Classifications

• • 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
  • 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
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • 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
  • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• • 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
  • 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
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/10—Spiro-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/10—Spiro-condensed systems

Definitions

• the present invention provides a pharmaceutical composition which has an excellent effect of inducing the degradation of G12V mutant KRAS protein and is useful as a G12V mutant KRAS inhibitor, for example, as an active ingredient of a pharmaceutical composition for treating pancreatic cancer and/or lung cancer. Concerning expected heterocyclic compounds.
• Pancreatic cancer which is mainly pancreatic ductal adenocarcinoma, has a very poor prognosis with a 5-year survival rate of less than 10% (CA Cancer J. Clin., 2016, 66, p.7-30). Approximately 460,000 new cases are reported annually (CA Cancer J. Clin., 2018, 68, p.394-424).
• the most effective treatment for pancreatic cancer is surgery, but because it is difficult to detect it early, the cancer often metastasizes, so surgical surgery is often not effective. If surgical treatment is not performed, chemotherapy or radiation therapy is recommended, but the survival rate is poor.
• FOLFIRINOX therapy (a multidrug combination treatment consisting of three chemotherapy drugs, 5-FU, irinotecan, and oxaliplatin, plus levofolinate) is used as a standard treatment for pancreatic cancer, but due to its high toxicity, it is not prescribed. Patients need to be selected carefully, as patients with ECOG Performance Status are limited to 1 or less (J. Clin. Oncol., 2018, 36, p.2545-2556).
• EGFR epidermal growth factor receptor
• erlotinib has been approved for combination therapy with gemcitabine, but overall survival is only extended by about 2 weeks compared to gemcitabine alone, which is not satisfactory. No therapeutic effect has been achieved, and highly effective therapeutic agents are still needed (J. Clin. Oncol., 2007, 25, p.1960-1966).
• lung cancer has the highest number of deaths, and it is reported that around 2.1 million people are newly infected each year around the world (World Cancer Report 2020).
• NSCLC non-small cell lung cancer
• adenocarcinoma and squamous cell carcinoma are classified as the most common types of NSCLC.
• adenocarcinoma is characterized by a peripheral localization in the lung.
• RAS protein is a small guanosine triphosphate (GTP)-binding protein of approximately 21 kDa consisting of 188-189 amino acids, and is one of the four major proteins (KRAS (KRAS4A and KRAS4B), NRAS, HRAS).
• GTP small guanosine triphosphate
• KRAS4A and KRAS4B major proteins
• NRAS NRAS
• HRAS guanosine triphosphate
• RAS protein is activated by the exchange of guanosine diphosphate (GDP) and GTP due to ligand stimulation of cell membrane receptors such as EGFR.
• GDP guanosine diphosphate
• Activated RAS binds to 20 types of effector proteins, including RAF, PI3K, and RALGDS, and activates downstream signal cascades.
• GTPase endogenous GTP hydrolysis
• GAPs GTPase-activating proteins
• Pancreatic ductal adenocarcinoma is said to occur in pancreatic intraepithelial neoplasia (PanIN), which progresses from a weakly atypical stage to a highly atypical stage, and KRAS gene mutations have already been observed in early-stage PanIN. Subsequently, abnormalities occur in the tumor suppressor genes INK4A, p53, and SMAD4, leading to malignancy (Nature Rev. Cancer, 2010, 10, p.683-695).
• KRAS mutations in the KRAS gene are observed in more than 90% of pancreatic ductal adenocarcinomas, with the majority being point mutations in codon 12 located in KRAS exon 2 (Cancer Cell 2017, 32, p.185-203 ). Furthermore, in lung cancer, RAS gene mutations are observed in 32% of lung adenocarcinomas. The breakdown of the mutation frequency is 96% in the KRAS gene, 3% in the NRAS gene, and 1% in the HRAS gene, and it has been reported that point mutations in KRAS exon 2 (codon 12, codon 13) are common (Nature Rev. Drug Discov., 2014, 13, p.828-851). Therefore, KRAS plays an important role in the carcinogenesis and development process of pancreatic cancer and lung adenocarcinoma.
• KRAS gene mutations include the KRAS G12V mutation, in which codon 12 glycine is replaced with valine, the KRAS G12D mutation, in which codon 12 is replaced with aspartic acid, and the KRAS G12C mutation, in which it is replaced with cysteine.
• KRAS G12V mutation in which codon 12 glycine is replaced with valine
• KRAS G12D mutation in which codon 12 is replaced with aspartic acid
• KRAS G12C mutation in which it is replaced with cysteine.
• Multiple G12C mutation-selective inhibitors have been developed in recent years, and among them, Sotorasib has been approved by the FDA as a treatment for non-small cell lung cancer (Drugs, 2021, 81, p.1573-1579).
• Patent Documents 1, 2, and 3 RAS inhibitors are disclosed in Patent Documents 1, 2, and 3, and compounds represented by the following formulas (A) and (B) are disclosed in Patent Documents 2 and 3, respectively (the symbols in the formula (For the meaning, refer to the relevant bulletin).
• Patent Documents 1, 2, and 3 describe that it is useful for cancers that have mutations in codon 12 of KRAS, and one of them includes G12V mutation, but they do not describe the effect on G12V mutant KRAS. .
• Patent Document 9 discloses a pan-KRAS inhibitor.
• bifunctional compounds collectively known as PROTAC (PROteolysis-TArgeting Chimera) and SNIPER (Specific and Nongenetic IAP-dependent Protein Eraser) have been discovered as a technology for inducing the degradation of target proteins. It is expected to be a new drug discovery modality (Drug. Discov. Today Technol., 2019, 31, p15-27).
• the bifunctional compound promotes the formation of a complex between the target protein and E3 ligase within the cell, and the degradation of the target protein is induced by utilizing the ubiquitin-proteasome system.
• the ubiquitin-proteasome system is one of the intracellular protein degradation mechanisms.
• a protein called E3 ligase recognizes the protein to be degraded and ubiquitinates it, allowing proteasome degradation to proceed.
• E3 ligase there are over 600 types of E3 ligase in living organisms, and they are roughly divided into four types: HECT-domain E3s, U-box E3s, monomeric RING E3s, and multi-subunit E3s.
• E3 ligases used in bifunctional degradation inducers such as PROTAC and SNIPER, and representative examples include Von Hippel-Lindau (VHL), celebron (CRBN), and inhibitor of apoptosis protein. (IAP), mouse double minute 2 homolog (MDM2), etc.
• VHL Von Hippel-Lindau
• CRBN inhibitor of apoptosis protein.
• IAP inhibitor of apoptosis protein.
• MDM2 mouse double minute 2 homolog
• a bifunctional compound is a compound in which a target protein ligand and an E3 ligase ligand are connected with a linker, and bifunctional compounds that degrade KRAS protein have been reported (Non-patent Document 1, Non-Patent Document 1, Patent Document 2, Patent Document 6, Patent Document 7, Patent Document 8, Patent Document 10 to Patent Document 22).
• a pharmaceutical composition for example, has an excellent effect of inducing the degradation of G12V mutant KRAS protein, and is useful as a G12V mutant KRAS inhibitor, and is useful for pancreatic cancer and/or lung cancer, especially G12V mutant KRAS positive pancreatic cancer and/or G12V mutant KRAS positive
• a heterocyclic compound that is expected to be useful as an active ingredient in a pharmaceutical composition for treating lung cancer.
• a heterocyclic compound of formula (I) particularly selected from the group consisting of quinazoline and quinoline, or linking a substituent at position 8 of a heterocyclic compound selected from the group consisting of quinazoline and quinoline with a ligand of E3 ligase using a linker.
• the present invention was completed based on the finding that the characteristic bifunctional compound of formula (I) has an excellent effect of inducing the degradation of G12V mutant KRAS protein and an inhibitory activity of G12V mutant KRAS.
• the present invention relates to a compound of formula (I) or a salt thereof, and a pharmaceutical composition containing the compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients.
• A is CR A or N
• R A is H or C 1-3 alkyl
• X 1 is -CH 2 -, -O- or -NR X1 -
• R X1 is H or optionally substituted C 1-3 alkyl
• R may form a group
• R 1 is naphthyl optionally substituted with OH
• R 1a and R 1b are the same or different from each other and are H, methyl, F or Cl
• R 1c is F, Cl, methyl or ethyl
• R2 is H, halogen, C1-3 alkyl, cyclopropyl, or vinyl, and the C1-3 alkyl is optionally substituted with
• a ring may be formed, and the spiro ring is substituted with 1 to 2 groups selected from the group consisting of C 1-3 alkyl, -O-(C 1-3 alkyl), OH, halogen and oxo. or R 3i present on two adjacent carbon atoms together with the two carbon atoms have a ring selected from the group consisting of C 3-6 cycloalkanes and 4- to 6-membered saturated heterocycles
• a fused ring may be formed, and the fused ring is substituted with 1 to 2 groups selected from the group consisting of C 1-3 alkyl, -O-(C 1-3 alkyl), OH, halogen, and oxo.
• R 3i present on two non-adjacent carbon atoms may combine with the two carbon atoms to form a crosslinked structure consisting of 1 to 2 carbon atoms, and have the crosslinked structure.
• the ring may be substituted with 1 to 2 groups selected from the group consisting of C 1-3 alkyl, -O-(C 1-3 alkyl), OH, halogen and oxo, R N1 and R N2 are the same or different from each other and are H or C 1-3 alkyl, or R N1 and R N2 may be combined with the nitrogen atom to which they are bonded to form an optionally substituted 4- to 6-membered saturated heterocyclic group, or R 3e and R N1 may be combined with the carbon atom and nitrogen atom to which they are bonded to form an optionally substituted 4- to 6-membered saturated heterocyclic group, X 2 is -O-, -NH-, or -N(C 1-3 alkyl)-, X 3 is O or S, X 4 is
• Ring B is a benzene ring or a 6-membered heterocycle containing 1 to 2 nitrogen atoms
• R Z1 is H, C 1-3 alkyl, -O-(C 1-3 alkyl), -NR Z4 2 , -CONR Z4 2 , or -NR Z4 COR Z5
• R Z2 is H or C 1-3 alkyl
• R Z3 is H or C 1-3 alkyl
• R Z4 are the same or different and each is H or C 1-3 alkyl
• R Z5 is C 1-3 alkyl
• L is bonded to ring B of the above formulas (XIII) to formula (XVIII), or to the benzene ring of formulas (XIX) and formulas (XX), m is 1 or 2
• G is CH or N, However, when G is N, Z is the above formula (XVII), formula (XVIII) or formula (XIX). )
• the present invention also provides a pharmaceutical composition containing a compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients, and in one embodiment, a pharmaceutical composition for treating pancreatic cancer.
• a pharmaceutical composition for treating G12V-mutated KRAS-positive pancreatic cancer in another embodiment, a pharmaceutical composition for treating metastatic pancreatic cancer; and in one embodiment, a pharmaceutical composition for treating locally advanced pancreatic cancer.
• it is a pharmaceutical composition for treating relapsed or refractory pancreatic cancer, and in another embodiment, it is a pharmaceutical composition for treating pancreatic cancer in untreated and/or previously treated patients,
• a pharmaceutical composition for treating metastatic G12V-mutated KRAS-positive pancreatic cancer is another embodiment is a pharmaceutical composition for treating locally advanced G12V-mutated KRAS-positive pancreatic cancer; or a pharmaceutical composition for treating refractory G12V mutant KRAS-positive pancreatic cancer; one embodiment relates to a pharmaceutical composition for treating G12V mutant KRAS-positive pancreatic cancer in untreated and/or previously treated patients.
• a pharmaceutical composition for treating pancreatic cancer containing a compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients contains a compound of formula (I) or a salt thereof.
• the present invention includes a therapeutic agent for G12V-mutated KRAS-positive pancreatic cancer.
• pancreatic cancer in one embodiment, G12V-mutated KRAS-positive pancreatic cancer, in another embodiment, metastatic pancreatic cancer, in another embodiment, locally advanced pancreatic cancer, in another embodiment, recurrent or refractory pancreatic cancer.
• pancreatic cancer in untreated and/or previously treated patients;
• locally advanced G12V-mutated pancreatic cancer in some embodiment, locally advanced G12V-mutated pancreatic cancer.
• a pharmaceutical composition for the treatment of KRAS-positive pancreatic cancer in some embodiments, relapsed or refractory G12V-mutated KRAS-positive pancreatic cancer, in some embodiments, G12V-mutated KRAS-positive pancreatic cancer in untreated and/or previously treated patients.
• a compound of formula (I) or a salt thereof for the production of pancreatic cancer in one embodiment, use of a compound of formula (I) or a salt thereof for the treatment of G12V-mutated KRAS-positive pancreatic cancer, pancreatic cancer
• a compound of formula (I) or a salt thereof for use in the treatment of G12V mutant KRAS-positive pancreatic cancer, and an effective amount of the compound of formula (I) or a salt thereof are administered to a subject.
• the present invention relates to a method for treating G12V-mutated KRAS-positive pancreatic cancer.
• the present invention also provides a pharmaceutical composition containing the compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients, in one embodiment, a pharmaceutical composition for the treatment of lung cancer, In one embodiment, it is a pharmaceutical composition for treating G12V-mutated KRAS-positive lung cancer, in another embodiment it is a pharmaceutical composition for treating metastatic lung cancer, in another embodiment it is a pharmaceutical composition for treating locally advanced lung cancer, One embodiment is a pharmaceutical composition for treating relapsed or refractory lung cancer, one embodiment is a pharmaceutical composition for treating lung cancer in untreated and/or previously treated patients, and one embodiment is for metastatic lung cancer.
• a pharmaceutical composition for treating G12V-mutated KRAS-positive lung cancer in one embodiment, a pharmaceutical composition for treating locally advanced G12V-mutated KRAS-positive lung cancer;
• the present invention relates to a pharmaceutical composition for treating lung cancer, and in one embodiment, it also relates to a pharmaceutical composition for treating G12V-mutated KRAS-positive lung cancer in untreated and/or previously treated patients.
• a pharmaceutical composition for treating lung cancer containing a compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients contains a compound of formula (I) or a salt thereof.
• the present invention also includes therapeutic agents for lung cancer, and in some embodiments, G12V mutant KRAS-positive lung cancer.
• the present invention also provides lung cancer, in one embodiment, G12V mutant KRAS-positive lung cancer, in another embodiment, metastatic lung cancer, in another embodiment, locally advanced lung cancer, in one embodiment, relapsed or refractory lung cancer,
• lung cancer in untreated and/or previously treated patients; in some embodiments, metastatic G12V mutant KRAS positive lung cancer; in some embodiments, locally advanced G12V mutant KRAS positive lung cancer; is a compound of formula (I) for the manufacture of a pharmaceutical composition for the treatment of relapsed or refractory G12V mutant KRAS-positive lung cancer, and in one embodiment, G12V mutant KRAS-positive lung cancer in untreated and/or previously treated patients.
• the compound of formula (I) or a salt thereof is administered to a subject, and an effective amount of the compound of formula (I) or a salt thereof for use in lung cancer, in one embodiment, G12V mutant KRAS positive lung cancer.
• the present invention also provides a compound of formula (I) or a salt thereof which is a G12V mutant KRAS protein degradation inducer and/or a G12V mutant KRAS inhibitor, a G12V mutant KRAS protein degradation inducer, and/or a G12V mutant KRAS inhibitor.
• the present invention also relates to a compound of formula (I) or a salt thereof, a G12V mutant KRAS proteolysis inducer containing the compound of formula (I) or a salt thereof, and/or a G12V mutant KRAS inhibitor for use as a compound of formula (I) or a salt thereof.
• the "subject” is a human or other animal in need of the treatment, and in one embodiment, a human in need of the prevention or treatment.
• the compound of formula (I) or a salt thereof has the effect of inducing the degradation of G12V mutant KRAS protein and the inhibitory activity of G12V mutant KRAS, and is effective against pancreatic cancer and/or lung cancer, especially G12V mutant KRAS positive pancreatic cancer and/or It can be used as a therapeutic agent for G12V-mutated KRAS-positive lung cancer.
• optionally substituted means unsubstituted or having 1 to 5 substituents. In one embodiment, it means that it is unsubstituted or has 1 to 3 substituents. In addition, when it has a plurality of substituents, those substituents may be the same or mutually different.
• C 1-12 alkyl means straight-chain or branched alkyl having 1 to 12 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl. , n-pentyl, n-hexyl, dodecyl, etc. (hereinafter, the number of carbon atoms will be expressed in the same way). In some embodiments, it is ethyl or dodecyl.
• C 1-6 alkyl is a straight-chain or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec -butyl, tert-butyl, n-pentyl or n-hexyl, in certain embodiments methyl, ethyl, n-propyl, isopropyl or sec-butyl, in certain embodiments methyl, ethyl, isopropyl or tert-butyl.
• C 1-3 alkyl is a straight-chain or branched alkyl having 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl or isopropyl, and in certain embodiments methyl or Ethyl, in some embodiments n-propyl or isopropyl, in some embodiments methyl or isopropyl, in some embodiments ethyl or isopropyl, in some embodiments methyl, in some embodiments ethyl. In some embodiments, it is isopropyl, and in some embodiments it is n-propyl.
• C 3-6 cycloalkane is a cycloalkane having 3 to 6 carbon atoms, such as cyclopropane, cyclobutane, cyclopentane, and cyclohexane.
• C 3-6 cycloalkyl is cycloalkyl having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. In some embodiments it is cyclobutyl, cyclopentyl or cyclohexyl, in some embodiments it is cyclobutyl or cyclopentyl, in some embodiments it is cyclopentyl or cyclohexyl, in some embodiments it is cyclopropyl or cyclobutyl, in some embodiments it is cyclopropyl. In some embodiments, it is cyclobutyl, in some embodiments it is cyclopentyl, and in some embodiments it is cyclohexyl.
• C 1-3 alkylene is a divalent group formed by removing a hydrogen atom from a C 1-3 alkyl, and is a divalent group formed by removing a hydrogen atom from a C 1-3 alkyl, and is a straight-chain or branched C 1-3 alkylene, such as methylene, ethylene, trimethylene, methylmethylene, 1,1-dimethylmethylene, etc. In some embodiments, it is linear or branched C 1-3 alkylene, in some embodiments it is methylene, ethylene or trimethylene, in some embodiments it is methylene or ethylene, in some embodiments it is methylene, In one embodiment, it is ethylene.
• a “saturated heterocycle” is a saturated hydrocarbon ring containing a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as a ring constituent atom. Moreover, the sulfur atom as a ring-constituting atom of the saturated heterocycle may be oxidized. Therefore, a “4- to 6-membered saturated heterocycle” refers to a 4- to 6-membered saturated hydrocarbon ring containing a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as a ring constituent atom. be.
• a certain embodiment of the "4- to 6-membered saturated heterocycle” is a 4- to 6-membered saturated heterocycle containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring constituent atoms. In some embodiments, it is oxetane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, oxazolidine, imidazolidine, piperazine, morpholine, thiomorpholine, or dioxothiomorpholine.
• a “saturated heterocyclic group” is a saturated hydrocarbon ring group containing a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as a ring constituent atom. Moreover, the sulfur atom as a ring-constituting atom of the saturated heterocyclic group may be oxidized. Therefore, a “4- to 6-membered saturated heterocyclic group” is a 4- to 6-membered saturated heterocyclic group containing a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as a ring-constituting atom.
• An embodiment of the "4- to 6-membered saturated heterocyclic group” includes a 4- to 6-membered saturated heterocyclic group containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring constituent atoms. It is the basis.
• An embodiment of a 4- to 6-membered saturated heterocyclic group containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms includes oxygen, sulfur, and nitrogen as ring-constituting atoms.
• it is a 5-membered saturated heterocyclic group containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring atoms;
• oxazolidinyl imidazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or dioxothiomorpholinyl
• oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, or dioxothio Morpholinyl in some embodiments oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, or morpholinyl
• oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl or piperidinyl in some embodiments is oxetanyl, tazolidinyl, imidazolidin
• “Divalent saturated heterocyclic group containing 1 to 2 nitrogen atoms” is a divalent group of 4- to 11-membered saturated heterocyclic group containing 1 to 2 nitrogen atoms as ring constituent atoms, and It may be a saturated heterocyclic divalent group having a ring or a fused ring.
• Certain embodiments of the "saturated heterocyclic divalent group containing 1 to 2 nitrogen atoms" include azetidinediyl, pyrrolidinediyl, imidazolidinediyl, piperidinediyl, piperadinediyl, azepandiyl, diazepandiyl, azocandiyl, diazocandiyl, azonanediyl, It is diazonanediyl or a divalent group represented by the following formulas (XXI) to (XXV).
• a certain embodiment of "a saturated heterocyclic divalent group containing 1 to 2 nitrogen atoms” is pyrrolidinediyl, piperazinediyl, or a divalent group represented by the following formula (XXI) or formula (XXII).
• Certain embodiments of "a saturated heterocyclic divalent group containing 1 to 2 nitrogen atoms” include pyrrolidinediyl, piperazinediyl, or a divalent group represented by the following formula (XXI), formula (XXII), or formula (XXV). It is a valence group.
• “Divalent saturated heterocyclic group containing two nitrogen atoms” refers to a divalent group of a 4- to 11-membered saturated heterocyclic group containing two nitrogen atoms as ring constituent atoms, including spiro rings and fused rings. It may also be a saturated heterocyclic divalent group having Certain embodiments of "a saturated heterocyclic divalent group containing two nitrogen atoms” include imidazolidinediyl, piperazinediyl, diazepanediyl, diazocandiyl, diazonanediyl, or those represented by the following formulas (XXI) to (XXV). It is a divalent group.
• a certain embodiment of "a saturated heterocyclic divalent group containing two nitrogen atoms” is piperazinediyl or a divalent group represented by the following formula (XXI) or formula (XXII).
• a certain embodiment of "a saturated heterocyclic divalent group containing two nitrogen atoms” is piperazinediyl or a divalent group represented by the following formula (XXI), formula (XXII) or formula (XXV).
• a “heterocycle” is an aromatic hydrocarbon ring containing a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as a ring constituent atom. Therefore, a "6-membered heterocycle containing 1 to 2 nitrogen atoms” is a 6-membered aromatic hydrocarbon ring containing 1 to 2 nitrogen atoms as ring constituent atoms, and in one embodiment, a pyridine ring. , a pyridazine ring, a pyrimidine ring, a pyrazine ring, a triazine ring, and in one embodiment, a pyridine ring.
• Heteroaryl is a heterocyclic group containing a heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen as a ring constituent atom. Therefore, “5-membered heteroaryl” is a 5-membered heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring constituent atoms.
• a certain embodiment of "5-membered heteroaryl” is a 5-membered heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring constituent atoms; , pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl or thiadiazolyl, in some embodiments pyrazolyl, imidazolyl, triazolyl, oxazolyl or thiazolyl, in some embodiments pyrazolyl, imidazolyl, oxazolyl or thiazolyl.
• it is pyrazolyl, imidazolyl, triazolyl or isoxazolyl, in some embodiments it is pyrazolyl, oxazolyl or thiazolyl, in some embodiments it is pyrazolyl, triazolyl or isoxazolyl, and in some embodiments it is pyrazolyl or thiazolyl.
• pyrazolyl or triazolyl in some embodiments is pyrazolyl, in some embodiments is imidazolyl, in some embodiments is oxazolyl, in some embodiments is thiazolyl, in some embodiments is triazolyl .
• 6-membered heteroaryl is a 6-membered heterocyclic group containing 1 to 3 nitrogen atoms as ring atoms.
• Certain embodiments of the "6-membered heteroaryl” include pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl; certain embodiments include pyridyl or pyridazinyl; certain embodiments include pyridyl or pyrimidinyl; and certain embodiments, pyridyl and triazinyl. In some embodiments, it is pyrimidinyl.
• Halogen means F, Cl, Br and I. In some embodiments it is F, Cl or Br, in some embodiments it is F or Cl, in some embodiments it is F or Br, in some embodiments it is F, in some embodiments it is Cl, in some embodiments is Br.
• Spiro ring means a polycyclic ring structure in which two ring structures are bonded by sharing one spiro atom, which is a quaternary carbon; It means a polycyclic ring structure in which two or more ring structures are bonded by sharing two or more adjacent atoms.
• bridged structure refers to a divalent chain structure that connects two non-adjacent atoms among the ring-constituting atoms of one ring.
• substituted with F, OH, OCH 3, cyclopropyl, N(C 1-3 alkyl optionally substituted with F) 2 , (C 1-3 alkyl optionally substituted with F) pyrrolidinyl, which may be substituted, and tetrahydrofuranyl and examples include F, OH, OCH 3 , N(CH 3 ) 2 , hydroxymethyl, methoxymethyl, difluoroethyl, cyclopropyl, which may be substituted, and tetrahydrofuranyl.
• F, OH, OCH 3 , N(CH 3 ) 2 Hydroxymethyl, methoxymethyl, optionally substituted cyclopropyl, tetrahydrofuranyl, optionally substituted tetrahydropyranyl, optionally substituted pyrrolidinyl, and in some embodiments, F, OH, OCH 3 , N (CH 3 ) 2 , hydroxymethyl, methoxymethyl, cyclopropyl, (hydroxymethyl)cyclopropyl, (methoxymethyl)cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, (hydroxymethyl)tetrahydropyranyl, (methoxymethyl)tetrahydropyrani
• F, OH, OCH 3 (methoxymethyl, methoxymethyl, cyclopropyl, (hydroxymethyl)cyclopropyl, (methoxymethyl)cyclopropyl, tetrahydrofuranyl, tetrahydropyranyl, (hydroxy
• An embodiment of the permissible substituents in “optionally substituted 5-membered heteroaryl” and “optionally substituted 6-membered heteroaryl” is a group selected from the group consisting of OH and OCH3 .
• it is C 1-3 alkyl optionally substituted with a group selected from the group consisting of OH and OCH 3
• it is C 1-3 alkyl, optionally substituted with OH.
• C 1-3 alkyl optionally substituted with OCH 3 in some embodiments is C 1-3 alkyl or halogen, in some embodiments is methyl, ethyl, methoxymethyl or F In some embodiments, it is methyl, ethyl or F.
• Optionally substituted 4- to 6-membered saturated heterocyclic group “optionally substituted pyrrolidinyl”, “optionally substituted C 3-6 cycloalkyl”, “optionally substituted Certain embodiments of substituents that are permissible in "a saturated heterocyclic divalent group containing 1 to 2 nitrogen atoms” and "a saturated heterocyclic divalent group containing 2 optionally substituted nitrogen atoms” include: C 1-3 alkyl optionally substituted with a group selected from the group consisting of F, OH, OCH 3 and N(CH 3 ) 2 , F, OH, OCH 3 , oxo or oxetanyl.
• F F, OH or OCH3
• it is OH or methyl
• it is optionally substituted with a group selected from the group consisting of F, OH and OCH3
• Alkyl or oxo in some embodiments C 1-3 alkyl optionally substituted with a group selected from the group consisting of F, OH, OCH 3 and N(CH 3 ) 2
• C 1-3 alkyl optionally substituted with F in some embodiments C 1-3 alkyl optionally substituted with OH, and in some embodiments C 1-3 alkyl optionally substituted with OCH 3
• It is 1-3 alkyl, and in some embodiments it is C 1-3 alkyl optionally substituted with N(CH 3 ) 2 , and
• C 1-3 alkyl optionally substituted with OH is methyl optionally substituted with 1 OH or ethyl optionally substituted with 1 to 2 OH.
• Examples are methyl, ethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl.
• methyl, ethyl or hydroxymethyl in some embodiments methyl or hydroxymethyl, in some embodiments hydroxymethyl or hydroxyethyl, in some embodiments hydroxymethyl, in some embodiments hydroxy It is ethyl.
• C 1-6 alkyl optionally substituted with OCH 3 and "C 1-3 alkyl optionally substituted with OCH 3", even if substituted with one OCH 3 It is preferably methyl or ethyl optionally substituted with 1-2 OCH 3 .
• Examples are methyl, ethyl, methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 1,2-dimethoxyethyl. In some embodiments, it is methoxymethyl or methoxyethyl, in some embodiments it is methoxymethyl, and in some embodiments it is methoxyethyl.
• C 1-6 alkyl optionally substituted with N(C 1-3 alkyl) 2 is "C 1-3 alkyl optionally substituted with N(CH 3 ) 2 ".
• methyl optionally substituted with 1 N(C 1-3 alkyl) 2 ethyl optionally substituted with 1 N(C 1-3 alkyl) 2 , or 1 n-propyl optionally substituted with N(C 1-3 alkyl) 2 .
• it is methyl optionally substituted with one N(C 1-3 alkyl) 2 or ethyl optionally substituted with one N(C 1-3 alkyl) 2 .
• C 1-3 alkyl optionally substituted with N(CH 3 ) 2 methyl optionally substituted with 1 N(CH 3 ) 2 or 1 N(CH 3 ) 2 3 ) Ethyl which may be substituted with 2 .
• it is methyl, ethyl, dimethylaminomethyl or dimethylaminoethyl, in some embodiments it is methyl or dimethylaminomethyl, in some embodiments it is dimethylaminomethyl, and in some embodiments it is dimethylaminoethyl.
• phenylene optionally substituted with F or Cl is phenylene optionally substituted with 1 to 2 F or Cl. In one embodiment, it is phenylene optionally substituted with one F, in another embodiment it is phenylene optionally substituted with one Cl, in another embodiment it is phenylene or fluorophenylene, In an embodiment, it is phenylene, in a certain embodiment it is 2-fluoro-1,4-phenylene, and in a certain embodiment it is 3-fluoro-1,4-phenylene.
• G12V mutation refers to a mutation in which the amino acid residue corresponding to the 12th codon in the wild-type protein is converted from glycine to valine.
• G12V mutant KRAS refers to KRAS having the above-mentioned "G12V mutation.”
• Pantenatic cancer is a malignant tumor that forms in the pancreas.
• pancreatic ductal carcinoma and pancreatic ductal adenocarcinoma in one embodiment pancreatic ductal carcinoma, and in another embodiment pancreatic ductal adenocarcinoma.
• it is metastatic pancreatic cancer, in some embodiments it is locally advanced pancreatic cancer, in some embodiments it is recurrent or refractory pancreatic cancer, and in some embodiments it is untreated and/or previously untreated pancreatic cancer. A patient with pancreatic cancer.
• lung cancer is a malignant tumor that forms in the lungs.
• small cell lung cancer and non-small cell lung cancer in some embodiments small cell lung cancer, and in some embodiments non-small cell lung cancer.
• the patient has metastatic lung cancer, in some embodiments, locally advanced lung cancer, in some embodiments, relapsed or refractory lung cancer, and in some embodiments, in untreated and/or previously treated patients. It is lung cancer.
• G12V mutant KRAS positive pancreatic cancer is G12V mutant KRAS positive pancreatic cancer.
• this is pancreatic cancer in which the KRAS G12V mutation occurs, and the positive rate for G12V-mutated KRAS is high.
• it is a G12V mutant KRAS-positive pancreatic ductal carcinoma, and in another embodiment it is a G12V mutant KRAS-positive pancreatic ductal adenocarcinoma.
• G12V mutant KRAS positive lung cancer is G12V mutant KRAS positive lung cancer.
• this is lung cancer in which the KRAS G12V mutation occurs, and the positive rate for G12V-mutated KRAS is high.
• One embodiment is G12V mutant KRAS positive small cell lung cancer, and one embodiment is G12V mutant KRAS positive non-small cell lung cancer.
• A is CR A or N, and R A is H or C 1-3 alkyl, a compound of formula (I) or a salt thereof.
• A is CR A or N, and R A is H, a compound of formula (I) or a salt thereof.
• (1-3) A compound of formula (I) or a salt thereof, wherein A is CR A or N, and R A is C 1-3 alkyl.
• X 1 is -CH 2 -, -O- or -NR X1 -, R X1 is H or optionally substituted C 1-3 alkyl, Alternatively, when X 1 is -NR X1 -, R A compound of formula (I) or a salt thereof which may form a group.
• X 1 is -O- or -NR X1 -, R X1 is H or optionally substituted C 1-3 alkyl, Alternatively, when X 1 is -NR X1 -, R A compound of formula (I) or a salt thereof which may form a group.
• X 1 is -O- or -NR X1 -, A compound of formula (I) or a salt thereof, wherein R X1 is H or C 1-3 alkyl. (2-4) A compound of formula (I) or a salt thereof, wherein X 1 is -O-.
• R 1 is naphthyl optionally substituted with OH, or the following formula (II) or formula (III), R 1a and R 1b are the same or different from each other and are H, methyl, F or Cl, A compound of formula (I) or a salt thereof, wherein R 1c is F, Cl, methyl or ethyl.
• R 1 is the following formula (II), R 1a is H, methyl, F or Cl; A compound of formula (I) or a salt thereof, wherein R 1c is F, Cl, methyl or ethyl.
• R 1 is the following formula (II), R 1a is F; A compound of formula (I) or a salt thereof, wherein R 1c is methyl.
• R 2 is H, halogen, C 1-3 alkyl, cyclopropyl, or vinyl, and the C 1-3 alkyl is optionally substituted with a group selected from the group consisting of OH and OCH 3 , of the formula A compound of (I) or a salt thereof.
• R 2 is cyclopropyl or vinyl.
• R 3 A compound of formula (I) or a salt thereof, wherein R 2 is cyclopropyl.
• R 3 is the following formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII) and a group selected from the group consisting of formula (XXVI),
• R 3a is -(CH 2 ) p CHR 3e -NR N1 R N2 ;-(CH 2 ) p CHR 3e -OR 3f ; C 1-3 alkyl, -C 1-3 alkylene-OR 3f , -C 1- a 4- to 6-membered saturated heterocyclic group optionally substituted with a group selected from the group consisting of 3alkylene-NR N1 R N2 and -NR N1 R N2 ; or C 1-3 alkyl, -C 1 C 3-6 cycloalkyl optionally substituted with a group selected from the group consisting of -3 alkylene-OR 3f , C 1-3 alkylene-NR N1 R N2 , -OR 3f
• a ring may be formed, and the spiro ring is substituted with 1 to 2 groups selected from the group consisting of C 1-3 alkyl, -O-(C 1-3 alkyl), OH, halogen and oxo. or R 3i present on two adjacent carbon atoms together with the two carbon atoms have a ring selected from the group consisting of C 3-6 cycloalkanes and 4- to 6-membered saturated heterocycles
• a fused ring may be formed, and the fused ring is substituted with 1 to 2 groups selected from the group consisting of C 1-3 alkyl, -O-(C 1-3 alkyl), OH, halogen, and oxo.
• R 3i present on two non-adjacent carbon atoms may combine with the two carbon atoms to form a crosslinked structure consisting of 1 to 2 carbon atoms, and have the crosslinked structure.
• the ring may be substituted with 1 to 2 groups selected from the group consisting of C 1-3 alkyl, -O-(C 1-3 alkyl), OH, halogen and oxo, R N1 and R N2 are the same or different from each other and are H or C 1-3 alkyl, or R N1 and R N2 may be combined with the nitrogen atom to which they are bonded to form an optionally substituted 4- to 6-membered saturated heterocyclic group, or R 3e and R N1 may be combined with the carbon atom and nitrogen atom to which they are bonded to form an optionally substituted 4- to 6-membered saturated heterocyclic group, X 2 is -O-, -NH-, or -N(C 1-3 alkyl)-, X 3 is O or S, X 4 is
• R 3 is a group selected from the group consisting of the following formula (IV), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI) and formula (XII),
• R 3a is -(CH 2 ) p CHR 3e -NR N1 R N2 ;-(CH 2 ) p CHR 3e -OR 3f ; C 1-3 alkyl, -C 1-3 alkylene-OR 3f , -C 1- a 4- to 6-membered saturated heterocyclic group optionally substituted with a group selected from the group consisting of 3alkylene-NR N1 R N2 and -NR N1 R N2 ; or C 1-3 alkyl, -C 1 C 3-6 cycloalkyl optionally substituted with a group selected from the group consisting of -3 alkylene-OR 3f , C 1-3 alkylene-NR N1 R N2 , -OR 3f , and -NR N1 R N2 ; can
• R 3 is a group selected from the group consisting of the following formula (IV), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI) and formula (XII),
• R 3a is -(CH 2 ) p CHR 3e -NR N1 R N2 ;
• R 3b is H or C 1-3 alkyl,
• R 3e is H;
• R 3g is an optionally substituted 6-membered heteroaryl,
• R 3h is H or F,
• R N1 and R N2 are the same or different from each other and are C 1-3 alkyl, or R N1 and R N2 may be combined with the nitrogen atom to which they are bonded to form an optionally substituted 4- to 6-membered saturated heterocyclic group
• X 2 is -O- or -NH-
• X 3 is O or S
• n is 1
• p is 1, a compound of formula (I) or a salt thereof.
• R 3 is a group selected from the group consisting of the following formula (IV), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI) and formula (XII),
• R 3a is -(CH 2 ) p CHR 3e -NR N1 R N2 ;
• R 3b is H or C 1-3 alkyl,
• R 3e is H;
• R 3g is an optionally substituted 6-membered heteroaryl,
• R 3h is H or F,
• R N1 and R N2 are the same or different from each other and are C 1-3 alkyl,
• X 2 is -O- or -NH-,
• X 3 is O or S,
• n is 1
• p is 1, a compound of formula (I) or a salt thereof.
• R 3 is a group selected from the group consisting of the following formula (IV), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI) and formula (XII),
• R 3a is -(CH 2 ) p CHR 3e -NR N1 R N2 ;
• R 3b is H;
• R 3e is H;
• R 3g is an optionally substituted 6-membered heteroaryl, R 3h is F;
• R N1 and R N2 are the same or different from each other and are C 1-3 alkyl;
• X 2 is -O- or -NH-, X 3 is O;
• R 3 is a group consisting of the following formula (IV-1), formula (VII-1), formula (VIII-1), formula (IX), formula (X), formula (XI) and formula (XII-1)
• R 4 is C 1-6 alkyl, piperidinyl or tetrahydropyranyl optionally substituted with R 4a , and the C 1-6 alkyl is F, OH, OCH 3, R 4a , cyclopropyl, N
• R 4a is optionally substituted with a group selected from the group consisting of (R 4a ) 2 , pyrrolidinyl optionally substituted with R 4a , and tetrahydrofuranyl, A compound of formula (I) or a salt thereof, wherein R 4a is optionally substituted C 1-3 alkyl.
• R 4 is C 1-6 alkyl optionally substituted with a group selected from the group consisting of OCH 3, N(R 4a ) 2 and pyrrolidinyl optionally substituted with R 4a , A compound of formula (I) or a salt thereof, wherein R 4a is optionally substituted C 1-3 alkyl.
• R 4 is OCH 3 or C 1-6 alkyl optionally substituted with N(C 1-3 alkyl ) 2 , piperidinyl or tetrahydropyranyl optionally substituted with C 1-3 alkyl, the formula A compound of (I) or a salt thereof.
• R 4 is OCH 3 , C 1-6 alkyl optionally substituted with a group selected from the group consisting of N(C 1-3 alkyl) 2 and pyrrolidinyl optionally substituted with R 4a , or tetrahydro is pyranyl, A compound of formula (I) or a salt thereof, wherein R 4a is optionally substituted C 1-3 alkyl.
• (7-1) A compound of formula (I) or a salt thereof, wherein Y is phenylene optionally substituted with F or Cl, or pyridinediyl.
• (7-2) A compound of formula (I) or a salt thereof, wherein Y is phenylene optionally substituted with F or Cl.
• (7-3) A compound of formula (I) or a salt thereof, wherein Y is phenylene.
• L is -(L 1 -L 2 -L 3 -L 4 -L 5 )-, L 1 , L 2 , L 3 , L 4 and L 5 are the same or different and are a bond, -O-, -NR L1 -, a saturated heterocycle containing 1 to 2 optionally substituted nitrogen atoms;
• a group selected from the group consisting of a divalent group of , an optionally substituted C 1-3 alkylene, and C O, A compound of formula (I) or a salt thereof, wherein R L1 is H or C 1-3 alkyl.
• L is the following formula (XXVII) to formula (XXXIV) A compound of formula (I) or a salt thereof, in which the carbon atom marked with * is bonded to Y.
• Z is selected from the group consisting of formula (XIII), formula (XIV), formula (XV), formula (XVI), formula (XVII), formula (XVIII), formula (XIX), and formula (XX) below.
• Ring B is a benzene ring or a 6-membered heterocycle containing 1 to 2 nitrogen atoms
• R Z1 is H, C 1-3 alkyl, -O-(C 1-3 alkyl), -NR Z4 2 , -CONR Z4 2 , or -NR Z4 COR Z5
• R Z2 is H or C 1-3 alkyl
• R Z3 is H or C 1-3 alkyl
• R Z4 are the same or different and each is H or C 1-3 alkyl
• R Z5 is C 1-3 alkyl
• L is bonded to ring B of the above formulas (XIII) to formula (XVIII), or to the benzene ring of formulas (XIX) and formulas (XX), and formula (
• Z is a group selected from the group consisting of the following formula (XIII), formula (XVII) and formula (XIX),
• Ring B is a benzene ring or a 6-membered heterocycle containing 1 to 2 nitrogen atoms
• R Z1 is H, C 1-3 alkyl, -O-(C 1-3 alkyl), -NR Z4 2 , -CONR Z4 2 , or -NR Z4 COR Z5
• R Z2 is H or C 1-3 alkyl
• R Z4 are the same or different and each is H or C 1-3 alkyl
• R Z5 is C 1-3 alkyl
• L is bonded to ring B of the above formula (XIII) or (XVII)
• m is 1 or 2, a compound of formula (I) or a salt thereof.
• Z is a group selected from the group consisting of the following formula (XIII), formula (XVII) and formula (XIX), Ring B is a benzene ring, R Z1 is H or C 1-3 alkyl, R Z2 is H or C 1-3 alkyl, In addition, L is bonded to ring B of the above formula (XIII) or (XVII) or to the benzene ring of formula (XIX), m is 1 or 2, a compound of formula (I) or a salt thereof.
• Z is a group selected from the group consisting of the following formula (XIII), formula (XVII) and formula (XIX), Ring B is a benzene ring, R Z1 is H; R Z2 is C 1-3 alkyl;
• L is bonded to ring B of the above formula (XIII) or (XVII) or to the benzene ring of formula (XIX), m is 1, a compound of formula (I) or a salt thereof.
• Z is a group selected from the group consisting of the following formula (XIII-1), formula (XVII-1) and formula (XIX-1), Note that L is a compound of formula (I) or a salt thereof, which is bonded to the benzene ring of formula (XIII-1) and formula (XVII-1) above.
• Z is the following formula (XIII) or formula (XVII), Ring B is a benzene ring, In addition, L is bonded to ring B of the above formulas (XIII) and (XVII), R Z1 is H; R Z2 is C 1-3 alkyl; m is 1, a compound of formula (I) or a salt thereof.
• the combination described in (11) above includes, for example, the following embodiments.
• a compound of formula (I) or a salt thereof (In the formula, A is CR A or N, R A is H; X 1 is -O-; R 1 is the following formula (II), R 1a is F; R 1c is methyl; R 2 is cyclopropyl; R 3 is a group selected from the group consisting of the following formula (IV), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI) and formula (XII), R 3a is -(CH 2 ) p CHR 3e -NR N1 R N2 ; R 3b is H; R 3e is H; R 3g is an optionally substituted 6-membered heteroaryl, R 3h is F; R N1 and R N2 are the same or different from each other and are C 1-3 alkyl; X 2 is -O- or -NH-, X 3 is O;
• a compound of formula (I) or a salt thereof is CR A or N, R A is H or C 1-3 alkyl, X 1 is -CH 2 -, -O- or -NR X1 -, R X1 is H or optionally substituted C 1-3 alkyl, Alternatively, when X 1 is -NR X1 -, R may form a group, R 1 is naphthyl optionally substituted with OH, or the following formula (II) or formula (III), R 1a and R 1b are the same or different from each other and are H, methyl, F or Cl, R 1c is F, Cl, methyl or ethyl; R2 is H, halogen, C1-3 alkyl, cyclopropyl, or vinyl, and the C1-3 alkyl is optionally substituted with a group selected from the group consisting of OH and OCH3 , R 3 is the following formula (IV), formula (V), formula (VI),
• a ring may be formed, and the spiro ring is substituted with 1 to 2 groups selected from the group consisting of C 1-3 alkyl, -O-(C 1-3 alkyl), OH, halogen and oxo. or R 3i present on two adjacent carbon atoms together with the two carbon atoms have a ring selected from the group consisting of C 3-6 cycloalkanes and 4- to 6-membered saturated heterocycles
• a fused ring may be formed, and the fused ring is substituted with 1 to 2 groups selected from the group consisting of C 1-3 alkyl, -O-(C 1-3 alkyl), OH, halogen, and oxo.
• R 3i present on two non-adjacent carbon atoms may combine with the two carbon atoms to form a crosslinked structure consisting of 1 to 2 carbon atoms, and have the crosslinked structure.
• the ring may be substituted with 1 to 2 groups selected from the group consisting of C 1-3 alkyl, -O-(C 1-3 alkyl), OH, halogen and oxo, R N1 and R N2 are the same or different from each other and are H or C 1-3 alkyl, or R N1 and R N2 may be combined with the nitrogen atom to which they are bonded to form an optionally substituted 4- to 6-membered saturated heterocyclic group, or R 3e and R N1 may be combined with the carbon atom and nitrogen atom to which they are bonded to form an optionally substituted 4- to 6-membered saturated heterocyclic group, X 2 is -O-, -NH-, or -N(C 1-3 alkyl)-, X 3 is O or S, X 4 is
• Ring B is a benzene ring or a 6-membered heterocycle containing 1 to 2 nitrogen atoms
• R Z1 is H, C 1-3 alkyl, -O-(C 1-3 alkyl), -NR Z4 2 , -CONR Z4 2 , or -NR Z4 COR Z5
• R Z2 is H or C 1-3 alkyl
• R Z3 is H or C 1-3 alkyl
• R Z4 are the same or different and each is H or C 1-3 alkyl
• R Z5 is C 1-3 alkyl
• L is bonded to ring B of the above formulas (XIII) to formula (XVIII), or to the benzene ring of formulas (XIX) and formulas (XX), m is 1 or 2
• G is CH or N, However, when G is N, Z is the above formula (XVII), formula (XVIII) or formula (XIX).
• X 1 is -O- or -NR X1 -, R X1 is H or optionally substituted C 1-3 alkyl, Alternatively, when X 1 is -NR X1 -, R may form a group, R 1 is the following formula (II), R 1a is H, methyl, F or Cl; R 1c is F, Cl, methyl or ethyl; R 2 is cyclopropyl or vinyl, R 3 is a group selected from the group consisting of the following formula (IV), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI) and formula (XII), R 3a is -(CH 2 ) p CHR 3e -NR N1 R N2 ;-(CH 2 ) p CHR 3e -OR 3f ; C 1-3 alkyl, -C 1-3 alkylene-OR 3f , -C 1- a 4- to 6-membered saturated heterocyclic group optionally substituted
• X 1 is -O- or -NR X1 -
• R X1 is H or C 1-3 alkyl
• R 3 is a group selected from the group consisting of the following formula (IV), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI) and formula (XII)
• R 3a is -(CH 2 ) p CHR 3e -NR N1 R N2
• R 3b is H or C 1-3 alkyl
• R 3e is H
• R 3g is an optionally substituted 6-membered heteroaryl
• R 3h is H or F
• R N1 and R N2 are the same or different from each other and are C 1-3 alkyl, or R N1 and R N2 may be combined with the nitrogen atom to which they are bonded to form an optionally substituted 4- to 6-membered saturated heterocyclic group
• X 2 is -O- or -NH-
• X 3 is O or S
• n is
• A is CR A or N, R A is H; X 1 is -O-; R 1 is the following formula (II), R 1a is F; R 1c is methyl; R 2 is cyclopropyl; R 3 is a group selected from the group consisting of the following formula (IV), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI) and formula (XII), R 3a is -(CH 2 ) p CHR 3e -NR N1 R N2 ; R 3b is H or C 1-3 alkyl, R 3e is H; R 3g is an optionally substituted 6-membered heteroaryl, R 3h is H or F, R N1 and R N2 are the same or different from each other and are C 1-3 alkyl, X 2 is -O- or -NH-, X 3 is O or S, n is 1, p is 1, R 4 is OCH 3 , C 1-6 alkyl optionally substituted with a group
• R 3 is a group consisting of the following formula (IV-1), formula (VII-1), formula (VIII-1), formula (IX), formula (X), formula (XI) and formula (XII-1) a group selected from L is the following formula (XXVII) to formula (XXXIV) 1 group selected from the group consisting of,
• the carbon atom marked with * combines with Y
• Z is a group selected from the group consisting of the following formula (XIII-1), formula (XVII-1) and formula (XIX-1),
• L is bonded to the benzene ring of the above formula (XIII-1) and formula (XVII-1), G is CH or N, However, when G is N, Z is the above formula (XVII-1) or formula (XIX-1), the compound or its salt according to the above (11-4).
• the compound of formula (I) may exist as tautomers or geometric isomers depending on the type of substituent.
• the compound of formula (I) may be described in only one isomer form, but the present invention also includes other isomers, and the isomers are separated or separated. It also includes mixtures of.
• the compound of formula (I) may have an asymmetric carbon atom or an axial asymmetry, and diastereomers based on this may exist.
• the present invention also encompasses separated diastereomers of compounds of formula (I) or mixtures thereof.
• the present invention also includes pharmaceutically acceptable prodrugs of the compound represented by formula (I).
• a pharmaceutically acceptable prodrug is a compound that has a group that can be converted to an amino group, hydroxyl group, carboxyl group, etc. by solvolysis or under physiological conditions.
• groups that form prodrugs include the groups described in Prog. Med., 5, 2157-2161 (1985) and "Drug Development” (Hirokawa Shoten, 1990), Vol. 7, Molecular Design 163-198. can be mentioned.
• the salt of the compound of formula (I) is a pharmaceutically acceptable salt of the compound of formula (I), and depending on the type of substituent, it may form an acid addition salt or a salt with a base.
• examples include the salts described in P. Heinrich Stahl, Handbook of Pharmaceutical Salts Properties, Selection, and Use, Wiley-VCH, 2008.
• inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, and maleic acid.
• Acid addition with organic acids such as 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, glutamic acid, etc.
• Salts, salts with inorganic metals such as sodium, potassium, magnesium, calcium, aluminum, etc.
• salts with organic bases such as methylamine, ethylamine, ethanolamine, etc.
• salts with various amino acids and amino acid derivatives such as acetylleucine, lysine, ornithine, etc. and ammonium salts.
• the present invention includes various hydrates and solvates of the compound of formula (I) and its salts, and crystal polymorphic substances.
• the present invention also includes all pharmaceutically acceptable compounds of formula (I) or salts thereof labeled with one or more radioactive or non-radioactive isotopes.
• suitable isotopes for use in isotopic labels of compounds of the invention include hydrogen (such as 2 H and 3 H), carbon (such as 11 C, 13 C and 14 C), nitrogen (such as 13 N and 15 N). ), oxygen ( 15 O, 17 O, and 18 O, etc.), fluorine ( 18 F, etc.), chlorine ( 36 Cl, etc.), iodine ( 123 I and 125 I, etc.), and sulfur ( 35 S, etc.) isotopes. wrapped.
• Radioactive isotopes such as tritium ( 3 H) and carbon-14 ( 14 C) may be used for this purpose due to their ease of labeling and detection.
• Substitution of heavier isotopes e.g. substitution of deuterium ( 2H ) for hydrogen, has therapeutic advantages due to improved metabolic stability (e.g. increased half-life in vivo, reduced dose requirements). , decreased drug interactions).
• Substitution with positron emitting isotopes (such as 11 C, 18 F, 15 O and 13 N) can be used in positron emission tomography (PET) studies to test substrate receptor occupancy.
• PET positron emission tomography
• Isotopically labeled compounds of the invention are generally prepared by conventional techniques known to those skilled in the art or by substituting suitable isotopically labeled reagents for unlabeled reagents. It can be manufactured by the same manufacturing method as in Example or Manufacturing Example.
• the compound of formula (I) and its salt can be produced by applying various known synthetic methods by utilizing the characteristics based on its basic structure or the types of substituents. At that time, depending on the type of functional group, it may be effective in terms of manufacturing technology to replace the functional group with an appropriate protecting group (a group that can be easily converted into the functional group) at the stage from raw materials to intermediates. There are cases. Examples of such protecting groups include those described in "Greene's Protective Groups in Organic Synthesis" by P. G. M. Wuts and T. W. Greene, 5th edition, John Wiley & Sons Inc., 2014. , may be appropriately selected and used depending on the reaction conditions.
• a pharmaceutically acceptable prodrug is a compound that has a group that can be converted to an amino group, hydroxyl group, carboxyl group, etc. by solvolysis or under physiological conditions.
• groups forming prodrugs include the groups described in Prog. Med., 5, 2157-2161 (1985) and "Drug Development” (Hirokawa Shoten, 1990), Vol. 7, Molecular Design 163-198. can be mentioned.
• prodrugs of the compound of formula (I) can be prepared by introducing a specific group at the stage from the raw material to the intermediate, or by performing a further reaction using the obtained compound of formula (I). It can be manufactured by The reaction can be carried out by applying conventional methods such as esterification, amidation, dehydration, etc. known to those skilled in the art.
• a typical method for producing the compound of formula (I) will be explained. Each manufacturing method can also be performed with reference to the references attached to the description. Note that the manufacturing method of the present invention is not limited to the examples shown below.
• DMF N,N-dimethylformamide
• DMAc N,N-dimethylacetamide
• THF tetrahydrofuran
• MeCN acetonitrile
• MeOH methanol
• EtOH ethanol
• iPrOH isopropyl alcohol
• tBuOH tert-butanol
• DOX 1,4 -Dioxane
• DMSO dimethyl sulfoxide
• TEA triethylamine
• DIPEA N,N-diisopropylethylamine
• tBuOK potassium tert-butoxide
• PdCl 2 (dppf) ⁇ CH 2 Cl 2 [1,1'-bis(diphenylphosphino) ) ferrocene] palladium(II) dichloride/dichloromethane adduct
• Pd/C palladium on carbon
• PyBOP (benzyl) ⁇ CH 2 Cl 2 : [1,1'-
• the compound (1) and the compound (2) are used in equal amounts or an excess amount of one of them is used, and a mixture thereof is heated in the presence of a condensing agent in a solvent inert to the reaction, preferably under cooling or heating.
• solvents include, but are not limited to, aromatic hydrocarbons such as toluene, ethers such as THF and DOX, halogenated hydrocarbons such as dichloromethane, alcohols, DMF, DMSO, ethyl acetate, MeCN, and Mixtures of these may be mentioned.
• condensing agents examples include PyBOP, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 1-(3 -dimethylaminopropyl)-3-ethylcarbodiimide or its hydrochloride, N,N'-dicyclohexylcarbodiimide (DCC), CDI, diphenylphosphoric azide (DPPA), and the like. It may be preferable to use additives (eg 1-hydroxybenzotriazole) in the reaction.
• additives eg 1-hydroxybenzotriazole
• reaction it may be advantageous to carry out the reaction in the presence of an organic base such as TEA, DIPEA or NMM, or an inorganic base such as potassium carbonate, sodium carbonate or potassium hydroxide in order to allow the reaction to proceed smoothly.
• organic base such as TEA, DIPEA or NMM
• inorganic base such as potassium carbonate, sodium carbonate or potassium hydroxide
• a method may be used in which compound (1) is converted into a reactive derivative and then subjected to an acylation reaction.
• reactive derivatives of carboxylic acids include acid halides obtained by reacting with halogenating agents such as phosphorus oxychloride and thionyl chloride, mixed acid anhydrides obtained by reacting with isobutyl chloroformate, etc., and 1-hydroxy
• reaction between these reactive derivatives and compound (2) is carried out in a solvent inert to the reaction of halogenated hydrocarbons, aromatic hydrocarbons, ethers, etc., under cooling to heating, preferably at -20 It can be carried out at temperatures between °C and 120°C.
• This production method is another method for producing the compound of formula (I).
• the compound of formula (I) can also be obtained by subjecting compound (3) to a deprotection reaction.
• the protecting groups shown here include tert-butoxycarbonyl group, triphenylmethyl group, tetrahydro-2H-pyran-2-yl group, methoxymethyl group, dimethylmethanediyl group, tert-butylsulfinyl group, etc. .
• This deprotection reaction is carried out by stirring under cooling to heating under reflux, usually for 0.1 hour to 5 days.
• solvents used here include, but are not limited to, alcohols such as MeOH and EtOH, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, diethyl ether, THF, DOX, and dimethoxyethane.
• ethers such as DMF, DMSO, MeCN or water, and mixtures thereof.
• deprotecting reagents include, but are not limited to, acids such as hydrogen chloride (DOX solution), trifluoroacetic acid, methanesulfonic acid, and phosphoric acid. By selecting a protecting group, deprotection can also be performed by catalytic hydrogenation reaction.
• protecting groups include benzyl group, p-methoxybenzyl group, benzyloxycarbonyl group, and the like. Deprotection can also be performed using a fluoride ion source such as tetra-n-butylammonium fluoride. Examples of protecting groups include tert-butyl(dimethyl)silyl group, (trimethylsilyl)ethoxymethyl group, and the like. Further, examples of protecting groups that can be deprotected under basic conditions include acetyl group, trifluoroacetyl group, benzoyl group, and the like. As references, for example, the following can be referred to: P. G. M. Wuts and T. W.
• This production method is a method for producing a compound of formula (I-2) in which A is N among compounds of formula (I) by reacting compound (4) and compound (5).
• the compound (4) and the compound (5) are used in equal amounts or an excess amount of one of them is used, and the mixture is heated in the presence of a condensing agent in a solvent inert to the reaction, preferably under cooling or heating. Stir at -20°C to 60°C, usually for 0.1 hour to 5 days.
• solvents include, but are not limited to, aromatic hydrocarbons such as toluene, ethers such as THF and DOX, halogenated hydrocarbons such as dichloromethane, alcohols, DMF, DMSO, ethyl acetate, MeCN, and Mixtures of these may be mentioned.
• condensing agents include PyBOP, HATU, CDI, PyAOP, and the like. It may be advantageous to carry out the reaction in the presence of an organic base such as TEA, DIPEA, or NMM, or an inorganic base such as potassium carbonate, sodium carbonate, or cesium carbonate in order to make the reaction proceed smoothly.
• compound (4) after converting compound (4) into a reactive derivative in which the 4-hydroxyl group of compound (4) is converted to a chloro group using a chlorinating reagent such as phosphorus oxychloride or thionyl chloride, TEA, DIPEA, pyridine, etc.
• a chlorinating reagent such as phosphorus oxychloride or thionyl chloride, TEA, DIPEA, pyridine, etc.
• the compound of formula (I-2) can also be obtained by adding compound (5) in the presence of an organic base such as or an inorganic base such as potassium carbonate, cesium carbonate, or potassium acetate.
• reaction between these reactive derivatives and compound (5) is carried out in a solvent inert to the reaction of halogenated hydrocarbons, aromatic hydrocarbons, ethers, etc., under cooling to heating, preferably at -20 It can be carried out at temperatures between °C and 120°C.
• LG 2 , LG 4 , LG 6 , LG 7 , LG 8 and LG 81 are the same or different and each represents a leaving group.
• PG 4 is a protecting group for OH
• PG 7 and PG 71 are , respectively, a protecting group for NH contained in R 1
• R 11 is a divalent group in which H is removed from NH contained in R 1
• PG 8 is a protecting group that can be removed by catalytic hydrogenation reaction conditions
• PG 81 indicates a protecting group for COOH.
• PG 4 , PG 7 , PG 71 , PG 8 and PG 81 are protective groups that can be removed under different deprotection conditions, and deprotection is performed stepwise.
• R LG2 represents a C 1-12 alkyl group
• BLG represents a boronic acid group, a boronic acid group protected by a boronic acid protecting group such as a boronic acid pinacol ester group, or a trifluoroborate group (hereinafter referred to as a boronic acid group).
• Cl, Br, I, methanesulfonyloxy group, p-toluenesulfonyloxy group, etc. are examples of the leaving group shown here. The same applies hereinafter.
• This production method is the first method for producing compound (1), which is the raw material compound of production method 1.
• This step is a method for producing compound (7) from compound (6).
• This reaction is carried out by stirring compound (6) under cooling to heating under reflux, usually for 0.1 hour to 5 days.
• the solvent used here include, but are not particularly limited to, alcohols, acetone, DMF, THF, and the like.
• a mixed solvent of the above solvent and water may be suitable for the reaction.
• reagents used in this reaction include, but are not particularly limited to, an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, and the like.
• references for this reaction for example, the following can be referred to. “Experimental Chemistry Course (5th edition)” edited by the Chemical Society of Japan, Volume 16 (2005) (Maruzen) Angew. Chem. Int. Ed. 2005, 44, p.1378-1382.
• This step is a method for producing compound (8) by protecting the hydroxyl group of compound (7) with a protecting group.
• a protecting group As an example, when protecting with a tert-butyl group, this reaction is carried out by stirring compound (7) in the presence of a tert-butyl protecting reagent under cooling to heating under reflux, usually for 0.1 hour to 5 days.
• the solvent used here include, but are not particularly limited to, ethers such as THF and DOX, halogenated hydrocarbons such as dichloromethane, tBuOH and DMF.
• tert-butyl protection reagents include, but are not particularly limited to, isobutene, 2-tert-butyl-1,3-diisopropylisourea, and the like.
• Compound (8) can also be produced by a dehydration condensation reaction between compound (7) and tBuOH. As references for this reaction, for example, the following can be referred to. 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
• This step is a method for producing compound (10) by an ipso-substitution reaction between compound (8) and R LG2 -SH, which is compound (9).
• R LG2 -SH used here include C 1-12 alkylthiols, such as ethanethiol, dodecanethiol.
• the compound (8) and the compound (9) are used in equal amounts or an excess amount of one of them, and the mixture thereof is heated under cooling to reflux, preferably in a solvent inert to the reaction or without a solvent. Stir at 0°C to 80°C, usually for 0.1 hour to 5 days.
• solvents used here include, but are not limited to, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, aromatic hydrocarbons such as benzene, toluene, and xylene, diethyl ether, and THF. , DOX, ethers such as 1,2-dimethoxyethane, DMF, DMAc, DMSO, ethyl acetate, MeCN, and mixtures thereof.
• halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform
• aromatic hydrocarbons such as benzene, toluene, and xylene
• diethyl ether diethyl ether
• THF diethyl ether
• DOX 1,2-dimethoxyethane
• ethers such as 1,2-dimethoxyethane, DMF, DMAc, DMSO, ethyl acetate, Me
• the reaction is carried out in the presence of organic bases such as TEA, DIPEA, NMM, 1,4-diazabicyclo[2.2.2]octane (DABCO), and tBuOK, and inorganic bases such as sodium hydride, potassium carbonate, sodium carbonate, and cesium carbonate. This may be advantageous in making the reaction proceed smoothly.
• organic bases such as TEA, DIPEA, NMM, 1,4-diazabicyclo[2.2.2]octane (DABCO), and tBuOK
• inorganic bases such as sodium hydride, potassium carbonate, sodium carbonate, and cesium carbonate. This may be advantageous in making the reaction proceed smoothly.
• This step is a method for producing compound (12) by an ipsosubstitution reaction between compound (10) and PG 8 -OH, which is compound (11).
• PG 8 -OH used here include benzyl alcohol, p-methoxybenzyl alcohol, and 1-phenylethanol.
• the reaction conditions are the same as in the third step of this raw material synthesis 1.
• This step is a method for producing compound (14) by a Suzuki-Miyaura coupling reaction between compound (12) and compound (13), a boronic acid derivative comprising an R 2 -boronic acid group.
• a boronic acid group used here include, but are not particularly limited to, boronic acid groups, boronic acid ester groups, boronic acid pinacol ester groups, triolborate bases, trifluoroborate bases, and the like.
• compound (12) and a boronic acid derivative consisting of an R 2 -boronic acid group, etc. are used in equal amounts or an excess amount of one of them is used, and the mixture is mixed with a base and a palladium catalyst in a solvent inert to the reaction.
• the mixture is stirred at room temperature to reflux under heating, preferably from 20°C to 140°C, usually for 0.1 hour to 5 days.
• solvents used here include, but are not limited to, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform, aromatic hydrocarbons such as benzene, toluene, and xylene, diethyl ether, and THF.
• ethers such as 1,2-dimethoxyethane
• alcohols such as MeOH, EtOH, isopropyl alcohol, butanol, amyl alcohol, DMF, DMSO, MeCN, 1,3-dimethylimidazolidin-2-one, water and Mixtures of these may be mentioned.
• the base include inorganic bases such as tripotassium phosphate, sodium carbonate, potassium carbonate, sodium hydroxide, and barium hydroxide.
• Palladium catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, PdCl 2 (dppf) ⁇ CH 2 Cl 2 , (1E,4E)-1,5-diphenylpenta-1 ,4-dien-3-one/palladium (3:2), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1 ,1'-biphenyl)]palladium(II) methanesulfonate, palladium(II) acetate, and the like.
• LG 6 is a halogen
• compound (14) (where R 2 is hydrogen) can be produced by dehalogenation reaction of compound (12) using a Pd catalyst and a reducing agent.
• This step is a method for producing compound (16) by a Suzuki-Miyaura coupling reaction between compound (14) and compound (15).
• the reaction conditions are the same as in the fifth step of this raw material synthesis 1.
• compound (16) has axial asymmetry, it can be obtained as a mixture of stereoisomers, but each stereoisomer can be obtained by performing a usual separation operation, such as separation using ODS column chromatography or silica gel column chromatography. Isomers can be isolated.
• This step is a method for producing compound (17) by oxidation reaction of compound (16).
• compound (16) is mixed with an equal or excess amount of an oxidizing agent in a solvent inert to the reaction, under cooling to heating, preferably at -20°C to 80°C, usually for 0.1 hour to 3 days.
• oxidation using m-chloroperbenzoic acid, perbenzoic acid, peracetic acid, sodium hypochlorite, or hydrogen peroxide is preferably used.
• solvents include aromatic hydrocarbons, ethers, halogenated hydrocarbons such as dichloromethane, DMF, DMSO, ethyl acetate, MeCN, and mixtures thereof.
• oxidizing agents include cumene hydroperoxide, oxone, activated manganese dioxide, chromic acid, potassium permanganate, sodium periodate, and the like. [Literature] Edited by the Chemical Society of Japan, "Experimental Chemistry Course", 5th edition, Volume 17, Maruzen, 2004. If compound (17) has axial chirality, it may be obtained as a mixture of stereoisomers. Each stereoisomer can be isolated by conventional separation operations, such as separation using ODS column chromatography or silica gel column chromatography, or separation by SFC using a chiral column.
• This step is a method for producing compound (19) by an ipsosubstitution reaction between compound (17) and compound (18).
• the reaction conditions are the same as in the third step of this raw material synthesis 1.
• This step is a method for producing compound (20) by deprotecting compound (19) by catalytic hydrogenation reaction.
• compound (19) is reacted in a hydrogen atmosphere under normal pressure to increased pressure, in a solvent inert to the reaction such as MeOH, EtOH, ethyl acetate, etc., in the presence of a metal catalyst, preferably under cooling to heating. This can be carried out by stirring at room temperature for 1 hour to 5 days.
• a palladium catalyst such as Pd/C or palladium black
• a platinum catalyst such as a platinum plate or platinum oxide
• a nickel catalyst such as reduced nickel or Raney nickel
• This step is a method for producing compound (22) from compound (20) and compound (21).
• the compound (20) and the compound (21) are used in equal amounts or an excess amount of one of them is used, and the mixture thereof is heated in the presence of a base in a solvent inert to the reaction, preferably under cooling or heating under reflux.
• the reaction is usually carried out at 0°C to 80°C for 0.1 hour to 5 days.
• the solvent used here is not particularly limited, but for example, aromatic hydrocarbons such as benzene, toluene, and xylene, alcohols such as MeOH and EtOH, diethyl ether, THF, DOX, 1,2-dimethoxyethane, etc.
• ethers such as dichloromethane, 1,2-dichloroethane, and chloroform, DMF, DMSO, ethyl acetate, MeCN, and mixtures thereof.
• bases include, but are not limited to, organic bases such as TEA, DIPEA, 1,8-diazabicyclo[5.4.0]-7-undecene, n-butyllithium, tBuOK, sodium hydroxide, sodium carbonate, and carbonate.
• inorganic bases such as potassium, cesium carbonate, and sodium hydride. It may be advantageous to carry out the reaction in the presence of a phase transfer catalyst such as tetra-n-butylammonium chloride.
• compound (21) is a compound in which the moiety corresponding to LG 81 is a hydroxy group, which is sulfonylated in the presence of a base.
• a compound in which LG 81 is a sulfonyloxy group can be produced.
• the sulfonylating reagent used here include, but are not particularly limited to, methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, and the like.
• the base include, but are not particularly limited to, TEA, DIPEA, pyridine, tetramethylethylenediamine, and the like.
• the following can be referred to. Synthesis 1999, 9, p.1633-1636
• the protecting groups PG 4 and PG 7 of compound (22) are deprotected, and the deprotected NH group contained in R 11 is protected with another protecting group PG 71 , thereby converting the compound ( 23).
• the reaction conditions are the same as those described in Production Method 2, and in addition to compound (22) and a deprotecting reagent, a protecting reagent for protecting the NH group with the PG 71 group is added to carry out the reaction. Can be done.
• This step is a method for producing compound (24) by reacting compound (23) and compound (5).
• the reaction conditions are the same as in Production Method 3.
• This step is a method for producing compound (1) by subjecting compound (24) to a deprotection reaction.
• the reaction conditions are similar to the steps described in Production Method 2.
• compound (3) which is a raw material compound of production method 2 A is N, -L 1 - of -L- is CO, and -L 2 - is -N(R L2 )- or a saturated heterocyclic divalent group containing 1 to 2 optionally substituted nitrogen atoms, -L 3 -L 4 -L 5 - is -L 35 -, and R L2 is H or C
• This step is a method for producing compound (26) by reacting compound (25) and compound (5).
• the reaction conditions are the same as in Production Method 3.
• This step is a method for producing compound (27) by hydrolyzing compound (26) under basic conditions. This reaction is carried out by stirring Compound (26) under cooling or heating under reflux, usually for 0.1 hour to 5 days.
• the solvent used here include, but are not particularly limited to, alcohols, acetone, DMF, THF, and the like. Further, a mixed solvent of the above solvent and water may be suitable for the reaction.
• the hydrolyzing reagent include, but are not particularly limited to, aqueous sodium hydroxide solution, aqueous potassium hydroxide solution, trimethyltin hydroxide, and the like. As references for this reaction, for example, the following can be referred to. “Experimental Chemistry Course (5th edition)” edited by the Chemical Society of Japan, Volume 16 (2005) (Maruzen) Angew. Chem. Int. Ed. 2005, 44, p.1378-1382.
• This step is a method for producing compound (3-1) by subjecting compound (27) and compound (2) to an amidation reaction.
• the reaction conditions are the same as the steps described in Production Method 1.
• compound (3) which is a raw material compound of production method 2 A is N, -L 1 - of -L- is CO, and -L 2 - is -N(R L2 )- or a saturated heterocyclic divalent group containing 1 to 2 optionally substituted nitrogen atoms, -L 3 -L 4 -L 5 - is -L 35 -, and R L2 is H or C
• This step is a method for producing compound (29) from compound (20) and compound (28).
• the reaction conditions are the same as in the tenth step of raw material synthesis 1.
• This step is a method for producing compound (30) by subjecting compound (29) to a deprotection reaction.
• the reaction conditions are the same as in the second step of raw material synthesis 2.
• This step is a method for producing compound (31) by subjecting compound (30) and compound (2) to an amidation reaction.
• the reaction conditions are the same as the steps described in Production Method 1.
• This step is a method for producing compound (3-1) by reacting compound (32) and compound (5).
• the reaction conditions are the same as in Production Method 3.
• compound (4) which is a raw material compound in production method 3
• -L 4 - included in -L- is -N(R L' )-
• -L 5 - is -CH 2 -. This is a method for producing a certain compound (4-1).
• This step is a method for producing compound (34) from compound (20) and compound (33).
• the reaction conditions are the same as in the tenth step of raw material synthesis 1.
• This step is a method for producing compound (35) by subjecting compound (34) to a deprotection reaction.
• the reaction conditions are similar to the steps described in Production Method 2.
• This step is carried out from compound (35) and compound (36) by reductive amination reaction when -R Z is -CHO, and by alkylation reaction when -R Z is -CH 2 -LG 81 . These are steps for obtaining compound (4-1).
• compound (35) and compound (36) are mixed in the same equivalent amount or in an excess equivalent amount of one of them, in the presence of a reducing agent and acetic acid, in a solvent inert to the reaction, from ice-cooling to room temperature. This is usually done by stirring for 1 hour to 5 days.
• Examples of the reducing agent used here include, but are not particularly limited to, NaBH(OAc) 3 , 2-picoline borane, NaBH 3 CN, and the like.
• the solvent used here is not particularly limited, but halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, ether solvents such as THF, diethyl ether, DOX, alcohol solvents such as MeOH, EtOH, MeCN, etc. are used. .
• the reaction conditions when -R Z is -CH 2 -LG 81 are the same as those in the tenth step of raw material synthesis 1.
• This production method uses compound (52) in which R 3 is formula (IV), formula (V) or formula (VI) and X 3 is O among compound (1) which is the raw material compound of production method 1. This is a method of manufacturing.
• This step is a method for producing compound (37) by an ipso-substitution reaction between compound (6) and R LG2 -SH, which is compound (9).
• the reaction conditions are the same as in the third step of raw material synthesis 1.
• This step is a method for producing compound (38) by an ipsosubstitution reaction between compound (37) and compound (11).
• the reaction conditions are the same as in the fourth step of raw material synthesis 1.
• This step is a method for producing compound (40) by an ipso-substitution reaction between compound (38) and compound (39) having an amino group protected with a protecting group PG 41 .
• the compound (38) and the compound (39) are used in equal amounts or in excess of one of them, and the mixture is heated in a solvent inert to the reaction under cooling to heating, preferably from -20°C to 60°C. Stir at °C for usually 0.1 hour to 5 days.
• solvents include, but are not limited to, aromatic hydrocarbons such as toluene, halogenated hydrocarbons such as dichloromethane, DMF, DMSO, ethyl acetate, MeCN, and mixtures thereof. It may be advantageous to carry out the reaction in the presence of an organic base such as TEA, DIPEA, or NMM, or an inorganic base such as potassium carbonate, sodium carbonate, or cesium carbonate in order to make the reaction proceed smoothly.
• an organic base such as TEA, DIPEA, or N
• This step is a method for producing compound (41) by a Suzuki-Miyaura coupling reaction between compound (40) and compound (13), a boronic acid derivative comprising an R 2 -boronic acid group.
• the reaction conditions are the same as in the fifth step of raw material synthesis 1.
• This step is a method for producing compound (42) by a Suzuki-Miyaura coupling reaction between compound (41) and compound (15).
• the reaction conditions are the same as in the fifth step of raw material synthesis 1.
• compound (42) has axial asymmetry, it can be obtained as a mixture of stereoisomers, but each stereoisomer can be obtained by performing a usual separation operation, such as separation using ODS column chromatography or silica gel column chromatography. Isomers can be isolated.
• This step is a method for producing compound (43) by oxidation reaction of compound (42).
• the reaction conditions are the same as in the seventh step of raw material synthesis 1.
• compound (43) has axial asymmetry, it may be obtained as a mixture of stereoisomers, but it can be obtained by ordinary separation operations, such as separation using ODS column chromatography or silica gel column chromatography, or using a chiral column. Each stereoisomer can be isolated by performing separation using SFC, etc.
• This step is a method for producing compound (44) by an ipsosubstitution reaction between compound (43) and compound (18).
• the reaction conditions are the same as in the third step of raw material synthesis 1.
• This step is a method for producing compound (45) by deprotecting compound (44) by catalytic hydrogenation reaction.
• the reaction conditions are the same as in the ninth step of raw material synthesis 1.
• This step is a method for producing compound (46) from compound (45) and compound (21).
• the reaction conditions are the same as in the tenth step of raw material synthesis 1.
• This step is a method for producing compound (47) by subjecting compound (46) to a deprotection reaction.
• the reaction conditions are similar to the steps described in Production Method 2.
• compound (51) is produced from compound (47) by ureation reaction using compound (48), carbamate reaction using compound (49), and amidation reaction using compound (50).
• This is the process of obtaining In the ureation reaction using compound (48) and the carbamate reaction using compound (49), compound (48) or compound (49) is used in an equivalent amount or in excess of one of compound (47).
• the mixture is stirred in the presence of a condensing agent, in a reaction-inert solvent, under cooling to heating, preferably at -20°C to 60°C, usually for 0.1 hour to 5 days.
• solvents include, but are not limited to, aromatic hydrocarbons such as toluene, ethers such as THF and DOX, halogenated hydrocarbons such as dichloromethane, alcohols, DMF, DMSO, ethyl acetate, MeCN, and Mixtures of these may be mentioned.
• condensing agents include CDI, triphosgene, bis(4-nitrophenyl) carbonate, 4-nitrophenyl chloroformate, and the like. It may be preferable to use additives (eg 1-hydroxybenzotriazole or dimethylaminopyridine) in the reaction.
• reaction conditions for the amidation reaction using compound (50) are the same as the steps described in Production Method 1.
• This step is a method for producing compound (52) by subjecting compound (51) to a deprotection reaction.
• the reaction conditions are similar to the steps described in Production Method 2.
• This production method is a second method for producing compound (1), which is the raw material compound of production method 1.
• This step is a method for producing compound (53) by deprotecting compound (17) by catalytic hydrogenation reaction.
• the reaction conditions are the same as in the ninth step of raw material synthesis 1.
• This step is a method for producing compound (54) from compound (53) and compound (21).
• the reaction conditions are the same as in the tenth step of raw material synthesis 1.
• This step is a method for producing compound (55) by an ipsosubstitution reaction between compound (54) and compound (18).
• the reaction conditions are the same as in the third step of raw material synthesis 1.
• This step is a method for producing compound (56) by subjecting compound (55) to a deprotection reaction.
• the reaction conditions are similar to the steps described in Production Method 2.
• This step is a method for producing compound (57) by reacting compound (56) and compound (5).
• the reaction conditions are the same as in Production Method 3.
• This step is a method for producing compound (1) by subjecting compound (57) to a deprotection reaction.
• the reaction conditions are similar to the steps described in Production Method 2.
• compound (3) which is a raw material compound of production method 2 A is N, -L 1 - included in -L- is CO, and -L 2 - is -N(R L2 )- or a saturated heterocyclic divalent group containing 1 to 2 optionally substituted nitrogen atoms, -L 3 -L 4 -L 5 - is -L 35 -, and R L2 is H or C 1
• A is N
• -L 1 - included in -L- is CO
• -L 2 - is -N(R L2 )- or a saturated heterocyclic divalent group containing 1 to 2 optionally substituted nitrogen atoms
• -L 3 -L 4 -L 5 - is -L 35 -
• R L2 is H or C 1
• This step is a method for producing compound (58) by subjecting compound (29) to a deprotection reaction.
• the reaction conditions are similar to the steps described in Production Method 2.
• This step is a method for producing compound (59) by reacting compound (58) and compound (5).
• the reaction conditions are the same as in Production Method 3.
• This step is a method for producing compound (60) by subjecting compound (59) to a deprotection reaction.
• the reaction conditions are the same as in the second step of raw material synthesis 2.
• This step is a method for producing compound (61) by subjecting compound (60) and compound (2) to an amidation reaction.
• the reaction conditions are the same as the steps described in Production Method 1.
• This production method is a method for producing compound (69), which is the raw material compound of production method 4.
• This step is a method for producing compound (62) by an ipsosubstitution reaction between compound (38) and compound (5).
• the reaction conditions are the same as in the third step of raw material synthesis 5.
• This step is a method for producing compound (63) by a Suzuki-Miyaura coupling reaction between compound (62) and compound (13), a boronic acid derivative comprising an R 2 -boronic acid group.
• the reaction conditions are the same as in the fifth step of raw material synthesis 1.
• This step is a method for producing compound (64) by a Suzuki-Miyaura coupling reaction between compound (63) and compound (15).
• the reaction conditions are the same as in the fifth step of raw material synthesis 1.
• compound (64) has axial chirality, it can be obtained as a mixture of stereoisomers, but each stereoisomer can be obtained by performing a usual separation operation such as ODS column chromatography or silica gel column chromatography. Isomers can be isolated.
• This step is a method for producing compound (65) by oxidation reaction of compound (64).
• the reaction conditions are the same as in the seventh step of raw material synthesis 1.
• compound (65) has axial asymmetry, it may be obtained as a mixture of stereoisomers, but it can be obtained by ordinary separation operations, such as separation using ODS column chromatography or silica gel column chromatography, or using a chiral column. Each stereoisomer can be isolated by performing separation using SFC, etc.
• This step is a method for producing compound (66) through an ipsosubstitution reaction between compound (65) and compound (18).
• the reaction conditions are the same as in the third step of raw material synthesis 1.
• This step is a method for producing compound (67) by deprotecting compound (66) by catalytic hydrogenation reaction.
• the reaction conditions are the same as in the ninth step of raw material synthesis 1.
• This step is a method for producing compound (68) from compound (67) and compound (21).
• the reaction conditions are the same as in the tenth step of raw material synthesis 1.
• This step is a method for producing compound (69) by subjecting compound (68) to a deprotection reaction.
• the reaction conditions are similar to the steps described in Production Method 2.
• This step is a method for producing compound (72) by a Suzuki-Miyaura coupling reaction between compound (70) and compound (71).
• the reaction conditions are the same as in the fifth step of raw material synthesis 1.
• This step is a method for producing compound (73), which is an aldehyde, from compound (72).
• the corresponding 1,2-diol compound is obtained by reacting compound (72) with osmium tetroxide in a reaction-inert solvent at room temperature under cooling in the presence of an organic base.
• Solvents used here include alcohols such as tBuOH, ethers such as THF, DOX, and 1,2-dimethoxyethane, aromatic hydrocarbons such as benzene, toluene, and xylene, acetone, and combinations of these and water. Examples include mixed solvents. Further, examples of the organic base used here include pyridine, 2,6-lutidine, etc., and examples of periodic acids used here include sodium periodate, periodic acid, etc.
• This step is a method for producing compound (75) through a reductive amination reaction using compound (73) and compound (74), which is an amine compound.
• the reaction conditions are the same as in the third step of raw material synthesis 4 when -R Z is -CHO.
• This step is a reaction in which compound (2-1) is obtained by subjecting compound (75) to a deprotection reaction.
• the reaction conditions are the same as in Production Method 2.
• Test Example 1 Evaluation of RAS G12V degrading effect on human KRAS G12V mutation-positive pancreatic cancer line PA-TU-8902 The RAS G12V degrading effect of the test compound was evaluated by measuring the RAS G12V expression level by Cell ELISA method. 36 ⁇ L of PA-TU-8902 cells (DSMZ, ACC 179) were seeded in a 384-well plate (Greiner bio-one) at 1.5 ⁇ 10 4 cells per well. Cell culture was carried out at 37° C. in the presence of 5% CO 2 using DMEM medium (Sigma-Aldrich) containing 10% fetal bovine serum (Cytiva).
• test compound (10 points in the range from 3 ⁇ M final concentration to 0.1 nM), the compound of Example No. 7 at a final concentration of 3 ⁇ M as a positive control, and dimethyl sulfoxide (DMSO), the solvent for the test compound, as a negative control were added to a fresh plate. It was diluted 100 times with medium, added 4 ⁇ L to each well, and cultured for 24 hours. The next day, the culture supernatant was removed, 20 ⁇ L of 4% paraformaldehyde phosphate buffer (FUJIFILM Wako) was added to each well, and the cells were fixed by standing at room temperature for 30 minutes.
• DMSO dimethyl sulfoxide
• PBS Phosphate buffered saline
• Triton X-100 Amersham Biosciences
• the decomposition rate at the concentration of the compound that showed the highest decomposition effect was set as Dmax, and based on the decomposition rate up to the concentration of the compound that showed Dmax, the 50% decomposition value (DC 50 ) of RAS G12V was subjected to Sigmoid-Emax model nonlinear regression analysis. Calculated. The results for several test compounds of formula (I) are shown in the table below.
• Test Example 2 Evaluation of ERK phosphorylation inhibitory effect on human KRAS G12V mutation-positive pancreatic cancer line PA-TU-8902.
• the inhibitory effect of the test compound on ERK phosphorylation is evaluated by measuring with Cell ELISA.
• PA-TU-8902 cells are seeded at 36 ⁇ L/well in a 384-well plate at 5.0x10 3 cells per well. Cell culture is performed under the same conditions as Test Example 1. The next day, the test compound (9 points ranging from final concentration 3 ⁇ M to 0.3 nM), trametinib (MEK inhibitor) at a final concentration of 300 nM as a positive control, and DMSO, the solvent for the test compound as a negative control, were mixed 100x in fresh medium.
• MEK inhibitor trametinib
• Centrifugation after the third wash is performed at 171xg for 17 seconds. After removing the supernatant, the plate is air-dried at room temperature for at least 3 hours, and the fluorescence signal at 800 nm is measured using Aerius.
• the signal value upon addition of DMSO is defined as 0% inhibition
• the signal value upon addition of 300 nM trametinib is defined as 100% inhibition
• the 50% inhibition value (IC 50 ) is calculated by Sigmoid-Emax model nonlinear regression analysis.
• Test Example 3 Evaluation of anchorage-independent cell growth inhibitory effect on human KRAS G12V mutation-positive pancreatic cancer line PA-TU-8902
• the anchorage-independent cell growth inhibitory effect of the test compound was evaluated by three-dimensional spheroid culture.
• PA-TU-8902 cells were seeded at 36 ⁇ L/well at 5 ⁇ 10 2 cells per well in a low cell adsorption U-bottom 384-well plate (Prime Surface: Sumitomo Bakelite). Cell culture was performed under the same conditions as Test Example 1.
• test compound 8 to 10 points with a final concentration ranging from 3 ⁇ M to 0.1 nM
• DMSO a solvent for the test compound as a negative control
• the signal value in the DMSO treatment was defined as 0% inhibition, and the signal value in the medium alone in the absence of cells was defined as 100% inhibition, and the 50% inhibition value (IC 50 ) was calculated by Sigmoid-Emax model nonlinear regression analysis.
• the results for several test compounds of formula (I) are shown in the table below. For Example No. 17, the inhibition rate at 30 nM was calculated. Note that 50% inhibition @30nM indicates that the test compound has 50% inhibitory activity at a concentration of 30nM.
• Test Example 4 Evaluation of anchorage-independent cell growth inhibitory effect on human KRAS G12V mutation-positive lung cancer line LCLC-97TM1
• the anchorage-independent cell growth inhibitory effect of the test compound was evaluated by three-dimensional spheroid culture.
• LCLC-97TM1 cells (DSMZ, ACC 388) were seeded at 36 ⁇ L/well in a low cell adsorption U-bottom 384-well plate (Prime Surface: Sumitomo Bakelite) at 7.5 ⁇ 10 2 cells per well.
• Cell culture was carried out at 37°C in the presence of 5% CO2 using RPMI-1640 medium (Fuji Film Wako Pure Chemical Industries, Ltd.) containing 10% fetal bovine serum.
• test compound (9 points with a final concentration ranging from 10 ⁇ M to 0.1 nM) and DMSO, a solvent for the test compound as a negative control, were diluted 100 times with fresh medium and 4 ⁇ L was added to each well. After culturing at 37°C in the presence of 5% CO2 for 6 days, 20 ⁇ L of CellTiter-Glo 2.0 (Promega) was added to each well. After stirring at room temperature for 1 hour using a plate mixer (FINE PCR), luminescent signals were measured using ARVO X3 (PerkinElmer).
• the signal value in the DMSO treatment was defined as a survival rate of 100%, and the signal value in the medium alone in the absence of cells was defined as a survival rate of 0%, and the 50% survival value (IC50) was calculated by Sigmoid-Emax model nonlinear regression analysis.
• Test Example 5 Evaluation of antitumor effect in human KRAS G12V mutation-positive pancreatic cancer line PA-TU-8902 tumor-bearing mice PA-TU-8902 cells are cultured under the same conditions as Test Example 1. PA-TU-8902 cells were collected and suspended in PBS, and 2 equivalents of VitroGel Hydrogel Matrix (TheWell Bioscience) was added to prepare a cell suspension of 1.0-3.0x10 cells/mL for 4-6 weeks. Inoculate subcutaneously into a male male nude mouse (BALB/c-nu(nu/nu), Charles River Japan) in a volume of 100 ⁇ L.
• the animals are divided into groups so that the tumor volumes and body weights are approximately equal between each group, and administration of the test compound is started the next day.
• the test is conducted with 5 animals each in the vehicle group and the test compound administration group.
• the compounds are ethanol (FUJIFILM Wako), 5% glucose solution (Otsuka Pharmaceutical), 1M hydrochloric acid (Kanto Kagaku), and 50% (2-hydroxypropyl)- ⁇ -cyclodextrin (HP- ⁇ CD) aqueous solution (ROQUETTE).
• [Tumor volume (mm 3 )] [Tumor major axis (mm)] x [Tumor minor axis (mm)] 2 x 0.5
• the tumor growth inhibition rate (%) by the test compound is calculated assuming that the tumor volume in the test compound administration group on the day before the start of administration is 100% inhibition and the tumor volume in the vehicle group on the final measurement day is 0% inhibition.
• the tumor regression rate (%) of the test compound is calculated by assuming that the tumor volume on the day before the start of administration is 0% regression and 0 tumor volume is 100% regression. Calculate.
• Test Example 6 Evaluation of antitumor effect in human G12V mutant KRAS-positive lung adenocarcinoma line LCLC-97TM1 tumor-bearing mice
• LCLC-97TM1 cells were collected and suspended in PBS, and twice the same volume of VitroGel Hydrogel Matrix (TheWell Bioscience) was added to prepare a cell suspension of 3.0x10 cells/100 ⁇ L per animal for 4-6 weeks.
• the cells were subcutaneously inoculated into male male nude mice (BALB/c-nu(nu/nu), Charles River Japan). Approximately 2-3 weeks after transplantation, the animals were divided into groups so that the tumor volumes among the groups were approximately equal, and administration of the test compound was started.
• the test is conducted with 5 animals each in the vehicle group and the test compound administration group, and the vehicle group is administered the vehicle, and the test compound administration group is administered a solution of the test compound in the solvent through the tail vein.
• the same solvent as in Test Example 5 was used.
• the drug is administered once a week, twice in total. Tumor diameter and body weight measurements were performed twice a week. The following formula was used to calculate the tumor volume.
• [Tumor volume (mm3)] [Tumor major axis (mm)] x [Tumor minor axis (mm)] 2 x 0.5
• the tumor growth inhibition rate (%) by the test compound was calculated based on the assumption that the tumor volume in the test compound administration group on the day before the start of administration was 100% inhibition, and the tumor volume in the vehicle group on the final measurement day was 0% inhibition. In addition, if the tumor volume in the test compound administration group is lower than the tumor volume on the day before the start of administration, the tumor regression rate (%) of the test compound is calculated by assuming that the tumor volume on the day before the start of administration is 0% regression and 0 tumor volume is 100% regression. was calculated.
• the effect of inducing the degradation of G12V mutant KRAS was confirmed in some compounds of formula (I). Furthermore, cell proliferation inhibitory effects on human G12V mutant KRAS-positive pancreatic cancer and/or lung cancer lines were confirmed in some compounds of formula (I). Furthermore, antitumor effects of some compounds of formula (I) in mice bearing human G12V mutant KRAS-positive lung cancer were confirmed. Therefore, the compound of formula (I) can be used for the treatment of pancreatic cancer and/or lung cancer, particularly KRAS G12V mutation-positive pancreatic cancer and/or lung cancer.
• compositions containing one or more compounds of formula (I) or salts thereof as active ingredients can be prepared using excipients commonly used in the art, such as pharmaceutical excipients and pharmaceutical carriers. It can be prepared by a commonly used method. Administration can be by oral administration using tablets, pills, capsules, granules, powders, liquids, etc., or parenterally via intra-articular, intravenous, intramuscular injections, transmucosal agents, inhalants, etc. It may be a form.
• Tablets, powders, granules, etc. are used as solid compositions for oral administration.
• one or more active ingredients are mixed with at least one inert excipient.
• the compositions may also contain inert additives such as lubricants, disintegrants, stabilizers and solubilizing agents in accordance with conventional methods. Tablets or pills may be coated with a sugar coating or a film of gastric or enteric substances, if necessary.
• Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs, and commonly used inert diluents such as purified water. Or contains EtOH.
• the liquid composition may also contain adjuvants such as solubilizing agents, wetting agents, suspending agents, sweetening agents, flavoring agents, aromatic agents, and preservatives.
• Injections for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions, or emulsions.
• Aqueous solvents include, for example, distilled water for injection or physiological saline.
• non-aqueous solvents include alcohols such as EtOH.
• Such compositions may further include tonicity agents, preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizers, or solubilizing agents. These are sterilized, for example, by filtration through bacteria-retaining filters, by incorporation of disinfectants or by irradiation. Moreover, these can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile injectable solvent before use.
• Transmucosal agents such as inhalants and nasal agents are used in solid, liquid or semi-solid form, and can be manufactured according to conventionally known methods. For example, known excipients, pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners, and the like may be added as appropriate.
• Administration can use a suitable inhalation or insufflation device.
• the compounds are administered alone or as a powder in a formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier, using known devices such as metered dose inhalation devices or nebulizers. be able to.
• Dry powder inhalers and the like may be for single or multiple doses and may utilize dry powder or powder-containing capsules. Alternatively, it may be in the form of a pressurized aerosol spray using a suitable propellant, for example a chlorofluoroalkane or a suitable gas such as carbon dioxide.
• the daily dose is approximately 0.001 to 100 mg/kg, preferably 0.1 to 30 mg/kg, and more preferably 0.1 to 10 mg/kg per body weight, and this is administered once or twice.
• Administer in 4 to 4 divided doses When administered intravenously, the appropriate daily dose is approximately 0.0001 to 10 mg/kg per body weight, administered once to multiple times a day.
• the pharmaceutical composition of the present invention contains 0.01 to 100% by weight, and in some embodiments, 0.01 to 50% by weight of one type of active ingredient. or more compounds of formula (I) or salts thereof.
• the compound of formula (I) can be used in combination with various therapeutic or preventive agents for diseases for which the aforementioned compound of formula (I) is thought to be effective.
• the combination may be administered simultaneously or separately, sequentially, or at desired time intervals.
• Co-administration formulations may be combined or separately formulated.
• the method for producing the compound of formula (I) will be explained in more detail based on Examples. Note that the present invention is not limited to the compounds described in the Examples below. In addition, the manufacturing method of each raw material compound is shown in the manufacturing examples. Furthermore, the method for producing the compound of formula (I) is not limited to the production method of the specific examples shown below, and the compound of formula (I) can be produced by a combination of these production methods or by a person skilled in the art. It can also be produced by a method that is obvious.
• naming software such as ACD/Name (registered trademark, Advanced Chemistry Development, Inc.) may be used to name compounds.
• concentration mol/L is expressed as M.
• a 1M aqueous sodium hydroxide solution means a 1 mol/L aqueous sodium hydroxide solution.
• Production example 4 7-bromo-4-tert-butoxy-2-(ethylsulfanyl)-8-fluoro-6-iodoquinazoline (32 g) and (1S)-1-phenylethan-1-ol (11 mL) in THF (400 tBuOK (10 g) was added to the solution (mL) under ice cooling, and the mixture was stirred for 1 hour under ice cooling under an argon atmosphere. The reaction was stopped by adding a saturated aqueous ammonium chloride solution under ice cooling.
• Production example 8 4-tert-butoxy-6-cyclopropyl-2-(ethanesulfonyl)-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-8-[( To a solution of 1S)-1-phenylethoxy]quinazoline (1386 mg) and (2S)-2-methoxypropan-1-ol (189 ⁇ L) in THF (20 mL) was added tBuOK (254 mg) in an ice-MeOH bath. The mixture was added and stirred for 30 minutes at the same temperature under a nitrogen atmosphere.
• a saturated aqueous ammonium chloride solution was added to the reaction mixture under ice cooling, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
• Production example 11 4-bromo-6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazole (100 g), 4,4,4',4',5,5,5',5'-octamethyl- Acetic acid was added to a mixture of 2,2'-bi-1,3,2-dioxaborolane (61.42 g), triphenylphosphine (10.57 g), potassium acetate (59.34 g), and DOX (1000 mL) at room temperature under a nitrogen atmosphere. Palladium(II) (4.52 g) was added. The reaction mixture was degassed and filled with nitrogen gas three times, and then stirred at 100° C. for 12 hours under a nitrogen atmosphere.
• Production example 12 4-tert-butoxy-6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy ]-8-[(1S)-1-phenylethoxy]quinazoline (1.25 g) in MeOH (15 mL) and THF (15 mL) was added sodium bicarbonate (1.62 g) and 10% Pd/C (approx. % water content, 609 mg), and the mixture was stirred at room temperature and pressure under a hydrogen atmosphere for 3 hours.
• Production example 17 4-[( ⁇ 4-tert-butoxy-6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2-[(2S) Add sodium hydroxide (1M aqueous solution, 1000 ⁇ L) to a solution of methyl -2-methoxypropoxy]quinazolin-8-yl ⁇ oxy)methyl]benzoate (100 mg) in THF (1 mL) and MeCN (1 mL) at room temperature. The mixture was added and stirred at 50°C for 5 hours.
• reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/MeOH/28% aqueous ammonia) to obtain N-[2-(dimethylamino)ethyl]-3-hydroxyazetidine-1-carboxylate.
• the amide (9.67 g) was obtained as an oil.
• Production example 21 4-[( ⁇ (7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-4-hydroxy-2- PyBOP (180 mg) and cesium carbonate (120 mg) were added to a solution of tert-butyl [(2S)-2-methoxypropoxy]quinazolin-8-yl ⁇ oxy)methyl]benzoate (100 mg) in THF (2 mL). It was added at room temperature and stirred for 1 hour at room temperature under an argon atmosphere.
• Production example 22 4-[( ⁇ (7M)-4-(3-cyanoazetidin-1-yl)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazole TFA (0.4 mL) was added at room temperature, and the mixture was stirred at the same temperature overnight.
• the reaction mixture was concentrated under reduced pressure, chloroform and saturated aqueous sodium hydrogen carbonate solution were added to the residue, extracted with chloroform/iPrOH (4/1), the organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. and concentrated under reduced pressure.
• Production example 29 4-[( ⁇ (7M)-6-cyclopropyl-7-[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-4-hydroxy-2- PyBOP (80 mg) and cesium carbonate (50 mg) were added to a solution of tert-butyl [(2S)-2-methoxypropoxy]quinazolin-8-yl ⁇ oxy)methyl]benzoate (50 mg) in THF (5 mL). The mixture was added at room temperature and stirred at room temperature for 1 hour under a nitrogen atmosphere.
• Production example 40 4-[( ⁇ 4-[(2S)-2-carbamoylazetidin-1-yl]-6-cyclopropyl-2-[3-(dimethylamino)-2,2-dimethylpropoxy]-7-(6 -Fluoro-5-methyl-1H-indazol-4-yl)quinazolin-8-yl ⁇ oxy)methyl]tert-butyl]benzoate (245 mg) and dichloromethane (5 mL) in a mixture of TFA (1.5 mL) at room temperature. and stirred at the same temperature for 5 hours. The reaction mixture was concentrated under reduced pressure.
• Production example 65 At room temperature, a suspension of 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (30 g) in N-methyl-2-pyrrolidone (60 mL) was added to trimethyl orthoacetate (32 mL). was added and stirred overnight at 110°C under an argon atmosphere. After the reaction mixture was returned to room temperature, MeOH was added and suspended. Insoluble materials were collected by filtration and dried under reduced pressure at 50° C. overnight to obtain methyl 2-acetamido-4-bromo-3-fluoro-5-iodobenzoate (21.5 g) as a solid.
• Production example 99 1,4 of 3-[(4-methoxyphenyl)methyl]-1,3-diazinan-2,4-dione (5 g) and tert-butyl(3-iodophenoxy)di(methyl)silane (7.85 g) -Copper (I) iodide (4.07 g), N,N'-dimethylethylenediamine (4.59 mL), and tripotassium phosphate (13.59 g) were added to a dioxane (200 mL) solution under a nitrogen atmosphere, and the mixture was heated at 120°C. The mixture was stirred for 16 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate.
• Production example 104 9-[2-(3- ⁇ 3-[(4-methoxyphenyl)methyl]-2,4-dioxo-1,3-diazinan-1-yl ⁇ phenoxy)ethyl]-3,9-diazaspiro[5.5]
• a mixture of tert-butyl undecane-3-carboxylate (180 mg) and trifluoromethanesulfonic acid (180 ⁇ L) was purged with nitrogen gas three times, and stirred at 65° C. for 2 hours under a nitrogen atmosphere.
• the crude product obtained by concentrating the reaction mixture under reduced pressure was combined with the crude product of a reaction conducted in the same manner (using 270 mg of raw material), dissolved in MeCN (5 mL), and subjected to reversed phase chromatography ( When purified with MeCN/0.05% TFA aqueous solution), 1- ⁇ 3-[2-(3,9-diazaspiro[5.5]undecane-3-yl)ethoxy]phenyl ⁇ -1,3-diazinane-2,4 -dione n(trifluoromethanesulfonic acid) salt (350 mg) was obtained as a solid.
• Example 2 HATU (38 mg) was converted into 4-[( ⁇ (7M)-4-(3-cyanoazetidin-1-yl)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl) )-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl ⁇ oxy)methyl]benzoic acid (57 mg), 3-(3-methyl-5- ⁇ [(3S)-3-methylpiperazine) -1-yl]methyl ⁇ -2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione n hydrochloride (40 mg), DIPEA (100 ⁇ L) and DMF (2 mL) and stirred at room temperature overnight.
• DIPEA 100 ⁇ L
• DMF 2 mL
• Example 3 TFA (0.4 mL) was added to [(3S,4R)-1- ⁇ 6-cyclopropyl-8-( ⁇ 4-[(2S)-4- ⁇ [1-(2,6-dioxopiperidin-3-yl) )-3-Methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl]methyl ⁇ -2-methylpiperazine-1-carbonyl]phenyl ⁇ methoxy)-7-[6-fluoro-5 -Methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinazolin-4-yl ⁇ -3-fluoropiperidin-4-yl] It was added to a mixture of tert-butyl carbamate (58 mg) and dichloromethane (1.2 mL), and the mixture was stirred at room temperature overnight.
• tert-butyl carbamate 58
• reaction mixture was concentrated under reduced pressure, and the residue was purified by ODS column chromatography (MeCN/0.1% formic acid aqueous solution). A saturated aqueous sodium bicarbonate solution was added to the fraction of the target product, and the mixture was extracted twice with chloroform/iPrOH (4/1), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
• Example 5 HATU (39 mg) was converted into 4-[( ⁇ (7M)-4-[(2S)-2-carbamoylazetidin-1-yl]-6-cyclopropyl-7-(6-fluoro-5-methyl-1H -indazol-4-yl)-2-[(2S)-2-methoxypropoxy]quinazolin-8-yl ⁇ oxy)methyl]benzoic acid (45 mg), 1-(1-methyl-6- ⁇ [(3S )-3-Methylpiperazin-1-yl]methyl ⁇ -1H-indazol-3-yl)-1,3-diazinan-2,4-dione n hydrochloride (34 mg), DIPEA (82 ⁇ L) and DMF (3 mL) and stirred at room temperature overnight.
• DIPEA 82 ⁇ L
• DMF 3 mL
• Example 20 1-(6- ⁇ [4-( ⁇ 4-[( ⁇ (7M)-6-cyclopropyl-7-(6-fluoro-5-methyl-1H-indazol-4-yl)-4-hydroxy-2 -[(2S)-2-methoxypropoxy]quinazolin-8-yl ⁇ oxy)methyl]phenyl ⁇ methyl)-3-oxopiperazin-1-yl]methyl ⁇ -1-methyl-1H-indazol-3-yl) PyBOP (63 mg) and cesium carbonate (40 mg) were added to a solution of -1,3-diazinane-2,4-dione (45 mg) in THF (5 mL) at room temperature, and the mixture was incubated at room temperature for 1 hour under a nitrogen atmosphere.
• n HCl n Hydrochloride (compounds with production example numbers indicate monohydrochloride to trihydrochloride), n TfOH: n trifluoromethanesulfonic acid (compounds with production example numbers indicate monohydrochloride).
• the compound of the present invention or a salt thereof has an excellent effect of inducing the degradation of G12V mutant KRAS protein, is useful as a G12V mutant KRAS inhibitor, and is effective in pharmaceutical compositions, for example, pharmaceutical compositions for treating pancreatic cancer and/or lung cancer. Can be used as an ingredient.

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• 2023
  • 2023-08-08 WO PCT/JP2023/028864 patent/WO2024034593A1/ja not_active Ceased
  • 2023-08-08 JP JP2024540481A patent/JPWO2024034593A1/ja active Pending
  • 2023-08-08 EP EP23852555.4A patent/EP4570795A1/en active Pending
  • 2023-08-08 CN CN202380058182.5A patent/CN119604495A/zh active Pending
  • 2023-08-08 TW TW112129763A patent/TW202413346A/zh unknown
  • 2023-08-08 US US19/102,139 patent/US20260042771A1/en active Pending

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