be substituted, pyrrolidinyl which may be substituted, and tetrahydrofuranyl which may be substituted, C _1-6 alkyl which may be substituted, tetrahydropyranyl which may be substituted, pyrazolyl which may be substituted, pyridinyl which may be substituted, or pyrimidinyl which may be substituted, or a salt thereof.

(5-5)

R ⁴ is a C _1-6 alkyl or tetrahydropyranyl compound or salt thereof that may be substituted with a group selected from the group consisting of F, OH, OCH ₃、CF₃、CHF₂, cyclopropyl that may be substituted, pyrrolidinyl that may be substituted, and tetrahydrofuranyl that may be substituted.

(5-6)

R ⁴ is a compound which may be substituted with a group selected from the group consisting of F, OH, OCH ₃、CF₃、CHF₂, cyclopropyl substituted with 1 methoxymethyl, pyrrolidinyl substituted with C _1-6 alkyl and tetrahydrofuranyl substituted with C _1-6 alkyl, tetrahydropyranyl substituted with C _1-6 alkyl, pyrazolyl substituted with C _1-6 alkyl, pyridinyl substituted with C _1-6 alkyl or pyrimidinyl substituted with C _1-6 alkyl, or a salt thereof.

(5-7)

R ⁴ is a compound or a salt thereof of C _1-6 alkyl or tetrahydropyranyl which may be substituted by a group selected from the group consisting of F, OH, OCH ₃、CF₃、CHF₂, cyclopropyl substituted by 1 methoxymethyl, pyrrolidinyl which may be substituted by C _1-6 alkyl, and tetrahydrofuranyl which may be substituted by C _1-6 alkyl.

(5-8)

R ⁴ is a C _1-6 alkyl or tetrahydropyranyl compound or salt thereof that may be substituted with a group selected from the group consisting of OCH ₃ and tetrahydrofuranyl.

(6-1)

R ⁵ is C _1-6 alkyl which can be substituted, C _3-6 cycloalkyl which can be substituted or a compound containing 1 hetero atom selected from the group consisting of oxygen, sulfur and nitrogen and 4-to 6-membered saturated heterocyclic group which can be substituted or a salt thereof.

(6-2)

A compound wherein R ⁵ is methyl, ethyl, isopropyl, tert-butyl, or C _3-6 cycloalkyl, or a salt thereof.

(6-3)

A compound wherein R ⁵ is ethyl, isopropyl, t-butyl, or C _3-6 cycloalkyl, or a salt thereof.

(6-4)

A compound wherein R ⁵ is isopropyl or C _3-6 cycloalkyl, or a salt thereof.

(6-5)

A compound wherein R ⁵ is isopropyl or a salt thereof.

(7-1)

R ^6a、R^6b, which are identical or different from each other, are H or C _1-6 alkyl which may be substituted, or R ^6a、R^6b, which may form, together with the carbon to which they are bonded, a C _3-6 cycloalkyl which may be substituted or a compound containing 1 heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, which may be substituted, a 4-to 6-membered saturated heterocyclic group, or a salt thereof.

(7-2)

R ^6a、R^6b, which are the same or different from each other, are H or C _1-3 alkyl, and the C _1-3 alkyl may be substituted with a group selected from the group consisting of F, OH, OCH ₃ and N (CH ₃)₂), or R ^6a、R^6b may form a C _3-6 cycloalkyl compound or a salt thereof together with the carbon to which they are bonded.

(7-3)

R ^6a、R^6b, which are the same or different from each other, are H or C _1-3 alkyl, and the C _1-3 alkyl may be substituted with a group selected from the group consisting of F, OH and N (CH ₃)₂), or R ^6a、R^6b may form a cyclopropyl compound or a salt thereof together with the carbon to which they are bonded.

(7-4)

A compound wherein R ^6a is H, R ^6b is C _1-3 alkyl which may be substituted with OH, or a salt thereof.

(7-5)

R ^6a is H, R ^6b is hydroxymethyl or a salt thereof.

(8-1)

R ⁷ is H, halogen, C _1-3 alkyl, -SO ₂CH₃、C_3-6 cycloalkyl, a 4-to 6-membered saturated heterocyclic group which may be substituted and contains 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen, a 5-membered heteroaryl group which may be substituted and contains 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen, or a 6-membered heteroaryl group containing 1 to 3 nitrogen atoms, or a salt thereof.

(8-2)

R ⁷ is H, halogen, C _1-3 alkyl, -SO ₂CH₃、C_3-6 cycloalkyl or a group selected from the group consisting of formula (IX), formula (X), formula (XI), formula (XII), formula (XIII), formula (XIV), formula (XV), formula (XVI), formula (XVII) and formula (XVIII) below,

R ^7a、R^7b are identical or different from each other, are H or C _1-3 -alkyl which may be substituted by OH, or salts thereof.

(8-3)

R ⁷ is halogen or a group selected from the group consisting of the following formula (IX), formula (X), formula (XI), formula (XII), formula (XIII) and formula (XIV),

(8-4)

R ⁷ is a group of the following formula (IX), formula (X), formula (XI) or formula (XII),

R ^7a is a compound of C _1-3 alkyl which may be substituted by OH or a salt thereof.

(8-5)

R ⁷ is the following formula (IX) or formula (XI),

A compound wherein R ^7a is C _1-3 alkyl or a salt thereof.

(8-6)

R ⁷ is the following formula (IX),

A compound wherein R ^7a is C _1-3 alkyl or a salt thereof.

(8-7)

A compound wherein R ⁷ is H or a salt thereof.

(9-1)

W is a phenylene group which may be substituted or a 6-membered heteroarene diradical which may be substituted and contains 1 to 3 nitrogen atoms, or a salt thereof.

(9-2)

W is the following formula (XIX),

W ¹ and W ²:

(i) W ¹ is CH, W ² is C-SO ₂CH₃, or

(Ii) W ¹、W² are the same or different from each other, CH, CF, CCl, CCH ₃ or N, wherein R ⁷ is a compound of H or a salt thereof in the case of the above (i).

(9-3)

W is the following formula (XIX),

W ¹、W² are identical or different from each other, are CH or N compounds or salts thereof.

(9-4)

W is the following formula (XIX),

W ¹、W² are the same or different from each other, are CH, CF, CCl, CCH ₃ or N compounds or salts thereof.

(9-5)

W is the following formula (XIX),

A compound or salt thereof wherein W ¹、W² is CH.

(10-1)

Compounds in which X is a bond, -CH ₂ -, -O-, -S-, or-NR ^4x-,R^4x is H or C _1-3 alkyl, or salts thereof.

(10-2)

A compound wherein X is-O-or-NR ^4x-、R^4x is H or C _1-3 alkyl, or a salt thereof.

(10-3)

And X is-O-or-NH-or a salt thereof.

(10-4)

A compound wherein X is-O-or a salt thereof.

(11-1)

And Y is phenylene or pyridyldiyl, and the phenylene may be substituted with F.

(11-2)

And Y is phenylene or pyridyldiyl or a salt thereof.

(11-3)

And Y is a phenylene group which may be substituted with F or a salt thereof.

(12-1)

L is- (L ¹-L²-L³-L⁴) -,

A compound wherein R ^L1 is H or C _1-3 alkyl or a salt thereof.

(12-2)

L is a bond, C _1-3 alkylene, C=O or a group selected from the group consisting of formula (XX), formula (XXI), formula (XXII), formula (XXIII), formula (XXIV) and formula (XXV) below,

R ^L1 is H or C _1-3 alkyl,

R ^L2、R^L3, identical or different from one another, are H, F, OH, OCH ₃ or C _1-3 alkyl which may be substituted,

R ^L is CH or N, and the total number of the components is,

And n is an integer of 1 to 2, or a salt thereof.

(12-3)

L is a bond, C=O or a group selected from the group consisting of the following formula (XX) and formula (XXII),

R ^L1 is H or C _1-3 alkyl,

And n is an integer of 1 to 2, or a salt thereof.

(12-4)

L is a bond, C=O or a group selected from the group consisting of the following formulas (XX) -1 and (XXII) -1,

(Wherein Y ^* represents a bond with Y.)

R ^L1 is a C _1-3 alkyl group,

R ^L2、R^L3 is H, and the hydrogen atom,

A compound wherein n is 1 or a salt thereof.

(12-5)

L is a bond, c=o, or a group selected from the group consisting of formula (XX) and formula (XXII), R ^L1 is C _1-3 alkyl, R ^L2、R^L3 is H, and n is 1, or a salt thereof.

(12-6)

And L is a bond, c=o, or a group selected from the group consisting of formula (XX) -1 and formula (XXII) -1, R ^L1 is C _1-3 alkyl, R ^L2、R^L3 is H, and n is 1, or a salt thereof.

(12-7)

And L is c=o or a group selected from the group consisting of formula (XX) and formula (XXII), R ^L1 is C _1-3 alkyl, R ^L2、R^L3 is H, and n is 1, or a salt thereof.

(12-8)

L is c=o or a group selected from the group consisting of formula (XX) -1 and formula (XXII) -1, R ^L1 is C _1-3 alkyl, R ^L2、R^L3 is H, n is 1, or a salt thereof.

(12-9)

And L is a bond or a compound of c=o or a salt thereof.

(12-10)

And L is a bond or a salt thereof.

(12-11)

And L is a compound or salt of c=o.

(13-1)

Z is NH or a 5-membered heteroarene diyl compound or salt thereof containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen.

(13-2)

Z is NH or a compound selected from the group consisting of the following formulas (XXVI), formula (XXVII), formula (XXVIII) and formula (XXIX), or a salt thereof.

(13-3)

Z is NH or a compound selected from the group consisting of the following formula (XXVI) -1, formula (XXVII) -1, formula (XXVIII) -1 and formula (XXIX) -1, or a salt thereof.

(Wherein L ^* represents a bond with L.)

(13-4)

Z is NH or a compound selected from the group consisting of the following formula (XXVI), formula (XXVII) and formula (XXVIII), or a salt thereof.

(13-5)

Z is NH or a compound selected from the group consisting of the following formula (XXVI) -1, formula (XXVII) -1 and formula (XXVIII) -1, or a salt thereof.

(Wherein L ^* represents a bond with L.)

(13-6)

Z is NH or a compound selected from the group consisting of the following formula (XXVI) and formula (XXVII) or a salt thereof.

(13-7)

Z is NH or a compound selected from the group consisting of the following formulas (XXVI) -1 and (XXVII) -1, or a salt thereof.

(Wherein L ^* represents a bond with L.)

(13-8)

Z is a compound selected from the group consisting of the formula (XXVI) and the formula (XXVII) or a salt thereof.

(13-9)

A compound wherein Z is a group selected from the group consisting of formula (XXVI) -1 and formula (XXVII) -1, or a salt thereof.

(13-10)

A compound wherein Z is NH or a salt thereof.

(13-11)

Z is a compound of the following formula (XXVII) or a salt thereof.

(13-12)

Z is a compound of the following formula (XXVII) -1 or a salt thereof.

(Wherein L ^* represents a bond with L.)

(14-1)

Y-L-Z is a compound of the following formula (VIII) or a salt thereof.

(14-2)

Y-L-Z is a compound of the following formula (VIII) -1 or a salt thereof.

(Wherein O-CH ₂ ^* represents a bond to a carbon atom of O-CH ₂ bonded to Y-L-Z.)

(15)

A compound or a salt thereof which is a combination of any two or more of the above-mentioned modes (1-1) to (14-2) and is not contradictory.

The combination of (15) above is specifically exemplified by the following means.

(15-1)

A compound of formula (I) or a salt thereof.

(In the formula (I),

A is CR ^A or N, and the total number of the components is N,

R ^A is H or C _1-3 alkyl,

R ^1c is F, cl, methyl or ethyl,

R ² is H, halogen, optionally substituted C _1-3 alkyl, cyclopropyl or vinyl,

R ³ is-P-Q or V,

P is-CH ₂ -, -O-or-N (R ^P) -,

R ^P is H or C _1-3 alkyl which can be substituted,

Q is the following formula (V) or formula (VI),

V is the following formula (VII),

M is a number from 0 to 2,

X is a bond, -CH ₂ -, -O-, -S-, or-NR ^4x -,

R ^4x is H or C _1-3 alkyl,

Y is phenylene or pyridyldiyl, which phenylene may be substituted by F,

L is- (L ¹-L²-L³-L⁴) -,

R ^L1 is H or C _1-3 alkyl,

Or Y-L-Z is the following formula (VIII). )

(15-2)

The compound according to the above (15-1), wherein,

Y is phenylene or pyridyldiyl, which phenylene may be substituted by F,

R ^L1 is H or C _1-3 alkyl,

R ^L is CH or N, and the total number of the components is,

N is an integer of 1 to 2,

Z is NH or a group selected from the group consisting of the following formulae (XXVI), formula (XXVII), formula (XXVIII) and formula (XXIX),

Or Y-L-Z is the following formula (VIII).

(15-3)

The compound according to the above (15-2), wherein,

R ¹ is a group of formula (IIa) or formula (IIIa),

R³：

(I) When A is CR ^A, it is-P-Q,

P is-O-,

(Ii) A is-P-Q or V when A is N,

P is-O-or-N (R ^P) -,

R ^P is H or C _1-3 alkyl,

V is the following formula (VII),

M is a number from 0 to 2,

R ⁴ is C _1-6 alkyl which may be substituted, 4-to 6-membered saturated heterocyclic group which may be substituted containing 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen, pyrazolyl which may be substituted, pyridinyl which may be substituted or pyrimidinyl which may be substituted,

R ⁵ is methyl, ethyl, isopropyl, tert-butyl or C _3-6 cycloalkyl,

R ^6a、R^6b, which are identical or different from each other, are H or C _1-3 alkyl, which C _1-3 alkyl may be substituted by a group selected from the group consisting of F, OH, OCH ₃ and N (CH ₃)₂), or R ^6a、R^6b may form, together with the carbon to which they are bonded, a C _3-6 cycloalkyl group,

R ⁷ is H, halogen, C _1-3 alkyl, -SO ₂CH₃、C_3-6 cycloalkyl or a group selected from the group consisting of formula (IX), formula (X), formula (XI), formula (XII), formula (XIII), formula (XIV), formula (XV), formula (XVI) formula (XVII) and formula (XVIII) below,

R ^7a、R^7b, identical or different from one another, are H or C _1-3 alkyl which may be substituted by OH,

W is the following formula (XIX),

W ¹ and W ²:

(i) W ¹ is CH, W ² is C-SO ₂CH₃, or

(Ii) W ¹、W² are identical or different from each other and are CH, CF, CCl, CCH ₃ or N,

Wherein, when W ¹ is CH and W ² is C-SO ₂CH₃, R ⁷ is H,

X is-O-or-NR ^4x -,

R ^4x is H or C _1-3 alkyl,

Y is phenylene or pyridyldiyl, which phenylene may be substituted by F,

R ^L1 is H or C _1-3 alkyl,

N is an integer of 1 to 2,

Or Y-L-Z is the following formula (VIII).

(15-4)

The compound according to the above (15-3), wherein,

A is CH or N, and the A is H or N,

R ² is halogen, C _1-3 alkyl, cyclopropyl or vinyl, the C _1-3 alkyl may be substituted with a group selected from the group consisting of OH and OCH ₃,

R³：

(I) When A is CH, it is-P-Q,

P is-O-,

(Ii) A is-P-Q or V when A is N,

P is-O-or-N (R ^P) -,

R ^P is H or C _1-3 alkyl,

V is the following formula (VII),

M is a number from 0 to 2,

R ⁴ is C _1-6 alkyl or tetrahydropyranyl which may be substituted with a group selected from the group consisting of F, OH, OCH ₃、CF₃、CHF₂, cyclopropyl which may be substituted, pyrrolidinyl which may be substituted and tetrahydrofuranyl which may be substituted,

W is the following formula (XIX),

W ¹、W² are identical or different from each other and are CH or N,

X is-O-or-NH-,

Y is phenylene or pyridyldiyl, which phenylene may be substituted by F,

L is a bond and is preferably a bond,

Z is the following formula (XXVII).

(15-5)

The compound according to the above (15-3), wherein,

A is N, and the number of the A is N,

R ³ is-P-Q,

P is-O-or-N (R ^P) -,

R ^P is H or C _1-3 alkyl,

Q is the following formula (V) or formula (VI),

M is a number from 0 to 2,

W is the following formula (XIX),

W ¹、W² are identical or different from each other and are CH, CF, CCl, CCH ₃ or N,

Y is phenylene or pyridyldiyl, which phenylene may be substituted by F,

R ^L1 is H or C _1-3 alkyl,

N is an integer of 1 to 2,

Z is NH or a group selected from the group consisting of the following formulas (XXVI), formula (XXVII), formula (XXVIII) and formula (XXIX).

(15-6)

The compound according to the above (15-3), wherein,

A is CH, and the A is CH,

R ³ is-P-Q,

P is-O-,

Q is the following formula (V) or formula (VI),

M is a number from 0 to 2,

W is the following formula (XIX),

Y is phenylene or pyridyldiyl, which phenylene may be substituted by F,

R ^L1 is H or C _1-3 alkyl,

N is an integer of 1 to 2,

(15-7)

The compound according to the above (15-3), wherein,

A is N, and the number of the A is N,

R ³ is V, and the R is H,

V is the following formula (VII),

M is a number from 0 to 2,

W is the following formula (XIX),

Y is phenylene or pyridyldiyl, which phenylene may be substituted by F,

R ^L1 is H or C _1-3 alkyl,

N is an integer of 1 to 2,

(15-8)

The compound according to the above (15-4), wherein,

A is N, and the number of the A is N,

R ¹ is the following formula (IIb),

R ³ is-P-Q,

P is-O-or-N (R ^P) -,

R ^P is H or C _1-3 alkyl,

Q is the following formula (V) or formula (VI),

M is 0 or 1 and the number of the groups,

X is-O-.

(15-9)

The compound according to the above (15-4), wherein,

A is CH, and the A is CH,

R ¹ is the following formula (IIb),

R ³ is-P-Q,

P is-O-,

Q is the following formula (V) or formula (VI),

M is 0 or 1 and the number of the groups,

X is-O-.

(15-10)

The compound according to the above (15-4), wherein,

A is N, and the number of the A is N,

R ¹ is the following formula (IIb),

R ³ is V, and the R is H,

V is the following formula (VII),

M is 0 or 1 and the number of the groups,

X is-O-.

(15-11)

The compound according to the above (15-8), wherein,

R ² is cyclopropyl, and the amino group is a cyclopropyl group,

R ³ is-P-Q,

P is-N (R ^P) -,

R ^P is H or C _1-3 alkyl,

Q is the following formula (V) or formula (VI),

M is 0 or 1 and the number of the groups,

R ⁴ is C _1-6 alkyl or tetrahydropyranyl which may be substituted by a group selected from the group consisting of OCH ₃ and tetrahydrofuranyl,

R ⁵ is isopropyl group, and the amino group is a hydroxyl group,

R ^6a is H, R ^6b is C _1-3 alkyl which can be substituted by OH,

R ^7a is C _1-3 alkyl which may be substituted by OH,

W is the following formula (XIX),

W ¹、W² is CH, and the two are all CH,

Y is phenylene which may be substituted by F.

(15-12)

The compound according to the above (15-8), wherein,

R ² is cyclopropyl, and the amino group is a cyclopropyl group,

R ³ is-P-Q,

P is-N (R ^P) -,

R ^P is methyl or ethyl, and the amino group is a methyl or ethyl,

Q is (VI),

M is 0 and is the number of the three-dimensional space,

R ⁵ is isopropyl group, and the amino group is a hydroxyl group,

R ^6a is H, R ^6b is hydroxymethyl,

R ⁷ is the following formula (IX) or formula (XI),

R ^7a is a C _1-3 alkyl group,

W is the following formula (XIX),

W ¹、W² is CH, and the two are all CH,

Y is phenylene which may be substituted by F.

(15-13)

The compound according to the above (15-12), wherein,

R ⁷ is the following formula (IX),

R ^7a is C _1-3 alkyl.

One embodiment of the compound of formula (IA) or a salt thereof in the present invention is shown below.

(16-1)

A compound wherein R ^1c is F, cl, methyl or ethyl, or a salt thereof.

(16-2)

R ¹ is a group of formula (IIa) or formula (IIIa),

(16-3)

R ¹ is a compound of the following formula (IIb) or a salt thereof.

(17-1)

E is CH or N, and the R is H,

G is CR ² or N, R ² is H, halogen, C _1-3 alkyl which may be substituted, cyclopropyl or vinyl,

A is CR ^A or N, R ^A is H or C _1-3 alkyl,

R ³ is-P-Q or V,

P is-CH ₂ -, -O-or-N (R ^P) -,

R ^P is H or C _1-3 alkyl which can be substituted,

Q is the following formula (V) or formula (VI),

V is the following formula (VII),

In addition, (i) when A is CR ^A, or (ii) when A is N and E or G is N,

A compound wherein m is 0 to 2 or a salt thereof.

(17-2)

E is CH, and the E is CH,

G is CR ²,R² is H, halogen, C _1-3 alkyl which may be substituted, cyclopropyl or vinyl,

A is CR ^A,R^A is H or C _1-3 alkyl,

R ³ is-P-Q or V,

P is-CH ₂ -, -O-or-N (R ^P) -,

R ^P is H or C _1-3 alkyl which can be substituted,

Q is the following formula (V) or formula (VI),

V is saturated or unsaturated 7-to 8-membered bridged heterocyclic group,

A compound wherein m is 0 to 2 or a salt thereof.

(17-3)

E is CH, and the E is CH,

G is CR ²,R² and is cyclopropyl,

A is CR ^A,R^A is H or C _1-3 alkyl,

R ³ is-P-Q or V,

P is-CH ₂ -, -O-or-N (R ^P) -,

R ^P is H or C _1-3 alkyl which can be substituted,

Q is the following formula (V) or formula (VI),

V is saturated or unsaturated 7-to 8-membered bridged heterocyclic group,

A compound wherein m is 0 to 2 or a salt thereof.

(17-4)

E is CH, and the E is CH,

A is CR ^A,R^A and H is H,

R ³ is V, and the R is H,

V is a saturated or unsaturated 7-to 8-membered bridged heterocyclic compound or a salt thereof.

(17-5)

E is CH, and the E is CH,

G is CR ²,R² and is cyclopropyl,

A is CR ^A,R^A and H is H,

R ³ is V, and the R is H,

(17-6)

E is N, and the number of the E is N,

A is N, and the number of the A is N,

R ³ is-P-Q or V,

P is-CH ₂ -, -O-or-N (R ^P) -,

R ^P is H or C _1-3 alkyl which can be substituted,

Q is the following formula (V) or formula (VI),

V is a saturated or unsaturated 7-to 8-membered bridged heterocyclic group of the following formula (VII),

A compound wherein m is 0 to 2 or a salt thereof.

(17-7)

E is N, and the number of the E is N,

G is CR ²,R² and is cyclopropyl,

A is N, and the number of the A is N,

R ³ is-P-Q or V,

P is-CH ₂ -, -O-or-N (R ^P) -,

R ^P is H or C _1-3 alkyl which can be substituted,

Q is the following formula (V) or formula (VI),

A compound wherein m is 0 to 2 or a salt thereof.

(18-1)

(18-2)

(19-1)

(19-2)

A compound wherein R ⁵ is isopropyl or C _3-6 cycloalkyl, or a salt thereof.

(20-1)

(20-2)

(21-1)

(21-2)

(22-1)

A compound wherein R ^Y is H or C _1-3 alkyl or a salt thereof.

(22-2)

L ^Y is-S- (optionally substituted C _1-3 alkylene) -, -SO ₂ - (optionally substituted C _1-3 alkylene) -, and-NR ^Y - (optionally substituted C _1-3 alkylene) -, - (C _1-3 alkylene which may be substituted) -O-, - (C _1-3 alkylene which may be substituted) -S-, - (C _1-3 alkylene which may be substituted) -SO ₂ -, - (C _1-3 alkylene which may be substituted) -NR ^Y -,

A compound wherein R ^Y is H or C _1-3 alkyl or a salt thereof.

(22-3)

L ^Y is-S- (optionally substituted C _1-3 alkylene) -, -SO ₂ - (optionally substituted C _1-3 alkylene) -, and-NR ^Y - (optionally substituted C _1-3 alkylene) -, - (C _1-3 alkylene which may be substituted) -S-, C _1-3 alkylene which may be substituted) -SO ₂ -, C _1-3 alkylene which may be substituted) -NR ^Y -,

A compound wherein R ^Y is H or C _1-3 alkyl or a salt thereof.

(22-4)

L ^Y is a compound of the formula-O- (optionally substituted C _1-3 alkylene) -or a salt thereof.

(23-1)

R ^P1 is OH or F, and the total number of the components is H,

R ^P2a is H or F,

A compound wherein R ^P2b is H or a salt thereof.

(23-2)

R ^P1 is F, and the total number of the components is F,

R ^P2a is H or F,

A compound wherein R ^P2b is H or a salt thereof.

(23-3)

R ^P1 is OH, and the hydroxyl radical is,

R ^P2a is H or F,

A compound wherein R ^P2b is H or a salt thereof.

(23-4)

R ^P1 is OH, and the hydroxyl radical is,

A compound or salt thereof wherein R ^P2a and R ^P2b are both H.

(24-1)

(24-2)

W is the following formula (XIX),

A compound or salt thereof wherein W ¹、W² is CH.

(25-1)

X is a bond, -CH ₂ -, -O-, -S-, or-NR ^4x -,

A compound wherein R ^4x is H or C _1-3 alkyl or a salt thereof.

(25-2)

A compound wherein X is-O-or a salt thereof.

(26-1)

And Y is phenylene or pyridyldiyl, and the phenylene may be substituted with F.

(26-2)

And Y is a phenylene group which may be substituted with F or a salt thereof.

(27-1)

L is- (L ¹-L²-L³-L⁴) -,

A compound wherein R ^L1 is H or C _1-3 alkyl or a salt thereof.

(27-2)

And L is a bond or a salt thereof.

(28-1)

(28-2)

Z is a compound of the following formula (XXVII) -1 or a salt thereof.

(Wherein L ^* represents a bond with L.)

(29-1)

Y-L-Z is a compound of the following formula (VIII) or a salt thereof.

(30)

A compound or a salt thereof which is a combination of any two or more of the above-mentioned modes (16-1) to (29-1) and is not contradictory.

The combination of the above (30) is specifically exemplified by the following modes.

(30-1)

A compound of formula (IA) or a salt thereof.

(In the formula (I),

A is CR ^A or N, and the total number of the components is N,

R ^A is H or C _1-3 alkyl,

E is CH or N, and the R is H,

G is CR ² or N, and the total number of the components is N,

R ^1c is F, cl, methyl or ethyl,

R ² is H, halogen, optionally substituted C _1-3 alkyl, cyclopropyl or vinyl,

R ³ is-P-Q or V,

P is-CH ₂ -, -O-or-N (R ^P) -,

R ^P is H or C _1-3 alkyl which can be substituted,

Q is the following formula (V) or formula (VI),

V is the following formula (VII),

In addition, (i) when A is CR ^A, or (ii) when A is N and E or G is N,

M is a number from 0 to 2,

R ^Y is H or C _1-3 alkyl,

R ^P1 is OH or F, and the total number of the components is H,

R ^P2a is H or F,

R ^P2b is H, and the hydrogen atom,

X is a bond, -CH ₂ -, -O-, -S-, or-NR ^4x -,

R ^4x is H or C _1-3 alkyl,

Y is phenylene or pyridyldiyl, which phenylene may be substituted by F,

L is- (L ¹-L²-L³-L⁴) -,

R ^L1 is H or C _1-3 alkyl,

Or Y-L-Z is the following formula (VIII). )

As examples of specific compounds included in the present invention, the following compounds are given as one embodiment.

A compound selected from the group consisting of:

(4R) -1- [ (2S) -2- {4- [4- ({ [ 6-cyclopropyl-7- (6-fluoro-5-methyl-1H-indazol-4-yl) -4- { methyl [ (3S) -pyrrolidin-3-yl ] amino } -2- { [ (2R) -oxolan-2-yl ] methoxy } quinazolin-8-yl ] oxy } methyl) phenyl ] -1H-1,2, 3-triazol-1-yl } -3-methylbutanoyl ] -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide,

(4R) -1- [ (2S) -2- {4- [4- ({ [ 6-cyclopropyl-7- (6-fluoro-5-methyl-1H-indazol-4-yl) -4- { methyl [ (3S) -pyrrolidin-3-yl ] amino } -2- { [ (2S) -oxolan-2-yl ] methoxy } quinazolin-8-yl ] oxy } methyl) phenyl ] -1H-1,2, 3-triazol-1-yl } -3-methylbutanoyl ] -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide,

(4R) -1- [ (2S) -2- {4- [4- ({ [ 6-cyclopropyl-7- (6-fluoro-5-methyl-1H-indazol-4-yl) -2- [ (2S) -2-methoxypropoxy ] -4- { methyl [ (3S) -pyrrolidin-3-yl ] amino } quinazolin-8-yl ] oxy } methyl) phenyl ] -1H-1,2, 3-triazol-1-yl } -3-methylbutanoyl ] -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide,

(4R) -1- [ (2S) -2- {4- [4- ({ [ 6-cyclopropyl-7- (6-fluoro-5-methyl-1H-indazol-4-yl) -2- [ (2S) -2-methoxypropoxy ] -4- { methyl [ (3S) -pyrrolidin-3-yl ] amino } quinazolin-8-yl ] oxy } methyl) phenyl ] -1H-1,2, 3-triazol-1-yl } -3-methylbutanoyl ] -N- { (1R) -1- [4- (1-ethyl-1H-pyrazol-5-yl) phenyl ] -2-hydroxyethyl } -4-hydroxy-L-prolinamide,

(4R) -1- [ (2S) -2- {4- [4- ({ [ 6-cyclopropyl-7- (6-fluoro-5-methyl-1H-indazol-4-yl) -2- [ (2S) -2-methoxypropoxy ] -4- { methyl [ (3S) -pyrrolidin-3-yl ] amino } quinazolin-8-yl ] oxy } methyl) -2-fluorophenyl ] -1H-1,2, 3-triazol-1-yl } -3-methylbutanoyl ] -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide,

(4R) -1- { (2S) -2- [4- (4- { [ (6-cyclopropyl-4- { ethyl [ (3S) -pyrrolidin-3-yl ] amino } -7- (6-fluoro-5-methyl-1H-indazol-4-yl) -2- [ (2S) -2-methoxypropoxy ] quinazolin-8-yl) oxy ] methyl } phenyl) -1H-1,2, 3-triazol-1-yl ] -3-methylbutanoyl } -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide, and

(4R) -1- [ (2S) -2- {4- [4- ({ [ 6-cyclopropyl-7- (6-fluoro-5-methyl-1H-indazol-4-yl) -2- [ (2S) -2-methoxypropoxy ] -4- { methyl [ (3R) -pyrrolidin-3-yl ] amino } quinazolin-8-yl ] oxy } methyl) phenyl ] -1H-1,2, 3-triazol-1-yl } -3-methylbutanoyl ] -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide.

A compound selected from the group consisting of:

(4R) -1- [ (2S) -2- {4- [4- ({ [ (7M) -6-cyclopropyl-7- (6-fluoro-5-methyl-1H-indazol-4-yl) -4- { methyl [ (3S) -pyrrolidin-3-yl ] amino } -2- { [ (2R) -oxopyrrolidin-2-yl ] methoxy } quinazolin-8-yl ] oxy } methyl) phenyl ] -1H-1,2, 3-triazol-1-yl } -3-methylbutanoyl ] -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide,

(4R) -1- [ (2S) -2- {4- [4- ({ [ (7M) -6-cyclopropyl-7- (6-fluoro-5-methyl-1H-indazol-4-yl) -4- { methyl [ (3S) -pyrrolidin-3-yl ] amino } -2- { [ (2S) -oxopyrrolidin-2-yl ] methoxy } quinazolin-8-yl ] oxy } methyl) phenyl ] -1H-1,2, 3-triazol-1-yl } -3-methylbutanoyl ] -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide,

(4R) -1- [ (2S) -2- {4- [4- ({ [ (7M) -6-cyclopropyl-7- (6-fluoro-5-methyl-1H-indazol-4-yl) -2- [ (2S) -2-methoxypropoxy ] -4- { methyl [ (3S) -pyrrolidin-3-yl ] amino } quinazolin-8-yl ] oxy } methyl) phenyl ] -1H-1,2, 3-triazol-1-yl } -3-methylbutanoyl ] -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide,

(4R) -1- [ (2S) -2- {4- [4- ({ [ (7M) -6-cyclopropyl-7- (6-fluoro-5-methyl-1H-indazol-4-yl) -2- [ (2S) -2-methoxypropoxy ] -4- { methyl [ (3S) -pyrrolidin-3-yl ] amino } quinazolin-8-yl ] oxy } methyl) phenyl ] -1H-1,2, 3-triazol-1-yl } -3-methylbutanoyl ] -N- { (1R) -1- [4- (1-ethyl-1H-pyrazol-5-yl) phenyl ] -2-hydroxyethyl } -4-hydroxy-L-prolinamide,

(4R) -1- [ (2S) -2- {4- [4- ({ [ (7M) -6-cyclopropyl-7- (6-fluoro-5-methyl-1H-indazol-4-yl) -2- [ (2S) -2-methoxypropoxy ] -4- { methyl [ (3S) -pyrrolidin-3-yl ] amino } quinazolin-8-yl ] oxy } methyl) -2-fluorophenyl ] -1H-1,2, 3-triazol-1-yl } -3-methylbutanoyl ] -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide,

(4R) -1- [ (2S) -2- (4- {4- [ ({ (7M) -6-cyclopropyl-4- { ethyl [ (3S) -pyrrolidin-3-yl ] amino } -7- (6-fluoro-5-methyl-1H-indazol-4-yl) -2- [ (2S) -2-methoxypropoxy ] quinazolin-8-yl } oxy) methyl ] phenyl } -1H-1,2, 3-triazol-1-yl) -3-methylbutanoyl ] -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide, and

(4R) -1- [ (2S) -2- {4- [4- ({ [ (7M) -6-cyclopropyl-7- (6-fluoro-5-methyl-1H-indazol-4-yl) -2- [ (2S) -2-methoxypropoxy ] -4- { methyl [ (3R) -pyrrolidin-3-yl ] amino } quinazolin-8-yl ] oxy } methyl) phenyl ] -1H-1,2, 3-triazol-1-yl } -3-methylbutanoyl ] -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide.

A compound selected from the group consisting of:

(4R) -1- [ (2S) -2- {4- [4- ({ [ (7P) -6-cyclopropyl-7- (6-fluoro-5-methyl-1H-indazol-4-yl) -4- { methyl [ (3S) -pyrrolidin-3-yl ] amino } -2- { [ (2R) -oxopyrrolidin-2-yl ] methoxy } quinazolin-8-yl ] oxy } methyl) phenyl ] -1H-1,2, 3-triazol-1-yl } -3-methylbutanoyl ] -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide,

(4R) -1- [ (2S) -2- {4- [4- ({ [ (7P) -6-cyclopropyl-7- (6-fluoro-5-methyl-1H-indazol-4-yl) -4- { methyl [ (3S) -pyrrolidin-3-yl ] amino } -2- { [ (2S) -oxopyrrolidin-2-yl ] methoxy } quinazolin-8-yl ] oxy } methyl) phenyl ] -1H-1,2, 3-triazol-1-yl } -3-methylbutanoyl ] -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide,

(4R) -1- [ (2S) -2- {4- [4- ({ [ (7P) -6-cyclopropyl-7- (6-fluoro-5-methyl-1H-indazol-4-yl) -2- [ (2S) -2-methoxypropoxy ] -4- { methyl [ (3S) -pyrrolidin-3-yl ] amino } quinazolin-8-yl ] oxy } methyl) phenyl ] -1H-1,2, 3-triazol-1-yl } -3-methylbutanoyl ] -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide,

(4R) -1- [ (2S) -2- {4- [4- ({ [ (7P) -6-cyclopropyl-7- (6-fluoro-5-methyl-1H-indazol-4-yl) -2- [ (2S) -2-methoxypropoxy ] -4- { methyl [ (3S) -pyrrolidin-3-yl ] amino } quinazolin-8-yl ] oxy } methyl) phenyl ] -1H-1,2, 3-triazol-1-yl } -3-methylbutanoyl ] -N- { (1R) -1- [4- (1-ethyl-1H-pyrazol-5-yl) phenyl ] -2-hydroxyethyl } -4-hydroxy-L-prolinamide,

(4R) -1- [ (2S) -2- {4- [4- ({ [ (7P) -6-cyclopropyl-7- (6-fluoro-5-methyl-1H-indazol-4-yl) -2- [ (2S) -2-methoxypropoxy ] -4- { methyl [ (3S) -pyrrolidin-3-yl ] amino } quinazolin-8-yl ] oxy } methyl) -2-fluorophenyl ] -1H-1,2, 3-triazol-1-yl } -3-methylbutanoyl ] -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide,

(4R) -1- [ (2S) -2- (4- {4- [ ({ (7P) -6-cyclopropyl-4- { ethyl [ (3S) -pyrrolidin-3-yl ] amino } -7- (6-fluoro-5-methyl-1H-indazol-4-yl) -2- [ (2S) -2-methoxypropoxy ] quinazolin-8-yl } oxy) methyl ] phenyl } -1H-1,2, 3-triazol-1-yl) -3-methylbutanoyl ] -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide, and

(4R) -1- [ (2S) -2- {4- [4- ({ [ (7P) -6-cyclopropyl-7- (6-fluoro-5-methyl-1H-indazol-4-yl) -2- [ (2S) -2-methoxypropoxy ] -4- { methyl [ (3R) -pyrrolidin-3-yl ] amino } quinazolin-8-yl ] oxy } methyl) phenyl ] -1H-1,2, 3-triazol-1-yl } -3-methylbutanoyl ] -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide.

In the compounds of formula (I) and formula (IA), depending on the kind of substituents, tautomers, geometrical isomers may exist. In the present specification, the compounds of formula (I) and formula (IA) are sometimes described as only one form of isomer, but the present invention also includes other isomers, isolated products of isomers, or mixtures thereof.

In addition, the compounds of formula (I) and (IA) may have asymmetric carbon atoms and asymmetric axes, and diastereoisomers based thereon may be present. The invention also includes isolated products of diastereomers of the compounds of formula (I) and formula (IA) or mixtures thereof.

Furthermore, the present invention also includes pharmaceutically acceptable prodrugs of the compounds of formula (I) and formula (IA). Pharmaceutically acceptable prodrugs refer to compounds having groups that are capable of being converted to amino, hydroxyl, carboxyl, etc. groups by solvolysis or under physiological conditions. Examples of the prodrug-forming groups include those described in prog.med.,1985,5, p.2157-2161, "development of medicines", volume 7 molecular design, book store, 1990, and p.163-198.

The salts of the compounds of the formulae (I) and (IA) are pharmaceutically acceptable salts of the compounds of the formulae (I) and (IA), and may form acid addition salts or salts with bases depending on the type of substituent. Examples of the salts include those described in P.Heinrich Stahl, handbook of Pharmaceutical Salts Properties, selection, and Use, wiley-VCH, 2008. Specifically, there may be mentioned: acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc., organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, xylene formyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid, etc.; salts with inorganic metals such as sodium, potassium, magnesium, calcium, and aluminum; salts with organic bases such as methylamine, ethylamine, ethanolamine, etc.; salts with various amino acids and amino acid derivatives such as acetylleucine, lysine, ornithine, etc.; ammonium salts, and the like.

Furthermore, the present invention also includes various hydrates, solvates and polymorphs of the compounds of formula (I) and formula (IA) and salts thereof.

In addition, the present invention includes all compounds of formula (I) and formula (IA) or salts thereof labeled with more than 1 pharmaceutically acceptable radioisotope, either radioactive or non-radioactive. Examples of preferred isotopes for isotopic labeling of the compounds of the present invention include isotopes of hydrogen (² H and ³ H, etc.), carbon (¹¹C、¹³ C and ¹⁴ C, etc.), nitrogen (¹³ N and ¹⁵ N, etc.), oxygen (¹⁵O、¹⁷ O and ¹⁸ O, etc.), fluorine (¹⁸ F, etc.), chlorine (³⁶ Cl, etc.), iodine (¹²³ I and ¹²⁵ I, etc.), sulfur (³⁵ S, etc.).

The isotopically labeled compounds of the present application can be used for studies such as tissue distribution studies of drugs and/or substrates. For example, from the viewpoint of ease of labeling and easiness of detection, a radioisotope such as tritium (³ H) or carbon 14 (¹⁴ C) can be used for this purpose.

Substitution to heavier isotopes, such as substitution of hydrogen to deuterium (² H), is sometimes therapeutically advantageous (e.g., increasing in vivo half-life, reducing the necessary amount, reducing drug interactions) due to increased metabolic stability.

Substitution to positron emitting isotopes (¹¹C、¹⁸F、¹⁵ O, ¹³ N, etc.) may be used in Positron Emission Tomography (PET) experiments for the purpose of assaying substrate receptor occupancy.

The isotopically labeled compounds of the present invention can be generally prepared by conventional methods known to those skilled in the art or by using an isotopically labeled suitable reagent in place of an unlabeled reagent, by the same production method as in examples or production examples, etc.

(Manufacturing method)

The compounds of formula (I) and formula (IA) and salts thereof can be produced by using various known synthetic methods based on the characteristics of the basic structure or the kind of substituents. In this case, depending on the kind of the functional group, the functional group may be replaced with an appropriate protecting group (a group that can be easily converted into the functional group) in advance at a stage from the raw material to the intermediate, which is effective in terms of manufacturing technology. Examples of such protecting groups include those described in p.g.m.wuts and t.w.greene, "Greene's Protective Groups in Organic Synthesis", 5 th edition, john Wiley & Sons inc., 2014, and the like, and may be appropriately selected and used according to the reaction conditions. In such a method, the desired compound can be obtained by introducing the protecting group and then reacting, and removing the protecting group as necessary.

In addition, prodrugs of compounds of formula (I) and formula (IA) can be produced by introducing a specific group at the stage from the starting material to the intermediate or further reacting the obtained compounds of formula (I) and formula (IA) in the same manner as the protecting group described above. The reaction may be carried out by applying a method known to those skilled in the art such as usual esterification, amidation, dehydration, etc.

Hereinafter, a representative production method of the compounds of the formulas (I) and (IA) will be described. The manufacturing methods may also be performed with reference to the references attached in this description. The manufacturing method of the present invention is not limited to the examples shown below. The compound of formula (IA) can be obtained by the same method as the typical production method of the compound of formula (I) using a starting compound corresponding to the compound of formula (IA).

In the present specification, the following abbreviations may be used.

DMF: n, N-dimethylformamide, DMAc: n, N-dimethylacetamide, THF: tetrahydrofuran, meCN: acetonitrile, meOH: methanol, etOH: ethanol, iPrOH: isopropanol, tBuOH: tertiary butanol, DOX:1, 4-dioxane, DMSO: dimethyl sulfoxide, TEA: triethylamine, DIPEA: n, N-diisopropylethylamine, tBuOK: potassium tert-butoxide, pdCl ₂(dppf)·CH₂Cl₂: [1,1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride dichloromethane adduct, pd/C: palladium on carbon, pyBOP: (Benzotriazol-1-yloxy) tripyrrolidinylHexafluorophosphoric acid, NMP: n-methyl-2-pyrrolidone.

(Manufacturing method 1)

( Wherein PG ¹ represents a protecting group for NH contained in R ³, R ³¹ represents a divalent group formed by removing H from NH contained in R ³, PG ² represents a protecting group or a hydrogen atom for NH or OH contained in R ¹, and R ¹¹ represents a divalent group formed by removing H from NH contained in R ¹. The same applies to the followings )

The compound of formula (I) can be obtained by subjecting compound (1) to a deprotection reaction. Examples of the protecting group which can be deprotected under acidic conditions include t-butoxycarbonyl, triphenylmethyl, tetrahydro-2H-pyran-2-yl, methoxymethyl, dimethylmethane diyl, t-butylsulfinyl and the like.

The reaction is carried out by stirring for usually 0.1 hour to 5 days under cooling to heating reflux. Examples of the solvent used herein are not particularly limited, and include: alcohols such as MeOH and EtOH; halogenated hydrocarbons such as methylene chloride, 1, 2-dichloroethane or chloroform; ethers such as diethyl ether, THF, DOX, dimethoxyethane, etc.; DMF, DMSO, meCN or water; and mixtures of these. Examples of the deprotecting reagent include, but are not particularly limited to, acids such as hydrogen chloride (DOX solution), trifluoroacetic acid, methanesulfonic acid, phosphoric acid, and p-toluenesulfonic acid.

Deprotection can also be achieved by catalytic hydrogenation by selection of protecting groups. Examples of the protecting group include benzyl, p-methoxybenzyl, and benzyloxycarbonyl. Alternatively, deprotection may be carried out using a fluoride ion source such as tetra-n-butylammonium fluoride. Examples of the protecting group include a tert-butyl (dimethyl) silyl group, a (trimethylsilyl) ethoxymethyl group, and the like. Examples of the protecting group which can be deprotected under alkaline conditions include an acetyl group, a trifluoroacetyl group, and a benzoyl group. Alternatively, as PG ¹、PG², deprotection may be performed in stages by selecting protecting groups capable of deprotection under different deprotection conditions.

As references for this reaction, for example, the following references can be referred to.

P.g.m.wuts and t.w.greene, "Greene's Protective Groups in Organic Synthesis", 5 th edition, john Wiley & Sons inc., 2014

When the compound (1) as a starting material has an axial asymmetry, the present reaction may be carried out using a stereoisomer obtained by once separating the compound (1).

The hydrochloride of the compound of formula (I) can be obtained by applying the following operation as a salt-forming reaction to the compound of formula (I).

The compound of formula (I), which is considered to form a salt with hydrochloric acid in terms of its chemical structural characteristics, was dissolved in CH ₂Cl₂ and MeOH, hydrogen chloride (4M DOX solution, 10 equivalents) was added under ice-cooling, and stirred under ice-cooling for 30 minutes. The reaction mixture was concentrated under reduced pressure, diethyl ether was added to the resulting residue, and the resulting solid was collected by filtration and dried under reduced pressure to give the hydrochloride salt of the compound of formula (I).

The hydrochloride salt of the compound of formula (I) can be obtained by applying the following operation as a desalting reaction.

The hydrochloride of the compound of formula (I) was purified by ODS column chromatography (MeCN/0.1% aqueous formic acid), and the fractions containing the target were collected, made basic with saturated aqueous sodium bicarbonate, and extracted with CHCl ₃/MeOH (5/1). The combined organic layers were dried over anhydrous sodium sulfate, the solution was concentrated under reduced pressure, and the resulting solid was washed with diethyl ether and dried under reduced pressure to give the compound of formula (I).

(Manufacturing method 2)

The compound of formula (IA) may be obtained by subjecting compound (87) to a deprotection reaction.

The reaction conditions were the same as in production method 1.

(Synthesis of raw materials 1)

The present production method is a first method for producing the compound (1) -1 contained in the raw material compound (1).

(First step)

This step is a method for producing compound (1) -1 by cycloaddition reaction of compound (2) and compound (3).

In the present reaction, the compound (2) and the compound (3) are used in equal amounts or in excess of one, and a mixture thereof is stirred for usually 0.1 hour to 5 days, preferably in the presence of a copper salt, further preferably in the presence of a copper salt and a reducing agent, in a solvent inert to the reaction or in the absence of a solvent, under cooling to a reflux under heating, preferably at 0℃to 100 ℃. Examples of the solvent used herein are not particularly limited, and include: halogenated hydrocarbons such as methylene chloride, 1, 2-dichloroethane, chloroform, etc.; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, THF, DOX, and 1, 2-dimethoxyethane; DMF, DMSO, ethyl acetate, meCN, tBuOH, water, and mixtures of these. Copper salts include CuI, cuSO4, and copper (I) triflate (CuOTf). Examples of the reducing agent include sodium ascorbate. The manner of carrying out the reaction in the presence of TEA, DIPEA, N-methylmorpholine (NMM), 2, 6-lutidine, tris [ (1-benzyl-1H-1, 2, 3-triazol-4-yl) methyl ] amine (TBTA) or the like is sometimes advantageous in terms of allowing the reaction to proceed smoothly.

[ Literature ]

Angew.Chem.Int.Ed.2002,41,p.2596-2599.

The present reaction may be carried out using a compound obtained by first subjecting PG ² of compound (2) to a deprotection reaction.

(Raw material Synthesis 2)

( Wherein R represents a C _1-3 alkyl group. The same applies to the followings )

The present production method is a second method for producing the compound (1) -1 contained in the raw material compound (1).

(First step)

This step is a method for producing compound (5) by cycloaddition reaction of compound (2) and compound (4).

The reaction conditions were the same as in the first step of raw material synthesis 1.

(Second step)

This step is a method for producing the compound (6) by hydrolyzing the compound (5).

The reaction is carried out by stirring the compound (5) under cooling to a reflux under heating for usually 0.1 hour to 5 days. Examples of the solvent used herein include, but are not particularly limited to, alcohols, acetone, DMF, TMF, and the like. In addition, a mixed solvent of the solvent and water is sometimes preferable for the reaction. Examples of the hydrolysis reagent include, but are not particularly limited to, aqueous sodium hydroxide solution, aqueous potassium hydroxide solution, and trimethyltin hydroxide.

Japanese society of chemistry "Experimental chemistry lecture (5 th edition)" 16 volume (2005) (pill)

Angew.Chem.Int.Ed.2005,44,p.1378-1382.

(Third step)

This step is a method for producing compound (1) -1 by amidation reaction of compound (6) with compound (7).

In the present reaction, the compound (6) and the compound (7) are used in equal amounts or in excess, and a mixture thereof is stirred for usually 0.1 hour to 5 days in the presence of a condensing agent in a solvent inert to the reaction, under cooling to heating, preferably-20 ℃ to 60 ℃. Examples of the solvent include, but are not particularly limited to: aromatic hydrocarbons such as toluene; ethers such as THF and DOX; halogenated hydrocarbons such as methylene chloride; alcohols; DMF, DMSO, ethyl acetate, meCN; and mixtures of these. As examples of condensing agents, there may be mentioned (benzotriazol-1-yloxy) tripyrrolidinyl hexafluorophosphate(PyBOP), O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide or its hydrochloride salt, N, N '-Dicyclohexylcarbodiimide (DCC), 1' -Carbonyldiimidazole (CDI), diphenyl azide phosphate (DPPA), and the like. The manner in which the additive (e.g., 1-hydroxybenzotriazole) is used is sometimes preferred for the reaction. The reaction may be carried out in the presence of an organic base such as TEA, DIPEA or NMM or an inorganic base such as potassium carbonate, sodium carbonate or potassium hydroxide, and it is advantageous in terms of smooth progress of the reaction.

In addition, a method of converting the compound (6) into a reactive derivative and then performing an acylation reaction may be used. Examples of the reactive derivative of carboxylic acid include an acid halide obtained by reacting with a halogenating agent such as phosphorus oxychloride or thionyl chloride, a mixed acid anhydride obtained by reacting with isobutyl chloroformate or the like, and an active ester obtained by condensing with 1-hydroxybenzotriazole or the like. The reaction of the reactive derivative with the compound (7) may be carried out in a solvent inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, etc., under cooling to heating, preferably at-20℃to 120 ℃.

[ Literature ]

S.R.Sandler and W.Karo, "Organic Functional Group Preparations", 2 nd edition, volume 1, ACADEMIC PRESS Inc., 1991

(Raw material Synthesis 3)

( Wherein PG ³ represents a protecting group for OH, LG ¹ represents a leaving group, and BLG represents a boric acid group or a trifluoroborate group (hereinafter, sometimes referred to as a boric acid group or the like) protected by a boric acid protecting group such as a boric acid group or a pinacol ester group. Examples of the leaving group shown here include Cl, br, methanesulfonyloxy, p-toluenesulfonyloxy, and the like. )

The present production method is a first method for producing the raw material compound (2).

(First step)

This step is a method for producing compound (10) by in situ substitution reaction of compound (8) -1 with compound (9).

In the present reaction, the compound (8) -1 and the compound (9) are used in equal amounts or in excess, and a mixture thereof is stirred for usually 0.1 hour to 5 days in a solvent inert to the reaction or in the absence of a solvent under cooling to a reflux under heating, preferably at 0℃to 80 ℃. Examples of the solvent used herein are not particularly limited, and include: halogenated hydrocarbons such as methylene chloride, 1, 2-dichloroethane, chloroform, etc.; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, THF, DOX, and 1, 2-dimethoxyethane; DMF, DMAc, DMSO, ethyl acetate, meCN; and mixtures of these. The reaction may be carried out in the presence of an organic base such as TEA, DIPEA, N-methylmorpholine (NMM) or 1, 4-diazabicyclo [2.2.2] octane (DABCO), or an inorganic base such as sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate or tBuOK, which is advantageous in terms of smooth progress.

In addition, the compound (10) can also be produced by subjecting a compound obtained by a Rheumatoid-Herbac reaction of the compound (8) -1 with the compound (9) to a catalytic hydrogenation reaction.

(Second step)

This step is a method for producing compound (12) by an in-situ substitution reaction of compound (10) with compound (11).

The reaction conditions were the same as in the first step of raw material synthesis 3.

In addition, the compound (12) can also be produced by coupling a compound in which a hydrogen atom of the compound (11) is converted into halogen with the root of the compound (10).

(Third step)

This step is a method for producing compound (13) -1 by in situ substitution reaction of compound (12) with PG ³ -OH.

As examples of PG ³ -OH used herein, benzyl alcohol, p-methoxybenzyl alcohol and 1-phenylethanol may be mentioned.

(Fourth step)

This step is a method for producing a compound (14) by a suzuki-miyaura coupling reaction of a compound (13) with a boric acid derivative composed of an R ² -boric acid group or the like, wherein the compound (13) contains any one of a compound (13) -1 obtained according to the third step of the present synthetic method and a compound (13) -2 obtained according to the following (raw material synthesis 14). Examples of the boric acid group and the like used herein are not particularly limited, and boric acid groups, boric acid ester groups, boric acid pinacol ester groups, triol borate groups, and trifluoro borate groups may be mentioned.

In the present reaction, the compound (13) and the boric acid derivative composed of R ² -boric acid group or the like are used in equal amounts or in excess, and the mixture thereof is stirred for usually 0.1 to 5 days in a solvent inert to the reaction in the presence of a base and a palladium catalyst at room temperature to a reflux under heating, preferably at 20℃to 140 ℃. Examples of the solvent used herein are not particularly limited, and include: halogenated hydrocarbons such as methylene chloride, 1, 2-dichloroethane, chloroform, etc.; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, THF, DOX, and 1, 2-dimethoxyethane; alcohols such as MeOH, etOH, isopropanol, butanol, and pentanol; DMF, DMSO, meCN, 1, 3-dimethylimidazolin-2-one, water; and mixtures of these. Examples of the base include inorganic bases such as potassium phosphate, sodium carbonate, potassium carbonate, sodium hydroxide, and barium hydroxide. Examples of the palladium catalyst include tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, [1,1 '-bis (diphenylphosphino) ferrocene ] palladium (II) dichloride, methylene chloride adducts, (1 e,4 e) -1, 5-diphenylpenta-1, 4-dien-3-one/palladium (3:2), (2-dicyclohexylphosphino-2', 6 '-diisopropyloxy-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) methanesulfonate, and palladium (II) acetate. The manner of carrying out the reaction in the presence of a ligand such as dicyclohexyl (2 ',6' -dimethoxybiphenyl-2-yl) phosphine, dicyclohexyl (2 ',6' -diisopropyloxy- [1,1 '-biphenyl ] -2-yl) phosphine, 1' -bis (diphenylphosphino) ferrocene, etc. is sometimes advantageous in terms of smooth progress of the reaction. In addition, the method of heating the mixture by microwave irradiation is sometimes advantageous in terms of smooth progress of the reaction.

[ Literature ]

J.Am.Chem.Soc.,2005,127,p.4685-4696

Org.Lett.2011,13,p.3948-3951

Org.Lett.2012,14,p.1278-1281

Compound (14) (here, R ² is hydrogen) can be produced by dehalogenation reaction using the Pd catalyst of compound (13) and a reducing agent.

[ Literature ]

J.Org.Chem.,1977,42,p.3491-3494

Tetrahedron Letters 2013,54,5207-5210

(Fifth step)

This step is a method for producing compound (16) by a suzuki-miyaura coupling reaction of compound (14) with compound (15).

The reaction conditions were the same as in the fourth step of raw material synthesis 3.

When the compound (16) has an axiasymmetric structure, it is obtained as a mixture of stereoisomers, and each stereoisomer can be isolated by performing a conventional resolution operation, for example, resolution using ODS column chromatography or silica gel column chromatography.

(Sixth step)

This step is a method for producing the compound (17) by deprotecting the compound (16) by catalytic hydrogenation.

The reaction can be carried out by stirring the compound (16) under a hydrogen atmosphere under normal pressure to pressure in a solvent inert to the reaction such as MeOH, etOH, ethyl acetate, etc., in the presence of a metal catalyst, under cooling to heating, preferably at room temperature for 1 hour to 5 days. As the metal catalyst, a palladium catalyst such as Pd/C or palladium black, a platinum catalyst such as a platinum plate or platinum oxide, a nickel catalyst such as reduced nickel or raney nickel, or the like is used.

(Seventh step)

This step is a method for producing the compound (2) by reacting the compound (17) with the compound (18).

The reaction is carried out by using the compound (17) and the compound (18) in equal amounts or in excess and allowing a mixture thereof to react in the presence of a base in a solvent inert to the reaction under cooling to a reflux under heating, preferably at 0 to 80℃for usually 0.1 hour to 5 days. The solvent used herein is not particularly limited, and examples thereof include: aromatic hydrocarbons such as benzene, toluene, and xylene; alcohols such as MeOH and EtOH; ethers such as diethyl ether, THF, DOX, and 1, 2-dimethoxyethane; halogenated hydrocarbons such as methylene chloride, 1, 2-dichloroethane, chloroform, etc.; DMF, DMSO, ethyl acetate, meCN; and mixtures of these. Examples of the base include, but are not particularly limited to, organic bases such as TEA, DIPEA, 1, 8-diazabicyclo [5.4.0] -7-undecene, n-butyllithium, tBuOK, and inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydride. The manner in which the reaction is carried out in the presence of a tetra-n-butylammonium chloride or the like transfer catalyst is sometimes advantageous.

Japanese chemical society, "Experimental chemistry lecture", 5 th edition, volume 14, charles, pill-like, 2005

The compound (2) may be obtained as a mixture of stereoisomers, and the compound (2) or the compound (2) having PG ² as a protecting group may be subjected to deprotection, and the resulting compound may be subjected to a conventional resolution operation, for example, resolution using ODS column chromatography or silica gel column chromatography, to isolate each stereoisomer.

The reaction conditions for the deprotection reaction used herein are the same as those described in production method 1.

In addition, in the compound (18), a compound having a hydroxyl group in a portion corresponding to LG ¹ is halogenated, whereby a compound having LG ¹ as a halogen can be produced. Examples of the halogenating agent used herein are not particularly limited, and examples thereof include thionyl chloride, phosphorus oxychloride, hydrobromic acid, phosphorus tribromide, and the like.

Japanese chemical society, "Experimental chemistry lecture", 5 th edition, volume 13, charles, pill-like, 2004 ]

Further, in the compound (18), a compound having a hydroxyl group in a portion corresponding to LG ¹ is sulfonylated in the presence of a base, whereby a compound having LG ¹ as a sulfonyloxy group can be produced. Examples of the sulfonylating agent used herein include, but are not particularly limited to, methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonyl anhydride, and the like. Examples of the base include, but are not particularly limited to, TEA, DIPEA, pyridine, and tetramethyl ethylenediamine.

Synthesis 1999,9,p.1633-1636

(Raw material Synthesis 4)

(Wherein R ^LG represents a C _1-12 alkyl group and n represents 1 or 2.)

The present production method is a second method for producing the raw material compound (16).

(First step)

This step is a method for producing compound (19) by in situ substitution reaction of compound (10) with R ^LG -SH. Examples of R ^LG -SH used herein include C _1-12 alkyl mercaptans such as ethanethiol and dodecanethiol.

(Second step)

This step is a process for producing compound (20) -1 by in situ substitution reaction of compound (19) with PG ³ -OH. As examples of PG ³ -OH used herein, benzyl alcohol, p-methoxybenzyl alcohol and 1-phenylethanol may be mentioned.

(Third step)

This step is a method for producing compound (21) by suzuki-miyaura coupling reaction of compound (20) with a boric acid derivative composed of R ² -boric acid group or the like, wherein compound (20) contains any one of compound (20) -1 obtained in the second step of the present synthetic method and compound (20) -2 obtained in the following (raw material synthesis 13).

Compound (21) (here, R ² is hydrogen) can be produced by dehalogenation reaction using the Pd catalyst of compound (20) and a reducing agent.

[ Literature ]

J.Org.Chem.,1977,42,p.3491-3494

Tetrahedron Letters 2013,54,5207-5210

(Fourth step)

This step is a method for producing compound (22) by a suzuki-miyaura coupling reaction of compound (21) with compound (15).

(Fifth step)

This step is a method for producing the compound (23) by oxidation reaction of the compound (22).

In the present reaction, compound (22) is treated with an equal or excessive amount of an oxidizing agent in a solvent inert to the reaction under cooling to heating, preferably-20℃to 80℃for usually 0.1 hour to 3 days. In this reaction, oxidation of m-chloroperbenzoic acid, perbenzoic acid, peracetic acid, sodium hypochlorite or hydrogen peroxide is preferably used. Examples of the solvent include halogenated hydrocarbons such as aromatic hydrocarbons, ethers, and methylene chloride, DMF, DMSO, ethyl acetate, meCN, and mixtures of these. Examples of the other oxidizing agent include cumene hydroperoxide, potassium monopersulfate (Oxone), active manganese dioxide, chromic acid, potassium permanganate, sodium periodate, and the like.

[ Literature ]

Japanese chemical society, "Experimental chemistry lecture", 5 th edition, volume 17, charpy, 2004)

(Sixth step)

This step is a method for producing compound (16) by in situ substitution reaction of compound (23) with compound (24).

(Raw material Synthesis 5)

The present production method is a second method for producing the raw material compound (2).

(First step)

This step is a method for producing the compound (25) by deprotecting the compound (23) -1 by catalytic hydrogenation.

The reaction conditions were the same as in the sixth step of raw material synthesis 3.

(Second step)

This step is a method for producing the compound (26) by reacting the compound (25) with the compound (18).

The reaction conditions were the same as in the seventh step of raw material synthesis 3.

(Third step)

This step is a method for producing compound (2) by an in-situ substitution reaction of compound (26) with compound (24).

(Raw material Synthesis 6)

(Wherein PG ⁴、PG⁵ represents a protecting group.)

The present production method is a method for producing the raw material compound (3).

(First step)

This step is a method for producing compound (28) by amidation reaction of compound (7) with compound (27).

The reaction conditions are the same as in the third step of raw material synthesis 2.

(Second step)

This step is a method for producing the compound (29) by subjecting the compound (28) to a deprotection reaction.

The reaction conditions were the same as those described in production method 1.

(Third step)

This step is a method for producing compound (31) by amidation reaction of compound (29) with compound (30).

(Fourth step)

This step is a method for producing the compound (32) by subjecting the compound (31) to a deprotection reaction.

(Fifth step)

This step is a method for producing the compound (3) by reacting the compound (32) with a diazonium reagent.

In this reaction, compound (32) is treated with an equal or excess amount of the diazonium reagent in a solvent inert to the reaction, under cooling to heating, preferably 0℃to 50℃for usually 0.1 hour to 3 days. Examples of the diazo transfer reagent include, but are not particularly limited to, trifluoromethanesulfonyl azide, imidazole-1-sulfonyl azide or salts thereof, and 2-azide-1, 3-dimethylimidazoleHexafluorophosphate (ADMP), and the like. It is sometimes advantageous to carry out the reaction in the presence of an organic base such as TEA, 4-Dimethylaminopyridine (DMAP), 2, 6-lutidine, and a catalytic amount of a copper salt such as CuSO ₄. Examples of the solvent include halogenated hydrocarbons such as THF and methylene chloride, meCN, alcohols, water, and mixtures of these.

[ Literature ]

J.Org.Chem.2012,77,p.1760-1764

Nature 2019,574,p.86-89

Org.Biomol.Chem.2014,12,p.4397-4406

(Raw material Synthesis 7)

(Wherein LG ² represents a leaving group, PG ⁶ represents a protecting group for NH.)

The present production method is a method for producing the raw material compounds (1) -2 or the raw material compounds (1) -3 contained in the raw material compound (1). Here, a production method when L ² in the starting compounds (1) to (3) is NR ^L1, pyrrolidinediyl, piperidediyl or piperazinediyl is shown.

(First step)

This step is a method for producing compound (2) -1 by reacting compound (17) with compound (33).

(Second step)

This step is a method for producing the compound (2) -2 by hydrolyzing the compound (2) -1.

The reaction conditions are the same as in the second step of raw material synthesis 2.

(Third step)

This step is a method for producing compound (1) -2 by amidation reaction of compound (32) with compound (2) -2.

(Fourth step)

This step is a method for producing compound (35) by amidation reaction of compound (32) with compound (34).

(Fifth step, sixth step)

This step is a method for producing the compound (1) -3 by amidation reaction of the compound (2) -2 with the compound obtained by carrying out deprotection reaction of the compound (35).

The reaction conditions for the deprotection reaction are the same as those described in production method 1. Examples of the protecting group which can be deprotected under acidic conditions include t-butoxycarbonyl, triphenylmethyl, tetrahydro-2H-pyran-2-yl, methoxymethyl, dimethylmethane diyl, t-butylsulfinyl and the like.

The reaction conditions for the amidation reaction are the same as in the third step of raw material synthesis 2.

(Raw material Synthesis 8)

(Wherein when Z is NH, A ¹ represents a hydrogen atom, A ² represents a halogen atom, when Z is A5-membered heteroarene diyl group containing 1 to 4 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen, A ¹ is a group selected from the group consisting of Cl, br and I, A ² represents a boric acid group or the like, A ¹ is a boric acid group or the like, A ² represents a group selected from the group consisting of Cl, br and I.)

The present production method is a method for producing the raw material compounds (1) -4 contained in the raw material compound (1).

(First step)

This step is a method for producing the compound (38) by an in-situ reaction of the compound (36) with the compound (37) or a Buchwald-Hartmax amination reaction when Z is NH.

The reaction conditions for the in situ reaction are the same as in the first step of raw material synthesis 3.

As references for the blowald-hattery amination reaction, for example, the following references can be referred to.

J.Am.Chem.Soc.,2020,142,p.15027-15037

In addition, this step is a method for producing compound (38) by a suzuki-miyaura coupling reaction of compound (36) with compound (37) when Z is a 5-membered heteroaryl group containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen.

Reference to the reaction when Z is the formula (XXIX) is made, for example, to the following.

J.Org.Chem.,2000,65,p.1516-1524

Chemical Communications 2014,50,p.1867-1870

Bioorg.Med.Chem.Lett.,2001,11,p.2061-2065

(Second step)

This step is a method for producing compound (39) by reacting compound (38) with compound (17).

In addition, in this step, compound (39) can be produced by a casting reaction between a compound (17) and a compound (38) having a hydroxyl group in the portion corresponding to LG ¹.

Reference to the casting reaction is made, for example, to the following.

Chem.Asian J.2007,2,p.1340-1355

(Third step)

This step is a method for producing the compound (40) by hydrolyzing the compound (39).

(Fourth step)

This step is a method for producing compounds (1) -4 by amidation reaction of compound (40) with compound (29).

(Raw material Synthesis 9)

(Wherein R ⁷ represents a group selected from the group consisting of formula (IX), formula (X), formula (XI), formula (XII), formula (XIII), formula (XIV), formula (XV), formula (XVI), formula (XVII) and formula (XVIII), PG ⁷ represents a protecting group, PG ⁸、PG⁹、PG¹⁰ are the same or different from each other, represent a hydrogen atom or a protecting group, A ³ represents a hydrogen atom, a carboxyl group or a boric acid group, etc., A ⁴ represents a hydrogen atom or a group selected from the group consisting of Cl, br and I, BLG ¹ represents a boric acid group, etc.)

The present production method is a method for producing a starting compound (7) when R ⁷ is a group selected from the group consisting of formula (IX), formula (X), formula (XI), formula (XII), formula (XIII), formula (XIV), formula (XV), formula (XVI), formula (XVII) and formula (XVIII).

(First step)

This step is a method for producing the compound (45) by, for example, a sultam-heck reaction of the compound (42) in which R ⁷ is the formula (IX) and the compound (41) when a ³ is a hydrogen atom.

In the present reaction, the compound (42) and the compound (41) are used in equal amounts or in excess, and a mixture thereof is stirred for usually 0.1 hour to 5 days in a solvent inert to the reaction in the presence of a base and a palladium catalyst at room temperature to a reflux under heating, preferably at 20℃to 140 ℃. Examples of the solvent used herein include, but are not particularly limited to, ethers such as diethyl ether, THF, DOX, 1, 2-dimethoxyethane, DMF, DMAc, DMSO, meCN, 1, 3-dimethylimidazolin-2-one, ethyl acetate, water, and mixtures of these. Examples of the base include bases such as potassium phosphate, sodium carbonate, potassium carbonate, and potassium acetate. Examples of the palladium catalyst include tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, [1,1 '-bis (diphenylphosphino) ferrocene ] palladium (II) dichloride, methylene chloride adducts, (1 e,4 e) -1, 5-diphenylpenta-1, 4-dien-3-one/palladium (3:2), (2-dicyclohexylphosphino-2', 6 '-diisopropyloxy-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) methanesulfonate, and palladium (II) acetate. In addition, the method of heating the mixture by microwave irradiation is sometimes advantageous in terms of smooth progress of the reaction.

As references for the reaction, for example, the following references can be referred to.

Synthesis 2020,52,p.2521-2527

PNAS2016,113,p.7124-7129

Or for example, a method for producing the compound (45) by a ullmann reaction of the compound (42) wherein R ⁷ is a group selected from the group consisting of the formula (XII), the formula (XIII), the formula (XIV), the formula (XV) and the formula (XVII) with the compound (41).

Angew.Chem.Int.Ed.,2003,42,p.5400-5449

In addition, this step is a method for producing the compound (45) by, for example, a decarbonation coupling reaction of the compound (42) in which R ⁷ is the formula (X) and the compound (41) when a ³ is a carboxyl group.

Science,2006,313,p.662-664

Further, this step is a method for producing the compound (45) by, for example, a bell wood-palace coupling reaction of the compound (42) in which R ⁷ is a group selected from the group consisting of the formula (IX), the formula (XI) and the formula (XVI) with the compound (41) when a ³ is a boric acid group or the like.

(Second step)

This step is a method for producing the compound (43) by a reaction in which the bromo group of the compound (41) is replaced with a boric acid group or the like.

Eur.J.Med.Chem.,2019,162,p.407-422

J.Org.Chem.2020,85,16,p.10966-10972

J.Am.Chem.Soc.,2010,132,p.17701-17703

(Third step)

This step is a method for producing compound (45) by a suzuki-miyaura coupling reaction of compound (44) with compound (43) when a ⁴ is a group selected from the group consisting of Cl, br and I.

In addition, this step is a method for producing the compound (45) by, for example, a Chan-Lam-Evans coupling reaction of the compound (44) which is a group selected from the group consisting of the formula (XII), the formula (XIII), the formula (XIV), the formula (XV) and the formula (XVII) with the compound (43) when A ⁴ is a hydrogen atom.

Adv.Synth.Catal.2020,362,p.3311-3331.

(Fourth step)

This step is a method for producing compound (7) by subjecting compound (45) to a deprotection reaction. Examples of the protecting group which can be deprotected under acidic conditions include t-butoxycarbonyl, triphenylmethyl, tetrahydro-2H-pyran-2-yl, methoxymethyl, dimethylmethane diyl, t-butylsulfinyl and the like.

(Synthesis of raw materials 10)

(Wherein PG ¹¹ represents a tert-butyl group, R ^3A represents-O-or-N (R ^P) -)

The present production method is a method for producing the raw material compounds (2) -3.

(First step)

This step is a method for producing the compound (46) by hydrolyzing the compound (8) -1.

The reaction is carried out by stirring the compound (8) -1 under cooling to a heated reflux for usually 0.1 hour to 5 days. Examples of the solvent used herein include, but are not particularly limited to, alcohols, acetone, DMF, THF, and the like. In addition, a mixed solvent of the solvent and water is sometimes preferable for the reaction. Examples of the hydrolysis reagent include, but are not particularly limited to, aqueous sodium hydroxide solution, aqueous potassium hydroxide solution, and the like.

Angew.Chem.Int.Ed.2005,44,p.1378-1382.

(Second step)

This step is a method for producing the compound (47) by protecting the hydroxyl group of the compound (46) with tert-butyl group (PG ¹¹).

The reaction is carried out by stirring the compound (46) under cooling to a heated reflux for usually 0.1 hour to 5 days. Examples of the solvent used herein include, but are not particularly limited to, ethers such as THF and DOX, halogenated hydrocarbons such as methylene chloride, tBuOH, DMF, and the like. Examples of the tertiary butyl protecting agent include, but are not particularly limited to, isobutylene, 2-tertiary butyl-1, 3-diisopropylisourea, and the like.

The compound (47) can be produced by a dehydration condensation reaction between the compound (46) and tBuOH.

P.g.m.wuts and T.W Greene, "Greene's Protective Groups in Organic Synthesis", 5 th edition, john Wiley & Sons inc., 2014

Org.Lett.,2012,14,17,p.4678-4681

(Third step)

This step is a method for producing compound (48) by in situ substitution reaction of compound (47) with R ^LG -SH.

The reaction conditions were the same as in the first step of raw material synthesis 4.

(Fourth step)

This step is a method for producing compound (49) by in situ substitution reaction of compound (48) with PG ³ -OH.

The reaction conditions were the same as in the third step of raw material synthesis 3.

(Fifth step)

This step is a method for producing the compound (50) by a suzuki-miyaura coupling reaction of the compound (49) with a boric acid derivative composed of an R ² -boric acid group or the like.

Compound (50) (here, R ² is hydrogen) can be produced by dehalogenation reaction using the Pd catalyst of compound (49) and a reducing agent.

[ Literature ]

J.Org.Chem.,1977,42,p.3491-3494

Tetrahedron Letters 2013,54,5207-5210

(Sixth step)

This step is a method for producing compound (51) by a suzuki-miyaura coupling reaction of compound (50) with compound (15).

The reaction conditions were the same as in the fifth step of raw material synthesis 3.

(Seventh step)

This step is a method for producing the compound (52) by oxidation reaction of the compound (51).

The reaction conditions were the same as in the fifth step of raw material synthesis 4.

The compound (52) may have an axial asymmetry, and may be obtained as a mixture of stereoisomers, and each stereoisomer may be isolated by performing a conventional resolution operation, for example, resolution using ODS column chromatography or silica gel column chromatography.

In order to be able to deprotect under different conditions from the later-introduced protecting group PG ¹, the compound (52) may be converted into another protecting group after the deprotection reaction.

Examples of the protecting group of the converted PG ² include tetrahydro-2H-pyran-2-yl and the like.

(Eighth step)

This step is a method for producing the compound (53) by performing deprotection by catalytic hydrogenation of the compound (52).

(Ninth step)

This step is a method for producing compound (54) by reacting compound (53) with compound (18).

(Tenth step)

This step is a method for producing compound (55) by in situ substitution reaction of compound (54) with compound (24).

The reaction conditions were the same as in the sixth step of raw material synthesis 4.

(Eleventh step)

This step is a method for producing the compound (56) by subjecting the compound (55) to a deprotection reaction.

(Twelfth step)

This step is a method for producing compound (2) -3 by reacting compound (56) with compound (9) -1.

In the present reaction, the compound (56) and the compound (9) -1 are used in equal amounts or in excess, and a mixture thereof is stirred for usually 0.1 hour to 5 days in the presence of a condensing agent, in a solvent inert to the reaction, under cooling to heating, preferably at-20℃to 60 ℃. Examples of the solvent include, but are not particularly limited to, aromatic hydrocarbons such as toluene, ethers such as THF and DOX, halogenated hydrocarbons such as methylene chloride, alcohols, DMF, DMSO, ethyl acetate, meCN, and mixtures of these. As examples of the condensing agent, pyBOP, HATU, CDI and the like are given. The reaction may be carried out in the presence of an organic base such as TEA, DIPEA or NMM or an inorganic base such as potassium carbonate, sodium carbonate or cesium carbonate, and it is advantageous in terms of smooth progress of the reaction.

(Raw material Synthesis 11)

The present production method is a method for producing (16) -1 wherein A is N in the raw material compound (16).

(First step)

This step is a method for producing compound (57) by an in-situ substitution reaction of compound (52) -1 with compound (24).

(Second step)

This step is a method for producing the compound (58) by subjecting the compound (57) to a deprotection reaction.

(Third step)

This step is a method for producing compound (16) -1 by reacting compound (58) with compound (9).

The reaction conditions were the same as in the twelfth step of the raw material synthesis 10.

(Raw materials Synthesis 12)

The present production method is a method for producing a raw material compound (57).

(First step)

This step is a method for producing compound (59) by an in-situ substitution reaction of compound (47) with compound (24).

The reaction conditions were the same as in the second step of raw material synthesis 3.

(Second step)

This step is a method for producing compound (60) by in situ substitution reaction of compound (59) with PG ³ -OH.

(Third step)

This step is a method for producing the compound (61) by a suzuki-miyaura coupling reaction of the compound (60) with a boric acid derivative composed of an R ² -boric acid group or the like.

Compound (61) (here, R ² is hydrogen) can be produced by dehalogenation reaction using the Pd catalyst of compound (60) and a reducing agent.

[ Literature ]

J.Org.Chem.,1977,42,p.3491-3494

Tetrahedron Letters 2013,54,5207-5210

(Fourth step)

This step is a method for producing compound (57) by a suzuki-miyaura coupling reaction of compound (61) with compound (15).

(Raw material Synthesis 13)

The present production method is a method for producing the raw material compound (20) -2.

(First step)

This step is a method for producing compound (8) -2 by chlorination of compound (62).

In the present reaction, the compound (62) and the chlorinating agent are used in equal amounts or in excess, and a mixture thereof is stirred for usually 0.1 hour to 5 days in a solvent inert to the reaction or in the absence of a solvent under cooling to a heating reflux, preferably at 60℃to a heating reflux. Examples of the solvent used herein include, but are not particularly limited to, aromatic hydrocarbons such as toluene, ethers such as THF and DOX, halogenated hydrocarbons such as methylene chloride, and the like. Examples of the chlorinating agent include phosphorus oxychloride and thionyl chloride. The manner of carrying out the reaction in the presence of an organic base such as TEA, DIPEA or NMM is sometimes advantageous in terms of smooth progress of the reaction.

(Second step)

This step is a method for producing compound (63) by in situ substitution reaction of compound (8) -2 with R ^LG -SH.

(Third step)

This step is a method for producing compound (64) by in situ substitution reaction of compound (63) with PG ³ -OH.

(Fourth step)

This step is a method for producing compound (20) -2 by in situ substitution reaction of compound (64) with compound (9) -1.

(Raw materials Synthesis 14)

The present production method is a method for producing the raw material compound (13) -2.

(First step)

This step is a method for producing compound (65) by in-situ substitution reaction of compound (8) -2 with compound (24).

In addition, compound (65) can be produced by coupling a compound that converts a hydrogen atom of compound (24) into a halogen with the root bank of compound (8) -2.

(Second step)

This step is a method for producing compound (66) by in situ substitution reaction of compound (65) with PG ³ -OH.

(Third step)

This step is a method for producing compound (13) -2 by an in-situ substitution reaction of compound (66) with compound (9) -1.

The reaction conditions are the same as in the first step of raw material synthesis 3, but the use of DMAc or the like as a solvent, the reaction at a reaction temperature of 0 ℃ to 120 ℃, and the use of potassium carbonate or the like as an inorganic base are sometimes advantageous in terms of smooth progress of the reaction.

(Raw material Synthesis 15)

(Wherein A ⁵ represents a group selected from the group consisting of Cl, br, mesylate and triflate, LG ³ represents a leaving group.)

The present production method is a method for producing a raw material compound (38) -1 and a raw material compound (38) -2 contained in a raw material compound (38).

(First step)

This step is a method for producing compound (70) -1 by reacting compound (67) with compound (69).

Chem.Commun.,2014,50,15,p.1867-1870

(Second step)

This step is a method for producing compound (70) -1 by the reaction of compound (69) with glyoxylic acid using an aryl-substituted tosylmethyl isonitrile (TosMIC) reagent.

J.Org.Chem.,2000,65,5,p.1516-1524

J.Am.Chem.Soc.,2007,129,3,p.490-491

(Third step)

This step is a process for the manufacture of compound (38) -1 by suzuki-miyaura coupling of compound (70) -1 with an alkoxymethylboronic acid derivative followed by deprotection under acidic conditions.

The reaction conditions of the suzuki-miyaura coupling reaction are the same as the fourth step of the raw material synthesis 3.

Examples of the alkoxymethylboronic acid derivative used herein include potassium (2-trimethylsilyl) -ethoxymethyltrifluoroborate.

Org.Lett.,2008,10,11,p.2135-2128

Org.Lett.,2011,13,15,p.3948-3951

The reaction conditions for the deprotection reaction under acidic conditions to be performed subsequently are the same as those described in production method 1. Examples of the acid used herein include trifluoroacetic acid and the like.

As references for deprotection reactions, for example, the following references can be referred to.

In addition, in this step, compound (38) -1 can be produced by suzuki-miyaura coupling reaction of compound (70) -1 with an acetoxymethylboronic acid derivative.

Org.Lett.,2012,14,5,p.1278-1281

(Fourth step)

This step is a method for producing compound (70) -2 by reacting compound (71) with compound (69).

In the present reaction, the compound (71) and the compound (69) are used in equal amounts or in excess, and a mixture thereof is stirred for usually 0.1 hour to 5 days in a solvent inert to the reaction or in the absence of a solvent under cooling to heating reflux, preferably at room temperature to heating reflux. Examples of the solvent used herein include, but are not particularly limited to, aromatic hydrocarbons such as toluene, ethers such as THF and DOX, halogenated hydrocarbons such as methylene chloride, DMF, DMSO, ethyl acetate, meCN, and the like. The reaction may be carried out in the presence of an organic base such as TEA, DIPEA or NMM or an inorganic base such as potassium carbonate, sodium carbonate or cesium carbonate, and it is advantageous in terms of smooth progress of the reaction.

(Fifth step)

This step is a process for the manufacture of compound (38) -2 by suzuki-miyaura coupling of compound (70) -2 with an alkoxymethylboronic acid derivative followed by deprotection under acidic conditions.

The reaction conditions are the same as in the third step of the raw material synthesis 15.

In addition, in this step, compound (38) -2 can be produced by suzuki-miyaura coupling reaction of compound (70) -2 with an acetoxymethylboronic acid derivative.

(Raw materials Synthesis 16)

( Wherein R ^3B represents a divalent group formed by removing 1 bond from a group selected from the group consisting of-P-Q, V and a saturated or unsaturated 7-to 8-membered bridged heterocyclic group, and X ¹ represents O or NR ^4x. The following is the same. )

The present production method is a method for producing a compound (87) -1 in which A and E in the raw material compound (87) of production method 2 are N, G is CR ², X is O or NR ^4x、L^Y is-O-CH ₂ -, L is a bond, and Z is the following formula (XXVII).

(First step)

This step is a method for producing compound (74) by reacting compound (72) with compound (73).

In this reaction, after converting the compound (72) into the corresponding enolate using an orthoester such as trimethyl orthoformate under acidic conditions, the compound (73) is added in an excess amount of one or both of the equivalent amounts, and the mixture is stirred in a solvent inert to the reaction under heating reflux, preferably at 60 ℃ to heating reflux, for usually 0.1 hour to 5 days. Examples of the solvent used herein include, but are not particularly limited to, aromatic hydrocarbons such as toluene, ethers such as THF and DOX, DMF, DMAc, and the like.

(Second step)

This step is a method for producing compound (75) from compound (74).

The reaction is carried out by stirring the compound (74) in a solvent inert to the reaction under heating reflux, preferably at 150℃to heating reflux, usually for 0.1 hour to 5 days. Examples of the solvent used herein include, but are not particularly limited to, NMP and the like.

(Third step)

This step is a method for producing compound (76) from compound (75).

In the present reaction, the compound (75) and the brominating agent are used in equal amounts or in excess, and a mixture thereof is stirred in a solvent inert to the reaction or in the absence of a solvent, under cooling to a reflux under heating, preferably at room temperature, for usually 0.1 hour to 5 days. Examples of the solvent used herein include, but are not particularly limited to, aromatic hydrocarbons such as toluene, ethers such as THF and DOX, halogenated hydrocarbons such as methylene chloride, DMF, and the like. Examples of the brominating agent include N-bromosuccinimide, N-bromophthalimide, 1, 3-dibromo-5, 5-dimethylhydantoin, dibromoisocyanuric acid, and the like.

(Fourth step)

This step is a method for producing compound (77) from compound (76).

The reaction conditions were the same as in the first step of the raw material synthesis 13.

(Fifth step)

This step is a method for producing compound (79) by in situ substitution reaction of compound (77) with compound (78).

(Sixth step)

This step is a method for producing compound (81) by in situ substitution reaction of compound (79) with compound (80).

(Seventh step)

This step is a method for producing compound (82) by in situ substitution reaction of compound (81) with PG ³ -OH.

(Eighth step)

This step is a method for producing compound (83) by a suzuki-miyaura coupling reaction of compound (82) with compound (15) which is a boric acid derivative.

When the compound (83) has an axiasymmetric structure, it is obtained as a mixture of stereoisomers, and each stereoisomer can be isolated by performing a conventional resolution operation, for example, resolution using ODS column chromatography or silica gel column chromatography.

In order to be able to deprotect under different conditions from the later-introduced protecting group PG ¹, the compound (83) may be converted into another protecting group after the deprotection reaction.

(Ninth step)

This step is a method for producing the compound (84) by deprotecting the compound (83) by catalytic hydrogenation.

(Tenth step)

This step is a method for producing compound (85) by reacting compound (84) with compound (18).

(Eleventh step)

This step is a method for producing compound (87) -1 by reacting compound (85) with compound (86).

The compounds of formula (I) and formula (IA) are isolated and purified as free compounds, salts, hydrates, solvates or polymorphs thereof or as amorphous solid forms of matter. Salts of the compounds of formula (I) and formula (IA) may also be produced by salt-forming reactions which are provided in conventional processes.

Isolation and purification can be carried out by ordinary chemical procedures such as extraction, fractional crystallization, and various fractional chromatographs.

The individual isomers may be produced by selecting an appropriate starting compound, or may be separated by utilizing differences in physicochemical properties between the isomers. For example, the optical isomer may be obtained by a general optical resolution method of a racemate (for example, fractional crystallization to a stereoisomer salt with an optically active base or acid, chromatography using a chiral column or the like), or may be produced from an appropriate optically active starting compound.

In addition, the compounds of formula (I) and formula (IA) or intermediates thereof sometimes have axial asymmetry, are obtained as a mixture of stereoisomers, and each stereoisomer may be isolated by performing a conventional resolution operation, for example, resolution using Octadecylsilyl (ODS) column chromatography, silica gel column chromatography.

The pharmacological activity of the compounds of formula (I) and formula (IA) was confirmed by the following test.

Experimental example 1 evaluation of KRAS decomposition of human G12D mutant KRAS-positive pancreatic cancer Strain AsPC-1 (CRL-1682; ATCC)

The KRAS degradation by the test compound was evaluated by measuring the KRAS G12D expression level by the cell ELISA method.

AsPC-1 cells were seeded at 2.0X10 ⁴ cells per well in 384-well plates (Greiner bio-one Co.) in 20. Mu.L each. For cell culture conditions, RPMI1640 (Sigma-Aldrich) medium containing 10% fetal bovine serum (Cytiva Co.) was used in the presence of 5% CO ₂ at 37 ℃.

The next day, the test compound (final concentration in the range of 10. Mu.M to 0.3nM, 10 spots) and DMSO (Fuji photo-pure Co., ltd.) as a solvent for the test compound as a negative control were diluted 500-fold with fresh medium, and 20. Mu.L of each of the wells was added thereto, followed by culturing overnight.

The next day, the culture supernatant was removed, 20. Mu.L of 4% paraformaldehyde phosphate buffer (Fuji photo-Co., ltd.) was added to each well, and the mixture was allowed to stand at room temperature for 30 minutes to fix the cells. The supernatant was removed, and 20. Mu.L of phosphate-buffered saline (PBS; fuji film and Wako pure chemical industries, ltd.) containing 0.1% Triton X-100 (Amersham Biosciences Co.) was added to each well. After standing at room temperature for 10 minutes, the supernatant was removed, 25. Mu.L of PBS was added to each well, and the supernatant was removed, thereby washing each well. The washing was performed 2 times in total. Then, the supernatant was removed, and 20. Mu.L of PBS containing 0.5% sodium dodecyl sulfate (SDS; invitrogen) was added to each well. After standing at room temperature for 10 minutes, the supernatant was removed by centrifugation (using a centrifugal dehydrator, the supernatant was removed by the same method as described below), 25. Mu.L of PBS was added to each well, and the supernatant was removed, thereby washing each well. The washing was performed 2 times in total. The supernatant was removed, and 20. Mu.L of a blocking solution (INTERCEPT BLOCKING BUFFER; li-COR Biosciences Co.) was added to each well. After leaving at room temperature for 30 minutes, the supernatant was removed, 20. Mu.L of a 1000-fold solution of an Anti- β -actin antibody (Anti-beta Actin antibody [ mAbcam 8226] -Loading Control; abcam) diluted with a blocking solution was added to the wells used as a positive control, and 20. Mu.L of a 1000-fold solution of an Anti-Ras (G12D Mutant Specific) antibody (Ras (G12 DMutant Specific) (D8H 7) Rabbit mAb #14429;Cell Signaling Technology) and an Anti- β -actin antibody (abcam) were added to the other wells and allowed to stand at 4℃overnight.

The next day, the supernatant was removed, 25. Mu.L of PBS was added to each well, and the supernatant was removed, thereby washing each well. The washing was performed 2 times in total. The supernatant was removed, and 20. Mu.L of a 1000-fold dilution of donkey anti-mouse IgG H & L (IRDye 680 RD) (Li-COR Biosciences) and goat anti-rabbit IgG H & L (IRDye 800 CW) (Li-COR Biosciences) as secondary antibodies was added to each well. After standing at room temperature for 1 hour, the supernatant was removed, 25. Mu.L of PBS was added to each well, and the supernatant was removed, thereby washing each well. The washing was performed 2 times in total. After removing the supernatant, the plate was air-dried at room temperature for 2 hours or more, and fluorescence signals at 700nm and 800nm were measured with Aerius (Li-COR Biosciences).

After correcting the signal value of RAS measured at a fluorescence wavelength of 800nm with the signal value of beta-actin measured at a fluorescence wavelength of 700nm, the signal value when DMSO was added was set to 0%, the signal value when staining with only anti-beta-actin antibody was set to 100%, and the 50% decomposition value (DC ₅₀) of KRAS was calculated by nonlinear regression analysis of the Sigmoid-Emax model. The results of several test compounds of formula (I) and formula (IA) are shown in the following table.

[ Table 1-1]

Ex	DC₅₀(nM)	Ex	DC₅₀(nM)	Ex	DC₅₀(nM)
						1	13	19	91	37	58
2	20	20	41	38	25
						3	47	21	33	39	37
4	35	22	59	40	47
						5	9	23	31	41	29
6	24	24	48	42	91
						7	40	25	75	43	41
8	18	26	22	44	43
						9	15	27	68	45	27
10	18	28	47	46	25
						11	10	29	20	47	26
12	61	30	121	48	38
						13	10	31	59	49	25
14	20	32	51	50	18
						15	99	33	33	51	14
16	26	34	53	52	11
						17	74	35	63	53	7
18	508	36	82	54	34

[ Tables 1-2]

Ex	DC₅₀(nM)
		55	10

Test example 2 evaluation of ERK phosphorylation inhibition by human G12D mutant KRAS positive pancreatic cancer strain AsPC-1

Phosphorylation of threonine 202 (Thr 202) and tyrosine 204 (Tyr 204) of ERK downstream of KRAS signal was measured by cell ELISA, whereby inhibition of ERK phosphorylation by test compounds was assessed.

AsPC-1 cells were seeded at 36 μl/well in 384-well plates at 2.0x10 ⁴ cells per well. For cell culture conditions, RPMI1640 medium containing 10% fetal bovine serum was used, performed in the presence of 5% co ₂ at 37 ℃.

The next day, the test compound (final concentration ranging from 10. Mu.M to 0.3nM, 10 spots), trimetinib (MEK inhibitor) as a positive control, and solvent DMSO as a negative control, were diluted 100-fold with fresh medium, and after adding 4. Mu.L each to each well, cultured overnight. After the incubation, 30. Mu.L of 30% glyoxal (40% glyoxal (Nacalai Tesque) was diluted with PBS) was added to each well, and the mixture was allowed to stand at room temperature for 60 minutes to fix the cells. After that, the plate was centrifuged to remove the supernatant (using a centrifugal dehydrator, the supernatant was removed by the same method as described below), and 20. Mu.L of PBS containing 0.1% Triton X-100 was added to each well. After leaving at room temperature for 10 minutes, the supernatant was removed, and the same operation was repeated. Then, 20. Mu.L of PBS containing 0.5% SDS was added to each well, and the mixture was allowed to stand at room temperature for 30 minutes, followed by removal of the supernatant. Next, 20. Mu.L of the blocking solution (INTERCEPT BLOCKING BUFFER) was added to each well, and the mixture was allowed to stand at room temperature for 1 hour. The supernatant was removed, and 15. Mu.L of a phosphorylated antibody (Phospho-p 44/42MAPK (Erk 1/2) (Thr 202/Tyr 204) (D13.14.4E) XP Rabbit mAb; cell SignalingTechnology) of ERK (Thr 202/Tyr 204) diluted 2500-fold with a blocking solution as a primary antibody was added to each well and allowed to stand at 4℃overnight.

The next day, the supernatant was removed, and 50. Mu.L of PBS containing 0.05% Tween-20 (Thermo FISHER SCIENTIFIC Co.) was added to each well, and the supernatant was removed, whereby each well was washed. The washing was performed 3 times in total. After washing, 15. Mu.L of goat anti-rabbit IgG H & L (IRDye 800 CW) diluted 1000-fold with blocking solution as secondary antibody was added to each well and allowed to stand at room temperature for 1 hour. The supernatant was removed, and each well was washed 3 times similarly after the reaction with PBS containing 0.05% Tween-20 and primary antibody. After removing the supernatant, the plate was air-dried at room temperature for 3 hours or more, and the fluorescent signal at 800nm was measured by Aerius.

The 50% inhibition value (IC ₅₀) was calculated by nonlinear regression analysis of the Sigmoid-Emax model, with the signal value at the time of DMSO addition set to 100% and the signal value at the time of 1. Mu.M addition set to 0%. The results of several test compounds of formula (I) and formula (IA) are shown in the following table.

[ Table 2-1]

Ex	IC₅₀(nM)	Ex	IC₅₀(nM)	Ex	IC₅₀(nM)
						1	7	19	95	37	32
2	9	20	38	38	36
						3	16	21	47	39	57
4	8	22	5	40	7
						5	12	23	13	41	9
6	5	24	15	42	6
						7	9	25	6	43	7
8	20	26	2	44	31
						9	11	27	7	45	16
10	8	28	5	46	6
						11	24	29	6	47	22
12	42	30	10	48	15
						13	8	31	20	49	32
14	4	32	37	50	8
						15	7	33	45	51	59
16	16	34	21	52	4
						17	7	35	12	53	9
18	100	36	21	54	5

[ Table 2-2]

Ex	IC₅₀(nM)
		55	4
56	17

Test example 3 evaluation of the inhibition of adherent independent cell proliferation of human G12D mutant KRAS-positive pancreatic cancer Strain AsPC-1

The inhibition of cell proliferation by the test compound was evaluated by spherical three-dimensional culture.

AsPC-1 cells were seeded at 36 μl/well in a cell low adsorption U-bottom 384-well plate (PrimeSurface: sumitomo electric company) at 5×10 ² cells per well. For cell culture conditions, RPMI1640 medium containing 10% fetal bovine serum was used, performed in the presence of 5% co ₂ at 37 ℃.

The next day, the test compound (final concentration ranging from 10. Mu.M to 0.3nM, 10 spots or 6 spots) and the solvent DMSO of the test compound as a negative control were diluted 100-fold with fresh medium, and 4. Mu.L of each was added to each well. After 6 days of incubation at 37℃in the presence of 5% CO ₂, 20. Mu.L of CellTiter-Glo2.0 (Promega Co.) was added to each well. After stirring at normal temperature for 1 hour using a flat plate mixer (FINEPCR Co.), the luminescence signal was measured by ARVO X3 (Perkinelmer Co.).

The signal value at DMSO treatment was set to 100%, the signal value at medium alone in the absence of cells was set to 0%, and the 50% inhibition value (IC ₅₀) was calculated by Sigmoid-Emax model nonlinear regression analysis. The results of several test compounds of formula (I) and formula (IA) are shown in the following table.

[ Table 3-1]

Ex	IC₅₀(nM)	Ex	IC₅₀(nM)	Ex	IC₅₀(nM)
						1	9	19	50	37	32
2	92	20	21	38	36
						3	7	21	53	39	39
4	7	22	5	40	6
						5	10	23	12	41	8
6	8	24	26	42	4
						7	23	25	6	43	6
8	16	26	3	44	17
						9	9	27	7	45	15
10	6	28	5	46	5
						11	19	29	7	47	15
12	41	30	12	48	16
						13	10	31	18	49	10
14	4	32	24	50	8
						15	7	33	24	51	44
16	14	34	13	52	4
						17	8	35	9	53	10
18	73	36	19	54	7

[ Table 3-2]

Ex	IC₅₀(nM)
		55	15
56	73

[ Tables 3-3]

Ex	IC₅₀(nM)
		57	95

Test example 4 evaluation of antitumor Effect of human G12D mutant KRAS-positive pancreatic cancer Strain PK-59 tumor-bearing mice

PK-59 cells (RIKEN BRC, RCB 1901) were cultured in RPMI1640 medium containing 10% fetal bovine serum in the presence of 5% CO ₂ at 37 ℃. PK-59 cells were recovered, suspended in PBS, prepared to 1.0 to 2.0X10/⁷/mL by adding an equal amount of matrigel (Becton, dickinson and Company), and the resulting cell suspension was subcutaneously implanted in 4 to 5-week-old male nude mice (CanN.Cg-Foxnl ^nu/CrlCrlj (nu/nu), CHARLES RIVER Laboratories Japan) at a capacity of 100. Mu.L. After about 2 weeks of implantation, the groups were grouped in such a way that the tumor volume and body weight were approximately the same between the groups, and administration of the test compound was started the next day. The test was performed in 5 groups of solvent and test compound administration. The compound was dissolved in ethanol (Fuji photo-pure chemical), 5% dextrose solution (tsukamurelca pharmaceutical), 1M hydrochloric acid (kandong chemical), 50% (2-hydroxypropyl) -beta-cyclodextrin (HP-beta CD) aqueous solution (ROQUETTE), HCO-40 (solar chemical), 1M sodium hydroxide aqueous solution (kandong chemical) at a liquid ratio of 4:84.4:1.1:1:9:0.5 in a solvent. The test compound or solvent dissolved with each solvent is administered into the tail vein. The administration was twice at intervals of once a week. Tumor diameter and body weight measurements were performed 2 times every 1 week. The tumor volume was calculated using the following formula.

[ Tumor volume (mm ³) ]= [ tumor major diameter (mm) ]× [ tumor minor diameter (mm) ] ² ×0.5

The tumor growth inhibition (%) by the test compound was calculated by setting the tumor volume of the test compound administration group at the day before the start of administration to 100% inhibition and the tumor volume of the solvent group at 2 weeks after the first administration to 0% inhibition. When the tumor volume of the test compound administration group was lower than the tumor volume of the day before the administration start, the tumor volume of the day before the administration start was set to 0% regression, and the tumor volume 0 was set to 100% regression, and the tumor regression rate (%) of the test compound was calculated. The results of several test compounds of formula (I) and formula (IA) are shown in the following table.

TABLE 4

Ex	Dosage (mg/kg)	The first administration has anti-tumor effect after 2 weeks
			9	10	81% Inhibition
11	10	6% Withdrawal
			13	10	26% Recession
50	10	20% Withdrawal
			53	10	53% Withdrawal

Test example 5 evaluation of KRAS G12D/SOS/c-Raf Complex formation inhibitory Effect

The inhibition of complex formation of these proteins by test compounds was investigated by time resolved fluorescence resonance energy transfer (TR-FRET) using human recombinant KRAS G12D, SOS and c-Raf proteins.

To 384 well plates (Corning Corp.) 40000nM to 40nM of biotinylated AviTag-KRAS G12D (amino acid region 1-185, GDP) (2.5. Mu.L; 400 nM) and test compound dissolved in assay buffer (50 mM HEPES [ Jena Corp. ],150mM NaCl[Nacalai Tesque Co., 5mM MgCl ₂ [ Thermo FISHER SCIENTIFIC Co., 0.05% Tween 20[ Sigma-Aldrich Corp. ], pH 7.0) were added in an amount of 2.5. Mu.L. To this was added c-Raf (amino acid region 51-131) GST (2.5. Mu.L; 130 nM) containing Son of Sevenless (SOS) (amino acid region 564-1049,2.5. Mu.L; 1.3. Mu.M), GTP (Sigma-Aldrich Co.; 2. Mu.M) and allowed to stand at room temperature for 1 hour. Next, a mixture (10. Mu.L) of LANCE Ulight-anti-GST (Perkinelmer; 120 nM) and LANCE Eu-W1024 labeled Streptoavidin (Perkinelmer; 100 ng/mL) was added, and the fluorescence intensities at 620nM and 665nM were measured using EnVision 2104 (Perkinelmer) at an excitation wavelength of 337 nM. After normalizing the value with the fluorescence intensity of the reference wavelength of 620nm, the signal value at the solvent treatment was set to 0% inhibition, the signal value at the time of no addition of GTP was set to 100% inhibition, and the 50% inhibition concentration (IC ₅₀) was calculated by Sigmoid-Emax model nonlinear regression analysis.

As a result of the above-described test, G12D mutant KRAS decomposition was confirmed for several compounds of the formula (I) and the formula (IA) (test example 1). In addition, inhibition of G12D mutant KRAS was confirmed (test example 5). Furthermore, the compounds of the formula (IA) and the dry type (I) showed an inhibition of the phosphorylation of ERK located downstream of the KRAS signal (test example 2). In addition, several compounds of the formula (I) and the formula (IA) were confirmed to have an inhibitory effect on cell proliferation of a human G12D mutant KRAS-positive pancreatic cancer strain (test example 3) and an antitumor effect in tumor-bearing mice of a human G12D mutant KRAS-positive pancreatic cancer strain (test example 4). Thus, the compounds of formula (I) and formula (IA) may be used in the treatment of pancreatic cancer, in particular G12D mutant KRAS positive pancreatic cancer, etc.

The pharmaceutical composition containing 1 or 2 or more of the compounds of formula (I) and formula (IA) or salts thereof as an active ingredient can be prepared by a method generally used using an excipient commonly used in the art, that is, a pharmaceutical excipient or a pharmaceutical carrier, and the like.

The administration may be by oral administration such as tablet, pill, capsule, granule, powder, liquid, etc., or parenteral administration such as intra-articular, intravenous, intramuscular, etc., by injection, transmucosal, inhalation, etc.

As the solid composition for oral administration, tablets, powders, granules and the like can be used. In such solid compositions, 1 or more than 2 active ingredients are mixed with at least one inert excipient. The compositions may contain inert additives, such as lubricants, disintegrants, stabilizers, dissolution aids, according to conventional methods. The tablets or pills may be coated with sugar coatings or films of gastric or enteric substances, as desired.

Liquid compositions for oral administration contain pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs and the like, containing inert diluents commonly used, such as purified water or EtOH. The liquid composition may contain, in addition to the inert diluent, an auxiliary agent such as a solubilizer, a wetting agent, a suspending agent, a sweetener, a flavoring agent, a fragrance, and a preservative.

Injections for parenteral administration contain sterile aqueous or nonaqueous solutions, suspensions or emulsions. The aqueous solvent includes, for example, distilled water for injection or physiological saline. Examples of the nonaqueous solvent include alcohols such as EtOH. Such compositions may also contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers or dissolution aids. They are sterilized, for example, by filtration through a bacteria-retaining filter, compounding of bactericides or irradiation. In addition, they can also be prepared as sterile solid compositions and used dissolved or suspended in sterile water or sterile injectable solvents prior to use.

The transmucosal agent such as inhalant and nasal agent may be solid, liquid or semi-solid, and may be produced by a conventionally known method. For example, a known excipient, a pH adjuster, a preservative, a surfactant, a lubricant, a stabilizer, a thickener, and the like can be appropriately added. Administration may use means for appropriate inhalation or blowing. For example, the compounds may be administered as solutions or suspensions, alone or in the form of powders forming a formulated mixture, or in combination with pharmaceutically acceptable carriers, using well-known devices such as metered dose inhalation devices or nebulizers. The dry powder inhaler and the like may be one or more dose inhalers, and dry powder or powder-containing capsules may be used. Or may be a pressurized aerosol spray using a suitable propellant, for example, a suitable gas such as chlorofluoroalkane or carbon dioxide.

In general, in the case of oral administration, the amount of administration for 1 day is suitably about 0.001 to 100mg/kg, preferably 0.1 to 30mg/kg, more preferably 0.1 to 10mg/kg per unit weight, and it is administered 1 time or divided into 2 to 4 times. In the case of intravenous administration, the amount administered per day is suitably from about 0.0001 to 10mg/kg per unit body weight, and is divided into a plurality of administrations from once a day. As the transmucosal agent, administration is carried out once a day to several times per unit weight of about 0.001 to 100 mg/kg. The amount to be administered may be appropriately determined in consideration of symptoms, age, sex, etc., according to the respective cases.

The pharmaceutical composition of the present invention contains 0.01 to 100% by weight, and in one embodiment contains 0.01 to 50% by weight of 1 or more compounds of formula (I) and formula (IA) or salts thereof as an active ingredient, although it varies depending on the route of administration, dosage form, site of administration, excipient or kind of additive.

The compounds of formula (I) and formula (IA) may be used in combination with various therapeutic or prophylactic agents for diseases in which the compounds of formula (I) and formula (IA) described above are considered to be effective. The combination may be administered simultaneously, or separately, either sequentially or at desired intervals. The simultaneous administration preparation may be a compounding agent or may be formulated separately.

Examples

The following describes in further detail the methods for producing the compounds of formula (I) and formula (IA) based on examples. The present invention is not limited to the compounds described in the following examples. The production methods of the raw material compounds are shown in the production examples. The production methods of the compounds of the formula (I) and the formula (IA) are not limited to the production methods of the specific examples shown below, and the compounds of the formula (I) and the formula (IA) may be produced by a combination of these production methods or a method obvious to those skilled in the art.

In the present specification, naming software such as ACD/Name (registered trademark, ADVANCED CHEMISTRY Development, inc.) may be used for naming the compound.

In addition, for convenience, the concentration mol/L is denoted as M. For example, 1M aqueous sodium hydroxide solution refers to 1mol/L aqueous sodium hydroxide solution.

The term "amorphous solid form" as used herein includes: the powder X-ray diffraction (XRD) pattern showed no peak morphology and a morphology with low crystallinity.

XRD was performed using Empyrean at the tube ball: cu, tube current: 40mA, tube voltage: 45kV, step size: 0.013 °, wavelength: Determination of diffraction angle range (2θ): measured at 2.5-40 deg.

Production example 1

7-Bromo-2, 4-dichloro-8-fluoro-6-iodoquinazoline (40 g) was suspended in THF (400 mL), and aqueous sodium hydroxide solution (1M, 190 mL) was added dropwise under ice cooling at an internal temperature of 10℃or less, followed by stirring for 2 hours. Into a conical flask containing hydrochloric acid (1M, 190 mL) and ice water (about 900 g), the reaction solution was poured in one portion and stirred at room temperature for about 30 minutes (until ice melted). Insoluble material was collected by filtration while washing with water, and dried under reduced pressure, whereby 7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-ol (33.56 g) was obtained as a solid.

Production example 2

To a mixture of 7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-ol (24.6 g) and THF (260 mL) heated to 60 ℃ was added dropwise 2-tert-butyl-1, 3-diisopropylisourea (73.4 g) under a nitrogen stream over 15 minutes. Stirred at this temperature for 2.5 hours. The mixture was cooled to room temperature and the colorless solid was filtered off while washing with THF (about 500 mL). To the solid obtained by concentrating the filtrate was added MeOH (210 mL), and the mixture was stirred at room temperature for 1 hour to be washed in suspension. The solid was filtered using MeOH (100 mL) to give 7-bromo-4-tert-butoxy-2-chloro-8-fluoro-6-iodoquinazoline (23.2 g) as a solid.

Production example 3

To a suspension of 7-bromo-4-tert-butoxy-2-chloro-8-fluoro-6-iodoquinazoline (21 g) in CH ₂Cl₂ (200 mL) was added ethanethiol (3.6 mL) and DABCO (7.7 g) at room temperature, and stirred overnight at room temperature under an argon atmosphere. The reaction was stopped by adding water under ice-cooling. CHCl ₃ was added, the organic and aqueous layers were separated, and the aqueous layer was extracted 3 times with CHCl ₃.

The collected organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 7-bromo-4-tert-butoxy-2- (ethylsulfanyl) -8-fluoro-6-iodoquinazoline (23.4 g) as a solid.

Production example 5

To a suspension of 7-bromo-4-tert-butoxy-2-chloro-8-fluoro-6-iodoquinazoline (15 g) and tetrahydro-2H-pyran-4-ol (4.67 mL) in DMF (75 mL)/THF (75 mL) under nitrogen atmosphere was added cesium carbonate (21.3 g) and DABCO (360 mg) under ice-cooling, stirred at the temperature of this state for 10 minutes, and stirred at room temperature overnight. The reaction mixture was filtered through celite (registered trademark), washed with ethyl acetate, water was added to the filtrate, and extracted 2 times with ethyl acetate. The combined organic layers were washed with a half saturated aqueous sodium chloride solution and a saturated aqueous sodium chloride solution in this order, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. To the resulting solid was added MeOH (50 ml) and stirred at room temperature for 30 min. The resulting solid was collected by filtration, washed with MeOH (40 ml), and dried under reduced pressure to give 7-bromo-4-tert-butoxy-8-fluoro-6-iodo-2- [ ("A") as a solidAlk-4-yl) oxy ] quinazoline (13.83 g).

Production example 6

To a solution of 7-bromo-4-tert-butoxy-2- (ethylsulfanyl) -8-fluoro-6-iodoquinazoline (32 g) and (1S) -1-phenylethan-1-ol (11 mL) in THF (400 mL) was added tBuOK (10 g) under ice cooling, and stirred under ice cooling under argon atmosphere for 1 hour. A saturated aqueous ammonium chloride solution was added under ice cooling to stop the reaction. Water and ethyl acetate were added, and the organic layer and the aqueous layer were separated, and the organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 7-bromo-4-tert-butoxy-2- (ethylsulfanyl) -6-iodo-8- [ (1S) -1-phenylethoxy ] quinazoline (36.6 g) as an oil.

Production example 9

7-Bromo-4-tert-butoxy-2- (ethylsulfanyl) -6-iodo-8- [ (1S) -1-phenylethoxy ] quinazoline (36.6 g), cyclopropylboronic acid (7.5 g), pdCl ₂(dppf)·CH₂Cl₂ (7.6 g), potassium phosphate (53 g), meCN (440 mL) and water (80 mL) were mixed at room temperature and stirred under argon atmosphere at 90℃for 4 hours. After allowing the reaction solution to return to room temperature, it was diluted with ethyl acetate and water. The organic layer and the aqueous layer were separated, and the organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 7-bromo-4-tert-butoxy-6-cyclopropyl-2- (ethylsulfanyl) -8- [ (1S) -1-phenylethoxy ] quinazoline (22.9 g) as an oil.

PREPARATION EXAMPLE 13

To 7-bromo-4-tert-butoxy-6-cyclopropyl-2- (ethylsulfanyl) -8- [ (1S) -1-phenylethoxy ] quinazoline (14.21 g) was added 6-fluoro-5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2- (triphenylmethyl) -2H-indazole (19.3 g), palladium (II) acetate (0.67 g), dicyclohexyl (2 ',6' -diisopropyloxy- [1,1' -biphenyl ] -2-yl) phosphine (2.67 g), anhydrous barium hydroxide (14.6 g) and DOX (500 mL)/water (100 mL), and after multiple degassing and argon substitution operations were performed, the mixture was heated and stirred overnight at 50℃under argon atmosphere. The reaction suspension which was left to cool naturally was filtered through celite (registered trademark) while being washed with ethyl acetate to remove grey insoluble matters. After concentrating the filtrate under reduced pressure to about 1/4, water was added and extraction was performed 2 times with ethyl acetate. The collected organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 4-tert-butoxy-6-cyclopropyl-2- (ethylsulfanyl) -7- [ 6-fluoro-5-methyl-2- (triphenylmethyl) -2H-indazol-4-yl ] -8- [ (1S) -1-phenylethoxy ] quinazoline (from an about 3.3:1 diastereomer mixture of axi-asymmetry, 16.44 g) as a solid.

PREPARATION EXAMPLE 14

Allowing 7-bromo-4-tert-butoxy-6-cyclopropyl-2- [ (] at room temperatureAlk-4-yl) oxy ] -8- [ (1S) -1-phenylethoxy ] quinazoline (500 mg) and 6-fluoro-5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2- (triphenylmethyl) -2H-indazole (670 mg) were dissolved in DOX (10 mL), palladium (II) acetate (22 mg), dicyclohexyl (2 ',6' -diisopropyloxy- [1,1' -biphenyl ] -2-yl) phosphine (87 mg), anhydrous barium hydroxide (870 mg) and water (1 mL) were added at room temperature and stirred for 45 minutes at 50 ℃. DOX (5 mL) and 6-fluoro-5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2- (triphenylmethyl) -2H-indazole (90 mg) were added at the temperature in this state, and stirred at the temperature in this state for 30 minutes. The reaction mixture was cooled naturally, ethyl acetate and celite (registered trademark) were added, and after stirring at room temperature for 30 minutes, the reaction solution was filtered through celite (registered trademark), and the filtrate was concentrated. The resulting residue was purified by silica gel chromatography (basic silica gel, hexane/ethyl acetate). To the resulting solid was added iPrOH (40 mL), stirred at 50℃for 1 hour, at room temperature for 2 hours, and the resulting solid was collected by filtration to give 4-tert-butoxy-6-cyclopropyl-7- [ 6-fluoro-5-methyl-2- (triphenylmethyl) -2H-indazol-4-yl ] -2- [ (-2- [ ] as a solidAlk-4-yl) oxy ] -8- [ (1S) -1-phenylethoxy ] quinazoline (from an axi-asymmetric about 1:1, a mixture of diastereomers of formula 1 296 mg). Concentrating the filtrate to obtain the target compound (7M) -4-tert-butoxy-6-cyclopropyl-7- [ 6-fluoro-5-methyl-2- (triphenylmethyl) -2H-indazol-4-yl ] -2- [ (-) -2- [ ] in solid formAlk-4-yl) oxy ] -8- [ (1S) -1-phenylethoxy ] quinazoline (single diastereomer, 409 mg).

Production example 15

(3S) -3- ({ 7-bromo-6-cyclopropyl-2- (ethylsulfanyl) -8- [ (1S) -1-phenylethoxy ] quinolin-4-yl } oxy) pyrrolidine-1-carboxylic acid tert-butyl ester (2.71 g), 6-fluoro-5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2- (triphenylmethyl) -2H-indazole (3.44 g), dicyclohexyl (2 ',6' -diisopropyloxy- [1,1' -biphenyl ] -2-yl) phosphine (531 mg), palladium (II) acetate (106 mg), anhydrous barium hydroxide (2.29 g) were suspended in DOX (110 mL) and water (22 mL) under an argon atmosphere, and stirred at 50℃for 15 minutes. 6-fluoro-5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2- (triphenylmethyl) -2H-indazole (1.6 g) was added and stirred at 50℃for a further 15 minutes. Cooled to room temperature, ethyl acetate and water were added, insoluble matters were removed by filtration through celite (registered trademark), and two layers of the filtrate were separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering off the drying agent, concentration under reduced pressure, the residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate) to give (3S) -3- ({ 6-cyclopropyl-2- (ethylsulfanyl) -7- [ 6-fluoro-5-methyl-2- (triphenylmethyl) -2H-indazol-4-yl ] -8- [ (1S) -1-phenylethoxy ] quinolin-4-yl } oxy) pyrrolidine-1-carboxylic acid tert-butyl ester (from an about 5:1 diastereomeric mixture of axial asymmetry, 3.88 g) as an oil.

To tert-butyl (3S) -3- ({ 6-cyclopropyl-2- (ethylsulfanyl) -7- [ 6-fluoro-5-methyl-2- (triphenylmethyl) -2H-indazol-4-yl ] -8- [ (1S) -1-phenylethoxy ] quinolin-4-yl } oxy) pyrrolidine-1-carboxylate (from a mixture of diastereomers of about 5:1, which were axi-asymmetric, 100 mg) was added MeOH (2 mL) and heated to 70℃to dissolve it. Stir at room temperature overnight for a further 3 days. The precipitation of solids (pale yellow suspension) was confirmed. The solid was filtered off and washed with a small amount of MeOH to give (3S) -3- ({ 6-cyclopropyl-2- (ethylsulfanyl) -7- [ 6-fluoro-5-methyl-2- (triphenylmethyl) -2H-indazol-4-yl ] -8- [ (1S) -1-phenylethoxy ] quinolin-4-yl } oxy) pyrrolidine-1-carboxylic acid tert-butyl ester (from an axiasymmetric about 1:1 mixture of diastereomers, 21 mg) as a powder. The filtrate was concentrated to give the target tert-butyl (3S) -3- ({ 6-cyclopropyl-2- (ethylsulfanyl) -7- [ 6-fluoro-5-methyl-2- (triphenylmethyl) -2H-indazol-4-yl ] -8- [ (1S) -1-phenylethoxy ] quinolin-4-yl } oxy) pyrrolidine-1-carboxylate (single diastereomer of unknown configuration, 70 mg) as a solid.

Likewise, to tert-butyl (3S) -3- ({ 6-cyclopropyl-2- (ethylsulfanyl) -7- [ 6-fluoro-5-methyl-2- (triphenylmethyl) -2H-indazol-4-yl ] -8- [ (1S) -1-phenylethoxy ] quinolin-4-yl } oxy) pyrrolidine-1-carboxylate (from a mixture of diastereomers of about 5:1, from the axis asymmetry, 2.95 g) was added EtOH (6 mL) and heated to 70deg.C to dissolve it. A trace of the powder of the axiasymmetric mixture (obtained as described above) was added at room temperature and stirred at room temperature overnight. The precipitated solid was collected by filtration and washed with a small amount of EtOH to give (3S) -3- ({ 6-cyclopropyl-2- (ethylsulfanyl) -7- [ 6-fluoro-5-methyl-2- (triphenylmethyl) -2H-indazol-4-yl ] -8- [ (1S) -1-phenylethoxy ] quinolin-4-yl } oxy) pyrrolidine-1-carboxylic acid tert-butyl ester (from an axi-asymmetric about 1:1 mixture of diastereomers, 699 mg) as a colorless powder. The filtrate was concentrated to give the target tert-butyl (3S) -3- ({ 6-cyclopropyl-2- (ethylsulfanyl) -7- [ 6-fluoro-5-methyl-2- (triphenylmethyl) -2H-indazol-4-yl ] -8- [ (1S) -1-phenylethoxy ] quinolin-4-yl } oxy) pyrrolidine-1-carboxylate (single diastereomer of unknown configuration, 2.33 g) as a foamy solid.

Production example 17

4-Tert-butoxy-6-cyclopropyl-2- (ethylsulfanyl) -7- [ 6-fluoro-5-methyl-2- (triphenylmethyl) -2H-indazol-4-yl ] -8- [ (1S) -1-phenylethoxy ] quinazoline (diastereomer mixture from about 3.3:1 of axial asymmetry, 33.71 g) was dissolved in CH ₂Cl₂ (500 mL), and m-chloroperbenzoic acid (containing about 30% and 22.4 g) (inner temperature: 5-10 ℃ C.) was added under ice cooling, and stirred at room temperature for 2 hours. To the reaction solution, an aqueous solution (300 mL) of sodium thiosulfate pentahydrate (11 g) and a saturated aqueous solution (300 mL) of sodium hydrogencarbonate were poured under ice-cooling, and after stirring at room temperature for 30 minutes, the mixture was extracted 2 times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 4-tert-butoxy-6-cyclopropyl-2- (ethanesulfonyl) -7- [ 6-fluoro-5-methyl-2- (triphenylmethyl) -2H-indazol-4-yl ] -8- [ (1S) -1-phenylethoxy ] quinazoline (from an axiasymmetric diastereomer mixture). To the resulting residue was added iPrOH (1000 mL), and stirred at room temperature overnight. The resulting solid was collected by filtration, washed with iPrOH, and dried under reduced pressure to give 4-tert-butoxy-6-cyclopropyl-2- (ethanesulfonyl) -7- [ 6-fluoro-5-methyl-2- (triphenylmethyl) -2H-indazol-4-yl ] -8- [ (1S) -1-phenylethoxy ] quinazoline (about 1:1 diastereomer mixture from axial asymmetry, 11.52 g) as a solid. The filtrate was concentrated under reduced pressure to give the targeted (7M) -4-tert-butoxy-6-cyclopropyl-2- (ethanesulfonyl) -7- [ 6-fluoro-5-methyl-2- (triphenylmethyl) -2H-indazol-4-yl ] -8- [ (1S) -1-phenylethoxy ] quinazoline (single diastereomer, 23.29 g) as a solid.

Production example 19

To a solution of (7M) -4-tert-butoxy-6-cyclopropyl-2- (ethanesulfonyl) -7- [ 6-fluoro-5-methyl-2- (triphenylmethyl) -2H-indazol-4-yl ] -8- [ (1S) -1-phenylethoxy ] quinazoline (2.00 g) in THF (50 mL) under a nitrogen atmosphere was added 4-methylbenzene-1-sulfonic acid monohydrate (230 mg) at room temperature and stirred at 50 ℃ for 1 hour. After the reaction solution was naturally cooled to room temperature, TEA (350. Mu.L) was added, followed by concentration under reduced pressure. The resulting residue was purified by silica gel chromatography (basic silica gel, hexane/ethyl acetate) to give (7M) -4-tert-butoxy-6-cyclopropyl-2- (ethanesulfonyl) -7- (6-fluoro-5-methyl-1H-indazol-4-yl) -8- [ (1S) -1-phenylethoxy ] quinazoline (740 mg) as a foamy solid.

Production example 20

To (7M) -4-tert-butoxy-6-cyclopropyl-8- [ (4-ethynylphenyl) methoxy ] -7- [ 6-fluoro-5-methyl-2- (triphenylmethyl) -2H-indazol-4-yl ] -2- [ (-d eTo an alk-4-yloxy ] quinazoline (2.11 g) was added THF (20 mL), and methanesulfonic acid (480. Mu.L) was added under ice-cooling, followed by stirring at room temperature for 4 hours. The reaction was stopped by pouring into a saturated aqueous sodium bicarbonate solution, and extraction was performed 3 times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (CHCl ₃/MeOH). Purifying again by silica gel column chromatography (basic silica gel, CHCl ₃/MeOH) to obtain (7M) -6-cyclopropyl-8- [ (4-ethynylphenyl) methoxy ] -7- (6-fluoro-5-methyl-1H-indazol-4-yl) -2- [. Sup.th-of-the-day in solid formAlk-4-yl) oxy ] quinazolin-4-ol (1.02 g).

Production example 21

To a solution of (7M) -4-tert-butoxy-6-cyclopropyl-2- (ethanesulfonyl) -7- (6-fluoro-5-methyl-1H-indazol-4-yl) -8- [ (1S) -1-phenylethoxy ] quinazoline (735 mg) in THF (10 mL) under a nitrogen atmosphere was added 3, 4-dinitro-2H-pyran (900 μl) and 4-methylbenzene-1-sulfonic acid monohydrate (35 mg) at room temperature. Stirred at room temperature overnight and the reaction was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (basic silica gel, hexane/ethyl acetate) to give (7M) -4-tert-butoxy-6-cyclopropyl-2- (ethanesulfonyl) -7- [ 6-fluoro-5-methyl-1- ] as a foamy solidAlk-2-yl) -1H-indazol-4-yl ] -8- [ (1S) -1-phenylethoxy ] quinazoline (735 mg).

Production example 23

Under argon atmosphere, to (7M) -4-tert-butoxy-6-cyclopropyl-2- (ethylsulfonyl) -7- [ 6-fluoro-5-methyl-1- ]To a solution of alk-2-yl) -1H-indazol-4-yl ] -8- [ (1S) -1-phenylethoxy ] quinazoline (730 mg) in MeOH (15 mL)/THF (15 mL) was added sodium bicarbonate (450 mg) and 10% Pd/C (aqueous about 50%, 250 mg) at room temperature. Stirring was carried out overnight at room temperature under normal pressure under a hydrogen atmosphere. After the substitution with argon gas, the reaction solution was filtered through celite (registered trademark) and washed with ethyl acetate. Concentrating the filtrate under reduced pressure to obtain (7M) -4-tert-butoxy-6-cyclopropyl-2- (ethanesulfonyl) -7- [ 6-fluoro-5-methyl-1- ] as a foamy solidAlk-2-yl) -1H-indazol-4-yl ] quinazolin-8-ol (630 mg).

PREPARATION EXAMPLE 25

To (3S) -3- [ { (7M) -6-cyclopropyl-7- [ 6-fluoro-5-methyl-1- ]To tert-butyl (1.90 g) of alk-2-yl) -1H-indazol-4-yl ] -2- [ (2S) -2-methoxypropoxy ] -8- [ (1S) -1-phenylethoxy ] quinazolin-4-yl } (meth) amino ] pyrrolidine-1-carboxylate was added MeOH (30 mL), 10% Pd/C (aqueous about 50%, 1.2 g) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through celite (registered trademark), and the filtrate was concentrated under reduced pressure and azeotroped with EtOH. Purifying the obtained residue by silica gel column chromatography (hexane/ethyl acetate), and obtaining (3S) -3- [ { (7M) -6-cyclopropyl-7- [ 6-fluoro-5-methyl-1- ] as a foamy solidAlkan-2-yl) -1H-indazol-4-yl ] -8-hydroxy-2- [ (2S) -2-methoxypropoxy ] quinazolin-4-yl } (methyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester (1.5 g).

Production example 29

Under nitrogen flow, (7M) -4-tert-butoxy-6-cyclopropyl-2- (ethylsulfonyl) -7- [ 6-fluoro-5-methyl-1- ] is addedThe alk-2-yl) -1H-indazol-4-yl ] quinazolin-8-ol (1.4 g) and cesium carbonate (2.4 g) were suspended in DMF (17 mL), 1- (chloromethyl) -4-ethynylbenzene (500 mg) was added at room temperature, and stirred at 60℃for 1.5 hours. To the reaction mixture was added water (100 ml), and extracted 2 times with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give (7M) -4-tert-butoxy-6-cyclopropyl-2- (ethanesulfonyl) -8- [ (4-ethynylphenyl) methoxy ] -7- [ 6-fluoro-5-methyl-1- ] as a foamy solidAlk-2-yl) -1H-indazol-4-yl ] quinazoline (1.47 g).

Production example 30

Under nitrogen atmosphere, to (3S) -3- [ { (7M) -6-cyclopropyl-7- [ 6-fluoro-5-methyl-1- ]To a mixture of tert-butyl (150 mg) of alk-2-yl) -1H-indazol-4-yl ] -8-hydroxy-2- [ (2S) -2-methoxypropoxy ] quinazolin-4-yl } (meth) amino ] pyrrolidine-1-carboxylate, 4- (chloromethyl) -1-ethynyl-2-fluorobenzene (52 mg) and DMF (2 mL) was added cesium carbonate (130 mg) at room temperature and stirred at 60℃for 1 hour. After the reaction mixture was naturally cooled to room temperature, ethyl acetate was added, the organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. Purifying the obtained residue by silica gel column chromatography (basic silica gel, hexane/ethyl acetate), and obtaining (3S) -3- [ { (7M) -6-cyclopropyl-8- [ (4-ethynyl-3-fluorophenyl) methoxy ] -7- [ 6-fluoro-5-methyl-1- ] in solid formAlkan-2-yl) -1H-indazol-4-yl ] -2- [ (2S) -2-methoxypropoxy ] quinazolin-4-yl } (meth) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester (117 mg).

Production example 36

To a solution of (7M) -4-tert-butoxy-6-cyclopropyl-2- (ethanesulfonyl) -7- [ 6-fluoro-5-methyl-2- (triphenylmethyl) -2H-indazol-4-yl ] -8- [ (1S) -1-phenylethoxy ] quinazoline (5.01 g) and (2S) -2-methoxypropane-1-ol (0.94 mL) in THF (60 mL) under nitrogen atmosphere was added tBuOK (1.00 g) under ice cooling, and stirred at this temperature for 30 minutes. Ice water and an aqueous ammonium chloride solution were added to the reaction solution to stop the reaction. The organic layer was washed with saturated aqueous sodium chloride solution, extracted 2 times with ethyl acetate, and dried over anhydrous magnesium sulfate. Purification by silica gel column chromatography (hexane/ethyl acetate) gave (7M) -4-tert-butoxy-6-cyclopropyl-7- [ 6-fluoro-5-methyl-2- (triphenylmethyl) -2H-indazol-4-yl ] -2- [ (2S) -2-methoxypropoxy ] -8- [ (1S) -1-phenylethoxy ] quinazoline (4.07 g) as a foamy solid.

Production example 54

Under nitrogen atmosphere, to (7M) -4-tert-butoxy-6-cyclopropyl-2- (ethylsulfonyl) -8- [ (4-ethynylphenyl) methoxy ] -7- [ 6-fluoro-5-methyl-1- ]To a solution of alk-2-yl) -1H-indazol-4-yl ] quinazoline (1.47 g) and (2S) -2-methoxypropan-1-ol (0.25 mL) in THF (11 mL) was added tBuOK (275 mg) with cooling from an ice/MeOH bath (-20 ℃ C. To-15 ℃ C.) and stirring at this temperature for 30 min. To the reaction mixture, a saturated aqueous ammonium chloride solution was added at this temperature, and extraction was performed 2 times with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. Concentrating the filtrate under reduced pressure to obtain (7M) -4-tert-butoxy-6-cyclopropyl-8- [ (4-ethynylphenyl) methoxy ] -7- [ 6-fluoro-5-methyl-1- ] as a foamy solidAlk-2-yl) -1H-indazol-4-yl ] -2- [ (2S) -2-methoxypropoxy ] quinazoline (1.43 g).

Production example 57

Under argon atmosphere, to (7M) -4-tert-butoxy-6-cyclopropyl-2- (ethylsulfonyl) -8- [ (4-ethynylphenyl) methoxy ] -7- [ 6-fluoro-5-methyl-1-To a solution of alk-2-yl) -1H-indazol-4-yl ] quinazoline (400 mg) and [ (2R) -oxolan-2-yl ] methanol (82 mg) in THF (8 mL) was added tBuOK (85 mg) under ice-cooling, and stirred at this temperature for 30 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and extracted 2 times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give (7M) -4-tert-butoxy-6-cyclopropyl-8- [ (4-ethynylphenyl) methoxy ] -7- [ 6-fluoro-5-methyl-1- ] as a foamy solidAlk-2-yl) -1H-indazol-4-yl ] -2- { [ (2R) -oxolan-2-yl ] methoxy } quinazoline (261 mg).

Production example 58

Under argon atmosphere, to (7M) -4-tert-butoxy-6-cyclopropyl-2- (ethylsulfonyl) -8- [ (4-ethynylphenyl) methoxy ] -7- [ 6-fluoro-5-methyl-1-To a solution of alk-2-yl) -1H-indazol-4-yl ] quinazoline (400 mg) and [ (2S) -oxolan-2-yl ] methanol (82 mg) in THF (8 mL) was added tBuOK (85 mg) under ice-cooling, and stirred at this temperature for 30 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and extracted 2 times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give (7M) -4-tert-butoxy-6-cyclopropyl-8- [ (4-ethynylphenyl) methoxy ] -7- [ 6-fluoro-5-methyl-1- ] as a foamy solidAlk-2-yl) -1H-indazol-4-yl ] -2- { [ (2S) -oxolan-2-yl ] methoxy } quinazoline (330 mg).

Production example 59

To (7M) -4-tert-butoxy-6-cyclopropyl-8- [ (4-ethynylphenyl) methoxy ] -7- [ 6-fluoro-5-methyl-1- ] under nitrogen atmosphereTo a solution of alk-2-yl) -1H-indazol-4-yl ] -2- [ (2S) -2-methoxypropoxy ] quinazoline (1.43 g) in THF (15 mL) was added 4-methylbenzene-1-sulfonic acid monohydrate (120 mg) at room temperature and stirred at 50℃for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give (7M) -6-cyclopropyl-8- [ (4-ethynylphenyl) methoxy ] -7- [ 6-fluoro-5-methyl-1- ] as a foam solidAlk-2-yl) -1H-indazol-4-yl ] -2- [ (2S) -2-methoxypropoxy ] quinazolin-4-ol (1.05 g).

Production example 60

To (7M) -4-tert-butoxy-6-cyclopropyl-8- [ (4-ethynylphenyl) methoxy ] -7- [ 6-fluoro-5-methyl-1-To a solution of alk-2-yl) -1H-indazol-4-yl ] -2- { [ (2R) -oxolan-2-yl ] methoxy } quinazoline (261 mg) in THF (5 mL) was added 4-methylbenzene-1-sulfonic acid monohydrate (10 mg) and 3, 4-dinitro-2H-pyran (1 mL) at room temperature, and stirred at that temperature overnight. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (basic silica gel, CHCl ₃/MeOH) to give (7M) -6-cyclopropyl-8- [ (4-ethynylphenyl) methoxy ] -7- [ 6-fluoro-5-methyl-1- ] as a foamy solidAlk-2-yl) -1H-indazol-4-yl ] -2- { [ (2R) -oxolan-2-yl ] methoxy } quinazolin-4-ol (215 mg).

Production example 61

To (7M) -4-tert-butoxy-6-cyclopropyl-8- [ (4-ethynylphenyl) methoxy ] -7- [ 6-fluoro-5-methyl-1-To a solution of alk-2-yl) -1H-indazol-4-yl ] -2- { [ (2S) -oxolan-2-yl ] methoxy } quinazoline (330 mg) in THF (5 mL) was added 4-methylbenzene-1-sulfonic acid monohydrate (11 mg) and 3, 4-dinitro-2H-pyran (1 mL) at room temperature, and stirred at that temperature overnight. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (basic silica gel, CHCl ₃/MeOH) to give (7M) -6-cyclopropyl-8- [ (4-ethynylphenyl) methoxy ] -7- [ 6-fluoro-5-methyl-1- ] as a foamy solidAlk-2-yl) -1H-indazol-4-yl ] -2- { [ (2S) -oxolan-2-yl ] methoxy } quinazolin-4-ol (282 mg).

Production example 62

Under the atmosphere of nitrogen, to (7M) -6-cyclopropyl-7- [ 6-fluoro-5-methyl-1- ]To a solution of alk-2-yl) -1H-indazol-4-yl ] -2- [ (2S) -2-methoxypropoxy ] -8- [ (1S) -1-phenylethoxy ] quinazolin-4-ol (1.63 g) in THF (20 mL) was added cesium carbonate (4.25 g) and PyBOP (2 g) in this order at room temperature, and the mixture was stirred at room temperature for 1 hour. Tert-butyl (3S) -3- (methylamino) pyrrolidine-1-carboxylate (1.58 g) was added at room temperature and stirred at 60℃for 2 hours. After the reaction mixture was cooled to room temperature, ethyl acetate was added thereto, and then it was filtered through celite (registered trademark). Concentrating the filtrate under reduced pressure, purifying the obtained residue by silica gel column chromatography (basic silica gel, hexane/ethyl acetate), and obtaining (3S) -3- [ { (7M) -6-cyclopropyl-7- [ 6-fluoro-5-methyl-1- ] as an oilAlkan-2-yl) -1H-indazol-4-yl ] -2- [ (2S) -2-methoxypropoxy ] -8- [ (1S) -1-phenylethoxy ] quinazolin-4-yl } (methyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester (1.9 g).

Production example 63

Under the atmosphere of nitrogen, to (7M) -6-cyclopropyl-8- [ (4-ethynylphenyl) methoxy ] -7- [ 6-fluoro-5-methyl-1- ]To a solution of alk-2-yl) -1H-indazol-4-yl ] -2- [ (2S) -2-methoxypropoxy ] quinazolin-4-ol (200 mg) in THF (4 mL) was added PyBOP (335 mg) and cesium carbonate (205 mg) at room temperature, and the mixture was stirred at room temperature for 1 hour. A solution of (3R) -3- (methylamino) pyrrolidine-1-carboxylic acid tert-butyl ester (300 mg) in THF (1 mL) and cesium carbonate (500 mg) were added at room temperature and stirred at 60℃for 2 hours. After the reaction mixture was cooled to room temperature, ethyl acetate was added thereto, and then it was filtered through celite (registered trademark). The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate) to give (3R) -3- [ { (7M) -6-cyclopropyl-8- [ (4-ethynylphenyl) methoxy ] -7- [ 6-fluoro-5-methyl-1- ] as an oil containing impuritiesAlkan-2-yl) -1H-indazol-4-yl ] -2- [ (2S) -2-methoxypropoxy ] quinazolin-4-yl } (meth) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester (313 mg).

PREPARATION EXAMPLE 73

Under the atmosphere of nitrogen, to (7M) -6-cyclopropyl-8- [ (4-ethynylphenyl) methoxy ] -7- [ 6-fluoro-5-methyl-1- ]To a solution of alk-2-yl) -1H-indazol-4-yl ] -2- [ (2S) -2-methoxypropoxy ] quinazolin-4-ol (1.05 g) in THF (15 mL) was added cesium carbonate (2.68 g) and PyBOP (1.20 g) in this order at room temperature, and the mixture was stirred at room temperature for 1 hour. Tert-butyl (3S) -3- (methylamino) pyrrolidine-1-carboxylate (0.94 mL) was added at room temperature and stirred overnight at 60 ℃. Ethyl acetate was added to the reaction solution, and the insoluble material was filtered through celite (registered trademark). The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate) to give (3S) -3- [ { (7M) -6-cyclopropyl-8- [ (4-ethynylphenyl) methoxy ] -7- [ 6-fluoro-5-methyl-1- ] as an oilAlkan-2-yl) -1H-indazol-4-yl ] -2- [ (2S) -2-methoxypropoxy ] quinazolin-4-yl } (meth) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester (1.62 g).

Production example 74

Under the atmosphere of nitrogen, to (7M) -6-cyclopropyl-8- [ (4-ethynylphenyl) methoxy ] -7- [ 6-fluoro-5-methyl-1- ]To a solution of alk-2-yl) -1H-indazol-4-yl ] -2- { [ (2R) -oxolan-2-yl ] methoxy } quinazolin-4-ol (106 mg) in THF (4 mL) was added cesium carbonate (265 mg) and PyBOP (120 mg) in this order at room temperature, and the mixture was stirred at room temperature for 1 hour. Tert-butyl (3S) -3- (methylamino) pyrrolidine-1-carboxylate (62. Mu.L) was added at room temperature and stirred overnight at room temperature. Tert-butyl (3S) -3- (methylamino) pyrrolidine-1-carboxylate (100. Mu.L) was added and stirred at 80℃for 2 hours. Ethyl acetate was added to the reaction solution, and insoluble matters were filtered off through celite (registered trademark). The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate) to give (3S) -3- { [ (7M) -6-cyclopropyl-8- [ (4-ethynylphenyl) methoxy ] -7- [ 6-fluoro-5-methyl-1- ] as an oilAlkan-2-yl) -1H-indazol-4-yl ] -2- { [ (2R) -oxolan-2-yl ] methoxy } quinazolin-4-yl ] (methyl) amino } pyrrolidine-1-carboxylic acid tert-butyl ester (211 mg).

Production example 75

Under the atmosphere of nitrogen, to (7M) -6-cyclopropyl-8- [ (4-ethynylphenyl) methoxy ] -7- [ 6-fluoro-5-methyl-1- ]To a solution of alk-2-yl) -1H-indazol-4-yl ] -2- { [ (2S) -oxolan-2-yl ] methoxy } quinazolin-4-ol (164 mg) in THF (4 mL) was added cesium carbonate (410 mg) and PyBOP (185 mg) in this order at room temperature, and stirred at room temperature for 1 hour. (3S) -3- (methylamino) pyrrolidine-1-carboxylic acid tert-butyl ester (96. Mu.L) was added and stirred overnight at room temperature. Tert-butyl (3S) -3- (methylamino) pyrrolidine-1-carboxylate (100. Mu.L) was added and stirred at 80℃for 2 hours. Ethyl acetate was added to the reaction solution, insoluble matters were filtered off through celite (registered trademark), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate) to give (3S) -3- { [ (7M) -6-cyclopropyl-8- [ (4-ethynylphenyl) methoxy ] -7- [ 6-fluoro-5-methyl-1- ] as an oilAlkan-2-yl) -1H-indazol-4-yl ] -2- { [ (2S) -oxolan-2-yl ] methoxy } quinazolin-4-yl ] (methyl) amino } pyrrolidine-1-carboxylic acid tert-butyl ester (199 mg).

Production example 79

Under the atmosphere of nitrogen, to (7M) -6-cyclopropyl-8- [ (4-ethynylphenyl) methoxy ] -7- [ 6-fluoro-5-methyl-1- ]To a solution of alk-2-yl) -1H-indazol-4-yl ] -2- [ (2S) -2-methoxypropoxy ] quinazolin-4-ol (100 mg) in THF (2 mL) was added PyBOP (165 mg), cesium carbonate (255 mg) in this order at room temperature, and the mixture was stirred at room temperature for 1 hour. Cesium carbonate (105 mg) and tert-butyl (3S) -3-aminopyrrolidine-1-carboxylate (130. Mu.L) were added at room temperature, and stirred at room temperature overnight. Ethyl acetate was added to the reaction solution, and insoluble materials were filtered through celite (registered trademark). The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate) to give (3S) -3- ({ (7M) -6-cyclopropyl-8- [ (4-ethynylphenyl) methoxy ] -7- [ 6-fluoro-5-methyl-1- ] as an oilAlkan-2-yl) -1H-indazol-4-yl ] -2- [ (2S) -2-methoxypropoxy ] quinazolin-4-yl } amino) pyrrolidine-1-carboxylic acid tert-butyl ester (143 mg).

Production example 83

Under nitrogen, to (3R) -3- [ { (7M) -6-cyclopropyl-8- [ (4-ethynylphenyl) methoxy ] -7- [ 6-fluoro-5-methyl-1- ] under an atmosphere of nitrogenTo a solution of tert-butyl (311 mg) of alk-2-yl) -1H-indazol-4-yl ] -2- [ (2S) -2-methoxypropoxy ] quinazolin-4-yl } (meth) amino ] pyrrolidine-1-carboxylate and (4R) -1- [ (2S) -2-azido-3-methylbutanoyl ] -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide (170 mg) in tBuOH (3 mL), THF (3 mL) and water (3 mL) were added sodium ascorbate (110 mg) and anhydrous copper (II) sulfate (30 mg) at room temperature and stirred at room temperature for 2 hours. An aqueous solution (13 mL) of disodium ethylenediamine tetraacetate (650 mg) was added, and after stirring at room temperature for 30 minutes, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, CHCl ₃/MeOH) to give (3R) -3- [ { (7M) -6-cyclopropyl-7- [ 6-fluoro-5-methyl-1- ] as a solidAlkylin-2-yl) -1H-indazol-4-yl ] -8- { [4- (1- { (2S) -1- [ (2S, 4R) -4-hydroxy-2- ({ (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } carbamoyl) pyrrolidin-1-yl ] -3-methyl-1-oxobutan-2-yl } -1H-1,2, 3-triazol-4-yl) phenyl ] methoxy } -2- [ (2S) -2-methoxypropoxy ] quinazolin-4-yl } (methyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester (312 mg).

Production example 84

To (3S) -3- [ { (7M) -6-cyclopropyl-8- [ (4-ethynylphenyl) methoxy ] -7- [ 6-fluoro-5-methyl-1- ] aTo a mixture of tert-butyl (133 mg), (4R) -1- [ (2S) -2-azido-3-methylbutanoyl ] -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide (80 mg), tBuOH (1.2 mL), THF (1.2 mL) and water (1.2 mL) was added sodium ascorbate (66 mg) and anhydrous copper (II) sulfate (27 mg) at room temperature, and stirred at room temperature for 3 hours. 2% aqueous ethylenediamine tetraacetic acid disodium salt solution and saturated aqueous sodium chloride solution were added, extraction was performed 2 times with CH ₂Cl₂, and the combined organic layers were dried over anhydrous magnesium sulfate. Insoluble matter was filtered off, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, CHCl ₃/MeOH) to give (3S) -3- [ { (7M) -6-cyclopropyl-7- [ 6-fluoro-5-methyl-1- ] as a solidAlkylin-2-yl) -1H-indazol-4-yl ] -8- { [4- (1- { (2S) -1- [ (2S, 4R) -4-hydroxy-2- ({ (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } carbamoyl) pyrrolidin-1-yl ] -3-methyl-1-oxobutan-2-yl } -1H-1,2, 3-triazol-4-yl) phenyl ] methoxy } -2- [ (2S) -2-methoxypropoxy ] quinazolin-4-yl } (ethyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester (178 mg).

Production example 92

To (3S) -3- [ { (7M) -6-cyclopropyl-8- [ (4-ethynyl-3-fluorophenyl) methoxy ] -7- [ 6-fluoro-5-methyl-1- ]To a solution of tert-butyl (2S) -2-methoxypropoxy ] quinazolin-4-yl } (methyl) amino ] pyrrolidine-1-carboxylate (115 mg) and (4R) -1- [ (2S) -2-azido-3-methylbutanoyl ] -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide (70 mg) in tBuOH (1 mL), THF (1 mL) and water (1 mL) was added sodium ascorbate (41 mg) and anhydrous copper (II) sulfate (11 mg) at room temperature and the mixture was stirred at room temperature for 1 hour. An aqueous solution (5 mL) of disodium ethylenediamine tetraacetate (230 mg) was added thereto, and the mixture was stirred at room temperature for 30 minutes, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, CHCl ₃/MeOH) to give (3S) -3- [ { (7M) -6-cyclopropyl-8- { [ 3-fluoro-4- (1- { (2S) -1- [ (2S, 4R) -4-hydroxy-2- ({ (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } carbamoyl) pyrrolidin-1-yl ] -3-methyl-1-oxobutan-2-yl } -1H-1,2, 3-triazol-4-yl) phenyl ] methoxy } -7- [ 6-fluoro-5-methyl-1- ] in solid formAlkan-2-yl) -1H-indazol-4-yl ] -2- [ (2S) -2-methoxypropoxy ] quinazolin-4-yl } (meth) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester (171 mg).

Production example 114

To (4R) -1- [ (2S) -2-azido-3-methylbutanoyl ] -N- { (1R) -1- [4- (1-ethyl-1H-pyrazol-5-yl) phenyl ] -2-hydroxyethyl } -4-hydroxy-L-prolinamide (80 mg), (3S) -3- [ { (7M) -6-cyclopropyl-8- [ (4-ethynylphenyl) methoxy ] -7- [ 6-fluoro-5-methyl-1-Alkyl-2-yl) -1H-indazol-4-yl ] -2- [ (2S) -2-methoxypropoxy ] quinazolin-4-yl } (methyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester (125 mg) tBuOH/THF/water (1: 1:1, 2.0 mL) was added with anhydrous copper (II) sulfate (10 mg) and sodium ascorbate (30 mg) at room temperature, and stirred at room temperature for 1 hour. To the reaction mixture was added ethylenediamine tetraacetic acid disodium salt (175 mg) at room temperature, and stirred at that temperature for 30 minutes. Water is added to the reaction mixture, stirred, and the resulting insoluble matter is collected by filtration to give (3S) -3- [ { (7M) -6-cyclopropyl-8- { [4- (1- { (2S) -1- [ (2S, 4R) -2- ({ (1R) -1- [4- (1-ethyl-1H-pyrazol-5-yl) phenyl ] -2-hydroxyethyl } carbamoyl) -4-hydroxypyrrolidin-1-yl ] -3-methyl-1-oxobutan-2-yl } -1H-1,2, 3-triazol-4-yl) phenyl ] methoxy } -7- [ 6-fluoro-5-methyl-1- ] as a solidAlkan-2-yl) -1H-indazol-4-yl ] -2- [ (2S) -2-methoxypropoxy ] quinazolin-4-yl } (meth) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester (225 mg).

Production example 115

To (4R) -1- [ (2S) -2-azido-3-methylbutanoyl ] -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide (120 mg) and (3S) -3- { [ (7M) -6-cyclopropyl-8- [ (4-ethynylphenyl) methoxy ] -7- [ 6-fluoro-5-methyl-1- ] under an argon atmosphereTo a solution of tert-butyl (2S) -oxolan-4-yl ] -2- { [ (2S) -oxolan-2-yl ] methoxy } quinazolin-4-yl ] (methyl) amino } pyrrolidine-1-carboxylate (199 mg) in tBuOH (1 mL), THF (1 mL) and water (1 mL), anhydrous copper (II) sulfate (18 mg) and sodium ascorbate (80 mg) were added at room temperature, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added ethylenediamine tetraacetic acid disodium salt (300 mg) at room temperature, and the mixture was stirred at that temperature for 1 hour. Water and ethyl acetate were added, and extraction was performed with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, CHCl ₃/MeOH) to give (3S) -3- { [ (7M) -6-cyclopropyl-7- [ 6-fluoro-5-methyl-1- ] as a foamy solidAlkan-2-yl) -1H-indazol-4-yl ] -8- { [4- (1- { (2S) -1- [ (2S, 4R) -4-hydroxy-2- ({ (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } carbamoyl) pyrrolidin-1-yl ] -3-methyl-1-oxobutan-2-yl } -1H-1,2, 3-triazol-4-yl) phenyl ] methoxy } -2 (2S) -oxopyrrolidin-2-yl ] methoxy } quinazolin-4-yl ] (methyl) amino } pyrrolidine-1-carboxylic acid tert-butyl ester (236 mg).

Production example 116

To (4R) -1- [ (2S) -2-azido-3-methylbutyryl ] -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide (75 mg) and (3S) -3- [ { (7M) -6-cyclopropyl-8- [ (4-ethynylphenyl) methoxy ] -7- [ 6-fluoro-5-methyl-1- ] under an atmosphere of argonAlkyl-2-yl) -1H-indazol-4-yl ] -2- [ (2S) -2-methoxypropoxy ] quinazolin-4-yl } (methyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester (230 mg) tBuOH/THF/water (1: 1:1, 2.0 mL) was added with anhydrous copper (II) sulfate (10 mg) and sodium ascorbate (30 mg) at room temperature, and stirred at room temperature for 1 hour. To the reaction mixture was added ethylenediamine tetraacetic acid disodium salt (175 mg) at room temperature, and the mixture was stirred at that temperature for 1 hour. To the reaction mixture was added water and CHCl ₃/MeOH (9/1). The aqueous and organic layers were separated and the aqueous layer was extracted with CHCl3/MeOH (9/1). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (basic silica gel, CHCl ₃/MeOH) to give (3S) -3- [ { (7M) -6-cyclopropyl-7- [ 6-fluoro-5-methyl-1- ] as a foamy solidAlkylin-2-yl) -1H-indazol-4-yl ] -8- { [4- (1- { (2S) -1- [ (2S, 4R) -4-hydroxy-2- ({ (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } carbamoyl) pyrrolidin-1-yl ] -3-methyl-1-oxobutan-2-yl } -1H-1,2, 3-triazol-4-yl) phenyl ] methoxy } -2- [ (2S) -2-methoxypropoxy ] quinazolin-4-yl } (methyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester (197 mg).

Production example 117

To (4R) -1- [ (2S) -2-azido-3-methylbutanoyl ] -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide (75 mg) and (3S) -3- { [ (7M) -6-cyclopropyl-8- [ (4-ethynylphenyl) methoxy ] -7- [ 6-fluoro-5-methyl-1- ] under an argon atmosphereTo a solution of tert-butyl (2R) -oxolan-2-yl ] -2- { [ (2R) -oxolan-2-yl ] methoxy } quinazolin-4-yl ] (methyl) amino } pyrrolidine-1-carboxylate (123 mg) in tBuOH (1 mL), THF (1 mL) and water (1 mL), anhydrous copper (II) sulfate (11 mg) and sodium ascorbate (50 mg) were added at room temperature, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added ethylenediamine tetraacetic acid disodium salt (200 mg) at room temperature, and the mixture was stirred at that temperature for 1 hour. Water and ethyl acetate were added, and extraction was performed with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, CHCl ₃/MeOH) to give (3S) -3- { [ (7M) -6-cyclopropyl-7- [ 6-fluoro-5-methyl-1- ] as a foamy solidAlkan-2-yl) -1H-indazol-4-yl ] -8- { [4- (1- { (2S) -1- [ (2S, 4R) -4-hydroxy-2- ({ (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } carbamoyl) pyrrolidin-1-yl ] -3-methyl-1-oxobutan-2-yl } -1H-1,2, 3-triazol-4-yl) phenyl ] methoxy } -2 (2R) -oxopyrrolidin-2-yl ] methoxy } quinazolin-4-yl ] (methyl) amino } pyrrolidine-1-carboxylic acid tert-butyl ester (156 mg).

Production example 124

To (3S) -3- ({ (7M) -6-cyclopropyl-8- [ (4-ethynylphenyl) methoxy ] -7- (6-fluoro-5-methyl-1H-indazol-4-yl) -2- [ (-d-a-M)To tert-butyl (75 mg) of alkyl-4-yl) oxy ] quinazolin-4-yl } amino) pyrrolidine-1-carboxylate were added tBuOH (1 mL), THF (1 mL) and water (1 mL), and (4R) -1- [ (2S) -2-azido-3-methylbutanoyl ] -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide (50 mg), copper (I) (10 mg) and sodium ascorbate (30 mg) were added while stirring at room temperature, and the mixture was stirred at 50℃for 3 hours. The reaction solution was cooled naturally, and 2% disodium edetate aqueous solution and ethyl acetate were added thereto, followed by vigorous stirring for 30 minutes. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in THF (1 mL) and water (0.10 mL), tris (2-carboxyethyl) phosphine hydrochloride (10 mg) was added and stirred overnight at room temperature, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (basic silica gel, CHCl ₃/MeOH) to give (3S) -3- ({ (7M) -6-cyclopropyl-7- (6-fluoro-5-methyl-1H-indazol-4-yl) -8- { [4- (1- { (2S) -1- [ (2S, 4R) -4-hydroxy-2- ({ (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } carbamoyl) pyrrolidin-1-yl ] -3-methyl-1-oxobutan-2-yl } -1H-1,2, 3-triazol-4-yl) phenyl ] methoxy } -2- [ -phenyl ] methoxy } -2- ] as a solidAlkyl-4-yl) oxy ] quinazolin-4-yl } amino) pyrrolidine-1-carboxylic acid tert-butyl ester (77 mg).

Production example 125

To a solution of tert-butyl [ (1R) -1- (4-bromophenyl) -2-hydroxyethyl ] carbamate (5.01 g) in DMAc (80 mL) was added 4-methyl-1, 3-thiazole (2.88 mL) and potassium acetate (3.11 g) at room temperature, each of which was degassed and replaced with argon 3 times, and then palladium acetate (356 mg) was added at room temperature and stirred at 100℃for 16 hours. After cooling at room temperature, ethyl acetate and water were added to the reaction mixture, and insoluble matter was removed by filtration through celite (registered trademark). To the filtrate was added water, and the aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Filtration, concentration, and purification of the residue by silica gel column chromatography (basic silica gel, hexane/ethyl acetate) gave tert-butyl { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } carbamate (4.66 g) as a solid.

Production example 126

To a solution of tert-butyl { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } carbamate (4.41 g) in CH ₂Cl₂ (50 mL) and MeOH (40 mL) was added a small amount of hydrogen chloride (4M DOX solution, 20 mL) at a time under ice-cooling, and the mixture was stirred at room temperature for 6 hours. Diethyl ether was added to the reaction mixture, and the solid was collected by filtration, washed with diethyl ether and dried under reduced pressure to give (2R) -2-amino-2- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethan-1-ol n hydrochloride (2.12 g) as a solid. The filtrate was concentrated under reduced pressure, and dried under reduced pressure with heating to give (2R) -2-amino-2- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethan-1-ol n hydrochloride (2.01 g) as a solid.

Production example 131

To a solution of tert-butyl { (1R) -1- [4- (1-ethyl-1H-pyrazol-5-yl) phenyl ] -2-hydroxyethyl } carbamate (3.34 g) in CH ₂Cl₂ (25 mL) and MeOH (25 mL) was added hydrogen chloride (4M DOX solution, 25.6 mL) at-20℃to-10℃under cooling, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to give (2R) -2-amino-2- [4- (1-ethyl-1H-pyrazol-5-yl) phenyl ] ethan-1-ol n-hydrochloride (3.06 g) as a solid.

Production example 133

A mixture of (2R) -2-amino-2- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethan-1-ol n hydrochloride (2.12 g), (4R) -1- (tert-butoxycarbonyl) -4-hydroxy-L-proline (1.76 g) and DMF (22 mL) was cooled with ice under an argon gas stream, DIPEA (4.7 mL) was added, and then HATU (3.02 g) was added in small amounts each time so that the internal temperature was maintained at 5℃or lower. The reaction mixture was stirred under ice-cooling for 1 hour, and at room temperature for 1 hour. The reaction mixture was cooled with ice, and after adding water (120 mL) and a saturated aqueous sodium chloride solution (50 mL), it was extracted 3 times with ethyl acetate. The aqueous layer was further extracted 3 times with ethyl acetate/iPrOH (9/1), and the combined organic layers were washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (CHCl ₃/MeOH) to give (2 s, 4R) -4-hydroxy-2- ({ (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } carbamoyl) pyrrolidine-1-carboxylic acid tert-butyl ester (3.09 g) as an oil.

Production example 134

To a mixture of (2R) -2-amino-2- [4- (1-ethyl-1H-pyrazol-5-yl) phenyl ] ethan-1-ol n hydrochloride (3.43 g), (4R) -1- (tert-butoxycarbonyl) -4-hydroxy-L-proline (2.81 g) and DMF (40 mL) was added DIPEA (7.8 mL) under ice cooling, HATU (4.5 g) was added small amounts each time under ice cooling, stirred under ice cooling for 1 hour, and stirred at room temperature for 1 hour. Water, a saturated aqueous sodium chloride solution and ethyl acetate were added under ice cooling, and the aqueous layer was separated. After the aqueous layer was extracted with ethyl acetate, it was extracted with ethyl acetate/iPrOH (9/1), and the organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Insoluble matter was filtered off, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl ₃/MeOH) to give (2 s, 4R) -2- ({ (1R) -1- [4- (1-ethyl-1H-pyrazol-5-yl) phenyl ] -2-hydroxyethyl } carbamoyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (5.01 g) as an oil.

Production example 135

To a solution of tert-butyl (2 s, 4R) -4-hydroxy-2- ({ (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } carbamoyl) pyrrolidine-1-carboxylate (3.09 g) in CH ₂Cl₂ (18 mL), meOH (18 mL) was added hydrogen chloride (4M DOX solution, 17 mL) under ice cooling, stirred under ice cooling for 1 hour, and stirred at room temperature for 4 hours. Concentrated under reduced pressure and dried to give (4R) -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide N-hydrochloride (2.92 g) as a solid.

Production example 136

To a solution of (2 s, 4R) -2- ({ (1R) -1- [4- (1-ethyl-1H-pyrazol-5-yl) phenyl ] -2-hydroxyethyl } carbamoyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (5.01 g) in CH ₂Cl₂ (35 mL), meOH (30 mL) was added hydrogen chloride (4M DOX solution, 28 mL) under cooling at-20 to-10 ℃ and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to give (4R) -N- { (1R) -1- [4- (1-ethyl-1H-pyrazol-5-yl) phenyl ] -2-hydroxyethyl } -4-hydroxy-L-prolinamide N hydrochloride (4.71 g) as a solid.

Production example 137

To a mixture of (4R) -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide N hydrochloride (3.81 g), N- (tert-butoxycarbonyl) -L-valine (2.16 g) and DMF (45 mL) was added DIPEA (6.2 mL), and HATU (3.61 g) was added in small amounts each time under ice cooling, stirred under ice cooling for 1 hour, and stirred at room temperature for 1 hour. Water, a saturated aqueous sodium chloride solution and ethyl acetate were added under ice cooling, and the aqueous layer was separated. After extracting the aqueous layer with ethyl acetate, it was extracted with ethyl acetate/iPrOH (9/1), and the combined organic layers were washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Insoluble matter was filtered off, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl ₃/MeOH) to give N- (tert-butoxycarbonyl) -L-valyl- (4R) -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide (4.43 g) as a solid.

Production example 138

To a solution of (4R) -N- { (1R) -1- [4- (1-ethyl-1H-pyrazol-5-yl) phenyl ] -2-hydroxyethyl } -4-hydroxy-L-prolinamide N hydrochloride (4.7 g), N- (tert-butoxycarbonyl) -L-valine (2.7 g) in DMF (55 mL) was added DIPEA (7.7 mL), and HATU (4.5 g) was added in small portions each time under ice cooling. After stirring for 1 hour under ice-cooling and stirring for 1 hour at room temperature, water/saturated brine (1/1) and ethyl acetate were added thereto under ice-cooling, and the mixture was separated. The aqueous layer was extracted 2 times with ethyl acetate and 2 times with ethyl acetate/iPrOH (9/1). The combined organic layers were washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Insoluble matter was filtered off, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (CHCl ₃/MeOH) to give N- (tert-butoxycarbonyl) -L-valyl- (4R) -N- { (1R) -1- [4- (1-ethyl-1H-pyrazol-5-yl) phenyl ] -2-hydroxyethyl } -4-hydroxy-L-prolinamide (5.01 g) as a solid.

Production example 139

To a solution of N- (tert-butoxycarbonyl) -L-valyl- (4R) -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide (4.43 g) in CH ₂Cl₂ (35 mL), meOH (35 mL) was added hydrogen chloride (4 MDOX solution, 20 mL) at-20-15℃under cooling, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure to give L-valyl- (4R) -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide N-hydrochloride (4.21 g) as a solid.

Production example 140

To a solution of N- (tert-butoxycarbonyl) -L-valyl- (4R) -N- { (1R) -1- [4- (1-ethyl-1H-pyrazol-5-yl) phenyl ] -2-hydroxyethyl } -4-hydroxy-L-prolinamide (4.92 g) in CH ₂Cl₂ (30 mL) and MeOH (30 mL) was slowly added hydrogen chloride (4M DOX solution, 22 mL) at-20 to-15℃under cooling, and the mixture was stirred at room temperature for 5 hours. Concentrated under reduced pressure to give L-valyl- (4R) -N- { (1R) -1- [4- (1-ethyl-1H-pyrazol-5-yl) phenyl ] -2-hydroxyethyl } -4-hydroxy-L-prolinamide N hydrochloride (5.18 g) as a solid.

Production example 141

To a mixture of L-valyl- (4R) -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide N hydrochloride (1.71 g), TEA (3.2 mL), THF (20 mL), meCN (20 mL), 2-azido-1, 3-dimethylimidazole was added in small portions each time for 10 minutes or more under ice coolingA solution of hexafluorophosphate (1.06 g) in MeCN (5 mL) was stirred under ice-cooling for 5 hours. Water, saturated aqueous sodium chloride solution and ethyl acetate were added, and the aqueous layer and the organic layer were separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate. Insoluble matter was filtered off, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl ₃/MeOH) to give (4R) -1- [ (2S) -2-azido-3-methylbutanoyl ] -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide (1.07 g) as a solid.

Production example 142

2-Azido-1, 3-dimethylimidazole was cooled with an ice/sodium chloride aqueous bath under an argon atmosphereA solution of hexafluorophosphate (2.7 g) in MeCN (10 mL) was added in small amounts over 20 minutes to a mixture of L-valyl- (4R) -N- { (1R) -1- [4- (1-ethyl-1H-pyrazol-5-yl) phenyl ] -2-hydroxyethyl } -4-hydroxy-L-prolinamide N-hydrochloride (4.27 g), DIPEA (8.54 mL), THF (55 mL) and MeCN (55 mL) at a time (internal temperature below 3 ℃). The reaction mixture was stirred for 2 hours with cooling with an ice/sodium chloride aqueous solution bath. Water, saturated aqueous sodium chloride solution and ethyl acetate were added, and the aqueous layer and the organic layer were separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate. After filtering off the drying agent, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl ₃/MeOH) to give (4R) -1- [ (2S) -2-azido-3-methylbutanoyl ] -N- { (1R) -1- [4- (1-ethyl-1H-pyrazol-5-yl) phenyl ] -2-hydroxyethyl } -4-hydroxy-L-prolinamide (2.81 g) as a solid.

Production example 143

Under argon atmosphere, to (3S) -3- ({ (7M) -6-cyclopropyl-8- [ (4-ethynylphenyl) methoxy ] -7- [ 6-fluoro-5-methyl-1- ] aTo a mixture of tert-butyl (220 mg) of alk-2-yl) -1H-indazol-4-yl ] -2- [ (2S) -2-methoxypropoxy ] quinazolin-4-yl } amino) pyrrolidine-1-carboxylate and DMF (2 mL) was added sodium hydride (55% mineral oil dispersion, 26 mg) with cooling with ice/MeOH bath, and stirred in this state for 30 minutes. Subsequently, ethyl iodide (0.08 mL) was added thereto, followed by stirring at room temperature for 1.5 hours. Ice water and saturated aqueous ammonium chloride solution were added, and extraction was performed 2 times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give (3S) -3- [ { (7M) -6-cyclopropyl-8- [ (4-ethynylphenyl) methoxy ] -7- [ 6-fluoro-5-methyl-1- ] as a solidAlkan-2-yl) -1H-indazol-4-yl ] -2- [ (2S) -2-methoxypropoxy ] quinazolin-4-yl } (ethyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester (137 mg).

Production example 144

To a mixture of tert-butyl N- [ (1R) -1- (4-bromophenyl) -2-hydroxyethyl ] carbamate (4.43 g), 1-ethyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-pyrazole (4.67 g), potassium carbonate (3.87 g), DOX (80 mL) and water (8 mL) was added PdCl ₂(dppf)·CH₂Cl₂ (1.14 g) under an argon atmosphere, and the mixture was stirred at 100℃for 16 hours. After naturally cooling to room temperature, ethyl acetate was added thereto, followed by filtration through celite (registered trademark), and concentration under reduced pressure was performed. The residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate) to give tert-butyl { (1R) -1- [4- (1-ethyl-1H-pyrazol-5-yl) phenyl ] -2-hydroxyethyl } carbamate (3.74 g) as a solid.

Production example 146

To a solution of trimethyltin (IV) hydroxide (575 mg) in 1, 2-dichloroethane (10 mL) under a nitrogen atmosphere was added (4R) -1- [ (2S) -2- (4- {4- [ ({ (7M) -4- { [ (3S) -1- (tert-butoxycarbonyl) pyrrolidin-3-yl ] (methyl) amino } -6-cyclopropyl-7- [ 6-fluoro-5-methyl-1- ] at room temperatureAlkan-2-yl) -1H-indazol-4-yl ] -2- [ (2S) -2-methoxypropoxy ] quinazolin-8-yl } oxy) methyl ] phenyl } -1H-1,2, 3-triazol-1-yl) -3-methylbutanoyl ] -4-hydroxy-L-prolinemethyl ester (695 mg) was stirred at 80℃for 65 hours. After cooling to room temperature, ice-cold 1M hydrochloric acid was added and extracted 2 times with CHCl ₃/MeOH (9/1). The combined organic layers were washed with 1M hydrochloric acid, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl ₃/MeOH) to give (4R) -1- [ (2S) -2- (4- {4- [ ({ (7M) -4- { [ (3S) -1- (tert-butoxycarbonyl) pyrrolidin-3-yl ] (methyl) amino } -6-cyclopropyl-7- [ 6-fluoro-5-methyl-1- ] as a solidAlk-2-yl) -1H-indazol-4-yl ] -2- [ (2S) -2-methoxypropoxy ] quinazolin-8-yl } oxy) methyl ] phenyl } -1H-1,2, 3-triazol-1-yl) -3-methylbutanoyl ] -4-hydroxy-L-proline (663 mg).

Production example 149

To (2R) -2-amino-2- (4-fluorophenyl) ethan-1-ol (18 mg), (4R) -1- [ (2S) -2- (4- {4- [ ({ (7M) -4- { [ (3S) -1- (tert-butoxycarbonyl) pyrrolidin-3-yl ] (methyl) amino } -6-cyclopropyl-7- [ 6-fluoro-5-methyl-1- ]To a mixture of alk-2-yl) -1H-indazol-4-yl ] -2- [ (2S) -2-methoxypropoxy ] quinazolin-8-yl } oxy) methyl ] phenyl } -1H-1,2, 3-triazol-1-yl) -3-methylbutanoyl ] -4-hydroxy-L-proline (90 mg) and DMF (0.25 mL) was added DIPEA (80. Mu.L) and HATU (40 mg) under ice-cooling. The mixture was warmed to room temperature and stirred overnight. Water (5 mL) and saturated aqueous sodium bicarbonate (1 mL) were added and stirred for 1 hour. The resulting solid was collected by filtration to give (3S) -3- [ { (7M) -6-cyclopropyl-7- [ 6-fluoro-5-methyl-1- ] as a colorless solidAlkan-2-yl) -1H-indazol-4-yl ] -8- { [4- (1- { (2S) -1- [ (2S, 4R) -2- { [ (1R) -1- (4-fluorophenyl) -2-hydroxyethyl ] carbamoyl } -4-hydroxypyrrolidin-1-yl ] -3-methyl-1-oxobutan-2-yl } -1H-1,2, 3-triazol-4-yl) phenyl ] methoxy } -2- [ (2S) -2-methoxypropoxy ] quinazolin-4-yl } (methyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester (87.5 mg).

Production example 163

To (7M) -4-tert-butoxy-6-cyclopropyl-7- [ 6-fluoro-5-methyl-2- (triphenylmethyl) -2H-indazol-4-yl ] -2- [ (2S) -2-methoxypropoxy ] -8- [ (1S) -1-phenylethoxy ] quinazoline (2.89 g) was added THF (40 mL), 3, 4-dinitro-2H-pyran (3.1 mL) and 4-methylbenzene-1-sulfonic acid monohydrate (330 mg), and after stirring at 50℃for 6 hours. After the reaction mixture was naturally cooled to room temperature, it was concentrated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added thereto, and extraction was performed 2 times with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give (7M) -6-cyclopropyl-7- [ 6-fluoro-5-methyl-1- ] as a foam solidAlk-2-yl) -1H-indazol-4-yl ] -2- [ (2S) -2-methoxypropoxy ] -8- [ (1S) -1-phenylethoxy ] quinazolin-4-ol (1.63 g).

Production example 171

To a mixture of tert-butyl (3S) -3- (methylamino) pyrrolidine-1-carboxylate (1.52 g), THF (15 mL), DOX (30 mL) and DIPEA (5 mL) under an argon atmosphere was added 7-bromo-2, 4-dichloro-8-fluoro-6-iodoquinazoline (3 g) with stirring under cooling with an ice/MeOH bath, and stirring at this temperature for 1.5 hours. A saturated aqueous ammonium chloride solution and ice water were poured into the reaction vessel, stirred in this state for 1.5 hours, and then insoluble matter was collected by filtration while washing with water, and dried under reduced pressure at 40℃for 5 hours to obtain tert-butyl (3S) -3- [ (7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-yl) (methyl) amino ] pyrrolidine-1-carboxylate (3.82 g) as a solid.

Production example 172

To a mixture of tert-butyl (3S) -3- [ { 6-cyclopropyl-2- (ethylsulfanyl) -7- [ 6-fluoro-5-methyl-2- (triphenylmethyl) -2H-indazol-4-yl ] -8- [ (1S) -1-phenylethoxy ] quinazolin-4-yl } (methyl) amino ] pyrrolidine-1-carboxylate (a mixture of diastereomers from the axis asymmetry of about 2.5:1, 25.5 g) and CH ₂Cl₂ (350 mL) was added m-chloroperbenzoic acid (containing about 30%, 14.5 g) with stirring under ice cooling, and stirred under argon atmosphere at room temperature for 2.5 hours. The reaction mixture was poured with ice water/saturated aqueous sodium thiosulfate solution/saturated aqueous sodium bicarbonate solution, stirred at room temperature for about 20 minutes, and then extracted with CHCl ₃. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give (3S) -3- [ { 6-cyclopropyl-2- (ethanesulfonyl) -7- [ 6-fluoro-5-methyl-2- (triphenylmethyl) -2H-indazol-4-yl ] -8- [ (1S) -1-phenylethoxy ] quinazolin-4-yl } (meth) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester (from a mixture of diastereomers of about 4.3:1, which was axiasymmetric, 5.37 g) as a solid, and (3S) -3- [ { 6-cyclopropyl-2- (ethanesulfonyl) -7- (6-fluoro-5-methyl-1H-indazol-4-yl) -8- [ (1S) -1-phenylethoxy ] quinazolin-4-yl } (meth) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester (from a mixture of about 2:1, which was axiasymmetric, 8.25 g) as a solid.

The resulting mixture of tert-butyl (3S) -3- [ { 6-cyclopropyl-2- (ethanesulfonyl) -7- (6-fluoro-5-methyl-1H-indazol-4-yl) -8- [ (1S) -1-phenylethoxy ] quinazolin-4-yl } (meth) amino ] pyrrolidine-1-carboxylate (from a mixture of diastereomers of about 2:1 that is axi-asymmetric, 7.9 g) and EtOH (80 mL) was stirred at room temperature for 3 days. Insoluble material was filtered off while rinsing with a small amount of EtOH, and dried under reduced pressure at 40 ℃ to give (3S) -3- [ { (7M) -6-cyclopropyl-2- (ethanesulfonyl) -7- (6-fluoro-5-methyl-1H-indazol-4-yl) -8- [ (1S) -1-phenylethoxy ] quinazolin-4-yl } (methyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester (single diastereomer, 4.42 g) as a solid.

For the (3S) -3- [ { 6-cyclopropyl-2- (ethanesulfonyl) -7- [ 6-fluoro-5-methyl-2- (triphenylmethyl) -2H-indazol-4-yl ] -8- [ (1S) -1-phenylethoxy ] quinazolin-4-yl } (methyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester (from the diastereomeric mixture of about 4.3:1, which was axiasymmetric), obtained in the previous reaction was similarly converted to (3S) -3- [ { (7M) -6-cyclopropyl-2- (ethanesulfonyl) -7- (6-fluoro-5-methyl-1H-indazol-4-yl) -8- [ (1S) -1-phenylethoxy ] quinazolin-4-yl } (methyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester (single diastereomer) by the following procedure.

To a mixture of tert-butyl (3S) -3- [ { 6-cyclopropyl-2- (ethanesulfonyl) -7- [ 6-fluoro-5-methyl-2- (triphenylmethyl) -2H-indazol-4-yl ] -8- [ (1S) -1-phenylethoxy ] quinazolin-4-yl } (methyl) amino ] pyrrolidine-1-carboxylate (from a mixture of diastereomers of about 4.3:1, which was axiasymmetric, 6.33 g) and THF (70 mL) was added 4-methylbenzene-1-sulfonic acid monohydrate (0.13 g), and stirred overnight under an argon atmosphere. 4-methylbenzene-1-sulfonic acid monohydrate (0.15 g) was added thereto, and the mixture was stirred at room temperature for 1 day. The reaction solvent was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give (3S) -3- [ { 6-cyclopropyl-2- (ethanesulfonyl) -7- (6-fluoro-5-methyl-1H-indazol-4-yl) -8- [ (1S) -1-phenylethoxy ] quinazolin-4-yl } (meth) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester (from about 5:1 diastereomer mixture of axial asymmetry, 3.21 g) as a solid. The resulting unprotected body (about 5:1 mixture of diastereomers from axial asymmetry, 3.2 g) was dissolved in EtOH (30 mL) and the mixture was stirred at room temperature for 1 day. The resulting insoluble material was filtered off while rinsing with a small amount of EtOH and dried overnight at 40 ℃ under reduced pressure to give (3S) -3- [ { (7M) -6-cyclopropyl-2- (ethanesulfonyl) -7- (6-fluoro-5-methyl-1H-indazol-4-yl) -8- [ (1S) -1-phenylethoxy ] quinazolin-4-yl } (methyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester (single diastereomer, 2.23 g) as a solid.

Production example 173

To a mixture of 4-bromo-6-fluoro-1H-indazole (235 g), TEA (183 mL), CH ₂Cl₂ (1880 mL) was added 1,1' - (chloromethane triyl) triphenyl (335 g) at room temperature, and the mixture was stirred at 25℃for 16 hours. The reaction mixture was poured into ice water (1.5L), the organic layer and the aqueous layer were separated, and the aqueous layer was extracted 3 times with CH ₂Cl₂ (400 mL). The combined organic layers were dried over anhydrous sodium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. Petroleum ether (550 mL) was added to the resulting residue and powdered (0 ℃ C., 2 hours), then filtered off, and dried under reduced pressure to give 4-bromo-6-fluoro-2- (triphenylmethyl) -2H-indazole (508.98 g) as a solid.

Production example 174

To a mixture of 4-bromo-6-fluoro-2- (triphenylmethyl) -2H-indazole (100 g) in 2-methyltetrahydrofuran (1000 mL) was added lithium diisopropylamide (2M THF solution, 214.28 mL) at-78deg.C under nitrogen atmosphere, and the mixture was stirred at-78deg.C for 2.5 hours. Methyl iodide (26.68 mL) was added at-78deg.C and stirred at 25deg.C for 2.5 hours. The reaction was stopped by adding water (2000 mL) and extracted 2 times with ethyl acetate (800 mL). The combined organic layers were dried over anhydrous sodium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. To the resulting residue was added ethyl acetate (50 mL)/petroleum ether (50 mL) and powdered, and then filtered off, and dried under reduced pressure to give 4-bromo-6-fluoro-5-methyl-2- (triphenylmethyl) -2H-indazole (81 g) as a solid.

Production example 175

To 4-bromo-6-fluoro-5-methyl-2- (triphenylmethyl) -2H-indazole (100 g), 4', 5', to a mixture of 5 '-octamethyl-2, 2' -bis-1, 3, 2-dioxaborane (61.42 g), triphenylphosphine (10.57 g), potassium acetate (59.34 g) and DOX (1000 mL) was added palladium acetate (4.52 g) at room temperature under a nitrogen atmosphere. After degassing and nitrogen filling of the reaction mixture were each performed 3 times, stirring was performed at 100℃for 12 hours under a nitrogen atmosphere. After cooling, water (1500 mL) was added and extracted 3 times with ethyl acetate (900 mL). The combined organic layers were dried over anhydrous sodium sulfate, and insoluble matter was filtered off. To the resulting solution was added activated carbon (50 g), and the mixture was stirred at 20℃for 1 hour and filtered while being washed 3 times with ethyl acetate (50 ml). The filtrate was concentrated, meOH (200 mL) was added to the resulting residue and powdered, filtered off, and dried under reduced pressure to give 6-fluoro-5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2- (triphenylmethyl) -2H-indazole (110 g) as a solid.

Production example 176

DIPEA (200. Mu.L) was added to a solution of (4-ethynyl-3-fluorophenyl) methanol (110 mg) in CH ₂Cl₂ (2 mL) under ice cooling under nitrogen atmosphere, followed by addition of methanesulfonyl chloride (80. Mu.L). After stirring the reaction mixture at room temperature overnight, water was added and extracted with CHCl ₃. The organic layer was washed with water and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. Insoluble materials were filtered off, and concentrated under reduced pressure to give 4- (chloromethyl) -1-ethynyl-2-fluorobenzene (122 mg) as an oil.

Production example 177

To a mixture of 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (10 g) and N-methyl-2-pyrrolidone (20 mL) was added trimethyl orthoacetate (10.5 mL), and the mixture was stirred at 110℃for 12 hours. After cooling to room temperature, meOH (20 ml) was added, and the resulting solid was collected by filtration while being washed with cooled methanol (about 60 ml), and dried under reduced pressure to give methyl 2-acetamide-4-bromo-3-fluoro-5-iodobenzoate (6.67 g) as a solid.

Production example 178

To a mixture of lithium bis (trimethylsilyl) amide (1.3M in THF, 100 mL) and THF (150 mL) under an argon atmosphere was added a small amount of methyl 2-acetamide-4-bromo-3-fluoro-5-iodobenzoate (18 g) at a time with cooling in a water bath. After stirring at 40℃for 1 hour, it was cooled to room temperature, water was added, and the mixture was washed with ethyl acetate 2 times. Hydrochloric acid (1M, 140 ml) and ice water were added to the aqueous layer under ice cooling to make it acidic, and stirred for a while. The precipitated solid was collected by filtration and dried under reduced pressure. The resulting solid was collected by filtration while being washed with methanol, and dried under reduced pressure to give 7-bromo-8-fluoro-4-hydroxy-6-iodoquinolin-2 (1H) -one (13.6 g) as a solid.

Production example 179

To 7-bromo-8-fluoro-4-hydroxy-6-iodoquinolin-2 (1H) -one (5 g) was added phosphorus oxychloride (24 mL) under an argon atmosphere, DIPEA (7 mL) was slowly added under ice cooling, and the mixture was stirred at 110℃for 1 hour. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. Ice water was added to the residue and stirred for 30 minutes. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give 7-bromo-2, 4-dichloro-8-fluoro-6-iodoquinoline (5.03 g).

Production example 180

DABCO (1.8 g) was added to a mixture of 7-bromo-2, 4-dichloro-8-fluoro-6-iodoquinoline (6.4 g) and DMAc (70 mL) under argon atmosphere, and stirred at 40℃for 2 hours. Ethanethiol (1.4 mL) was added and stirred at 60℃for 1 hour. Cooled to room temperature, water was added, stirred for 5 minutes, the resulting solid was filtered off and dried under reduced pressure. The obtained solid was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 7-bromo-4-chloro-2- (ethylsulfanyl) -8-fluoro-6-iodoquinoline (5.76 g) as a solid.

Production example 181

To a solution of (1S) -1-phenylethan-1-ol (1.56 mL) in dehydrated THF (40 mL) under argon atmosphere was added tBuOK (1.39 g), and the mixture was stirred at room temperature for 30 minutes, and the prepared mixture was added dropwise to a mixture of 7-bromo-4-chloro-2- (ethylsulfanyl) -8-fluoro-6-iodoquinoline (5.5 g) and dehydrated THF (40 mL) under ice cooling for 20 minutes, and stirred at that temperature for 10 minutes. To a solution of (1S) -1-phenylethan-1-ol (0.45 mL) in dehydrated THF (10 mL) was additionally added tBuOK (415 mg) under an argon atmosphere, and the mixture was stirred at room temperature for 10 minutes, and the prepared mixture was slowly added dropwise to the previous reaction mixture under ice-cooling, and stirred at that temperature for 10 minutes. Saturated aqueous ammonium chloride, ice and ethyl acetate were added and the solution was separated. The aqueous layer was extracted with ethyl acetate 2 times, and the combined organic layers were washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Insoluble matter was filtered off, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 7-bromo-4-chloro-2- (ethylsulfanyl) -6-iodo-8- [ (1S) -1-phenylethoxy ] quinoline (4.9 g) as an oil. The fractions mixed with a small amount of impurities were concentrated to give 7-bromo-4-chloro-2- (ethylsulfanyl) -6-iodo-8- [ (1S) -1-phenylethoxy ] quinoline (1.56 g) as an oil.

Production example 182

To a solution of tert-butyl (3S) -3-hydroxypyrrolidine-1-carboxylate (2.7 g) in DMAc (20 mL) under argon atmosphere was added tBuOK (1.59 g), and the mixture was stirred at room temperature for 10 minutes, and the prepared mixture was added dropwise to a mixture of 7-bromo-4-chloro-2- (ethylsulfanyl) -6-iodo-8- [ (1S) -1-phenylethoxy ] quinoline (6.46 g) and DMAc (40 mL) under ice-cooling, and stirred at that temperature for 30 minutes. Saturated aqueous ammonium chloride, ice and ethyl acetate were added, stirred, and the mixture was separated. The aqueous layer was extracted with ethyl acetate 2 times, and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (hexane/ethyl acetate) gave (3S) -3- ({ 7-bromo-2- (ethylsulfanyl) -6-iodo-8- [ (1S) -1-phenylethoxy ] quinolin-4-yl } oxy) pyrrolidine-1-carboxylic acid tert-butyl ester (4.6 g) as a solid.

Production example 183

To a mixture of tert-butyl N- [ (1R) -1- (4-bromophenyl) -2-hydroxyethyl ] carbamate (1 g), 2-dimethoxypropane (3.3 mL) and acetone (15 mL) was added boron trifluoride diethyl ether complex (26. Mu.L), and the mixture was stirred at room temperature for 1 hour. TEA (66. Mu.L) was added and stirred at room temperature for 10 minutes. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give (4R) -4- (4-bromophenyl) -2, 2-dimethyl-1, 3-propanediol in solid formOxazolidine-3-carboxylic acid tert-butyl ester (1.09 g).

Production example 184

To (4R) -4- (4-bromophenyl) -2, 2-dimethyl-1, 3-)Oxazolidine-3-carboxylic acid tert-butyl ester (300 mg), 1,3-Copper (I) iodide (32 mg), rac- (1R, 2R) -cyclohexane-1, 2-diamine (20. Mu.L), and potassium carbonate (290 mg) were added to a solution of oxazolidin-2-one (183 mg) in DOX (1.69 mL) at room temperature. Stirring was carried out at 140℃for 2 hours under microwave irradiation and at 150℃for 1 hour. Ethyl acetate and water were added thereto, and filtration was performed through celite (registered trademark). Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give (4R) -2, 2-dimethyl-4- [4- (2-oxo-1, 3- ] in solid formOxazolidin-3-yl) phenyl ] -1,3-Oxazolidine-3-carboxylic acid tert-butyl ester (120 mg).

Production example 185

(4R) -4- (4-bromophenyl) -2, 2-dimethyl-1, 3-)Oxazolidine-3-carboxylic acid tert-butyl ester (858 mg), 2-methyl-1H-imidazole (500 mg), copper (I) iodide (95 mg), quinolin-8-ol (138 mg), potassium carbonate (670 mg) were suspended in DMSO (10 mL) and reacted under microwave irradiation under argon atmosphere at 150℃for 3 hours. After cooling to room temperature, ethyl acetate and water were added, extraction was performed 2 times with ethyl acetate, and the combined organic layers were washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate) to give (4R) -2, 2-dimethyl-4- [4- (2-methyl-1H-imidazol-1-yl) phenyl ] -1, 3-propanediol as an oilOxazolidine-3-carboxylic acid tert-butyl ester (500 mg).

Production example 187

Bis (tri-t-butylphosphine) palladium (0) (18 mg) was added to 4-methyl-1, 3-Oxazole-5-carboxylic acid (178 mg), tetra-n-butylammonium chloride (195 mg), (4R) -4- (4-bromophenyl) -2, 2-dimethyl-1, 3-In a mixture of tert-butyl oxazolidine-3-carboxylate (250 mg), cesium carbonate (344 mg) and DMF (2.5 mL) was stirred at 170℃for 30 min under microwave irradiation. After cooling to room temperature, the mixture was diluted with ethyl acetate, insoluble matters were removed by filtration through celite (registered trademark), and the filtrate was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (CHCl ₃/MeOH) to give (4R) -2, 2-dimethyl-4- [4- (4-methyl-1, 3- ] in solid formOxazol-5-yl) phenyl ] -1, 3-)Oxazolidine-3-carboxylic acid tert-butyl ester (215 mg).

Production example 188

Addition of (3S) -3- { [ (7M) -6-cyclopropyl-8- [ (4-ethynylphenyl) methoxy ] -7- [ 6-fluoro-5-methyl-1- ] anAlkyl-2-yl) -1H-indazol-4-yl ] -2- { [ (2S, 3S) -3-hydroxybutan-2-yl ] oxy } quinazolin-4-yl ] (methyl) amino } pyrrolidine-1-carboxylic acid tert-butyl ester (60 mg), dehydrated THF (2 mL) and methyl iodide (35 μl) were added sodium hydride (55% dispersion in mineral oil, 10 mg) under stirring under an argon atmosphere with cooling in an ice/MeOH bath, and stirred at room temperature overnight. An ice/saturated aqueous ammonium chloride solution was added to the reaction vessel, and extraction was performed 2 times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give (3S) -3- { [ (7M) -6-cyclopropyl-8- [ (4-ethynylphenyl) methoxy ] -7- [ 6-fluoro-5-methyl-1- ] as a solidAlkan-2-yl) -1H-indazol-4-yl ] -2- { [ (2S, 3S) -3-methoxybutan-2-yl ] oxy } quinazolin-4-yl ] (methyl) amino } pyrrolidine-1-carboxylic acid tert-butyl ester (50 mg).

Production example 192

Cesium carbonate (2.3 g) was added to a mixture of tetrahydro-2H-pyran-4-ol (272. Mu.L), 7-bromo-2, 4-dichloro-8-fluoro-6-iodoquinoline (1 g), DABCO (280 mg) and DMAc (10 mL) under an argon atmosphere, stirred at 60℃for 6 hours and 80℃for 3 hours. After naturally cooling to room temperature, ethyl acetate and water were added, and the mixture was stirred at room temperature for 30 minutes. The precipitated solid was collected by filtration and dried under reduced pressure. Purifying the obtained solid by silica gel column chromatography (hexane/ethyl acetate) to obtain 7-bromo-4-chloro-8-fluoro-6-iodo-2- [ (] in solid formAlk-4-yl) oxy ] quinoline (692 mg).

Production example 203

To a mixture of 7-bromo-2, 4-dichloro-8-fluoro-6-iodoquinoline (10 g), DABCO (3.3 g), cesium carbonate (23.3 g) and DMAc (100 mL) was added (2S) -2-methoxypropane-1-ol (3 mL) under an argon atmosphere, and after stirring at room temperature for 1.5 hours, stirring at 60℃for 12 hours. Naturally cooling to room temperature, adding water and ethyl acetate, stirring for a period of time, separating the two layers, and extracting the water layer with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Insoluble matter was filtered off, and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 7-bromo-4-chloro-8-fluoro-6-iodo-2- [ (2S) -2-methoxypropoxy ] quinoline (5.97 g) as a solid.

Production example 204

To a solution of 7-bromo-4-chloro-8-fluoro-6-iodo-2- [ (2S) -2-methoxypropoxy ] quinoline (6.47 g) and (1S) -1-phenylethan-1-ol (3.34 mL) in THF (50 mL) under an argon atmosphere was added tBuOK (3.06 g) in a cooling bath (about-10 ℃ C.) and stirred at this temperature for 30 minutes. Saturated aqueous ammonium chloride was added thereto under ice-cooling, and extraction was performed 2 times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Insoluble matter was filtered off, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 7-bromo-4-chloro-6-iodo-2- [ (2S) -2-methoxypropoxy ] -8- [ (1S) -1-phenylethoxy ] quinoline (4.67 g) as an oil.

Production example 205

To a solution of 7-bromo-4-chloro-6-iodo-2- [ (2S) -2-methoxypropoxy ] -8- [ (1S) -1-phenylethoxy ] quinoline (1.6 g) in DMAc (5 mL) was added (1S, 4S) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (832 mg) and potassium carbonate (768 mg) at room temperature, and the mixture was stirred overnight at 120 ℃. (1S, 4S) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (278 mg) and potassium carbonate (384 mg) were added at 120℃and stirred at this temperature overnight. Cooled to room temperature, saturated aqueous ammonium chloride was added, and extraction was performed 2 times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give (1S, 4S) -5- { 7-bromo-6-iodo-2- [ (2S) -2-methoxypropoxy ] -8- [ (1S) -1-phenylethoxy ] quinolin-4-yl } -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (1.02 g) as a foamy solid.

Production example 206

A mixture of 7-bromo-4-chloro-6-iodo-2- [ (2S) -2-methoxypropoxy ] -8- [ (1S) -1-phenylethoxy ] quinoline (377 mg), (3S) -3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (250 mg), potassium carbonate (130 mg), DMAc (5 mL) was stirred under argon atmosphere at 130℃for 7 days. Cooled to room temperature, water was added, and extraction was performed 2 times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (hexane/ethyl acetate) gave (3S) -3- ({ 7-bromo-6-iodo-2- [ (2S) -2-methoxypropoxy ] -8- [ (1S) -1-phenylethoxy ] quinolin-4-yl } amino) pyrrolidine-1-carboxylic acid tert-butyl ester (259 mg) as a foamy solid.

Production example 207

(3S) -3- ({ 7-bromo-6-iodo-2- [ (2S) -2-methoxypropoxy ] -8- [ (1S) -1-phenylethoxy ] quinolin-4-yl } amino) pyrrolidine-1-carboxylic acid tert-butyl ester (285 mg) was dissolved in DMF (3 mL), sodium hydride (60% in oil dispersion, 19 mg) was added under ice cooling, and stirred at room temperature for 1 hour. Methyl iodide (28. Mu.L) was added at room temperature, and stirred at that temperature for 1 hour. Ice and saturated aqueous ammonium chloride solution were added, and extraction was performed 2 times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (hexane/ethyl acetate) gave (3S) -3- [ { 7-bromo-6-iodo-2- [ (2S) -2-methoxypropoxy ] -8- [ (1S) -1-phenylethoxy ] quinolin-4-yl } (methyl) amino ] pyrrolidine-1-carboxylic acid tert-butyl ester (238 mg) as a foamy solid.

Production example 210

A mixture of (1S, 4S) -5- { 7-bromo-6-cyclopropyl-2- [ (2S) -2-methoxypropoxy ] -8- [ (1S) -1-phenylethoxy ] quinolin-4-yl } -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (0.75 g), 6-fluoro-5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2- (triphenylmethyl) -2H-indazole (900 mg), dicyclohexyl (2 ',6' -diisopropyloxy- [1,1' -biphenyl ] -2-yl) phosphine (138 mg), palladium (II) acetate (31 mg), anhydrous barium hydroxide (0.61 g), DOX (30 mL) and water (6 mL) was stirred at 50℃for 30 minutes under an argon atmosphere. 6-fluoro-5-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2- (triphenylmethyl) -2H-indazole (600 mg) was added at this temperature and stirred at 50℃for a further 1 hour. Cooled at room temperature, ethyl acetate and water were added, insoluble matters were removed by filtration through celite (registered trademark), and two layers of the filtrate were separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After filtration of the insoluble material, concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give (1S, 4S) -5- { 6-cyclopropyl-7- [ 6-fluoro-5-methyl-2- (triphenylmethyl) -2H-indazol-4-yl ] -2- [ (2S) -2-methoxypropoxy ] -8- [ (1S) -1-phenylethoxy ] quinolin-4-yl } -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (from about 4:1 diastereomeric mixture of axi, 866 mg) as a solid. To the resulting solid (866 mg) was added MeOH (5 mL), and the mixture was heated to 60 ℃ to dissolve the MeOH, and stirred at room temperature under an argon atmosphere for 3 days. The precipitated solid was collected by filtration while being washed with a small amount of MeOH to give (1S, 4S) -5- { 6-cyclopropyl-7- [ 6-fluoro-5-methyl-2- (triphenylmethyl) -2H-indazol-4-yl ] -2- [ (2S) -2-methoxypropoxy ] -8- [ (1S) -1-phenylethoxy ] quinolin-4-yl } -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (almost single diastereomer of unknown configuration, 200 mg) as a solid.

Production example 218

To a mixture of methyl 3-cyclopropyl-3-oxopropionate (17 mL) and trimethyl orthoformate (20 mL) was added concentrated sulfuric acid (500. Mu.L) under ice-cooling, and the mixture was stirred at room temperature under argon atmosphere overnight. The reaction solution was concentrated under reduced pressure at room temperature and dried for 4 hours. To the residue, 5-aminopyrimidine-2, 4 (1H, 3H) -dione (11.4 g) and DMAc (300 mL) were added at room temperature and stirred overnight at 110℃under an argon atmosphere. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the resulting solid was collected by filtration, and dried overnight at 50℃under reduced pressure to give methyl 3-cyclopropyl-3- [ (2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidin-5-yl) amino ] prop-2-enoate (22.3 g) as a solid.

Production example 219

Methyl 3-cyclopropyl-3- [ (2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidin-5-yl) amino ] prop-2-enoate (870 mg) was dissolved in NMP (17 mL) at room temperature and stirred under argon atmosphere at 220℃for 5 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the resultant solid was collected by filtration, and dried at 50℃under reduced pressure for 1 hour to give 6-cyclopropylpyrido [3,2-d ] pyrimidine-2, 4, 8-triol (230 mg) as a solid.

Production example 220

To a solution of 6-cyclopropylpyrido [3,2-d ] pyrimidine-2, 4, 8-triol (5.71 g) in DMF (90 mL) was added N-bromosuccinimide (9.3 g) under ice-cooling, and the mixture was stirred at room temperature overnight. Water was added under ice-cooling, and the resulting solid was collected by filtration and dried at 50℃under reduced pressure for 3 hours to give 7-bromo-6-cyclopropylpyrido [3,2-d ] pyrimidine-2, 4, 8-triol (2.12 g) as a solid.

Production example 221

To a mixture of 7-bromo-6-cyclopropylpyrido [3,2-d ] pyrimidine-2, 4, 8-triol (2.11 g) and N, N-diethylaniline (3.4 mL) was added phosphorus oxychloride (38.2 g) at room temperature and stirred overnight at 100℃under an argon atmosphere. The reaction solution was concentrated under reduced pressure, meCN (35 mL) and DIPEA (6 mL) were added to the residue under ice-cooling, and after stirring for 1 minute, tert-butyl (1 s,4 s) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate (1.96 g) was added under ice-cooling, and stirring was continued at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give (1S, 4S) -5- (7-bromo-2, 8-dichloro-6-cyclopropylpyrido [3,2-d ] pyrimidin-4-yl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (1.29 g) as a solid.

Manufacturing example 222

(1S, 4S) -5- (7-bromo-2, 8-dichloro-6-cyclopropylpyrido [3,2-d ] pyrimidin-4-yl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (2.4 g), DMF (20 mL), THF (20 mL) and tetrahydro-2H-pyran-4-ol (2.2 mL) were mixed at room temperature, and cesium carbonate (7.6 g) and DABCO (100 mg) were added under ice cooling. After stirring overnight at 50℃under an argon atmosphere, a saturated aqueous ammonium chloride solution was added under ice-cooling to stop the reaction. Water and ethyl acetate were added, the organic layer and the aqueous layer were separated, and the aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give (1S, 4S) -5- { 7-bromo-8-chloro-6-cyclopropyl-2- [ (-) -Alkan-4-yl) oxy ] pyrido [3,2-d ] pyrimidin-4-yl } -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (1.23 g).

Production example 225

To (1S, 4S) -5- { 6-cyclopropyl-7- [ 6-fluoro-5-methyl-2- (triphenylmethyl) -2H-indazol-4-yl ] -2- {To a solution of tert-butyl alk-4-yl) oxy ] -8- [ (1S) -1-phenylethoxy ] pyrido [3,2-d ] pyrimidin-4-yl } -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate (470 mg) in THF (10 mL) was added 4-methylbenzene-1-sulfonic acid monohydrate (60 mg) and 3, 4-dinitro-2H-pyran (1.1 mL) under ice-cooling, and the mixture was stirred overnight at room temperature under an argon atmosphere. After TEA (0.4 mL) was added under ice-cooling, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, hexane/ethyl acetate) to give (1S, 4S) -5- { 6-cyclopropyl-7- [ 6-fluoro-5-methyl-1- ] as a solidAlkan-2-yl) -1H-indazol-4-yl ] -2- [ ((x-x) -2- [ (x-y) and x-y)Alkan-4-yl) oxy ] -8- [ (1S) -1-phenylethoxy ] pyrido [3,2-d ] pyrimidin-4-yl } -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (291 mg).

The compounds shown in the following tables were produced in the same manner as in the production method of the production example shown above. The production methods, structures, and physicochemical data of the compounds of each production example are shown in the following tables.

Example 2

To 3- ({ (7M) -6-cyclopropyl-7- [ 6-fluoro-5-methyl-1- ]Alkan-2-yl) -1H-indazol-4-yl ] -8- { [4- (1- { (2S) -1- [ (2S, 4R) -4-hydroxy-2- ({ (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } carbamoyl) pyrrolidin-1-yl ] -3-methyl-1-oxobutan-2-yl } -1H-1,2, 3-triazol-4-yl) phenyl ] methoxy } -2- [. Sup.To a mixture of tert-butyl (355 mg) of alk-4-yloxy ] quinazolin-4-yl } oxy) azetidine-1-carboxylate and CH ₂Cl₂ (10 mL) was added phosphoric acid (85%, 500. Mu.L), and the mixture was stirred at room temperature overnight. After adding saturated aqueous sodium bicarbonate to the mixture, CHCl ₃/MeOH (5/1) and water were added and stirred at room temperature for 30 minutes. Extraction with CHCl ₃/MeOH (5/1), drying the combined organic layers over anhydrous sodium sulfate, filtration, concentration under reduced pressure, and recovery of (4R) -1- [ (2S) -2- (4- {4- [ ({ (7M) -4- [ (azetidin-3-yl) oxy ] -6-cyclopropyl-7- (6-fluoro-5-methyl-1H-indazol-4-yl) -2- [ (-a-M-ethyl) was achieved as a solidAlkan-4-yl) oxy ] quinazolin-8-yl } oxy) methyl ] phenyl } -1H-1,2, 3-triazol-1-yl) -3-methylbutanoyl ] -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide (355 mg).

Example 9

Under nitrogen atmosphere, to (3S) -3- { [ (7M) -6-cyclopropyl-7- [ 6-fluoro-5-methyl-1- ]Alkan-2-yl) -1H-indazol-4-yl ] -8- { [4- (1- { (2S) -1- [ (2S, 4R) -4-hydroxy-2- ({ (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } carbamoyl) pyrrolidin-1-yl ] -3-methyl-1-oxobutan-2-yl } -1H-1,2, 3-triazol-4-yl) phenyl ] methoxy } -2 (2R) -oxopyrrolidin-2-yl ] methoxy } quinazolin-4-yl ] (methyl) amino } pyrrolidine-1-carboxylic acid tert-butyl ester (156 mg) in CH ₂Cl₂ (2 mL) was added with trifluoroacetic acid (0.5 mL) under ice-cooling and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, meCN, saturated aqueous sodium bicarbonate and water were added to the residue, and stirred at room temperature for 20 minutes. The reaction solution was purified by ODS column chromatography (MeCN/0.1% aqueous formic acid), and the fraction containing the objective was concentrated. The residue was dissolved in CHCl ₃/iPrOH (9/1), saturated aqueous sodium bicarbonate was added and extracted 2 times with CHCl ₃/MeOH (5/1). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (4R) -1- [ (2S) -2- {4- [4- ({ [ (7M) -6-cyclopropyl-7- (6-fluoro-5-methyl-1H-indazol-4-yl) -4- { methyl [ (3S) -pyrrolidin-3-yl ] amino } -2- { [ (2R) -oxolan-2-yl ] methoxy } quinazolin-8-yl ] oxy } methyl) phenyl ] -1H-1,2, 3-triazol-1-yl } -3-methylbutanoyl ] -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide (47 mg) as a foamy solid.

Example 10

Under nitrogen atmosphere, to (3S) -3- { [ (7M) -6-cyclopropyl-7- [ 6-fluoro-5-methyl-1- ]Alkan-2-yl) -1H-indazol-4-yl ] -8- { [4- (1- { (2S) -1- [ (2S, 4R) -4-hydroxy-2- ({ (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } carbamoyl) pyrrolidin-1-yl ] -3-methyl-1-oxobutan-2-yl } -1H-1,2, 3-triazol-4-yl) phenyl ] methoxy } -2 (2S) -oxopyrrolidin-2-yl ] methoxy } quinazolin-4-yl ] (methyl) amino } pyrrolidine-1-carboxylic acid tert-butyl ester (236 mg) in CH ₂Cl₂ (2 mL) was added with trifluoroacetic acid (0.5 mL) under ice-cooling and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, meCN, saturated aqueous sodium bicarbonate and water were added to the residue, and stirred at room temperature for 20 minutes. The reaction solution was purified by ODS column chromatography (MeCN/0.1% aqueous formic acid), and the fraction containing the objective was concentrated. The residue was dissolved in CHCl ₃/iPrOH (9/1), saturated aqueous sodium bicarbonate was added and extracted 2 times with CHCl ₃/MeOH (5/1). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (4R) -1- [ (2S) -2- {4- [4- ({ [ (7M) -6-cyclopropyl-7- (6-fluoro-5-methyl-1H-indazol-4-yl) -4- { methyl [ (3S) -pyrrolidin-3-yl ] amino } -2- { [ (2S) -oxolan-2-yl ] methoxy } quinazolin-8-yl ] oxy } methyl) phenyl ] -1H-1,2, 3-triazol-1-yl } -3-methylbutanoyl ] -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide as a foamy solid (103 mg).

Example 11

Under nitrogen atmosphere, to (3S) -3- [ { (7M) -6-cyclopropyl-7- [ 6-fluoro-5-methyl-1- ]To a solution of tert-butyl 8- { [4- (1- { (2S) -1- [ (2S, 4R) -4-hydroxy-2- ({ (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } carbamoyl) pyrrolidin-1-yl ] -3-methyl-1-oxobutan-2-yl } -1H-1,2, 3-triazol-4-yl) phenyl ] methoxy } -2- [ (2S) -2-methoxypropoxy ] quinazolin-4-yl } (methyl) amino ] pyrrolidine-1-carboxylate (197 mg) in CH ₂Cl₂ (2 mL) was added trifluoroacetic acid (0.5 mL) under ice cooling and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, meCN, saturated aqueous sodium bicarbonate and water were added to the residue, and stirred at room temperature for 20 minutes. The reaction solution was purified by ODS column chromatography (MeCN/0.1% aqueous formic acid), and the fraction containing the objective was concentrated. The residue was dissolved in CHCl ₃/iPrOH (9/1), saturated aqueous sodium bicarbonate was added and extracted 2 times with CHCl ₃/MeOH (5/1). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (4R) -1- [ (2S) -2- {4- [4- ({ [ (7M) -6-cyclopropyl-7- (6-fluoro-5-methyl-1H-indazol-4-yl) -2- [ (2S) -2-methoxypropoxy ] -4- { methyl [ (3S) -pyrrolidin-3-yl ] amino } quinazolin-8-yl ] oxy } methyl) phenyl ] -1H-1,2, 3-triazol-1-yl } -3-methylbutanoyl ] -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide (65 mg) as a foamy solid.

Example 13

To (3S) -3- [ { (7M) -6-cyclopropyl-8- { [4- (1- { (2S) -1- [ (2S, 4R) -2- ({ (1R) -1- [4- (1-ethyl-1H-pyrazol-5-yl) phenyl ] -2-hydroxyethyl } carbamoyl) -4-hydroxypyrrolidin-1-yl ] -3-methyl-1-oxobutan-2-yl } -1H-1,2, 3-triazol-4-yl) phenyl ] methoxy } -7- [ 6-fluoro-5-methyl-1- (-d-a-To a solution of tert-butyl (2S) -2-methoxypropoxy ] quinazolin-4-yl (methyl) amino ] pyrrolidine-1-carboxylate (224 mg) in CH ₂Cl₂ (1 mL) was added TFA (1 mL) at room temperature. Stir at room temperature for 2 hours. The reaction solvent was concentrated under reduced pressure, meCN, saturated aqueous sodium bicarbonate and water were added to the residue, and stirred at room temperature for 20 minutes.

The resulting suspension was purified by ODS column chromatography (MeCN/0.1% aqueous formic acid), and the target fraction was concentrated under reduced pressure. The residue was dissolved in CHCl ₃/iPrOH (9/1), saturated aqueous sodium bicarbonate was added and extracted 2 times with CHCl ₃/MeOH (5/1). The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and concentrated as a foamy solid to give (4R) -1- [ (2S) -2- {4- [4- ({ [ (7M) -6-cyclopropyl-7- (6-fluoro-5-methyl-1H-indazol-yl) -2- [ (2S) -2-methoxypropoxy ] -4- { methyl [ (3S) -pyrrolidin-3-yl ] amino } quinazolin-8-yl ] oxy } methyl) phenyl ] -1H-1,2, 3-triazol-1-yl } -3-methylbutanoyl ] -N- { (1R) -1- [4- (1-ethyl-1H-pyrazol-5-yl) phenyl ] -2-hydroxyethyl } -4-hydroxy-L-prolinamide (109 mg).

Example 44

To (3S) -3- [ { (7M) -6-cyclopropyl-8- { [ 3-fluoro-4- (1- { (2S) -1- [ (2S, 4R) -4-hydroxy-2- ({ (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } carbamoyl) pyrrolidin-1-yl ] -3-methyl-1-oxobutan-2-yl } -1H-1,2, 3-triazol-4-yl) phenyl ] methoxy } -7- [ 6-fluoro-5-methyl-1- ] under a nitrogen atmosphereTo a solution of tert-butyl (2S) -2- [ (2S) -2-methoxypropoxy ] quinazolin-4-yl } (meth) amino ] pyrrolidine-1-carboxylate (169 mg) in CH ₂Cl₂ (2 mL), trifluoroacetic acid (1 mL) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate solution and extracted 2 times with CHCl ₃/MeOH (9/1). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by ODS column chromatography (MeCN/0.1% aqueous formic acid). To the fractions containing the target were added saturated aqueous sodium bicarbonate and extracted 2 times with CHCl ₃/MeOH (9/1). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (4R) -1- [ (2S) -2- {4- [4- ({ [ (7M) -6-cyclopropyl-7- (6-fluoro-5-methyl-1H-indazol-4-yl) -2- [ (2S) -2-methoxypropoxy ] -4- { methyl [ (3S) -pyrrolidin-3-yl ] amino } quinazolin-8-yl ] oxy } methyl) -2-fluorophenyl ] -1H-1,2, 3-triazol-1-yl } -3-methylbutanoyl ] -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide (92 mg) as a solid.

Example 50

To (3S) -3- [ { (7M) -6-cyclopropyl-7- [ 6-fluoro-5-methyl-1- ]To a mixture of tert-butyl 8- { [4- (1- { (2S) -1- [ (2S, 4R) -4-hydroxy-2- ({ (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } carbamoyl) pyrrolidin-1-yl ] -3-methyl-1-oxobutan-2-yl } -1H-1,2, 3-triazol-4-yl) phenyl ] methoxy } -2- [ (2S) -2-methoxypropoxy ] quinazolin-4-yl } (ethyl) amino ] pyrrolidine-1-carboxylate (175 mg) and CH ₂Cl₂ (3 mL) was added trifluoroacetic acid (1 mL) under ice/MeOH bath cooling and stirred at room temperature for 2 hours under argon atmosphere. The resulting reaction mixture was concentrated under reduced pressure, ice water, saturated aqueous sodium bicarbonate and CHCl ₃/MeOH (10/1) were added to the residue, and the mixture was stirred for 20 minutes and then separated. The aqueous layer was again extracted with CHCl ₃/MeOH (10/1) and the combined organic layers were dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (basic silica gel, CHCl ₃/MeOH) to give (4R) -1- [ (2S) -2- (4- {4- [ ({ (7M) -6-cyclopropyl-4- { ethyl [ (3S) -pyrrolidin-3-yl ] amino } -7- (6-fluoro-5-methyl-1H-indazol-4-yl) -2- [ (2S) -2-methoxypropoxy ] quinazolin-8-yl } oxy) methyl ] phenyl } -1H-1,2, 3-triazol-1-yl) -3-methylbutanoyl ] -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide (101 mg) as a solid.

Example 53

Under nitrogen atmosphere, to (3R) -3- [ { (7M) -6-cyclopropyl-7- [ 6-fluoro-5-methyl-1- ]To a solution of tert-butyl 8- { [4- (1- { (2S) -1- [ (2S, 4R) -4-hydroxy-2- ({ (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } carbamoyl) pyrrolidin-1-yl ] -3-methyl-1-oxobutan-2-yl } -1H-1,2, 3-triazol-4-yl) phenyl ] methoxy } -2- [ (2S) -2-methoxypropoxy ] quinazolin-4-yl } (methyl) amino ] pyrrolidine-1-carboxylate (310 mg) in CH ₂Cl₂ (3 mL) was added trifluoroacetic acid (1.5 mL) under ice cooling, followed by stirring at room temperature for 2 hours. To the mixture was added saturated aqueous sodium bicarbonate and extracted 2 times with CHCl ₃/MeOH (9/1). The combined organic layers were dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The resulting residue was purified by ODS column chromatography (MeCN/0.1% aqueous formic acid). Fractions containing the target were combined, saturated aqueous sodium bicarbonate was added and extracted 2 times with CHCl ₃/MeOH (9/1). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. After dissolving the residue in EtOH, it was concentrated under reduced pressure to give (4R) -1- [ (2S) -2- {4- [4- ({ [ (7M) -6-cyclopropyl-7- (6-fluoro-5-methyl-1H-indazol-4-yl) -2- [ (2S) -2-methoxypropoxy ] -4- { methyl [ (3R) -pyrrolidin-3-yl ] amino } quinazolin-8-yl ] oxy } methyl) phenyl ] -1H-1,2, 3-triazol-1-yl } -3-methylbutanoyl ] -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide (117 mg) as a solid.

Example 57

To (1S, 4S) -5- { 6-cyclopropyl-7- [ 6-fluoro-5-methyl-1-Alkan-2-yl) -1H-indazol-4-yl ] -8- { [4- (1- { (2S) -1- [ (2S, 4R) -4-hydroxy-2- ({ (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } carbamoyl) pyrrolidin-1-yl ] -3-methyl-1-oxobutan-2-yl } -1H-1,2, 3-triazol-4-yl) phenyl ] methoxy } -2- [. Sup.To a solution of tert-butyl (axi-asymmetric mixture, 120 mg) of Alkyloxy ] pyrido [3,2-d ] pyrimidin-4-yl } -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate (5 mL) was added methanesulfonic acid (0.3 mL) under ice-cooling, and the mixture was stirred at 50℃for 3 hours. After TEA (2 mL) was added under ice-cooling, the reaction solution was concentrated under reduced pressure. The residue was purified by ODS column chromatography (0.1% aqueous formic acid/0.1% MeCN) and fractions on the low polarity side of the two peaks having the molecular weight of the target were collected, and CHCl3/iPrOH (3/1) and saturated aqueous sodium hydrogencarbonate solution were added at room temperature. The organic and aqueous layers were separated and the aqueous layer was extracted 3 times with CHCl3/iPrOH (3/1). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in a small amount of ethyl acetate/iPrOH (10/1), and hexane was added. The precipitated solid was collected by filtration, washed with water and dried overnight at 50℃under reduced pressure to give (4R) -1- [ (2S) -2- (4- {4- [ ({ 6-cyclopropyl-4- [ (1S, 4S) -2, 5-diazabicyclo [2.2.1] heptan-2-yl ] -7- (6-fluoro-5-methyl-1H-indazol-4-yl) -2- [ ] as a solidAlkan-4-yl) oxy ] pyrido [3,2-d ] pyrimidin-8-yl } oxy) methyl ] phenyl } -1H-1,2, 3-triazol-1-yl) -3-methylbutanoyl ] -4-hydroxy-N- { (1R) -2-hydroxy-1- [4- (4-methyl-1, 3-thiazol-5-yl) phenyl ] ethyl } -L-prolinamide (single axis asymmetry, 40.4 mg).

The example compounds shown in the following table were produced in the same manner as the production method of the example shown above. The production methods and physicochemical data of the compounds of the examples are shown in the following tables.

In the tables described below, the following abbreviations may be used.

PEx: manufacturing example No. Ex: example No. PSyn: manufacturing example number, syn manufactured by the same method: example numbers produced by the same method (e.g., syn:9 indicates that produced by the same method as in example 9), str: the chemical formula (a compound with a "×" in the chemical formula indicates that the axial or central asymmetry of the compound is unique). n HCl: n hydrochloride (the compound with the manufacturing example number represents monohydrochloride to dihydrochloride), DAT: physicochemical data, esi+: m/z values in mass spectrometry (ionization method ESI, when not stated, [ M+H ] ⁺), ESI-: the M/z values in the mass spectrometry (ionization ESI, when not stated, are the delta value (ppm) of the peak in ¹ H-NMR (500 MHz) at 27℃in [ M-H ] ^-)、NMR：DMSO-d₆ ], the delta value (ppm) of the peak in ¹ H-NMR (500 MHz) at 100℃in DMSO-d ₆, s: singlet (spectrum), d: doublet (spectrum), dd: doublet (spectrum), ddd: doublet (spectrum), t: triplet (spectrum), q: quartet (spectrum), M: multiplet (spectrum), br: broad (spectrum) (e.g., br s).

[ Table 5-1]

[ Table 5-2]

[ Tables 5-3]

[ Tables 5-4]

[ Tables 5-5]

[ Tables 5-6]

[ Tables 5-7]

[ Tables 5-8]

[ Tables 5 to 9]

[ Tables 5 to 10]

[ Tables 5-11]

[ Tables 5-12]

[ Tables 5-13]

[ Tables 5 to 14]

[ Tables 5 to 15]

[ Tables 5 to 16]

[ Tables 5-17]

[ Tables 5-18]

[ Tables 5 to 19]

[ Tables 5-20]

[ Tables 5-21]

[ Tables 5-22]

[ Tables 5-23]

[ Tables 5 to 24]

[ Tables 5-25]

[ Tables 5-26]

[ Tables 5-27]

[ Tables 5-28]

[ Tables 5-29]

[ Tables 5-30]

[ Tables 5-31]

[ Tables 5-32]

[ Tables 5-33]

[ Tables 5-34]

[ Tables 5-35]

[ Tables 5-36]

[ Tables 5-37]

[ Tables 5-38]

[ Tables 5-39]

[ Tables 5-40]

[ Tables 5-41]

[ Tables 5-42]

[ Tables 5-43]

[ Tables 5-44]

[ Tables 5-45]

[ Tables 5-46]

[ Tables 5-47]

[ Tables 5-48]

[ Tables 5-49]

[ Tables 5-50]

[ Tables 5-51]

[ Tables 5-52]

[ Tables 5-53]

[ Tables 5-54]

[ Tables 5-55]

[ Tables 5-56]

[ Tables 5-57]

[ Tables 5-58]

[ Tables 5-59]

[ Tables 5-60]

[ Tables 5-61]

[ Tables 5-62]

[ Tables 5-63]

[ Tables 5-64]

[ Tables 5-65]

[ Tables 5-66]

[ Tables 5-67]

[ Table 6-1]

[ Table 6-2]

[ Table 6-3]

PEx	PSyn	DAT
			34	29	ESI+：820.7
35	29	ESI+：877.6[M+Na]+
			36	36	ESI+：841.6
37	36	ESI+：823.7
			38	36	ESI+：823.7
39	36	ESI+∶807.7
			40	36	ESI+∶845.7
41	36	ESI+∶841.7
			42	36	ESI+∶819.8
43	36	ESI+：803.6
			44	36	ESI+：821.7
45	36	ESI+：807.8
			46	36	ESI+：843.7
47	36	ESI+：825.7
			48	36	ESI+：807.8
49	36	ESI+：837.7
			50	36	ESI+：863.6
51	36	ESI+：963.7
			52	36	ESI+：851.8
53	36	ESI+：876.8
			54	54	ESI+：693.6
55	36	ESI+：863.4
			56	36	ESI+：851.5
57	57	ESI+：705.5
			58	58	ESI+：705.5
59	59	ESI+：637.4
			60	60	ESI+∶649.5
61	61	ESI+∶649.5
			62	62	ESI+：809.8
63	63	ESI+∶819.8
			64	62	ESI+∶805.8
65	62	ESI+∶806.6
			66	62	ESI+∶805.6
67	62	ESI+∶831.7
			68	62	ESI+∶819.7
69	62	ESI+∶844.8

[ Tables 6 to 4]

PEx	PSyn	DAT
			70	62	ESI+∶818.7
71	62	ESI+∶831.7
			72	62	ESI+：819.7
73	73	ESI+：819.7
			74	74	ESI+：831.8
75	75	ESI+：831.8
			76	62	ESI+：805.5
77	62	ESI+：833.4
			78	62	ESI+：831.7
79	79	ESI+：805.5
			80	62	ESI+：806.3
81	62	ESI+：804.4
			82	62	ESI+：733.4
83	83	ESI+：1313.8[M+Ma]+
			84	84	ESI+：1305.6
85	83	ESI+：1277.8
			86	83	ESI+：1279.7
87	83	ESI+：1317.7
			88	83	ESI-：1307.7
89	83	ESI+：1279.8
			90	83	ESI+：1310.2
91	83	ESI+：1314.7[M+Ma]+
			92	92	ESI+：1332.5[M+Ma]+
93	83	ESI+：1327.8
			94	83	ESI+：1314.7
95	83	ESI+：1279.7
			96	83	ESI+：1315.8
97	83	ESI+：1298.4
			98	83	ESI+：1280.8
99	83	ESI+：1276.5
			100	83	ESI+：1293.7
101	83	ESI+：1313.7[M+Na]+
			102	83	ESI+：1279.3
103	83	ESI+：1304.6
			104	83	ESI+：1101.8
105	83	ESI+：1101.8

[ Tables 6 to 5]

PEx	PSyn	DAT
			106	83	ESI+：1457.6[M+Na]+
107	83	ESI+：1328.1[M+Na]+
			1 08	83	ESI+：1292.9
109	83	ESI+：1318.0
			1 10	83	ESI+：1313.0[M+Na]+
111	83	ESI+：1089.8
			112	83	ESI+：1304.3
113	83	ESI+：1314.8[M+Na]+
			114	114	ESI+：1312.0[M+Na]+
115	115	ESI+：1303.3
			116	116	ESI+：1291.9
117	117	ESI+：1 304.2
			118	83	ESI+：1277.8
119	83	ESI+：1277.2
			120	83	ESI+：1306.5
121	83	ESI+：1326.0[M+Na]+
			122	83	ESI+：1277.4
123	83	ESI+：1278.3
			124	124	ESI+：1205.4
125	125	ESI+：335.2
			126	126	ESI+：235.2
127	126	ESI+：205.3
			128	126	ESI+：233.3
129	126	ESI+：218.2
			130	126	ESI+：219.1
131	131	ESI+：232.2
			132	126	ESI+：245.1[M+Na]+
133	133	ESI+：448.3
			134	134	ESI+：445.3
135	135	ESI+：348.2
			136	136	ESI+：345.2
1 37	137	ESI+：547.4
			138	1 38	ESI+：544.3
139	139	ESI+：447.3
			140	140	ESI+：444.3
141	141	ESI+：473.3

[ Tables 6 to 6]

PEx	PSyn	DAT
			142	142	ESI+：470.3
143	143	ESI+：833.6
			144	144	ESI+：332.2
145	144	ESI+：333.4
			146	146	ESI+：1076.1
147	146	ESI+：1087.8
			148	146	ESI+：1087.8
149	149	ESI+：1213.5
			150	149	ESI+：1262.7
151	149	ESI+：1286.8
			152	149	ESI+：1287.7
153	149	ESI+：1301.6
			154	149	ESI+：1323.7[M+Na]+
155	149	ESI+：1286.9
			156	149	ESI+：1288.6
157	149	ESI+：1300.9
			158	149	ESI+：1290.2
159	149	ESI+：1297.0[M+Na]+
			160	149	ESI+：1280.3
161	149	ESI+：1276.2
			162	149	ESI+：1273.7
163	163	ESI+：627.5
			164	163	ESI+：623.5
165	163	ESI+：649.6
			166	163	ESI+：637.3
167	163	ESI+：662.5
			168	163	ESI+：649.3
169	163	ESI+：637.5
			170	163	ESI+：649.4
171	171	ESI+：585.2，587.1

[ Tables 6 to 7]

[ Tables 6 to 8]

PEx	PSyn	DAT
			191	188	ESI+：837.7
192	192	ESI+：485.9，487.9，489.8
			193	181	ESI+：588.0
194	182	ESI+：741.1
			195	9	ESI+：655.2
196	13	ESI+：965.3
			197	23	ESI+：861.4
198	29	ESI+：975.4
			199	19	ESI+：733.4
200	124	ESI+：1205.8
			201	139	ESI+：245.2
202	141	ESI+：271.2

[ Tables 6 to 9]

PEx	PSyn	DAT
			203	203	ESI+：474.0
204	204	ESI+：598.1，600.2[M+Na]+
			205	205	ESI+：740.3
206	206	ESI+：728.2
			207	207	ESI+：740.2
208	9	ESI+：654.4
			209	9	ESI+：656.6
210	210	ESI+：964.7
			211	210	ESI+：966.8
212	23	ESI+：860.6
			213	23	ESI+：862.7
214	29	ESI+：974.7
			215	29	ESI+：976.8
216	117	ESI+：1446.7
			217	117	ESI+：1448.7

[ Tables 6 to 10]

PEx	PSyn	DAT
			218	218	ESI+：252.1
219	219	ESI+：220.1
			220	220	ESI+：298.0
221	221	ESI+：514.2，516.2
			222	222	ESI+：580.3，582.2
223	6	ESI+：668.5
			224	13	ESI+：978.6
225	225	ESI+：820.6
			226	23	ESI+：716.5
227	29	ESI+：830.6
			228	117	ESI+：1324.8[M+Na]+

[ Table 7-1]

[ Table 7-2]

[ Table 7-3]

[ Tables 7 to 4]

[ Tables 7 to 5]

[ Tables 7 to 6]

[ Tables 7 to 7]

[ Tables 7 to 8]

[ Tables 7 to 9]

[ Tables 7 to 10]

[ Tables 7 to 11]

[ Tables 7 to 12]

[ Tables 7 to 13]

[ Tables 7 to 14]

[ Tables 7 to 15]

[ Tables 7 to 16]

[ Tables 7 to 17]

Tables 7 to 18

[ Tables 7 to 19]

[ Tables 7 to 20]

[ Table 8-1]

[ Table 8-2]

[ Tables 8-3]

[ Tables 8 to 4]

[ Tables 8 to 5]

Ex	Syn	DAT
			55	9	ESI+：1104.4
56	9	ESI+：1107.9

[ Tables 8 to 6]

Ex	Syn	DAT
			57	57	ES1+：1118.5

As examples of specific compounds of the formula (I) and the formula (IA) included in the present invention, compounds having any of the following structures are shown. These compounds may also be produced by the representative production methods, production examples and production methods of the examples shown above or a combination of these production methods or a method obvious to those skilled in the art.

Further, these compounds have excellent action of inducing the degradation of G12D mutant KRAS protein, and are expected to be useful as inhibitors of G12D mutant KRAS, and can be used as active ingredients in pharmaceutical compositions, for example, pharmaceutical compositions for the treatment of pancreatic cancer.

[ Table 9-1]

[ Table 9-2]

[ Tables 9-3]

[ Tables 9 to 4]

[ Tables 9 to 5]

[ Tables 9 to 6]

[ Tables 9 to 7]

[ Tables 9 to 8]

[ Tables 9 to 9]

[ Tables 9 to 10]

[ Tables 9 to 11]

Industrial applicability

The compound of the present invention or a salt thereof has an excellent effect of inducing the decomposition of G12D mutant KRAS protein, is useful as a G12D mutant KRAS inhibitor, and can be used as an active ingredient of a pharmaceutical composition, for example, a pharmaceutical composition for the treatment of pancreatic cancer.

Claims

1. A compound of formula (IA) or a salt thereof,

In the formula (IA),

A is CR ^A or N, and the total number of the components is N,

R ^A is H or C _1-3 alkyl,

E is CH or N, and the R is H,

G is CR ² or N, and the total number of the components is N,

R ^1c is F, cl, methyl or ethyl,

R ² is H, halogen, optionally substituted C _1-3 alkyl, cyclopropyl or vinyl,

R ³ is-P-Q or V,

P is-CH ₂ -, -O-or-N (R ^P) -,

R ^P is H or C _1-3 alkyl which can be substituted,

Q is the following formula (V) or formula (VI),

V is the following formula (VII),

In addition, (i) when A is CR ^A, or (ii) when A is N and E or G is N,

M is a number from 0 to 2,

R ^Y is H or C _1-3 alkyl,

R ^P1 is OH or F, and the total number of the components is H,

R ^P2a is H or F,

R ^P2b is H, and the hydrogen atom,

X is a bond, -CH ₂ -, -O-, -S-, or-NR ^4x -,

R ^4x is H or C _1-3 alkyl,

Y is phenylene or pyridyldiyl, which phenylene may be substituted by F,

L is- (L ¹-L²-L³-L⁴) -,

R ^L1 is H or C _1-3 alkyl,

Or Y-L-Z is the following formula (VIII),

2. A compound of formula (I) or a salt thereof,

In the formula (I) of the present invention,

A is CR ^A or N, and the total number of the components is N,

R ^A is H or C _1-3 alkyl,

R ^1c is F, cl, methyl or ethyl,

R ² is H, halogen, optionally substituted C _1-3 alkyl, cyclopropyl or vinyl,

R ³ is-P-Q or V,

P is-CH ₂ -, -O-or-N (R ^P) -,

R ^P is H or C _1-3 alkyl which can be substituted,

Q is the following formula (V) or formula (VI),

V is the following formula (VII),

M is a number from 0 to 2,

X is a bond, -CH ₂ -, -O-, -S-, or-NR ^4x -,

R ^4x is H or C _1-3 alkyl,

Y is phenylene or pyridyldiyl, which phenylene may be substituted by F,

L is- (L ¹-L²-L³-L⁴) -,

R ^L1 is H or C _1-3 alkyl,

Or Y-L-Z is the following formula (VIII),

3. The compound or salt according to claim 2, wherein,

Y is phenylene or pyridyldiyl, which phenylene may be substituted by F,

R ^L1 is H or C _1-3 alkyl,

R ^L is CH or N, and the total number of the components is,

N is an integer of 1 to 2,

Z is NH or a group selected from the group consisting of the following formulas (XXVI), formula (XXVII), formula (XXVIII) and formula (XXIX),

Or Y-L-Z is the following formula (VIII),

4. The compound according to claim 3, wherein R ¹ is the following formula (IIa) or formula (IIIa),

R ^1a、R^1b are identical or different from each other and are H, methyl, F or Cl, R ³:

(i) When A is CR ^A, it is-P-Q,

P is-O-,

(Ii) When A is N, it is-P-Q or V, P is-O-or-N (R ^P) -,

R ^P is H or C _1-3 alkyl,

In either case of (i) and (ii), Q is a compound of formula (V) or formula (VI) below,

V is the following formula (VII),

M is a number from 0 to 2,

R ⁵ is methyl, ethyl, isopropyl, tert-butyl or C _3-6 cycloalkyl,

W is the following formula (XIX),

W ¹ and W ²:

(i) W ¹ is CH, W ² is C-SO ₂CH₃, or

(Ii) W ¹、W² are identical or different from each other and are CH, CF, CCl, CCH ₃ or N, where R ⁷ is H when W ¹ is CH and W ² is C-SO ₂CH₃,

X is-O-or-NR ^4x -,

R ^4x is H or C _1-3 alkyl,

Y is phenylene or pyridyldiyl, which phenylene may be substituted by F,

R ^L1 is H or C _1-3 alkyl,

N is an integer of 1 to 2,

Or Y-L-Z is the following formula (VIII),

5. The compound or salt according to claim 4, wherein,

A is CH or N, and the A is H or N,

R³：

(I) When A is CH, it is-P-Q,

P is-O-,

(Ii) A is-P-Q or V when A is N,

P is-O-or-N (R ^P) -,

R ^P is H or C _1-3 alkyl,

V is the following formula (VII),

M is a number from 0 to 2,

W is the following formula (XIX),

W ¹、W² are identical or different from each other and are CH or N,

X is-O-or-NH-,

Y is phenylene or pyridyldiyl, which phenylene may be substituted by F,

L is a bond and is preferably a bond,

Z is the following formula (XXVII),

6. The compound or salt according to claim 4, wherein,

A is N, and the number of the A is N,

R ³ is-P-Q,

P is-O-or-N (R ^P) -,

R ^P is H or C _1-3 alkyl,

Q is the following formula (V) or formula (VI),

M is a number from 0 to 2,

W is the following formula (XIX),

Y is phenylene or pyridyldiyl, which phenylene may be substituted by F,

R ^L1 is H or C _1-3 alkyl,

N is an integer of 1 to 2,

7. The compound or salt according to claim 4, wherein,

A is CH, and the A is CH,

R ³ is-P-Q,

P is-O-,

Q is the following formula (V) or formula (VI),

M is a number from 0 to 2,

W is the following formula (XIX),

Y is phenylene or pyridyldiyl, which phenylene may be substituted by F,

R ^L1 is H or C _1-3 alkyl,

N is an integer of 1 to 2,

8. The compound or salt according to claim 4, wherein,

A is N, and the number of the A is N,

R ³ is V, and the R is H,

V is the following formula (VII),

M is a number from 0 to 2,

W is the following formula (XIX),

Y is phenylene or pyridyldiyl, which phenylene may be substituted by F,

R ^L1 is H or C _1-3 alkyl,

N is an integer of 1 to 2,

9. The compound or salt according to claim 5, wherein,

A is N, and the number of the A is N,

R ¹ is the following formula (IIb),

R ³ is-P-Q,

P is-O-or-N (R ^P) -,

R ^P is H or C _1-3 alkyl,

Q is the following formula (V) or formula (VI),

M is 0 or 1 and the number of the groups,

X is-O-.

10. The compound or salt according to claim 9, wherein,

R ² is cyclopropyl, and the amino group is a cyclopropyl group,

R ³ is-P-Q,

P is-N (R ^P) -,

R ^P is H or C _1-3 alkyl,

Q is the following formula (V) or formula (VI),

M is 0 or 1 and the number of the groups,

R ⁵ is isopropyl group, and the amino group is a hydroxyl group,

R ^6a is H, R ^6b is C _1-3 alkyl which can be substituted by OH,

R ^7a is C _1-3 alkyl which may be substituted by OH,

W is the following formula (XIX),

W ¹、W² is CH, and the two are all CH,

Y is phenylene which may be substituted by F.

11. A compound or salt thereof according to claim 1 or claim 2, wherein the compounds of formula (I) and formula (IA) are selected from the group consisting of:

12. A pharmaceutical composition comprising a compound of claim 1 or claim 2, or a salt thereof, and one or more pharmaceutically acceptable excipients.

13. The pharmaceutical composition according to claim 12, which is a pharmaceutical composition for the treatment of pancreatic cancer.

14. Use of a compound of claim 1 or claim 2, or a salt thereof, in the manufacture of a pharmaceutical composition for the treatment of pancreatic cancer.

15. A compound according to claim 1 or claim 2, or a salt thereof, for use in the treatment of pancreatic cancer.

16. Use of a compound of claim 1 or claim 2, or a salt thereof, in the treatment of pancreatic cancer.

17. A method of treating pancreatic cancer comprising the step of administering to a subject an effective amount of a compound of claim 1 or claim 2, or a salt thereof.