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WO2024261256A1 - PHARMACEUTICAL COMPOSITION COMPRISING A pan-KRAS DEGRADER - Google Patents

PHARMACEUTICAL COMPOSITION COMPRISING A pan-KRAS DEGRADER Download PDF

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Publication number
WO2024261256A1
WO2024261256A1 PCT/EP2024/067466 EP2024067466W WO2024261256A1 WO 2024261256 A1 WO2024261256 A1 WO 2024261256A1 EP 2024067466 W EP2024067466 W EP 2024067466W WO 2024261256 A1 WO2024261256 A1 WO 2024261256A1
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formula
group
optionally substituted
alkyl
compound
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French (fr)
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Yoshihiro NISHIZONO
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Astellas Pharma Inc
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Astellas Pharma Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the present invention relates to the medical use of compounds, and compositions comprising the compounds, in the treatment of colorectal cancer and/or lung cancer.
  • the present invention relates to bifunctional compounds comprising a substituent at the 8-position of a heterocyclic compound selected from the group consisting of quinazoline and quinoline bound, optionally via a linker, to a ligand of an E3 ligase, which have excellent degradation-inducing action on G12V mutant, G12D mutant and G12C mutant KRAS protein, and are useful as G12V mutant, G12D mutant and G12C mutant KRAS inhibitors, and their use in the treatment of colorectal and/or lung cancer.
  • Colorectal cancer is a cancer with a high morbidity and fatality in the world, and about 1.8 million new cases are reported every year in the world (World Cancer Report 2020).
  • the most effective treatment for colorectal cancer is a surgery, whereas chemotherapy, radiotherapy, and the like have been significantly advanced recently.
  • Large scale clinical trials performed mainly in Europe and America have revealed that a combination of chemotherapy and anti-cancer agents is effective for colorectal cancer and contributes to tumor regression and prognosis prolongation (J. Clin. Oncol., 22, p.229-237, 2004).
  • molecular target drugs such as an anti-vascular endothelial growth factor (VEGF) antibody or an anti-epidermal growth factor receptor (EGFR) antibody
  • VEGF vascular endothelial growth factor
  • EGFR anti-epidermal growth factor receptor
  • an anti-EGFR antibody it has been revealed that mutations in a KRAS gene is a negative predictive factor for the efficacy (Cancer Res., 66, p.3992- 3995, 2006), and anti-EGFR antibody drugs are applicable only to patients harboring wild-type RAS genes in colorectal cancer.
  • lung cancer is the most common cancer type worldwide. Approximately 1.8 million deaths and 2.1 million new cases are reported every year in the world (World Cancer Report 2020). Especially, non-small cell lung cancer (NSCLC) is reported to account for 80 to 85% of lung cancer (American Cancer Society, Cancer Facts and Figures, 2016). Surgical therapy is considered at early stage, but surgery is rarely adopted and chemotherapy or radiotherapy becomes a main therapy at late stage. Based on the cytomorphology, adenocarcinoma and squamous cell carcinoma are classified as the most typical type of NSCLC. These cancers follow a similar clinical course, but adenocarcinoma is characterized by localization in the lung periphery.
  • RAS proteins are low molecular weight guanosine triphosphate (GTP)-binding proteins of about 21 kDa constituted of 188-189 amino acids and include four main types (KRAS (KRAS 4A and KRAS 4B), NRAS and HRAS) produced by a KRAS gene, an NRAS gene and HRAS gene.
  • RAS proteins are in an active GTP-bound form or an inactive guanosine diphosphate (GDP)-bound form.
  • RAS proteins are activated by nucleotide exchange of GDP to GTP due to, for example, ligand stimulation of a membrane receptor, such as EGFR.
  • the activated RAS proteins bind to effector proteins as much as twenty, such as RAF, PI3K, and RALGDS, to activate the downstream signal cascade.
  • the activate form RAS proteins are converted to the inactive form by hydrolysis of GTP due to the intrinsic GTP hydrolysis (GTPase) activity.
  • GTPase activity is enhanced by a GTPase-activating protein (GAP). Therefore, RAS proteins have an important function of "molecular switch" in an intracellular signal transduction pathway for EGFR or the like, and play a critical role in the processes of cell growth, proliferation, angiogenesis, and the like (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).
  • a mutation of a RAS gene has been in 32% of lung adenocarcinoma.
  • the breakdown of the frequency of the mutation is 96% in KRAS genes, 3% in NRAS genes, and 1% in HRAS genes, and it is reported especially in the KRAS exon 2 (codon 12, codon 13) (Nature Rev. Drug Discov., 2014, 13, p.828-851).
  • KRAS G12V mutation in which glycine at the codon 12 is substituted with valine KRAS G12D mutation in which glycine at the codon 12 is substituted with aspartic acid
  • KRAS G12C mutation in which glycine is substituted with cysteine are particularly known.
  • Sotorasib and Adagrasib have been approved by FDA as a therapeutic agent for non-small cell lung cancer (Drugs, 2021, 81, p.1573-1579; Drugs, 2023, 83, p.275-285).
  • KRAS G12V mutation is observed in about 22% of pancreatic cancer, in 6% or more of colorectal cancer, and also in about 5% of lung adenocarcinoma (Nat. Rev. Cancer, 2018, 18, p.767-777).
  • a therapeutic agent for a KRAS mutation other than the KRAS G12C mutation is highly expected.
  • WO 2016/049565, WO 2016/049568, and WO 2017/172979 disclose RAS inhibitors, and WO 2016/049568 and WO 2017/172979 disclose compounds represented by the following formulae (A) and (B), respectively (refer to the documents for the meanings of the signs in the formulae).
  • WO 2021/041671, WO 2021/106231, and WO 2021/107160 disclose KRAS G12D mutation inhibitors.
  • WO 2022/132200 discloses pan-RAS inhibitors.
  • bifunctional compounds collectively called as PROTAC (proteolysis-targeting chimera) or SNIPER (specific and nongenetic lAP-dependent protein eraser) are found and are expected as one novel technique of drug development modality (Drug. Discov. Today Technol., 2019, 31, pl5-27).
  • Such a bifunctional compound promotes formation of a composite of the target protein in a cell, and degradation of the target protein is induced by using the ubiquitin-proteasome system.
  • the ubiquitin-proteasome system is one of intracellular protein degradation mechanisms.
  • An E3 ligase protein recognizes a protein to be degraded to ubiquitinate the protein, whereby degradation by proteasome is promoted.
  • E3 ligases Six hundreds or more E3 ligases are present in an organism, and are roughly divided into four types of HECT-domain E3s, U-box E3s, monomeric RING E3s, and multisubunit E3s.
  • E3 ligases used as a bifunctional degradation inducer which are PROTAC, SNIPER, or the like are currently limited, and typical examples thereof include von Hippel-Lindau (VHL), celebron (CRBN), inhibitor of apoptosis protein (IAP), and mouse double minute 2 homolog (MDM2).
  • VHL von Hippel-Lindau
  • CRBN celebron
  • IAP inhibitor of apoptosis protein
  • MDM2 mouse double minute 2 homolog
  • VHL is reported in WO 2013/106643
  • CRBN is reported in WO 2015/160845.
  • the bifunctional compounds are compounds in which a ligand of a target protein and a ligand of an E3 ligase are bound via a linker, and some bifunctional compounds for degrading a KRAS protein have ever been reported (Cell. Chem. Biol., 2020, 27, pl9- 31; ACS Cent. Sci., 2020, 6, pl367-1375; US 2018/0015087; WO 2019/195609; WO 2020/018788, WO 2021/051034; WO 2022/087335; WO2022/061348;
  • compounds of formula (I) as defined herein are useful for treating colorectal cancer and/or lung cancer in view of their degradation-inducing action, for example, on G12V mutant, G12D mutant and G12C mutant KRAS protein, and their activity as G12V mutant, G12D mutant and G12C mutant KRAS inhibitors.
  • heterocyclic compounds of formula (I), in particular, bifunctional compounds of the formula (I) comprising a substituent at the 8-position of a heterocyclic compound selected from the group consisting of quinazoline and quinoline bound, optionally via a linker, to a ligand of an E3 ligase has excellent degradation-inducing action on G12V mutant, G12D mutant and G12C mutant KRAS protein, and G12V mutant, G12D mutant and G12C mutant KRAS inhibitory activity and that the compounds are useful (in particular as the active ingredient in a pharmaceutical composition) for treating colorectal and/or lung cancer (and particularly G12V mutant, G12D mutant and/or G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and/or G12C mutant KRAS-positive lung cancer)
  • a compound of formula (I) or a salt thereof for use in the treatment of colorectal cancer and/or lung cancer in particular, G12V mutant, G12D mutant and/or G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and/or G12C mutant KRAS-positive lung cancer, wherein (in formula (I)),
  • A is CR A or N, wherein R A is H or C1-3 alkyl,
  • X 1 is -CH2- or -O-
  • R 1 is naphthyl optionally substituted with OH or the formula (II) below, wherein R la is H, methyl, F or Cl, and
  • R lb is F, Cl, methyl or ethyl
  • R 2 is H, halogen, C1-3 alkyl optionally substituted with a group selected from the group consisting of OH and OCH3, cyclopropyl or vinyl
  • R 3 is a group selected from the group consisting of the formula (III), the formula (IV), the formula (V), the formula (VI), the formula (VII), the formula (VIII), the formula (IX), the formula (X), the formula (XI) and the formula (XXXV) below, wherein R 3a is -(CH2)pCHR 3f -NR N1 R N2 ; -(CH2)pCHR 3f -OR 3g ; a 4-membered to 6- membered saturated heterocyclic group which is optionally substituted with a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR 3g , C1-3 alkylene- NR N1 R N2 and -NR N1 R N2 and which contains one or two hetero atoms selected from the group consisting of oxygen, sulfur and
  • a pharmaceutical composition in particular, a pharmaceutical composition for treating colorectal cancer and/or lung cancer, and more particularly, a pharmaceutical composition for treating G12V mutant, G12D mutant and/or G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and/or G12C mutant KRAS-positive lung cancer, comprising the compound of the formula (I) or a salt thereof, as defined herein, and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition includes a therapeutic agent for treating colorectal cancer and/or lung cancer, in particular, G12V mutant, G12D mutant and/or G12C mutant KRAS-positive cancer, the therapeutic agent comprising the compound of the formula (I) or a salt thereof, as defined herein.
  • the use of the compound of formula (I), or salt thereof, as defined herein, for the manufacture of a pharmaceutical composition for treating colorectal cancer and/or lung cancer in particular, G12V mutant, G12D mutant and/or G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and/or G12C mutant KRAS-positive lung cancer.
  • a method for treating colorectal cancer and/or lung cancer in particular, G12V mutant, G12D mutant and/or G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and/or G12C mutant KRAS-positive lung cancer, the method including administering an effective amount of the compound of formula (I) or a salt thereof, as defined herein, to a subject in need thereof.
  • the term “subject” denotes a human or another animal that needs the treatment, and in an embodiment, the “subject” is a human who needs the prevention or treatment.
  • the compound of formula (I), or salt thereof, as defined herein has been found induce degradation of G12V mutant, G12D mutant and/or G12C mutant KRAS protein and/or to be G12V mutant, G12D mutant and/or G12C mutant KRAS inhibitors. Accordingly, in particular embodiments of all aspects of the invention defined herein, the compound of formula (I), or salt thereof, is a G12V mutant, G12D mutant and/or G12C mutant KRAS protein degradation inducer and/or a G12V mutant, G12D mutant and/or G12C mutant KRAS protein inhibitor.
  • a method of inducing degradation of G12V mutant, G12D mutant and/or G12C mutant KRAS protein and/or inhibiting the function of G12V mutant, G12D mutant and/or G12C mutant KRAS in a subject comprising administering an effective amount of a compound of formula (I) or a salt thereof, to a patient in need thereof.
  • the colorectal cancer and/or lung cancer is G12V mutant, G12D mutant and G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and G12C mutant KRAS-positive lung cancer.
  • a compound of formula (I) or a salt thereof, as defined herein for use in the treatment of G12V mutant, G12D mutant and G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and G12C mutant KRAS-positive lung cancer.
  • a pharmaceutical composition in particular, a pharmaceutical composition for treating G12V mutant, G12D mutant and G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and G12C mutant KRAS-positive lung cancer, comprising the compound of the formula (I) or a salt thereof, as defined herein, and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition includes a therapeutic agent for treating colorectal cancer and/or lung cancer, in particular, a G12V mutant, G12D mutant and G12C mutant KRAS-positive cancer, the therapeutic agent comprising the compound of the formula (I) or a salt thereof, as defined herein.
  • a method for treating G12V mutant, G12D mutant and G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and G12C mutant KRAS-positive lung cancer including administering an effective amount of the compound of formula (I) or a salt thereof, as defined herein, to a subject in need thereof.
  • the colorectal cancer and/or lung cancer is G12V mutant and G12D mutant KRAS-positive colorectal cancer and/or G12V mutant and G12D mutant KRAS-positive lung cancer.
  • a compound of formula (I) or a salt thereof, as defined herein for use in the treatment of G12V mutant and G12D mutant KRAS-positive colorectal cancer and/or G12V mutant and G12D mutant KRAS-positive lung cancer.
  • a pharmaceutical composition in particular, a pharmaceutical composition for treating G12V mutant and G12D mutant KRAS- positive colorectal cancer and/or G12V mutant and G12D mutant KRAS-positive lung cancer, comprising the compound of the formula (I) or a salt thereof, as defined herein, and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition includes a therapeutic agent for treating colorectal cancer and/or lung cancer, in particular, a G12V mutant and G12D mutant KRAS-positive cancer, the therapeutic agent comprising the compound of the formula (I) or a salt thereof, as defined herein.
  • a method for treating G12V mutant and G12D mutant KRAS-positive colorectal cancer and/or G12V mutant and G12D mutant KRAS-positive lung cancer including administering an effective amount of the compound of formula (I) or a salt thereof, as defined herein, to a subject in need thereof.
  • the colorectal cancer and/or lung cancer is G12V mutant KRAS-positive colorectal cancer and/or G12V mutant KRAS-positive lung cancer.
  • a compound of formula (I) or a salt thereof, as defined herein for use in the treatment of G12V mutant KRAS-positive colorectal cancer and/or G12V mutant KRAS-positive lung cancer.
  • a pharmaceutical composition in particular, a pharmaceutical composition for treating G12V mutant KRAS-positive colorectal cancer and/or G12V mutant KRAS-positive lung cancer, comprising the compound of the formula (I) or a salt thereof, as defined herein, and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition includes a therapeutic agent for treating colorectal cancer and/or lung cancer, in particular, a G12V mutant KRAS- positive cancer, the therapeutic agent comprising the compound of the formula (I) or a salt thereof, as defined herein.
  • the use of the compound of formula (I), or salt thereof, as defined herein for the manufacture of a pharmaceutical composition for treating G12D mutant KRAS-positive colorectal cancer and G12D mutant KRAS- positive lung cancer.
  • a method for treating G12D mutant KRAS- positive colorectal cancer and/or G12D mutant KRAS-positive lung cancer including administering an effective amount of the compound of formula (I) or a salt thereof, as defined herein, to a subject in need thereof.
  • the colorectal cancer and/or lung cancer is G12D mutant KRAS-positive colorectal cancer and/or G12D mutant KRAS-positive lung cancer.
  • a pharmaceutical composition in particular, a pharmaceutical composition for treating G12D mutant KRAS-positive colorectal cancer and/or G12D mutant KRAS-positive lung cancer, comprising the compound of the formula (I) or a salt thereof, as defined herein, and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition includes a therapeutic agent for treating colorectal cancer and/or lung cancer, in particular, a G12D mutant KRAS- positive cancer, the therapeutic agent comprising the compound of the formula (I) or a salt thereof, as defined herein.
  • a method for treating G12C mutant KRAS- positive colorectal cancer and/or G12C mutant KRAS-positive lung cancer including administering an effective amount of the compound of formula (I) or a salt thereof, as defined herein, to a subject in need thereof.
  • the colorectal cancer and/or lung cancer is G12C mutant KRAS-positive colorectal cancer and/or G12C mutant KRAS-positive lung cancer.
  • a pharmaceutical composition in particular, a pharmaceutical composition for treating G12C mutant KRAS-positive colorectal cancer and/or G12C mutant KRAS-positive lung cancer, comprising the compound of the formula (I) or a salt thereof, as defined herein, and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition includes a therapeutic agent for treating colorectal cancer and/or lung cancer, in particular, a G12C mutant KRAS- positive cancer, the therapeutic agent comprising the compound of the formula (I) or a salt thereof, as defined herein.
  • a method for treating G12C mutant KRAS- positive colorectal cancer and/or G12C mutant KRAS-positive lung cancer including administering an effective amount of the compound of formula (I) or a salt thereof, as defined herein, to a subject in need thereof.
  • the colorectal cancer and/or lung cancer (including G12V mutant, G12D mutant and/or G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and/or G12C mutant KRAS-positive lung cancer; G12V mutant, G12D mutant and G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and G12C mutant KRAS-positive lung cancer; G12V mutant and G12D mutant KRAS-positive colorectal cancer and/or G12V mutant and G12D mutant KRAS- positive lung cancer; G12V mutant KRAS-positive colorectal cancer and/or G12V mutant KRAS-positive lung cancer; G12D mutant KRAS-positive colorectal cancer and/or G12D mutant KRAS-positive lung cancer; G12D mutant KRAS-positive colorectal cancer and/or G12D mutant KRAS-positive lung cancer; and G12C mutant KRAS-positive colorec
  • the colorectal cancer and/or lung cancer (including G12V mutant, G12D mutant and/or G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and/or G12C mutant KRAS-positive lung cancer; G12V mutant, G12D mutant and G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and G12C mutant KRAS-positive lung cancer; G12V mutant and G12D mutant KRAS-positive colorectal cancer and/or G12V mutant and G12D mutant KRAS- positive lung cancer; G12V mutant KRAS-positive colorectal cancer and/or G12V mutant KRAS-positive lung cancer; G12D mutant KRAS-positive colorectal cancer and/or G12D mutant KRAS-positive lung cancer; G12D mutant KRAS-positive colorectal cancer and/or G12D mutant KRAS-positive lung cancer; and G12C mutant KRAS-positive colorec
  • colorectal cancer including G12V mutant, G12D mutant and/or G12C mutant KRAS-positive colorectal cancer; G12V mutant, G12D mutant and G12C mutant KRAS-positive colorectal cancer; G12V mutant and G12D mutant KRAS- positive colorectal cancer; G12V mutant KRAS-positive colorectal cancer; G12D mutant KRAS-positive colorectal cancer; and G12C mutant KRAS-positive colorectal cancer
  • lung cancer including G12V mutant, G12D mutant and/or G12C mutant KRAS-positive lung cancer; G12V mutant, G12D mutant and G12C mutant KRAS-positive lung cancer; G12V mutant and G12D mutant KRAS-positive lung cancer; G12V mutant KRAS-positive lung cancer; G12D mutant KRAS-positive lung cancer; and G12C mutant KRAS-positive lung cancer
  • “optionally substituted” means being unsubstituted or having one to five substituents. In an aspect, the term means being unsubstituted or having one to three substituents.
  • C1-12 alkyl is linear or branched alkyl having 1 to 12 carbon atoms, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- butyl, n-pentyl, n-hexyl, dodecyl and the like (the numbers of carbon atoms are described similarly below). An aspect thereof is ethyl or dodecyl.
  • C1-6 alkyl is linear or branched alkyl having one to six carbon atoms, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert-butyl, n-pentyl and n-hexyl.
  • An aspect thereof is methyl, ethyl, n-propyl, isopropyl or sec-butyl; another aspect is methyl, ethyl, isopropyl or tert-butyl; and another aspect is methyl, ethyl, n-propyl, isopropyl or n-butyl.
  • C 1-3 alkyl is linear or branched alkyl having one to three carbon atoms, and examples thereof include methyl, ethyl, n-propyl and isopropyl.
  • An aspect thereof is methyl or ethyl; another aspect is n-propyl or isopropyl; another aspect is methyl or isopropyl; another aspect is ethyl or isopropyl; another aspect is methyl; another aspect is ethyl; another aspect is isopropyl; and another aspect is n-propyl.
  • the "C2-3 alkyl” is linear or branched alkyl having two or three carbon atoms, and examples thereof include ethyl, n-propyl and isopropyl. An aspect thereof is ethyl; another aspect is isopropyl; and another aspect is n-propyl.
  • the "C 3-6 cycloalkyl” is cycloalkyl having three to six carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • An aspect thereof is cyclobutyl, cyclopentyl or cyclohexyl; another aspect is cyclobutyl or cyclopentyl; another aspect is cyclopentyl or cyclohexyl; another aspect is cyclopropyl or cyclobutyl; another aspect is cyclopropyl; another aspect is cyclobutyl; another aspect is cyclopentyl; and another aspect is cyclohexyl.
  • C1-3 alkylene is a divalent group formed by removing a hydrogen atom from C1- 3 alkyl and is linear or branched C 1-3 alkylene, such as for example methylene, ethylene, trimethylene, methylmethylene methylethylene, and 1,1-dimethylmethylene.
  • An aspect thereof is linear or branched C1-3 alkylene; another aspect is methylene, ethylene or trimethylene; another aspect is methylene or ethylene; another aspect is methylene; and another aspect is ethylene.
  • C2-3 alkylene is a divalent group formed by removing a hydrogen atom from C2-3 alkyl and is linear or branched C 2-3 alkylene, such as for example ethylene, trimethylene, methylmethylene methylethylene, and 1,1-dimethylmethylene.
  • An aspect thereof is linear or branched C2-3 alkylene; another aspect is ethylene or trimethylene; another aspect is ethylene; and another aspect is trimethylene.
  • the "saturated heterocyclic group” is a saturated hydrocarbon ring group containing a hetero atom selected from the group consisting of oxygen, sulfur and nitrogen as a ring-constituting atom.
  • the sulfur atom as the ring-constituting atom of the saturated heterocyclic group may be oxidized.
  • the "4-membered to 6-membered saturated heterocyclic group” is a 4- membered to 6-membered saturated heterocyclic group containing a hetero atom selected from the group consisting of oxygen, sulfur and nitrogen as a ring-constituting atom.
  • An aspect of the "4-membered to 6-membered saturated heterocyclic group” is a 4-membered to 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring- constituting atoms.
  • An aspect of the 4-membered to 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms is a 4-membered to 6-membered saturated heterocyclic group containing one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen as a ring-constituting atom; another aspect is a 5-membered or 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms; another aspect is a 4-membered saturated heterocyclic group containing one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen as a ring-constituting atom; another aspect is a 5-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms; another aspect is a 6-member
  • heteroaryl is a heterocyclic group containing a hetero atom selected from the group consisting of oxygen, sulfur and nitrogen as a ring-constituting atom.
  • the "5-membered heteroaryl” is a heterocyclic group of a 5-membered ring containing one to four hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms.
  • An aspect of the "5-membered heteroaryl” is a heterocyclic group of a 5-membered ring containing one to three hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms; another aspect is pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl; another aspect is pyrazolyl, imidazolyl, triazolyl, oxazolyl or thiazolyl; another aspect is pyrazolyl, imidazolyl, oxazolyl or thiazolyl; another aspect is pyrazolyl, imidazolyl, oxazolyl or thiazolyl; another aspect is pyrazolyl, imidazolyl, triazolyl or isoxazolyl; another aspect is
  • the "6-membered heteroaryl” is a heterocyclic group of a 6-membered ring containing one to three nitrogen atoms as ring-constituting atoms.
  • An aspect of the "6-membered heteroaryl” is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl; another aspect is pyridyl or pyridazinyl; another aspect is pyridyl or pyrimidinyl; another aspect is pyridyl; and another aspect is pyrimidinyl.
  • the "6-membered heteroarenediyl” is a divalent group obtained by removing any one hydrogen from "6-membered heteroaryl".
  • the "C3-6 cycloalkane” is cycloalkane having three to six carbon atoms, such as for example cyclopropane, cyclobutane, cyclopentane and cyclohexane.
  • the "saturated hetero ring” is a saturated hydrocarbon ring containing a hetero atom selected from the group consisting of oxygen, sulfur and nitrogen as a ring-constituting atom.
  • the sulfur atom as the ring-constituting atom of the saturated hetero ring may be oxidized.
  • the "4-membered to 6-membered saturated hetero ring” is a saturated hydrocarbon ring of a 4-membered ring to 6-membered ring containing a hetero atom selected from the group consisting of oxygen, sulfur and nitrogen as a ring-constituting atom.
  • the sulfur atom as the ring-constituting atom of the saturated hetero ring may be oxidized.
  • An aspect of the "4-membered to 6-membered saturated hetero ring” is a 4-membered to 6-membered saturated hetero ring containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms.
  • An aspect of the "4-membered to 6-membered saturated hetero ring" is oxetane, tetra hydrofuran, tetra hydropyran, azetidine, pyrrolidine, piperidine, oxazolidine, imidazolidine, piperazine, morpholine, thiomorpholine or dioxothiomorpholine.
  • the "spiro ring” is a multicyclic structure in which two cyclic structures are bound with one common spiro atom, which is a quaternary carbon.
  • the "ring having a cross-linked structure” is a cyclic structure having a divalent chain structure linked to two non-neighboring atoms of the ring-constituting atoms of one ring.
  • An aspect of the "ring having a cross-linked structure” is diazabicyclo[2.2.2]octane, diazabicyclo[3.2.1]octane, diazabicyclo[3.1.1]heptane, diazabicyclo[2.2.1]heptane or azabicyclo[3.2.1]octane.
  • halogen means F, Cl, Br and I.
  • An aspect thereof is F, Cl or Br; another aspect is F or Cl; another aspect is F or Br; another aspect is F; another aspect is Cl; and another aspect is Br.
  • An aspect of the substituent acceptable in the "optionally substituted Ci-6 alkyl” and the “optionally substituted C1-3 alkyl” is F, OH, OCH3, N(CHs)2, optionally substituted C3-6 cycloalkyl, azabicyclo[3.3.0]octanyl or an optionally substituted 4-membered to 6- membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen.
  • An aspect thereof is F, OH, OCH3, N(CHS)2, hydroxymethyl, methoxymethyl, difluoroethyl, optionally substituted cyclopropyl, tetrahydrofuranyl, optionally substituted tetrahydropyranyl, morpholinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl or azabicyclo[3.3.0]octanyl; another aspect is F, OH, OCH3, N(CHs)2, hydroxymethyl, methoxymethyl, optionally substituted cyclopropyl, tetrahydrofuranyl, optionally substituted tetra hydro pyranyl or optionally substituted pyrrolidinyl; another aspect is F, OH, OCH3, N(CH3)2, hydroxymethyl, methoxymethyl, cyclopropyl, (hydroxymethyl)cyclopropyl, (methoxymethyl)cyclopropyl, tetrahydrofuranyl, t
  • An aspect of the substituent acceptable in the "optionally substituted 5-membered heteroaryl", the “optionally substituted 6-membered heteroaryl”, the “optionally substituted 6-membered heteroarenediyl", the “optionally substituted C3-6 cycloalkyl", the “optionally substituted pyrazolyl”, the “optionally substituted pyridyl”, the “optionally substituted pyrimidinyl”, the “optionally substituted phenylene” and the “optionally substituted cyclopropyl” is C1-3 alkyl optionally substituted with a group selected from the group consisting of OH and OCH3, -SO2CH3, halogen, OH, OCH3 or C3-6 cycloalkyl.
  • An aspect thereof is C1-3 alkyl optionally substituted with a group selected from the group consisting of OH and OCH3; another aspect is C1-3 alkyl optionally substituted with OH; another aspect is C1-3 alkyl optionally substituted with OCH3; another aspect is C1-3 alkyl or halogen; another aspect is methyl, ethyl, methoxymethyl or F; and another aspect is methyl, ethyl or F.
  • An aspect of the substituent acceptable in the "optionally substituted 4-membered to 6-membered saturated heterocyclic group", the “optionally substituted pyrrolidinyl", the “optionally substituted piperidinyl”, the “optionally substituted oxetanyl”, the “optionally substituted tetrahydrofuranyl” and the “optionally substituted tetra hyd ropyra nyl” is C1-3 alkyl optionally substituted with a group selected from the group consisting of F, OH and OCH3, F, OH, OCH3, oxo or oxetanyl.
  • An aspect thereof is F, OH or OCH3; another aspect is OH or methyl; another aspect is C1-3 alkyl optionally substituted with a group selected from the group consisting of F, OH and OCH3, F, oxo or oxetanyl; another aspect is C1-3 alkyl optionally substituted with a group selected from the group consisting of F, OH and OCH3 or oxo; another aspect is C1-3 alkyl optionally substituted with a group selected from the group consisting of F, OH and OCH3; another aspect is C1-3 alkyl optionally substituted with F; another aspect is C1-3 alkyl optionally substituted with OH; another aspect is C1-3 alkyl optionally substituted with OCH3; and another aspect is C1-3 alkyl.
  • An aspect of the substituent acceptable in the "optionally substituted pyrrolidinediyl", the “optionally substituted piperidinediyl”, the “optionally substituted piperazinediyl” and the “optionally substituted C1-3 alkylene” is F, OH, OCH3 or optionally substituted C1-3 alkyl.
  • An aspect thereof is F, OH, OCH3, methyl, ethyl, hydroxymethyl or methoxymethyl; and another aspect is F, OH, OCH3 or methyl.
  • C1-3 alkyl optionally substituted with F is methyl optionally substituted with F or ethyl optionally substituted with F.
  • examples thereof include methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl and trifluoroethyl.
  • An aspect thereof is methyl, ethyl, monofluoromethyl, difluoromethyl or difluoroethyl; another aspect is monofluoromethyl or difluoromethyl; another aspect is monofluoromethyl or difluoroethyl; another aspect is difluoromethyl or difluoroethyl; another aspect is monofluoromethyl; another aspect is difluoromethyl; another aspect is difluoroethyl; and another aspect is 2,2-difluoroethyl.
  • C1-3 alkyl optionally substituted with OH is methyl optionally substituted with one OH or ethyl optionally substituted with one or two OH.
  • examples thereof include methyl, ethyl, hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl and 1,2-di hydroxyethyl.
  • An aspect thereof is methyl, ethyl or hydroxymethyl; another aspect is methyl or hydroxymethyl; another aspect is hydroxymethyl or hydroxyethyl; another aspect is hydroxymethyl; and another aspect is hydroxyethyl.
  • C1-3 alkyl optionally substituted with OCH3 is methyl optionally substituted with one OCH3, ethyl optionally substituted with one or two OCH3 or propyl optionally substituted with one to three OCH3.
  • Examples thereof include methyl, ethyl, methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 1,2-dimethoxyethyl and 2- methoxypropyl.
  • An aspect thereof is methoxymethyl or methoxyethyl; another aspect is methoxymethyl; another aspect is methoxyethyl; and another aspect is 2- methoxypropyl.
  • phenylene optionally substituted with F is phenylene optionally substituted with one or two F.
  • An aspect thereof is phenylene optionally substituted with one F; another aspect is phenylene or fluorophenylene; another aspect is phenylene; another aspect is 2-fluoro-l,4-phenylene; and another aspect is 3-fluoro- 1,4-phenylene.
  • the "mutant KRAS” is KRAS having a mutation, and examples thereof include G12V mutant KRAS, G12D mutant KRAS and G12C mutant KRAS.
  • the "G12V mutation” represents a mutation in which the amino acid residue corresponding to the codon 12 in a wild type protein is converted from glycine to valine.
  • the "G12V mutant KRAS" represents KRAS having the "G12V mutation”.
  • the "G12D mutation” represents a mutation in which the amino acid residue corresponding to the codon 12 in a wild type protein is converted from glycine to aspartic acid.
  • the "G12D mutant KRAS" represents KRAS having the "G12D mutation”.
  • the "G12C mutation” represents a mutation in which the amino acid residue corresponding to the codon 12 in a wild type protein is converted from glycine to cysteine.
  • the "G12C mutant KRAS" represents KRAS having the "G12C mutation”.
  • the "G12C mutation” represents a mutation in which the amino acid residue corresponding to the codon 12 in a wild type protein is converted from glycine to cysteine.
  • the "G12C mutant KRAS" represents KRAS having the "G12C mutation”.
  • G12D Mutation represents a mutation in which the amino acid residue corresponding to the codon 12 in a wild type protein is converted from glycine to aspartic acid.
  • G12D Mutant KRAS represents KRAS having the "G12D mutation”.
  • colonal cancer is a malignant tumor occurring in the large intestine
  • lung cancer is a malignant tumor occurring in the lung.
  • colorectal cancer and lung cancer is a metastatic, locally advanced, recurrent, and/or refractory cancer.
  • colorectal cancer and lung cancer is a cancer of a patient who has been untreated or who has a medical history.
  • colorectal cancer is colon cancer or rectal cancer.
  • lung cancer is small cell lung cancer or non-small cell lung cancer.
  • the "G12V mutant, G12D mutant and/or G12C mutant KRAS-positive colorectal cancer” is colorectal cancer that is positive for at least one of G12V mutant, G12D mutant and G12C mutant KRAS.
  • Examples thereof include colorectal cancer having at least one of KRAS G12V mutation, G12D mutation and G12C mutation and colorectal cancer which has a high positive rate for at least one of G12V mutant, G12D mutant and G12C mutant KRAS.
  • the "G12V mutant, G12D mutant and/or G12C mutant KRAS-positive lung cancer” is lung cancer that is positive for at least one of G12V mutant, G12D mutant and G12C mutant KRAS.
  • Examples thereof include lung cancer having at least one of KRAS G12V mutation, G12D mutation and G12C mutation and lung cancer which has a high positive rate for at least one of G12V mutant, G12D mutant and G12C mutant KRAS.
  • the "G12V mutant, G12D mutant and G12C mutant KRAS-positive colorectal cancer” is colorectal cancer that is positive for G12V mutant, G12D mutant and G12C mutant KRAS.
  • Examples thereof include colorectal cancer having KRAS G12V mutation, G12D mutation and G12C mutation and colorectal cancer which has a high positive rate for G12V mutant, G12D mutant and G12C mutant KRAS.
  • the "G12V mutant, G12D mutant and G12C mutant KRAS-positive lung cancer” is lung cancer that is positive for G12V mutant, G12D mutant and G12C mutant KRAS.
  • Examples thereof include lung cancer having at least one of KRAS G12V mutation, G12D mutation and G12C mutation and lung cancer which has a high positive rate for G12V mutant, G12D mutant and G12C mutant KRAS.
  • the "G12V mutant and G12D mutant KRAS-positive colorectal cancer” is colorectal cancer that is positive for G12V mutant and G12D mutant KRAS.
  • Examples thereof include colorectal cancer having KRAS G12V mutation and G12D mutation and colorectal cancer which has a high positive rate for G12V mutant and G12D mutant KRAS.
  • the "G12V mutant and G12D mutant KRAS-positive lung cancer” is lung cancer that is positive for G12V mutant and G12D mutant KRAS. Examples thereof include lung cancer having KRAS G12V mutation and G12D mutation and lung cancer which has a high positive rate for G12V mutant and G12D mutant KRAS.
  • the "G12V mutant KRAS-positive colorectal cancer” is colorectal cancer that is positive for G12V mutant KRAS. Examples thereof include colorectal cancer having KRAS G12V mutation and colorectal cancer which has a high positive rate for G12V mutant KRAS.
  • the "G12V mutant KRAS-positive lung cancer” is lung cancer that is positive for G12V mutant KRAS. Examples thereof include lung cancer having KRAS G12V mutation and lung cancer which has a high positive rate for G12V mutant KRAS.
  • the "G12D mutant KRAS-positive colorectal cancer” is colorectal cancer that is positive for G12D mutant KRAS.
  • Examples thereof include colorectal cancer having KRAS G12D mutation and colorectal cancer which has a high positive rate for G12D mutant KRAS.
  • the "G12D mutant KRAS-positive lung cancer” is lung cancer that is positive for G12D mutant KRAS.
  • Examples thereof include lung cancer having KRAS G12D mutation and lung cancer which has a high positive rate for G12D mutant KRAS.
  • the "G12C mutant KRAS-positive colorectal cancer” is colorectal cancer that is positive for G12C mutant KRAS.
  • Examples thereof include colorectal cancer having KRAS G12C mutation and colorectal cancer which has a high positive rate for G12C mutant KRAS.
  • the "G12C mutant KRAS-positive lung cancer” is lung cancer that is positive for G12C mutant KRAS.
  • Examples thereof include lung cancer having KRAS G12C mutation and lung cancer which has a high positive rate for G12C mutant KRAS.
  • R 3 is a group selected from the group consisting of the formula (III), the formula (IV), the formula (V), the formula (VI), the formula (VII), the formula (VIII), the formula (IX), the formula (X), the formula (XI) and the formula (XXXV) below.
  • R 3a is - (CH2)pCHR 3f -NR N 1 R N2 ; -(CH2) P CHR 3f -OR 3g ; a 5-membered to 6-membered saturated heterocyclic group which is optionally substituted with a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR 3g , C1-3 alkylene-NR N1 R N2 and -NR N1 R N2 and which contains one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms; or C3-6 cycloalkyl optionally substituted with a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR 3g , C1-3 alkylene-NR N1 R N2 , -OR 3g and -NR N 1 R N2 .
  • R 3a is - (CH2)pCHR 3f -NR N 1 R N2 ; -(CH2) P CHR 3f -OR 3g ; pyrrolidinyl optionally substituted with C1-3 alkyl; piperidinyl optionally substituted with C1-3 alkyl; or C3-6 cycloalkyl optionally substituted with a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene- OR 3g , C1-3 alkylene-NR N1 R N2 , -OR 3g and -NR N 1 R N2 .
  • R 3c is - (CH 2 ) P CHR 3f -NR N 1 R N2 ; -(CH 2 ) P CHR 3f -OR 3g ; pyrrolidinyl optionally substituted with C1-3 alkyl; piperidinyl optionally substituted with C1-3 alkyl; or C3-6 cycloalkyl optionally substituted with a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene- OR 3g , C1-3 alkyl-NR N 1 R N2 , -OR 3g and -NR N1 R N2 , with the proviso that X 2 in the formula (IV-a) is -O- or -NH- when R 3c is -(CH 2 ) P CHR 3f -NR N1 R N2 .
  • R 3d is - (CH2)pCHR 3f -NR N 1 R N2 or a 4-membered to 6-membered saturated heterocyclic group which is optionally substituted with a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-NR N1 R N2 and -NR N 1 R N2 and which contains one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms.
  • R 3i 's which are the same as or different from each other, are groups selected from the group consisting of H, OH, optionally substituted C1-3 alkyl, -O-optionally substituted C1-3 alkyl, -NH- optionally substituted C1-3 alkyl, -N-(optionally substituted C1-3 alkyl)z, halogen, -CN and oxo, or two R 3 ' groups on a same carbon atom, together with the neighboring carbon atom, may form a ring selected from the group consisting of C3-6 cycloalkane and a 4- membered to 6-membered saturated hetero ring containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms to form a spiro ring as the compound of the formula (XXXV), where the spiro ring is optionally substituted with one or two groups selected from the group consisting of the formula (XXXV), where the spiro
  • R 3 ' groups on two neighboring carbon atoms, together with the two carbon atoms, may form a ring selected from the group consisting of C3-6 cycloalkane and a 4-membered to 6-membered saturated hetero ring containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms to form a condensed ring as the compound of the formula (XXXV), where the condensed ring is optionally substituted with one or two groups selected from the group consisting of C1-3 alkyl, -O-(Ci-3 alkyl), OH, halogen and oxo, or
  • R 3 ' groups on two carbon atoms which are not neighboring, together with the two carbon atoms, may form a cross-linked structure composed of one or two carbon atoms, where the compound of the formula (XXXV) having the cross-linked structure is optionally substituted with one or two groups selected from the group consisting of C1-3 alkyl, -O-(Ci-3 alkyl), OH, halogen and oxo.
  • R N1 and R N2 together with the nitrogen atom to which they are attached, may form an optionally substituted 4-membered to 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, or
  • R 3f and R N1 together with the carbon atom and the nitrogen atom to which they are attached, may form an optionally substituted 4-membered to 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms.
  • R N1 and R N2 together with the nitrogen atom to which they are attached, may form an optionally substituted 4-membered to 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms.
  • R 4 is Ci-6 alkyl optionally substituted with a group selected from the group consisting of F, OH, OCH3, R 4a , cyclopropyl, N(R 4a )z, pyrrolidinyl optionally substituted with R 4a and tetra hydrofuranyl optionally substituted with R 4a ; piperidinyl optionally substituted with R 4b ; or tetra hydropyranyl optionally substituted with R 4a , where R 4a is C1-3 alkyl optionally substituted with F, and
  • R 4b is C1-3 alkyl substituted with one to three F.
  • R 4 is C1-6 alkyl optionally substituted with a group selected from the group consisting of F, OH, OCH3, R 4a , cyclopropyl, N(R 4a )z, pyrrolidinyl optionally substituted with R 4a and tetra hydrofuranyl; piperidinyl optionally substituted with R 4b ; or tetra hydro pyranyl, where R 4a is C1-3 alkyl, and
  • R 4b is C1-3 alkyl substituted with one to three F.
  • R 4 is C1-6 alkyl optionally substituted with a group selected from the group consisting of OCH3, R 4a , N(R 4a )z, pyrrolidinyl optionally substituted with R 4a and tetra hydrofuranyl; piperidinyl optionally substituted with R 4b ; or tetrahydropyranyl, where R 4a is C1-3 alkyl, and
  • R 4b is C1-3 alkyl substituted with one to three F.
  • R 6a and R 6b which are the same as or different from each other, are H or Ci-6 alkyl optionally substituted with a group selected from the group consisting of F, OH, OCH 3 and N(CH 3 ) 2 , or
  • R 6a and R 6b together with the carbon to which they are attached, may form optionally substituted C3-6 cycloalkane or an optionally substituted 4-membered to 6- membered saturated hetero ring containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms.
  • R 6a and R 6b which are the same as or different from each other, are H or C1-6 alkyl optionally substituted with a group selected from the group consisting of F, OH, OCH3 and N(CH 3 ) 2 , or
  • R 6a and R 6b together with the carbon to which they are attached, may form optionally substituted C3-6 cycloalkane.
  • R 6a and R 6b which are the same as or different from each other, are H or C1-6 alkyl optionally substituted with a group selected from the group consisting of OH and N(CH 3 ) 2 .
  • R 6a is H
  • R 6b is C1-6 alkyl optionally substituted with OH.
  • R 7 is an optionally substituted 4-membered to 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, optionally substituted 5-membered heteroaryl containing one to four hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen or 6-membered heteroaryl containing one to three nitrogen atoms.
  • R 7 is a group selected from the group consisting of the formula (XXIII), the formula (XXIV), the formula (XXV), the formula (XXVI), the formula (XXVII), the formula (XXVIII), the formula (XXIX), the formula (XXX), the formula (XXXI), the formula (XXXII) and the formula (XXXIII) below, where R 7a and R 7b , which are the same as or different from each other, are H or Ci-3 alkyl optionally substituted with OH.
  • R 7 is a group selected from the group consisting of the formula (XXIII), the formula (XXIV), the formula (XXVI), the formula (XXVIII) and the formula (XXXIII) below, where R 7a and R 7b , which are the same as or different from each other, are H or Ci-3 alkyl optionally substituted with OH.
  • R 7 is a group selected from the group consisting of the formula (XXIII), the formula (XXIV), the formula (XXVI), the formula (XXVIII) and the formula (XXXIII), where R 7a and R 7b , which are the same as or different from each other, are H or Ci-3 alkyl.
  • R 7 is a group selected from the group consisting of the formula (XXIII), the formula (XXIV) and the formula (XXVIII) below, where R 7a and R 7b , which are the same as or different from each other, are H or Ci-3 alkyl.
  • W 2 is CH, CF, CO, CCH3 or N.
  • R L2 and R L3 which are the same as or different from each other, are H, F, OH, OCH3 or optionally substituted C1-3 alkyl,
  • R L is CH or N, and m is 1 or 2.
  • R L2 and R L3 which are the same as or different from each other, are H, F, OH, OCH3 or optionally substituted C1-3 alkyl, and m is 1 or 2.
  • R L2 and R L3 are both H, and m is 1.
  • O-CH2* represents bond to the carbon atom of O-CH2 which is attached to Y-L-Z.
  • A is CR A or N, where R A is H or C1-3 alkyl,
  • X 1 is -CH 2 - or -O-
  • R 1 is naphthyl optionally substituted with OH or the formula (II) below, where R la is H, methyl, F or Cl, and
  • R lb is F, Cl, methyl or ethyl
  • R 2 is H, halogen, C1-3 alkyl optionally substituted with a group selected from the group consisting of OH and OCH3, cyclopropyl or vinyl,
  • R 3 is a group selected from the group consisting of the formula (III), the formula (IV), the formula (V), the formula (VI), the formula (VII), the formula (VIII), the formula (IX), the formula (X), the formula (XI) and the formula (XXXV) below, where R 3a is -(CH 2 ) P CHR 3f -NR N1 R N2 ; -(CH 2 ) P CHR 3f -OR 3g ; a 4-membered to 6- membered saturated heterocyclic group which is optionally substituted with a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR 3g , C1-3 alkylene- NR N1 R N2 and -NR N 1 R N2 and which contains one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms; or C3-6 cycloalkyl optionally substituted with a group selected from the group consisting of Ci-
  • R 3b is H or C1-3 alkyl
  • R 3c and R 3d are -(CH 2 ) P CHR 3f -NR N1 R N2 ; -(CH 2 ) P CHR 3f -OR 3g ; a 4-membered to 6- membered saturated heterocyclic group which is optionally substituted with a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR 3g , C1-3 alkylene- NR N1 R N2 and -NR N 1 R N2 and which contains one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms; or C3-6 cycloalkyl optionally substituted with a group selected from the group consisting of C1- 3 alkyl, C1-3 alkylene-OR 3g , C1-3 alkylene-NR N1 R N2 , -OR 3g and -NR N1 R N2 ,
  • R 3e is -O-C 2 -3 alkylene-NR N1 R N2
  • R 3f is H, F or C1-3 alkyl
  • R 3g is H or C1-3 alkyl
  • R 3h is optionally substituted 5-membered heteroaryl containing one to four hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen or optionally substituted 6-membered heteroaryl containing one to three nitrogen atoms
  • R 3i groups which are the same as or different from each other, are groups selected from the group consisting of H, OH, optionally substituted C 1-3 alkyl, -O- optionally substituted C 1-3 alkyl, -NH-optionally substituted C 1-3 alkyl, -N-(optionally substituted C 1-3 alkyl) 2 , halogen, -CN and oxo, or two R 3i groups on a same carbon atom, together with the neighboring carbon atom, may form a ring selected from the group consisting of C3-6 cyclo
  • R 1 is the formula (II) below, where R 1a is H, methyl, F or Cl, and R 1b is F, Cl, methyl or ethyl, R 2 is halogen, C 1-3 alkyl optionally substituted with a group selected from the group consisting of OH and OCH3, cyclopropyl or vinyl, R 3 is a group selected from the group consisting of the formula (III), the formula (IV), the formula (V), the formula (VIII-a) and the formula (X) below, where R 3a is -(CH 2 ) p CHR 3f -NR N1 R N2 ; -(CH 2 ) p CHR 3f -OR 3g ; a 4-membered to 6- membered saturated heterocyclic group which is optionally substituted with a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR 3g , C1-3 alky
  • R 3 is a group selected from the group consisting of the formula (III-a), the formula (IV-a) and the formula (V-a) below, where R 3a is -(CH2)pCHR 3f -NR N1 R N2 , R 3b is H, R 3c is C 3-6 cycloalkyl optionally substituted with -NR N1 R N2 , R 3f is H, R N1 and R N2 , which are the same as or different from each other, are both C1-3 alkyl, X 2 is -O- or -NH-, X 3 is O, and p is 1, R 4 is C1-6 alkyl optionally substituted with OCH3, R 5 is isopropyl, R 6a is H, R 6b is C 1-6 alkyl optionally substituted with OH, R 7 is a group selected from the group consisting of the formula (XXIII), the formula (XXIV) and
  • a compound of formula (I), or a salt thereof, for use in the treatment of colorectal cancer and/or lung cancer in particular, G12V mutant, G12D mutant and/or G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and/or G12C mutant KRAS-positive lung cancer (including G12V mutant, G12D mutant and G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and G12C mutant KRAS-positive lung cancer; G12V mutant and G12D mutant KRAS- positive colorectal cancer and/or G12V mutant and G12D mutant KRAS-positive lung cancer; G12V mutant KRAS-positive colorectal cancer and/or G12V mutant and/or G12V mutant KRAS-positive lung cancer; G12V mutant KRAS-positive colorectal cancer and/or G12V mutant and/or G12V mutant KRAS-positive lung cancer; G12V mutant KRAS-
  • a pharmaceutical composition in particular, a pharmaceutical composition for treating colorectal cancer and/or lung cancer, and more particularly, a pharmaceutical composition for treating G12V mutant, G12D mutant and/or G12C mutant KRAS- positive colorectal cancer and/or G12V mutant, G12D mutant and/or G12C mutant KRAS-positive lung cancer (including G12V mutant, G12D mutant and G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and G12C mutant KRAS-positive lung cancer; G12V mutant and G12D mutant KRAS-positive colorectal cancer and/or G12V mutant and G12D mutant KRAS-positive lung cancer; G12V mutant KRAS-positive colorectal cancer and/or G12V mutant KRAS-positive lung cancer; G12D mutant KRAS-positive colorectal cancer and/or G12V mutant KRAS-positive lung cancer; G12D mutant KRAS-positive colorectal cancer and/or G12V mutant
  • a method for treating colorectal cancer and/or lung cancer in particular, G12V mutant, G12D mutant and/or G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and/or G12C mutant KRAS-positive lung cancer (including G12V mutant, G12D mutant and G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and G12C mutant KRAS-positive lung cancer; G12V mutant and G12D mutant KRAS-positive colorectal cancer and/or G12V mutant and G12D mutant KRAS-positive lung cancer; G12V mutant KRAS-positive colorectal cancer and/or G12V mutant KRAS-positive lung cancer; G12D mutant KRAS-positive colorectal cancer and/or G12D mutant KRAS-positive lung cancer; and G12C mutant KRAS-positive colorectal cancer and/or G12C mutant KRAS-positive lung cancer), the method including administering an effective
  • a compound of formula (I), or salt thereof as defined herein for use as a G12V mutant, G12D mutant and/or G12C mutant KRAS protein degradation inducer and/or a G12V mutant, G12D mutant and/or G12C mutant KRAS inhibitor, wherein the compound of formula (I), or salt thereof, is as defined in any one of (1-1) to (15) or (16-1) to (16-8); a pharmaceutical composition comprising the compound of the formula (I), or a salt thereof, as defined herein, that is a G12V mutant, G12D mutant and/or G12C mutant KRAS protein degradation inducer and/or a G12V mutant, G12D mutant and/or G12C mutant KRAS inhibitor, wherein the compound of formula (I), or salt thereof, is as defined in any one of (1-1) to (15) or (16-1) to (16-8); the pharmaceutical composition comprising the compound of the formula (I) or a salt thereof for use as a G12V mutant, G12D mutant
  • Examples of specific compounds of formula (I) that may be used in the various aspects of the invention include the following compounds: (1s,3R)-3-(dimethylamino)cyclobutyl 3-( ⁇ 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-oxazol-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 ⁇ amino)azetidine-1-carboxylate, (1s,3R)-3-(
  • the compound of the formula (I) may have tautomers or geometrical isomers depending on the type of the substituent.
  • the compound of the formula (I) is sometimes described only as one of isomers, but the present invention includes isomers other than the above one and includes separated isomers or mixtures thereof.
  • the compound of the formula (I) may have an asymmetric carbon atom or an axial chirality and may have diastereomers based on them.
  • the present invention includes separated diastereomers of the compound of the formula (I) or mixtures thereof.
  • the present invention also includes pharmaceutically acceptable prodrugs of the compound represented by the formula (I).
  • a pharmaceutically acceptable prodrug is a compound having a group that can be converted into an amino group, a hydroxy group, a carboxyl group or the like by solvolysis or under physiological conditions.
  • groups to form a prodrug include groups described in Prog. Med., 1985, 5, p.2157-2161 or in "Iyakuhin no Kaihatsu (development of pharmaceuticals)", Vol.7, Bunshi-sekkei (molecular design), Hirokawa Shoten, 1990, p.163-198.
  • the salt of the compound of the formula (I) is a pharmaceutically acceptable salt of the compound of the formula (I) and may be an acid addition salt or a salt formed with a base depending on the type of the substituent.
  • Examples thereof include salts shown in P. Heinrich Stahl, Handbook of Pharmaceutical Salts Properties, Selection, and Use, Wiley-VCH, 2008. Specific examples include an acid addition salt with an inorganic acid, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid, or with an organic acid, 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, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid and glutamic acid, a salt with an inorganic metal, such as sodium, potassium, magnesium, calcium and aluminum, a salt with an organic base, such
  • the present invention also includes various hydrates, solvates and crystal polymorphism substances of the compound of the formula (I) and a salt thereof.
  • the present invention also includes all the compounds of the formula (I) or salts thereof which are pharmaceutically acceptable and labeled with one or more radioactive or nonradioactive isotopes.
  • Examples of preferable isotopes used for isotope labeling of the compound of the present invention include isotopes of hydrogen ( 2 H, 3 H and the like), carbon ( 11 C, 13 C, 14 C and the like), nitrogen ( 13 N, 15 N and the like), oxygen ( 15 O, 17 O, 18 O and the like), fluorine ( 18 F and the like), chlorine ( 36 Cl and the like) and iodine ( 123 I, 125 I and the like) and sulfur ( 35 S and the like).
  • the isotopically labeled compound of the invention of the present application can be used for studies such as histological distribution study of drugs and/or substrates and the like.
  • a radioisotope such as tritium ( 3 H) and carbon-14 ( 14 C) can be used for the purpose due to easiness of labeling and convenience of detection.
  • Replacement with a heavier isotope, for example replacement of hydrogen with deuterium ( 2 H), is sometimes therapeutically advantageous because metabolic stability improves (for example, increased in vivo half-life, decreased required dose and declined drug interaction).
  • Replacement with a positron-emitting isotope 11 C, 18 F, 15 O, 13 N or the like
  • PET positron emission tomography
  • the isotopically labeled compound of the present invention can be generally produced by a conventional method known to a person skilled in the art or by a production method similar to those in the Examples or the Production Examples or the like using an appropriate isotopically labeled reagent instead of an unlabeled reagent.
  • Preparation of the compounds of the invention The compound of the formula (I) and a salt thereof can be produced by applying various known synthetic methods using characteristics based on the basic structure or the type of substituent thereof.
  • the protective group include protective groups described in P. G. M.
  • a reaction is carried out with the protective group introduced, and then the protective group is removed, as required, whereby a desired compound can be obtained.
  • a prodrug of the compound of the formula (I) can be produced by introducing a special group in a process from a raw material to an intermediate as for the above protective group or by further carrying out a reaction using the compound of the formula (I) obtained.
  • This reaction can be carried out by applying a method known to a person skilled in the art, such as common esterification, amidation and dehydration. Typical methods for producing the compound of the formula (I) will be explained below. The production methods can also be carried out referring to a reference attached to the explanation. Note that the production method of the present invention is not limited to the examples described below. In this specification, the following abbreviations are sometimes used.
  • CDI l,l'-carbonyldiimidazole
  • HATU O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • Tr trityl
  • R 1A and R 3A represent divalent groups in which H has been removed from a functional group of R 1 or R 3 to which a protective group can be introduced.
  • PG 1 and PG 2 represent protective groups. In some cases, one of the protective groups is absent. The same applies below.
  • the compound of the formula (I) can be obtained by subjecting a compound (1) to a deprotection reaction. Furthermore, the compound can also be sometimes obtained by subjecting NH2 contained in R 3 to an alkylation reaction after subjecting to a deprotection reaction.
  • the protective groups shown here include a tertbutoxycarbonyl group, a triphenylmethyl group, a tetrahydro-2H-pyran-2-yl group, a methoxymethyl group, a dimethylmethanediyl group, a tert-butylsulfinyl group and the like.
  • the compound is stirred from under cooling to under reflux with heat generally for 0.1 hours to five days.
  • the solvent used here include, but are not particularly limited to, an alcohol, such as MeOH, EtOH and iPrOH, a halogenated hydrocarbon, such as dichloromethane, 1,2-dichloroethane and chloroform, an ether, such as diethyl ether, THF, DOX and dimethoxyethane, DMF, DMSO, MeCN or water and a mixture thereof.
  • Examples of the deprotection reagent include, but are not particularly limited to, an acid, such as hydrogen chloride (DOX solution), trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid and phosphoric acid.
  • DOX solution hydrogen chloride
  • trifluoroacetic acid methanesulfonic acid
  • p-toluenesulfonic acid phosphoric acid
  • the deprotection can be performed by a catalytic hydrogenation reaction.
  • the protective group include a benzyl group, a p-methoxybenzyl group, a benzyloxycarbonyl group and the like.
  • the deprotection can also be performed using a fluoride ion source such as tetra-n-butylammonium fluoride.
  • the protective group include a tert-butyl (d imethyl)silyl group, a (trimethylsilyl)ethoxymethyl group and the like.
  • examples of the protective group which can be deprotected under basic conditions include an acetyl group, a trifluoroacetyl group, a benzoyl group and the like.
  • protective groups which can be deprotected under different deprotection conditions can be selected for PG 1 and PG 2 , and the deprotection can be performed stepwise.
  • the alkylation reaction is performed using formaldehyde or an alkyl having a formyl group, by stirring in the presence of a reductant, in a solvent inactive for the reaction, at -45°C to under reflux with heat, preferably at 0°C to at room temperature, generally for 0.1 hours to five days.
  • a solvent inactive for the reaction at -45°C to under reflux with heat, preferably at 0°C to at room temperature, generally for 0.1 hours to five days.
  • the solvent used here include, but are not particularly limited to, an alcohol, such as methanol and ethanol, an ether, such as diethyl ether, tetra hydrofuran (THF), dioxane and dimethoxyethane, a halogenated hydrocarbon, such as dichloromethane, 1,2-dichloroethane and chloroform and a mixture thereof.
  • the reductant is sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride or the like. Performing the reaction in the presence of a dehydrator such as molecular sieves or an acid such as acetic acid, hydrochloric acid and titanium(IV) isopropoxide complex is sometimes preferable.
  • a dehydrator such as molecular sieves or an acid such as acetic acid, hydrochloric acid and titanium(IV) isopropoxide complex is sometimes preferable.
  • the compound (1) as a raw material has an axial chirality
  • a stereoisomer which is obtained by once separating the compound (1) may be used for this reaction.
  • the hydrochloride of the compound of the formula (I) can be obtained.
  • the compound of the formula (I) which is believed to form a salt with hydrochloric acid from the characteristics of the chemical structure is dissolved in CH2CI2 and MeOH and stirred under ice cooling for 30 minutes after adding hydrogen chloride (4M DOX solution, 10 equivalents) under ice cooling.
  • the reaction mixture is concentrated under reduced pressure, and diethyl ether is added to the resulting residue.
  • the produced solid is taken by filtration and is dried under reduced pressure, thus obtaining the hydrochloride of the compound of the formula (I).
  • the compound of the formula (I) can be obtained, but the method is not limited to this method.
  • the hydrochloride of the compound of the formula (I) is purified by ODS column chromatography (MeCN/0.1% aqueous formic acid solution), and a fraction containing the target substance is collected and is made basic with saturated aqueous sodium hydrogen carbonate solution. Then the solution is subjected to extraction with CHCh/MeOH (5/1). The combined organic layer is dried over anhydrous sodium sulfate, and the solution is concentrated under reduced pressure. The resulting solid is washed with diethyl ether and dried under reduced pressure, thus obtaining the compound of the formula (I).
  • This production method is a first method for producing a compound (1)-1 included in the raw material compound (1).
  • This step is a method for producing the compound ( 1)- 1 by a cycloaddition reaction of a compound (2) and a compound (3).
  • the compound (2) and the compound (3) are used in an equal amount or with one compound thereof in an excess amount, and the mixture of the compounds is stirred preferably in the presence of a copper salt, further preferably in the presence of a copper salt and a reductant, in a solvent inactive for the reaction or with no solvent, from under cooling to under reflux with heat, preferably at 0°C to 100°C, generally for 0.1 hours to five days.
  • Examples of the solvent used here include, but are not particularly limited to, a halogenated hydrocarbon, such as dichloromethane, 1,2- dichloroethane and chloroform, an aromatic hydrocarbon, such as benzene, toluene and xylene, an ether, such as diethyl ether, THF, DOX and 1,2-dimethoxyethane, DMF, DMSO, ethyl acetate, MeCN, tBuOH, water and a mixture thereof.
  • the copper salt is Cui, CuSO4, copper(I) trifluoromethanesulfonate (CuOTf) or the like.
  • the reductant is sodium ascorbate or the like.
  • Performing the reaction in the presence of TEA, DIPEA, N-methylmorpholine (NMM), 2,6-lutidine, tris[(l-benzyl-lH-l,2,3-triazol-4- yl)methyl]amine (TBTA) or the like is sometimes advantageous for smoothly promoting the reaction.
  • R represents a C1-3 alkyl group. The same applies below.
  • This production method is a second method for producing the compound ( 1)- 1 included in the raw material compound (1).
  • This step is a method for producing a compound (5) by a cycloaddition reaction of the compound (2) and a compound (4).
  • the reaction conditions are the same as in the first step of the Raw Material Synthesis 1.
  • This step is a method for producing a compound (6) by hydrolysis of the compound (5).
  • This reaction is performed by stirring the compound (5) from under cooling to under reflux with heat generally for 0.1 hours to five days.
  • the solvent used here include, but are not particularly limited to, an alcohol, acetone, DMF, THF and the like.
  • a mixed solvent of the above solvent and water is sometimes suitable for the reaction.
  • the hydrolysis reagent include, but are not particularly limited to, an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, trimethyltin hydroxide and the like. For example, the following can be referred as a reference about this reaction.
  • This step is a method for producing the compound (1)-1 by an amidation reaction of the compound (6) and a compound (7).
  • the compound (6) and the compound (7) are used in an equal amount or with one compound thereof in an excess amount, and the mixture of the compounds is stirred in the presence of a condensing agent, in a solvent inactive for the reaction, from under cooling to under heating, preferably at -20°C to 60°C, generally for 0.1 hours to five days.
  • a condensing agent in a solvent inactive for the reaction, from under cooling to under heating, preferably at -20°C to 60°C, generally for 0.1 hours to five days.
  • the solvent include, but are not particularly limited to, an aromatic hydrocarbon, such as toluene, an ether, such as THF and DOX, a halogenated hydrocarbon, such as dichloromethane, an alcohol, DMF, DMSO, ethyl acetate, MeCN and a mixture thereof.
  • condensing agent examples include (benzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), O-(7- azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide or the hydrochloride thereof, N,N'- dicyclohexylcarbodiimide (DCC), l,l'-carbonyldiimidazole (CDI), diphenylphosphoryl azide (DPPA) and the like.
  • DCC N,N'- dicyclohexylcarbodiimide
  • CDI l,l'-carbonyldiimidazole
  • DPPA diphenylphosphoryl azide
  • an additive for example, 1-hydroxybenzotriazole
  • an organic base such as TEA, DIPEA and NMM
  • an inorganic base such as potassium carbonate, sodium carbonate and potassium hydroxide
  • the compound (6) is converted into a reactive derivative, which is then subjected to an acylation reaction
  • the reactive derivative of a carboxylic acid include an acid halogenation product obtained by a reaction with a halogenating agent, such as phosphorus oxychloride and thionyl chloride, a mixed acid anhydride obtained by a reaction with isobutyl chloroformate or the like, an active ester obtained by condensation with 1- hydroxybenzotriazole or the like and the like.
  • reaction of such a reactive derivative and the compound (7) can be performed in a solvent inactive for the reaction, such as a halogenated hydrocarbon, an aromatic hydrocarbon and an ether, from under cooling to under heating, preferably at -20°C to 120°C.
  • a solvent inactive for the reaction such as a halogenated hydrocarbon, an aromatic hydrocarbon and an ether
  • R 3B represents NR 3aa R 3bb , OR 3cc or R 3dd
  • PG 1A and PG 3 represent protective groups.
  • R 3B represents a divalent group in which H has been removed from a functional group to which a protective group can be introduced and from a functional group to which a carbonyl group or a carboxyl group can be introduced in any of NR 3a R 3b , OR 3c and R 3d .
  • R 1 may have PG 2 . The same applies below.
  • This production method is a second method for producing a compound (l)-2 included in the raw material compound (1).
  • This step is a method for producing a compound (9) by a cycloaddition reaction of a compound (8) and the compound (3).
  • the reaction conditions are the same as in the first step of the Raw Material Synthesis 1.
  • This step is a method for producing a compound (10) by subjecting the compound (9) to a deprotection reaction.
  • the reaction conditions are the same as in the deprotection reaction of the Production Method 1.
  • This step is a method for producing the compound (l)-2 by adding a compound (11) after a reaction of the compound (10) and a carbonylation reagent or a method for producing the compound (l)-2 by an amidation reaction of the compound (10) and a compound (12).
  • This step is performed by reacting the compound (10) with a carbonylation reagent in an equal amount or an excess amount in a solvent inactive for the reaction, from under cooling to under heating, preferably at -20°C to 80°C, generally for 0.1 hours to around a day. Subsequently, the compound (11) in an equal amount or an excess amount is added to the obtained reaction mixture, and this mixture is reacted from under cooling to under heating, preferably at -20°C to 80°C, for 0.1 hours to around a day.
  • the carbonylation reagent include l,l'-carbonyldiimidazole, 4-nitrophenyl chloroformate, diphosgene, triphosgene, phenyl chloroformate and the like.
  • Examples of the solvent used here include, but are not particularly limited to, a halogenated hydrocarbon, such as dichloromethane, 1,2-dichloroethane and chloroform, an aromatic hydrocarbon, such as benzene, toluene and xylene, an ether, such as diethyl ether, tetra hydrofuran, dioxane and dimethoxyethane, N,N-dimethylformamide, dimethylsulfoxide, ethyl acetate, acetonitrile or a mixture thereof.
  • a base such as triethylamine is sometimes advantageous for smoothly promoting the reaction.
  • R LG represents a C1-12 alkyl group
  • LG 1 represents a leaving group
  • BLG represents a boronic acid group, a boronic acid group protected with a protective group of boronic acid, such as a boronic acid pinacol ester group, or a trifluoroboric acid salt group (sometimes referred to as a boronic acid group or the like below).
  • Examples of the leaving group shown here include Cl, Br, a methanesulfonyloxy group, a p-toluenesulfonyloxy group and the like.
  • This production method is a method for producing a compound (2)-l included in the raw material compound (2).
  • This step is a method for producing a compound (14) by hydrolysis of a compound (13).
  • This reaction is performed by stirring the compound (13) from under cooling to under reflux with heat, generally for 0.1 hours to five days.
  • the solvent used here include, but are not particularly limited to, an alcohol, acetone, DMF, THF and the like.
  • a mixed solvent of the above solvent and water is sometimes suitable for the reaction.
  • the hydrolysis reagent include, but are not particularly limited to, an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution and the like.
  • This step is a method for producing a compound (15) by protecting the hydroxy group of the compound (14) with a protective group.
  • this reaction is performed by stirring the compound (14) from under cooling to under reflux with heat, generally for 0.1 hours to five days.
  • the solvent used here include, but are not particularly limited to, an ether, such as THF and DOX, a halogenated hydrocarbon, such as dichloromethane, tBuOH, DMF and the like.
  • the tert-butyl protective reagent include, but are not particularly limited to, isobutene, 2- tert-butyl-l,3-diisopropylisourea and the like.
  • the compound (15) can be produced by a dehydration condensation reaction of the compound (14) and tBuOH.
  • This step is a method for producing a compound (16) by an ipso substitution reaction of the compound (15) and R LG -SH.
  • R LG -SH examples include C1-12 alkylthiols, for example, ethanethiol and dodecanethiol.
  • the compound (15) and the R LG -SH are used in an equal amount or with one compound thereof in an excess amount, and the mixture of the compounds is stirred in a solvent inactive for the reaction or with no solvent, from under cooling to under reflux with heat, preferably at 0°C to 80°C, generally for 0.1 hours to five days.
  • solvent used here examples include, but are not particularly limited to, a halogenated hydrocarbon, such as dichloromethane, 1,2-dichloroethane and chloroform, an aromatic hydrocarbon, such as benzene, toluene and xylene, an ether, such as diethyl ether, THF, DOX and 1,2-dimethoxyethane, DMF, DMAc, DMSO, ethyl acetate, MeCN and a mixture thereof.
  • a halogenated hydrocarbon such as dichloromethane, 1,2-dichloroethane and chloroform
  • an aromatic hydrocarbon such as benzene, toluene and xylene
  • an ether such as diethyl ether, THF, DOX and 1,2-dimethoxyethane
  • DMF diethyl ether
  • DMAc 1,2-dimethoxyethane
  • DMSO ethyl acetate
  • MeCN MeCN
  • Performing the reaction in the presence of an organic base such as TEA, DIPEA, N-methylmorpholine (NMM), 1,4- diazabicyclo[2.2.2]octane (DABCO) and tBuOK
  • an organic base such as TEA, DIPEA, N-methylmorpholine (NMM), 1,4- diazabicyclo[2.2.2]octane (DABCO) and tBuOK
  • an inorganic base such as sodium hydride, potassium carbonate, sodium carbonate and cesium carbonate
  • This step is a method for producing a compound (17) by an ipso substitution reaction of the compound (16) and PG 5 -OH.
  • PG 5 -OH used here include benzyl alcohol, p-methoxybenzyl alcohol and 1-phenylethanol.
  • the reaction conditions are the same as in the third step of the Raw Material Synthesis 4.
  • This step is a method for producing a compound (18) by a Suzuki-Miyaura coupling reaction of the compound (17) and a boronic acid derivative composed of an R 2 -boronic acid group or the like.
  • boronic acid group or the like used here examples include, but are not particularly limited to, a boronic acid group, a boronic acid ester group, a boronic acid pinacol ester group, a triol borate salt group and a trifluoroboric acid salt group.
  • the compound (17) and the boronic acid derivative composed of an R 2 -boronic acid group or the like are used in an equal amount or with one compound thereof in an excess amount, and the mixture of the compounds is stirred in a solvent inactive for the reaction, in the presence of a base and a palladium catalyst, from at room temperature to under reflux with heat, preferably at 20°C to 140°C, generally for 0.1 hours to five days.
  • Examples of the solvent used here include, but are not particularly limited to, a halogenated hydrocarbon, such as dichloromethane, 1,2- dichloroethane and chloroform, an aromatic hydrocarbon, such as benzene, toluene and xylene, an ether, such as diethyl ether, THF, DOX and 1,2-dimethoxyethane, an alcohol, such as MeOH, EtOH, isopropyl alcohol, butanol and amyl alcohol, DMF, DMSO, MeCN, l,3-dimethylimidazolidin-2-one, water and a mixture thereof.
  • a halogenated hydrocarbon such as dichloromethane, 1,2- dichloroethane and chloroform
  • an aromatic hydrocarbon such as benzene, toluene and xylene
  • an ether such as diethyl ether, THF, DOX and 1,2-dimethoxyethane
  • an alcohol such as MeOH, EtOH, is
  • the base is an inorganic base, such as tripotassium phosphate, sodium carbonate, potassium carbonate, sodium hydroxide and barium hydroxide.
  • the palladium catalyst is tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, [l,l'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct, (lE,4E)-l,5-diphenylpenta-l,4-dien-3-one/palladium (3:2) and (2-dicyclohexylphosphino-2',6'-diisopropoxy-l,l'-biphenyl)[2-(2'-amino-l,l'- biphenyl)]palladium(II) methanesulfonate, palladium(II) acetate or the
  • a ligand such as dicyclohexyl(2',6'- dimethoxybiphenyl-2-yl)phosphine, dicyclohexyl(2',6'-diisopropoxy-[l,l'-biphenyl]-2- yl)phosphine and l,l'-bis(diphenylphosphino)ferrocene, is sometimes advantageous for smoothly promoting the reaction.
  • heating the mixture by microwave irradiation is sometimes advantageous for smoothly promoting the reaction.
  • the compound (18) (R 2 is hydrogen here) can be produced by a dehalogenation reaction of the compound (17) using a Pd catalyst and a reductant.
  • This step is a method for producing a compound (20) by a Suzuki-Miyaura coupling reaction of the compound (18) and a compound (19).
  • the reaction conditions are the same as in the fifth step of the Raw Material Synthesis 4.
  • the compound (18) When the compound (18) has an axial chirality, the compound (18) is obtained as a mixture of stereoisomers, and each stereoisomer can be isolated by separation using a common separation operation, for example, ODS column chromatography or silica gel column chromatography.
  • This step is a method for producing a compound (21) by an oxidation reaction of the compound (20).
  • a compound (22) is treated with an oxidant in an equal amount or an excess amount in a solvent inactive for the reaction, from under cooling to under heating, preferably at -20°C to 80°C, generally for 0.1 hours to three days.
  • oxidation with m-chloroperbenzoic acid, perbenzoic acid, peracetic acid, sodium hypochlorite or hydrogen peroxide is suitably used.
  • the solvent include an aromatic hydrocarbon, an ether, a halogenated hydrocarbon such as dichloromethane, DMF, DMSO, ethyl acetate, MeCN and a mixture thereof.
  • the oxidant include cumene hydroperoxide, Oxone, active manganese dioxide, chromic acid, potassium permanganate, sodium periodate and the like.
  • the compound (21) When the compound (21) has an axial chirality, the compound (21) is sometimes obtained as a mixture of stereoisomers, and each stereoisomer can be isolated by separation using a common separation operation, for example, ODS column chromatography or silica gel column chromatography.
  • PG 2 After subjecting the compound (21) to a deprotection reaction, PG 2 is sometimes converted to another protective group so that deprotection can be performed under different conditions from those of the protective group PG 1 to be introduced later.
  • reaction conditions of the deprotection reaction used here are the same as in the step described in the Production Method 1.
  • Examples of the protective group of PG 2 to be converted subsequently include a tetrahydro-2H-pyran-2-yl group and the like.
  • This step is a method for producing the compound (22) by deprotection by a catalytic hydrogenation reaction of the compound (21).
  • This reaction can be performed by stirring the compound (21) under hydrogen atmosphere, from under normal pressure to under increased pressure, in a solvent inactive for the reaction, such as MeOH, EtOH, ethyl acetate and THF, in the presence of a metal catalyst, from under cooling to under heating, preferably at room temperature, for an hour to five days.
  • a palladium catalyst such as Pd/C and palladium black
  • a platinum catalyst such as a platinum plate and platinum oxide
  • a nickel catalyst such as reduced nickel and Raney nickel, or the like is used.
  • This step is a method for producing a compound (24) by a reaction of the compound (22) and a compound (23).
  • This reaction is performed using the compound (22) and the compound (23) in an equal amount or with one compound thereof in an excess amount by reacting a mixture of the compounds in the presence of a base, in a solvent inactive for the reaction, from under cooling to under reflux with heat, preferably at 0°C to 80°C, generally for 0.1 hours to five days.
  • the solvent used here is not particularly limited, and examples thereof include an aromatic hydrocarbon, such as benzene, toluene and xylene, an alcohol, such as MeOH and EtOH, an ether, such as diethyl ether, THF, DOX and 1,2- dimethoxyethane, a halogenated hydrocarbon, such as dichloromethane, 1,2- dichloroethane and chloroform, DMF, DMSO, ethyl acetate, MeCN and a mixture thereof.
  • aromatic hydrocarbon such as benzene, toluene and xylene
  • an alcohol such as MeOH and EtOH
  • an ether such as diethyl ether, THF, DOX and 1,2- dimethoxyethane
  • a halogenated hydrocarbon such as dichloromethane, 1,2- dichloroethane and chloroform
  • DMF dimethyl methoxyethane
  • DMSO ethyl acetate
  • MeCN eth
  • the base examples include, but are not particularly limited to, for example, an organic base, such as TEA, DIPEA, l,8-diazabicyclo[5.4.0]-7-undecene, n-butyllithium and tBuOK, and an inorganic base, such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium hydride.
  • an organic base such as TEA, DIPEA, l,8-diazabicyclo[5.4.0]-7-undecene, n-butyllithium and tBuOK
  • an inorganic base such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium hydride.
  • a phase transfer catalyst such as tetra-n-butylammonium chloride
  • the compound (24) in which LG 1 is halogen can be produced by halogenation of a compound in which the moiety corresponding to LG 1 is a hydroxy group.
  • the halogenating agent used here include, but are not particularly limited to, for example, thionyl chloride, phosphorus oxychloride, hydrobromic acid, phosphorus tribromide and the like. For example, the following can be referred as a reference about this reaction.
  • the compound (24) in which LG 1 is a sulfonyloxy group can be produced by sulfonylation of a compound in which the moiety corresponding to LG 1 is a hydroxy group in the presence of a base.
  • a base examples include, but are not particularly limited to, for example, TEA, DIPEA, pyridine, tetramethylethylenediamine and the like.
  • This step is a method for producing a compound (26) by an ipso substitution reaction of the compound (24) and a compound (25).
  • the reaction conditions are the same as in the third step of the Raw Material Synthesis 4.
  • This step is a method for producing a compound (27) by subjecting the compound (26) to a deprotection reaction.
  • reaction conditions are the same as in the step described in the Production Method 1.
  • This step is a method for producing the compound (2)-l by a reaction of the compound (27) and a compound (28).
  • the compound (27) and the compound (28) are used in an equal amount or with one compound thereof in an excess amount, and the mixture of the compounds is stirred in the presence of a condensing agent, in a solvent inactive for the reaction, from under cooling to under heating, preferably at -20°C to 60°C, generally for 0.1 hours to five days.
  • a condensing agent in a solvent inactive for the reaction, from under cooling to under heating, preferably at -20°C to 60°C, generally for 0.1 hours to five days.
  • the solvent include, but are not particularly limited to, an aromatic hydrocarbon, such as toluene, an ether, such as THF and DOX, a halogenated hydrocarbon, such as dichloromethane, an alcohol, DMF, DMSO, ethyl acetate, MeCN and a mixture thereof.
  • Examples of the condensing agent include PyBOP, HATU, CDI and the like.
  • an organic base such as TEA, DIPEA and NMM
  • an inorganic base such as potassium carbonate, sodium carbonate and cesium carbonate
  • This production method is a method for producing the raw material compound (26).
  • This step is a method for producing the compound (28) by an ipso substitution reaction of the compound (15) and the compound (25).
  • the reaction conditions are the same as in the third step of the Raw Material Synthesis 4.
  • the compound (28) can be produced by Negishi coupling of a compound in which a hydrogen atom of the compound (25) has been converted to halogen and the compound (15).
  • This step is a method for producing a compound (29) by an ipso substitution reaction of the compound (28) and PG 5 -OH.
  • the reaction conditions are the same as in the third step of the Raw Material Synthesis 4.
  • This step is a method for producing a compound (30) by a Suzuki-Miyaura coupling reaction of the compound (29) and a boronic acid derivative composed of an R 2 -boronic acid group or the like.
  • the reaction conditions are the same as in the fifth step of the Raw Material Synthesis 4.
  • the compound (30) (R 2 is hydrogen here) can be produced by a dehalogenation reaction of the compound (29) using a Pd catalyst and a reductant.
  • This step is a method for producing a compound (31) by a Suzuki-Miyaura coupling reaction of the compound (30) and the compound (19).
  • the reaction conditions are the same as in the fifth step of the Raw Material Synthesis 4.
  • This step is a method for producing a compound (32) by deprotection by a catalytic hydrogenation reaction of the compound (31).
  • the reaction conditions are the same as in the eighth step of the Raw Material Synthesis 4.
  • This step is a method for producing the compound (26) by a reaction of the compound (32) and the compound (23).
  • the reaction conditions are the same as in the ninth step of the Raw Material Synthesis 4.
  • This production method is a method for producing the raw material compound (2)-l.
  • This step is a method for producing a compound (33) by subjecting the compound (31) to a deprotection reaction.
  • reaction conditions are the same as in the step described in the Production Method 1.
  • the compound (31) When the compound (31) has an axial chirality, the compound (31) is sometimes obtained as a mixture of stereoisomers, and each stereoisomer can be isolated by separation using a common separation operation, for example, ODS column chromatography or silica gel column chromatography.
  • PG 2 After subjecting the compound (31) to a deprotection reaction, PG 2 is sometimes converted to another protective group so that deprotection can be performed under different conditions from those of the protective group PG 1 to be introduced later.
  • This step is a method for producing a compound (34) by a reaction of the compound (33) and the compound (28).
  • the reaction conditions are the same as in the twelfth step of the Raw Material Synthesis 4.
  • This step is a method for producing a compound (35) by deprotection by a catalytic hydrogenation reaction of the compound (34).
  • the reaction conditions are the same as in the eighth step of the Raw Material Synthesis 4.
  • This step is a method for producing the compound (2)-l by a reaction of the compound (35) and the compound (23).
  • the reaction conditions are the same as in the ninth step of the Raw Material Synthesis 4.
  • This production method is a method for producing a compound (8)-l included in the raw material compound (8).
  • This step is a method for producing a compound (37) by a chlorination reaction of a compound (36).
  • This reaction is performed using the compound (36) and a chlorinating agent in an equal amount or with one compound thereof in an excess amount by stirring the mixture of the compounds in a solvent inactive for the reaction or with no solvent, from under cooling to under reflux with heat, preferably at 60°C to under reflux with heat, generally for 0.1 hours to five days.
  • a solvent inactive for the reaction or with no solvent examples include, but are not particularly limited to, an aromatic hydrocarbon such as toluene, an ether, such as THF and DOX, a halogenated hydrocarbon, such as dichloromethane, and the like.
  • the chlorinating agent include phosphorus oxychloride, thionyl chloride and the like. Performing the reaction in the presence of an organic base, such as TEA, DIPEA and NMM, is sometimes advantageous for smoothly promoting the reaction.
  • This step is a method for producing a compound (38) by an ipso substitution reaction of the compound (37) and R LG -SH.
  • This step is a method for producing a compound (39) by an ipso substitution reaction of the compound (38) and PG 5 -OH.
  • the reaction conditions are the same as in the third step of the Raw Material Synthesis 4.
  • This step is a method for producing a compound (41) by an ipso substitution reaction of the compound (39) and a compound (40).
  • the compound (39) and the compound (40) are used in an equal amount or with one compound thereof in an excess amount, and the mixture of the compounds is stirred in a solvent inactive for the reaction or with no solvent, from under cooling to under reflux with heat, preferably at 0°C to 80°C, generally for 0.1 hours to five days.
  • solvent used here examples include, but are not particularly limited to, a halogenated hydrocarbon, such as dichloromethane, 1,2-dichloroethane and chloroform, an aromatic hydrocarbon, such as benzene, toluene and xylene, an ether, such as diethyl ether, THF, DOX and 1,2-dimethoxyethane, DMF, DMAc, DMSO, ethyl acetate, MeCN and a mixture thereof.
  • a halogenated hydrocarbon such as dichloromethane, 1,2-dichloroethane and chloroform
  • an aromatic hydrocarbon such as benzene, toluene and xylene
  • an ether such as diethyl ether, THF, DOX and 1,2-dimethoxyethane
  • DMF diethyl ether
  • DMAc 1,2-dimethoxyethane
  • DMSO ethyl acetate
  • MeCN MeCN
  • an organic base such as TEA, DIPEA, N-methylmorpholine (NMM), 1,4- diazabicyclo[2.2.2]octane (DABCO) and tBuOK
  • an inorganic base such as sodium hydride, potassium carbonate, sodium carbonate and cesium carbonate
  • This step is a method for producing a compound (42) by a Suzuki-Miyaura coupling reaction of the compound (41) and a boronic acid derivative composed of an R 2 -boronic acid group or the like.
  • the reaction conditions are the same as in the fifth step of the Raw Material Synthesis 4.
  • This step is a method for producing a compound (43) by a Suzuki-Miyaura coupling reaction of the compound (42) and the compound (19).
  • the reaction conditions are the same as in the fifth step of the Raw Material Synthesis 4.
  • This step is a method for producing a compound (44) by an oxidation reaction of the compound (43).
  • the reaction conditions are the same as in the seventh step of the Raw Material Synthesis 4.
  • This step is a method for producing a compound (45) by deprotection by a catalytic hydrogenation reaction of the compound (44).
  • the reaction conditions are the same as in the eighth step of the Raw Material Synthesis 4.
  • This step is a method for producing a compound (46) by a reaction of the compound (45) and the compound (23).
  • the reaction conditions are the same as in the ninth step of the Raw Material Synthesis 4.
  • This step is a method for producing the compound (8)-l by an ipso substitution reaction of the compound (46) and the compound (25).
  • the reaction conditions are the same as in the third step of the Raw Material Synthesis 4.
  • This production method is a method for producing the compound (8)- 1 included in the raw material compound (8).
  • This step is a method for producing a compound (47) by an ipso substitution reaction of the compound (44) and the compound (25).
  • the reaction conditions are the same as in the third step of the Raw Material Synthesis 4.
  • This step is a method for producing a compound (48) by deprotection by a catalytic hydrogenation reaction of the compound (47).
  • the reaction conditions are the same as in the eighth step of the Raw Material Synthesis 4.
  • This step is a method for producing the compound (8)-l by a reaction of the compound (48) and the compound (23).
  • This production method is a method for producing the raw material compound (47).
  • This step is a method for producing a compound (49) by an ipso substitution reaction of the compound (37) and the compound (25).
  • the reaction conditions are the same as in the third step of the Raw Material Synthesis 4.
  • the compound (49) can be produced by Negishi coupling of a compound in which a hydrogen atom of the compound (25) has been converted to halogen and the compound (37).
  • This step is a method for producing a compound (50) by an ipso substitution reaction of the compound (49) and PG 5 -OH.
  • the reaction conditions are the same as in the third step of the Raw Material Synthesis 4.
  • This step is a method for producing a compound (51) by an ipso substitution reaction of the compound (50) and the compound (40).
  • the reaction conditions are the same as in the fourth step of the Raw Material Synthesis 7.
  • This step is a method for producing a compound (52) by a Suzuki-Miyaura coupling reaction of the compound (51) and a boronic acid derivative composed of an R 2 -boronic acid group or the like.
  • the reaction conditions are the same as in the fifth step of the Raw Material Synthesis 4.
  • This step is a method for producing the compound (47) by a Suzuki-Miyaura coupling reaction of the compound (52) and the compound (19).
  • the reaction conditions are the same as in the fifth step of the Raw Material Synthesis 4.
  • This production method is a method for producing a compound (2)-2 included in the raw material compound (2).
  • This step is a method for producing a compound (53) by subjecting the compound (47) to a deprotection reaction.
  • the reaction conditions are the same as in the deprotection reaction of the Production Method 1.
  • This step is a method for producing a compound (54) by adding the compound (11) after a reaction of the compound (53) and a carbonylation reagent or a method for producing the compound (54) by an amidation reaction of the compound (53) and the compound (12).
  • the reaction conditions are the same as in the third step of the Raw Material Synthesis 3.
  • This step is a method for producing a compound (55) by deprotection by a catalytic hydrogenation reaction of the compound (54).
  • the reaction conditions are the same as in the eighth step of the Raw Material Synthesis 4.
  • This step is a method for producing the compound (2)-2 by a reaction of the compound (55) and the compound (23).
  • the reaction conditions are the same as in the ninth step of the Raw Material Synthesis 4.
  • This production method is a method for producing the raw material compound (3).
  • This step is a method for producing a compound (58) by an amidation reaction of a compound (56) and a compound (57).
  • the reaction conditions are the same as in the third step of the Raw Material Synthesis 2.
  • This step is a method for producing a compound (59) by subjecting the compound (58) to a deprotection reaction.
  • reaction conditions are the same as in the step described in the Production Method 1.
  • This step is a method for producing the compound (3) by a reaction of the compound (59) and a diazo-transfer reagent.
  • the compound (59) is treated with the diazo-transfer reagent in an equal amount or an excess amount in a solvent inactive for the reaction, from under cooling to under heating, preferably at 0°C to 50°C, generally for 0.1 hours to three days.
  • the diazo-transfer reagent include, but are not particularly limited to, for example, trifluoromethanesulfonyl azide, imidazole-l-sulfonyl azide or a salt thereof, 2-azido-l,3-dimethylimidazolinium hexafluorophosphate (ADMP) and the like.
  • Performing the reaction in the presence of an organic base, such as TEA, 4- dimethylaminopyridine (DMAP) and 2,6-lutidine, and a catalytic amount of a copper salt, such as CuSCU, is sometimes advantageous.
  • organic base such as TEA, 4- dimethylaminopyridine (DMAP) and 2,6-lutidine
  • a catalytic amount of a copper salt such as CuSCU
  • the solvent include THF, a halogenated hydrocarbon such as dichloromethane, MeCN, an alcohol, water and a mixture thereof.
  • LG 2 represents a leaving group
  • This production method is a method for producing a raw material compound (l)-3 included in the raw material compound (1).
  • This step is a method for producing a compound (61) by a reaction of the compound (32) and a compound (60).
  • the reaction conditions are the same as in the ninth step of the Raw Material Synthesis 4.
  • This step is a method for producing a compound (62) by subjecting the compound (61) to a deprotection reaction.
  • This step is a method for producing a compound (63) by a reaction of the compound (62) and the compound (28).
  • reaction conditions are the same as in the twelfth step of the Raw Material Synthesis 4.
  • This step is a method for producing a compound (2)-3 by hydrolysis of the compound (63).
  • reaction conditions are the same as in the second step of the Raw Material Synthesis 2.
  • This step is a method for producing the compound (l)-3 by an amidation reaction of the compound (2)-3 and the compound (59).
  • the reaction conditions are the same as in the third step of the Raw Material Synthesis 2.
  • This production method is a method for producing a raw material compound (l)-4 included in the raw material compound (1).
  • L 2 is NR L1 , pyrrolidinediyl, piperidinediyl or piperazinediyl is shown.
  • This step is a method for producing a compound (65) by an amidation reaction of the compound (59) and a compound (64).
  • the reaction conditions are the same as in the third step of the Raw Material Synthesis 2.
  • reaction conditions of the deprotection reaction are the same as in the step described in the Production Method 1.
  • reaction conditions of the amidation reaction are the same as in the third step of the Raw Material Synthesis 2.
  • LG 3 represents a leaving group.
  • a 1 represents a hydrogen atom
  • a 2 represents halogen.
  • a 2 represents a boronic acid group or the like in the case where A 1 is a group selected from the group consisting of Cl, Br and I
  • a 2 represents a group selected from the group consisting of Cl, Br and I in the case where A 1 is a boronic acid group or the like.
  • This production method is a method for producing a raw material compound (l)-5 included in the raw material compound (1).
  • This step is a method for producing a compound (68) by an ipso reaction or a Buchwald- Hartwig amination reaction of a compound (66) and a compound (67) when Z is NH.
  • this step is a method for producing the compound (68) by a Suzuki-Miyaura coupling reaction of the compound (66) and the compound (67) when Z is 5-membered heteroaryl containing one to four hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen.
  • the reaction conditions are the same as in the fifth step of the Raw Material Synthesis 4.
  • This step is a method for producing a compound (69) by a reaction of the compound (68) and the compound (32).
  • the reaction conditions are the same as in the ninth step of the Raw Material Synthesis 4.
  • the compound (69) can also be produced by a Mitsunobu reaction of a compound in which the moiety corresponding to LG 3 of the compound
  • This step is a method for producing a compound (70) by hydrolysis of the compound
  • reaction conditions are the same as in the second step of the Raw Material Synthesis 2.
  • This step is a method for producing the compound (l)-4 by an amidation reaction of a compound (70)-l and a compound (71).
  • R 6aa and R 6bb represent divalent groups in which H has been removed from a functional group of R 6a and R 6b into which a protective group can be introduced.
  • PG 9 , PG 10 and PG 11 which are the same as or different from each other, represent a hydrogen atom or a protective group, and PG 12 represents a protective group.
  • a 3 represents a hydrogen atom, a carboxyl group, a boronic acid group or the like.
  • This production method is a method for producing the raw material compound (56).
  • This step is a method for producing a compound (74) by a Mizoroki-Heck reaction of a compound (73) in which R 7 is the formula (XXIII) for example and a compound (72) when A 3 is a hydrogen atom.
  • the compound (72) and the compound (73) are used in an equal amount or with one compound thereof in an excess amount, and the mixture of the compounds is stirred in a solvent inactive for the reaction, in the presence of a base and a palladium catalyst, from at room temperature to under reflux with heat, preferably at 20°C to 140°C, generally for 0.1 hours to five days.
  • a solvent inactive for the reaction in the presence of a base and a palladium catalyst, from at room temperature to under reflux with heat, preferably at 20°C to 140°C, generally for 0.1 hours to five days.
  • the solvent used here include, but are not particularly limited to, an ether, such as diethyl ether, THF, DOX and 1,2-dimethoxyethane, DMF, DMAc, DMSO, MeCN, 1,3- dimethylimidazolidin-2-one, ethyl acetate, water and a mixture thereof.
  • the base is a base, such as tripotassium phosphate, sodium carbonate, potassium carbonate and potassium acetate.
  • the palladium catalyst is tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, [1,1'- bis(diphenylphosphino)ferrocene]palladium(II) dichloride ⁇ dichloromethane adduct, (lE,4E)-l,5-diphenylpenta-l,4-dien-3-one/palladium (3:2), (2- dicyclohexylphosphino-2', 6'-diisopro poxy- l,l'-biphenyl) [2-(2'-amino- 1,1'- biphenyl)]palladium(II) methanesulfonate, palladium(II) acetate or the like.
  • reaction For example, the following can be referred as a reference about the reaction.
  • this is a method for producing the compound (74) by an Ullmann reaction of the compound (73) in which R 7 is a group selected from the group consisting of the formula (XXVI), the formula (XXVIII) and the formula (XXXIII) for example and the compound (72).
  • reaction For example, the following can be referred as a reference about the reaction.
  • this step is a method for producing the compound (74) by a decarbonation coupling reaction of the compound (73) in which R 7 is the formula (XXIV) for example and the compound (72) when A 3 is a carboxyl group.
  • reaction For example, the following can be referred as a reference about the reaction.
  • this step is a method for producing the compound (74) by a Suzuki-Miyaura coupling reaction of the compound (73) in which R 7 is the formula (XXIII) for example and the compound (72) when A 3 is a boronic acid group or the like.
  • the reaction conditions are the same as in the fifth step of the Raw Material Synthesis 4.
  • This step is a method for producing the compound (56) by subjecting the compound (74) to a deprotection reaction.
  • reaction conditions are the same as in the step described in the Production Method 1.
  • This production method is a method for producing a raw material compound (68)-l and a raw material compound (68)-2 included in the raw material compound (68).
  • This step is a method for producing a compound (78) by a reaction of a compound (75) and a compound (77).
  • reaction For example, the following can be referred as a reference about the reaction.
  • This step is a method for producing the compound (78) by a reaction of the compound (77) and glyoxylic acid using a toluenesulfonylmethyl isocyanide (TosMIC) reagent substituted with aryl.
  • TosMIC toluenesulfonylmethyl isocyanide
  • reaction For example, the following can be referred as a reference about the reaction.
  • This step is a method for producing the compound (68)-l by a Suzuki-Miyaura coupling reaction of the compound (78) and an alkoxymethyl boronic acid derivative and by subsequently subjecting to a deprotection reaction under acidic conditions.
  • alkoxymethyl boronic acid derivative used here is potassium (2-trimethylsilyl)-ethoxymethyl trifluoroborate.
  • reaction For example, the following can be referred as a reference about the reaction.
  • reaction conditions of the deprotection reaction under the acidic conditions performed subsequently are the same as in the step described in the Production Method 1.
  • acid used here include trifluoroacetic acid and the like.
  • the compound (68)-l can be produced by a Suzuki- Miyaura coupling reaction of the compound (78) and an acetoxymethyl boronic acid derivative.
  • reaction For example, the following can be referred as a reference about the reaction.
  • This step is a method for producing a compound (80) by a reaction of a compound (79) and the compound (77).
  • This reaction is performed using the compound (79) and the compound (77) in an equal amount or with one compound thereof in an excess amount by stirring the mixture of the compounds in a solvent inactive for the reaction or with no solvent, from under cooling to under reflux with heat, preferably from at room temperature to under reflux with heat, generally for 0.1 hours to five days.
  • a solvent inactive for the reaction or with no solvent examples include, but are not particularly limited to, an aromatic hydrocarbon, such as toluene, an ether, such as THF and DOX, a halogenated hydrocarbon, such as dichloromethane, DMF, DMSO, ethyl acetate, MeCN and the like.
  • an organic base such as TEA, DIPEA and NMM
  • an inorganic base such as potassium carbonate, sodium carbonate and cesium carbonate
  • This step is a method for producing the compound (68)-2 by a Suzuki-Miyaura coupling reaction of the compound (80) and an alkoxymethyl boronic acid derivative and by subsequently subjecting to a deprotection reaction under acidic conditions.
  • the reaction conditions are the same as in the third step of the Raw Material Synthesis 16.
  • the compound (68)-2 can be produced by a Suzuki- Miyaura coupling reaction of the compound (80) and an acetoxymethyl boronic acid derivative.
  • the compound of the formula (I) is isolated and purified as a free compound, a salt, hydrate, solvate or crystal polymorphous substance thereof or a substance in amorphous solid form.
  • a salt of the compound of the formula (I) can also be produced by subjecting the compound to a salt formation reaction which is an ordinary method.
  • the isolation and purification are performed by applying a common chemical operation, such as extraction, fractional crystallization and various types of fraction chromatography.
  • an optical isomer can be obtained by a general optical resolution method of a racemate (for example, fractional crystallization for inducing to a diastereomer salt with an optically active base or acid, chromatography using a chiral column or the like and the like) and can also be produced from an appropriate optically active raw material compound.
  • a general optical resolution method of a racemate for example, fractional crystallization for inducing to a diastereomer salt with an optically active base or acid, chromatography using a chiral column or the like and the like
  • the compound of the formula (I) or an intermediate thereof sometimes has an axial chirality and is obtained as a mixture of stereoisomers, and each stereoisomer can be isolated by separation using a common separation operation, for example, octadecylsilyl (ODS) column chromatography or silica gel column chromatography.
  • ODS octadecylsilyl
  • a pharmaceutical composition that contains one or two or more compounds of the formula (I) or salts thereof as active ingredients can be prepared by a usually used method using an excipient usually used in the art, that is, a pharmaceutical excipient, a pharmaceutical carrier or the like.
  • the administration may be either oral administration with a tablet, pill, capsule, granule, powder, liquid or other agent or parenteral administration with an intraarticular, intravenous, intramuscular or other injection, a transmucosal agent, an inhalant or the like.
  • a tablet, powder, granular or other agent is used as a solid composition for oral administration.
  • one or two or more active ingredients are mixed with at least one inactive excipient.
  • the composition may contain an inactive additive, for example, a lubricant, a disintegrator, a stabilizer or a dissolution aid, according to an ordinary method.
  • a tablet or pill may be coated with a sugar coating or a film soluble in the stomach or intestine, when needed.
  • Liquid compositions for oral administration include a pharmaceutically acceptable emulsion, solution, suspension, syrup or elixir agent and the like and contain a generally used inactive diluent, for example, purified water or EtOH.
  • the liquid composition may contain, in addition to the inactive diluent, an adjuvant, such as a solubilizer, a wetting agent and a suspending agent, a sweetening agent, a flavor, a fragrant or a preservative.
  • an adjuvant such as a solubilizer, a wetting agent and a suspending agent, a sweetening agent, a flavor, a fragrant or a preservative.
  • the injection agents for parenteral administration include a sterile aqueous or nonaqueous solution, suspension or emulsion agent.
  • aqueous solvent include distilled water for injection or physiological saline.
  • nonaqueous solvent is an alcohol, such as EtOH.
  • Such a composition may further contain an isotonizing agent, a preservative, a wetting agent, an emulsifier, a dispersant, a stabilizer or a dissolution aid. These are sterilized, for example, by filtration through a bacteria keeping filter, incorporation of a microbicide or irradiation.
  • such a composition can be produced as a sterile solid composition, which is dissolved or suspended in sterile water or a sterile solvent for injection before use.
  • the transmucosal agent such as an inhalant or a transnasal agent
  • a solid, liquid or semi-solid form can be produced according to a conventionally known method.
  • a known excipient and in addition, a pH modifier, a preservative, a surfactant, a lubricant, a stabilizer, a thickener or the like may be appropriately added.
  • the administration can be performed by using an appropriate device for inhalation or insufflation.
  • the agent can be administered using a known device, such as a metering and administering inhalation device, or an atomizer, as a compound alone or a powder of a mixture formulated, or as a solution or a suspension in combination with a pharmaceutically acceptable carrier.
  • a dry powder inhaler or the like may be for a single administration or multiple administrations, and dry powder or powder-containing capsule can be used.
  • the agent may be used in a form of a pressurized aerosol spray or the like using an appropriate ejection agent, for example, a suitable gas, such as a chlorofluoroalkane or carbon dioxide.
  • the daily dose is appropriately about 0.001 to 100 mg/kg body weight, preferably 0.1 to 30 mg/kg body weight, further preferably 0.1 to 10 mg/kg body weight, and the dose is given at once or is divided into two to four times.
  • the daily dose is appropriately about 0.0001 to 10 mg/kg body weight and is given at once or is divided into multiple times in a day.
  • the daily dose of a transmucosal agent is about 0.001 to 100 mg/kg body weight and is given at once or is divided into multiple times in a day. The dose is appropriately decided depending on the individual case taking the symptom, age, sex and the like into account.
  • the pharmaceutical composition of the present invention contains 0.01 to 100% by weight, in an aspect, 0.01 to 50% by weight, of one or more compounds of the formula (I) or salts thereof which are active ingredients.
  • the compound of the formula (I) can be used in combination with various therapeutic agents or preventive agents for a disease to which the compound of the formula (I) is considered to have an effectiveness.
  • the combination use may be simultaneous administration or separate administration either sequential or with a desired interval.
  • a simultaneous administration preparation may be a formulated agent or may be separately formulated.
  • the compounds for use, pharmaceutical compositions, methods and uses described herein may have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better treatment profile than other treatments for the same indications known in the prior art.
  • the compound of the formula (I) or a salt thereof has a degradationinducing action on a G12V mutant, G12D mutant and G12C mutant KRAS protein, and a G12V mutant, G12D mutant and G12C mutant KRAS inhibitory activity, and can be used, particularly as an active ingredient of a pharmaceutical composition, for treating a cancer of colorectal cancer and/or lung cancer, in particular, a G12V mutant, G12D mutant and G12C mutant KRAS-positive cancer.
  • the production method of the compound of the formula (I) will be explained in further detail below based on the Examples. Note that, the present invention is not to be limited to the compounds described in the following Examples. The production methods of raw material compounds are also shown in the Production Examples. The production method of the compound of the formula (I) is not limited only to the production methods of specific Examples described below, and the compound of the formula (I) can also be produced by a combination of the production methods or a method that is obvious to a person skilled in the art.
  • IM aqueous sodium hydroxide solution means an aqueous sodium hydroxide solution of 1 mol/L.
  • the "amorphous solid form" described in this specification includes both a form showing no peak in a powder X-ray diffraction (XRD) pattern and a form having low crystallinity.
  • XRD powder X-ray diffraction
  • 2-tert-butyl-l,3-diisopropylisourea (73.4 g) was added dropwise over 15 minutes to a mixture of 7-bromo-2-chloro-8-fluoro-6-iodoquinazolin- 4-ol (24.6 g) and THF (260 mL) heated to 60°C, and the mixture was stirred at the same temperature for 2.5 hours. The mixture was allowed to cool to room temperature, and the insoluble matter was removed by filtration while washing it with THF (500 mL). The filtrate was concentrated, and MeOH (210 mL) was added to the resulting solid. The mixture was stirred at room temperature for an hour, suspended and washed.
  • lithium bis(trimethylsilyl)amide (IM THF solution, 160 mL) was added using a dropping funnel over 20 minutes to a suspension of methyl 2-acetamide-4-bromo-3-fluoro-5-iodobenzoate (21.5 g) in THF (250 mL). Then, the mixture was stirred under argon atmosphere at 40°C for an hour. Water was added under ice cooling to stop the reaction, and the mixture was diluted with ethyl acetate and water. The organic layer and the aqueous layer were separated by a separation operation, and the organic layer was subjected to extraction twice with water.
  • DABCO 1.3 g was added to a suspension of 7-bromo-2,4- dichloro-8-fluoro-6-iodoquinoline (4.4 g) in N-methyl-2-pyrrolidone (45 mL), and after the mixture was stirred at 40°C for two hours, ethanethiol (850 pL) was added. The mixture was stirred at 60°C for four hours. After cooling to room temperature, water (200 mL) was added, and the mixture was stirred at room temperature for 30 minutes.
  • reaction suspension which was allowed to cool was filtered through celite (registered trademark) while washing it with ethyl acetate, and the grey insoluble matter was removed by filtration. After the filtrate was concentrated under reduced pressure to around 1/4, water was added, and extraction with ethyl acetate was performed twice. The collected organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate.
  • Aqueous sodium thiosulfate solution was added under ice cooling, and after the mixture was stirred at room temperature for 30 minutes, extraction with chloroform was performed twice. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated.
  • reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/MeOH), thus obtaining 3- ⁇ [tert- butyldi(methyl)silyl]oxy ⁇ -N- ⁇ 2-[(oxan-2-yl)oxy]ethyl ⁇ azetidine-l-carboxyamide (1.96 g) as an oily substance.
  • boron trifluoride diethyl ether complex (520 pL) was added to a suspension of tert-butyl [(lR)-l-(4-bromophenyl)-2- hydroxyethyl]carbamate (20 g) and 2,2-dimethoxypropane (66 mL) in acetone (300 mL), and the mixture was stirred at room temperature for an hour.
  • TEA 1.3 mL was added, and after the mixture was stirred at room temperature for 10 minutes, the reaction mixture was concentrated under reduced pressure.
  • reaction mixture was allowed to cool to room temperature, and ethyl acetate and water were added. After filtration through celite (registered trademark), the filtrate was subjected to extraction with ethyl acetate three times. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated.
  • HATU (13.8 g) was added to a DMF (150 mL) solution of N-(tert- butoxycarbonyl)-L-valyl-(4R)-4-hydroxy-L-proline (10 g), (2R)-2-amino-2-[4-(4- methyl-l,3-thiazol-5-yl)phenyl]ethan-l-ol n-hydrochloride (9.3 g) and DIPEA (21 mL), and the mixture was stirred under ice cooling for an hour. Under ice cooling, the reaction mixture was diluted with ethyl acetate and water, and the organic layer and the aqueous layer were separated by a separation operation.
  • l-(fluorosulfonyl)-2,3-dimethyl-lH-imidazol-3-ium trifluoromethanesulfonate (14.8 g) was added to a methyl tert-butyl ether (70 mL), water (60 mL) and MeCN (10 mL) solution of sodium azide (4 g), and the mixture was stirred at room temperature for an hour. The mixture was moved to a separatory funnel using methyl tert-butyl ether and water, and the organic layer and the aqueous layer were separated. The organic layer was washed once with water, and thus a solution of an azidation reagent was prepared.
  • the prepared solution of the azidation reagent was added dropwise from a separatory funnel to the reaction mixture under ice cooling, and the mixture was stirred at room temperature overnight.
  • the reaction mixture was diluted with ethyl acetate and water, and the organic layer and the aqueous layer were separated by a separation operation.
  • the organic layer was washed with saturated aqueous sodium chloride solution twice and dried over anhydrous sodium sulfate.
  • the reaction mixture was cooled with ice, and after water (120 mL) and saturated aqueous sodium chloride solution (50 mL) were added, extraction with ethyl acetate was performed three times.
  • the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate.
  • the aqueous layer was subjected to extraction with ethyl acetate/iPrOH (9/1) three times, and the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate.
  • reaction mixture was concentrated, and the residue was purified by basic silica gel column chromatography (chloroform/MeOH), thus obtaining (4R)-4-hydroxy-N- ⁇ (lR)- 2-hydroxy-l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl ⁇ -L-prolinamide (27.01 g) as a solid.
  • reaction solution was concentrated under reduced pressure, and an iPrOH (3 mL) solution of (7M)-4- [(azetidin-3-yl)oxy]-6-cyclopropyl-7-[6-fluoro-5-methyl-l-(oxan-2-yl)-lH-indazol-4- yl]-2-[(2S)-2-methoxypropoxy]-8-[(lS)-l-phenylethoxy]quinoline (100 mg) was added to the residue at room temperature, and the mixture was stirred under nitrogen atmosphere at 90°C overnight.
  • Disodium ethylenediamine tetraacetate (1.2 g) was added at room temperature, and after the mixture was stirred at room temperature for an hour, saturated aqueous sodium hydrogen carbonate solution was added. The mixture was filtered through celite (registered trademark) using chloroform.
  • the residue was purified by ODS chromatography (0.1% formic acid MeCN/0.1% aqueous formic acid solution), and a fraction containing the target substance was collected. After dilution with chloroform/iPrOH (3/1) at room temperature, saturated aqueous sodium hydrogen carbonate solution was added. The organic layer and the aqueous layer were separated by a separation operation, and the aqueous layer was subjected to extraction with chloroform/iPrOH (3/1) three times. The collected organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. When the residue was dissolved in a small amount of dichloromethane/iPrOH (10/1) and hexane was added, a solid precipitated.
  • the residue was purified by ODS chromatography (0.1% formic acid MeCN/0.1% aqueous formic acid solution), and a fraction containing the target substance was collected. After dilution with chloroform/iPrOH (3/1) at room temperature, saturated aqueous sodium hydrogen carbonate solution was added. The organic layer and the aqueous layer were separated by a separation operation, and the aqueous layer was subjected to extraction with chloroform/iPrOH (3/1) three times. The collected organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. When the residue was dissolved in a small amount of dichloromethane/iPrOH (10/1) and hexane was added, a solid precipitated.
  • DIPEA (220 pL) and triphosgene (31 mg) were added to a mixture of N,N-dimethyl-3- azetidinemethanamine dihydrochloride (60 mg) in dichloromethane (3 mL) under ice cooling, and the mixture was stirred under nitrogen atmosphere at room temperature for an hour.
  • DIPEA 250 pL
  • triphosgene 35 mg
  • the organic layer and the aqueous layer were separated by a separation operation, and the aqueous layer was subjected to extraction with chloroform/iPrOH (3/1) three times.
  • the collected organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. When the residue was dissolved in a small amount of ethyl acetate/iPrOH (10/1) and hexane was added, a solid precipitated.
  • the residue was purified by ODS chromatography (MeCN/0.1% aqueous formic acid solution), and the target fraction was concentrated to around 10 mL. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was stirred at room temperature for an hour.
  • Triphosgene (215 mg) was dissolved in dichloromethane (30 mL), and (ls,3s)-3- (dimethylamino)cyclobutan-l-ol (265 mg) and DIPEA (1.28 mL) were added under ice cooling. The mixture was stirred under nitrogen atmosphere under ice cooling for 20 minutes and at room temperature for 30 minutes, and thus a solution of an active substance was prepared.
  • N,N-dimethyl-3- azetidinemethanamine dihydrochloride (47 mg) was suspended in dichloromethane (2 mL), and DIPEA (200 pL) and triphosgene (24 mg) were added under ice cooling. The mixture was stirred under nitrogen atmosphere at room temperature for an hour. This was added to the reaction mixture under ice cooling, and the mixture was stirred under nitrogen atmosphere under ice cooling for an hour and at room temperature for 30 minutes. Piperidine (60 pL) was added under ice cooling, and the mixture was stirred under ice cooling for 10 minutes and at room temperature for 30 minutes.
  • reaction mixture was concentrated under reduced pressure, and THF (3 mL), ice and saturated aqueous sodium hydrogen carbonate solution (3 mL) were added to the residue. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was subjected to extraction with chloroform/MeOH (10/1) three times and filtered using a phase separator.
  • reaction mixture was concentrated under reduced pressure, and the residue was dissolved in THF (5 mL). Saturated aqueous sodium hydrogen carbonate solution was added under ice cooling, and the mixture was stirred under ice cooling for 30 minutes. The reaction mixture was diluted with chloroform and water, and the organic layer and the aqueous layer were separated by a separation operation. The aqueous layer was subjected to extraction with chloroform/iPrOH (3/1) three times. The collected organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the residue was purified by ODS chromatography (0.1% formic acid MeCN/0.1% aqueous formic acid solution), and a fraction including a peak at the low polarity side was collected and concentrated under reduced pressure to a liquid volume of 2-5 mL.
  • ODS chromatography 0.1% formic acid MeCN/0.1% aqueous formic acid solution
  • a fraction including a peak at the low polarity side was collected and concentrated under reduced pressure to a liquid volume of 2-5 mL.
  • saturated aqueous sodium hydrogen carbonate solution was added to the residue under ice cooling, a solid precipitated.
  • the mixture was stirred under argon atmosphere at room temperature for two hours, and disodium ethylenediamine tetraacetate (15 mg) and ethyl acetate (about 5 mL) were added to the reaction mixture.
  • the mixture was stirred vigorously at room temperature for an hour.
  • Saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution were added, and extraction with chloroform/iPrOH (4/1) was performed three times.
  • the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (chloroform/MeOH).
  • the resulting residue was dissolved in dichloromethane (1 mL), and TFA (1 mL) was added at room temperature. The mixture was stirred for three hours. The reaction mixture was concentrated, and THF (3 mL) and saturated aqueous sodium hydrogen carbonate solution were added to the residue. The mixture was stirred for an hour. Saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution were added, and the reaction mixture was subjected to extraction with chloroform/iPrOH (4/1) three times. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by ODS chromatography (MeCN/0.1% aqueous formic acid solution), and the target fraction was collected.
  • the resulting foam-like solid was dissolved in dichloromethane (3 mL), and TFA (220 pL) was added at room temperature. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and THF (3 mL), ice and saturated aqueous sodium hydrogen carbonate solution (3 mL) were added to the residue. The mixture was stirred at room temperature for an hour. The reaction mixture was subjected to extraction with chloroform/MeOH (7/1) three times, filtered using a phase separator and concentrated under reduced pressure.
  • Str chemical structural formula (A compound with in the chemical structural formula represents that the compound is a mixture of diastereomers with axial chirality of about 3.5: 1.
  • a compound with "##” in the chemical structural formula represents that the axial chirality of the compound is single but the configuration is undetermined.
  • a compound with "###” in the chemical structural formula represents that the compound is a mixture of diastereomers with axial chirality of about 3.5: 1 but the configuration is undetermined.
  • n HCI n-hydrochloride (A compound with a Production Example No. represents a monohydrochloride to a trihydrochloride.)
  • n TFA n-trifluoroacetate (A compound with a Production Example No. represents a monotrifluoroacetate to tritrifluoroacetate.)
  • NMR 6 value (ppm) of peak in 1 H-NMR (500 MHz) in DMSO-d 6 at 27°C
  • NMR (100°C) 6 value (ppm) of peak in 1 H-NMR (500 MHz) in DMSO-de at 100°C
  • s singlet (spectrum), d: doublet (spectrum), dd: double doublet (spectrum), ddd: double double doublet (spectrum), t: triplet (spectrum), dt: double triplet (spectrum), q: quartet (spectrum), m: multiplet (spectrum), br: broad (spectrum) (example: br s).
  • SW-403 cells (DSMZ, ACC 294) or GP2d cells (ECACC, 95090714) were seeded at 500 cells/well in low-attachment 384-well round-bottom white plates (Sumitomo Bakelite).
  • SW-403 cells were cultured in Leibovitz's L-15 Medium (Thermo Fisher Scientific) and incubated at 37°C in 0% CO2.
  • GP2d cells were cultured in Dulbecco's Modified Eagle's Medium (DMEM; Sigma-Aldrich) and incubated at 37°C in 5% CO2. All media were supplemented with 10% heat-inactivated fetal bovine serum (FBS).
  • FBS heat-inactivated fetal bovine serum
  • investigated compounds were added to each well to give a final concentration of 0.1, 0.3, 1.0, 3.0, 10, 30, 100, 300 or 1000 nmol/L.
  • the wells for DMSO treatment were also prepared.
  • the final concentration of DMSO in each well was 0.1% (volume/volume).
  • cell viability was determined using a CellTiter-Glo 2.0 Assay (Promega).
  • CellTiter-Glo Reagent was added to each well and luminescence intensity was measured using a multi-label reader ARVO-X3 (Perkin Elmer).
  • LCLC-97TM1 cells (DSMZ, ACC 388) or NCI-H358 cells (ATCC, CRL-5807) were seeded at 750 or 500 cells/well in low-attachment 384-well round-bottom white plates, respectively.
  • LCLC-97TM1 cells and NCI-H358 cells were cultured in RPMI-1640 Medium (FUJIFILM Wako Pure Chemical Corporation) supplemented with 10% heat-inactivated FBS. The cells were incubated at 37°C in 5% CO2.
  • investigated compounds was added to each well to give a final concentration of 0.1, 0.3, 1.0, 3.0, 10, 30, 100, 300, 1000, 3000 or 10000 nmol/L.
  • the wells for DMSO treatment were also prepared.
  • the final concentration of DMSO in each well was 0.1% (volume/volume).
  • cell viability was determined using a CellTiter-Glo 2.0 Assay.
  • CellTiter- Gio Reagent was added to each well and luminescence intensity was measured using a multi-label reader ARVO-X3.
  • SW-403 cells were cultured in Leibovitz's L-15 Medium supplemented with 10% heat- inactivated FBS. The cells were incubated at 37°C in 0% CO2. SW-403 cells were suspended at 8.0 x 10 6 cells/mL as a mixture of 2: 1 amounts of VitroGel Hydrogel Matrix (TheWell Bioscience Inc.) and phosphate buffered saline (PBS). Cell suspension was subcutaneously inoculated into from 4 to 6 weeks old nude mice (BALB/c nu [nu/nu]) (The Jackson Laboratories Japan, Inc.) at 8.0 x 10 5 cells/0.1 mL/mouse and allowed to grow.
  • BALB/c nu [nu/nu] The Jackson Laboratories Japan, Inc.
  • SW-403 xenograft mice were randomized based on tumor volume. Each group had 5 individuals and received intravenous administration of either vehicle or investigated compounds. The compounds were dissolved in 4% ethanol/0.5% (2-hydroxyprppyl)-[3-cyclodextrin/9% PEG-40 hydrogenated castor oil in 5% glucose solution. The compounds were administered once a week for a total of two doses. Tumor diameters and body weights were measured two to three times a week. Tumor volume was calculated as follows:
  • the day of the randomization was designated as day 0.
  • Tumor volume [mm 3 ] (length of tumor [mm]) x (width of tumor [mm]) 2 x 0.5
  • tumor growth inhibition rate was calculated using the following formula:
  • Tumor growth inhibition rate 100 x [1 - (difference of mean tumor volume of each group on day 14 and day 0 [mm 3 ]) / (difference of mean tumor volume in vehicle group on day 14 and day 0 [mm 3 ])]
  • LCLC-97TM1 cells were cultured in RPMI-1640 Medium supplemented with 10% heat- inactivated FBS. These cells were incubated at 37°C in 5% CO2. LCLC-97TM1 cells were suspended at 3.0 x 10 7 cells/mL as a mixture of 2: 1 amounts of VitroGel Hydrogel Matrix and PBS. Cell suspension was subcutaneously inoculated into from 4 to 6 weeks old nude mice at 3.0 x 10 6 cells/0.1 mL/mouse and allowed to grow.
  • LCLC-97TM1 xenograft mice Two to three weeks after inoculation, LCLC-97TM1 xenograft mice were randomized based on tumor volume. Each group had 5 individuals and received intravenous administration of either vehicle or investigated compounds. The compounds were dissolved in the same vehicle as experiment example 3. The compounds were administered once a week for a total of two doses. Tumor diameters and body weights were measured two to three times a week.
  • Tumor volume and tumor growth inhibition rate were calculated using the same formula as experiment example 3.
  • tumor regression rate was calculated in groups whose tumor growth inhibition exceeded 100% as follows:
  • Tumor regression rate [%] 100 x [1 - (mean tumor volume of each group on day 14 [mm 3 ]) / (mean tumor volume of each group on day 0 [mm 3 ])

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Abstract

There is provided herein a compound of formula (I) wherein R1, R2, R3, R4, A, X1, Y, L, Z, R5, R6a, R6b, W and R7 are as defined herein, for use in the treatment of colorectal and/or lung cancer.

Description

PHARMACEUTICAL COMPOSITION COMPRISING A pan-KRAS DEGRADER
Field of the Invention
The present invention relates to the medical use of compounds, and compositions comprising the compounds, in the treatment of colorectal cancer and/or lung cancer. In particular, the present invention relates to bifunctional compounds comprising a substituent at the 8-position of a heterocyclic compound selected from the group consisting of quinazoline and quinoline bound, optionally via a linker, to a ligand of an E3 ligase, which have excellent degradation-inducing action on G12V mutant, G12D mutant and G12C mutant KRAS protein, and are useful as G12V mutant, G12D mutant and G12C mutant KRAS inhibitors, and their use in the treatment of colorectal and/or lung cancer.
Background of the Invention
The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.
Colorectal cancer is a cancer with a high morbidity and fatality in the world, and about 1.8 million new cases are reported every year in the world (World Cancer Report 2020). The most effective treatment for colorectal cancer is a surgery, whereas chemotherapy, radiotherapy, and the like have been significantly advanced recently. Large scale clinical trials performed mainly in Europe and America have revealed that a combination of chemotherapy and anti-cancer agents is effective for colorectal cancer and contributes to tumor regression and prognosis prolongation (J. Clin. Oncol., 22, p.229-237, 2004). In addition to chemotherapy, molecular target drugs, such as an anti-vascular endothelial growth factor (VEGF) antibody or an anti-epidermal growth factor receptor (EGFR) antibody, are used as a first-line drug in combination with the chemotherapy. Regarding an anti-EGFR antibody, it has been revealed that mutations in a KRAS gene is a negative predictive factor for the efficacy (Cancer Res., 66, p.3992- 3995, 2006), and anti-EGFR antibody drugs are applicable only to patients harboring wild-type RAS genes in colorectal cancer.
In addition, lung cancer is the most common cancer type worldwide. Approximately 1.8 million deaths and 2.1 million new cases are reported every year in the world (World Cancer Report 2020). Especially, non-small cell lung cancer (NSCLC) is reported to account for 80 to 85% of lung cancer (American Cancer Society, Cancer Facts and Figures, 2016). Surgical therapy is considered at early stage, but surgery is rarely adopted and chemotherapy or radiotherapy becomes a main therapy at late stage. Based on the cytomorphology, adenocarcinoma and squamous cell carcinoma are classified as the most typical type of NSCLC. These cancers follow a similar clinical course, but adenocarcinoma is characterized by localization in the lung periphery.
RAS proteins are low molecular weight guanosine triphosphate (GTP)-binding proteins of about 21 kDa constituted of 188-189 amino acids and include four main types (KRAS (KRAS 4A and KRAS 4B), NRAS and HRAS) produced by a KRAS gene, an NRAS gene and HRAS gene. RAS proteins are in an active GTP-bound form or an inactive guanosine diphosphate (GDP)-bound form. RAS proteins are activated by nucleotide exchange of GDP to GTP due to, for example, ligand stimulation of a membrane receptor, such as EGFR. The activated RAS proteins bind to effector proteins as much as twenty, such as RAF, PI3K, and RALGDS, to activate the downstream signal cascade. On the other hand, the activate form RAS proteins are converted to the inactive form by hydrolysis of GTP due to the intrinsic GTP hydrolysis (GTPase) activity. The GTPase activity is enhanced by a GTPase-activating protein (GAP). Therefore, RAS proteins have an important function of "molecular switch" in an intracellular signal transduction pathway for EGFR or the like, and play a critical role in the processes of cell growth, proliferation, angiogenesis, and the like (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).
Substitution of an amino acid by spontaneous mutation of the RAS gene results in a constant activated state due to hypofunction of RAS as GTPase or hyporeactivity to GAP, and then, downstream signals are continuously activated. The excessive signaling causes carcinogenesis nor cancer growth acceleration. In 30 to 40% of colorectal cancer, a mutation is observed in a KRAS gene and in many cases, the mutation is spontaneous point mutation particularly in the KRAS exon 2 (codon 12, codon 13) (Ann. Oncol., 27, p.1746-1753, 2016). Effectiveness of existing anti-cancer agents has not been demonstrated on colorectal cancer with a KRAS mutation, and unmet medical needs for this segment are high. In addition, in lung cancer, a mutation of a RAS gene has been in 32% of lung adenocarcinoma. The breakdown of the frequency of the mutation is 96% in KRAS genes, 3% in NRAS genes, and 1% in HRAS genes, and it is reported especially in the KRAS exon 2 (codon 12, codon 13) (Nature Rev. Drug Discov., 2014, 13, p.828-851). As a mutation of a KRAS gene, KRAS G12V mutation in which glycine at the codon 12 is substituted with valine, KRAS G12D mutation in which glycine at the codon 12 is substituted with aspartic acid and KRAS G12C mutation in which glycine is substituted with cysteine are particularly known. In recent years, a number of G12C mutant selective inhibitors have been developed, and among them, Sotorasib and Adagrasib have been approved by FDA as a therapeutic agent for non-small cell lung cancer (Drugs, 2021, 81, p.1573-1579; Drugs, 2023, 83, p.275-285).
On the other hand, KRAS G12V mutation is observed in about 22% of pancreatic cancer, in 6% or more of colorectal cancer, and also in about 5% of lung adenocarcinoma (Nat. Rev. Cancer, 2018, 18, p.767-777). Thus, a therapeutic agent for a KRAS mutation other than the KRAS G12C mutation is highly expected.
WO 2016/049565, WO 2016/049568, and WO 2017/172979 disclose RAS inhibitors, and WO 2016/049568 and WO 2017/172979 disclose compounds represented by the following formulae (A) and (B), respectively (refer to the documents for the meanings of the signs in the formulae).
Figure imgf000004_0001
(A)
Figure imgf000004_0002
(B)
WO 2021/041671, WO 2021/106231, and WO 2021/107160 disclose KRAS G12D mutation inhibitors. WO 2022/132200 discloses pan-RAS inhibitors. In recent years, as a technique for inducing degradation of a target protein, bifunctional compounds collectively called as PROTAC (proteolysis-targeting chimera) or SNIPER (specific and nongenetic lAP-dependent protein eraser) are found and are expected as one novel technique of drug development modality (Drug. Discov. Today Technol., 2019, 31, pl5-27). Such a bifunctional compound promotes formation of a composite of the target protein in a cell, and degradation of the target protein is induced by using the ubiquitin-proteasome system. The ubiquitin-proteasome system is one of intracellular protein degradation mechanisms. An E3 ligase protein recognizes a protein to be degraded to ubiquitinate the protein, whereby degradation by proteasome is promoted.
Six hundreds or more E3 ligases are present in an organism, and are roughly divided into four types of HECT-domain E3s, U-box E3s, monomeric RING E3s, and multisubunit E3s. E3 ligases used as a bifunctional degradation inducer which are PROTAC, SNIPER, or the like are currently limited, and typical examples thereof include von Hippel-Lindau (VHL), celebron (CRBN), inhibitor of apoptosis protein (IAP), and mouse double minute 2 homolog (MDM2). In particular, VHL is reported in WO 2013/106643 and CRBN is reported in WO 2015/160845.
The bifunctional compounds are compounds in which a ligand of a target protein and a ligand of an E3 ligase are bound via a linker, and some bifunctional compounds for degrading a KRAS protein have ever been reported (Cell. Chem. Biol., 2020, 27, pl9- 31; ACS Cent. Sci., 2020, 6, pl367-1375; US 2018/0015087; WO 2019/195609; WO 2020/018788, WO 2021/051034; WO 2022/087335; WO2022/061348;
WO2022/148421; WO 2022/173032).
Summary of the Invention
It has now surprisingly been found that compounds of formula (I) as defined herein have properties that make them useful in the treatment of lung cancer and/or colorectal cancer.
Without wishing to be bound by theory, it is believed that compounds of formula (I) as defined herein are useful for treating colorectal cancer and/or lung cancer in view of their degradation-inducing action, for example, on G12V mutant, G12D mutant and G12C mutant KRAS protein, and their activity as G12V mutant, G12D mutant and G12C mutant KRAS inhibitors. In particular, the inventors have found that heterocyclic compounds of formula (I), in particular, bifunctional compounds of the formula (I) comprising a substituent at the 8-position of a heterocyclic compound selected from the group consisting of quinazoline and quinoline bound, optionally via a linker, to a ligand of an E3 ligase, has excellent degradation-inducing action on G12V mutant, G12D mutant and G12C mutant KRAS protein, and G12V mutant, G12D mutant and G12C mutant KRAS inhibitory activity and that the compounds are useful (in particular as the active ingredient in a pharmaceutical composition) for treating colorectal and/or lung cancer (and particularly G12V mutant, G12D mutant and/or G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and/or G12C mutant KRAS-positive lung cancer)
Detailed description of the Invention
In a first aspect of the invention, there is provided a compound of formula (I) or a salt thereof for use in the treatment of colorectal cancer and/or lung cancer, in particular, G12V mutant, G12D mutant and/or G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and/or G12C mutant KRAS-positive lung cancer,
Figure imgf000006_0001
wherein (in formula (I)),
A is CRA or N, wherein RA is H or C1-3 alkyl,
X1 is -CH2- or -O-,
R1 is naphthyl optionally substituted with OH or the formula (II) below,
Figure imgf000006_0002
wherein Rla is H, methyl, F or Cl, and
Rlb is F, Cl, methyl or ethyl,
R2 is H, halogen, C1-3 alkyl optionally substituted with a group selected from the group consisting of OH and OCH3, cyclopropyl or vinyl, R3 is a group selected from the group consisting of the formula (III), the formula (IV), the formula (V), the formula (VI), the formula (VII), the formula (VIII), the formula (IX), the formula (X), the formula (XI) and the formula (XXXV) below,
Figure imgf000007_0001
wherein R3a is -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; a 4-membered to 6- membered saturated heterocyclic group which is optionally substituted with a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene- NRN1RN2 and -NRN1RN2 and which contains one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms; or C3-6 cycloalkyl optionally substituted with a group selected from the group consisting of C1- 3 alkyl, C1-3 alkylene-OR3g, C1-3 alkyl-NRN1RN2, -OR3g and -NRN1RN2, R3b is H or C1-3 alkyl, R3c and R3d are -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; a 4-membered to 6- membered saturated heterocyclic group which is optionally substituted with a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene- NRN1RN2 and -NRN1RN2 and which contains one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms; or C3-6 cycloalkyl optionally substituted with a group selected from the group consisting of C1- 3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, -OR3g and -NRN1RN2, R3e is -O-C2-3 alkylene-NRN1RN2, R3f is H, F or C1-3 alkyl, R3g is H or C1-3 alkyl, R3h is optionally substituted 5-membered heteroaryl containing one to four hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring- constituting atoms or optionally substituted 6-membered heteroaryl containing one to three nitrogen atoms, R3i groups, which are the same as or different from each other, are groups selected from the group consisting of H, OH, optionally substituted C1-3 alkyl, -O- optionally substituted C1-3 alkyl, -NH-optionally substituted C1-3 alkyl, -N-(optionally substituted C1-3 alkyl)2, halogen, -CN and oxo, or two R3i groups on a same carbon atom, together with the neighboring carbon atom, may form a ring selected from the group consisting of C3-6 cycloalkane and a 4- membered to 6-membered saturated hetero ring containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms to form a spiro ring as the compound of the formula (XXXV), wherein the spiro ring is optionally substituted with one or two groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen and oxo, or R3i groups on two neighboring carbon atoms, together with the two carbon atoms, may form a ring selected from the group consisting of C3-6 cycloalkane and a 4-membered to 6-membered saturated hetero ring containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms to form a condensed ring as the compound of the formula (XXXV), wherein the condensed ring is optionally substituted with one or two groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen and oxo, or R3i groups on two carbon atoms which are not neighboring, together with the two carbon atoms, may form a cross-linked structure composed of one or two carbon atoms, wherein the compound of the formula (XXXV) having the cross-linked structure is optionally substituted with one or two groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen and oxo, RN1 and RN2, which are the same as or different from each other, are H or C1-3 alkyl, or RN1 and RN2, together with the nitrogen atom to which they are attached, may form an optionally substituted 4-membered to 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, or R3f and RN1, together with the carbon atom and the nitrogen atom to which they are attached, may form an optionally substituted 4-membered to 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, X2 is -O-, -NH- or -N(C1-3 alkyl)-, X3 is O or S, X4 is -CH2-, -CH2-CH2- or -O-CH2-, n is 1 or 2, p is 1 or 2, and q is an integer of 1 to 8, with the proviso that X2 in the formula (IV) is -O-, -NH- or -N(C2-3 alkyl)- when R3c is -(CH2)pCHR3f-NRN1RN2, R4 is C1-6 alkyl optionally substituted with a group selected from the group consisting of F, OH, OCH3, R4a, cyclopropyl, N(R4a)2, pyrrolidinyl optionally substituted with R4a and tetrahydrofuranyl optionally substituted with R4a; piperidinyl optionally substituted with R4b; or tetrahydropyranyl optionally substituted with R4a, wherein R4a is C1-3 alkyl optionally substituted with F, and R4b is C1-3 alkyl substituted with one to three F, R5 is methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, C3-6 cycloalkylmethyl or C3-6 cycloalkyl, R6a and R6b, which are the same as or different from each other, are H or C1-6 alkyl optionally substituted with a group selected from the group consisting of F, OH, OCH3 and N(CH3)2, or R6a and R6b, together with the carbon to which they are attached, may form optionally substituted C3-6 cycloalkane or an optionally substituted 4-membered to 6- membered saturated hetero ring containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, R7 is an optionally substituted 4-membered to 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, optionally substituted 5-membered heteroaryl containing one to four hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms or 6- membered heteroaryl containing one to three nitrogen atoms, W is optionally substituted phenylene or optionally substituted 6-membered heteroarenediyl containing one to three nitrogen atoms, Y is phenylene optionally substituted with F or Cl or pyridinediyl, L is -(L1-L2-L3-L4)-, wherein L1, L2, L3 and L4, which are the same as or different from each other, are groups selected from the group consisting of a bond, -O-, -NRL1-, optionally substituted pyrrolidinediyl, optionally substituted piperidinediyl, optionally substituted piperazinediyl, optionally substituted C1-3 alkylene and C=O, wherein RL1 is H or C1-3 alkyl, and Z is NH or 5-membered heteroarenediyl containing one to four hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, or Y-L-Z is the formula (XII) below,
Figure imgf000009_0001
. When a sign in a chemical formula in this specification is used in another chemical formula, the same sign represents the same meaning unless otherwise specified. In a further aspect of the invention, there is provided a pharmaceutical composition, in particular, a pharmaceutical composition for treating colorectal cancer and/or lung cancer, and more particularly, a pharmaceutical composition for treating G12V mutant, G12D mutant and/or G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and/or G12C mutant KRAS-positive lung cancer, comprising the compound of the formula (I) or a salt thereof, as defined herein, and one or more pharmaceutically acceptable excipients. The pharmaceutical composition includes a therapeutic agent for treating colorectal cancer and/or lung cancer, in particular, G12V mutant, G12D mutant and/or G12C mutant KRAS-positive cancer, the therapeutic agent comprising the compound of the formula (I) or a salt thereof, as defined herein. In a further aspect of the invention, there is provided the use of the compound of formula (I), or salt thereof, as defined herein, for the manufacture of a pharmaceutical composition for treating colorectal cancer and/or lung cancer, in particular, G12V mutant, G12D mutant and/or G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and/or G12C mutant KRAS-positive lung cancer. In a further aspect of the invention, there is provided the use of the compound of formula (I), or a salt thereof, as defined herein, for treating colorectal cancer and/or lung cancer, in particular, G12V mutant, G12D mutant and/or G12C mutant KRAS- positive colorectal cancer and/or G12V mutant, G12D mutant and/or G12C mutant KRAS-positive lung cancer. In a further aspect of the invention, there is provided a method for treating colorectal cancer and/or lung cancer, in particular, G12V mutant, G12D mutant and/or G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and/or G12C mutant KRAS-positive lung cancer, the method including administering an effective amount of the compound of formula (I) or a salt thereof, as defined herein, to a subject in need thereof. As used herein the term “subject” denotes a human or another animal that needs the treatment, and in an embodiment, the “subject” is a human who needs the prevention or treatment. Compounds of formula (I), or salts thereof, as defined herein have been found induce degradation of G12V mutant, G12D mutant and/or G12C mutant KRAS protein and/or to be G12V mutant, G12D mutant and/or G12C mutant KRAS inhibitors. Accordingly, in particular embodiments of all aspects of the invention defined herein, the compound of formula (I), or salt thereof, is a G12V mutant, G12D mutant and/or G12C mutant KRAS protein degradation inducer and/or a G12V mutant, G12D mutant and/or G12C mutant KRAS protein inhibitor. In further aspects, there are provided a compound of formula (I), or salt thereof as defined herein, for use as a G12V mutant, G12D mutant and/or G12C mutant KRAS protein degradation inducer and/or a G12V mutant, G12D mutant and/or G12C mutant KRAS inhibitor; a pharmaceutical composition comprising the compound of the formula (I), or a salt thereof, as defined herein, that is a G12V mutant, G12D mutant and/or G12C mutant KRAS protein degradation inducer and/or a G12V mutant, G12D mutant and/or G12C mutant KRAS inhibitor; a pharmaceutical composition comprising the compound of the formula (I) or a salt thereof for use as a G12V mutant, G12D mutant and/or G12C mutant KRAS protein degradation inducer and/or a G12V mutant, G12D mutant and/or G12C mutant KRAS inhibitor; and a pharmaceutical composition comprising a G12V mutant, G12D mutant and/or G12C mutant KRAS protein degradation inducer and/or a G12V mutant, G12D mutant and/or G12C mutant KRAS inhibitor containing the compound of the formula (I) or a salt thereof. In a further aspect, there is provided a method of inducing degradation of G12V mutant, G12D mutant and/or G12C mutant KRAS protein and/or inhibiting the function of G12V mutant, G12D mutant and/or G12C mutant KRAS in a subject, comprising administering an effective amount of a compound of formula (I) or a salt thereof, to a patient in need thereof. In particular embodiments, the colorectal cancer and/or lung cancer is G12V mutant, G12D mutant and G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and G12C mutant KRAS-positive lung cancer. Accordingly, in an embodiment, there is provided a compound of formula (I) or a salt thereof, as defined herein, for use in the treatment of G12V mutant, G12D mutant and G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and G12C mutant KRAS-positive lung cancer. In a further embodiment, there is provided a pharmaceutical composition, in particular, a pharmaceutical composition for treating G12V mutant, G12D mutant and G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and G12C mutant KRAS-positive lung cancer, comprising the compound of the formula (I) or a salt thereof, as defined herein, and one or more pharmaceutically acceptable excipients. The pharmaceutical composition includes a therapeutic agent for treating colorectal cancer and/or lung cancer, in particular, a G12V mutant, G12D mutant and G12C mutant KRAS-positive cancer, the therapeutic agent comprising the compound of the formula (I) or a salt thereof, as defined herein. In a further embodiment, there is provided the use of the compound of formula (I), or salt thereof, as defined herein, for the manufacture of a pharmaceutical composition for treating G12V mutant, G12D mutant and G12C mutant KRAS-positive colorectal cancer and G12V mutant, G12D mutant and G12C mutant KRAS-positive lung cancer. In a further embodiment, there is provided the use of the compound of formula (I), or a salt thereof, as defined herein, for treating G12V mutant, G12D mutant and G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and G12C mutant KRAS-positive lung cancer. In a further embodiment, there is provided a method for treating G12V mutant, G12D mutant and G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and G12C mutant KRAS-positive lung cancer, the method including administering an effective amount of the compound of formula (I) or a salt thereof, as defined herein, to a subject in need thereof. In particular embodiments, the colorectal cancer and/or lung cancer is G12V mutant and G12D mutant KRAS-positive colorectal cancer and/or G12V mutant and G12D mutant KRAS-positive lung cancer. Accordingly, in an embodiment, there is provided a compound of formula (I) or a salt thereof, as defined herein, for use in the treatment of G12V mutant and G12D mutant KRAS-positive colorectal cancer and/or G12V mutant and G12D mutant KRAS-positive lung cancer. In a further embodiment, there is provided a pharmaceutical composition, in particular, a pharmaceutical composition for treating G12V mutant and G12D mutant KRAS- positive colorectal cancer and/or G12V mutant and G12D mutant KRAS-positive lung cancer, comprising the compound of the formula (I) or a salt thereof, as defined herein, and one or more pharmaceutically acceptable excipients. The pharmaceutical composition includes a therapeutic agent for treating colorectal cancer and/or lung cancer, in particular, a G12V mutant and G12D mutant KRAS-positive cancer, the therapeutic agent comprising the compound of the formula (I) or a salt thereof, as defined herein. In a further embodiment, there is provided the use of the compound of formula (I), or salt thereof, as defined herein, for the manufacture of a pharmaceutical composition for treating G12V mutant and G12D mutant KRAS-positive colorectal cancer and G12V mutant and G12D mutant KRAS-positive lung cancer. In a further embodiment, there is provided the use of the compound of formula (I), or a salt thereof, as defined herein, for treating G12V mutant and G12D mutant KRAS- positive colorectal cancer and/or G12V mutant and G12D mutant KRAS-positive lung cancer. In a further embodiment, there is provided a method for treating G12V mutant and G12D mutant KRAS-positive colorectal cancer and/or G12V mutant and G12D mutant KRAS-positive lung cancer, the method including administering an effective amount of the compound of formula (I) or a salt thereof, as defined herein, to a subject in need thereof. In particular embodiments, the colorectal cancer and/or lung cancer is G12V mutant KRAS-positive colorectal cancer and/or G12V mutant KRAS-positive lung cancer. Accordingly, in an embodiment, there is provided a compound of formula (I) or a salt thereof, as defined herein, for use in the treatment of G12V mutant KRAS-positive colorectal cancer and/or G12V mutant KRAS-positive lung cancer. In a further embodiment, there is provided a pharmaceutical composition, in particular, a pharmaceutical composition for treating G12V mutant KRAS-positive colorectal cancer and/or G12V mutant KRAS-positive lung cancer, comprising the compound of the formula (I) or a salt thereof, as defined herein, and one or more pharmaceutically acceptable excipients. The pharmaceutical composition includes a therapeutic agent for treating colorectal cancer and/or lung cancer, in particular, a G12V mutant KRAS- positive cancer, the therapeutic agent comprising the compound of the formula (I) or a salt thereof, as defined herein. In a further embodiment, there is provided the use of the compound of formula (I), or salt thereof, as defined herein, for the manufacture of a pharmaceutical composition for treating G12D mutant KRAS-positive colorectal cancer and G12D mutant KRAS- positive lung cancer. In a further embodiment, there is provided the use of the compound of formula (I), or a salt thereof, as defined herein, for treating G12D mutant KRAS-positive colorectal cancer and/or G12D mutant KRAS-positive lung cancer. In a further embodiment, there is provided a method for treating G12D mutant KRAS- positive colorectal cancer and/or G12D mutant KRAS-positive lung cancer, the method including administering an effective amount of the compound of formula (I) or a salt thereof, as defined herein, to a subject in need thereof. In particular embodiments, the colorectal cancer and/or lung cancer is G12D mutant KRAS-positive colorectal cancer and/or G12D mutant KRAS-positive lung cancer. Accordingly, in an embodiment, there is provided a compound of formula (I) or a salt thereof, as defined herein, for use in the treatment of G12D mutant KRAS-positive colorectal cancer and/or G12D mutant KRAS-positive lung cancer. In a further embodiment, there is provided a pharmaceutical composition, in particular, a pharmaceutical composition for treating G12D mutant KRAS-positive colorectal cancer and/or G12D mutant KRAS-positive lung cancer, comprising the compound of the formula (I) or a salt thereof, as defined herein, and one or more pharmaceutically acceptable excipients. The pharmaceutical composition includes a therapeutic agent for treating colorectal cancer and/or lung cancer, in particular, a G12D mutant KRAS- positive cancer, the therapeutic agent comprising the compound of the formula (I) or a salt thereof, as defined herein. In a further embodiment, there is provided the use of the compound of formula (I), or salt thereof, as defined herein, for the manufacture of a pharmaceutical composition for treating G12D mutant KRAS-positive colorectal cancer and G12D mutant KRAS- positive lung cancer. In a further embodiment, there is provided the use of the compound of formula (I), or a salt thereof, as defined herein, for treating G12C mutant KRAS-positive colorectal cancer and/or G12C mutant KRAS-positive lung cancer. In a further embodiment, there is provided a method for treating G12C mutant KRAS- positive colorectal cancer and/or G12C mutant KRAS-positive lung cancer, the method including administering an effective amount of the compound of formula (I) or a salt thereof, as defined herein, to a subject in need thereof. In particular embodiments, the colorectal cancer and/or lung cancer is G12C mutant KRAS-positive colorectal cancer and/or G12C mutant KRAS-positive lung cancer. Accordingly, in an embodiment, there is provided a compound of formula (I) or a salt thereof, as defined herein, for use in the treatment of G12C mutant KRAS-positive colorectal cancer and/or G12C mutant KRAS-positive lung cancer. In a further embodiment, there is provided a pharmaceutical composition, in particular, a pharmaceutical composition for treating G12C mutant KRAS-positive colorectal cancer and/or G12C mutant KRAS-positive lung cancer, comprising the compound of the formula (I) or a salt thereof, as defined herein, and one or more pharmaceutically acceptable excipients. The pharmaceutical composition includes a therapeutic agent for treating colorectal cancer and/or lung cancer, in particular, a G12C mutant KRAS- positive cancer, the therapeutic agent comprising the compound of the formula (I) or a salt thereof, as defined herein. In a further embodiment, there is provided the use of the compound of formula (I), or salt thereof, as defined herein, for the manufacture of a pharmaceutical composition for treating G12C mutant KRAS-positive colorectal cancer and G12C mutant KRAS- positive lung cancer. In a further embodiment, there is provided the use of the compound of formula (I), or a salt thereof, as defined herein, for treating G12C mutant KRAS-positive colorectal cancer and/or G12C mutant KRAS-positive lung cancer. In a further embodiment, there is provided a method for treating G12C mutant KRAS- positive colorectal cancer and/or G12C mutant KRAS-positive lung cancer, the method including administering an effective amount of the compound of formula (I) or a salt thereof, as defined herein, to a subject in need thereof. In an embodiment, the colorectal cancer and/or lung cancer (including G12V mutant, G12D mutant and/or G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and/or G12C mutant KRAS-positive lung cancer; G12V mutant, G12D mutant and G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and G12C mutant KRAS-positive lung cancer; G12V mutant and G12D mutant KRAS-positive colorectal cancer and/or G12V mutant and G12D mutant KRAS- positive lung cancer; G12V mutant KRAS-positive colorectal cancer and/or G12V mutant KRAS-positive lung cancer; G12D mutant KRAS-positive colorectal cancer and/or G12D mutant KRAS-positive lung cancer; and G12C mutant KRAS-positive colorectal cancer and/or G12C mutant KRAS-positive lung cancer) is a metastatic, locally advanced, recurrent, and/or refractory cancer. In an embodiment, the colorectal cancer and/or lung cancer (including G12V mutant, G12D mutant and/or G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and/or G12C mutant KRAS-positive lung cancer; G12V mutant, G12D mutant and G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and G12C mutant KRAS-positive lung cancer; G12V mutant and G12D mutant KRAS-positive colorectal cancer and/or G12V mutant and G12D mutant KRAS- positive lung cancer; G12V mutant KRAS-positive colorectal cancer and/or G12V mutant KRAS-positive lung cancer; G12D mutant KRAS-positive colorectal cancer and/or G12D mutant KRAS-positive lung cancer; and G12C mutant KRAS-positive colorectal cancer and/or G12C mutant KRAS-positive lung cancer) is a cancer of a patient who has been untreated or who has a medical history. In an embodiment, colorectal cancer (including G12V mutant, G12D mutant and/or G12C mutant KRAS-positive colorectal cancer; G12V mutant, G12D mutant and G12C mutant KRAS-positive colorectal cancer; G12V mutant and G12D mutant KRAS- positive colorectal cancer; G12V mutant KRAS-positive colorectal cancer; G12D mutant KRAS-positive colorectal cancer; and G12C mutant KRAS-positive colorectal cancer) is colon cancer or rectal cancer. In an embodiment, lung cancer (including G12V mutant, G12D mutant and/or G12C mutant KRAS-positive lung cancer; G12V mutant, G12D mutant and G12C mutant KRAS-positive lung cancer; G12V mutant and G12D mutant KRAS-positive lung cancer; G12V mutant KRAS-positive lung cancer; G12D mutant KRAS-positive lung cancer; and G12C mutant KRAS-positive lung cancer) is small cell lung cancer or non-small cell lung cancer. The invention will be explained in detail below. In this specification, "optionally substituted" means being unsubstituted or having one to five substituents. In an aspect, the term means being unsubstituted or having one to three substituents. Note that when there are multiple substituents, the substituents may be the same as or different from each other. The "C1-12 alkyl" is linear or branched alkyl having 1 to 12 carbon atoms, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- butyl, n-pentyl, n-hexyl, dodecyl and the like (the numbers of carbon atoms are described similarly below). An aspect thereof is ethyl or dodecyl. Similarly, the "C1-6 alkyl" is linear or branched alkyl having one to six carbon atoms, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert-butyl, n-pentyl and n-hexyl. An aspect thereof is methyl, ethyl, n-propyl, isopropyl or sec-butyl; another aspect is methyl, ethyl, isopropyl or tert-butyl; and another aspect is methyl, ethyl, n-propyl, isopropyl or n-butyl. Similarly, the "C1-3 alkyl" is linear or branched alkyl having one to three carbon atoms, and examples thereof include methyl, ethyl, n-propyl and isopropyl. An aspect thereof is methyl or ethyl; another aspect is n-propyl or isopropyl; another aspect is methyl or isopropyl; another aspect is ethyl or isopropyl; another aspect is methyl; another aspect is ethyl; another aspect is isopropyl; and another aspect is n-propyl. Similarly, the "C2-3 alkyl" is linear or branched alkyl having two or three carbon atoms, and examples thereof include ethyl, n-propyl and isopropyl. An aspect thereof is ethyl; another aspect is isopropyl; and another aspect is n-propyl. The "C3-6 cycloalkyl" is cycloalkyl having three to six carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. An aspect thereof is cyclobutyl, cyclopentyl or cyclohexyl; another aspect is cyclobutyl or cyclopentyl; another aspect is cyclopentyl or cyclohexyl; another aspect is cyclopropyl or cyclobutyl; another aspect is cyclopropyl; another aspect is cyclobutyl; another aspect is cyclopentyl; and another aspect is cyclohexyl. The "C1-3 alkylene" is a divalent group formed by removing a hydrogen atom from C1- 3 alkyl and is linear or branched C1-3 alkylene, such as for example methylene, ethylene, trimethylene, methylmethylene methylethylene, and 1,1-dimethylmethylene. An aspect thereof is linear or branched C1-3 alkylene; another aspect is methylene, ethylene or trimethylene; another aspect is methylene or ethylene; another aspect is methylene; and another aspect is ethylene. In the same way, the "C2-3 alkylene" is a divalent group formed by removing a hydrogen atom from C2-3 alkyl and is linear or branched C2-3 alkylene, such as for example ethylene, trimethylene, methylmethylene methylethylene, and 1,1-dimethylmethylene. An aspect thereof is linear or branched C2-3 alkylene; another aspect is ethylene or trimethylene; another aspect is ethylene; and another aspect is trimethylene. The "saturated heterocyclic group" is a saturated hydrocarbon ring group containing a hetero atom selected from the group consisting of oxygen, sulfur and nitrogen as a ring-constituting atom. The sulfur atom as the ring-constituting atom of the saturated heterocyclic group may be oxidized. Thus, the "4-membered to 6-membered saturated heterocyclic group" is a 4- membered to 6-membered saturated heterocyclic group containing a hetero atom selected from the group consisting of oxygen, sulfur and nitrogen as a ring-constituting atom. An aspect of the "4-membered to 6-membered saturated heterocyclic group" is a 4-membered to 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring- constituting atoms. An aspect of the 4-membered to 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms is a 4-membered to 6-membered saturated heterocyclic group containing one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen as a ring-constituting atom; another aspect is a 5-membered or 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms; another aspect is a 4-membered saturated heterocyclic group containing one hetero atom selected from the group consisting of oxygen, sulfur and nitrogen as a ring-constituting atom; another aspect is a 5-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms; another aspect is a 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms; another aspect is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, oxazolidinyl, imidazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl or dioxothiomorpholinyl; another aspect is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl or dioxothiomorpholinyl; another aspect is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl or morpholinyl; another aspect is oxetanyl, tetra hydrofuranyl, tetrahydropyranyl, pyrrolidinyl or piperidinyl; another aspect is oxetanyl, tetra hydrofuranyl or tetra hydropyranyl; another aspect is pyrrolidinyl or piperidinyl; another aspect is oxetanyl; another aspect is tetra hydrofuranyl; another aspect is tetra hydropyranyl; another aspect is pyrrolidinyl; another aspect is piperidinyl; another aspect is morpholinyl; and another aspect is oxazolidinyl.
The "heteroaryl" is a heterocyclic group containing a hetero atom selected from the group consisting of oxygen, sulfur and nitrogen as a ring-constituting atom.
Thus, the "5-membered heteroaryl" is a heterocyclic group of a 5-membered ring containing one to four hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms.
An aspect of the "5-membered heteroaryl" is a heterocyclic group of a 5-membered ring containing one to three hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms; another aspect is pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl; another aspect is pyrazolyl, imidazolyl, triazolyl, oxazolyl or thiazolyl; another aspect is pyrazolyl, imidazolyl, oxazolyl or thiazolyl; another aspect is pyrazolyl, imidazolyl, triazolyl or isoxazolyl; another aspect is pyrazolyl, oxazolyl or thiazolyl; another aspect is pyrazolyl, triazolyl or isoxazolyl; another aspect is pyrazolyl or thiazolyl; another aspect is pyrazolyl or triazolyl; another aspect is pyrazolyl; another aspect is imidazolyl; another aspect is oxazolyl; another aspect is thiazolyl; and another aspect is triazolyl. The "5-membered heteroarenediyl" is a divalent group obtained by removing any one hydrogen from "5-membered heteroaryl".
The "6-membered heteroaryl" is a heterocyclic group of a 6-membered ring containing one to three nitrogen atoms as ring-constituting atoms. An aspect of the "6-membered heteroaryl" is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl; another aspect is pyridyl or pyridazinyl; another aspect is pyridyl or pyrimidinyl; another aspect is pyridyl; and another aspect is pyrimidinyl. The "6-membered heteroarenediyl" is a divalent group obtained by removing any one hydrogen from "6-membered heteroaryl".
The "C3-6 cycloalkane" is cycloalkane having three to six carbon atoms, such as for example cyclopropane, cyclobutane, cyclopentane and cyclohexane. The "saturated hetero ring" is a saturated hydrocarbon ring containing a hetero atom selected from the group consisting of oxygen, sulfur and nitrogen as a ring-constituting atom. The sulfur atom as the ring-constituting atom of the saturated hetero ring may be oxidized. Thus, the "4-membered to 6-membered saturated hetero ring" is a saturated hydrocarbon ring of a 4-membered ring to 6-membered ring containing a hetero atom selected from the group consisting of oxygen, sulfur and nitrogen as a ring-constituting atom. The sulfur atom as the ring-constituting atom of the saturated hetero ring may be oxidized. An aspect of the "4-membered to 6-membered saturated hetero ring" is a 4-membered to 6-membered saturated hetero ring containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms. An aspect of the "4-membered to 6-membered saturated hetero ring" is oxetane, tetra hydrofuran, tetra hydropyran, azetidine, pyrrolidine, piperidine, oxazolidine, imidazolidine, piperazine, morpholine, thiomorpholine or dioxothiomorpholine.
The "spiro ring" is a multicyclic structure in which two cyclic structures are bound with one common spiro atom, which is a quaternary carbon.
The "ring having a cross-linked structure" is a cyclic structure having a divalent chain structure linked to two non-neighboring atoms of the ring-constituting atoms of one ring. An aspect of the "ring having a cross-linked structure" is diazabicyclo[2.2.2]octane, diazabicyclo[3.2.1]octane, diazabicyclo[3.1.1]heptane, diazabicyclo[2.2.1]heptane or azabicyclo[3.2.1]octane.
The "halogen" means F, Cl, Br and I. An aspect thereof is F, Cl or Br; another aspect is F or Cl; another aspect is F or Br; another aspect is F; another aspect is Cl; and another aspect is Br.
An aspect of the substituent acceptable in the "optionally substituted Ci-6 alkyl" and the "optionally substituted C1-3 alkyl" is F, OH, OCH3, N(CHs)2, optionally substituted C3-6 cycloalkyl, azabicyclo[3.3.0]octanyl or an optionally substituted 4-membered to 6- membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen. An aspect thereof is F, OH, OCH3, N(CHS)2, hydroxymethyl, methoxymethyl, difluoroethyl, optionally substituted cyclopropyl, tetrahydrofuranyl, optionally substituted tetrahydropyranyl, morpholinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl or azabicyclo[3.3.0]octanyl; another aspect is F, OH, OCH3, N(CHs)2, hydroxymethyl, methoxymethyl, optionally substituted cyclopropyl, tetrahydrofuranyl, optionally substituted tetra hydro pyranyl or optionally substituted pyrrolidinyl; another aspect is F, OH, OCH3, N(CH3)2, hydroxymethyl, methoxymethyl, cyclopropyl, (hydroxymethyl)cyclopropyl, (methoxymethyl)cyclopropyl, tetrahydrofuranyl, tetra hyd ropyra nyl , ( hyd roxy methy l)tetra hyd ropy ra ny I,
(methoxymethyl)tetrahydropyranyl, pyrrolidinyl or methylpyrrolidinyl; another aspect is F, OH, OCH3, (methoxymethyl)cyclopropyl, tetra hydrofuranyl or methylpyrrolidinyl; another aspect is F, OH or cyclopropyl; another aspect is F, OH or OCH3; another aspect is OH or OCH3; another aspect is F or OCH3; another aspect is OH; another aspect is F; and another aspect is OCH3.
An aspect of the substituent acceptable in the "optionally substituted 5-membered heteroaryl", the "optionally substituted 6-membered heteroaryl", the "optionally substituted 6-membered heteroarenediyl", the "optionally substituted C3-6 cycloalkyl", the "optionally substituted pyrazolyl", the "optionally substituted pyridyl", the "optionally substituted pyrimidinyl", the "optionally substituted phenylene" and the "optionally substituted cyclopropyl" is C1-3 alkyl optionally substituted with a group selected from the group consisting of OH and OCH3, -SO2CH3, halogen, OH, OCH3 or C3-6 cycloalkyl. An aspect thereof is C1-3 alkyl optionally substituted with a group selected from the group consisting of OH and OCH3; another aspect is C1-3 alkyl optionally substituted with OH; another aspect is C1-3 alkyl optionally substituted with OCH3; another aspect is C1-3 alkyl or halogen; another aspect is methyl, ethyl, methoxymethyl or F; and another aspect is methyl, ethyl or F.
An aspect of the substituent acceptable in the "optionally substituted 4-membered to 6-membered saturated heterocyclic group", the "optionally substituted pyrrolidinyl", the "optionally substituted piperidinyl", the "optionally substituted oxetanyl", the "optionally substituted tetrahydrofuranyl" and the "optionally substituted tetra hyd ropyra nyl" is C1-3 alkyl optionally substituted with a group selected from the group consisting of F, OH and OCH3, F, OH, OCH3, oxo or oxetanyl. An aspect thereof is F, OH or OCH3; another aspect is OH or methyl; another aspect is C1-3 alkyl optionally substituted with a group selected from the group consisting of F, OH and OCH3, F, oxo or oxetanyl; another aspect is C1-3 alkyl optionally substituted with a group selected from the group consisting of F, OH and OCH3 or oxo; another aspect is C1-3 alkyl optionally substituted with a group selected from the group consisting of F, OH and OCH3; another aspect is C1-3 alkyl optionally substituted with F; another aspect is C1-3 alkyl optionally substituted with OH; another aspect is C1-3 alkyl optionally substituted with OCH3; and another aspect is C1-3 alkyl. An aspect of the substituent acceptable in the "optionally substituted pyrrolidinediyl", the "optionally substituted piperidinediyl", the "optionally substituted piperazinediyl" and the "optionally substituted C1-3 alkylene" is F, OH, OCH3 or optionally substituted C1-3 alkyl. An aspect thereof is F, OH, OCH3, methyl, ethyl, hydroxymethyl or methoxymethyl; and another aspect is F, OH, OCH3 or methyl.
An aspect of the "C1-3 alkyl optionally substituted with F" is methyl optionally substituted with F or ethyl optionally substituted with F. Examples thereof include methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl and trifluoroethyl. An aspect thereof is methyl, ethyl, monofluoromethyl, difluoromethyl or difluoroethyl; another aspect is monofluoromethyl or difluoromethyl; another aspect is monofluoromethyl or difluoroethyl; another aspect is difluoromethyl or difluoroethyl; another aspect is monofluoromethyl; another aspect is difluoromethyl; another aspect is difluoroethyl; and another aspect is 2,2-difluoroethyl.
An aspect of the "C1-3 alkyl optionally substituted with OH" is methyl optionally substituted with one OH or ethyl optionally substituted with one or two OH. Examples thereof include methyl, ethyl, hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl and 1,2-di hydroxyethyl. An aspect thereof is methyl, ethyl or hydroxymethyl; another aspect is methyl or hydroxymethyl; another aspect is hydroxymethyl or hydroxyethyl; another aspect is hydroxymethyl; and another aspect is hydroxyethyl.
An aspect of the "C1-3 alkyl optionally substituted with OCH3" is methyl optionally substituted with one OCH3, ethyl optionally substituted with one or two OCH3 or propyl optionally substituted with one to three OCH3. Examples thereof include methyl, ethyl, methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 1,2-dimethoxyethyl and 2- methoxypropyl. An aspect thereof is methoxymethyl or methoxyethyl; another aspect is methoxymethyl; another aspect is methoxyethyl; and another aspect is 2- methoxypropyl.
An aspect of the "phenylene optionally substituted with F" is phenylene optionally substituted with one or two F. An aspect thereof is phenylene optionally substituted with one F; another aspect is phenylene or fluorophenylene; another aspect is phenylene; another aspect is 2-fluoro-l,4-phenylene; and another aspect is 3-fluoro- 1,4-phenylene.
The "mutant KRAS" is KRAS having a mutation, and examples thereof include G12V mutant KRAS, G12D mutant KRAS and G12C mutant KRAS. The "G12V mutation" represents a mutation in which the amino acid residue corresponding to the codon 12 in a wild type protein is converted from glycine to valine.
The "G12V mutant KRAS" represents KRAS having the "G12V mutation".
The "G12D mutation" represents a mutation in which the amino acid residue corresponding to the codon 12 in a wild type protein is converted from glycine to aspartic acid.
The "G12D mutant KRAS" represents KRAS having the "G12D mutation".
The "G12C mutation" represents a mutation in which the amino acid residue corresponding to the codon 12 in a wild type protein is converted from glycine to cysteine.
The "G12C mutant KRAS" represents KRAS having the "G12C mutation".
The "G12C mutation" represents a mutation in which the amino acid residue corresponding to the codon 12 in a wild type protein is converted from glycine to cysteine.
The "G12C mutant KRAS" represents KRAS having the "G12C mutation".
As used herein, "G12D Mutation" represents a mutation in which the amino acid residue corresponding to the codon 12 in a wild type protein is converted from glycine to aspartic acid.
As used herein, "G12D Mutant KRAS" represents KRAS having the "G12D mutation".
As used herein, "colorectal cancer" is a malignant tumor occurring in the large intestine, and "lung cancer" is a malignant tumor occurring in the lung.
In an embodiment, colorectal cancer and lung cancer is a metastatic, locally advanced, recurrent, and/or refractory cancer. In an embodiment, colorectal cancer and lung cancer is a cancer of a patient who has been untreated or who has a medical history. In an embodiment, colorectal cancer is colon cancer or rectal cancer. In an embodiment, lung cancer is small cell lung cancer or non-small cell lung cancer.
The "G12V mutant, G12D mutant and/or G12C mutant KRAS-positive colorectal cancer" is colorectal cancer that is positive for at least one of G12V mutant, G12D mutant and G12C mutant KRAS. Examples thereof include colorectal cancer having at least one of KRAS G12V mutation, G12D mutation and G12C mutation and colorectal cancer which has a high positive rate for at least one of G12V mutant, G12D mutant and G12C mutant KRAS.
The "G12V mutant, G12D mutant and/or G12C mutant KRAS-positive lung cancer" is lung cancer that is positive for at least one of G12V mutant, G12D mutant and G12C mutant KRAS. Examples thereof include lung cancer having at least one of KRAS G12V mutation, G12D mutation and G12C mutation and lung cancer which has a high positive rate for at least one of G12V mutant, G12D mutant and G12C mutant KRAS.
The "G12V mutant, G12D mutant and G12C mutant KRAS-positive colorectal cancer" is colorectal cancer that is positive for G12V mutant, G12D mutant and G12C mutant KRAS. Examples thereof include colorectal cancer having KRAS G12V mutation, G12D mutation and G12C mutation and colorectal cancer which has a high positive rate for G12V mutant, G12D mutant and G12C mutant KRAS.
The "G12V mutant, G12D mutant and G12C mutant KRAS-positive lung cancer" is lung cancer that is positive for G12V mutant, G12D mutant and G12C mutant KRAS. Examples thereof include lung cancer having at least one of KRAS G12V mutation, G12D mutation and G12C mutation and lung cancer which has a high positive rate for G12V mutant, G12D mutant and G12C mutant KRAS.
The "G12V mutant and G12D mutant KRAS-positive colorectal cancer" is colorectal cancer that is positive for G12V mutant and G12D mutant KRAS. Examples thereof include colorectal cancer having KRAS G12V mutation and G12D mutation and colorectal cancer which has a high positive rate for G12V mutant and G12D mutant KRAS.
The "G12V mutant and G12D mutant KRAS-positive lung cancer" is lung cancer that is positive for G12V mutant and G12D mutant KRAS. Examples thereof include lung cancer having KRAS G12V mutation and G12D mutation and lung cancer which has a high positive rate for G12V mutant and G12D mutant KRAS. The "G12V mutant KRAS-positive colorectal cancer" is colorectal cancer that is positive for G12V mutant KRAS. Examples thereof include colorectal cancer having KRAS G12V mutation and colorectal cancer which has a high positive rate for G12V mutant KRAS.
The "G12V mutant KRAS-positive lung cancer" is lung cancer that is positive for G12V mutant KRAS. Examples thereof include lung cancer having KRAS G12V mutation and lung cancer which has a high positive rate for G12V mutant KRAS.
The "G12D mutant KRAS-positive colorectal cancer" is colorectal cancer that is positive for G12D mutant KRAS. Examples thereof include colorectal cancer having KRAS G12D mutation and colorectal cancer which has a high positive rate for G12D mutant KRAS.
The "G12D mutant KRAS-positive lung cancer" is lung cancer that is positive for G12D mutant KRAS. Examples thereof include lung cancer having KRAS G12D mutation and lung cancer which has a high positive rate for G12D mutant KRAS.
The "G12C mutant KRAS-positive colorectal cancer" is colorectal cancer that is positive for G12C mutant KRAS. Examples thereof include colorectal cancer having KRAS G12C mutation and colorectal cancer which has a high positive rate for G12C mutant KRAS.
The "G12C mutant KRAS-positive lung cancer" is lung cancer that is positive for G12C mutant KRAS. Examples thereof include lung cancer having KRAS G12C mutation and lung cancer which has a high positive rate for G12C mutant KRAS.
Particular features of the compound of the formula (I) or a salt thereof, for use in the treatment of colorectal and/or lung cancer in accordance with the invention, (or contained in the pharmaceutical composition of the invention, or for use in the methods of treatment and/or in the manufacture of a medicament described herein)) that may be mentioned are described below.
(1-1) The compound of formula (I) or a salt thereof in which A is CRA or N, where RA is H or Ci-3 alkyl.
(1-2) The compound of formula (I) or a salt thereof in which A is CRA or N, where RA is H. (1-3) The compound of formula (I) or a salt thereof in which A is N.
(1-4) The compound of formula (I) or a salt thereof in which A is CH.
(2-1) The compound of formula (I) or a salt thereof in which X1 is -CH2- or -O-.
(2-2) The compound of formula (I) or a salt thereof in which X1 is -O-.
(3-1) The compound of formula (I) or a salt thereof in which R1 is naphthyl optionally substituted with OH or the formula (II) below,
Figure imgf000026_0001
where Rla is H, methyl, F or Cl, and Rlb is F, Cl, methyl or ethyl.
(3-2) The compound of formula (I) or a salt thereof in which R1 is the formula (II), where Rla is H, methyl, F or Cl, and Rlb is F, Cl, methyl or ethyl.
(3-3) The compound of formula (I) or a salt thereof in which R1 is the formula (II), where Rla is H, methyl, F or Cl, and Rlb is methyl.
(3-4) The compound of formula (I) or a salt thereof in which R1 is the formula (Il-a) below.
Figure imgf000026_0002
(4-1) The compound of formula (I) or a salt thereof in which R2 is H, halogen, C1-3 alkyl optionally substituted with a group selected from the group consisting of OH and OCH3, cyclopropyl or vinyl. (4-2) The compound of formula (I) or a salt thereof in which R2 is halogen, C1-3 alkyl optionally substituted with a group selected from the group consisting of OH and OCH3, cyclopropyl or vinyl.
(4-3) The compound of formula (I) or a salt thereof in which R2 is halogen, C1-3 alkyl, cyclopropyl or vinyl.
(4-4) The compound of formula (I) or a salt thereof in which R2 is cyclopropyl.
(5-1-1) The compound of formula (I) or a salt thereof in which R3 is a group selected from the group consisting of the formula (III), the formula (IV), the formula (V), the formula (VI), the formula (VII), the formula (VIII), the formula (IX), the formula (X), the formula (XI) and the formula (XXXV) below.
Figure imgf000027_0001
(5-1-2) The compound of formula (I) or a salt thereof in which R3 is a group selected from the group consisting of the formula (III), the formula (IV), the formula (V), the formula (VI), the formula (VII), the formula (VIII), the formula (IX), the formula (X) and the formula (XI) below.
Figure imgf000027_0002
(5-1-3) The compound of formula (I) or a salt thereof in which R3 is a group selected from the group consisting of the formula (III), the formula (IV), the formula (V), the formula (VUI-a) and the formula (X) below.
Figure imgf000028_0001
(5-1-4) The compound of formula (I) or a salt thereof in which R3 is a group selected from the group consisting of the formula (Ill-a), the formula (IV-a), the formula (V-a), the formula (VUI-a) and the formula (X) below.
Figure imgf000028_0002
(5-1-5) The compound of formula (I) or a salt thereof in which R3 is a group selected from the group consisting of the formula (Ill-a), the formula (IV-a) and the formula (V-a) below.
Figure imgf000028_0003
(5-2-1) The compound of formula (I) or a salt thereof in which R3a is - (CH2)pCHR3f-NRN 1RN2; -(CH2)PCHR3f-OR3g; a 5-membered to 6-membered saturated heterocyclic group which is optionally substituted with a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2 and -NRN1RN2 and which contains one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms; or C3-6 cycloalkyl optionally substituted with a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, -OR3g and -NRN 1RN2.
(5-2-2) The compound of formula (I) or a salt thereof in which R3a is - (CH2)pCHR3f-NRN 1RN2; -(CH2)PCHR3f-OR3g; pyrrolidinyl optionally substituted with C1-3 alkyl; piperidinyl optionally substituted with C1-3 alkyl; or C3-6 cycloalkyl optionally substituted with a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene- OR3g, C1-3 alkylene-NRN1RN2, -OR3g and -NRN 1RN2.
(5-2-3) The compound of formula (I) or a salt thereof in which R3a is -
(CH2)PCHR3f-NRN 1RN2 or -(CH2)PCHR3f-OR3g.
(5-2-4) The compound of formula (I) or a salt thereof in which R3a is -
(CH2)PCHR3f-NRN 1RN2.
(5-3-1) The compound of formula (I) or a salt thereof in which R3b is H or C1-3 alkyl.
(5-3-2) The compound of formula (I) or a salt thereof in which R3b is H or methyl.
(5-3-3) The compound of formula (I) or a salt thereof in which R3b is H.
(5-4-1) The compound of formula (I) or a salt thereof in which R3c and R3d are -
(CH2)PCHR3f-NRN 1RN2; -(CH2)PCHR3f-OR3g; a 4-membered to 6-membered saturated heterocyclic group which is optionally substituted with a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2 and -NRN1RN2 and which contains one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms; or C3-6 cycloalkyl optionally substituted with a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkyl-NRN 1RN2, -OR3g and -NRN 1RN2, with the proviso that X2 in the formula (IV) is -O-, -NH- or -N(C2-3 alkyl)- when R3c is -(CH2)PCHR3f-NRN1RN2.
(5-4-2) The compound of formula (I) or a salt thereof in which R3c is - (CH2)PCHR3f-NRN 1RN2; -(CH2)PCHR3f-OR3g; pyrrolidinyl optionally substituted with C1-3 alkyl; piperidinyl optionally substituted with C1-3 alkyl; or C3-6 cycloalkyl optionally substituted with a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene- OR3g, C1-3 alkyl-NRN 1RN2, -OR3g and -NRN1RN2, with the proviso that X2 in the formula (IV-a) is -O- or -NH- when R3c is -(CH2)PCHR3f-NRN1RN2.
(5-4-3) The compound of formula (I) or a salt thereof in which R3c is - (CH2)PCHR3f-NRN 1RN2; pyrrolidinyl optionally substituted with C1-3 alkyl; or C3-6 cycloalkyl optionally substituted with -NRN1RN2, and X2 in the formula (IV-a) is -O- or - NH-. (5-4-4) The compound of formula (I) or a salt thereof in which R3c is C3-6 cycloalkyl optionally substituted with -NRN1RN2.
(5-4-5) The compound of formula (I) or a salt thereof in which R3d is - (CH2)pCHR3f-NRN 1RN2 or a 4-membered to 6-membered saturated heterocyclic group which is optionally substituted with a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-NRN1RN2 and -NRN 1RN2 and which contains one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms.
(5-5-1) The compound of formula (I) or a salt thereof in which R3e is -O-C2-3 alkylene-NRN1RN2.
(5-6-1) The compound of formula (I) or a salt thereof in which R3f is H, F or Ci- 3 alkyl.
(5-6-2) The compound of formula (I) or a salt thereof in which R3f is H or C1-3 alkyl.
(5-6-3) The compound of formula (I) or a salt thereof in which R3f is H.
(5-7-1) The compound of formula (I) or a salt thereof in which R3g is H or C1-3 alkyl.
(5-7-2) The compound of formula (I) or a salt thereof in which R3g is H.
(5-8-1) The compound of formula (I) or a salt thereof in which R3h is optionally substituted 5-membered heteroaryl containing one to four hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen or optionally substituted 6- membered heteroaryl containing one to three nitrogen atoms.
(5-8-2) The compound of formula (I) or a salt thereof in which R3h is optionally substituted 6-membered heteroaryl containing one to three nitrogen atoms.
(5-9-1) The compound of formula (I) or a salt thereof in which R3i's, which are the same as or different from each other, are groups selected from the group consisting of H, OH, optionally substituted C1-3 alkyl, -O-optionally substituted C1-3 alkyl, -NH- optionally substituted C1-3 alkyl, -N-(optionally substituted C1-3 alkyl)z, halogen, -CN and oxo, or two R3' groups on a same carbon atom, together with the neighboring carbon atom, may form a ring selected from the group consisting of C3-6 cycloalkane and a 4- membered to 6-membered saturated hetero ring containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms to form a spiro ring as the compound of the formula (XXXV), where the spiro ring is optionally substituted with one or two groups selected from the group consisting of C1-3 alkyl, -O-(Ci-3 alkyl), OH, halogen and oxo, or
R3' groups on two neighboring carbon atoms, together with the two carbon atoms, may form a ring selected from the group consisting of C3-6 cycloalkane and a 4-membered to 6-membered saturated hetero ring containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms to form a condensed ring as the compound of the formula (XXXV), where the condensed ring is optionally substituted with one or two groups selected from the group consisting of C1-3 alkyl, -O-(Ci-3 alkyl), OH, halogen and oxo, or
R3' groups on two carbon atoms which are not neighboring, together with the two carbon atoms, may form a cross-linked structure composed of one or two carbon atoms, where the compound of the formula (XXXV) having the cross-linked structure is optionally substituted with one or two groups selected from the group consisting of C1-3 alkyl, -O-(Ci-3 alkyl), OH, halogen and oxo.
(5-10-1) The compound of formula (I) or a salt thereof in which RN1 and RN2, which are the same as or different from each other, are H or C1-3 alkyl, or
RN1 and RN2, together with the nitrogen atom to which they are attached, may form an optionally substituted 4-membered to 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, or
R3f and RN1, together with the carbon atom and the nitrogen atom to which they are attached, may form an optionally substituted 4-membered to 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms.
(5-10-2) The compound of formula (I) or a salt thereof in which RN1 and RN2, which are the same as or different from each other, are H or C1-3 alkyl, or
RN1 and RN2, together with the nitrogen atom to which they are attached, may form an optionally substituted 4-membered to 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms.
(5-10-3) The compound of formula (I) or a salt thereof in which RN1 and RN2, which are the same as or different from each other, are both C1-3 alkyl.
(5-10-4) The compound of formula (I) or a salt thereof in which RN1 is C1-3 alkyl, and RN2 is H.
(5-11-1) The compound of formula (I) or a salt thereof in which X2 is -O-, -NH- or -N(CI-3 alkyl)-.
(5-11-2) The compound of formula (I) or a salt thereof in which X2 is -O- or -NH- or -N(CH3)-.
(5-11-3) The compound of formula (I) or a salt thereof in which X2 is -O- or -NH-.
(5-11-4) The compound of formula (I) or a salt thereof in which X2 is -NH-.
(5-11-5) The compound of formula (I) or a salt thereof in which X2 is -O-.
(5-12-1) The compound of formula (I) or a salt thereof in which X3 is O or S.
(5-12-2) The compound of formula (I) or a salt thereof in which X3 is O.
(5-13-1) The compound of formula (I) or a salt thereof in which X4 is -CH2-, -CH2- CH2- or -O-CH2-.
(5-14-1) The compound of formula (I) or a salt thereof in which n is 1 or 2, and p is 1 or 2.
(5-14-2) The compound of formula (I) or a salt thereof in which p is 1 or 2.
(5-14-3) The compound of formula (I) or a salt thereof in which p is 1.
(5-15-1) The compound of formula (I) or a salt thereof in which q is an integer of
1 to 8. (6-1) The compound of formula (I) or a salt thereof in which R4 is Ci-6 alkyl optionally substituted with a group selected from the group consisting of F, OH, OCH3, R4a, cyclopropyl, N(R4a)z, pyrrolidinyl optionally substituted with R4a and tetra hydrofuranyl optionally substituted with R4a; piperidinyl optionally substituted with R4b; or tetra hydropyranyl optionally substituted with R4a, where R4a is C1-3 alkyl optionally substituted with F, and
R4b is C1-3 alkyl substituted with one to three F.
(6-2) The compound of formula (I) or a salt thereof in which R4 is C1-6 alkyl optionally substituted with a group selected from the group consisting of F, OH, OCH3, R4a, cyclopropyl, N(R4a)z, pyrrolidinyl optionally substituted with R4a and tetra hydrofuranyl; piperidinyl optionally substituted with R4b; or tetra hydro pyranyl, where R4a is C1-3 alkyl, and
R4b is C1-3 alkyl substituted with one to three F.
(6-3) The compound of formula (I) or a salt thereof in which R4 is C1-6 alkyl optionally substituted with a group selected from the group consisting of OCH3, R4a, N(R4a)z, pyrrolidinyl optionally substituted with R4a and tetra hydrofuranyl; piperidinyl optionally substituted with R4b; or tetrahydropyranyl, where R4a is C1-3 alkyl, and
R4b is C1-3 alkyl substituted with one to three F.
(6-4) The compound of formula (I) or a salt thereof in which R4 is C1-6 alkyl optionally substituted with a group selected from the group consisting of OCH3 and tetra hydrofuranyl; or tetra hydropyranyl.
(6-5) The compound of formula (I) or a salt thereof in which R4 is C1-6 alkyl optionally substituted with OCH3 or tetra hydropyranyl.
(6-6) The compound of formula (I) or a salt thereof in which R4 is C1-6 alkyl optionally substituted with OCH3.
(7-1) The compound of formula (I) or a salt thereof in which R5 is methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, C3-6 cycloalkylmethyl or C3-6 cycloalkyl.
(7-2) The compound of formula (I) or a salt thereof in which R5 is ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl or C3-6 cycloalkyl. (7-3) The compound of formula (I) or a salt thereof in which R5 is isopropyl or secbutyl.
(7-4) The compound of formula (I) or a salt thereof in which R5 is isopropyl.
(8-1) The compound of formula (I) or a salt thereof in which
R6a and R6b, which are the same as or different from each other, are H or Ci-6 alkyl optionally substituted with a group selected from the group consisting of F, OH, OCH3 and N(CH3)2, or
R6a and R6b, together with the carbon to which they are attached, may form optionally substituted C3-6 cycloalkane or an optionally substituted 4-membered to 6- membered saturated hetero ring containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms.
(8-2) The compound of formula (I) or a salt thereof in which
R6a and R6b, which are the same as or different from each other, are H or C1-6 alkyl optionally substituted with a group selected from the group consisting of F, OH, OCH3 and N(CH3)2, or
R6a and R6b, together with the carbon to which they are attached, may form optionally substituted C3-6 cycloalkane.
(8-3) The compound of formula (I) or a salt thereof in which R6a and R6b, which are the same as or different from each other, are H or C1-6 alkyl optionally substituted with a group selected from the group consisting of OH and N(CH3)2.
(8-4) The compound of formula (I) or a salt thereof in which
R6a is H, and R6b is C1-6 alkyl optionally substituted with OH.
(8-5) The compound of formula (I) or a salt thereof in which R6a is H, and R6b is hydroxymethyl.
(9-1) The compound of formula (I) or a salt thereof in which R7 is an optionally substituted 4-membered to 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, optionally substituted 5-membered heteroaryl containing one to four hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen or 6-membered heteroaryl containing one to three nitrogen atoms. (9-2) The compound of formula (I) or a salt thereof in which R7 is a group selected from the group consisting of the formula (XXIII), the formula (XXIV), the formula (XXV), the formula (XXVI), the formula (XXVII), the formula (XXVIII), the formula (XXIX), the formula (XXX), the formula (XXXI), the formula (XXXII) and the formula (XXXIII) below,
Figure imgf000035_0001
where R7a and R7b, which are the same as or different from each other, are H or Ci-3 alkyl optionally substituted with OH.
(9-3) The compound of formula (I) or a salt thereof in which R7 is a group selected from the group consisting of the formula (XXIII), the formula (XXIV), the formula (XXVI), the formula (XXVIII) and the formula (XXXIII) below,
Figure imgf000035_0002
where R7a and R7b, which are the same as or different from each other, are H or Ci-3 alkyl optionally substituted with OH.
(9-4) The compound of formula (I) or a salt thereof in which R7 is a group selected from the group consisting of the formula (XXIII), the formula (XXIV), the formula (XXVI), the formula (XXVIII) and the formula (XXXIII), where R7a and R7b, which are the same as or different from each other, are H or Ci-3 alkyl.
(9-5) The compound of formula (I) or a salt thereof in which R7 is a group selected from the group consisting of the formula (XXIII), the formula (XXIV) and the formula (XXVIII) below,
Figure imgf000036_0001
where R7a and R7b, which are the same as or different from each other, are H or Ci-3 alkyl.
(9-6) The compound of formula (I) or a salt thereof in which R7 is a group selected from the group consisting of the formula (XXIII-a), the formula (XXIV-a) and the formula (XXVIII-a) below.
Figure imgf000036_0002
(9-7) The compound of formula (I) or a salt thereof in which R7 is the formula (XXIII- a) below.
Figure imgf000036_0003
(9-8) The compound of formula (I) or a salt thereof in which R7 is the formula (XXVIII- a) below.
Figure imgf000036_0004
(XXVI I I-a)
(9-9) The compound of formula (I) or a salt thereof in which R7 is the formula (XXIV- a) below.
Figure imgf000036_0005
(10-1) The compound of formula (I) or a salt thereof in which W is optionally substituted phenylene or optionally substituted 6-membered heteroarenediyl containing one to three nitrogen atoms. (10-2) The compound of formula (I) or a salt thereof in which W is the formula (XXXIV) below,
Figure imgf000037_0001
where W1 is CH, CF, CO or CCH3, and
W2 is CH, CF, CO, CCH3 or N.
(10-3) The compound of formula (I) or a salt thereof in which W is the formula (XXXIV), where W1 is CH, and W2 is CH or N.
(10-4) The compound of formula (I) or a salt thereof in which W is the formula (XXXIV), where W1 and W2 are both CH.
(11-1) The compound of formula (I) or a salt thereof in which Y is phenylene optionally substituted with F or Cl or pyridinediyl.
(11-2) The compound of formula (I) or a salt thereof in which Y is phenylene optionally substituted with F or Cl.
(11-3) The compound of formula (I) or a salt thereof in which Y is phenylene.
(12-1) The compound of formula (I) or a salt thereof in which L is -(L1-L2-L3-L4)-, where L1, L2, L3 and L4, which are the same as or different from each other, are groups selected from the group consisting of a bond, -O-, -NRL1-, optionally substituted pyrrolidinediyl, optionally substituted piperidinediyl, optionally substituted piperazinediyl, optionally substituted C1-3 alkylene and C=O, where RL1 is H or C1-3 alkyl.
(12-2) The compound of formula (I) or a salt thereof in which L is a bond, C1-3 alkylene, C=O or a group selected from the group consisting of the formula (XIII), the formula (XIV), the formula (XV), the formula (XVI), the formula (XVII) and the formula (XVIII) below,
Figure imgf000038_0001
where RL1 is H or C1-3 alkyl,
RL2 and RL3, which are the same as or different from each other, are H, F, OH, OCH3 or optionally substituted C1-3 alkyl,
RL is CH or N, and m is 1 or 2.
(12-3) The compound of formula (I) or a salt thereof in which L is a bond, C=O or a group selected from the group consisting of the formula (XIII) and the formula (XIV) below,
Figure imgf000038_0002
where RL1 is H or C1-3 alkyl,
RL2 and RL3, which are the same as or different from each other, are H, F, OH, OCH3 or optionally substituted C1-3 alkyl, and m is 1 or 2.
(12-4) The compound of formula (I) or a salt thereof in which L is a bond, C=O or a group selected from the group consisting of the formula (XIII) and the formula (XIV), RL1 is C1-3 alkyl,
RL2 and RL3 are both H, and m is 1.
(12-5) The compound of formula (I) or a salt thereof in which L is a bond or C=O.
(12-6) The compound of formula (I) or a salt thereof in which L is a bond.
(12-7) The compound of formula (I) or a salt thereof in which L is C=O. (13-1) The compound of formula (I) or a salt thereof in which Z is NH or 5-membered heteroarenediyl containing one to four hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms.
(13-2) The compound of formula (I) or a salt thereof in which Z is NH or a group selected from the group consisting of the formula (XIX), the formula (XX), the formula (XXI) and the formula (XXII) below.
Figure imgf000039_0001
(13-3) The compound of formula (I) or a salt thereof in which Z is NH or a group selected from the group consisting of the formula (XIX-a), the formula (XX-a), the formula (XXI-a) and the formula (XXII-a) below.
Figure imgf000039_0002
(In the formulae, * represents bond to L.)
(13-4) The compound of formula (I) or a salt thereof in which Z is a group selected from the group consisting of the formula (XIX), the formula (XX), the formula (XXI) and the formula (XXII).
(13-5) The compound of formula (I) or a salt thereof in which Z is a group selected from the group consisting of the formula (XIX-a), the formula (XX-a), the formula (XXI- a) and the formula (XXII-a).
(In the formulae, * represents bond to L.)
(13-6) The compound of formula (I) or a salt thereof in which Z is the formula (XX) below.
Figure imgf000039_0003
(13-7) The compound of formula (I) or a salt thereof in which Z is the formula (XX-a) below.
Figure imgf000040_0001
(In the formula, * represents bond to L.)
(13-8) The compound of formula (I) or a salt thereof in which Z is NH.
(14-1) The compound of formula (I) or a salt thereof in which Y-L-Z is the formula (XII) below.
Figure imgf000040_0002
(14-2) The compound of formula (I) or a salt thereof in which Y-L-Z is the formula (XH-a) below.
Figure imgf000040_0003
(In the formula, O-CH2* represents bond to the carbon atom of O-CH2 which is attached to Y-L-Z.)
(15) The compound of formula (I) or a salt thereof which is a combination of any compatible two or more of the aspects described in (1-1) to (14-2) above.
Specific examples of the combination described in (15) above include the aspects below.
(16-1) The compound of the formula (I) or a salt thereof.
Figure imgf000040_0004
(In the formula,
A is CRA or N, where RA is H or C1-3 alkyl,
X1 is -CH2- or -O-,
R1 is naphthyl optionally substituted with OH or the formula (II) below,
Figure imgf000041_0001
where Rla is H, methyl, F or Cl, and
Rlb is F, Cl, methyl or ethyl,
R2 is H, halogen, C1-3 alkyl optionally substituted with a group selected from the group consisting of OH and OCH3, cyclopropyl or vinyl,
R3 is a group selected from the group consisting of the formula (III), the formula (IV), the formula (V), the formula (VI), the formula (VII), the formula (VIII), the formula (IX), the formula (X), the formula (XI) and the formula (XXXV) below,
Figure imgf000041_0002
where R3a is -(CH2)PCHR3f-NRN1RN2; -(CH2)PCHR3f-OR3g; a 4-membered to 6- membered saturated heterocyclic group which is optionally substituted with a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene- NRN1RN2 and -NRN 1RN2 and which contains one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms; or C3-6 cycloalkyl optionally substituted with a group selected from the group consisting of Ci-
3 alkyl, C1-3 alkylene-OR3g, C1-3 alkyl-NRN1RN2, -OR3g and -NRN 1RN2,
R3b is H or C1-3 alkyl,
R3c and R3d are -(CH2)PCHR3f-NRN1RN2; -(CH2)PCHR3f-OR3g; a 4-membered to 6- membered saturated heterocyclic group which is optionally substituted with a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene- NRN1RN2 and -NRN 1RN2 and which contains one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms; or C3-6 cycloalkyl optionally substituted with a group selected from the group consisting of C1- 3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, -OR3g and -NRN1RN2,
R3e is -O-C2-3 alkylene-NRN1RN2, R3f is H, F or C1-3 alkyl, R3g is H or C1-3 alkyl, R3h is optionally substituted 5-membered heteroaryl containing one to four hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen or optionally substituted 6-membered heteroaryl containing one to three nitrogen atoms, R3i groups, which are the same as or different from each other, are groups selected from the group consisting of H, OH, optionally substituted C1-3 alkyl, -O- optionally substituted C1-3 alkyl, -NH-optionally substituted C1-3 alkyl, -N-(optionally substituted C1-3 alkyl)2, halogen, -CN and oxo, or two R3i groups on a same carbon atom, together with the neighboring carbon atom, may form a ring selected from the group consisting of C3-6 cycloalkane and a 4- membered to 6-membered saturated hetero ring containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms to form a spiro ring as the compound of the formula (XXXV), where the spiro ring is optionally substituted with one or two groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen and oxo, or R3i groups on two neighboring carbon atoms, together with the two carbon atoms, may form a ring selected from the group consisting of C3-6 cycloalkane and a 4-membered to 6-membered saturated hetero ring containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms to form a condensed ring as the compound of the formula (XXXV), where the condensed ring is optionally substituted with one or two groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen and oxo, or R3i groups on two carbon atoms which are not neighboring, together with the two carbon atoms, may form a cross-linked structure composed of one or two carbon atoms, where the compound of the formula (XXXV) having the cross-linked structure is optionally substituted with one or two groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen and oxo, RN1 and RN2, which are the same as or different from each other, are H or C1-3 alkyl, or RN1 and RN2, together with the nitrogen atom to which they are attached, may form an optionally substituted 4-membered to 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, or R3f and RN1, together with the carbon atom and the nitrogen atom to which they are attached, may form an optionally substituted 4-membered to 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, X2 is -O-, -NH- or -N(C1-3 alkyl)-, X3 is O or S, X4 is -CH2-, -CH2-CH2- or -O-CH2-, n is 1 or 2, p is 1 or 2, and q is an integer of 1 to 8, with the proviso that X2 in the formula (IV) is -O-, -NH- or -N(C2-3 alkyl)- when R3c is -(CH2)pCHR3f-NRN1RN2, R4 is C1-6 alkyl optionally substituted with a group selected from the group consisting of F, OH, OCH3, R4a, cyclopropyl, N(R4a)2, pyrrolidinyl optionally substituted with R4a and tetrahydrofuranyl optionally substituted with R4a; piperidinyl optionally substituted with R4b; or tetrahydropyranyl optionally substituted with R4a, where R4a is C1-3 alkyl optionally substituted with F, and R4b is C1-3 alkyl substituted with one to three F, R5 is methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, C3-6 cycloalkylmethyl or C3-6 cycloalkyl, R6a and R6b, which are the same as or different from each other, are H or C1-6 alkyl optionally substituted with a group selected from the group consisting of F, OH, OCH3 and N(CH3)2, or R6a and R6b, together with the carbon to which they are attached, may form optionally substituted C3-6 cycloalkane or an optionally substituted 4-membered to 6- membered saturated hetero ring containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, R7 is an optionally substituted 4-membered to 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, optionally substituted 5-membered heteroaryl containing one to four hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen or 6-membered heteroaryl containing one to three nitrogen atoms, W is optionally substituted phenylene or optionally substituted 6-membered heteroarenediyl containing one to three nitrogen atoms, Y is phenylene optionally substituted with F or Cl or pyridinediyl, L is -(L1-L2-L3-L4)-, where L1, L2, L3 and L4, which are the same as or different from each other, are groups selected from the group consisting of a bond, -O-, -NRL1-, optionally substituted pyrrolidinediyl, optionally substituted piperidinediyl, optionally substituted piperazinediyl, optionally substituted C1-3 alkylene and C=O, where RL1 is H or C1-3 alkyl, and Z is NH or 5-membered heteroarenediyl containing one to four hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, or Y-L-Z is the formula (XII) below.)
Figure imgf000044_0001
(16-2) The compound of formula (I) described in (16-1) above or a salt thereof in which R3 is a group selected from the group consisting of the formula (III), the formula (IV), the formula (V), the formula (VI), the formula (VII), the formula (VIII), the formula (IX), the formula (X) and the formula (XI) below,
Figure imgf000044_0002
where R3a is -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; a 4-membered to 6- membered saturated heterocyclic group which is optionally substituted with a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene- NRN1RN2 and -NRN1RN2 and which contains one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms; or C3-6 cycloalkyl optionally substituted with a group selected from the group consisting of C1- 3 alkyl, C1-3 alkylene-OR3g, C1-3 alkyl-NRN1RN2, -OR3g and -NRN1RN2, R3b is H or C1-3 alkyl, R3c and R3d are -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; a 4-membered to 6- membered saturated heterocyclic group which is optionally substituted with a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene- NRN1RN2 and -NRN1RN2 and which contains one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms; or C3-6 cycloalkyl optionally substituted with a group selected from the group consisting of C1- 3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, -OR3g and -NRN1RN2, R3e is -O-C2-3 alkylene-NRN1RN2, R3f is H, F or C1-3 alkyl, R3g is H or C1-3 alkyl, R3h is optionally substituted 5-membered heteroaryl containing one to four hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen or optionally substituted 6-membered heteroaryl containing one to three nitrogen atoms, RN1 and RN2, which are the same as or different from each other, are H or C1-3 alkyl, or RN1 and RN2, together with the nitrogen atom to which they are attached, may form an optionally substituted 4-membered to 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, or R3f and RN1, together with the carbon atom and the nitrogen atom to which they are attached, may form an optionally substituted 4-membered to 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, X2 is -O-, -NH- or -N(C1-3 alkyl)-, X3 is O or S, n is 1 or 2, and p is 1 or 2, with the proviso that X2 in the formula (IV) is -O-, -NH- or -N(C2-3 alkyl)- when R3c is -(CH2)pCHR3f-NRN1RN2. (16-3) The compound of formula (I) described in (16-2) above or a salt thereof in which Y is phenylene optionally substituted with F or Cl or pyridinediyl, L is a bond, C1-3 alkylene, C=O or a group selected from the group consisting of the formula (XIII), the formula (XIV), the formula (XV), the formula (XVI), the formula (XVII) and the formula (XVIII) below,
Figure imgf000045_0001
where RL1 is H or C1-3 alkyl, RL2 and RL3, which are the same as or different from each other, are H, F, OH, OCH3 or optionally substituted C1-3 alkyl, 30 RL is CH or N, and m is 1 or 2, and Z is NH or a group selected from the group consisting of the formula (XIX), the formula (XX), the formula (XXI) and the formula (XXII) below,
Figure imgf000046_0001
(16-4) The compound of formula (I) described in (16-3) above or a salt thereof in which A is CRA or N, where RA is H, X1 is -O-, R6a and R6b, which are the same as or different from each other, are H or C1-6 alkyl optionally substituted with a group selected from the group consisting of F, OH, OCH3 and N(CH3)2, or R6a and R6b, together with the carbon to which they are attached, may form optionally substituted C3-6 cycloalkane, R7 is a group selected from the group consisting of the formula (XXIII), the formula (XXIV), the formula (XXV), the formula (XXVI), the formula (XXVII), the formula (XXVIII), the formula (XXIX), the formula (XXX), the formula (XXXI), the formula (XXXII) and the formula (XXXIII) below,
Figure imgf000046_0002
where R7a and R7b, which are the same as or different from each other, are H or C1-3 alkyl optionally substituted with OH, and W is the formula (XXXIV) below, 25
Figure imgf000046_0003
where W1 is CH, CF, CCl or CCH3, and W2 is CH, CF, CCl, CCH3 or N. (16-5) The compound of formula (I) described in (16-4) above or a salt thereof in which R1 is the formula (II) below,
Figure imgf000047_0001
where R1a is H, methyl, F or Cl, and R1b is F, Cl, methyl or ethyl, R2 is halogen, C1-3 alkyl optionally substituted with a group selected from the group consisting of OH and OCH3, cyclopropyl or vinyl, R3 is a group selected from the group consisting of the formula (III), the formula (IV), the formula (V), the formula (VIII-a) and the formula (X) below,
Figure imgf000047_0002
where R3a is -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; a 4-membered to 6- membered saturated heterocyclic group which is optionally substituted with a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene- NRN1RN2 and -NRN1RN2 and which contains one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms; or C3-6 cycloalkyl optionally substituted with a group selected from the group consisting of C1- 3 alkyl, C1-3 alkylene-OR3g, C1-3 alkyl-NRN1RN2, -OR3g and -NRN1RN2, R3b is H or methyl, R3c and R3d are -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; a 4-membered to 6- membered saturated heterocyclic group which is optionally substituted with a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene- NRN1RN2 and -NRN1RN2 and which contains one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms; or C3-6 cycloalkyl optionally substituted with a group selected from the group consisting of C1- 3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, -OR3g and -NRN1RN2, R3f is H, F or C1-3 alkyl, R3g is H or C1-3 alkyl, RN1 and RN2, which are the same as or different from each other, are H or C1-3 alkyl, or RN1 and RN2, together with the nitrogen atom to which they are attached, may form an optionally substituted 4-membered to 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, or R3f and RN1, together with the carbon atom and the nitrogen atom to which they are attached, may form an optionally substituted 4-membered to 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, X2 is -O-, -NH- or -N(C1-3 alkyl)-, X3 is O or S, n is 1 or 2, and p is 1 or 2, with the proviso that X2 in the formula (IV) is -O-, -NH- or -N(C2-3 alkyl)- when R3c is -(CH2)pCHR3f-NRN1RN2, Y is phenylene optionally substituted with F or Cl or pyridinediyl, L is a bond, C=O or a group selected from the group consisting of the formula (XIII) and the formula (XIV) below,
Figure imgf000048_0001
where RL1 is H or C1-3 alkyl, RL2 and RL3, which are the same as or different from each other, are H, F, OH, OCH3 or optionally substituted C1-3 alkyl, and m is 1 or 2, and Z is NH or a group selected from the group consisting of the formula (XIX), the formula (XX), the formula (XXI) and the formula (XXII) below,
Figure imgf000048_0002
(16-6) The compound of formula (I) described in (16-5) above or a salt thereof in which R3 is a group selected from the group consisting of the formula (III-a), the formula (IV-a), the formula (V-a), the formula (VIII-a) and the formula (X) below,
Figure imgf000049_0001
where R3a is -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; pyrrolidinyl optionally substituted with C1-3 alkyl; piperidinyl optionally substituted with C1-3 alkyl; or C3-6 cycloalkyl optionally substituted with a group selected from the group consisting of C1- 3 alkyl, C1-3 alkylene-OR3g, C1-3 alkyl-NRN1RN2, -OR3g and -NRN1RN2, R3b is H or methyl, R3c is -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; pyrrolidinyl optionally substituted with C1-3 alkyl; piperidinyl optionally substituted with C1-3 alkyl; or C3-6 cycloalkyl optionally substituted with a group selected from the group consisting of C1- 3 alkyl, C1-3 alkylene-OR3g, C1-3 alkyl-NRN1RN2, -OR3g and -NRN1RN2, R3f is H, F or C1-3 alkyl, R3g is H or C1-3 alkyl, RN1 and RN2, which are the same as or different from each other, are H or C1-3 alkyl, or RN1 and RN2, together with the nitrogen atom to which they are attached, may form an optionally substituted 4-membered to 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, or R3f and RN1, together with the carbon atom and the nitrogen atom to which they are attached, may form an optionally substituted 4-membered to 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, X2 is -O- or -NH- or -N(CH3)-, X3 is O or S, and p is 1 or 2, with the proviso that X2 in the formula (IV-a) is -O- or -NH- when R3c is - (CH2)pCHR3f-NRN1RN2, R4 is C1-6 alkyl optionally substituted with a group selected from the group consisting of F, OH, OCH3, R4a, cyclopropyl, N(R4a)2, pyrrolidinyl optionally substituted with R4a and tetrahydrofuranyl; piperidinyl optionally substituted with R4b; or tetrahydropyranyl, where R4a is C1-3 alkyl, and R4b is C1-3 alkyl substituted with one to three F, R7 is a group selected from the group consisting of the formula (XXIII), the formula (XXIV), the formula (XXVI), the formula (XXVIII) and the formula (XXXIII) below,
Figure imgf000050_0001
where R7a and R7b, which are the same as or different from each other, are H or C1-3 alkyl optionally substituted with OH, Y is phenylene optionally substituted with F or Cl, and Z is NH or a group selected from the group consisting of the formula (XIX), the formula (XX), the formula (XXI) and the formula (XXII) below.
Figure imgf000050_0002
(16-7) The compound of formula (I) described in (16-6) above or a salt thereof in which R1 is the formula (II-a) below,
Figure imgf000050_0003
R2 is cyclopropyl, R3 is a group selected from the group consisting of the formula (III-a), the formula (IV-a), the formula (V-a), the formula (VIII-a) and the formula (X) below,
Figure imgf000050_0004
where R3a is -(CH2)pCHR3f-NRN1RN2 or -(CH2)pCHR3f-OR3g, R3b is H, R3c is -(CH2)pCHR3f-NRN1RN2; pyrrolidinyl optionally substituted with C1-3 alkyl; or C3-6 cycloalkyl optionally substituted with -NRN1RN2, R3f is H, R3g is H, RN1 and RN2, which are the same as or different from each other, are H or C1-3 alkyl, or RN1 and RN2, together with the nitrogen atom to which they are attached, may form an optionally substituted 4-membered to 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, X2 is -O- or -NH-, X3 is O or S, and p is 1 or 2, R4 is C1-6 alkyl optionally substituted with a group selected from the group consisting of OCH3, R4a, N(R4a)2, pyrrolidinyl optionally substituted with R4a and tetrahydrofuranyl; piperidinyl optionally substituted with R4b; or tetrahydropyranyl, where R4a is C1-3 alkyl, and R4b is C1-3 alkyl substituted with one to three F, R5 is isopropyl or sec-butyl, R6a and R6b, which are the same as or different from each other, are H or C1-6 alkyl optionally substituted with a group selected from the group consisting of OH and N(CH3)2, R7 is a group selected from the group consisting of the formula (XXIII), the formula (XXIV), the formula (XXVI), the formula (XXVIII) and the formula (XXXIII) below,
Figure imgf000051_0001
where R7a and R7b, which are the same as or different from each other, are H or C1-3 alkyl, W is the formula (XXXIV) below,
Figure imgf000051_0002
where W1 is CH, and W2 is CH or N, Y is phenylene, and L is a bond or C=O. (16-8) The compound of formula (I) described in (16-7) above or a salt thereof in which R3 is a group selected from the group consisting of the formula (III-a), the formula (IV-a) and the formula (V-a) below,
Figure imgf000052_0001
where R3a is -(CH2)pCHR3f-NRN1RN2, R3b is H, R3c is C3-6 cycloalkyl optionally substituted with -NRN1RN2, R3f is H, RN1 and RN2, which are the same as or different from each other, are both C1-3 alkyl, X2 is -O- or -NH-, X3 is O, and p is 1, R4 is C1-6 alkyl optionally substituted with OCH3, R5 is isopropyl, R6a is H, R6b is C1-6 alkyl optionally substituted with OH, R7 is a group selected from the group consisting of the formula (XXIII), the formula (XXIV) and the formula (XXVIII) below,
Figure imgf000052_0002
where R7a and R7b, which are the same as or different from each other, are H or C1-3 alkyl, W is the formula (XXXIV) below,
Figure imgf000052_0003
where W1 and W2 are both CH, L is a bond, and Z is a group selected from the group consisting of the formula (XIX), the formula (XX), the formula (XXI) and the formula (XXII) below.
Figure imgf000052_0004
For the avoidance of doubt, the particular features defined in (1-1) to (15), including all combinations thereof, and particularly the combinations defined in (16-1) to (16-8) apply to all aspects of the invention. Accordingly, particular embodiments of the invention that may be mentioned, are listed below. A compound of formula (I), or a salt thereof, for use in the treatment of colorectal cancer and/or lung cancer, in particular, G12V mutant, G12D mutant and/or G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and/or G12C mutant KRAS-positive lung cancer (including G12V mutant, G12D mutant and G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and G12C mutant KRAS-positive lung cancer; G12V mutant and G12D mutant KRAS- positive colorectal cancer and/or G12V mutant and G12D mutant KRAS-positive lung cancer; G12V mutant KRAS-positive colorectal cancer and/or G12V mutant KRAS- positive lung cancer; G12D mutant KRAS-positive colorectal cancer and/or G12D mutant KRAS-positive lung cancer; and G12C mutant KRAS-positive colorectal cancer and/or G12C mutant KRAS-positive lung cancer), wherein the compound of formula (I), or salt thereof, is as defined in any one of (1-1) to (15) or (16-1) to (16-8). A pharmaceutical composition, in particular, a pharmaceutical composition for treating colorectal cancer and/or lung cancer, and more particularly, a pharmaceutical composition for treating G12V mutant, G12D mutant and/or G12C mutant KRAS- positive colorectal cancer and/or G12V mutant, G12D mutant and/or G12C mutant KRAS-positive lung cancer (including G12V mutant, G12D mutant and G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and G12C mutant KRAS-positive lung cancer; G12V mutant and G12D mutant KRAS-positive colorectal cancer and/or G12V mutant and G12D mutant KRAS-positive lung cancer; G12V mutant KRAS-positive colorectal cancer and/or G12V mutant KRAS-positive lung cancer; G12D mutant KRAS-positive colorectal cancer and/or G12D mutant KRAS- positive lung cancer; and G12C mutant KRAS-positive colorectal cancer and/or G12C mutant KRAS-positive lung cancer), comprising the compound of the formula (I) or a salt thereof, and one or more pharmaceutically acceptable excipients, wherein the compound of formula (I), or salt thereof, is as defined in any one of (1-1) to (15) or (16-1) to (16-8). The use of the compound of the formula (I), or salt thereof, as defined herein, for the manufacture of a pharmaceutical composition for treating colorectal cancer and/or lung cancer, in particular, G12V mutant, G12D mutant and/or G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and/or G12C mutant KRAS- positive lung cancer (including G12V mutant, G12D mutant and G12C mutant KRAS- positive colorectal cancer and/or G12V mutant, G12D mutant and G12C mutant KRAS- positive lung cancer; G12V mutant and G12D mutant KRAS-positive colorectal cancer and/or G12V mutant and G12D mutant KRAS-positive lung cancer; G12V mutant KRAS-positive colorectal cancer and/or G12V mutant KRAS-positive lung cancer; G12D mutant KRAS-positive colorectal cancer and/or G12D mutant KRAS-positive lung cancer; and G12C mutant KRAS-positive colorectal cancer and/or G12C mutant KRAS- positive lung cancer), wherein the compound of formula (I), or salt thereof, is as defined in any one of (1-1) to (15) or (16-1) to (16-8). The use of the compound of the formula (I), or a salt thereof, as defined herein, for treating colorectal cancer and/or lung cancer, in particular, G12V mutant, G12D mutant and/or G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and/or G12C mutant KRAS-positive lung cancer (including G12V mutant, G12D mutant and G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and G12C mutant KRAS-positive lung cancer; G12V mutant and G12D mutant KRAS-positive colorectal cancer and/or G12V mutant and G12D mutant KRAS-positive lung cancer; G12V mutant KRAS-positive colorectal cancer and/or G12V mutant KRAS- positive lung cancer; G12D mutant KRAS-positive colorectal cancer and/or G12D mutant KRAS-positive lung cancer; and G12C mutant KRAS-positive colorectal cancer and/or G12C mutant KRAS-positive lung cancer), wherein the compound of formula (I), or salt thereof, is as defined in any one of (1-1) to (15) or (16-1) to (16-8). A method for treating colorectal cancer and/or lung cancer, in particular, G12V mutant, G12D mutant and/or G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and/or G12C mutant KRAS-positive lung cancer (including G12V mutant, G12D mutant and G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and G12C mutant KRAS-positive lung cancer; G12V mutant and G12D mutant KRAS-positive colorectal cancer and/or G12V mutant and G12D mutant KRAS-positive lung cancer; G12V mutant KRAS-positive colorectal cancer and/or G12V mutant KRAS-positive lung cancer; G12D mutant KRAS-positive colorectal cancer and/or G12D mutant KRAS-positive lung cancer; and G12C mutant KRAS-positive colorectal cancer and/or G12C mutant KRAS-positive lung cancer), the method including administering an effective amount of the compound of the formula (I) or a salt thereof, as defined herein, to a subject in need thereof, , wherein the compound of formula (I), or salt thereof, is as defined in any one of (1-1) to (15) or (16-1) to (16-8). In further aspects, there is provided a compound of formula (I), or salt thereof as defined herein, for use as a G12V mutant, G12D mutant and/or G12C mutant KRAS protein degradation inducer and/or a G12V mutant, G12D mutant and/or G12C mutant KRAS inhibitor, wherein the compound of formula (I), or salt thereof, is as defined in any one of (1-1) to (15) or (16-1) to (16-8); a pharmaceutical composition comprising the compound of the formula (I), or a salt thereof, as defined herein, that is a G12V mutant, G12D mutant and/or G12C mutant KRAS protein degradation inducer and/or a G12V mutant, G12D mutant and/or G12C mutant KRAS inhibitor, wherein the compound of formula (I), or salt thereof, is as defined in any one of (1-1) to (15) or (16-1) to (16-8); the pharmaceutical composition comprising the compound of the formula (I) or a salt thereof for use as a G12V mutant, G12D mutant and/or G12C mutant KRAS protein degradation inducer and/or a G12V mutant, G12D mutant and/or G12C mutant KRAS inhibitor, wherein the compound of formula (I), or salt thereof, is as defined in any one of (1-1) to (15) or (16-1) to (16-8); and a pharmaceutical composition comprising a G12V mutant, G12D mutant and/or G12C mutant KRAS protein degradation inducer and/or a G12V mutant, G12D mutant and/or G12C mutant KRAS inhibitor containing the compound of the formula (I) or a salt thereof, wherein the compound of formula (I), or salt thereof, is as defined in any one of (1-1) to (15) or (16-1) to (16-8). Examples of specific compounds of formula (I) that may be used in the various aspects of the invention include the following compounds: (1s,3R)-3-(dimethylamino)cyclobutyl 3-({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-oxazol-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}amino)azetidine-1-carboxylate, (1s,3R)-3-(dimethylamino)cyclobutyl 3-({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- (1H-1,2,4-triazol-1-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}amino)azetidine-1-carboxylate, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1-{3- [(dimethylamino)methyl]azetidine-1-carbonyl}azetidin-3-yl)oxy]-7-(6-fluoro-5- methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-8- yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N- {(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1-{3- [(dimethylamino)methyl]azetidine-1-carbonyl}azetidin-3-yl)oxy]-7-(6-fluoro-5- methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-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-oxazol-5-yl)phenyl]ethyl}-L-prolinamide, (1s,3R)-3-(dimethylamino)cyclobutyl 3-({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-[(2S)-2- methoxypropoxy]quinazolin-4-yl}amino)azetidine-1-carboxylate, (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1-{[2- (dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-(6-fluoro-5-methyl-1H- indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-8-yl}oxy)methyl]phenyl}-1H- 1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4- triazol-1-yl)phenyl]ethyl}-L-prolinamide, (1s,3R)-3-(dimethylamino)cyclobutyl 3-({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- (1H-1,2,4-triazol-1-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]quinolin-4- yl}oxy)azetidine-1-carboxylate and (4R)-1-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(1-{3- [(dimethylamino)methyl]azetidine-1-carbonyl}azetidin-3-yl)oxy]-7-(6-fluoro-5- methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-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, or a salt thereof. Further examples of specific compounds of formula (I) that may be used in the various aspects of the invention include the following compounds: (1s,3R)-3-(dimethylamino)cyclobutyl 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-oxazol-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}amino)azetidine-1-carboxylate, (1s,3R)-3-(dimethylamino)cyclobutyl 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-(1H-1,2,4-triazol-1-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}amino)azetidine-1-carboxylate, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1-{3- [(dimethylamino)methyl]azetidine-1-carbonyl}azetidin-3-yl)oxy]-7-(6-fluoro-5- methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-8- yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N- {(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1-{3- [(dimethylamino)methyl]azetidine-1-carbonyl}azetidin-3-yl)oxy]-7-(6-fluoro-5- methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-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-oxazol-5-yl)phenyl]ethyl}-L-prolinamide, (1s,3R)-3-(dimethylamino)cyclobutyl 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-[(2S)-2- methoxypropoxy]quinazolin-4-yl}amino)azetidine-1-carboxylate, (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1-{[2- (dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-(6-fluoro-5-methyl-1H- indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-8-yl}oxy)methyl]phenyl}-1H- 1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4- triazol-1-yl)phenyl]ethyl}-L-prolinamide, (1s,3R)-3-(dimethylamino)cyclobutyl 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-(1H-1,2,4-triazol-1-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]quinolin-4-yl}oxy)azetidine-1-carboxylate and (4R)-1-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(1-{3- [(dimethylamino)methyl]azetidine-1-carbonyl}azetidin-3-yl)oxy]-7-(6-fluoro-5- methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-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, or a salt thereof. Yet further examples of specific compounds of formula (I) that may be used in the various aspects of the invention include the following compounds: (1s,3R)-3-(dimethylamino)cyclobutyl 3-({(7P)-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-oxazol-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}amino)azetidine-1-carboxylate, (1s,3R)-3-(dimethylamino)cyclobutyl 3-({(7P)-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-(1H-1,2,4-triazol-1-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}amino)azetidine-1-carboxylate, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1-{3- [(dimethylamino)methyl]azetidine-1-carbonyl}azetidin-3-yl)oxy]-7-(6-fluoro-5- methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-8- yl}oxy)methyl]phenyl}-1H-1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N- {(1R)-2-hydroxy-1-[4-(1H-1,2,4-triazol-1-yl)phenyl]ethyl}-L-prolinamide, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1-{3- [(dimethylamino)methyl]azetidine-1-carbonyl}azetidin-3-yl)oxy]-7-(6-fluoro-5- methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-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-oxazol-5-yl)phenyl]ethyl}-L-prolinamide, (1s,3R)-3-(dimethylamino)cyclobutyl 3-({(7P)-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-[(2S)-2- methoxypropoxy]quinazolin-4-yl}amino)azetidine-1-carboxylate, (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1-{[2- (dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-(6-fluoro-5-methyl-1H- indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-8-yl}oxy)methyl]phenyl}-1H- 1,2,3-triazol-1-yl)-3-methylbutanoyl]-4-hydroxy-N-{(1R)-2-hydroxy-1-[4-(1H-1,2,4- triazol-1-yl)phenyl]ethyl}-L-prolinamide, (1s,3R)-3-(dimethylamino)cyclobutyl 3-({(7P)-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-(1H-1,2,4-triazol-1-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]quinolin-4-yl}oxy)azetidine-1-carboxylate and (4R)-1-[(2S)-2-(4-{4-[({(7P)-6-cyclopropyl-4-[(1-{3- [(dimethylamino)methyl]azetidine-1-carbonyl}azetidin-3-yl)oxy]-7-(6-fluoro-5- methyl-1H-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-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, or a salt thereof. The compound of the formula (I) may have tautomers or geometrical isomers depending on the type of the substituent. In this specification, the compound of the formula (I) is sometimes described only as one of isomers, but the present invention includes isomers other than the above one and includes separated isomers or mixtures thereof. In addition, the compound of the formula (I) may have an asymmetric carbon atom or an axial chirality and may have diastereomers based on them. The present invention includes separated diastereomers of the compound of the formula (I) or mixtures thereof. Furthermore, the present invention also includes pharmaceutically acceptable prodrugs of the compound represented by the formula (I). A pharmaceutically acceptable prodrug is a compound having a group that can be converted into an amino group, a hydroxy group, a carboxyl group or the like by solvolysis or under physiological conditions. Examples of groups to form a prodrug include groups described in Prog. Med., 1985, 5, p.2157-2161 or in "Iyakuhin no Kaihatsu (development of pharmaceuticals)", Vol.7, Bunshi-sekkei (molecular design), Hirokawa Shoten, 1990, p.163-198. In addition, the salt of the compound of the formula (I) is a pharmaceutically acceptable salt of the compound of the formula (I) and may be an acid addition salt or a salt formed with a base depending on the type of the substituent. Examples thereof include salts shown in P. Heinrich Stahl, Handbook of Pharmaceutical Salts Properties, Selection, and Use, Wiley-VCH, 2008. Specific examples include an acid addition salt with an inorganic acid, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid, or with an organic acid, 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, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid and glutamic acid, a salt with an inorganic metal, such as sodium, potassium, magnesium, calcium and aluminum, a salt with an organic base, such as methylamine, ethylamine and ethanolamine, a salt with various amino acids and amino acid derivatives, such as acetylleucine, lysine and ornithine, an ammonium salt and the like. Furthermore, the present invention also includes various hydrates, solvates and crystal polymorphism substances of the compound of the formula (I) and a salt thereof. The present invention also includes all the compounds of the formula (I) or salts thereof which are pharmaceutically acceptable and labeled with one or more radioactive or nonradioactive isotopes. Examples of preferable isotopes used for isotope labeling of the compound of the present invention include isotopes of hydrogen (2H, 3H and the like), carbon (11C, 13C, 14C and the like), nitrogen (13N, 15N and the like), oxygen (15O, 17O, 18O and the like), fluorine (18F and the like), chlorine (36Cl and the like) and iodine (123I, 125I and the like) and sulfur (35S and the like). The isotopically labeled compound of the invention of the present application can be used for studies such as histological distribution study of drugs and/or substrates and the like. For example, a radioisotope such as tritium (3H) and carbon-14 (14C) can be used for the purpose due to easiness of labeling and convenience of detection. Replacement with a heavier isotope, for example replacement of hydrogen with deuterium (2H), is sometimes therapeutically advantageous because metabolic stability improves (for example, increased in vivo half-life, decreased required dose and declined drug interaction). Replacement with a positron-emitting isotope (11C, 18F, 15O, 13N or the like) can be used for positron emission tomography (PET) for testing the substrate acceptor occupancy. The isotopically labeled compound of the present invention can be generally produced by a conventional method known to a person skilled in the art or by a production method similar to those in the Examples or the Production Examples or the like using an appropriate isotopically labeled reagent instead of an unlabeled reagent. Preparation of the compounds of the invention The compound of the formula (I) and a salt thereof can be produced by applying various known synthetic methods using characteristics based on the basic structure or the type of substituent thereof. Here, depending on the type of functional group, it is sometimes effective as a production technique to substitute the functional group with an appropriate protective group (a group that can be easily converted to the functional group) in the process from a raw material to an intermediate. Examples of the protective group include protective groups described in P. G. M. Wuts and T. W. Greene, "Greene's Protective Groups in Organic Synthesis", 5th edition, John Wiley & Sons Inc., 2014 and the like, and a group appropriately selected from the protective groups is used depending on the reaction conditions. In such a method, a reaction is carried out with the protective group introduced, and then the protective group is removed, as required, whereby a desired compound can be obtained. In addition, a prodrug of the compound of the formula (I) can be produced by introducing a special group in a process from a raw material to an intermediate as for the above protective group or by further carrying out a reaction using the compound of the formula (I) obtained. This reaction can be carried out by applying a method known to a person skilled in the art, such as common esterification, amidation and dehydration. Typical methods for producing the compound of the formula (I) will be explained below. The production methods can also be carried out referring to a reference attached to the explanation. Note that the production method of the present invention is not limited to the examples described below. In this specification, the following abbreviations are sometimes used. DMF: N,N-dimethylformamide, DMAc: N,N-dimethylacetamide, THF: tetrahydrofuran, MeCN: acetonitrile, MeOH: methanol, EtOH: ethanol, iPrOH: isopropylalcohol, tBuOH: tert-butanol, DOX: 1,4-dioxane, DMSO: dimethyl sulfoxide, TFA: trifluoroacetic acid, TEA: triethylamine, DIPEA: N,N-diisopropylethylamine, tBuOK : potassium tert-butoxide, PdChCdppf) -CHzCIz : [l,l'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane adduct,
Pd/C: palladium carbon,
PyBOP: (benzotriazol- l-yloxy)tripyrrolidinophosphonium hexafluorophosphate,
TBAF: tetra-n-butylammonium fluoride,
DABCO: l,4-diazabicyclo[2.2.2]octane,
CDI: l,l'-carbonyldiimidazole,
HATU: O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate,
Tr: trityl.
Figure imgf000062_0001
(In the formula, R1A and R3A represent divalent groups in which H has been removed from a functional group of R1 or R3 to which a protective group can be introduced. PG1 and PG2 represent protective groups. In some cases, one of the protective groups is absent. The same applies below.)
The compound of the formula (I) can be obtained by subjecting a compound (1) to a deprotection reaction. Furthermore, the compound can also be sometimes obtained by subjecting NH2 contained in R3 to an alkylation reaction after subjecting to a deprotection reaction. Examples of the protective groups shown here include a tertbutoxycarbonyl group, a triphenylmethyl group, a tetrahydro-2H-pyran-2-yl group, a methoxymethyl group, a dimethylmethanediyl group, a tert-butylsulfinyl group and the like.
In the deprotection reaction, the compound is stirred from under cooling to under reflux with heat generally for 0.1 hours to five days. Examples of the solvent used here include, but are not particularly limited to, an alcohol, such as MeOH, EtOH and iPrOH, a halogenated hydrocarbon, such as dichloromethane, 1,2-dichloroethane and chloroform, an ether, such as diethyl ether, THF, DOX and dimethoxyethane, DMF, DMSO, MeCN or water and a mixture thereof. Examples of the deprotection reagent include, but are not particularly limited to, an acid, such as hydrogen chloride (DOX solution), trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid and phosphoric acid.
By selecting a protective group, the deprotection can be performed by a catalytic hydrogenation reaction. Examples of the protective group include a benzyl group, a p-methoxybenzyl group, a benzyloxycarbonyl group and the like. The deprotection can also be performed using a fluoride ion source such as tetra-n-butylammonium fluoride. Examples of the protective group include a tert-butyl (d imethyl)silyl group, a (trimethylsilyl)ethoxymethyl group and the like. Furthermore, examples of the protective group which can be deprotected under basic conditions include an acetyl group, a trifluoroacetyl group, a benzoyl group and the like. Moreover, protective groups which can be deprotected under different deprotection conditions can be selected for PG1 and PG2, and the deprotection can be performed stepwise.
The alkylation reaction is performed using formaldehyde or an alkyl having a formyl group, by stirring in the presence of a reductant, in a solvent inactive for the reaction, at -45°C to under reflux with heat, preferably at 0°C to at room temperature, generally for 0.1 hours to five days. Examples of the solvent used here include, but are not particularly limited to, an alcohol, such as methanol and ethanol, an ether, such as diethyl ether, tetra hydrofuran (THF), dioxane and dimethoxyethane, a halogenated hydrocarbon, such as dichloromethane, 1,2-dichloroethane and chloroform and a mixture thereof. The reductant is sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride or the like. Performing the reaction in the presence of a dehydrator such as molecular sieves or an acid such as acetic acid, hydrochloric acid and titanium(IV) isopropoxide complex is sometimes preferable.
For example, the following can be referred as a reference.
P. G. M. Wuts and T. W. Greene, "Greene's Protective Groups in Organic Synthesis", 5th edition, John Wiley & Sons Inc., 2014
A. R. Katritzky and R. J. K. Taylor, "Comprehensive Organic Functional Group Transformations II", vol. 2, Elsevier Pergamon, 2005
Note that when the compound (1) as a raw material has an axial chirality, a stereoisomer which is obtained by once separating the compound (1) may be used for this reaction. By subjecting the compound of the formula (I), for example, to the following operation as a salt formation reaction, the hydrochloride of the compound of the formula (I) can be obtained.
The compound of the formula (I) which is believed to form a salt with hydrochloric acid from the characteristics of the chemical structure is dissolved in CH2CI2 and MeOH and stirred under ice cooling for 30 minutes after adding hydrogen chloride (4M DOX solution, 10 equivalents) under ice cooling. The reaction mixture is concentrated under reduced pressure, and diethyl ether is added to the resulting residue. The produced solid is taken by filtration and is dried under reduced pressure, thus obtaining the hydrochloride of the compound of the formula (I).
By subjecting the hydrochloride of the compound of the formula (I), for example, to the following operation as a desalting reaction, the compound of the formula (I) can be obtained, but the method is not limited to this method.
The hydrochloride of the compound of the formula (I) is purified by ODS column chromatography (MeCN/0.1% aqueous formic acid solution), and a fraction containing the target substance is collected and is made basic with saturated aqueous sodium hydrogen carbonate solution. Then the solution is subjected to extraction with CHCh/MeOH (5/1). The combined organic layer is dried over anhydrous sodium sulfate, and the solution is concentrated under reduced pressure. The resulting solid is washed with diethyl ether and dried under reduced pressure, thus obtaining the compound of the formula (I).
Figure imgf000064_0001
This production method is a first method for producing a compound (1)-1 included in the raw material compound (1).
First Step This step is a method for producing the compound ( 1)- 1 by a cycloaddition reaction of a compound (2) and a compound (3).
In this reaction, the compound (2) and the compound (3) are used in an equal amount or with one compound thereof in an excess amount, and the mixture of the compounds is stirred preferably in the presence of a copper salt, further preferably in the presence of a copper salt and a reductant, in a solvent inactive for the reaction or with no solvent, from under cooling to under reflux with heat, preferably at 0°C to 100°C, generally for 0.1 hours to five days. Examples of the solvent used here include, but are not particularly limited to, a halogenated hydrocarbon, such as dichloromethane, 1,2- dichloroethane and chloroform, an aromatic hydrocarbon, such as benzene, toluene and xylene, an ether, such as diethyl ether, THF, DOX and 1,2-dimethoxyethane, DMF, DMSO, ethyl acetate, MeCN, tBuOH, water and a mixture thereof. The copper salt is Cui, CuSO4, copper(I) trifluoromethanesulfonate (CuOTf) or the like. The reductant is sodium ascorbate or the like. Performing the reaction in the presence of TEA, DIPEA, N-methylmorpholine (NMM), 2,6-lutidine, tris[(l-benzyl-lH-l,2,3-triazol-4- yl)methyl]amine (TBTA) or the like is sometimes advantageous for smoothly promoting the reaction.
References
Angew. Chem. Int. Ed. 2002, 41, p.2596-2599.
Note that a compound obtained by subjecting PG2 of the compound (2) first to a deprotection reaction may be used for this reaction.
Raw Material Synthesis 2
Figure imgf000066_0001
(In the formulae, R represents a C1-3 alkyl group. The same applies below.)
This production method is a second method for producing the compound ( 1)- 1 included in the raw material compound (1).
First Step
This step is a method for producing a compound (5) by a cycloaddition reaction of the compound (2) and a compound (4).
The reaction conditions are the same as in the first step of the Raw Material Synthesis 1.
Second Step
This step is a method for producing a compound (6) by hydrolysis of the compound (5).
This reaction is performed by stirring the compound (5) from under cooling to under reflux with heat generally for 0.1 hours to five days. Examples of the solvent used here include, but are not particularly limited to, an alcohol, acetone, DMF, THF and the like. In addition, a mixed solvent of the above solvent and water is sometimes suitable for the reaction. Examples of the hydrolysis reagent include, but are not particularly limited to, an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, trimethyltin hydroxide and the like. For example, the following can be referred as a reference about this reaction.
The Chemical Society of Japan, "Jikken Kagaku Koza (lectures on experimental chemistry) (5th edition)", Vol. 16 (2005) (Maruzen)
Angew. Chem. Int. Ed. 2005, 44, p.1378-1382.
Third Step
This step is a method for producing the compound (1)-1 by an amidation reaction of the compound (6) and a compound (7).
In this reaction, the compound (6) and the compound (7) are used in an equal amount or with one compound thereof in an excess amount, and the mixture of the compounds is stirred in the presence of a condensing agent, in a solvent inactive for the reaction, from under cooling to under heating, preferably at -20°C to 60°C, generally for 0.1 hours to five days. Examples of the solvent include, but are not particularly limited to, an aromatic hydrocarbon, such as toluene, an ether, such as THF and DOX, a halogenated hydrocarbon, such as dichloromethane, an alcohol, DMF, DMSO, ethyl acetate, MeCN and a mixture thereof. Examples of the condensing agent include (benzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), O-(7- azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide or the hydrochloride thereof, N,N'- dicyclohexylcarbodiimide (DCC), l,l'-carbonyldiimidazole (CDI), diphenylphosphoryl azide (DPPA) and the like. Use of an additive (for example, 1-hydroxybenzotriazole) is sometimes preferred for the reaction. Performing the reaction in the presence of an organic base, such as TEA, DIPEA and NMM, or an inorganic base, such as potassium carbonate, sodium carbonate and potassium hydroxide, is sometimes advantageous for smoothly promoting the reaction.
Alternatively, a method in which the compound (6) is converted into a reactive derivative, which is then subjected to an acylation reaction, can be used. Examples of the reactive derivative of a carboxylic acid include an acid halogenation product obtained by a reaction with a halogenating agent, such as phosphorus oxychloride and thionyl chloride, a mixed acid anhydride obtained by a reaction with isobutyl chloroformate or the like, an active ester obtained by condensation with 1- hydroxybenzotriazole or the like and the like. The reaction of such a reactive derivative and the compound (7) can be performed in a solvent inactive for the reaction, such as a halogenated hydrocarbon, an aromatic hydrocarbon and an ether, from under cooling to under heating, preferably at -20°C to 120°C. References
S. R. Sandler and W. Karo, "Organic Functional Group Preparations", 2nd edition, Vol. 1, Academic Press Inc., 1991
The Chemical Society of Japan, "Jikken Kagaku Koza (lectures on experimental chemistry (5th edition)", Vol. 16 (2005) (Maruzen)
Figure imgf000068_0001
(In the formulae, R3B represents NR3aaR3bb, OR3cc or R3dd, and PG1A and PG3 represent protective groups. R3B represents a divalent group in which H has been removed from a functional group to which a protective group can be introduced and from a functional group to which a carbonyl group or a carboxyl group can be introduced in any of NR3aR3b, OR3c and R3d. R1 may have PG2. The same applies below.)
This production method is a second method for producing a compound (l)-2 included in the raw material compound (1).
First Step This step is a method for producing a compound (9) by a cycloaddition reaction of a compound (8) and the compound (3).
The reaction conditions are the same as in the first step of the Raw Material Synthesis 1.
Second Step
This step is a method for producing a compound (10) by subjecting the compound (9) to a deprotection reaction.
The reaction conditions are the same as in the deprotection reaction of the Production Method 1.
Third Step
This step is a method for producing the compound (l)-2 by adding a compound (11) after a reaction of the compound (10) and a carbonylation reagent or a method for producing the compound (l)-2 by an amidation reaction of the compound (10) and a compound (12).
This step is performed by reacting the compound (10) with a carbonylation reagent in an equal amount or an excess amount in a solvent inactive for the reaction, from under cooling to under heating, preferably at -20°C to 80°C, generally for 0.1 hours to around a day. Subsequently, the compound (11) in an equal amount or an excess amount is added to the obtained reaction mixture, and this mixture is reacted from under cooling to under heating, preferably at -20°C to 80°C, for 0.1 hours to around a day. Examples of the carbonylation reagent include l,l'-carbonyldiimidazole, 4-nitrophenyl chloroformate, diphosgene, triphosgene, phenyl chloroformate and the like. Examples of the solvent used here include, but are not particularly limited to, a halogenated hydrocarbon, such as dichloromethane, 1,2-dichloroethane and chloroform, an aromatic hydrocarbon, such as benzene, toluene and xylene, an ether, such as diethyl ether, tetra hydrofuran, dioxane and dimethoxyethane, N,N-dimethylformamide, dimethylsulfoxide, ethyl acetate, acetonitrile or a mixture thereof. Performing the reaction in the presence of a base, such as triethylamine is sometimes advantageous for smoothly promoting the reaction.
The reaction conditions of the amidation reaction of the compound (10) and the compound (12) are the same as in the third step of the Raw Material Synthesis 2. Reference
S. R. Sandler and W. Karo, "Organic Functional Group Preparations", 2nd edition,
Vol. 2, Academic Press Inc., 1991
Raw Material Synthesis 4
Figure imgf000070_0001
Figure imgf000071_0001
(In the formulae, PG4 and PG5 represent protective groups. RLG represents a C1-12 alkyl group, and LG1 represents a leaving group. BLG represents a boronic acid group, a boronic acid group protected with a protective group of boronic acid, such as a boronic acid pinacol ester group, or a trifluoroboric acid salt group (sometimes referred to as a boronic acid group or the like below). Examples of the leaving group shown here include Cl, Br, a methanesulfonyloxy group, a p-toluenesulfonyloxy group and the like.)
This production method is a method for producing a compound (2)-l included in the raw material compound (2).
First Step
This step is a method for producing a compound (14) by hydrolysis of a compound (13).
This reaction is performed by stirring the compound (13) from under cooling to under reflux with heat, generally for 0.1 hours to five days. Examples of the solvent used here include, but are not particularly limited to, an alcohol, acetone, DMF, THF and the like. In addition, a mixed solvent of the above solvent and water is sometimes suitable for the reaction. Examples of the hydrolysis reagent include, but are not particularly limited to, an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution and the like.
For example, the following can be referred as a reference about this reaction.
The Chemical Society of Japan, "Jikken Kagaku Koza (lectures on experimental chemistry (5th edition)", Vol. 16 (2005) (Maruzen)
Angew. Chem. Int. Ed. 2005, 44, p.1378-1382. Second Step
This step is a method for producing a compound (15) by protecting the hydroxy group of the compound (14) with a protective group.
When the group is protected with a tert-butyl group as an example, this reaction is performed by stirring the compound (14) from under cooling to under reflux with heat, generally for 0.1 hours to five days. Examples of the solvent used here include, but are not particularly limited to, an ether, such as THF and DOX, a halogenated hydrocarbon, such as dichloromethane, tBuOH, DMF and the like. Examples of the tert-butyl protective reagent include, but are not particularly limited to, isobutene, 2- tert-butyl-l,3-diisopropylisourea and the like.
Moreover, the compound (15) can be produced by a dehydration condensation reaction of the compound (14) and tBuOH.
For example, the following can be referred as a reference about this reaction.
P. G. M. Wuts and T. W. Greene, "Greene's Protective Groups in Organic Synthesis", 5th edition, John Wiley & Sons Inc., 2014
Org. Lett., 2012, 14, 17, p.4678-4681
Third Step
This step is a method for producing a compound (16) by an ipso substitution reaction of the compound (15) and RLG-SH.
Examples of the RLG-SH used here include C1-12 alkylthiols, for example, ethanethiol and dodecanethiol. In this reaction, the compound (15) and the RLG-SH are used in an equal amount or with one compound thereof in an excess amount, and the mixture of the compounds is stirred in a solvent inactive for the reaction or with no solvent, from under cooling to under reflux with heat, preferably at 0°C to 80°C, generally for 0.1 hours to five days. Examples of the solvent used here include, but are not particularly limited to, a halogenated hydrocarbon, such as dichloromethane, 1,2-dichloroethane and chloroform, an aromatic hydrocarbon, such as benzene, toluene and xylene, an ether, such as diethyl ether, THF, DOX and 1,2-dimethoxyethane, DMF, DMAc, DMSO, ethyl acetate, MeCN and a mixture thereof. Performing the reaction in the presence of an organic base, such as TEA, DIPEA, N-methylmorpholine (NMM), 1,4- diazabicyclo[2.2.2]octane (DABCO) and tBuOK, or an inorganic base, such as sodium hydride, potassium carbonate, sodium carbonate and cesium carbonate, is sometimes advantageous for smoothly promoting the reaction.
Fourth Step
This step is a method for producing a compound (17) by an ipso substitution reaction of the compound (16) and PG5-OH. Examples of the PG5-OH used here include benzyl alcohol, p-methoxybenzyl alcohol and 1-phenylethanol.
The reaction conditions are the same as in the third step of the Raw Material Synthesis 4.
Fifth Step
This step is a method for producing a compound (18) by a Suzuki-Miyaura coupling reaction of the compound (17) and a boronic acid derivative composed of an R2-boronic acid group or the like.
Examples of the boronic acid group or the like used here include, but are not particularly limited to, a boronic acid group, a boronic acid ester group, a boronic acid pinacol ester group, a triol borate salt group and a trifluoroboric acid salt group.
In this reaction, the compound (17) and the boronic acid derivative composed of an R2-boronic acid group or the like are used in an equal amount or with one compound thereof in an excess amount, and the mixture of the compounds is stirred in a solvent inactive for the reaction, in the presence of a base and a palladium catalyst, from at room temperature to under reflux with heat, preferably at 20°C to 140°C, generally for 0.1 hours to five days. Examples of the solvent used here include, but are not particularly limited to, a halogenated hydrocarbon, such as dichloromethane, 1,2- dichloroethane and chloroform, an aromatic hydrocarbon, such as benzene, toluene and xylene, an ether, such as diethyl ether, THF, DOX and 1,2-dimethoxyethane, an alcohol, such as MeOH, EtOH, isopropyl alcohol, butanol and amyl alcohol, DMF, DMSO, MeCN, l,3-dimethylimidazolidin-2-one, water and a mixture thereof. The base is an inorganic base, such as tripotassium phosphate, sodium carbonate, potassium carbonate, sodium hydroxide and barium hydroxide. The palladium catalyst is tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, [l,l'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct, (lE,4E)-l,5-diphenylpenta-l,4-dien-3-one/palladium (3:2) and (2-dicyclohexylphosphino-2',6'-diisopropoxy-l,l'-biphenyl)[2-(2'-amino-l,l'- biphenyl)]palladium(II) methanesulfonate, palladium(II) acetate or the like. Performing the reaction in the presence of a ligand, such as dicyclohexyl(2',6'- dimethoxybiphenyl-2-yl)phosphine, dicyclohexyl(2',6'-diisopropoxy-[l,l'-biphenyl]-2- yl)phosphine and l,l'-bis(diphenylphosphino)ferrocene, is sometimes advantageous for smoothly promoting the reaction. In addition, heating the mixture by microwave irradiation is sometimes advantageous for smoothly promoting the reaction.
References
J. Am. Chem. Soc., 2005, 127, p.4685-4696
Org. Lett. 2011, 13, p.3948-3951
Org. Lett. 2012, 14, p.1278-1281
The compound (18) (R2 is hydrogen here) can be produced by a dehalogenation reaction of the compound (17) using a Pd catalyst and a reductant.
Reference]
J. Org. Chem., 1977, 42, p.3491-3494 Tetrahedron Letters 2013, 54, 5207-5210
Sixth Step
This step is a method for producing a compound (20) by a Suzuki-Miyaura coupling reaction of the compound (18) and a compound (19).
The reaction conditions are the same as in the fifth step of the Raw Material Synthesis 4.
When the compound (18) has an axial chirality, the compound (18) is obtained as a mixture of stereoisomers, and each stereoisomer can be isolated by separation using a common separation operation, for example, ODS column chromatography or silica gel column chromatography.
Seventh Step
This step is a method for producing a compound (21) by an oxidation reaction of the compound (20). In this reaction, a compound (22) is treated with an oxidant in an equal amount or an excess amount in a solvent inactive for the reaction, from under cooling to under heating, preferably at -20°C to 80°C, generally for 0.1 hours to three days. In this reaction, oxidation with m-chloroperbenzoic acid, perbenzoic acid, peracetic acid, sodium hypochlorite or hydrogen peroxide is suitably used. Examples of the solvent include an aromatic hydrocarbon, an ether, a halogenated hydrocarbon such as dichloromethane, DMF, DMSO, ethyl acetate, MeCN and a mixture thereof. Other examples of the oxidant include cumene hydroperoxide, Oxone, active manganese dioxide, chromic acid, potassium permanganate, sodium periodate and the like.
Reference
The Chemical Society of Japan, "Jikken Kagaku Koza (lectures on experimental chemistry)", 5th edition, Vol. 17, Maruzen, 2004
When the compound (21) has an axial chirality, the compound (21) is sometimes obtained as a mixture of stereoisomers, and each stereoisomer can be isolated by separation using a common separation operation, for example, ODS column chromatography or silica gel column chromatography.
After subjecting the compound (21) to a deprotection reaction, PG2 is sometimes converted to another protective group so that deprotection can be performed under different conditions from those of the protective group PG1 to be introduced later.
The reaction conditions of the deprotection reaction used here are the same as in the step described in the Production Method 1.
Examples of the protective group of PG2 to be converted subsequently include a tetrahydro-2H-pyran-2-yl group and the like.
For example, the following can be referred as a reference about this reaction.
P. G. M. Wuts and T. W. Greene, "Greene's Protective Groups in Organic Synthesis", 5th edition, John Wiley & Sons Inc., 2014
Eighth Step
This step is a method for producing the compound (22) by deprotection by a catalytic hydrogenation reaction of the compound (21). This reaction can be performed by stirring the compound (21) under hydrogen atmosphere, from under normal pressure to under increased pressure, in a solvent inactive for the reaction, such as MeOH, EtOH, ethyl acetate and THF, in the presence of a metal catalyst, from under cooling to under heating, preferably at room temperature, for an hour to five days. As the metal catalyst, a palladium catalyst, such as Pd/C and palladium black, a platinum catalyst, such as a platinum plate and platinum oxide, a nickel catalyst, such as reduced nickel and Raney nickel, or the like is used.
Ninth Step
This step is a method for producing a compound (24) by a reaction of the compound (22) and a compound (23).
This reaction is performed using the compound (22) and the compound (23) in an equal amount or with one compound thereof in an excess amount by reacting a mixture of the compounds in the presence of a base, in a solvent inactive for the reaction, from under cooling to under reflux with heat, preferably at 0°C to 80°C, generally for 0.1 hours to five days. The solvent used here is not particularly limited, and examples thereof include an aromatic hydrocarbon, such as benzene, toluene and xylene, an alcohol, such as MeOH and EtOH, an ether, such as diethyl ether, THF, DOX and 1,2- dimethoxyethane, a halogenated hydrocarbon, such as dichloromethane, 1,2- dichloroethane and chloroform, DMF, DMSO, ethyl acetate, MeCN and a mixture thereof. Examples of the base include, but are not particularly limited to, for example, an organic base, such as TEA, DIPEA, l,8-diazabicyclo[5.4.0]-7-undecene, n-butyllithium and tBuOK, and an inorganic base, such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium hydride. Performing the reaction in the presence of a phase transfer catalyst, such as tetra-n-butylammonium chloride, is sometimes advantageous.
For example, the following can be referred as a reference about this reaction.
The Chemical Society of Japan, "Jikken Kagaku Koza (lectures on experimental chemistry)", 5th edition, Vol. 14, Maruzen, 2005
The compound (24) in which LG1 is halogen can be produced by halogenation of a compound in which the moiety corresponding to LG1 is a hydroxy group. Examples of the halogenating agent used here include, but are not particularly limited to, for example, thionyl chloride, phosphorus oxychloride, hydrobromic acid, phosphorus tribromide and the like. For example, the following can be referred as a reference about this reaction.
The Chemical Society of Japan, "Jikken Kagaku Koza (lectures on experimental chemistry)", 5th edition, Vol. 13, Maruzen, 2004
Furthermore, the compound (24) in which LG1 is a sulfonyloxy group can be produced by sulfonylation of a compound in which the moiety corresponding to LG1 is a hydroxy group in the presence of a base. Examples of the sulfonylation reagent used here include, but are not particularly limited to, for example, methanesulfonyl chloride, p- toluenesulfonylchloride, methanesulfonic anhydride and the like. Examples of the base include, but are not particularly limited to, for example, TEA, DIPEA, pyridine, tetramethylethylenediamine and the like.
For example, the following can be referred as a reference about this reaction.
Synthesis 1999, 9, p.1633-1636
Tenth Step
This step is a method for producing a compound (26) by an ipso substitution reaction of the compound (24) and a compound (25).
The reaction conditions are the same as in the third step of the Raw Material Synthesis 4.
Eleventh Step
This step is a method for producing a compound (27) by subjecting the compound (26) to a deprotection reaction.
The reaction conditions are the same as in the step described in the Production Method 1.
Twelfth Step
This step is a method for producing the compound (2)-l by a reaction of the compound (27) and a compound (28).
In this reaction, the compound (27) and the compound (28) are used in an equal amount or with one compound thereof in an excess amount, and the mixture of the compounds is stirred in the presence of a condensing agent, in a solvent inactive for the reaction, from under cooling to under heating, preferably at -20°C to 60°C, generally for 0.1 hours to five days. Examples of the solvent include, but are not particularly limited to, an aromatic hydrocarbon, such as toluene, an ether, such as THF and DOX, a halogenated hydrocarbon, such as dichloromethane, an alcohol, DMF, DMSO, ethyl acetate, MeCN and a mixture thereof. Examples of the condensing agent include PyBOP, HATU, CDI and the like. Performing the reaction in the presence of an organic base, such as TEA, DIPEA and NMM, or an inorganic base, such as potassium carbonate, sodium carbonate and cesium carbonate, is sometimes advantageous for smoothly promoting the reaction.
Raw Material Synthesis 5
Figure imgf000078_0001
This production method is a method for producing the raw material compound (26).
First Step
This step is a method for producing the compound (28) by an ipso substitution reaction of the compound (15) and the compound (25).
The reaction conditions are the same as in the third step of the Raw Material Synthesis 4.
Moreover, the compound (28) can be produced by Negishi coupling of a compound in which a hydrogen atom of the compound (25) has been converted to halogen and the compound (15).
Second Step This step is a method for producing a compound (29) by an ipso substitution reaction of the compound (28) and PG5-OH.
The reaction conditions are the same as in the third step of the Raw Material Synthesis 4.
Third Step
This step is a method for producing a compound (30) by a Suzuki-Miyaura coupling reaction of the compound (29) and a boronic acid derivative composed of an R2-boronic acid group or the like.
The reaction conditions are the same as in the fifth step of the Raw Material Synthesis 4.
The compound (30) (R2 is hydrogen here) can be produced by a dehalogenation reaction of the compound (29) using a Pd catalyst and a reductant.
References
3. Org. Chem., 1977, 42, p.3491-3494
Tetrahedron Letters 2013, 54, 5207-5210
Fourth Step
This step is a method for producing a compound (31) by a Suzuki-Miyaura coupling reaction of the compound (30) and the compound (19).
The reaction conditions are the same as in the fifth step of the Raw Material Synthesis 4.
Fifth Step
This step is a method for producing a compound (32) by deprotection by a catalytic hydrogenation reaction of the compound (31).
The reaction conditions are the same as in the eighth step of the Raw Material Synthesis 4.
Sixth Step
This step is a method for producing the compound (26) by a reaction of the compound (32) and the compound (23). The reaction conditions are the same as in the ninth step of the Raw Material Synthesis 4.
Raw Material Synthesis 6
Figure imgf000080_0001
This production method is a method for producing the raw material compound (2)-l.
First Step
This step is a method for producing a compound (33) by subjecting the compound (31) to a deprotection reaction.
The reaction conditions are the same as in the step described in the Production Method 1.
When the compound (31) has an axial chirality, the compound (31) is sometimes obtained as a mixture of stereoisomers, and each stereoisomer can be isolated by separation using a common separation operation, for example, ODS column chromatography or silica gel column chromatography.
After subjecting the compound (31) to a deprotection reaction, PG2 is sometimes converted to another protective group so that deprotection can be performed under different conditions from those of the protective group PG1 to be introduced later.
Second Step
This step is a method for producing a compound (34) by a reaction of the compound (33) and the compound (28). The reaction conditions are the same as in the twelfth step of the Raw Material Synthesis 4.
Third Step
This step is a method for producing a compound (35) by deprotection by a catalytic hydrogenation reaction of the compound (34).
The reaction conditions are the same as in the eighth step of the Raw Material Synthesis 4.
Fourth Step
This step is a method for producing the compound (2)-l by a reaction of the compound (35) and the compound (23).
The reaction conditions are the same as in the ninth step of the Raw Material Synthesis 4.
Figure imgf000081_0001
Figure imgf000082_0001
This production method is a method for producing a compound (8)-l included in the raw material compound (8).
This step is a method for producing a compound (37) by a chlorination reaction of a compound (36).
This reaction is performed using the compound (36) and a chlorinating agent in an equal amount or with one compound thereof in an excess amount by stirring the mixture of the compounds in a solvent inactive for the reaction or with no solvent, from under cooling to under reflux with heat, preferably at 60°C to under reflux with heat, generally for 0.1 hours to five days. Examples of the solvent used here include, but are not particularly limited to, an aromatic hydrocarbon such as toluene, an ether, such as THF and DOX, a halogenated hydrocarbon, such as dichloromethane, and the like. Examples of the chlorinating agent include phosphorus oxychloride, thionyl chloride and the like. Performing the reaction in the presence of an organic base, such as TEA, DIPEA and NMM, is sometimes advantageous for smoothly promoting the reaction.
Second Step
This step is a method for producing a compound (38) by an ipso substitution reaction of the compound (37) and RLG-SH.
The reaction conditions are the same as in the third step of the Raw Material Synthesis 4. Third Step
This step is a method for producing a compound (39) by an ipso substitution reaction of the compound (38) and PG5-OH.
The reaction conditions are the same as in the third step of the Raw Material Synthesis 4.
Fourth Step
This step is a method for producing a compound (41) by an ipso substitution reaction of the compound (39) and a compound (40).
In this reaction, the compound (39) and the compound (40) are used in an equal amount or with one compound thereof in an excess amount, and the mixture of the compounds is stirred in a solvent inactive for the reaction or with no solvent, from under cooling to under reflux with heat, preferably at 0°C to 80°C, generally for 0.1 hours to five days. Examples of the solvent used here include, but are not particularly limited to, a halogenated hydrocarbon, such as dichloromethane, 1,2-dichloroethane and chloroform, an aromatic hydrocarbon, such as benzene, toluene and xylene, an ether, such as diethyl ether, THF, DOX and 1,2-dimethoxyethane, DMF, DMAc, DMSO, ethyl acetate, MeCN and a mixture thereof. Performing the reaction in the presence of an organic base such as TEA, DIPEA, N-methylmorpholine (NMM), 1,4- diazabicyclo[2.2.2]octane (DABCO) and tBuOK, or an inorganic base, such as sodium hydride, potassium carbonate, sodium carbonate and cesium carbonate, is sometimes advantageous for smoothly promoting the reaction.
Fifth Step
This step is a method for producing a compound (42) by a Suzuki-Miyaura coupling reaction of the compound (41) and a boronic acid derivative composed of an R2-boronic acid group or the like.
The reaction conditions are the same as in the fifth step of the Raw Material Synthesis 4.
Sixth Step
This step is a method for producing a compound (43) by a Suzuki-Miyaura coupling reaction of the compound (42) and the compound (19). The reaction conditions are the same as in the fifth step of the Raw Material Synthesis 4.
Seventh Step
This step is a method for producing a compound (44) by an oxidation reaction of the compound (43).
The reaction conditions are the same as in the seventh step of the Raw Material Synthesis 4.
Eighth Step
This step is a method for producing a compound (45) by deprotection by a catalytic hydrogenation reaction of the compound (44).
The reaction conditions are the same as in the eighth step of the Raw Material Synthesis 4.
Ninth Step
This step is a method for producing a compound (46) by a reaction of the compound (45) and the compound (23).
The reaction conditions are the same as in the ninth step of the Raw Material Synthesis 4.
Tenth Step
This step is a method for producing the compound (8)-l by an ipso substitution reaction of the compound (46) and the compound (25).
The reaction conditions are the same as in the third step of the Raw Material Synthesis 4.
Raw Material Synthesis 8
Figure imgf000085_0001
This production method is a method for producing the compound (8)- 1 included in the raw material compound (8).
First Step
This step is a method for producing a compound (47) by an ipso substitution reaction of the compound (44) and the compound (25).
The reaction conditions are the same as in the third step of the Raw Material Synthesis 4.
Second Step
This step is a method for producing a compound (48) by deprotection by a catalytic hydrogenation reaction of the compound (47).
The reaction conditions are the same as in the eighth step of the Raw Material Synthesis 4.
Third Step
This step is a method for producing the compound (8)-l by a reaction of the compound (48) and the compound (23).
Raw Material Synthesis 9
Figure imgf000086_0001
This production method is a method for producing the raw material compound (47).
First Step
This step is a method for producing a compound (49) by an ipso substitution reaction of the compound (37) and the compound (25).
The reaction conditions are the same as in the third step of the Raw Material Synthesis 4.
Moreover, the compound (49) can be produced by Negishi coupling of a compound in which a hydrogen atom of the compound (25) has been converted to halogen and the compound (37).
Second Step
This step is a method for producing a compound (50) by an ipso substitution reaction of the compound (49) and PG5-OH.
The reaction conditions are the same as in the third step of the Raw Material Synthesis 4.
Third Step
This step is a method for producing a compound (51) by an ipso substitution reaction of the compound (50) and the compound (40).
The reaction conditions are the same as in the fourth step of the Raw Material Synthesis 7.
Fourth Step This step is a method for producing a compound (52) by a Suzuki-Miyaura coupling reaction of the compound (51) and a boronic acid derivative composed of an R2-boronic acid group or the like.
The reaction conditions are the same as in the fifth step of the Raw Material Synthesis 4.
Fifth Step
This step is a method for producing the compound (47) by a Suzuki-Miyaura coupling reaction of the compound (52) and the compound (19).
The reaction conditions are the same as in the fifth step of the Raw Material Synthesis 4.
Figure imgf000087_0001
This production method is a method for producing a compound (2)-2 included in the raw material compound (2).
First Step
This step is a method for producing a compound (53) by subjecting the compound (47) to a deprotection reaction.
The reaction conditions are the same as in the deprotection reaction of the Production Method 1.
Second Step This step is a method for producing a compound (54) by adding the compound (11) after a reaction of the compound (53) and a carbonylation reagent or a method for producing the compound (54) by an amidation reaction of the compound (53) and the compound (12).
The reaction conditions are the same as in the third step of the Raw Material Synthesis 3.
Third Step
This step is a method for producing a compound (55) by deprotection by a catalytic hydrogenation reaction of the compound (54).
The reaction conditions are the same as in the eighth step of the Raw Material Synthesis 4.
Fourth Step
This step is a method for producing the compound (2)-2 by a reaction of the compound (55) and the compound (23).
The reaction conditions are the same as in the ninth step of the Raw Material Synthesis 4.
Figure imgf000088_0001
(In the formulae, PG6 represents a protective group.)
This production method is a method for producing the raw material compound (3).
First Step This step is a method for producing a compound (58) by an amidation reaction of a compound (56) and a compound (57).
The reaction conditions are the same as in the third step of the Raw Material Synthesis 2.
Second Step
This step is a method for producing a compound (59) by subjecting the compound (58) to a deprotection reaction.
The reaction conditions are the same as in the step described in the Production Method 1.
Third Step
This step is a method for producing the compound (3) by a reaction of the compound (59) and a diazo-transfer reagent.
In this reaction, the compound (59) is treated with the diazo-transfer reagent in an equal amount or an excess amount in a solvent inactive for the reaction, from under cooling to under heating, preferably at 0°C to 50°C, generally for 0.1 hours to three days. Examples of the diazo-transfer reagent include, but are not particularly limited to, for example, trifluoromethanesulfonyl azide, imidazole-l-sulfonyl azide or a salt thereof, 2-azido-l,3-dimethylimidazolinium hexafluorophosphate (ADMP) and the like. Performing the reaction in the presence of an organic base, such as TEA, 4- dimethylaminopyridine (DMAP) and 2,6-lutidine, and a catalytic amount of a copper salt, such as CuSCU, is sometimes advantageous. Examples of the solvent include THF, a halogenated hydrocarbon such as dichloromethane, MeCN, an alcohol, water and a mixture thereof.
References
3. Org. Chem. 2012, 77, p.1760-1764
Nature 2019, 574, p.86-89
Org. Biomol. Chem. 2014, 12, p.4397-4406
Raw Material Synthesis 12
Figure imgf000090_0001
(In the formula, LG2 represents a leaving group.)
This production method is a method for producing a raw material compound (l)-3 included in the raw material compound (1).
First Step
This step is a method for producing a compound (61) by a reaction of the compound (32) and a compound (60).
The reaction conditions are the same as in the ninth step of the Raw Material Synthesis 4.
Second Step
This step is a method for producing a compound (62) by subjecting the compound (61) to a deprotection reaction.
The reaction conditions are the same as in the step described in the Production Method 1. Third Step
This step is a method for producing a compound (63) by a reaction of the compound (62) and the compound (28).
The reaction conditions are the same as in the twelfth step of the Raw Material Synthesis 4.
Fourth Step
This step is a method for producing a compound (2)-3 by hydrolysis of the compound (63).
The reaction conditions are the same as in the second step of the Raw Material Synthesis 2.
Fifth Step
This step is a method for producing the compound (l)-3 by an amidation reaction of the compound (2)-3 and the compound (59).
The reaction conditions are the same as in the third step of the Raw Material Synthesis 2.
Figure imgf000091_0001
(In the formulae, PG7 represents a protective group of NH.) This production method is a method for producing a raw material compound (l)-4 included in the raw material compound (1). Here, a production method of the raw material compound (l)-4 in which L2 is NRL1, pyrrolidinediyl, piperidinediyl or piperazinediyl is shown.
First Step
This step is a method for producing a compound (65) by an amidation reaction of the compound (59) and a compound (64).
The reaction conditions are the same as in the third step of the Raw Material Synthesis 2.
Second Step and Third Step
These steps are a method for producing the compound (l)-4 by an amidation reaction of a compound obtained by a deprotection reaction of the compound (65) and the compound (2)-3.
The reaction conditions of the deprotection reaction are the same as in the step described in the Production Method 1.
The reaction conditions of the amidation reaction are the same as in the third step of the Raw Material Synthesis 2.
Figure imgf000092_0001
Figure imgf000093_0001
(In the formulae, LG3 represents a leaving group. When Z is NH, A1 represents a hydrogen atom, and A2 represents halogen. When Z is 5-membered heteroarenediyl containing one to four hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen, A2 represents a boronic acid group or the like in the case where A1 is a group selected from the group consisting of Cl, Br and I, and A2 represents a group selected from the group consisting of Cl, Br and I in the case where A1 is a boronic acid group or the like.)
This production method is a method for producing a raw material compound (l)-5 included in the raw material compound (1).
First Step
This step is a method for producing a compound (68) by an ipso reaction or a Buchwald- Hartwig amination reaction of a compound (66) and a compound (67) when Z is NH.
The reaction conditions of the ipso reaction are the same as in the fourth step of the Raw Material Synthesis 7.
For example, the following can be referred as a reference about the Buchwald- Hartwig amination reaction.
J. Am. Chem. Soc., 2020, 142, p.15027-15037
Moreover, this step is a method for producing the compound (68) by a Suzuki-Miyaura coupling reaction of the compound (66) and the compound (67) when Z is 5-membered heteroaryl containing one to four hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen.
The reaction conditions are the same as in the fifth step of the Raw Material Synthesis 4.
For example, the following can be referred as a reference about the reaction in which Z is the formula (XXIX) here.
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 a compound (69) by a reaction of the compound (68) and the compound (32).
The reaction conditions are the same as in the ninth step of the Raw Material Synthesis 4.
Moreover, in this step, the compound (69) can also be produced by a Mitsunobu reaction of a compound in which the moiety corresponding to LG3 of the compound
(68) is a hydroxy group and the compound (32).
For example, the following can be referred as a reference about the Mitsunobu reaction here.
Chem. Asian J. 2007, 2, p.1340 - 1355
Third Step
This step is a method for producing a compound (70) by hydrolysis of the compound
(69).
The reaction conditions are the same as in the second step of the Raw Material Synthesis 2.
Fourth Step
This step is a method for producing the compound (l)-4 by an amidation reaction of a compound (70)-l and a compound (71).
The reaction conditions are the same as in the third step of the Raw Material
Synthesis 2.
Raw Material Synthesis 15
Figure imgf000094_0001
(In the formulae, R6aa and R6bb represent divalent groups in which H has been removed from a functional group of R6a and R6b into which a protective group can be introduced. PG9, PG10 and PG11, which are the same as or different from each other, represent a hydrogen atom or a protective group, and PG12 represents a protective group. A3 represents a hydrogen atom, a carboxyl group, a boronic acid group or the like.)
This production method is a method for producing the raw material compound (56).
First Step
This step is a method for producing a compound (74) by a Mizoroki-Heck reaction of a compound (73) in which R7 is the formula (XXIII) for example and a compound (72) when A3 is a hydrogen atom.
In this reaction, the compound (72) and the compound (73) are used in an equal amount or with one compound thereof in an excess amount, and the mixture of the compounds is stirred in a solvent inactive for the reaction, in the presence of a base and a palladium catalyst, from at room temperature to under reflux with heat, preferably at 20°C to 140°C, generally for 0.1 hours to five days. Examples of the solvent used here include, but are not particularly limited to, an ether, such as diethyl ether, THF, DOX and 1,2-dimethoxyethane, DMF, DMAc, DMSO, MeCN, 1,3- dimethylimidazolidin-2-one, ethyl acetate, water and a mixture thereof. The base is a base, such as tripotassium phosphate, sodium carbonate, potassium carbonate and potassium acetate. The palladium catalyst is tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, [1,1'- bis(diphenylphosphino)ferrocene]palladium(II) dichloride ■ dichloromethane adduct, (lE,4E)-l,5-diphenylpenta-l,4-dien-3-one/palladium (3:2), (2- dicyclohexylphosphino-2', 6'-diisopro poxy- l,l'-biphenyl) [2-(2'-amino- 1,1'- biphenyl)]palladium(II) methanesulfonate, palladium(II) acetate or the like. In addition, heating the mixture by microwave irradiation is sometimes advantageous for smoothly promoting the reaction.
For example, the following can be referred as a reference about the reaction.
Synthesis 2020, 52, p.2521-2527
PNAS 2016, 113, p.7124-7129
Alternatively, this is a method for producing the compound (74) by an Ullmann reaction of the compound (73) in which R7 is a group selected from the group consisting of the formula (XXVI), the formula (XXVIII) and the formula (XXXIII) for example and the compound (72).
For example, the following can be referred as a reference about the reaction.
Angew. Chem. Int. Ed., 2003, 42, p.5400-5449 Moreover, this step is a method for producing the compound (74) by a decarbonation coupling reaction of the compound (73) in which R7 is the formula (XXIV) for example and the compound (72) when A3 is a carboxyl group.
For example, the following can be referred as a reference about the reaction.
Science, 2006, 313, p.662-664
Furthermore, this step is a method for producing the compound (74) by a Suzuki-Miyaura coupling reaction of the compound (73) in which R7 is the formula (XXIII) for example and the compound (72) when A3 is a boronic acid group or the like.
The reaction conditions are the same as in the fifth step of the Raw Material Synthesis 4.
Second Step
This step is a method for producing the compound (56) by subjecting the compound (74) to a deprotection reaction.
The reaction conditions are the same as in the step described in the Production Method 1.
Figure imgf000096_0001
(In the formulae, A5 represents a group selected from the group consisting of Cl, Br, mesylate and triflate, and LG3 represents a leaving group.) This production method is a method for producing a raw material compound (68)-l and a raw material compound (68)-2 included in the raw material compound (68).
First Step
This step is a method for producing a compound (78) by a reaction of a compound (75) and a compound (77).
For example, the following can be referred as a reference about the reaction.
Chem. Commun., 2014, 50, 15, p.1867-1870
[0207]
Second Step
This step is a method for producing the compound (78) by a reaction of the compound (77) and glyoxylic acid using a toluenesulfonylmethyl isocyanide (TosMIC) reagent substituted with aryl.
For example, the following can be referred as a reference about the reaction.
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 method for producing the compound (68)-l by a Suzuki-Miyaura coupling reaction of the compound (78) and an alkoxymethyl boronic acid derivative and by subsequently subjecting to a deprotection reaction under acidic conditions.
The reaction conditions of the Suzuki-Miyaura coupling reaction are the same as in the fifth step of the Raw Material Synthesis 4.
An example of the alkoxymethyl boronic acid derivative used here is potassium (2-trimethylsilyl)-ethoxymethyl trifluoroborate.
For example, the following can be referred as a reference about the reaction.
Org. Lett., 2008, 10, 11, p.2135-2128
Org. Lett., 2011, 13, 15, p.3948-3951
The reaction conditions of the deprotection reaction under the acidic conditions performed subsequently are the same as in the step described in the Production Method 1. Examples of the acid used here include trifluoroacetic acid and the like.
For example, the following can be referred as a reference about the deprotection reaction. P. G. M. Wuts and T. W. Greene, "Greene's Protective Groups in Organic Synthesis", 5th edition, John Wiley & Sons Inc., 2014
Moreover, in this step, the compound (68)-l can be produced by a Suzuki- Miyaura coupling reaction of the compound (78) and an acetoxymethyl boronic acid derivative.
For example, the following can be referred as a reference about the reaction.
Org. Lett., 2012, 14, 5, p.1278-1281
Fourth Step
This step is a method for producing a compound (80) by a reaction of a compound (79) and the compound (77).
This reaction is performed using the compound (79) and the compound (77) in an equal amount or with one compound thereof in an excess amount by stirring the mixture of the compounds in a solvent inactive for the reaction or with no solvent, from under cooling to under reflux with heat, preferably from at room temperature to under reflux with heat, generally for 0.1 hours to five days. Examples of the solvent used here include, but are not particularly limited to, an aromatic hydrocarbon, such as toluene, an ether, such as THF and DOX, a halogenated hydrocarbon, such as dichloromethane, DMF, DMSO, ethyl acetate, MeCN and the like. Performing the reaction in the presence of an organic base, such as TEA, DIPEA and NMM, or an inorganic base, such as potassium carbonate, sodium carbonate and cesium carbonate, is sometimes advantageous for smoothly promoting the reaction.
Fifth Step
This step is a method for producing the compound (68)-2 by a Suzuki-Miyaura coupling reaction of the compound (80) and an alkoxymethyl boronic acid derivative and by subsequently subjecting to a deprotection reaction under acidic conditions.
The reaction conditions are the same as in the third step of the Raw Material Synthesis 16.
Moreover, in this step, the compound (68)-2 can be produced by a Suzuki- Miyaura coupling reaction of the compound (80) and an acetoxymethyl boronic acid derivative.
The compound of the formula (I) is isolated and purified as a free compound, a salt, hydrate, solvate or crystal polymorphous substance thereof or a substance in amorphous solid form. A salt of the compound of the formula (I) can also be produced by subjecting the compound to a salt formation reaction which is an ordinary method.
The isolation and purification are performed by applying a common chemical operation, such as extraction, fractional crystallization and various types of fraction chromatography.
Various types of isomers can be produced by selecting an appropriate raw material compound or can be separated by using a difference in physiochemical properties between the isomers. For example, an optical isomer can be obtained by a general optical resolution method of a racemate (for example, fractional crystallization for inducing to a diastereomer salt with an optically active base or acid, chromatography using a chiral column or the like and the like) and can also be produced from an appropriate optically active raw material compound.
In addition, the compound of the formula (I) or an intermediate thereof sometimes has an axial chirality and is obtained as a mixture of stereoisomers, and each stereoisomer can be isolated by separation using a common separation operation, for example, octadecylsilyl (ODS) column chromatography or silica gel column chromatography.
Pharmaceutical compositions
A pharmaceutical composition that contains one or two or more compounds of the formula (I) or salts thereof as active ingredients can be prepared by a usually used method using an excipient usually used in the art, that is, a pharmaceutical excipient, a pharmaceutical carrier or the like.
The administration may be either oral administration with a tablet, pill, capsule, granule, powder, liquid or other agent or parenteral administration with an intraarticular, intravenous, intramuscular or other injection, a transmucosal agent, an inhalant or the like.
As a solid composition for oral administration, a tablet, powder, granular or other agent is used. In such a solid composition, one or two or more active ingredients are mixed with at least one inactive excipient. The composition may contain an inactive additive, for example, a lubricant, a disintegrator, a stabilizer or a dissolution aid, according to an ordinary method. A tablet or pill may be coated with a sugar coating or a film soluble in the stomach or intestine, when needed. Liquid compositions for oral administration include a pharmaceutically acceptable emulsion, solution, suspension, syrup or elixir agent and the like and contain a generally used inactive diluent, for example, purified water or EtOH. The liquid composition may contain, in addition to the inactive diluent, an adjuvant, such as a solubilizer, a wetting agent and a suspending agent, a sweetening agent, a flavor, a fragrant or a preservative.
The injection agents for parenteral administration include a sterile aqueous or nonaqueous solution, suspension or emulsion agent. Examples of the aqueous solvent include distilled water for injection or physiological saline. An example of the nonaqueous solvent is an alcohol, such as EtOH. Such a composition may further contain an isotonizing agent, a preservative, a wetting agent, an emulsifier, a dispersant, a stabilizer or a dissolution aid. These are sterilized, for example, by filtration through a bacteria keeping filter, incorporation of a microbicide or irradiation. In addition, such a composition can be produced as a sterile solid composition, which is dissolved or suspended in sterile water or a sterile solvent for injection before use.
The transmucosal agent, such as an inhalant or a transnasal agent, is used in a solid, liquid or semi-solid form and can be produced according to a conventionally known method. For example, a known excipient and in addition, a pH modifier, a preservative, a surfactant, a lubricant, a stabilizer, a thickener or the like may be appropriately added. The administration can be performed by using an appropriate device for inhalation or insufflation. For example, the agent can be administered using a known device, such as a metering and administering inhalation device, or an atomizer, as a compound alone or a powder of a mixture formulated, or as a solution or a suspension in combination with a pharmaceutically acceptable carrier. A dry powder inhaler or the like may be for a single administration or multiple administrations, and dry powder or powder-containing capsule can be used. Alternatively, the agent may be used in a form of a pressurized aerosol spray or the like using an appropriate ejection agent, for example, a suitable gas, such as a chlorofluoroalkane or carbon dioxide.
In the case of a common oral administration, the daily dose is appropriately about 0.001 to 100 mg/kg body weight, preferably 0.1 to 30 mg/kg body weight, further preferably 0.1 to 10 mg/kg body weight, and the dose is given at once or is divided into two to four times. In the case of intravenous administration, the daily dose is appropriately about 0.0001 to 10 mg/kg body weight and is given at once or is divided into multiple times in a day. In addition, the daily dose of a transmucosal agent is about 0.001 to 100 mg/kg body weight and is given at once or is divided into multiple times in a day. The dose is appropriately decided depending on the individual case taking the symptom, age, sex and the like into account.
Depending on the route of administration, dosage form, site of administration and types of excipient and additive, the pharmaceutical composition of the present invention contains 0.01 to 100% by weight, in an aspect, 0.01 to 50% by weight, of one or more compounds of the formula (I) or salts thereof which are active ingredients.
The compound of the formula (I) can be used in combination with various therapeutic agents or preventive agents for a disease to which the compound of the formula (I) is considered to have an effectiveness. The combination use may be simultaneous administration or separate administration either sequential or with a desired interval. A simultaneous administration preparation may be a formulated agent or may be separately formulated.
Advantageous Effects of Invention
The compounds for use, pharmaceutical compositions, methods and uses described herein may have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better treatment profile than other treatments for the same indications known in the prior art.
In particular, the compound of the formula (I) or a salt thereof has a degradationinducing action on a G12V mutant, G12D mutant and G12C mutant KRAS protein, and a G12V mutant, G12D mutant and G12C mutant KRAS inhibitory activity, and can be used, particularly as an active ingredient of a pharmaceutical composition, for treating a cancer of colorectal cancer and/or lung cancer, in particular, a G12V mutant, G12D mutant and G12C mutant KRAS-positive cancer.
Examples
The production method of the compound of the formula (I) will be explained in further detail below based on the Examples. Note that, the present invention is not to be limited to the compounds described in the following Examples. The production methods of raw material compounds are also shown in the Production Examples. The production method of the compound of the formula (I) is not limited only to the production methods of specific Examples described below, and the compound of the formula (I) can also be produced by a combination of the production methods or a method that is obvious to a person skilled in the art.
Note that, in this specification, a compound is sometimes named by using a naming soft, such as ACD/Name (registered trademark, Advanced Chemistry Development, Inc.).
For the purpose of convenience, the concentration mol/L is shown as M. For example, IM aqueous sodium hydroxide solution means an aqueous sodium hydroxide solution of 1 mol/L.
The "amorphous solid form" described in this specification includes both a form showing no peak in a powder X-ray diffraction (XRD) pattern and a form having low crystallinity.
Production Example 1
In THF (310 mL), 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (30.9 g) was suspended, and sodium hydroxide (IM aqueous solution, 147 mL) was added dropwise under ice cooling to keep the internal temperature at 12°C or lower. The mixture was stirred under ice cooling for two hours. The reaction solution was poured into a conical flask containing hydrogen chloride (IM aqueous solution, 147 mL) and water (700 mL) under ice cooling, and the mixture was stirred for two hours at room temperature. The insoluble matter was taken by filtration while washing it with water and dried at 40°C overnight under reduced pressure, thus obtaining 7-bromo-2-chloro-8-fluoro-6- iodoquinazolin-4-ol (24.6 g) as a solid.
Production Example 2
Under nitrogen atmosphere, 2-tert-butyl-l,3-diisopropylisourea (73.4 g) was added dropwise over 15 minutes to a mixture of 7-bromo-2-chloro-8-fluoro-6-iodoquinazolin- 4-ol (24.6 g) and THF (260 mL) heated to 60°C, and the mixture was stirred at the same temperature for 2.5 hours. The mixture was allowed to cool to room temperature, and the insoluble matter was removed by filtration while washing it with THF (500 mL). The filtrate was concentrated, and MeOH (210 mL) was added to the resulting solid. The mixture was stirred at room temperature for an hour, suspended and washed. The insoluble matter was taken by filtration using MeOH (100 mL), thus obtaining 7-bromo- 4-tert-butoxy-2-chloro-8-fluoro-6-iodoquinazoline (23.2 g) as a solid. Production Example 3
At room temperature, trimethyl orthoacetate (32 mL) was added to a suspension of 2- amino-4-bromo-3-fluoro-5-iodobenzoic acid (30 g) in N-methyl-2-pyrrolidone (60 mL), and the mixture was stirred under argon atmosphere at 110°C overnight. The reaction mixture was brought to room temperature and then suspended in MeOH added thereto. The insoluble matter was taken by filtration and dried under reduced pressure at 50°C overnight, thus obtaining methyl 2-acetamide-4-bromo-3-fluoro-5-iodobenzoate (21.5 g) as a solid.
Production Example 4
Under argon atmosphere under ice cooling, lithium bis(trimethylsilyl)amide (IM THF solution, 160 mL) was added using a dropping funnel over 20 minutes to a suspension of methyl 2-acetamide-4-bromo-3-fluoro-5-iodobenzoate (21.5 g) in THF (250 mL). Then, the mixture was stirred under argon atmosphere at 40°C for an hour. Water was added under ice cooling to stop the reaction, and the mixture was diluted with ethyl acetate and water. The organic layer and the aqueous layer were separated by a separation operation, and the organic layer was subjected to extraction twice with water. When hydrogen chloride (IM aqueous solution, 200 mL) was added slowly to the collected aqueous layer under ice cooling, a solid precipitated. The insoluble matter was taken by filtration, washed with water and MeOH and then dried under reduced pressure at 50°C overnight, thus obtaining 7-bromo-8-fluoro-6-iodoquinoline-2,4-diol (17.7 g) as a solid.
Production Example 5
Under nitrogen atmosphere, DIPEA (30 mL) was added dropwise over five minutes to a suspension of 7-bromo-8-fluoro-6-iodoquinoline-2,4-diol (21.24 g) in phosphoryl chloride (95.2 mL) under ice cooling, and the mixture was stirred at 110°C for two hours. After the reaction mixture was allowed to cool to room temperature, MeCN (100 mL) was added, and the mixture was stirred under ice cooling for 30 minutes. The insoluble matter was taken by filtration using MeCN (100 mL). The resulting solid was suspended in MeCN (50 mL) and ice water (200 mL) and stirred for 30 minutes. The insoluble matter was taken by filtration using water/MeCN (5/1, 250 mL), thus obtaining 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinoline (18.95 g) as a solid. Production Example 6
To a suspension of 7-bromo-4-tert-butoxy-2-chloro-8-fluoro-6-iodoquinazoline (29 g) in dichloromethane (300 mL), ethanethiol (5 mL) and DABCO (11 g) were added at room temperature, and the mixture was stirred under argon atmosphere at room temperature overnight. Under ice cooling, water was added to stop the reaction. Chloroform was added, and the organic layer and the aqueous layer were separated by a separation operation. The aqueous layer was subjected to extraction with chloroform three times. The collected organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, thus obtaining 7-bromo-4- tert-butoxy-2-(ethylsulfanyl)-8-fluoro-6-iodoquinazoline (32 g) as a solid.
Production Example 7
To a suspension of 7-bromo-4-tert-butoxy-2-chloro-8-fluoro-6-iodoquinazoline (5 g) in DMF (25 mL) and THF (25 mL), 4- hydroxytetra hydro pyran (1.45 mL), DABCO (120 mg) and cesium carbonate (7 g) were added at room temperature, and the mixture was stirred under nitrogen atmosphere at room temperature overnight. The reaction mixture was diluted by adding ethyl acetate, and the insoluble matter was removed by filtration through celite (registered trademark). Saturated aqueous ammonium chloride solution was added to the filtrate, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (chloroform/ethyl acetate), thus obtaining 7-bromo-4-tert- butoxy-8-fluoro-6-iodo-2-[(oxan-4-yl)oxy]quinazoline (3.9 g) as a solid.
Production Example 8
Under argon atmosphere, DABCO (1.3 g) was added to a suspension of 7-bromo-2,4- dichloro-8-fluoro-6-iodoquinoline (4.4 g) in N-methyl-2-pyrrolidone (45 mL), and after the mixture was stirred at 40°C for two hours, ethanethiol (850 pL) was added. The mixture was stirred at 60°C for four hours. After cooling to room temperature, water (200 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The insoluble matter was taken by filtration and dried under reduced pressure, thus obtaining 7-bromo-4-chloro-2-(ethylsulfanyl)-8-fluoro-6-iodoquinoline (4.33 g) as a solid. Production Example 9
To a THF (400 mL) solution of 7-bromo-4-tert-butoxy-2-(ethylsulfanyl)-8-fluoro-6- iodoquinazoline (32 g) and (IS)-l-phenylethan-l-ol (11 mL), tBuOK (10 g) was added under ice cooling, and the mixture was stirred under argon atmosphere, under ice cooling for an hour. 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. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane/ethyl acetate), thus obtaining 7-bromo-4- tert-butoxy-2-(ethylsulfanyl)-6-iodo-8-[(lS)-l-phenylethoxy]quinazoline (36.6 g) as an oily substance.
Production Example 12
Under nitrogen atmosphere, 7-bromo-4-chloro-2-(ethylsulfanyl)-8-fluoro-6- iodoquinoline (4.3 g) was dissolved in THF (40 mL), and (IS)-l-phenylethan-l-ol (1.28 mL) was added at room temperature. In an ice salt bath, tBuOK (1.14 g) was added, and the mixture was stirred at the same temperature for three hours. After the reaction mixture was poured to saturated aqueous ammonium chloride solution to which ice and ethyl acetate were added, the mixture was stirred and subjected to extraction with ethyl acetate twice. The combined organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After the drying agent was removed by filtration, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), thus obtaining 7-bromo-4-chloro-2- (ethylsulfanyl)-6-iodo-8-[(lS)-l-phenylethoxy]quinoline (4.85 g) as an oily substance.
Production Example 13
In DMAc (10 mL), l-(tert-butoxycarbonyl)-3-hydroxyazetidine (1 g) was dissolved, and tBuOK (600 mg) was added under argon atmosphere. The mixture was stirred at room temperature for 10 minutes, and thus an alkoxide solution was prepared. In DMAc (10 mL), 7-bromo-4-chloro-2-(ethylsulfanyl)-6-iodo-8-[(lS)-l- phenylethoxy]quinoline (2.12 g) was dissolved, and the prepared alkoxide solution was added dropwise under argon atmosphere in an ice salt bath. The mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. The insoluble matter was taken by filtration. The resulting solid was purified by silica gel column chromatography (from hexane/chloroform to chloroform/MeOH), thus obtaining tert-butyl 3-({7-bromo-2-(ethylsulfanyl)-6-iodo-8-[(lS)-l- phenylethoxy]quinolin-4-yl}oxy)azetidine-l-carboxylate (2.48 g) as a foam-like solid.
Production Example 14
At room temperature, 7-bromo-4-tert-butoxy-2-(ethylsulfanyl)-6-iodo-8-[(lS)-l- phenylethoxy]quinazoline (36.6 g), cyclopropylboronic acid (7.5 g), PdCh (dppf)-CH2CI2 (7.6 g), tripotassium phosphate (53 g), MeCN (440 mL) and water (80 mL) were mixed and stirred under argon atmosphere at 90°C for four hours. The reaction solution was brought to room temperature and then diluted with ethyl acetate and water. The organic layer and the aqueous layer were separated, and the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane/ethyl acetate), thus obtaining 7-bromo-4-tert-butoxy-6-cyclopropyl-2-(ethylsulfanyl)-8-[(lS)-l- phenylethoxy]quinazoline (22.9 g) as an oily substance.
Production Example 17
Under argon atmosphere, a mixture of tert-butyl 3-({7-bromo-2-(ethylsulfanyl)-6- iodo-8-[(lS)-l-phenylethoxy]quinolin-4-yl}oxy)azetidine-l-carboxylate (2.48 g), cyclopropylboronic acid (500 mg), PdCI2 (dppf)-CH2CI2 (300 mg), tripotassium phosphate (2.9 g), MeCN (40 mL) and water (8 mL) was stirred at 90°C for six hours. After allowing to cool to room temperature, ethyl acetate and water were added, and the mixture was filtered through celite (registered trademark). The filtrate was subjected to extraction with ethyl acetate, and the combined organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After the drying agent was removed by filtration, the mixture was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/chloroform), thus obtaining tert-butyl 3-({7-bromo- 6-cyclopropyl-2-(ethylsulfanyl)-8-[(lS)-l-phenylethoxy]quinolin-4-yl}oxy)azetidine- 1-carboxylate (2.09 g) as a foam-like solid.
Production Example 18 To a mixture of 4-bromo-6-fluoro-lH-indazole (235 g), TEA (183 mL) and dichloromethane (1880 mL), l,l',l"-(chloromethanetriyl)tribenzene (335 g) was added, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was poured to ice water (1.5 L), and the organic layer and the aqueous layer were separated. The aqueous layer was subjected to extraction with dichloromethane (400 mL) three times. After the combined organic layer was dried over anhydrous sodium sulfate, the insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was pulverized (0°C, two hours) by adding petroleum ether (550 mL), then taken by filtration and dried under reduced pressure, thus obtaining 4-bromo-6-fluoro-2-(triphenylmethyl)-2H-indazole (508.98 g) as a solid.
Production Example 19
To a mixture of 4-bromo-6-fluoro-2-(triphenylmethyl)-2H-indazole (100 g) in 2- methyltetra hydrofuran (1000 mL), lithium diisopropylamide (2M THF solution, 214.28 mL) was added at -78°C under nitrogen atmosphere, and the mixture was stirred at - 78°C for 2.5 hours. Methyl iodide (26.68 mL) was added at -78°C, and the mixture was stirred at 25°C for 2.5 hours. Water (2000 mL) was added to stop the reaction, and extraction with ethyl acetate (800 mL) was performed twice. After the combined organic layer was dried over anhydrous sodium sulfate, the insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was pulverized by adding ethyl acetate (50 mL)/petroleum ether (50 mL), then taken by filtration and dried under reduced pressure, thus obtaining 4- bromo-6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazole (81 g) as a solid.
Production Example 20
To a mixture of 4-bromo-6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazole (100 g), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane (61.42 g), triphenylphosphine (10.57 g), potassium acetate (59.34 g) and DOX (1000 mL), palladium(II) acetate (4.52 g) was added under nitrogen atmosphere at room temperature. After the reaction mixture was deaerated and filled with nitrogen gas each three times, the mixture was stirred under nitrogen atmosphere at 100°C for 12 hours. After cooling, water (1500 mL) was added, and extraction with ethyl acetate (900 mL) was performed three times. After the combined organic layer was dried over anhydrous sodium sulfate, the insoluble matter was removed by filtration. Activated carbon (50 g) was added to the resulting solution, and the mixture was stirred at 20°C for an hour and filtered while washing it with ethyl acetate (50 mL) three times. The filtrate was concentrated, and the resulting residue was pulverized by adding MeOH (200 mL), taken by filtration and dried under reduced pressure, thus obtaining 6- fluoro-5-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2- (triphenylmethyl)-2H-indazole (110 g) as a solid.
Production Example 21
To 7-bromo-4-tert-butoxy-6-cyclopropyl-2-(ethylsulfanyl)-8-[(lS)-l- phenylethoxy]quinazoline (14.21 g), 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-2-(triphenylmethyl)-2H-indazole (19.3 g), palladium(II) acetate (0.67 g), dicyclohexyl(2',6'-diisopropoxy-[l,l'-biphenyl]-2-yl)phosphine (2.67 g), anhydrous barium hydroxide (14.6 g), DOX (500 mL) and water (100 mL) were added, and after deaeration and substitution operation with argon gas were performed several times, the mixture was stirred with heating under argon atmosphere at 50°C overnight. The reaction suspension which was allowed to cool was filtered through celite (registered trademark) while washing it with ethyl acetate, and the grey insoluble matter was removed by filtration. After the filtrate was concentrated under reduced pressure to around 1/4, water was added, and extraction with ethyl acetate was performed twice. The collected organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate), thus obtaining 4-tert-butoxy-6- cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4- yl]-8-[(lS)-l-phenylethoxy]quinazoline (a diastereomer mixture of about 3.3: 1 derived from axial chirality, 16.44 g) as a solid.
Production Example 24
In DOX (100 mL), tert-butyl 3-({7-bromo-6-cyclopropyl-2-(ethylsulfanyl)-8-[(lS)-l- phenylethoxy]quinolin-4-yl}oxy)azetidine-l-carboxylate (4.98 g) was dissolved, and 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2- (triphenylmethyl)-2H-indazole (5.7 g), palladium(II) acetate (238 mg), dicyclohexyl(2',6'-diisopropoxy-[l,l'-biphenyl]-2-yl)phosphine (1 g), barium hydroxide (4.3 g) and water (10 mL) were added at room temperature. The mixture was stirred under argon atmosphere at 50°C for an hour. To the reaction mixture, 6- fluoro-5-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2- (triphenylmethyl)-2H-indazole (1 g) was added at the same temperature, and the mixture was stirred under argon atmosphere at 50°C for an hour. The reaction mixture was allowed to cool to room temperature, and ethyl acetate was added. After filtration through celite (registered trademark) and washing with ethyl acetate, water was added to the filtrate, and extraction with ethyl acetate was performed twice. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated. The residue was purified by basic silica gel column chromatography (hexane/chloroform), thus obtaining tert-butyl 3-({6-cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5-methyl-2- (triphenylmethyl)-2H-indazol-4-yl]-8-[(lS)-l-phenylethoxy]quinolin-4- yl}oxy)azetidine-l-carboxylate (a diastereomer mixture of about 3.5: 1 derived from axial chirality, 5.98 g) as a foam-like solid.
Production Example 25
MeOH (120 mL) was added to tert-butyl 3-({6-cyclopropyl-2-(ethylsulfanyl)-7-[6- fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(lS)-l- phenylethoxy]quinolin-4-yl}oxy)azetidine-l-carboxylate (a diastereomer mixture of about 3.5: 1 derived from axial chirality, 5.98 g), and the mixture was stirred at 50°C for an hour and then stirred at room temperature overnight. The insoluble matter, tert-butyl 3-({6-cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5-methyl-2-
(triphenylmethyl)-2H-indazol-4-yl]-8-[(lS)-l-phenylethoxy]quinolin-4- yl}oxy)azetidine-l-carboxylate (a diastereomer mixture of about 1 : 1 derived from axial chirality, 1.82 g) was removed by filtration while washing it with MeOH, and the filtrate was concentrated under reduced pressure, thus obtaining the target tert-butyl 3-({(7M)-6-cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)- 2H-indazol-4-yl]-8-[(lS)-l-phenylethoxy]quinolin-4-yl}oxy)azetidine-l-carboxylate (a single diastereomer, 3.43 g) as a foam-like solid.
Production Example 27
In dichloromethane (300 mL), 4-tert-butoxy-6-cyclopropyl-2-(ethylsulfanyl)-7-[6- fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(lS)-l- phenylethoxy]quinazoline (a diastereomer mixture of about 3.7: 1 derived from axial chirality, 22.6 g) was dissolved, and m-chloroperbenzoic acid (about 30% water content, 15 g) was added (internal temperature: 5-10°C) under ice cooling. The mixture was stirred under nitrogen atmosphere for two hours at room temperature. An aqueous solution (300 mL) of sodium thiosulfate pentahydrate (14 g) and saturated aqueous sodium hydrogen carbonate solution (300 mL) were poured to the reaction mixture under ice cooling, and after the mixture was stirred for 30 minutes at room temperature, extraction with ethyl acetate was performed twice. The combined organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. To the resulting residue, iPrOH (600 mL) was added, and the mixture was stirred at room temperature overnight. The resulting insoluble matter was taken by filtration, washed with iPrOH and dried under reduced pressure, thus obtaining 4-tert-butoxy-6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl- 2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(lS)-l-phenylethoxy]quinazoline (a diastereomer mixture of about 1 : 1 derived from axial chirality, 9.45 g) as a solid. The filtrate was concentrated, thus obtaining 4-tert-butoxy-6-cyclopropyl-2- (ethanesulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(lS)- l-phenylethoxy]quinazoline (a single diastereomer with undetermined configuration of axial chirality, 15.5 g) as a foam-like solid.
Production Example 29
In MeOH (30 mL), tert-butyl 3-({(7M)-6-cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5- methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[(lS)-l-phenylethoxy]quinolin-4- yl}oxy)azetidine-l-carboxylate (2.93 g) was suspended, and methanesulfonic acid (1.1 mL) was added at room temperature. The mixture was stirred at room temperature for 30 minutes and stirred at 40°C overnight. The reaction mixture was allowed to cool to room temperature, and saturated aqueous sodium hydrogen carbonate solution was added. Extraction with chloroform/iPrOH (9/1) was performed three times, and the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was dissolved in THF (40 mL), and 4- methylbenzene-l-sulfonic acid monohydrate (740 mg) and 3,4-dihydro-2H-pyran (3 mL) were added at room temperature. The mixture was stirred at room temperature overnight. Basic silica gel was added to the reaction mixture, and after concentration, the residue was purified by basic silica gel column chromatography (hexane/chloroform), thus obtaining (7M)-4-[(azetidin-3-yl)oxy]-6-cyclopropyl-2- (ethylsulfanyl)-7-[6-fluoro-5-methyl-l-(oxan-2-yl)-lH-indazol-4-yl]-8-[(lS)-l- phenylethoxy]quinoline (1.65 g) as an oily substance.
Production Example 30
In DMF (15 mL), (7M)-4-[(azetidin-3-yl)oxy]-6-cyclopropyl-2-(ethylsulfanyl)-7-[6- fluoro-5-methyl-l-(oxan-2-yl)-lH-indazol-4-yl]-8-[(lS)-l-phenylethoxy]quinoline (1.65 g) was dissolved, and TEA (825 pL) and N-[2- (trimethylsilyl)ethoxycarbonyloxy]succinimide (750 mg) were added under ice cooling. The mixture was stirred under nitrogen atmosphere under ice cooling for 30 minutes. Water was added to the reaction mixture under ice cooling, and after the mixture was stirred at the same temperature for 30 minutes, the resulting powder was taken by filtration and dried under reduced pressure, thus obtaining 2-(trimethylsilyl)ethyl 3- ({(7M)-6-cyclopropyl-2-(ethylsulfanyl)-7-[6-fluoro-5-methyl-l-(oxan-2-yl)-lH- indazol-4-yl]-8-[(lS)-l-phenylethoxy]quinolin-4-yl}oxy)azetidine-l-carboxylate (2.11 g) as a solid.
Production Example 31
In dichloromethane (50 mL), 2-(trimethylsilyl)ethyl 3-({(7M)-6-cyclopropyl-2- (ethylsulfanyl)-7-[6-fluoro-5-methyl-l-(oxan-2-yl)-lH-indazol-4-yl]-8-[(lS)-l- phenylethoxy]quinolin-4-yl}oxy)azetidine-l-carboxylate (2.1 g) was dissolved, and m- chloroperbenzoic acid (about 30% water content, 1.6 g) was added under ice cooling. The mixture was stirred at the same temperature for 30 minutes. Aqueous sodium thiosulfate solution was added under ice cooling, and after the mixture was stirred at room temperature for 30 minutes, extraction with chloroform was performed twice. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), thus obtaining 2-(trimethylsilyl)ethyl 3-({(7M)-6-cyclopropyl- 2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-l-(oxan-2-yl)-lH-indazol-4-yl]-8-[(lS)-l- phenylethoxy]quinolin-4-yl}oxy)azetidine-l-carboxylate (1.57 g) as a foam-like solid.
Production Example 33
Under argon atmosphere, sodium hydrogen carbonate (1.55 g) and 10% Pd/C (about 50% water content, 994 mg) were added to a MeOH (70 mL) and THF (70 mL) solution of 4-tert-butoxy-6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-2-
(triphenylmethyl)-2H-indazol-4-yl]-8-[(lS)-l-phenylethoxy]quinazoline (3 g) at room temperature. The mixture was stirred under hydrogen atmosphere at normal temperature under normal pressure overnight. After substitution with argon, the reaction mixture was filtered through celite (registered trademark) using chloroform/iPrOH (4/1, 100 mL) and EtOH/water (10/1, 100 mL) and concentrated. Ethyl acetate was added to the residue, and the mixture was washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate. Filtration and concentration were performed, thus obtaining 4-tert-butoxy-6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-2- (triphenylmethyl)-2H-indazol-4-yl]quinazolin-8-ol (2.7 g) as a foam-like solid.
Production Example 36
In MeOH (20 mL) and THF (20 mL), 2-(trimethylsilyl)ethyl 3-({(7M)-6-cyclopropyl-2- (ethanesulfonyl)-7-[6-fluoro-5-methyl-l-(oxan-2-yl)-lH-indazol-4-yl]-8-[(lS)-l- phenylethoxy]quinolin-4-yl}oxy)azetidine-l-carboxylate (1.57 g) was dissolved, and 10% Pd/C (about 50% water content, 800 mg) was added at room temperature. The mixture was stirred under hydrogen atmosphere at normal temperature under normal pressure overnight. At room temperature, 10% Pd/C (about 50% water content, 1200 mg) was added, and the mixture was further stirred under hydrogen atmosphere at normal temperature under normal pressure overnight. The reaction mixture was substituted with argon, and celite (registered trademark) and chloroform were added. After filtration through celite (registered trademark) and washing with chloroform, the filtrate was concentrated, thus obtaining 2-(trimethylsilyl)ethyl 3-({(7M)-6- cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-l-(oxan-2-yl)-lH-indazol-4-yl]- 8-hydroxyquinolin-4-yl}oxy)azetidine-l-carboxylate (1.42 g) as a foam-like solid.
Production Example 37
In DMF (50 mL), 4-tert-butoxy-6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5- methyl-2-(triphenylmethyl)-2H-indazol-4-yl]quinazolin-8-ol (8.25 g) was dissolved, and cesium carbonate (14 g) and l-(chloromethyl)-4-ethynylbenzene (1.95 g) were added at room temperature. The mixture was stirred under nitrogen atmosphere at room temperature overnight. Water and ethyl acetate were added to the reaction mixture, and extraction with ethyl acetate was performed twice. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), thus obtaining 4-tert- butoxy-6-cyclopropyl-2-(ethanesulfonyl)-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro- 5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]quinazoline (6.07 g) as a solid.
Production Example 40
In DMF (30 mL), 2-(trimethylsilyl)ethyl 3-({(7M)-6-cyclopropyl-2-(ethanesulfonyl)-7- [6-fluoro-5-methyl-l-(oxan-2-yl)-lH-indazol-4-yl]-8-hydroxyquinolin-4- yl}oxy)azetidine-l-carboxylate (1.41 g) was dissolved, and cesium carbonate (3.2 g) and l-(chloromethyl)-4-ethynylbenzene (0.32 g) were added at room temperature. The mixture was stirred under nitrogen atmosphere at room temperature for 20 hours. Water was added to the reaction mixture, and extraction with ethyl acetate was performed twice. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated. The residue was purified by basic silica gel column chromatography (hexane/chloroform), thus obtaining 2-(trimethylsilyl)ethyl 3-({(7M)- 6-cyclopropyl-2-(ethanesulfonyl)-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5- methyl-l-(oxan-2-yl)-lH-indazol-4-yl]quinolin-4-yl}oxy)azetidine-l-carboxylate (1.19 g) as a foam-like solid.
Production Example 41
To a THF (30 mL) solution of 4-tert-butoxy-6-cyclopropyl-2-(ethanesulfonyl)-8-[(4- ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4- yl]quinazoline (2 g) and (2S)-2-methoxypropan-l-ol (0.35 mL), tBuOK (340 mg) was added under ice cooling, and the mixture was stirred under argon atmosphere under ice cooling for 30 minutes. 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. The aqueous layer was subjected to extraction twice with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), thus obtaining (7M)-4-tert-butoxy-6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6- fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(2S)-2- methoxypropoxy]quinazoline (2.09 g) as a foam-like solid.
Production Example 50
To a THF (25 mL) solution of (7M)-4-tert-butoxy-6-cyclopropyl-8-[(4- ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]- 2-[(2S)-2-methoxypropoxy]quinazoline (2.09 g), 4-methylbenzene-l-sulfonic acid monohydrate (380 mg) and 3,4-dihydro-2H-pyran (0.5 mL) were added under ice cooling, and the mixture was stirred under argon atmosphere at room temperature overnight. Under ice cooling, TEA (2 mL) was added, and then the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate), thus obtaining (7M)-6- cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-l-(oxan-2-yl)-lH- indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinazolin-4-ol (1.35 g) as a foam-like solid.
Production Example 58
In THF (2 mL), (2S)-2-methoxypropan-l-ol (70 mg) was dissolved, and tBuOK (85 mg) was added at room temperature. The mixture was stirred under nitrogen atmosphere at room temperature for 10 minutes, and thus an alkoxide solution was prepared. In THF (8 mL), 2-(trimethylsilyl)ethyl 3-({(7M)-6-cyclopropyl-2- (ethanesulfonyl)-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-l-(oxan-2-yl)- lH-indazol-4-yl]quinolin-4-yl}oxy)azetidine-l-carboxylate (400 mg) was dissolved, and the prepared alkoxide solution was added in a MeOH ice bath. The mixture was stirred under nitrogen atmosphere at the same temperature for 30 minutes. Water was poured to the reaction mixture, and extraction with ethyl acetate was performed twice. The organic layer was washed with saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane/ethyl acetate), thus obtaining 2-(trimethylsilyl)ethyl 3-({(7M)-6-cyclopropyl- 8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-l-(oxan-2-yl)-lH-indazol-4-yl]- 2-[(2S)-2-methoxypropoxy]quinolin-4-yl}oxy)azetidine-l-carboxylate (361 mg) as a foam-like solid.
Production Example 63
Under ice cooling, DIPEA (15 mL) and bis(4-nitrophenyl) carbonate (5.8 g) were added to a DMF (60 mL) solution of tert- butyl [(ls,3s)-3-hydroxycyclobutyl]carbamate (3.6 g), and the mixture was stirred under argon atmosphere at room temperature for an hour. Under ice cooling, benzyl azetidin-3-ylcarbamate (3 g) was added, and the mixture was stirred under argon atmosphere at room temperature for two hours. Under ice cooling, the reaction mixture was diluted with ethyl acetate and water. The organic layer and the aqueous layer were separated by a separation operation, and the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (hexane/ethyl acetate), thus obtaining (ls,3s)-3-[(tert- butoxycarbonyl)amino]cyclobutyl 3-{[(benzyloxy)carbonyl]amino}azetidine-l- carboxylate (4.81 g) as a solid containing impurities. Production Example 67
Under ice cooling, CDI (940 mg) was added to a THF (30 mL) solution of 2-[(oxan-2- yl)oxy]ethan-l-amine (700 mg), and after the mixture was stirred at room temperature for two hours, the reaction mixture was concentrated under reduced pressure. To the residue, iPrOH (30 mL) and 3-{[tert- butyldi(methyl)silyl]oxy}azetidine (1.8 g) were added at room temperature, and the mixture was stirred under argon atmosphere at 80°C overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/MeOH), thus obtaining 3-{[tert- butyldi(methyl)silyl]oxy}-N-{2-[(oxan-2-yl)oxy]ethyl}azetidine-l-carboxyamide (1.96 g) as an oily substance.
Production Example 74
Under ice cooling, DIPEA (4.1 mL) and triphosgene (630 mg) were added to a dichloromethane (30 mL) solution of N,N-dimethyl-3-azetidinemethanamine dihydrochloride (1100 mg), and the mixture was stirred under nitrogen atmosphere at room temperature for an hour. Under ice cooling, benzyl azetidin-3-ylcarbamate (1.5 g), pyridine (1 mL) and 4-(dimethylamino)pyridine (150 mg) were added, and the mixture was stirred under nitrogen atmosphere at room temperature for three hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (chloroform/MeOH), thus obtaining benzyl (l-{3-[(dimethylamino)methyl]azetidine-l-carbonyl}azetidin-3-yl)carbamate (2050 mg) as an oily substance containing impurities.
Production Example 76
Under ice cooling, DIPEA (2.6 mL) and thiophosgene (0.29 mL) were added to a dichloromethane (20 mL) solution of N,N-dimethyl-3-azetidinemethanamine dihydrochloride (700 mg), and the mixture was stirred under argon atmosphere at room temperature for an hour. Under ice cooling, tert-butyl azetidin-3-ylcarbamate (780 mg), pyridine (0.6 mL) and 4-(dimethylamino)pyridine (90 mg) were added, and the mixture was stirred under argon atmosphere at room temperature for two hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (hexane/ethyl acetate), thus obtaining tert-butyl (l-{3-[(dimethylamino)methyl]azetidine-l-carbothioyl}azetidin- 3-yl)carbamate (432 mg) as an oily substance. Production Example 77
To a suspension of benzyl azetidin-3-yl(methyl)carbamate (2.4 g) and 4- (dimethylamino)butanoic acid hydrochloride (2.19 g) in DMF (30 mL), DIPEA (8.6 mL) was added under ice cooling, and the mixture was stirred under nitrogen atmosphere at room temperature for five minutes. HATU (4.56 g) was added under ice cooling, and the mixture was stirred under nitrogen atmosphere at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and extraction with ethyl acetate was performed five times. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, then filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/MeOH) and then purified by basic silica gel column chromatography (hexane/ethyl acetate), thus obtaining benzyl {l-[4-(dimethylamino)butanoyl]azetidin-3-yl}methylcarbamate (2504 mg) as an oily substance.
Production Example 78
Sodium hydride (60%, dispersed in liquid paraffin, 85 mg) was added to a DMF (5 mL) solution of tert-butyl [(lr,3r)-3-hydroxycyclobutyl]carbamate (200 mg) and 2-chloro- N,N-dimethylacetamide (143 mg) under ice cooling, and the mixture was stirred under nitrogen atmosphere at room temperature overnight. At room temperature, water was added, and extraction with ethyl acetate was performed three times. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography (from hexane/ethyl acetate to chloroform/MeOH), thus obtaining tert-butyl {(lr,3r)-3-[2-(dimethylamino)-2- oxoethoxy]cyclobutyl}carbamate (131 mg) as a solid.
Production Example 79
At room temperature, 10% Pd/C (about 50% water content, 1.5 g) was added to a THF (50 mL) and MeOH (50 mL) solution of (ls,3s)-3-[(tert- butoxycarbonyl)amino]cyclobutyl 3-{[(benzyloxy)carbonyl]amino}azetidine-l- carboxylate (4.81 g), and the mixture was stirred under hydrogen atmosphere at normal temperature under normal pressure overnight. After substitution with argon, a small amount of celite (registered trademark) and water-containing EtOH were added, and then the mixture was stirred at room temperature for 10 minutes. After filtration through celite (registered trademark) using water-containing EtOH, toluene was added to the filtrate, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/MeOH/28% ammonia water), thus obtaining (ls,3s)-3-[(tert-butoxycarbonyl)amino]cyclobutyl 3- aminoazetidine-l-carboxylate (2.19 g) as a solid.
Production Example 84
Under ice cooling, TBAF (IM THF solution, 11 mL) was added to a THF (25 mL) solution of 3-{[tert-butyldi(methyl)silyl]oxy}-N-{2-[(oxan-2-yl)oxy]ethyl}azetidine-l- carboxyamide (1.96 g), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/MeOH), thus obtaining 3- hydroxy-N-{2-[(oxan-2-yl)oxy]ethyl}azetidine-l-carboxamide (1.46 g) as an oily substance.
Production Example 85
TFA (3 mL) was added to a dichloromethane (15 mL) solution of tert-butyl ( l-{[2- (dimethylamino)ethyl]carbamoyl}azetidin-3-yl)carbamate (1100 mg) at room temperature, and the mixture was stirred under nitrogen atmosphere at room temperature for six hours. The reaction mixture was concentrated under reduced pressure, thus obtaining 3-amino-N-[2-(dimethylamino)ethyl]azetidine-l- carboxamide n-(trifluoroacetic acid) salt (3000 mg) as an oily substance.
Production Example 86
Hydrogen chloride (4M DOX solution, 14 mL) was added to a dichloromethane (16 mL) and MeOH (16 mL) solution of tert-butyl [(3S)-l-{[2- (dimethylamino)ethyl]carbamoyl}pyrrolidin-3-yl](methyl)carbamate (1600 mg) under ice cooling, and the mixture was stirred under nitrogen atmosphere at room temperature for four hours. The reaction mixture was concentrated under reduced pressure, thus obtaining (3S)-N-[2-(dimethylamino)ethyl]-3- (methylamino)pyrrolidine-l-carboxyamide n-hydrochloride (1800 mg) as a foam-like solid.
Production Example 89 Under nitrogen atmosphere, borane dimethyl sulfide complex (2M THF solution, 361 pL) was added to a THF (10 mL) solution of tert-butyl {(lr,3r)-3-[2-(dimethylamino)- 2-oxoethoxy]cyclobutyl}carbamate (131 mg) at room temperature, and the mixture was stirred at room temperature for eight hours. Borane dimethyl sulfide complex (2M THF solution, 361 pL) was added under nitrogen atmosphere at room temperature, and the mixture was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution were added at room temperature, and extraction with chloroform/iPrOH (4/1) was performed three times. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (from hexane/ethyl acetate to chloroform/MeOH), thus obtaining tertbutyl {(lr,3r)-3-[2-(dimethylamino)ethoxy]cyclobutyl}carbamate (115 mg) as a solid.
Production Example 91
To a MeOH (10 mL) and TEA (10 mL) solution of (2R)-2-amino-2-(6-chloropyridin-3- yl)ethan-l-ol dihydrochloride (3.58 g), di-tert-butyl dicarbonate (4.77 g) was added, and the mixture was stirred at 25°C for two hours. Water was added to the reaction mixture, and extraction with ethyl acetate was performed three times. The collected organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/MeOH), thus obtaining tert-butyl [(lR)-l-(6-chloropyridin-3-yl)-2- hydroxyethyl]carbamate (4.3 g) as a solid.
Production Example 92
Under nitrogen atmosphere, boron trifluoride diethyl ether complex (520 pL) was added to a suspension of tert-butyl [(lR)-l-(4-bromophenyl)-2- hydroxyethyl]carbamate (20 g) and 2,2-dimethoxypropane (66 mL) in acetone (300 mL), and the mixture was stirred at room temperature for an hour. TEA (1.3 mL) was added, and after the mixture was stirred at room temperature for 10 minutes, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), thus obtaining tert-butyl (4R)-4-(4-bromophenyl)-2,2-dimethyl-l,3-oxazolidine-3-carboxylate (21.4 g) as a solid.
Production Example 94 In DMSO (10 mL), tert-butyl (4R)-4-(4-bromophenyl)-2,2-dimethyl-l,3-oxazolidine-3- carboxylate (3 g) was suspended, and 1,2,4-triazole (1.4 g), copper(I) iodide (315 mg), 8-quinolinol (495 mg) and potassium carbonate (2.4 g) were added at room temperature. The mixture was stirred under nitrogen atmosphere at 150°C overnight. Water was added to the reaction mixture, and extraction with ethyl acetate was performed three times. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), thus obtaining tert-butyl (4R)-2,2-dimethyl-4-[4-(lH-l,2,4- triazol-l-yl)phenyl]-l,3-oxazolidine-3-carboxylate (2.45 g) as a solid.
Production Example 97
To a DMAc (80 mL) solution of tert-butyl [(lR)-l-(4-bromophenyl)-2- hydroxyethyl]carbamate (5.01 g), 4-methyl-l,3-thiazole (2.88 mL) and potassium acetate (3.11 g) were added at room temperature, and after performing deaeration and argon substitution each three times, palladium(II) acetate (356 mg) was added at room temperature. The mixture was stirred under argon atmosphere at 100°C for 16 hours. After cooling to room temperature, ethyl acetate and water were added to the reaction mixture, and the insoluble matter was removed by filtration through celite (registered trademark). Water was added to the filtrate, and the aqueous layer was subjected to extraction with ethyl acetate three times. The combined organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified by basic silica gel column chromatography (hexane/ethyl acetate), thus obtaining tert-butyl {(lR)-2-hydroxy-l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl}carbamate (4.66 g) as a solid.
Production Example 100
Hydrogen chloride (4M DOX solution, 20 mL) was added portionwise to a dichloromethane (50 mL) and MeOH (40 mL) solution of tert-butyl {(lR)-2-hydroxy- l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl}carbamate (4.41 g) under ice cooling, and the mixture was stirred at room temperature for six hours. Diethyl ether was added to the reaction mixture, and the solid was taken by filtration, washed with diethyl ether and dried under reduced pressure, thus obtaining (2R)-2-amino-2-[4-(4-methyl- l,3-thiazol-5-yl)phenyl]ethan-l-ol n-hydrochloride (2.12 g) as a solid. The filtrate was concentrated under reduced pressure and dried by heating under reduced pressure, thus obtaining (2R)-2-amino-2-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethan-l-ol n- hydrochloride (2.01 g) as a solid.
Production Example 101
Under ice cooling, hydrogen chloride (4M DOX solution, 11 mL) was added to a dichloromethane (15 mL) solution of tert-butyl (4R)-2,2-dimethyl-4-[4-(lH-l,2,4- triazol-l-yl)phenyl]-l,3-oxazolidine-3-carboxylate (1.54 g), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, thus obtaining (2R)-2-amino-2-[4-(lH-l,2,4-triazol-l- yl)phenyl]ethan-l-ol n-hydrochloride (1.1 g) as a solid.
Production Example 106
A suspension of tert-butyl [(lR)-l-(4-bromophenyl)-2-hydroxyethyl]carbamate (15 g) in dichloromethane (100 mL) was cooled with ice, and TEA (9 mL) and methanesulfonyl chloride (4.4 mL) were added. The mixture was stirred under argon atmosphere at the same temperature for an hour. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was subjected to extraction with chloroform, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, thus obtaining (2R)-2-(4-bromophenyl)-2-[(tert-butoxycarbonyl)amino]ethyl methanesulfonate (19 g) as a solid.
Production Example 107
A mixture of (2R)-2-(4-bromophenyl)-2-[(tert-butoxycarbonyl)amino]ethyl methanesulfonate (13 g), dimethylamine (9.5M aqueous solution, 37 mL) and THF (30 mL) was stirred at room temperature for an hour and at 50°C overnight. After the reaction mixture was allowed to cool to room temperature, water was added, and the mixture was subjected to extraction with chloroform and dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography (chloroform/MeOH), thus obtaining tert-butyl [(lR)-l-(4-bromophenyl)-2-(dimethylamino)ethyl]carbamate (7.89 g) as a solid.
Production Example 110 At room temperature, tert-butyl (4R)-4-(4-bromophenyl)-2,2-dimethyl-l,3- oxazolidine-3-carboxylate (3 g), 4-methyl-l,3-oxazole-5-carboxylic acid (2.16 g), tetra-n-butylammonium chloride (2.34 g), cesium carbonate (4.11 g), bis(tri-tert- butylphosphine)palladium(O) (225 mg) and N-methyl-2-pyrrolidone (30 mL) were added, and the mixture was stirred under argon atmosphere at 160°C for an hour. The reaction mixture was allowed to cool to room temperature, and ethyl acetate and water were added. After filtration through celite (registered trademark), the filtrate was subjected to extraction with ethyl acetate three times. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), thus obtaining tert-butyl (4R)-2,2- dimethyl-4-[4-(4-methyl-l,3-oxazol-5-yl)phenyl]-l,3-oxazolidine-3-carboxylate (1.51 g) as an oily substance.
Production Example 112
Under ice cooling, HATU (13.8 g) was added to a DMF (150 mL) solution of N-(tert- butoxycarbonyl)-L-valyl-(4R)-4-hydroxy-L-proline (10 g), (2R)-2-amino-2-[4-(4- methyl-l,3-thiazol-5-yl)phenyl]ethan-l-ol n-hydrochloride (9.3 g) and DIPEA (21 mL), and the mixture was stirred under ice cooling for an hour. Under ice cooling, the reaction mixture was diluted with ethyl acetate and water, and the organic layer and the aqueous layer were separated by a separation operation. The organic layer was washed with saturated aqueous sodium chloride solution twice and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography (chloroform/MeOH), thus obtaining N-(tert-butoxycarbonyl)-L-valyl-(4R)-4-hydroxy-N-{(lR)-2-hydroxy-l-[4- (4-methyl-l,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (16.47 g) as a foam-like solid.
Production Example 113
Under ice cooling, DIPEA (4 mL) and HATU (2.2 g) were added to a suspension of (2R)- 2-amino-2-[4-(lH-l,2,4-triazol-l-yl)phenyl]ethan-l-ol n-hydrochloride (1.1 g) and N- (tert-butoxycarbonyl)-L-valyl-(4R)-4-hydroxy-L-proline (3 g) in dichloromethane (20 mL), and the mixture was stirred under argon atmosphere at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/MeOH), thus obtaining N-(tert-butoxycarbonyl)-L-valyl-(4R)-4-hydroxy-N-{(lR)-2-hydroxy-l-[4- (lH-l,2,4-triazol-l-yl)phenyl]ethyl}-L-prolinamide (1.77 g) as a solid. Production Example 118
Under ice cooling, l-(fluorosulfonyl)-2,3-dimethyl-lH-imidazol-3-ium trifluoromethanesulfonate (14.8 g) was added to a methyl tert-butyl ether (70 mL), water (60 mL) and MeCN (10 mL) solution of sodium azide (4 g), and the mixture was stirred at room temperature for an hour. The mixture was moved to a separatory funnel using methyl tert-butyl ether and water, and the organic layer and the aqueous layer were separated. The organic layer was washed once with water, and thus a solution of an azidation reagent was prepared. Under ice cooling, TFA (23 mL) was added to a dichloromethane (200 mL) solution of N-(tert-butoxycarbonyl)-L-valyl- (4R)-4-hydroxy-N-{(lR)-2-hydroxy-l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl}-L- prolinamide (16.47 g), and after the mixture was stirred at room temperature for four hours, the reaction mixture was concentrated under reduced pressure. DMSO (150 mL), water (30 mL) and potassium hydrogen carbonate (12.5 g) were added to the residue under ice cooling, and the mixture was stirred under ice cooling for 10 minutes. The prepared solution of the azidation reagent was added dropwise from a separatory funnel to the reaction mixture under ice cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and water, and the organic layer and the aqueous layer were separated by a separation operation. The organic layer was washed with saturated aqueous sodium chloride solution twice and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography (chloroform/MeOH), thus obtaining (4R)-l-[(2S)-2-azido-3-methylbutanoyl]-4- hydroxy-N-{(lR)-2-hydroxy-l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl}-L- prolinamide (11.6 g) as a foam-like solid.
Production Example 119
To a mixture of sodium azide (373 mg), methyl tert-butyl ether (6 mL) and water (6 mL), l-(fluorosulfonyl)-2,3-dimethyl-lH-imidazol-3-ium trifluoromethanesulfonate (2304 mg) and MeCN (0.3 mL) were added under ice cooling, and the mixture was stirred at the same temperature for 30 minutes and allowed to stand at room temperature for an hour. The aqueous layer was suctioned with a pipette and removed, and thus a solution of an azidation reagent was prepared. TFA (3 mL) was added to a dichloromethane (15 mL) solution of N-(tert-butoxycarbonyl)-L-valyl-(4R)-4-hydroxy- N-{(lR)-2-hydroxy-l-[4-(lH-l,2,4-triazol-l-yl)phenyl]ethyl}-L-prolinamide (2417 mg), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DMSO (6 mL) and water (3 mL), and potassium hydrogen carbonate (7026 mg) and the prepared solution of the azidation reagent were added at room temperature using methyl tertbutyl ether (3 mL). The mixture was stirred at room temperature for three hours, and saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution were added at room temperature. Extraction with chloroform/iPrOH (4/1) was performed six times. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (from hexane/ethyl acetate to chloroform/MeOH), thus obtaining (4R)-l-[(2S)-2-azido-3-methylbutanoyl]-4- hydroxy-N-{(lR)-2-hydroxy-l-[4-(lH-l,2,4-triazol-l-yl)phenyl]ethyl}-L-prolinamide (1503 mg) as a solid.
Production Example 123
Hydrogen chloride (4M DOX solution, 5 mL) was added to a MeOH (5 mL) solution of N-(tert-butoxycarbonyl)-L-valyl-(4R)-N-{(lR)-2-(dimethylamino)-l-[4-(4-methyl- l,3-thiazol-5-yl)phenyl]ethyl}-4-hydroxy-L-prolinamide (1.89 g), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, thus obtaining L-valyl-(4R)-N-{(lR)-2-(dimethylamino)-l-[4-(4- methyl-l,3-thiazol-5-yl)phenyl]ethyl}-4-hydroxy-L-prolinamide n-hydrochloride (2.14 g) as a solid.
Production Example 124
Under argon atmosphere, a mixture of (4R)-l-(tert-butoxycarbonyl)-4-hydroxy-L- proline (1.76 g), (2R)-2-amino-2-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethan-l-ol n- hydrochloride (2.12 g) and DMF (22 mL) was cooled with ice, and DIPEA (4.7 mL) and HATU (3.02 g) were added portionwise in a manner that the internal temperature was kept at 5°C or lower. The reaction mixture was stirred under ice cooling for an hour and at room temperature for an hour. The reaction mixture was cooled with ice, and after water (120 mL) and saturated aqueous sodium chloride solution (50 mL) were added, extraction with ethyl acetate was performed three times. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The aqueous layer was subjected to extraction with ethyl acetate/iPrOH (9/1) three times, and the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The organic layers were combined and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/MeOH), thus obtaining tert-butyl (2S,4R)-4-hydroxy-2-({(lR)-2-hydroxy-l-[4-(4-methyl-l,3- thiazol-5-yl)phenyl]ethyl}carbamoyl)pyrrolidine-l-carboxylate (3.09 g) as an oily substance.
Production Example 125
In EtOH (100 mL), tert-butyl (2S,4R)-4-hydroxy-2-({(lR)-2-hydroxy-l-[4-(4-methyl- l,3-thiazol-5-yl)phenyl]ethyl}carbamoyl)pyrrolidine-l-carboxylate (38.5 g) was dissolved, and methanesulfonic acid (26 mL) was added at room temperature. The mixture was stirred under nitrogen atmosphere at room temperature for three hours. The reaction mixture was concentrated, and the residue was purified by basic silica gel column chromatography (chloroform/MeOH), thus obtaining (4R)-4-hydroxy-N-{(lR)- 2-hydroxy-l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (27.01 g) as a solid.
Production Example 129
Under ice cooling, CDI (55 mg) was added to a THF (3 mL) solution of N-(tert- butoxycarbonyl)-N-methyl-l,2-ethylenediamine (60 mg), and the mixture was stirred under nitrogen atmosphere at room temperature for an hour. The reaction solution was concentrated under reduced pressure, and an iPrOH (3 mL) solution of (7M)-4- [(azetidin-3-yl)oxy]-6-cyclopropyl-7-[6-fluoro-5-methyl-l-(oxan-2-yl)-lH-indazol-4- yl]-2-[(2S)-2-methoxypropoxy]-8-[(lS)-l-phenylethoxy]quinoline (100 mg) was added to the residue at room temperature, and the mixture was stirred under nitrogen atmosphere at 90°C overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (from hexane/ethyl acetate to hexane/chloroform and further chloroform/MeOH), thus obtaining tert-butyl (2-{[3-({(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-l-(oxan-2-yl)- lH-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]-8-[(lS)-l-phenylethoxy]quinolin-4- yl}oxy)azetidine-l-carbonyl]amino}ethyl)methylcarbamate (117 mg) as a foam-like solid.
Production Example 132
To an iPrOH (13 mL) and water (2 mL) solution of L-valyl-(4R)-N-{(lR)-2- (dimethylamino)-l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl}-4-hydroxy-L- prolinamide n-hydrochloride (1.34 g), potassium carbonate (1.6 g), copper(II) sulfate pentahydrate (67 mg) and lH-imidazole-l-sulfonyl=azide=mono(tetrafluoroboric acid) salt (715 mg) were added at room temperature, and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture, iPrOH was added, and the filtrate obtained by filtration through celite (registered trademark) and washing with iPrOH was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (chloroform/MeOH) and then purified by silica gel column chromatography (chloroform/MeOH), thus obtaining (4R)-l-[(2S)-2-azido-3- methylbutanoyl]-N-{(lR)-2-(dimethylamino)-l-[4-(4-methyl-l,3-thiazol-5- yl)phenyl]ethyl}-4-hydroxy-L-prolinamide (725 mg) as a foam-like solid.
Production Example 133
In toluene (300 mL), 8-(benzyloxy)-4-tert-butoxy-6-cyclopropyl-7-[6-fluoro-5- methyl-l-(oxan-2-yl)-lH-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazoline (30 g) was dissolved, and 4-methylbenzene-l-sulfonic acid monohydrate (759 mg) was added at 25°C. The mixture was stirred under nitrogen atmosphere at 60°C for two hours. The mixture was combined with a reaction mixture obtained in the same manner (using 13 g of the raw material compound), and saturated aqueous sodium hydrogen carbonate solution and water were added. Extraction with ethyl acetate was performed three times. The collected organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate), thus obtaining a product (21.95 g).
TFA (4.74 mL) was added to a dichloromethane (20 mL) solution of a part (4 g) of the obtained product and triisopropylsilane (3.29 mL) at 0°C, and the mixture was stirred at 25°C for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and extraction with dichloromethane was performed three times. The collected organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The reaction was performed again under the same conditions, and the crude products obtained from the two batches were combined and then purified by silica gel column chromatography (dichloromethane/MeOH) twice. The residue was suspended in dichloromethane (24 mL), and the suspension was stirred at 25°C for 12 hours. The insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by supercritical fluid chromatography (Cellulose-2 column, 0.1% ammonia water/MeOH), and a fraction including a peak at the high polarity side was collected, thus obtaining a product (a single diastereomer, 2.8 g). To a dichloromethane (5 mL) solution of a part (500 mg) of the obtained product and 3,4-dihydro-2H-pyran (127 pL), 4-methylbenzene-l-sulfonic acid monohydrate (48 mg) was added, and the mixture was stirred at 25°C for 52 hours. Water was added to the reaction mixture, and extraction with dichloromethane was performed three times. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate), thus obtaining (7M)-8-(benzyloxy)-6-cyclopropyl-7- [6-fluoro-5-methyl-l-(oxan-2-yl)-lH-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-4-ol (480 mg) as a solid.
Production Example 134
To a THF (15 mL) solution of (7M)-6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6- fluoro-5-methyl-l-(oxan-2-yl)-lH-indazol-4-yl]-2-[(2S)-2- methoxypropoxy]quinazolin-4-ol (380 mg), PyBOP (560 mg) and cesium carbonate (340 mg) were added under ice cooling, and the mixture was stirred under argon atmosphere at room temperature for an hour. Under ice cooling, (ls,3s)-3-[(tert- butoxycarbonyl)amino]cyclobutyl 3-aminoazetidine-l-carboxylate (600 mg) and DIPEA (1.3 mL) were added, and the mixture was stirred under argon atmosphere at 50°C for an hour. The reaction mixture was filtered through celite (registered trademark) using chloroform. The filtrate was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (hexane/ethyl acetate), thus obtaining (ls,3R)-3-[(tert-butoxycarbonyl)amino]cyclobutyl 3-({(7M)- 6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-l-(oxan-2-yl)-lH- indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl}amino)azetidine-l- carboxylate (573 mg) as a solid.
Production Example 162
To a tBuOH (5 mL), water (5 mL) and THF (5 mL) solution of (ls,3R)-3-[(tert- butoxycarbonyl)amino]cyclobutyl 3-({(7M)-6-cyclopropyl-8-[(4- ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-l-(oxan-2-yl)-lH-indazol-4-yl]-2- [(2S)-2-methoxypropoxy]quinazolin-4-yl}amino)azetidine-l-carboxylate (573 mg), (4R)-l-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-N-{(lR)-2-hydroxy-l-[4-(4- methyl-l,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (320 mg) and sodium ascorbate (320 mg), copper(II) sulfate pentahydrate (170 mg) was added at room temperature, and the mixture was stirred at room temperature for an hour. Disodium ethylenediamine tetraacetate (1.2 g) was added at room temperature, and after the mixture was stirred at room temperature for an hour, saturated aqueous sodium hydrogen carbonate solution was added. The mixture was filtered through celite (registered trademark) using chloroform. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/MeOH), thus obtaining (ls,3R)-3-[(tert-butoxycarbonyl)amino]cyclobutyl 3-({(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-l-(oxan-2-yl)-lH-indazol-4-yl]-8-{[4- (l-{(2S)-l-[(2S,4R)-4-hydroxy-2-({(lR)-2-hydroxy-l-[4-(4-methyl-l,3-thiazol-5- yl)phenyl]ethyl}ca rba moyl)pyrrolidin- l-yl]-3-methyl-l-oxobutan-2-yl}-lH- 1,2,3- triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4- yl}amino)azetidine-l-carboxylate (773 mg) as a foam-like solid.
Production Example 186
To a mixture of 2-(trimethylsilyl)ethyl 3-({(7M)-6-cyclopropyl-8-[(4- ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-l-(oxan-2-yl)-lH-indazol-4-yl]-2- [(2S)-2-methoxypropoxy]quinolin-4-yl}oxy)azetidine-l-carboxylate (120 mg) and (4R)-l-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-N-{(lR)-2-hydroxy-l-[4-(lH- l,2,4-triazol-l-yl)phenyl]ethyl}-L-prolinamide (90 mg) in tBuOH (1 mL), THF (1 mL) and water (1 mL), anhydrous copper(II) sulfate (25 mg) and sodium ascorbate (66 mg) were added at room temperature, and the mixture was stirred under nitrogen atmosphere at room temperature for 30 minutes. Basic silica gel was added to the reaction mixture, and after concentration, the residue was purified by basic silica gel column chromatography (from hexane/chloroform to chloroform/MeOH), thus obtaining 2-(trimethylsilyl)ethyl 3-({(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-l- (oxan-2-yl)-lH-indazol-4-yl]-8-{[4-(l-{(2S)-l-[(2S,4R)-4-hydroxy-2-({(lR)-2- hydroxy-l-[4-(lH-l,2,4-triazol-l-yl)phenyl]ethyl}carbamoyl)pyrrolidin-l-yl]-3- methyl-l-oxobutan-2-yl}-lH-l,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2- methoxypropoxy]quinolin-4-yl}oxy)azetidine-l-carboxylate (197 mg) as a solid.
Production Example 188
To a tBuOH (5 mL), THF (10 mL) and water (5 mL) solution of tert-butyl 3-({(7M)-6- cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-2-(triphenylmethyl)- 2H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinolin-4-yl}oxy)azetidine-l- carboxylate (700 mg) and (4R)-l-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-N- {(lR)-2-hydroxy-l-[4-(lH-l,2,4-triazol-l-yl)phenyl]ethyl}-L-prolinamide (350 mg), anhydrous copper(II) sulfate (126 mg) and sodium ascorbate (350 mg) were added at room temperature, and the mixture was stirred under nitrogen atmosphere at room temperature for 30 minutes. Basic silica gel was added to the reaction mixture, and after concentration, the residue was purified by basic silica gel column chromatography (chloroform/MeOH). The target fraction was concentrated under reduced pressure.
The residue was dissolved in MeOH (10 mL), and methanesulfonic acid (469 pL) was added at room temperature. The mixture was stirred under nitrogen atmosphere at room temperature for 30 minutes and at 40°C for four hours. DIPEA (1.4 mL) was added to the reaction mixture at room temperature, and the reaction mixture was concentrated. The residue was purified by basic silica gel column chromatography (chloroform/MeOH), thus obtaining (4R)-l-[(2S)-2-(4-{4-[({(7M)-4-[(azetidin-3- yl)oxy]-6-cyclopropyl-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-2-[(2S)-2- methoxypropoxy]quinolin-8-yl}oxy)methyl]phenyl}-lH-l,2,3-triazol-l-yl)-3- methylbutanoyl]-4-hydroxy-N-{(lR)-2-hydroxy-l-[4-(lH-l,2,4-triazol-l- yl)phenyl]ethyl}-L-prolinamide (723 mg) as a solid.
Production Example 190
To a tBuOH (1 mL), THF (1 mL) and water (1 mL) solution of 2-(trimethylsilyl)ethyl 3- ({(7M)-6-cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-l-(oxan- 2-yl)-lH-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinolin-4-yl}oxy)azetidine-l- carboxylate (47 mg) and (4R)-l-[(2S)-2-azido-3-methylbutanoyl]-4-hydroxy-N- {(lR)-2-hydroxy-l-[4-(4-methyl-l,3-oxazol-5-yl)phenyl]ethyl}-L-prolinamide (33 mg), anhydrous copper(II) sulfate (11 mg) and sodium ascorbate (30 mg) were added at room temperature, and the mixture was stirred under nitrogen atmosphere at room temperature for 20 minutes. Basic silica gel was added to the reaction mixture, and after concentration, the residue was purified by basic silica gel column chromatography (chloroform/MeOH). The target fraction was concentrated.
The residue was dissolved in THF (3 mL), and TBAF (IM THF solution, 300 pL) was added at room temperature. The mixture was stirred under nitrogen atmosphere at 40°C for an hour. The reaction mixture was concentrated and purified by basic silica gel column chromatography (chloroform/MeOH), thus obtaining (4R)-l-[(2S)-2-(4-{4- [({(7M)-4-[(azetidin-3-yl)oxy]-6-cyclopropyl-7-[6-fluoro-5-methyl-l-(oxan-2-yl)-lH- indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinolin-8-yl}oxy)methyl]phenyl}-lH-
1.2.3-triazol-l-yl)-3-methylbutanoyl]-4-hydroxy-N-{(lR)-2-hydroxy-l-[4-(4-methyl-
1.3-oxazol-5-yl)phenyl]ethyl}-L-prolinamide (54 mg) as a solid.
Production Example 192 Under ice cooling, methanesulfonic acid (2 mL) was added to an iPrOH (15 mL) solution of (ls,3R)-3-[(tert-butoxycarbonyl)amino]cyclobutyl 3-({(7M)-6-cyclopropyl-7-[6- fluoro-5-methyl-l-(oxan-2-yl)-lH-indazol-4-yl]-8-{[4-(l-{(2S)-l-[(2S,4R)-4- hydroxy-2-({(lR)-2-hydroxy-l-[4-(4-methyl-l,3-thiazol-5- yl)phenyl]ethyl}ca rbamoyl)pyrrolidin- l-yl]-3-methyl- l-oxobutan-2-yl}- 1H- 1,2,3- triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4- yl}amino)azetidine-l-carboxylate (773 mg), and the mixture was stirred at 40°C for four hours. Under ice cooling, TEA (15 mL) was added, and then the reaction mixture was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (chloroform/MeOH), thus obtaining (ls,3R)-3- aminocyclobutyl 3-({(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-8- {[4-(l-{(2S)-l-[(2S,4R)-4-hydroxy-2-({(lR)-2-hydroxy-l-[4-(4-methyl-l,3-thiazol- 5-yl)phenyl]ethyl}carbamoyl)pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-yl}-lH-l,2,3- triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4- yl}amino)azetidine-l-carboxylate (769 mg) as a solid.
Production Example 193
Under ice cooling, TBAF (IM THF solution, 300 pL) was added to a THF (4 mL) solution of 2-(trimethylsilyl)ethyl 3-({(7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-l-(oxan-2-yl)- lH-indazol-4-yl]-8-{[4-(l-{(2S)-l-[(2S,4R)-4-hydroxy-2-({(lR)-2-hydroxy-l-[4- (lH-l,2,4-triazol-l-yl)phenyl]ethyl}ca rbamoyl)pyrrolidin-l-yl]-3-methyl-l-oxobutan- 2-yl}-lH-l,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinolin-4- yl}oxy)azetidine-l-carboxylate (195 mg), and the mixture was stirred at room temperature for an hour. TBAF (IM THF solution, 300 pL) was added at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and purified by basic silica gel column chromatography (chloroform/MeOH), thus obtaining (4R)-l-[(2S)-2-(4-{4- [({(7M)-4-[(azetidin-3-yl)oxy]-6-cyclopropyl-7-[6-fluoro-5-methyl-l-(oxan-2-yl)-lH- indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinolin-8-yl}oxy)methyl]phenyl}-lH- l,2,3-triazol-l-yl)-3-methylbutanoyl]-4-hydroxy-N-{(lR)-2-hydroxy-l-[4-(lH-l,2,4- triazol-l-yl)phenyl]ethyl}-L-prolinamide (157 mg) as a foam-like solid.
Production Example 195
To a THF (6 mL) solution of 2-(trimethylsilyl)ethyl 4-{[(7M)-6-cyclopropyl-4-[(l-{[2- (dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-[6-fluoro-5-methyl-l-(oxan-2- yl)-lH-indazol-4-yl]-8-{[4-(l-{(2S)-l-[(2S,4R)-4-hydroxy-2-({(lR)-2-hydroxy-l-[4- (4-methyl- l,3-thiazol-5-yl)phenyl]ethyl}carbamoyl)pyrrolidin- l-yl]-3-methyl-l- oxobutan-2-yl}-lH-l,2,3-triazol-4-yl)phenyl]methoxy}quinazolin-2- yl]oxy}piperidine-l-carboxylate (317 mg), TBAF (IM THF solution, 800 pL) and acetic acid (30 pL) were added at room temperature, and the mixture was stirred under argon atmosphere at 60°C for 15 hours. After allowing to cool to room temperature, chloroform/MeOH (5/1) and saturated aqueous ammonium chloride solution were added, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (chloroform/MeOH), thus obtaining (4R)-l-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(l-{[2- (dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-[6-fluoro-5-methyl-l-(oxan-2- yl)-lH-indazol-4-yl]-2-[(piperidin-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-lH-
1.2.3-triazol-l-yl)-3-methylbutanoyl]-4-hydroxy-N-{(lR)-2-hydroxy-l-[4-(4-methyl-
1.3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (348 mg) as a foam-like solid.
Production Example 196
In 1,2-dichloroethane (15 mL), (4R)-l-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(l-{[2- (dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-[6-fluoro-5-methyl-l-(oxan-2- yl)-lH-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-lH-
1.2.3-triazol-l-yl)-3-methylbutanoyl]-4-hydroxy-L-proline methyl ester (820 mg) was dissolved, and trimethyltin hydroxide (681 mg) was added. The mixture was stirred at 85°C for 24 hours. Water, saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution were added at room temperature, and extraction with chloroform/iPrOH (4/1) was performed five times. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated, thus obtaining (4R)-l-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(l-{[2- (dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-[6-fluoro-5-methyl-l-(oxan-2- yl)-lH-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-lH- l,2,3-triazol-l-yl)-3-methylbutanoyl]-4-hydroxy-L-proline (1119 mg) as a foam-like solid.
Production Example 197
To a dichloromethane (5 mL) solution of (4R)-l-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(l- {[2-(dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-[6-fluoro-5-methyl-l- (oxan-2-yl)-lH-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}- lH-l,2,3-triazol-l-yl)-3-methylbutanoyl]-4-hydroxy-L-proline (50 mg), HATU (27 mg), DIPEA (64 pl) and (2R)-2-amino-2-[4-(lH-pyrazol-l-yl)phenyl]ethan-l-ol n- hydrochloride (26 mg) were added at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (from hexane/ethyl acetate to chloroform/MeOH), thus obtaining (4R)-l-[(2S)-2-(4-{4-[({6- cyclopropyl-4-[(l-{[2-(dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-[6- fluoro-5-methyl-l-(oxan-2-yl)-lH-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-8- yl}oxy)methyl]phenyl}-lH-l,2,3-triazol-l-yl)-3-methylbutanoyl]-4-hydroxy-N- {(lR)-2-hydroxy-l-[4-(lH-pyrazol-l-yl)phenyl]ethyl}-L-prolinamide (34 mg) as a foam-like solid.
Production Example 198
To a DMF (2 mL) solution of (4R)-l-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(l-{[2- (dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-[6-fluoro-5-methyl-l-(oxan-2- yl)-lH-indazol-4-yl]-2-[(piperidin-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-lH-
1.2.3-triazol-l-yl)-3-methylbutanoyl]-4-hydroxy-N-{(lR)-2-hydroxy-l-[4-(4-methyl-
1.3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (50 mg), DIPEA (40 pL) and 2,2- difluoroethyl triflate (15 pL) were added under ice cooling, and the mixture was stirred under argon atmosphere at the same temperature for an hour. Saturated aqueous sodium chloride solution and chloroform/MeOH (4/1) were added to the reaction mixture, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure, thus obtaining (4R)-l-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-2-{[l-(2,2- difluoroethyl)piperidin-4-yl]oxy}-4-[(l-{[2- (dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-[6-fluoro-5-methyl-l-(oxan-2- yl)-lH-indazol-4-yl]quinazolin-8-yl}oxy)methyl]phenyl}-lH-l,2,3-triazol-l-yl)-3- methylbutanoyl]-4-hydroxy-N-{(lR)-2-hydroxy-l-[4-(4-methyl-l,3-thiazol-5- yl)phenyl]ethyl}-L-prolinamide (58.5 mg) as an oily substance.
Production Example 199
To a THF (1 mL) and MeCN (1 mL) solution of methyl 4-[({6-cyclopropyl-4-[(l-{[2- (dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-[6-fluoro-5-methyl-l-(oxan-2- yl)-lH-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinazolin-8- yl}oxy)methyl]benzoate (81 mg), sodium hydroxide (IM aqueous solution, 500 pL) was added at room temperature, and the mixture was stirred at 50°C for five hours. After hydrogen chloride (IM aqueous solution, 0.5 mL) and water were added, extraction with chloroform/iPrOH (4/1) was peformed, and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, thus obtaining 4-[({6-cyclopropyl-4-[(l-{[2-(dimethylamino)ethyl]carbamoyl}azetidin-3- yl)oxy]-7-[6-fluoro-5-methyl-l-(oxan-2-yl)-lH-indazol-4-yl]-2-[(2S)-2- methoxypropoxy]quinazolin-8-yl}oxy)methyl]benzoic acid (72 mg) as a solid.
In the same manner as in the production methods of the Production Examples shown above, the compounds shown in the tables below were produced. In addition, the production methods, the structures and the physiochemical data of the compounds of the Production Examples are shown in the tables below.
Example 1
Under ice cooling, methanesulfonic acid (180 pL) was added to an iPrOH (5 mL) solution of (ls,3R)-3-[(tert-butoxycarbonyl)amino]cyclobutyl 3-({(7M)-6-cyclopropyl-7-[6- fluoro-5-methyl-l-(oxan-2-yl)-lH-indazol-4-yl]-8-{[4-(l-{(2S)-l-[(2S,4R)-4- hydroxy-2-({(lR)-2-hydroxy-l-[4-(4-methyl-l,3-oxazol-5- yl)phenyl]ethyl}carbamoyl)pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-yl}-lH- 1,2,3- triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4- yl}amino)azetidine-l-carboxylate (95 mg), and the mixture was stirred at 50°C for four hours. The reaction mixture was diluted with chloroform and then filtered through a short column filled with basic silica gel using chloroform/MeOH (9/1), and the filtrate was concentrated under reduced pressure.
THF (5 mL), formaldehyde (37% aqueous solution, 50 pL) and sodium triacetoxyborohydride (60 mg) were added to the residue under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate solution was added under ice cooling to stop the reaction. After dilution with chloroform/iPrOH (3/1), the organic layer and the aqueous layer were separated by a separation operation, and the aqueous layer was subjected to extraction with chloroform/iPrOH (3/1) three times. The collected organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by ODS chromatography (0.1% formic acid MeCN/0.1% aqueous formic acid solution), and a fraction containing the target substance was collected. After dilution with chloroform/iPrOH (3/1) at room temperature, saturated aqueous sodium hydrogen carbonate solution was added. The organic layer and the aqueous layer were separated by a separation operation, and the aqueous layer was subjected to extraction with chloroform/iPrOH (3/1) three times. The collected organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. When the residue was dissolved in a small amount of dichloromethane/iPrOH (10/1) and hexane was added, a solid precipitated. The insoluble matter was taken by filtration, washed with water and then dried under reduced pressure at 50°C overnight, thus obtaining (ls,3R)-3-(dimethylamino)cyclobutyl 3-({(7M)-6-cyclopropyl-7-(6- fluoro-5-methyl-lH-indazol-4-yl)-8-{[4-(l-{(2S)-l-[(2S,4R)-4-hydroxy-2-({(lR)-2- hydroxy-l-[4-(4-methyl-l,3-oxazol-5-yl)phenyl]ethyl}carbamoyl)pyrrolidin-l-yl]-3- methyl- l-oxobutan-2-yl}- 1H- 1,2, 3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2- methoxypropoxy]quinazolin-4-yl}amino)azetidine-l-carboxylate (33.9 mg) as a solid.
Example 2
Under ice cooling, methanesulfonic acid (0.13 mL) was added to an iPrOH (5 mL) solution of (ls,3R)-3-[(tert-butoxycarbonyl)amino]cyclobutyl 3-({(7M)-6-cyclopropyl- 7-[6-fluoro-5-methyl-l-(oxan-2-yl)-lH-indazol-4-yl]-8-{[4-(l-{(2S)-l-[(2S,4R)-4- hydroxy-2-({(lR)-2-hydroxy-l-[4-(lH-l,2,4-triazol-l- yl)phenyl]ethyl}ca rbamoyl)pyrrolidin- l-yl]-3-methyl- l-oxobutan-2-yl}- 1H- 1,2,3- triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4- yl}amino)azetidine-l-carboxylate (52 mg), and the mixture was stirred at 50°C for four hours. The reaction mixture was diluted with chloroform and then filtered through a short column filled with basic silica gel using chloroform/MeOH (9/1), and the filtrate was concentrated under reduced pressure.
THF (5 mL), formaldehyde (37% aqueous solution, 30 pL) and sodium triacetoxyborohydride (40 mg) were added to the residue under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate solution was added under ice cooling to stop the reaction. After dilution with chloroform/iPrOH (3/1), the organic layer and the aqueous layer were separated by a separation operation, and the aqueous layer was subjected to extraction with chloroform/iPrOH (3/1) three times. The collected organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by ODS chromatography (0.1% formic acid MeCN/0.1% aqueous formic acid solution), and a fraction containing the target substance was collected. After dilution with chloroform/iPrOH (3/1) at room temperature, saturated aqueous sodium hydrogen carbonate solution was added. The organic layer and the aqueous layer were separated by a separation operation, and the aqueous layer was subjected to extraction with chloroform/iPrOH (3/1) three times. The collected organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. When the residue was dissolved in a small amount of dichloromethane/iPrOH (10/1) and hexane was added, a solid precipitated. The insoluble matter was taken by filtration, washed with water and then dried under reduced pressure at 50°C overnight, thus obtaining (ls,3R)-3-(dimethylamino)cyclobutyl 3-({(7M)-6-cyclopropyl-7-(6- fluoro-5-methyl-lH-indazol-4-yl)-8-{[4-(l-{(2S)-l-[(2S,4R)-4-hydroxy-2-({(lR)-2- hydroxy-l-[4-(lH-l,2,4-triazol-l-yl)phenyl]ethyl}carbamoyl)pyrrolidin-l-yl]-3- methyl-l-oxobutan-2-yl}-lH-l,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2- methoxypropoxy]quinazolin-4-yl}amino)azetidine-l-carboxylate (38.2 mg) as a solid.
Example 5
DIPEA (220 pL) and triphosgene (31 mg) were added to a mixture of N,N-dimethyl-3- azetidinemethanamine dihydrochloride (60 mg) in dichloromethane (3 mL) under ice cooling, and the mixture was stirred under nitrogen atmosphere at room temperature for an hour. Under ice cooling, (4R)-l-[(2S)-2-(4-{4-[({(7M)-4-[(azetidin-3-yl)oxy]- 6-cyclopropyl-7-[6-fluoro-5-methyl-l-(oxan-2-yl)-lH-indazol-4-yl]-2-[(2S)-2- methoxypropoxy]quinolin-8-yl}oxy)methyl]phenyl}-lH-l,2,3-triazol-l-yl)-3- methylbutanoyl]-4-hydroxy-N-{(lR)-2-hydroxy-l-[4-(lH-l,2,4-triazol-l- yl)phenyl]ethyl}-L-prolinamide (60 mg) was added, and the mixture was stirred under nitrogen atmosphere at room temperature for an hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and after extraction with chloroform three times, the organic layer was collected using a phase separator and concentrated. The residue was purified by basic silica gel column chromatography (chloroform/MeOH), and the target fraction was concentrated.
The residue was dissolved in MeOH (2 mL), and methanesulfonic acid (100 pL) was added at room temperature. The mixture was stirred under nitrogen atmosphere at room temperature overnight. The reaction mixture was concentrated and purified by ODS chromatography (MeCN/0.1% aqueous formic acid solution), and the target fraction was concentrated. The residue was dissolved in MeCN and water, and saturated aqueous sodium hydrogen carbonate solution was added. After extraction with chloroform/iPrOH (9/1) three times, the combined organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated. The residue was suspended in ethyl acetate, and the insoluble matter was taken by filtration and dried under reduced pressure, thus obtaining (4R)-l-[(2S)-2-(4-{4-[({(7M)-6- cyclopropyl-4-[(l-{3-[(dimethylamino)methyl]azetidine-l-carbonyl}azetidin-3- yl)oxy]-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin- 8-yl}oxy)methyl]phenyl}-lH-l,2,3-triazol-l-yl)-3-methylbutanoyl]-4-hydroxy-N- {(lR)-2-hydroxy-l-[4-(lH-l,2,4-triazol-l-yl)phenyl]ethyl}-L-prolinamide (33 mg) as a solid. Example 6
DIPEA (250 pL) and triphosgene (35 mg) were added to a mixture of N,N-dimethyl-3- azetidinemethanamine dihydrochloride (68 mg) in dichloromethane (3 mL) under ice cooling, and the mixture was stirred under nitrogen atmosphere at room temperature for an hour. Under ice cooling, (4R)-l-[(2S)-2-(4-{4-[({(7M)-4-[(azetidin-3-yl)oxy]- 6-cyclopropyl-7-[6-fluoro-5-methyl-l-(oxan-2-yl)-lH-indazol-4-yl]-2-[(2S)-2- methoxypropoxy]quinolin-8-yl}oxy)methyl]phenyl}-lH-l,2,3-triazol-l-yl)-3- methylbutanoyl]-4-hydroxy-N-{(lR)-2-hydroxy-l-[4-(4-methyl-l,3-oxazol-5- yl)phenyl]ethyl}-L-prolinamide (52 mg) was added, and the mixture was stirred under nitrogen atmosphere at room temperature for an hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and after extraction with chloroform three times, the organic layer was collected using a phase separator and concentrated. The residue was purified by basic silica gel column chromatography (chloroform/MeOH), and the target fraction was concentrated.
The residue was dissolved in MeOH (3 mL), and methanesulfonic acid (150 pL) was added at room temperature. The mixture was stirred under nitrogen atmosphere at room temperature overnight. The reaction mixture was concentrated and purified by ODS chromatography (MeCN/0.1% aqueous formic acid solution), and the target fraction was concentrated. The residue was dissolved in MeCN and water, and saturated aqueous sodium hydrogen carbonate solution was added. After extraction with chloroform/iPrOH (9/1) three times, the combined organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated. The residue was suspended in ethyl acetate, and the insoluble matter was taken by filtration and dried under reduced pressure, thus obtaining (4R)-l-[(2S)-2-(4-{4-[({(7M)-6- cyclopropyl-4-[(l-{3-[(dimethylamino)methyl]azetidine-l-carbonyl}azetidin-3- yl)oxy]-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin- 8-yl}oxy)methyl]phenyl}-lH-l,2,3-triazol-l-yl)-3-methylbutanoyl]-4-hydroxy-N- {(lR)-2-hydroxy-l-[4-(4-methyl-l,3-oxazol-5-yl)phenyl]ethyl}-L-prolinamide (30 mg) as a solid.
Example 11
Under ice cooling, formaldehyde (37% aqueous solution, 0.4 mL) and sodium triacetoxyborohydride (500 mg) were added to a THF (15 mL) solution of (ls,3R)-3- aminocyclobutyl 3-({(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-8- {[4-(l-{(2S)-l-[(2S,4R)-4-hydroxy-2-({(lR)-2-hydroxy-l-[4-(4-methyl-l,3-thiazol- 5-yl)phenyl]ethyl}carbamoyl)pyrrolidin-l-yl]-3-methyl-l-oxobutan-2-yl}-lH-l,2,3- triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinazolin-4- yl}amino)azetidine-l-carboxylate (769 mg), and the mixture was stirred at room temperature for an hour. Saturated aqueous sodium hydrogen carbonate solution was added under ice cooling to stop the reaction. After dilution with chloroform/iPrOH (3/1) at room temperature, the organic layer and the aqueous layer were separated by a separation operation, and the aqueous layer was subjected to extraction with chloroform/iPrOH (3/1) three times. The collected organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by ODS chromatography (0.1% formic acid MeCN/0.1% aqueous formic acid solution) twice, and a fraction containing the target substance was collected. Chloroform/iPrOH (3/1) and saturated aqueous sodium hydrogen carbonate solution were added at room temperature. The organic layer and the aqueous layer were separated by a separation operation, and the aqueous layer was subjected to extraction with chloroform/iPrOH (3/1) three times. The collected organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. When the residue was dissolved in a small amount of ethyl acetate/iPrOH (10/1) and hexane was added, a solid precipitated. The insoluble matter was taken by filtration, washed with water and then dried under reduced pressure at 50°C overnight, thus obtaining (ls,3R)-3-(dimethylamino)cyclobutyl 3-({(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl- lH-indazol-4-yl)-8-{[4-(l-{(2S)-l-[(2S,4R)-4-hydroxy-2-({(lR)-2-hydroxy-l-[4-(4- methyl-l,3-thiazol-5-yl)phenyl]ethyl}carbamoyl)pyrrolidin-l-yl]-3-methyl-l- oxobutan-2-yl}-lH-l,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2- methoxypropoxy]quinazolin-4-yl}amino)azetidine-l-carboxylate (370 mg) as a solid.
Example 12
In THF (15 mL), N,N-dimethylethylenediamine (230 pL) was dissolved, and CDI (335 mg) was added under ice cooling. The mixture was stirred at room temperature for an hour. Under ice cooling, an iPrOH (15 mL) solution of (4R)-l-[(2S)-2-(4-{4- [({(7M)-4-[(azetidin-3-yl)oxy]-6-cyclopropyl-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-
2-[(2S)-2-methoxypropoxy]quinolin-8-yl}oxy)methyl]phenyl}-lH-l,2,3-triazol-l-yl)-
3-methylbutanoyl]-4-hydroxy-N-{(lR)-2-hydroxy-l-[4-(lH-l,2,4-triazol-l- yl)phenyl]ethyl}-L-prolinamide (720 mg) was added, and the mixture was stirred at room temperature for 30 minutes and at 50°C for an hour. The reaction mixture was allowed to cool, and saturated aqueous sodium hydrogen carbonate solution was added. The mixture was subjected to extraction with chloroform/iPrOH (9/1) three times, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by ODS chromatography (MeCN/0.1% aqueous formic acid solution), and the target fraction was concentrated to around 10 mL. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was stirred at room temperature for an hour. The insoluble matter was taken by filtration, washed with water and dried under reduced pressure at 40°C, thus obtaining (4R)-l-[(2S)-2-(4- {4-[({(7M)-6-cyclopropyl-4-[(l-{[2-(dimethylamino)ethyl]ca rbamoyl}azetidin-3- yl)oxy]-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin- 8-yl}oxy)methyl]phenyl}-lH-l,2,3-triazol-l-yl)-3-methylbutanoyl]-4-hydroxy-N- {(lR)-2-hydroxy-l-[4-(lH-l,2,4-triazol-l-yl)phenyl]ethyl}-L-prolinamide (501 mg) as a solid.
Example 13
Triphosgene (215 mg) was dissolved in dichloromethane (30 mL), and (ls,3s)-3- (dimethylamino)cyclobutan-l-ol (265 mg) and DIPEA (1.28 mL) were added under ice cooling. The mixture was stirred under nitrogen atmosphere under ice cooling for 20 minutes and at room temperature for 30 minutes, and thus a solution of an active substance was prepared. The prepared solution of the active substance was added dropwise to a mixture of (4R)-l-[(2S)-2-(4-{4-[({(7M)-4-[(azetidin-3-yl)oxy]-6- cyclopropyl-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-2-[(2S)-2- methoxypropoxy]quinolin-8-yl}oxy)methyl]phenyl}-lH-l,2,3-triazol-l-yl)-3- methylbutanoyl]-4-hydroxy-N-{(lR)-2-hydroxy-l-[4-(lH-l,2,4-triazol-l- yl)phenyl]ethyl}-L-prolinamide (800 mg) in dichloromethane (20 mL) under ice cooling, and the mixture was stirred under nitrogen atmosphere under ice cooling for 30 minutes. Piperidine (160 pL) was added under ice cooling, and the mixture was stirred under ice cooling for 10 minutes and at room temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and after extraction with chloroform/iPrOH (9/1) three times, the organic layer was collected using a phase separator and concentrated. The residue was purified by ODS chromatography (MeCN/0.1% aqueous formic acid solution), and the target fraction was concentrated to around 5 mL. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was stirred at room temperature for an hour. The insoluble matter was taken by filtration and dried under reduced pressure, thus obtaining (ls,3R)-3-(dimethylamino)cyclobutyl 3-({(7M)-6- cyclopropyl-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-8-{[4-(l-{(2S)-l-[(2S,4R)-4- hydroxy-2-({(lR)-2-hydroxy-l-[4-(lH-l,2,4-triazol-l- yl)phenyl]ethyl}ca rbamoyl)pyrrolidin- l-yl]-3-methyl- l-oxobutan-2-yl}- 1H- 1,2,3- triazol-4-yl)phenyl]methoxy}-2-[(2S)-2-methoxypropoxy]quinolin-4- yl}oxy)azetidine-l-carboxylate (635 mg) as a solid. Example 14
In dichloromethane (2 mL), N,N-dimethyl-3-azetidinemethanamine dihydrochloride (47 mg) was suspended, and DIPEA (200 pL) and triphosgene (24 mg) were added under ice cooling. The mixture was stirred under nitrogen atmosphere at room temperature for an hour. Under ice cooling, (4R)-l-[(2S)-2-(4-{4-[({(7M)-4- [(azetidin-3-yl)oxy]-6-cyclopropyl-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-2-[(2S)-2- methoxypropoxy]quinolin-8-yl}oxy)methyl]phenyl}-lH-l,2,3-triazol-l-yl)-3- methylbutanoyl]-4-hydroxy-N-{(lR)-2-hydroxy-l-[4-(4-methyl-l,3-thiazol-5- yl)phenyl]ethyl}-L-prolinamide (90 mg) was added, and the mixture was stirred under nitrogen atmosphere under ice cooling for an hour. In another flask, N,N-dimethyl-3- azetidinemethanamine dihydrochloride (47 mg) was suspended in dichloromethane (2 mL), and DIPEA (200 pL) and triphosgene (24 mg) were added under ice cooling. The mixture was stirred under nitrogen atmosphere at room temperature for an hour. This was added to the reaction mixture under ice cooling, and the mixture was stirred under nitrogen atmosphere under ice cooling for an hour and at room temperature for 30 minutes. Piperidine (60 pL) was added under ice cooling, and the mixture was stirred under ice cooling for 10 minutes and at room temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and after extraction with chloroform/iPrOH (9/1) three times, the organic layer was collected using a phase separator and concentrated. The residue was purified by ODS chromatography (MeCN/0.1% aqueous formic acid solution), and the target fraction was concentrated. The residue was dissolved in MeCN/water, and saturated aqueous sodium hydrogen carbonate solution was added. After extraction with chloroform/iPrOH (9/1) three times, the combined organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated, thus obtaining (4R)-l-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(l-{3-
[(dimethylamino)methyl]azetidine-l-carbonyl}azetidin-3-yl)oxy]-7-(6-fluoro-5- methyl-lH-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-8- yl}oxy)methyl]phenyl}-lH-l,2,3-triazol-l-yl)-3-methylbutanoyl]-4-hydroxy-N- {(lR)-2-hydroxy-l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (28 mg) as a solid.
Example 15
TFA (300 pL) was added to a dichloromethane (3 mL) solution of (4R)-l-{(2S)-2-[4- (4-{[(6-cyclopropyl-7-[6-fluoro-5-methyl-l-(oxan-2-yl)-lH-indazol-4-yl]-2-[(oxan-4- yl)oxy]-4-{[l-(pyrimidin-2-yl)azetidin-3-yl]amino}quinazolin-8- yl)oxy]methyl}phenyl)-lH-l,2,3-triazol-l-yl]-3-methylbutanoyl}-4-hydroxy-N- {(lR)-2-hydroxy-l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (76 mg) at room temperature, and the mixture was stirred under nitrogen atmosphere at room temperature for four hours. The reaction mixture was concentrated under reduced pressure, and THF (3 mL), ice and saturated aqueous sodium hydrogen carbonate solution (3 mL) were added to the residue. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was subjected to extraction with chloroform/MeOH (10/1) three times and filtered using a phase separator. The filtrate was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (chloroform/MeOH), thus obtaining (4R)-l-[(2S)-2-{4-[4- ({[6-cyclopropyl-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-2-[(oxan-4-yl)oxy]-4-{[l- (pyrimidin-2-yl)azetidin-3-yl]amino}quinazolin-8-yl]oxy}methyl)phenyl]-lH-l,2,3- triazol-l-yl}-3-methylbutanoyl]-4-hydroxy-N-{(lR)-2-hydroxy-l-[4-(4-methyl-l,3- thiazol-5-yl)phenyl]ethyl}-L-prolinamide (37 mg) as a foam-like solid.
Example 28
Under ice cooling, TFA (0.3 mL) was added to a dichloromethane (10 mL) solution of (4R)-l-{(2S,3S)-2-[4-(4-{[(6-cyclopropyl-4-{[(3S)-l-{[2-
(dimethylamino)ethyl]carbamoyl}pyrrolidin-3-yl]oxy}-7-[6-fluoro-5-methyl-l-(oxan- 2-yl)-lH-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinazolin-8- yl)oxy]methyl}phenyl)-lH-l,2,3-triazol-l-yl]-3-methylpentanoyl}-4-hydroxy-N- {(lR)-2-hydroxy-l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (260 mg), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in THF (5 mL). Saturated aqueous sodium hydrogen carbonate solution was added under ice cooling, and the mixture was stirred under ice cooling for 30 minutes. The reaction mixture was diluted with chloroform and water, and the organic layer and the aqueous layer were separated by a separation operation. The aqueous layer was subjected to extraction with chloroform/iPrOH (3/1) three times. The collected organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by ODS chromatography (0.1% formic acid MeCN/0.1% aqueous formic acid solution), and a fraction including a peak at the low polarity side was collected and concentrated under reduced pressure to a liquid volume of 2-5 mL. When saturated aqueous sodium hydrogen carbonate solution was added to the residue under ice cooling, a solid precipitated. The insoluble matter was taken by filtration, washed with water and then dried under reduced pressure at 50°C overnight, thus obtaining (4R)-l-{(2S,3S)-2-[4-(4-{[(6-cyclopropyl-4-{[(3S)-l-{[2- (dimethylamino)ethyl]carbamoyl}pyrrolidin-3-yl]oxy}-7-(6-fluoro-5-methyl-lH- indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl)oxy]methyl}phenyl)-lH- l,2,3-triazol-l-yl]-3-methylpentanoyl}-4-hydroxy-N-{(lR)-2-hydroxy-l-[4-(4- methyl-l,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (a single diastereomer with undetermined configuration of axial chirality, 41.2 mg) as a solid.
Example 34
To a mixture of 2-(dimethylamino)ethyl 3-({(7M)-6-cyclopropyl-8-[(4- ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-l-(oxan-2-yl)-lH-indazol-4-yl]-2- [(2S)-2-methoxypropoxy]quinazolin-4-yl}amino)azetidine-l-carboxylate (35 mg) in THF (1 mL), tBuOH (1 mL) and water (1 mL), (4R)-l-[(2S)-2-azido-3- methylbutanoyl]-4-hydroxy-N-{(lR)-2-hydroxy-l-[4-(4-methyl-l,3-thiazol-5- yl)phenyl]ethyl}-L-prolinamide (21 mg), sodium ascorbate (19 mg) and anhydrous copper(II) sulfate (7 mg) were added at room temperature. The mixture was stirred under argon atmosphere at room temperature for two hours, and disodium ethylenediamine tetraacetate (15 mg) and ethyl acetate (about 5 mL) were added to the reaction mixture. The mixture was stirred vigorously at room temperature for an hour. Saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution were added, and extraction with chloroform/iPrOH (4/1) was performed three times. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (chloroform/MeOH).
The resulting residue was dissolved in dichloromethane (1 mL), and TFA (1 mL) was added at room temperature. The mixture was stirred for three hours. The reaction mixture was concentrated, and THF (3 mL) and saturated aqueous sodium hydrogen carbonate solution were added to the residue. The mixture was stirred for an hour. Saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution were added, and the reaction mixture was subjected to extraction with chloroform/iPrOH (4/1) three times. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by ODS chromatography (MeCN/0.1% aqueous formic acid solution), and the target fraction was collected. After saturated aqueous sodium hydrogen carbonate solution was added, extraction with chloroform/iPrOH (4/1) was performed three times. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, thus obtaining 2-(dimethylamino)ethyl 3-({(7M)-6-cyclopropyl-7-(6-fluoro-5-methyl- lH-indazol-4-yl)-8-{[4-(l-{(2S)-l-[(2S,4R)-4-hydroxy-2-({(lR)-2-hydroxy-l-[4-(4- methyl-l,3-thiazol-5-yl)phenyl]ethyl}carbamoyl)pyrrolidin-l-yl]-3-methyl-l- oxobutan-2-yl}-lH-l,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2- methoxypropoxy]quinazolin-4-yl}amino)azetidine-l-carboxylate (12 mg) as a solid.
Example 39
A mixture of (4R)-l-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(l-{[2- (dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-[6-fluoro-5-methyl-l-(oxan-2- yl)-lH-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-lH- l,2,3-triazol-l-yl)-3-methylbutanoyl]-4-hydroxy-L-proline (50 mg), DIPEA (50 pL), (3S)-3-amino-3-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]propan-l-ol n-hydrochloride (30 mg), HATU (30 mg) and dichloromethane (3 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (chloroform/MeOH).
TFA (75 pL) was added to a dichloromethane (3 mL) solution of the resulting solid, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in THF (3 mL). Saturated aqueous sodium hydrogen carbonate solution was added under ice cooling, and the mixture was stirred at room temperature for an hour. Chloroform and water were added to the reaction mixture, and after separation with a phase separator, the aqueous layer was subjected to extraction with chloroform/MeOH (4/1) three times. The filtrate was concentrated under reduced pressure, and the residue was purified by ODS chromatography (MeCN/0.1% aqueous formic acid solution). The target fraction was concentrated. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and after extraction with chloroform/iPrOH (5/1) twice, the collected organic layer was concentrated under reduced pressure, thus obtaining (4R)-l-[(2S)-2-(4-{4-[({6-cyclopropyl-4-[(l-{[2-
(dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-(6-fluoro-5-methyl-lH- indazol-4-yl)-2-[(oxan-4-yl)oxy]quinazolin-8-yl}oxy)methyl]phenyl}-lH-l,2,3- triazol-l-yl)-3-methylbutanoyl]-4-hydroxy-N-{(lS)-3-hydroxy-l-[4-(4-methyl-l,3- thiazol-5-yl)phenyl]propyl}-L-prolinamide (14.8 mg) as a solid.
Example 40
To a DMF (2 mL) solution of 4-[({6-cyclopropyl-4-[(l-{[2- (dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-[6-fluoro-5-methyl-l-(oxan-2- yl)-lH-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl}oxy)methyl]benzoic acid (29 mg), L-valyl-(4R)-4-hydroxy-N-{(lR)-2-hydroxy-l-[4-(4-methyl-l,3-thiazol- 5-yl)phenyl]ethyl}-L-prolinamide n-hydrochloride (26 mg), DIPEA (60 pL) and PyBOP (25 mg) were added under ice cooling, and the mixture was stirred under argon atmosphere at room temperature for three hours. Saturated aqueous sodium hydrogen carbonate solution and chloroform/MeOH (7/1) were added to the reaction mixture, and extraction with chloroform/MeOH (7/1) was peformed twice using a phase separator. The filtrate was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (chloroform/MeOH).
The resulting foam-like solid was dissolved in dichloromethane (3 mL), and TFA (220 pL) was added at room temperature. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and THF (3 mL), ice and saturated aqueous sodium hydrogen carbonate solution (3 mL) were added to the residue. The mixture was stirred at room temperature for an hour. The reaction mixture was subjected to extraction with chloroform/MeOH (7/1) three times, filtered using a phase separator and concentrated under reduced pressure. The residue was purified by ODS chromatography (MeOH/aqueous ammonium hydrogen carbonate solution), thus obtaining N-{4-[({6- cyclopropyl-4-[(l-{[2-(dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-(6- fluoro-5-methyl-lH-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8- yl}oxy)methyl]benzoyl}-L-valyl-(4R)-4-hydroxy-N-{(lR)-2-hydroxy-l-[4-(4-methyl-
1.3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (5 mg) as a solid.
Example 41
DIPEA (90 pL), 1-hydroxybenzotriazole (15 mg) and l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (21 mg) were added to a DMF (2 mL) solution of (4R)- l-[(2S)-2-(4-{4-[({(7M)-4-[(azetidin-3-yl)oxy]-6-cyclopropyl-7-(6-fluoro-5-methyl- lH-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-8-yl}oxy)methyl]phenyl}-lH-
1.2.3-triazol-l-yl)-3-methylbutanoyl]-4-hydroxy-N-{(lR)-2-hydroxy-l-[4-(lH-l,2,4- triazol-l-yl)phenyl]ethyl}-L-prolinamide (80 mg) and 4-(dimethylamino)butanoic acid hydrochloride (25 mg), and mixture was stirred under argon atmosphere at room temperature overnight. Chloroform/iPrOH (4/1) was added, and water and saturated aqueous sodium chloride solution were added. The organic layer and the aqueous layer were separated, and the aqueous layer was subjected to extraction with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by ODS chromatography (MeCN/0.1% aqueous formic acid solution). Saturated aqueous sodium hydrogen carbonate solution was added to the target fraction, and after extraction with chloroform/iPrOH (4/1) twice, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was washed with hexane and dried under reduced pressure, thus obtaining (4R)-l-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-({l-[4-
(dimethylamino)butanoyl]azetidin-3-yl}oxy)-7-(6-fluoro-5-methyl-lH-indazol-4-yl)-
2-[(2S)-2-methoxypropoxy]quinolin-8-yl}oxy)methyl]phenyl}-lH-l,2,3-triazol-l-yl)-
3-methylbutanoyl]-4-hydroxy-N-{(lR)-2-hydroxy-l-[4-(lH-l,2,4-triazol-l- yl)phenyl]ethyl}-L-prolinamide (28 mg) as a solid.
Example 43
Anhydrous copper(II) sulfate (13 mg) and sodium ascorbate (33 mg) were added to a tBuOH (1 mL), THF (1 mL) and water (1 mL) solution of tert-butyl (2-{[3-({(7M)-6- cyclopropyl-8-[(4-ethynylphenyl)methoxy]-7-[6-fluoro-5-methyl-l-(oxan-2-yl)-lH- indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinolin-4-yl}oxy)azetidine-l- carbonyl]amino}ethyl)methylcarbamate (60 mg) and (4R)-l-[(2S)-2-azido-3- methylbutanoyl]-4-hydroxy-N-{(lR)-2-hydroxy-l-[4-(4-methyl-l,3-thiazol-5- yl)phenyl]ethyl}-L-prolinamide (40 mg) at room temperature, and the mixture was stirred under nitrogen atmosphere at room temperature for 20 minutes. Basic silica gel was added to the reaction mixture, and after concentration, the residue was purified by basic silica gel column chromatography (chloroform/MeOH). The target fraction was concentrated.
The residue was dissolved in MeOH (2 mL), and methanesulfonic acid (50 pL) was added at room temperature. The mixture was stirred at room temperature for 30 minutes and at 50°C for six hours. The reaction mixture was concentrated and purified by ODS chromatography (MeCN/0.1% aqueous formic acid solution), and the target fraction was concentrated. The residue was dissolved in MeCN/water, and saturated aqueous sodium hydrogen carbonate solution was added. After extraction with chloroform/iPrOH (9/1) twice, the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated.
The residue was suspended in THF (2 mL), and formaldehyde (37% aqueous solution, 50 pL) and sodium triacetoxyborohydride (45 mg) were added at room temperature. After the mixture was stirred at room temperature for 10 minutes, water (0.1 mL) was added, and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and after extraction with chloroform/iPrOH (9/1) three times, the combined organic layer was separated with a phase separator and concentrated. The residue was purified by basic silica gel column chromatography (chloroform/MeOH), and the target fraction was concentrated. The residue was suspended in water, filtered and dried under reduced pressure, thus obtaining (4R)-l-[(2S)-2-(4-{4-[({(7M)-6- cyclopropyl-4-[(l-{[2-(dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-(6- fluoro-5-methyl-lH-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-8- yl}oxy)methyl]phenyl}-lH-l,2,3-triazol-l-yl)-3-methylbutanoyl]-4-hydroxy-N- {(lR)-2-hydroxy-l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide (15 mg) as a solid.
In the same manner as in the production methods of the Examples shown above, the compounds of the Examples shown in the tables below were produced. In addition, the production methods and the physiochemical data of the compounds of the Examples are shown in the tables below.
In the tables presented below, the following abbreviations are sometimes used.
PEx: Production Example No.,
Ex: Example No.,
PSyn: Production Example No. produced by the same method,
Syn: Example No. produced by the same method (for example, Syn 1 represents that it was produced by the same method as for Example 1),
Str: chemical structural formula (A compound with
Figure imgf000144_0001
in the chemical structural formula represents that the compound is a mixture of diastereomers with axial chirality of about 3.5: 1. A compound with "##" in the chemical structural formula represents that the axial chirality of the compound is single but the configuration is undetermined. A compound with "###" in the chemical structural formula represents that the compound is a mixture of diastereomers with axial chirality of about 3.5: 1 but the configuration is undetermined.), n HCI: n-hydrochloride (A compound with a Production Example No. represents a monohydrochloride to a trihydrochloride.), n TFA: n-trifluoroacetate (A compound with a Production Example No. represents a monotrifluoroacetate to tritrifluoroacetate.),
DAT: physiochemical data,
ESI+ : m/z value in mass spectrometry (ionization method ESI, [M + H]+ unless otherwise specified),
ESI-: m/z value in mass spectrometry (ionization method ESI, [M-H]- unless otherwise specified),
NMR: 6 value (ppm) of peak in 1H-NMR (500 MHz) in DMSO-d6 at 27°C, NMR (100°C): 6 value (ppm) of peak in 1H-NMR (500 MHz) in DMSO-de at 100°C, s: singlet (spectrum), d: doublet (spectrum), dd: double doublet (spectrum), ddd: double double doublet (spectrum), t: triplet (spectrum), dt: double triplet (spectrum), q: quartet (spectrum), m: multiplet (spectrum), br: broad (spectrum) (example: br s).
Table 1 - Production Examples (Intermediates)
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
817 k
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Table 2 - Characterisation data
Figure imgf000179_0001
Figure imgf000180_0001
Table 2 continued
Figure imgf000181_0001
Table 2 Continued
Figure imgf000182_0001
Figure imgf000183_0001
Table 2 Continued
Figure imgf000183_0002
Figure imgf000184_0001
Table 2 continued
Figure imgf000184_0002
Figure imgf000185_0001
Table 2 Continued
Figure imgf000185_0002
Table 3 - Example compounds
Figure imgf000186_0001
Table 3 Continued
Figure imgf000187_0001
Table 3 Continued
Figure imgf000188_0001
Table 3 Continued
Figure imgf000189_0001
Table 3 Continued
Figure imgf000190_0001
Table 3 Continued
Figure imgf000191_0001
Table 3 Continued
Figure imgf000192_0001
Table 3 Continued
Figure imgf000193_0001
Table 3 Continued
Figure imgf000194_0001
Table 3 Continued
Figure imgf000195_0001
Table 3 Continued
Figure imgf000196_0001
Table 3 Continued
Figure imgf000197_0001
Table 3 Continued
Figure imgf000198_0001
Table 3 Continued
Figure imgf000199_0001
Table 3 Continued
Figure imgf000200_0001
Table 4 - Characterisation data for Example compounds
Figure imgf000201_0001
Table 4 Continued
Figure imgf000202_0001
Table 4 Continued
Figure imgf000203_0001
Figure imgf000204_0001
Biological example 1
Evaluation of inhibitory activity on cell viability in human colorectal cancer cell line SW- 403 harboring KRAS G12V mutation and GP2d harboring KRAS G12D mutation under spheroid culture conditions.
Under spheroid culture condition, the inhibitory activity of investigated compounds on cell viability was evaluated.
SW-403 cells (DSMZ, ACC 294) or GP2d cells (ECACC, 95090714) were seeded at 500 cells/well in low-attachment 384-well round-bottom white plates (Sumitomo Bakelite).
SW-403 cells were cultured in Leibovitz's L-15 Medium (Thermo Fisher Scientific) and incubated at 37°C in 0% CO2. GP2d cells were cultured in Dulbecco's Modified Eagle's Medium (DMEM; Sigma-Aldrich) and incubated at 37°C in 5% CO2. All media were supplemented with 10% heat-inactivated fetal bovine serum (FBS).
On the following day, investigated compounds were added to each well to give a final concentration of 0.1, 0.3, 1.0, 3.0, 10, 30, 100, 300 or 1000 nmol/L. The wells for DMSO treatment were also prepared. The final concentration of DMSO in each well was 0.1% (volume/volume). On the 6th day after the addition of investigated compounds, cell viability was determined using a CellTiter-Glo 2.0 Assay (Promega). CellTiter-Glo Reagent was added to each well and luminescence intensity was measured using a multi-label reader ARVO-X3 (Perkin Elmer). Cell viability with luminescence intensity was normalized as 100% (average of luminescence intensity of cells treated with DMSO only) and 0% (average of luminescence intensity without cells). The half maximal (50%) inhibitory concentration (ICso) values of investigated compounds were calculated by Sigmoid-Emax non-linear regression analysis.
The IC50 values of investigated compounds are shown in the table below.
Figure imgf000205_0001
Biological example 2
Evaluation of inhibitory activity on cell viability in human lung cancer cell line LCLC- 97TM1 harboring KRAS G12V mutation and NCI-H358 harboring KRAS G12C mutation under spheroid culture conditions.
Under spheroid culture condition, the inhibitory activity of investigated compounds on cell viability was evaluated.
LCLC-97TM1 cells (DSMZ, ACC 388) or NCI-H358 cells (ATCC, CRL-5807) were seeded at 750 or 500 cells/well in low-attachment 384-well round-bottom white plates, respectively.
LCLC-97TM1 cells and NCI-H358 cells were cultured in RPMI-1640 Medium (FUJIFILM Wako Pure Chemical Corporation) supplemented with 10% heat-inactivated FBS. The cells were incubated at 37°C in 5% CO2.
On the following day, investigated compounds was added to each well to give a final concentration of 0.1, 0.3, 1.0, 3.0, 10, 30, 100, 300, 1000, 3000 or 10000 nmol/L. The wells for DMSO treatment were also prepared. The final concentration of DMSO in each well was 0.1% (volume/volume). On the 6th day after the addition of investigated compounds, cell viability was determined using a CellTiter-Glo 2.0 Assay. CellTiter- Gio Reagent was added to each well and luminescence intensity was measured using a multi-label reader ARVO-X3.
Cell viability with luminescence intensity was normalized as 100% (average of luminescence intensity of cells treated with DMSO only) and 0% (average of luminescence intensity without cells). The ICso values of investigated compounds were calculated by Sigmoid-Emax non-linear regression analysis.
The ICso values of investigated compounds are shown in the table below.
Figure imgf000206_0001
Biological example 3
Evaluation of anti-tumor activity in human colorectal cancer cell line SW-403 xenograft model harboring KRAS G12V mutation.
SW-403 cells were cultured in Leibovitz's L-15 Medium supplemented with 10% heat- inactivated FBS. The cells were incubated at 37°C in 0% CO2. SW-403 cells were suspended at 8.0 x 106 cells/mL as a mixture of 2: 1 amounts of VitroGel Hydrogel Matrix (TheWell Bioscience Inc.) and phosphate buffered saline (PBS). Cell suspension was subcutaneously inoculated into from 4 to 6 weeks old nude mice (BALB/c nu [nu/nu]) (The Jackson Laboratories Japan, Inc.) at 8.0 x 105 cells/0.1 mL/mouse and allowed to grow.
Two to three weeks after inoculation, SW-403 xenograft mice were randomized based on tumor volume. Each group had 5 individuals and received intravenous administration of either vehicle or investigated compounds. The compounds were dissolved in 4% ethanol/0.5% (2-hydroxyprppyl)-[3-cyclodextrin/9% PEG-40 hydrogenated castor oil in 5% glucose solution. The compounds were administered once a week for a total of two doses. Tumor diameters and body weights were measured two to three times a week. Tumor volume was calculated as follows:
The day of the randomization was designated as day 0.
Tumor volume [mm3] = (length of tumor [mm]) x (width of tumor [mm])2 x 0.5
In addition, tumor growth inhibition rate was calculated using the following formula:
Tumor growth inhibition rate [%] = 100 x [1 - (difference of mean tumor volume of each group on day 14 and day 0 [mm3]) / (difference of mean tumor volume in vehicle group on day 14 and day 0 [mm3])]
The results of investigated compounds are shown in the table below.
Figure imgf000207_0001
Biological example 4
Evaluation of anti-tumor activity in human lung cancer cell line LCLC-97TM1 xenograft model harboring KRAS G12V mutation
LCLC-97TM1 cells were cultured in RPMI-1640 Medium supplemented with 10% heat- inactivated FBS. These cells were incubated at 37°C in 5% CO2. LCLC-97TM1 cells were suspended at 3.0 x 107 cells/mL as a mixture of 2: 1 amounts of VitroGel Hydrogel Matrix and PBS. Cell suspension was subcutaneously inoculated into from 4 to 6 weeks old nude mice at 3.0 x 106 cells/0.1 mL/mouse and allowed to grow.
Two to three weeks after inoculation, LCLC-97TM1 xenograft mice were randomized based on tumor volume. Each group had 5 individuals and received intravenous administration of either vehicle or investigated compounds. The compounds were dissolved in the same vehicle as experiment example 3. The compounds were administered once a week for a total of two doses. Tumor diameters and body weights were measured two to three times a week.
Tumor volume and tumor growth inhibition rate were calculated using the same formula as experiment example 3. In addition, tumor regression rate was calculated in groups whose tumor growth inhibition exceeded 100% as follows:
Tumor regression rate [%] = 100 x [1 - (mean tumor volume of each group on day 14 [mm3]) / (mean tumor volume of each group on day 0 [mm3])
The results of investigated compounds are shown in the table below.
Figure imgf000208_0001
Biological example 5
Evaluation of anti-tumor activity in human colorectal cancer cell line GP2d xenograft model harboring KRAS G12D mutation.
GP2d cells are cultured in DMEM Medium supplemented with 10% heat-inactivated FBS. The cells are incubated at 37°C in 5% CO2. GP2d cells are suspended at 4.0 x 107 cells/mL as a mixture of 2: 1 amounts of VitroGel Hydrogel Matrix (TheWell Bioscience Inc.) and PBS. Cell suspension is subcutaneously inoculated into from 4 to 6 weeks old nude mice at 4.0 x 106 cells/0.1 mL/mouse and allowed to grow.
Two to three weeks after inoculation, GP2d xenograft mice are randomized based on tumor volume. Each group has 5 individuals and receives intravenous administration of either vehicle or investigated compounds. The compounds are dissolved in the same vehicle as experiment example 3. The compounds are administered once a week for a total of two doses. Tumor diameters and body weights are measured two to three times a week.
Tumor volume, tumor growth inhibition rate and tumor regression rate are calculated using the same formula as experiment example 3 and 4.
Biological example 6 Evaluation of anti-tumor activity in human lung cancer cell line NCI-H358 xenograft model harboring KRAS G12C mutation.
NCI-H358 cells are cultured in RPMI-1640 Medium supplemented with 10% heat- inactivated FBS. The cells are incubated at 37°C in 5% CO2. NCI-H358 cells are suspended at 5.0 x 107 cells/mL as a mixture of 2: 1 amounts of VitroGel Hydrogel Matrix and PBS. Cell suspension is subcutaneously inoculated into from 4 to 6 weeks old nude mice at 5.0 x 106 cells/0.1 mL/mouse and allowed to grow.
Two to three weeks after inoculation, NCI-H358 xenograft mice are randomized based on tumor volume. Each group has 5 individuals and receives intravenous administration of either vehicle or investigated compounds. The compounds are dissolved in the same vehicle as experiment example 3. The compounds are administered once a week for a total of two doses. Tumor diameters and body weights are measured two to three times a week.
Tumor volume, tumor growth inhibition rate and tumor regression rate are calculated using the same formula as experiment example 3 and 4.
Biological examples conclusion
On the basis of the results of the biological examples described above, the compounds of the invention described in this patent are expected to be effective to colorectal and lung cancers, especially cancers having one or more of the KRAS G12V, G12D and G12C mutations.

Claims

Claims
1. A compound of the formula (I) or a salt thereof, for use in the treatment of colorectal cancer and/or lung cancer,
Figure imgf000210_0001
wherein (in formula (I)),
A is CRA or N, wherein RA is H or C1-3 alkyl,
X1 is -CH2- or -O-,
R1 is naphthyl optionally substituted with OH or the formula (II) below,
Figure imgf000210_0002
wherein Rla is H, methyl, F or Cl, and
Rlb is F, Cl, methyl or ethyl,
R2 is H, halogen, C1-3 alkyl optionally substituted with a group selected from the group consisting of OH and OCH3, cyclopropyl or vinyl,
R3 is a group selected from the group consisting of the formula (III), the formula (IV), the formula (V), the formula (VI), the formula (VII), the formula (VIII), the formula (IX), the formula (X), the formula (XI) and the formula (XXXV) below,
Figure imgf000210_0003
wherein R3a is -(CH2)PCHR3f-NRN 1RN2; -(CH2)PCHR3f-OR3g; a 5-membered or 6- membered saturated heterocyclic group which is optionally substituted with a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene- NRN1RN2 and -NRN 1RN2 and which contains one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms; or C3-6 cycloalkyl optionally substituted with a group selected from the group consisting of C1- 3 alkyl, C1-3 alkylene-OR3g, C1-3 alkyl-NRN1RN2, -OR3g and -NRN1RN2, R3b is H or C1-3 alkyl, R3c and R3d are -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; a 4-membered to 6- membered saturated heterocyclic group which is optionally substituted with a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene- NRN1RN2 and -NRN1RN2 and which contains one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms; or C3-6 cycloalkyl optionally substituted with a group selected from the group consisting of C1- 3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, -OR3g and -NRN1RN2, R3e is -O-C2-3 alkylene-NRN1RN2, R3f is H, F or C1-3 alkyl, R3g is H or C1-3 alkyl, R3h is optionally substituted 5-membered heteroaryl containing one to four hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring- constituting atoms or optionally substituted 6-membered heteroaryl containing one to three nitrogen atoms, R3i groups, which are the same as or different from each other, are groups selected from the group consisting of H, OH, optionally substituted C1-3 alkyl, -O- optionally substituted C1-3 alkyl, -NH-optionally substituted C1-3 alkyl, -N-(optionally substituted C1-3 alkyl)2, halogen, -CN and oxo, or two R3i groups on a same carbon atom, together with the neighboring carbon atom, may form a ring selected from the group consisting of C3-6 cycloalkane and a 4- membered to 6-membered saturated hetero ring containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms to form a spiro ring as the compound of the formula (XXXV), wherein the spiro ring is optionally substituted with one or two groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen and oxo, or R3i groups on two neighboring carbon atoms, together with the two carbon atoms, may form a ring selected from the group consisting of C3-6 cycloalkane and a 4-membered to 6-membered saturated hetero ring containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms to form a condensed ring as the compound of the formula (XXXV), wherein the condensed ring is optionally substituted with one or two groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen and oxo, or R3i groups on two carbon atoms which are not neighboring, together with the two carbon atoms, may form a cross-linked structure composed of one or two carbon atoms, wherein the compound of the formula (XXXV) having the cross-linked structure is optionally substituted with one or two groups selected from the group consisting of C1-3 alkyl, -O-(C1-3 alkyl), OH, halogen and oxo, RN1 and RN2, which are the same as or different from each other, are H or C1-3 alkyl, or RN1 and RN2, together with the nitrogen atom to which they are attached, may form an optionally substituted 4-membered to 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, or R3f and RN1, together with the carbon atom and the nitrogen atom to which they are attached, may form an optionally substituted 4-membered to 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, X2 is -O-, -NH- or -N(C1-3 alkyl)-, X3 is O or S, X4 is -CH2-, -CH2-CH2- or -O-CH2-, n is 1 or 2, p is 1 or 2, and q is an integer of 1 to 8, with the proviso that X2 in the formula (IV) is -O-, -NH- or -N(C2-3 alkyl)- when R3c is -(CH2)pCHR3f-NRN1RN2, R4 is C1-6 alkyl optionally substituted with a group selected from the group consisting of F, OH, OCH3, R4a, cyclopropyl, N(R4a)2, pyrrolidinyl optionally substituted with R4a and tetrahydrofuranyl optionally substituted with R4a; piperidinyl optionally substituted with R4b; or tetrahydropyranyl optionally substituted with R4a, wherein R4a is C1-3 alkyl optionally substituted with F, and R4b is C1-3 alkyl substituted with one to three F, R5 is methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, C3-6 cycloalkylmethyl or C3-6 cycloalkyl, R6a and R6b, which are the same as or different from each other, are H or C1-6 alkyl optionally substituted with a group selected from the group consisting of F, OH, OCH3 and N(CH3)2, or R6a and R6b, together with the carbon to which they are attached, may form optionally substituted C3-6 cycloalkane or an optionally substituted 4-membered to 6- membered saturated hetero ring containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, R7 is an optionally substituted 4-membered to 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, optionally substituted 5-membered heteroaryl containing one to four hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms or 6- membered heteroaryl containing one to three nitrogen atoms,
W is optionally substituted phenylene or optionally substituted 6-membered heteroarenediyl containing one to three nitrogen atoms,
Y is phenylene optionally substituted with F or Cl or pyridinediyl,
L is -(L1-L2-L3-L4)-, wherein L1, L2, L3 and L4, which are the same as or different from each other, are groups selected from the group consisting of a bond, -O-, -NRL1-, optionally substituted pyrrolidinediyl, optionally substituted piperidinediyl, optionally substituted piperazinediyl, optionally substituted C1-3 alkylene and C=O, wherein RL1 is H or C1-3 alkyl, and
Z is NH or 5-membered heteroarenediyl containing one to four hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, or Y-L-Z is the formula (XII) below,
Figure imgf000213_0001
2. The compound, or salt thereof, for use according to Claim 1, wherein R3 is a group selected from the group consisting of the formula (III), the formula (IV), the formula (V), the formula (VI), the formula (VII), the formula (VIII), the formula (IX), the formula (X) and the formula (XI) below,
Figure imgf000213_0002
wherein R3a is -(CH2)PCHR3f-NRN1RN2; -(CH2)PCHR3f-OR3g; a 4-membered to 6- membered saturated heterocyclic group which is optionally substituted with a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene- NRN1RN2 and -NRN 1RN2 and which contains one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms; or C3-6 cycloalkyl optionally substituted with a group selected from the group consisting of C1- 3 alkyl, C1-3 alkylene-OR3g, C1-3 alkyl-NRN1RN2, -OR3g and -NRN1RN2, R3b is H or C1-3 alkyl, R3c and R3d are -(CH2)pCHR3f-NRN1RN2; -(CH2)pCHR3f-OR3g; a 4-membered to 6- membered saturated heterocyclic group which is optionally substituted with a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene- NRN1RN2 and -NRN1RN2 and which contains one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms; or C3-6 cycloalkyl optionally substituted with a group selected from the group consisting of C1- 3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene-NRN1RN2, -OR3g and -NRN1RN2, R3e is -O-C2-3 alkylene-NRN1RN2, R3f is H, F or C1-3 alkyl, R3g is H or C1-3 alkyl, R3h is optionally substituted 5-membered heteroaryl containing one to four hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring- constituting atoms or optionally substituted 6-membered heteroaryl containing one to three nitrogen atoms, RN1 and RN2, which are the same as or different from each other, are H or C1-3 alkyl, or RN1 and RN2, together with the nitrogen atom to which they are attached, may form an optionally substituted 4-membered to 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, or R3f and RN1, together with the carbon atom and the nitrogen atom to which they are attached, may form an optionally substituted 4-membered to 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, X2 is -O-, -NH- or -N(C1-3 alkyl)-, X3 is O or S, n is 1 or 2, and p is 1 or 2, with the proviso that X2 in the formula (IV) is -O-, -NH- or -N(C2-3 alkyl)- when R3c is -(CH2)pCHR3f-NRN1RN2.
3. The compound, or salt thereof, for use according to Claim 1 or Claim 2, wherein Y is phenylene optionally substituted with F or Cl or pyridinediyl, L is a bond, C1-3 alkylene, C=O or a group selected from the group consisting of the formula (XIII), the formula (XIV), the formula (XV), the formula (XVI), the formula (XVII) and the formula (XVIII) below,
Figure imgf000215_0001
wherein RL1 is H or C1-3 alkyl,
RL2 and RL3, which are the same as or different from each other, are H, F, OH, OCH3 or optionally substituted C1-3 alkyl,
RL is CH or N, and m is 1 or 2, and
Z is NH or a group selected from the group consisting of the formula (XIX), the formula (XX), the formula (XXI) and the formula (XXII) below,
Figure imgf000215_0002
4. The compound, or salt thereof, for use according to any one of Claims 1 to 3, wherein A is CRA or N, wherein RA is H,
X1 is -O-,
R6a and R6b, which are the same as or different from each other, are H or C1-6 alkyl optionally substituted with a group selected from the group consisting of F, OH, OCH3 and N(CH3)2, or
R6a and R6b, together with the carbon to which they are attached, may form optionally substituted C3-6 cycloalkane,
R7 is a group selected from the group consisting of the formula (XXIII), the formula (XXIV), the formula (XXV), the formula (XXVI), the formula (XXVII), the formula (XXVIII), the formula (XXIX), the formula (XXX), the formula (XXXI), the formula (XXXII) and the formula (XXXIII) below,
Figure imgf000216_0001
wherein R7a and R7b, which are the same as or different from each other, are H or Ci-3 alkyl optionally substituted with OH, and
W is the formula (XXXIV) below, w-w
HJ2 H
(XXXIV) wherein W1 is CH, CF, CO or CCH3, and
W2 is CH, CF, CO, CCH3 or N.
5. The compound, or salt thereof, for use according to any one of Claims 1 to 4, wherein R1 is the formula (II) below,
Figure imgf000216_0002
wherein Rla is H, methyl, F or Cl, and
Rlb is F, Cl, methyl or ethyl,
R2 is halogen, C1-3 alkyl optionally substituted with a group selected from the group consisting of OH and OCH3, cyclopropyl or vinyl,
R3 is a group selected from the group consisting of the formula (III), the formula (IV), the formula (V), the formula (VUI-a) and the formula (X) below,
Figure imgf000216_0003
wherein R3a is -(CH2)PCHR3f-NRN 1RN2; -(CH2)PCHR3f-OR3g; a 5-membered or 6- membered saturated heterocyclic group which is optionally substituted with a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene- NRN1RN2 and -NRN 1RN2 and which contains one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms; or C3-6 cycloalkyl optionally substituted with a group selected from the group consisting of Ci- 3 alkyl, Ci-3 alkylene-OR3g, C1-3 alkyl-NRN1RN2, -OR3g and -NRN 1RN2,
R3b is H or methyl,
R3c and R3d are -(CH2)PCHR3f-NRN1RN2; -(CH2)PCHR3f-OR3g; a 4-membered to 6- membered saturated heterocyclic group which is optionally substituted with a group selected from the group consisting of C1-3 alkyl, C1-3 alkylene-OR3g, C1-3 alkylene- NRN1RN2 and -NRN 1RN2 and which contains one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms; or C3-6 cycloalkyl optionally substituted with a group selected from the group consisting of Ci- 3 alkyl, C1-3 alkylene-OR3g, C1-3 alkyl-NRN1RN2, -OR3g and -NRN 1RN2,
R3f is H, F or C1-3 alkyl,
R3g is H or C1-3 alkyl,
RN1 and RN2, which are the same as or different from each other, are H or C1-3 alkyl, or
RN1 and RN2, together with the nitrogen atom to which they are attached, may form an optionally substituted 4-membered to 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, or
R3f and RN 1, together with the carbon atom and the nitrogen atom to which they are attached, may form an optionally substituted 4-membered to 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms,
X2 is -O-, -NH- or -N(CI-3 alkyl)-,
X3 is O or S, n is 1 or 2, and p is 1 or 2, with the proviso that X2 in the formula (IV) is -O-, -NH- or -N(C2-3 alkyl)- when R3c is -(CH2)PCHR3f-NRN1RN2,
Y is phenylene optionally substituted with F or Cl or pyridinediyl,
L is a bond, C=O or a group selected from the group consisting of the formula (XIII) and the formula (XIV) below,
Figure imgf000217_0001
wherein RL1 is H or C1-3 alkyl,
RL2 and RL3, which are the same as or different from each other, are H, F, OH, OCH3 or optionally substituted C1-3 alkyl, and m is 1 or 2, and Z is NH or a group selected from the group consisting of the formula (XIX), the formula (XX), the formula (XXI) and the formula (XXII) below,
Figure imgf000218_0001
6. The compound, or salt thereof, for use according to any one of Claims 1 to 5, wherein R3 is a group selected from the group consisting of the formula (Ill-a), the formula (IV-a), the formula (V-a), the formula (VUI-a) and the formula (X) below,
Figure imgf000218_0002
wherein R3a is -(CH2)PCHR3f-NRN 1RN2; -(CH2)PCHR3f-OR3g; pyrrolidinyl optionally substituted with C1-3 alkyl; piperidinyl optionally substituted with C1-3 alkyl; or C3-6 cycloalkyl optionally substituted with a group selected from the group consisting of Ci- 3 alkyl, C1-3 alkylene-OR3g, C1-3 alkyl-NRN1RN2, -OR3g and -NRN 1RN2,
R3b is H or methyl,
R3c is -(CH2)PCHR3f-NRN1RN2; -(CH2)PCHR3f-OR3g; pyrrolidinyl optionally substituted with C1-3 alkyl; piperidinyl optionally substituted with C1-3 alkyl; or C3-6 cycloalkyl optionally substituted with a group selected from the group consisting of Ci- 3 alkyl, C1-3 alkylene-OR3g, C1-3 alkyl-NRN1RN2, -OR3g and -NRN 1RN2,
R3f is H, F or C1-3 alkyl,
R3g is H or C1-3 alkyl,
RN1 and RN2, which are the same as or different from each other, are H or C1-3 alkyl, or
RN1 and RN2, together with the nitrogen atom to which they are attached, may form an optionally substituted 4-membered to 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, or
R3f and RN 1, together with the carbon atom and the nitrogen atom to which they are attached, may form an optionally substituted 4-membered to 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms, X2 is -O- or -NH- or -N(CH3)-,
X3 is O or S, and p is 1 or 2, with the proviso that X2 in the formula (IV-a) is -O- or -NH- when R3c is - (CH2)PCHR3f-NRN1RN2,
R4 is Ci-6 alkyl optionally substituted with a group selected from the group consisting of F, OH, OCH3, R4a, cyclopropyl, N(R4a)2, pyrrolidinyl optionally substituted with R4a and tetra hydrofuranyl; piperidinyl optionally substituted with R4b; or tetra hydropyranyl, wherein R4a is C1-3 alkyl, and
R4b is C1-3 alkyl substituted with one to three F,
R7 is a group selected from the group consisting of the formula (XXIII), the formula (XXIV), the formula (XXVI), the formula (XXVIII) and the formula (XXXIII) below,
Figure imgf000219_0001
wherein R7a and R7b, which are the same as or different from each other, are H or C1-3 alkyl optionally substituted with OH,
Y is phenylene optionally substituted with F or Cl, and
Z is NH or a group selected from the group consisting of the formula (XIX), the formula (XX), the formula (XXI) and the formula (XXII) below.
Figure imgf000219_0002
7. The compound, or salt thereof, for use according to any one of Claims 1 to 6, wherein R1 is the formula (Il-a) below,
Figure imgf000219_0003
R2 is cyclopropyl,
R3 is a group selected from the group consisting of the formula (Ill-a), the formula (IV-a), the formula (V-a), the formula (VUI-a) and the formula (X) below,
Figure imgf000220_0001
wherein R3a is -(CH2)PCHR3f-NRN 1RN2 or -(CH2)PCHR3f-OR3g,
R3b is H,
R3c is -(CH2)PCHR3f-NRN1RN2; pyrrolidinyl optionally substituted with C1-3 alkyl; or C3-6 cycloalkyl optionally substituted with -NRN 1RN2,
R3f is H,
R3g is H,
RN1 and RN2, which are the same as or different from each other, are H or C1-3 alkyl, or
RN1 and RN2, together with the nitrogen atom to which they are attached, may form an optionally substituted 4-membered to 6-membered saturated heterocyclic group containing one or two hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen as ring-constituting atoms,
X2 is -O- or -NH-,
X3 is O or S, and p is 1 or 2,
R4 is C1-6 alkyl optionally substituted with a group selected from the group consisting of OCH3, R4a, N(R4a)2, pyrrolidinyl optionally substituted with R4a and tetra hydrofuranyl; piperidinyl optionally substituted with R4b; or tetrahydropyranyl, wherein R4a is C1-3 alkyl, and
R4b is C1-3 alkyl substituted with one to three F,
R5 is isopropyl or sec-butyl,
R6a and R6b, which are the same as or different from each other, are H or C1-6 alkyl optionally substituted with a group selected from the group consisting of OH and N(CH3)2,
R7 is a group selected from the group consisting of the formula (XXIII), the formula (XXIV), the formula (XXVI), the formula (XXVIII) and the formula (XXXIII) below,
Figure imgf000220_0002
wherein R7a and R7b, which are the same as or different from each other, are H or C1-3 alkyl, W is the formula (XXXIV) below,
Figure imgf000221_0001
wherein W1 is CH, and
W2 is CH or N,
Y is phenylene, and
L is a bond or C=O.
8. The compound, or salt thereof, for use according to any one of Claims 1 to 7, wherein R3 is a group selected from the group consisting of the formula (Ill-a), the formula (IV-a) and the formula (V-a) below,
Figure imgf000221_0002
wherein R3a is -(CH2)PCHR3f-NRN1RN2,
R3b is H,
R3c is C3-6 cycloalkyl optionally substituted with -NRN1RN2,
R3f is H,
RN1 and RN2, which are the same as or different from each other, are both C1-3 alkyl,
X2 is -O- or -NH-,
X3 is O, and p is 1,
R4 is C1-6 alkyl optionally substituted with OCH3,
R5 is isopropyl,
R6a is H,
R6b is C1-6 alkyl optionally substituted with OH,
R7 is a group selected from the group consisting of the formula (XXIII), the formula (XXIV) and the formula (XXVIII) below,
Figure imgf000221_0003
wherein R7a and R7b, which are the same as or different from each other, are H or C1-3 alkyl,
W is the formula (XXXIV) below,
Figure imgf000222_0001
wherein W1 and W2 are both CH,
L is a bond, and
Z is a group selected from the group consisting of the formula (XIX), the formula (XX), the formula (XXI) and the formula (XXII) below.
Figure imgf000222_0002
9. The compound, or salt thereof, for use according to any one of Claims 1 to 8, wherein the compound of the formula (I) is selected from the group consisting of:
(ls,3R)-3-(dimethylamino)cyclobutyl 3-({(7M)-6-cyclopropyl-7-(6-fluoro-5- methyl-lH-indazol-4-yl)-8-{[4-(l-{(2S)-l-[(2S,4R)-4-hydroxy-2-({(lR)-2-hydroxy- l-[4-(4-methyl-l,3-oxazol-5-yl)phenyl]ethyl}carbamoyl)pyrrolidin-l-yl]-3-methyl-l- oxobutan-2-yl}-lH-l,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2- methoxypropoxy]quinazolin-4-yl}amino)azetidine-l-carboxylate, (ls,3R)-3-(dimethylamino)cyclobutyl 3-({(7M)-6-cyclopropyl-7-(6-fluoro-5- methyl-lH-indazol-4-yl)-8-{[4-(l-{(2S)-l-[(2S,4R)-4-hydroxy-2-({(lR)-2-hydroxy- l-[4-(lH-l,2,4-triazol-l-yl)phenyl]ethyl}carbamoyl)pyrrolidin-l-yl]-3-methyl-l- oxobutan-2-yl}-lH-l,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2- methoxypropoxy]quinazolin-4-yl}amino)azetidine-l-carboxylate, (4R)-l-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(l-{3-
[(dimethylamino)methyl]azetidine-l-carbonyl}azetidin-3-yl)oxy]-7-(6-fluoro-5- methyl-lH-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-8- yl}oxy)methyl]phenyl}-lH-l,2,3-triazol-l-yl)-3-methylbutanoyl]-4-hydroxy-N- {(lR)-2-hydroxy-l-[4-(lH-l,2,4-triazol-l-yl)phenyl]ethyl}-L-prolinamide,
(4R)-l-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(l-{3-
[(dimethylamino)methyl]azetidine-l-carbonyl}azetidin-3-yl)oxy]-7-(6-fluoro-5- methyl-lH-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-8- yl}oxy)methyl]phenyl}-lH-l,2,3-triazol-l-yl)-3-methylbutanoyl]-4-hydroxy-N- {(lR)-2-hydroxy-l-[4-(4-methyl-l,3-oxazol-5-yl)phenyl]ethyl}-L-prolinamide, (ls,3R)-3-(dimethylamino)cyclobutyl 3-({(7M)-6-cyclopropyl-7-(6-fluoro-5- methyl-lH-indazol-4-yl)-8-{[4-(l-{(2S)-l-[(2S,4R)-4-hydroxy-2-({(lR)-2-hydroxy- l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl}carbamoyl)pyrrolidin-l-yl]-3-methyl-l- oxobutan-2-yl}-lH-l,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2- methoxypropoxy]quinazolin-4-yl}amino)azetidine-l-carboxylate, (4R)-l-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(l-{[2- (dimethylamino)ethyl]carbamoyl}azetidin-3-yl)oxy]-7-(6-fluoro-5-methyl-lH- indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-8-yl}oxy)methyl]phenyl}-lH-
I,2,3-triazol-l-yl)-3-methylbutanoyl]-4-hydroxy-N-{(lR)-2-hydroxy-l-[4-(lH-l,2,4- triazol-l-yl)phenyl]ethyl}-L-prolinamide,
(ls,3R)-3-(dimethylamino)cyclobutyl 3-({(7M)-6-cyclopropyl-7-(6-fluoro-5- methyl-lH-indazol-4-yl)-8-{[4-(l-{(2S)-l-[(2S,4R)-4-hydroxy-2-({(lR)-2-hydroxy- l-[4-(lH-l,2,4-triazol-l-yl)phenyl]ethyl}carbamoyl)pyrrolidin-l-yl]-3-methyl-l- oxobutan-2-yl}-lH-l,2,3-triazol-4-yl)phenyl]methoxy}-2-[(2S)-2- methoxypropoxy]quinolin-4-yl}oxy)azetidine-l-carboxylate and (4R)-l-[(2S)-2-(4-{4-[({(7M)-6-cyclopropyl-4-[(l-{3- [(dimethylamino)methyl]azetidine-l-carbonyl}azetidin-3-yl)oxy]-7-(6-fluoro-5- methyl-lH-indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinolin-8- yl}oxy)methyl]phenyl}-lH-l,2,3-triazol-l-yl)-3-methylbutanoyl]-4-hydroxy-N- {(lR)-2-hydroxy-l-[4-(4-methyl-l,3-thiazol-5-yl)phenyl]ethyl}-L-prolinamide.
10. A pharmaceutical composition, for treating colorectal and/or lung cancer, comprising a compound of formula (I), or salt thereof, as defined in any one of Claims 1 to 9 and one or more pharmaceutically acceptable excipient.
II. Use of a compound of formula (I), or a salt thereof, as defined in any one of Claims 1 to 9 for the manufacture of a medicament for the treatment of colorectal cancer and/or lung cancer.
12. A method for treating colorectal cancer and/or lung cancer, the method comprising administering a pharmaceutically effective amount of a compound of formula (I), or salt thereof, as defined in any one of Claims 1 to 9 to a subject in need thereof.
13. The compound for use, pharmaceutical composition, use, or method as defined in any one of Claims 1 to 12, wherein the colorectal cancer and/or lung cancer is G12V mutant, G12D mutant and/or G12C mutant KRAS-positive colorectal cancer and/or G12V mutant, G12D mutant and/or G12C mutant KRAS-positive lung cancer.
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