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  • 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
  • C07D487/08—Bridged systems
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  • 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
• • 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
  • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • 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
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  • 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
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  • 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
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
  • A61K47/545—Heterocyclic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
  • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
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  • 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
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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  • 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
  • C07D471/04—Ortho-condensed systems
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  • 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
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

• the present invention is useful as a pharmaceutical composition, which has an excellent effect of inducing the degradation of G12D mutant KRAS protein, and/or as a G12D mutant KRAS inhibitor, and is expected to be useful as an active ingredient of a pharmaceutical composition for treating pancreatic cancer, for example.
• the present invention relates to a heterocyclic compound.
• 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.
• FOLFRINOX therapy (a multidrug combination treatment consisting of three chemotherapy drugs, 5-FU, irinotecan, and oxaliplatin, plus levofolinate) is used as a standard therapy for pancreatic cancer, but it is highly toxic and 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).
• 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 plays an important role in the carcinogenesis and development process of pancreatic cancer.
• KRAS gene mutations include KRAS G12C mutation and KRAS G12D mutation, but while G12C mutation KRAS occurs frequently in non-small cell lung cancer, it accounts for a few percent in pancreatic cancer (Cancer Cell 2014, 25, p.272 -281), and other therapeutic agents for KRAS mutations are desired. G12D mutant KRAS is observed in approximately 34% of pancreatic cancers, and it has been reported that the proportion is highest among all KRAS mutations (Nat. Rev. Cancer, 2018, 18, p.767-777).
• 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.
• Patent Documents 1, 2, and 3 describe that it is useful for cancers in which KRAS codon 12 mutations exist, one of which includes the G12D mutation, but the effect on G12D-mutated KRAS-positive cancers is not described. Not yet.
• KRAS G12D inhibitors are disclosed in Patent Documents 9, 10, 11, 12, 13, 14, 15, and 16.
• 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 More than 600 types of E3 ligase exist 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 linked 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 12, Patent Document 17). Furthermore, Patent Document 18 and Patent Document 19 report bifunctional compounds that reduce the level of G12D mutant KRAS protein, and Patent Document 20, Patent Document 21, and Patent Document 22 report a bifunctional compound that reduces the level of G12D mutant KRAS protein. Quinazoline compounds have been reported for derivatization. However, other than Patent Documents 18 to 22, there are currently no reports suggesting that bifunctional compounds degrade G12D mutant KRAS proteins.
• the pharmaceutical composition has an excellent effect of inducing the degradation of G12D mutant KRAS protein, and/or is useful as a G12D mutant KRAS inhibitor, and is effective as a pharmaceutical composition for treating pancreatic cancer, particularly G12D mutant KRAS-positive pancreatic cancer.
• a heterocyclic compound expected to be useful as a component is provided.
• a heterocyclic compound of formula (I) for example, a heterocyclic compound selected from the group consisting of quinazoline and quinoline.
• the bifunctional compound of formula (I) which is characterized in that the substituent at position 8 and the E3 ligase ligand are linked via a linker, has an excellent effect of inducing degradation of the G12D mutant KRAS protein, and/or The present invention was completed based on the finding that G12D mutant KRAS has inhibitory activity.
• 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, optionally substituted C 1-3 alkyl or cyano
• Q is CR Q or N
• R Q is H, halogen, optionally substituted C 1-3 alkyl, C 3-6 cycloalkyl, or vinyl
• E is CH or N, Naphthyl, in which R 1 is optionally substituted with one or two groups selected from the group consisting of optionally substituted C 1-3 alkyl, cyano, OH, and halogen, or the following formula (II) , one group selected from the group consisting of formula (III) and formula (IV), R 1a , R 1b and R 1c are the same or different from each other and are H, optionally substituted C 1-3 alkyl, vinyl or halogen;
• m is an integer from 0-2
• R 3 is optionally substituted C 1-6 alkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl
• X is a bond, -CH 2 -, -O-, -S-, or -NR 4X -
• R 4X is H or optionally substituted C 1-3 alkyl
• Y 1 is -O-(optionally substituted C 1-3 alkylene)- *Y2
• a substituent at the 2-position of a heterocyclic compound selected from the group consisting of quinazoline and quinoline and an E3 ligase for example, a substituent at the 2-position of a heterocyclic compound selected from the group consisting of quinazoline and quinoline and an E3 ligase. It may also be a bifunctional compound of formula (XXI) characterized in that the ligand is linked by a linker. That is, the present invention also relates to a compound of formula (XXI) or a salt thereof, and a pharmaceutical composition containing the compound of formula (XXI) or a salt thereof and one or more pharmaceutically acceptable excipients. related.
• A is CR A or N
• R A is H, optionally substituted C 1-3 alkyl or cyano
• Q is CR Q or N
• R Q is H, halogen, optionally substituted C 1-3 alkyl, C 3-6 cycloalkyl, or vinyl
• E is CH or N, Naphthyl, in which R 1 is optionally substituted with one or two groups selected from the group consisting of optionally substituted C 1-3 alkyl, cyano, OH, and halogen, or the following formula (II) , one group selected from the group consisting of formula (III) and formula (IV), R 1a , R 1b and R 1c are the same or different from each other and are H, optionally substituted C 1-3 alkyl, vinyl or halogen;
• R 2 is -V 1 -V 2 or W
• V 1 is a bond, -CH 2 -, -O-, -S- or -N(R V1 )-
• m is an integer from 0-2
• R 3P is optionally substituted C 1-6 alkylene, optionally substituted heterocycloalkylene, or optionally substituted heteroarylene
• X is a bond, -CH2- , -O-, -S-, or -NR4X-
• R 4X is H or optionally substituted C 1-3 alkyl
• Y 1 is -O-(optionally substituted C 1-3 alkylene)- *Y2
• -SO 2 (substituted C 1-3 alkylene which may be substituted)- *Y2 , -NR Y -(C 1-3 alkylene which may be substituted)- *Y2 ,
• Linker is a group that chemically connects R 3P and EUB
• EUB is a group capable of binding to one E3 ubiquitin ligase selected from the group consisting of cereblon, IAP, MDM2, DCAF11, DCAF15, DCAF16, BIRC2, KEAP1, RNF4, RNF114, FEM1B, and AhR.
• a substituent at the 7-position of a heterocyclic compound selected from the group consisting of quinazoline and quinoline and an E3 ligase for example, a substituent at the 7-position of a heterocyclic compound selected from the group consisting of quinazoline and quinoline and an E3 ligase. It may also be a bifunctional compound of formula (XXII), which is characterized in that the ligand is linked by a linker. That is, the present invention also relates to a compound of formula (XXII) or a salt thereof, and a pharmaceutical composition containing the compound of formula (XXII) or a salt thereof and one or more pharmaceutically acceptable excipients. related.
• A is CR A or N
• R A is H, optionally substituted C 1-3 alkyl or cyano
• Q is CR Q or N
• R Q is H, halogen, optionally substituted C 1-3 alkyl, C 3-6 cycloalkyl, or vinyl
• E is CH or N, Naphthylene or the following formula (II- 22A ), formula (II-22B), formula (II-22C), formula (III-22A), formula (III-22B), formula (III-22C) and formula (III-22D)
• R 1a , R 1b and R 1c are the same or different from each other and are H, optionally substituted C 1-3 alkyl, vinyl or halogen
• R 2 is -V 1 -V 2 or W
• V 1 is a bond, -CH 2 -, -O-, -S- or -N(R V1 )-
• R V1 is H or optionally substituted C 1-3 alkyl
• V 2 is the following
• m is an integer from 0-2
• R 3 is optionally substituted C 1-6 alkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl
• X is a bond, -CH2- , -O-, -S-, or -NR4X-
• R 4X is H or optionally substituted C 1-3 alkyl
• Y 1 is -O-(optionally substituted C 1-3 alkylene)- *Y2
• -SO 2 (substituted C 1-3 alkylene which may be substituted)- *Y2 , -NR Y -(C 1-3 alkylene which may be substituted)- *Y2 ,
• Linker is a group that chemically connects R 1P and EUB
• EUB is a group capable of binding to one E3 ubiquitin ligase selected from the group consisting of cereblon, IAP, MDM2, DCAF11, DCAF15, DCAF16, BIRC2, KEAP1, RNF4, RNF114, FEM1B, and AhR.
• a bifunctional compound of formula (XXIII) characterized by GDB-Linker-EUB may be used. That is, the present invention also relates to a compound of formula (XXIII) or a salt thereof, and a pharmaceutical composition containing the compound of formula (XXIII) or a salt thereof and one or more pharmaceutically acceptable excipients. related.
• GDB is a group that has the ability to bind to G12D mutant KRAS protein
• -Linker - EUB is one group selected from the group consisting of the following formulas (LE-1) to (LE-40).
• 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 G12D-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 G12D-mutant KRAS-positive pancreatic cancer one embodiment is a pharmaceutical composition for treating locally advanced G12D-mutant KRAS-positive pancreatic cancer, and one embodiment is a pharmaceutical composition for treating metastatic G12D-mutated KRAS-positive pancreatic cancer.
• one embodiment relates to a pharmaceutical composition for treating G12D-mutated KRAS-positive pancreatic cancer in untreated and/or previously treated patients.
• the pharmaceutical composition containing the compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients may be used to treat pancreatic cancer containing the compound of formula (I) or a salt thereof.
• Embodiments include therapeutic agents for G12D-mutated KRAS-positive pancreatic cancer.
• pancreatic cancer in one embodiment, G12D mutant 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; in some embodiments, metastatic G12D-mutated KRAS-positive pancreatic cancer; in some embodiments, locally advanced G12D-mutated pancreatic cancer
• a pharmaceutical composition for the treatment of KRAS-positive pancreatic cancer in some embodiments, relapsed or refractory G12D-mutated KRAS-positive pancreatic cancer, in some embodiments, G12D-mutated KRAS-positive pancreatic cancer in untreated and/or previously treated patients.
• pancreatic cancer Use of a compound of formula (I) or a salt thereof for the manufacture of pancreatic cancer, in some embodiments G12D mutant KRAS positive pancreatic cancer, in some embodiments metastatic pancreatic cancer, in some embodiments locally advanced pancreatic cancer Pancreatic cancer, in some embodiments, relapsed or refractory pancreatic cancer, in some embodiments, pancreatic cancer in untreated and/or previously treated patients, in some embodiments, metastatic G12D-mutated KRAS-positive pancreatic cancer; In some embodiments, locally advanced G12D-mutated KRAS-positive pancreatic cancer; in some embodiments, relapsed or refractory G12D-mutant KRAS-positive pancreatic cancer; in some embodiments, G12D in previously untreated and/or previously treated patients.
• metastatic pancreatic cancer is locally advanced pancreatic cancer, in some embodiments, relapsed or refractory pancreatic cancer, in some embodiments, pancreatic cancer in untreated and/or previously treated patients, and in some embodiments, metastatic G12D mutation.
• KRAS-positive pancreatic cancer in some embodiments locally advanced G12D-mutated KRAS-positive pancreatic cancer, in some embodiments relapsed or refractory G12D-mutated KRAS-positive pancreatic cancer, in some embodiments untreated and/or previously treated
• a compound of formula (I) or a salt thereof for use in the treatment of G12D-mutated KRAS-positive pancreatic cancer in a patient and a pancreatic treatment comprising administering to a subject an effective amount of the compound of formula (I) or a salt thereof.
• G12D mutant KRAS positive pancreatic cancer in some embodiments, metastatic pancreatic cancer, in some embodiments, locally advanced pancreatic cancer, in some embodiments, relapsed or refractory pancreatic cancer, in some embodiments
• metastatic G12D-mutated KRAS-positive pancreatic cancer in some embodiments, locally advanced G12D-mutated KRAS-positive pancreatic cancer;
• the present invention relates to a method for treating recurrent or refractory G12D-mutant KRAS-positive pancreatic cancer, and in one embodiment, it relates to a method for treating G12D-mutated KRAS-positive pancreatic cancer in untreated and/or previously treated patients.
• the present invention also provides a compound of formula (I) or a salt thereof which is a G12D mutant KRAS proteolysis inducer and/or a G12D mutant KRAS inhibitor, used as a G12D mutant KRAS protein degradation inducer and/or a G12D mutant KRAS inhibitor.
• the present invention also relates to a compound of formula (I) or a salt thereof, a G12D mutant KRAS proteolysis inducer and/or a G12D mutant KRAS inhibitor containing the compound of formula (I) or a salt thereof.
• the present invention also provides, in certain embodiments, a pharmaceutical composition containing a compound of formula (XXI), formula (XXII) or formula (XXIII) or a salt thereof, and one or more pharmaceutically acceptable excipients.
• a pharmaceutical composition for treating pancreatic cancer in one embodiment, a pharmaceutical composition for treating G12D-mutated KRAS-positive pancreatic cancer, in another embodiment, a pharmaceutical composition for treating metastatic pancreatic cancer;
• a pharmaceutical composition for treating locally advanced pancreatic cancer in one embodiment a pharmaceutical composition for treating relapsed or refractory pancreatic cancer, and in another embodiment for treating pancreatic cancer of untreated and/or previously treated pancreatic cancer.
• a pharmaceutical composition for treating cancer in one embodiment a pharmaceutical composition for treating metastatic G12D mutant KRAS-positive pancreatic cancer, and in another embodiment a pharmaceutical composition for treating locally advanced G12D mutant KRAS-positive pancreatic cancer.
• it is a pharmaceutical composition for treating relapsed or refractory G12D-mutated KRAS-positive pancreatic cancer, and in one embodiment, it is a pharmaceutical composition for treating G12D-mutated KRAS-positive pancreatic cancer in untreated and/or previously treated patients.
• the present invention relates to a pharmaceutical composition for the treatment of.
• a pharmaceutical composition containing a compound of formula (XXI), formula (XXII), or formula (XXIII) or a salt thereof, and one or more pharmaceutically acceptable excipients is a compound of formula (XXI), formula A therapeutic agent for pancreatic cancer containing (XXII) or a compound of formula (XXIII) or a salt thereof, in one embodiment, G12D containing a compound of formula (XXI), formula (XXII) or formula (XXIII) or a salt thereof Includes therapeutic agents for mutant KRAS-positive pancreatic cancer.
• the present invention also relates to the following.
• Pancreatic cancer in some embodiments, G12D mutant KRAS-positive pancreatic cancer, in some embodiments, metastatic pancreatic cancer, in some embodiments, locally advanced pancreatic cancer, in some embodiments, relapsed or refractory pancreatic cancer. In some embodiments, pancreatic cancer in untreated and/or previously treated patients; in some embodiments, metastatic G12D mutant KRAS positive pancreatic cancer; in some embodiments, locally advanced G12D mutant KRAS positive pancreatic cancer.
• a formula for the manufacture of a pharmaceutical composition for the treatment of relapsed or refractory G12D-mutated KRAS-positive pancreatic cancer and in some embodiments, G12D-mutated KRAS-positive pancreatic cancer in untreated and/or previously treated patients.
• (XXI) use of a compound of formula (XXII) or formula (XXIII) or a salt thereof;
• Pancreatic cancer in some embodiments, G12D mutant KRAS-positive pancreatic cancer, in some embodiments, metastatic pancreatic cancer, in some embodiments, locally advanced pancreatic cancer, in some embodiments, relapsed or refractory pancreatic cancer.
• pancreatic cancer in untreated and/or previously treated patients; in some embodiments, metastatic G12D mutant KRAS positive pancreatic cancer; in some embodiments, locally advanced G12D mutant KRAS positive pancreatic cancer.
• pancreatic cancer in untreated and/or previously treated patients; in some embodiments, metastatic G12D mutant KRAS positive pancreatic cancer; in some embodiments, locally advanced G12D mutant KRAS positive pancreatic cancer.
• the compound of formula (I), formula (XXI), formula (XXII) or formula (XXIII) or a salt thereof has an action of inducing the degradation of G12D mutant KRAS protein and/or an inhibitory activity of G12D mutant KRAS protein, It can be used as a therapeutic agent for cancer, particularly G12D-mutated KRAS-positive pancreatic 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 a straight-chain or branched alkyl having 1-12 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 refers to straight-chain or branched alkyl having 1-6 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, n-propyl, isopropyl or tert-butyl, in some embodiments methyl, ethyl, n-propyl, isopropyl, n-butyl, in some embodiments methyl, ethyl, n-propyl, in some embodiments methyl, n-propyl In some embodiments, it is methyl, in some embodiments it is ethyl, and
• C 1-3 alkyl is a straight-chain or branched alkyl having 1-3 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 methyl or n-propyl, in some embodiments ethyl or isopropyl, In some embodiments, it is methyl, in some embodiments it is ethyl, in some embodiments it is isopropyl, and in some embodiments it is n-propyl.
• C 3-6 cycloalkyl refers to cycloalkyl having 3-6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and 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 in which the carbon atom of the "C 1-3 alkyl” has another bond. Examples include methylene, ethylene, trimethylene, methylmethylene, 1,1-dimethylmethylene, and the like. 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.
• Heterocycloalkyl is a 4- to 7-membered saturated heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring atoms; may contain unsaturated bonds. Moreover, the sulfur atom as a ring-constituting atom of the saturated heterocyclic group may be oxidized.
• heterocycloalkyl is "4- to 6-membered heterocycloalkyl containing 1-2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring constituent atoms",
• An embodiment is “4-6 membered heterocycloalkyl containing 1-2 oxygen atoms as a ring constituent atom”
• a certain embodiment is "4-6 membered heterocycloalkyl containing 1 oxygen atom as a ring constituent atom”.
• it is a 4- to 6-membered heterocycloalkyl containing 1 to 2 nitrogen atoms as ring atoms, and in some embodiments, it is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, oxazolidinyl, imidazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, in some embodiments oxetanyl, tetrahydropyranyl or tetrahydrofuranyl, in some embodiments tetrahydropyranyl or Tetrahydrofuranyl, in some embodiments tetrahydropyranyl, in some embodiments tetrahydrofuranyl, in some embodiments azetidinyl, pyrrolidinyl, piperidinyl or piperazin
• Heterocycloalkylene is a divalent group of the above-mentioned “heterocycloalkyl” in which the nitrogen atom or carbon atom constituting the ring has another bond.
• a certain embodiment of “heterocycloalkylene” is "4- to 6-membered heterocycloalkylene containing 1-2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring-constituting atoms," and
• An embodiment is a “4-6 membered heterocycloalkylene containing 1-2 oxygen atoms as a ring constituent atom"
• a certain embodiment is a "4-6 membered heterocycloalkylene containing 1 oxygen atom as a ring constituent atom”.
• it is a 4- to 6-membered heterocycloalkylene containing 1 to 2 nitrogen atoms as ring atoms, and in some embodiments, it is oxetanediyl, tetrahydrofurandiyl, tetrahydropyran.
• diyl azetidinediyl, pyrrolidinediyl, piperidinediyl, oxazolidinediyl, imidazolidinediyl, piperadinediyl, morpholinediyl, thiomorpholinediyl, dioxothiomorpholinediyl, and in some embodiments oxetanediyl, tetrahydropyrandiyl or tetrahydrofurandiyl.
• it is tetrahydropyrandiyl or tetrahydrofurandiyl, in some embodiments it is tetrahydropyrandiyl, in some embodiments it is tetrahydrofurandiyl, in some embodiments it is azetidinediyl, pyrrolidinediyl, piperidinediyl or piperazinediyl. In some embodiments, it is piperidinediyl or piperazinediyl, in some embodiments it is piperidinediyl, and in some embodiments it is piperazinediyl.
• “Bridged heterocycloalkyl” is a 7- to 9-membered bridged heterocyclic group containing 1-2 nitrogen atoms as ring atoms. In one embodiment, it is a saturated 7- to 9-membered bridged heterocyclic group containing 1-2 nitrogen atoms as ring constituent atoms, and in another embodiment, it is a saturated 7-membered bridged heterocyclic group containing 2 nitrogen atoms as ring constituent atoms It is a 9-membered bridged heterocycloalkyl, and in one embodiment, it is a saturated 7- to 9-membered heterocycloalkyl containing two nitrogen atoms as ring constituent atoms, and one of the two nitrogen atoms is bonded to one hydrogen atom.
• diazabicyclo[2.2.2]octanyl diazabicyclo[3.2.1]octanyl, diazabicyclo[3.2.1]oct-6-enyl, diazabicyclo[3.2.1]oct-2-enyl, diazabicyclo[3.1.1] Heptanyl, diazabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.1]hept-5-enyl, and in certain embodiments diazabicyclo[2.2.2]octanyl, diazabicyclo[3.2.1]octanyl, diazabicyclo[3.1.1] Heptanyl or diazabicyclo[2.2.1]heptanyl, in some embodiments diazabicyclo[2.2.1]heptanyl or diazabicyclo[3.2.1]octanyl, and in some embodiments diazabicyclo[2.2.1]heptanyl, Examples include diazabicyclo[3.2.1]octanyl, certain embodiments include 2,5-
• Bridged heterocycloalkylene is a divalent group of the above-mentioned “bridged heterocycloalkyl” in which the nitrogen atom or carbon atom constituting the ring has another bond. In some embodiments, it is a saturated 7- to 9-membered bridged heterocycloalkylene containing 2 nitrogen atoms, and in some embodiments it is a saturated 7- to 9-membered bridged heterocycloalkylene containing 2 nitrogen atoms, in which one nitrogen atom is one hydrogen atom. It is a saturated 7- to 9-membered bridged heterocycloalkylene bonded to atoms.
• diazabicyclo[2.2.2]octanediyl diazabicyclo[3.2.1]octanediyl, diazabicyclo[3.1.1]heptanediyl, diazabicyclo[2.2.1]heptanediyl, diazabicyclo[3.3.1]nonanediyl.
• diazabicyclo[2.2.2]octanediyl diazabicyclo[3.2.1]octanediyl, diazabicyclo[3.2.1]oct-6-enediyl, diazabicyclo[3.2.1]oct-2-enediyl, diazabicyclo[3.1.
• Bridged piperazinyl is piperazinyl that has a bridged structure on the carbon atoms on the ring, and the bridged structure is composed of carbon atoms.
• it is diazabicyclo[3.1.1]heptanyl; in some embodiments, it is 2,5-diazabicyclo[2.2.1]heptanyl; in some embodiments, it is 3,8-diazabicyclo[3.2.1]octanyl; is 2,5-diazabicyclo[2.2.1]heptanyl, and in certain embodiments is 3,8-diazabicyclo[3.2.1]octanyl.
• “Bridged piperazindiyl” is a divalent group in which the nitrogen atom constituting the ring of the "bridged piperazinyl” has another bond.
• it is diazabicyclo[3.1.1]heptanediyl, in some embodiments it is 2,5-diazabicyclo[2.2.1]heptanediyl, and in some embodiments it is 3,8-diazabicyclo[3.2.1]octanediyl. In one embodiment, it is 2,5-diazabicyclo[2.2.1]heptanediyl, and in one embodiment, it is 3,8-diazabicyclo[3.2.1]octanediyl.
• “Spiroheterocycloalkyl” is a saturated 7- to 9-membered heterocyclocyclic group containing 1-2 nitrogen atoms as ring atoms and having a spiro atom. In one embodiment, it is a saturated 7- to 9-membered heterocyclocyclic group containing two nitrogen atoms as ring constituent atoms and having a spiro atom. For example, diazaspiro[3.3]heptanyl, diazaspiro[3.4]octanyl, diazaspiro[3.5]nonanyl, diazaspiro[4.4]nonanyl. In some embodiments, it is 2,6-diazaspiro[3.4]octanyl, and in some embodiments, it is 2,6-diazaspiro[3.3]heptanyl.
• Spiroheterocycloalkylene is a divalent group of the above “spiroheterocycloalkyl” that has two nitrogen atoms as ring constituent atoms, and each of the two nitrogen atoms has a bond.
• spiroheterocycloalkyl that has two nitrogen atoms as ring constituent atoms, and each of the two nitrogen atoms has a bond.
• 2,6-diazaspiro[3.3]heptanediyl 2,6-diazaspiro[3.4]octanediyl, 2,7-diazaspiro[3.5]nonanediyl, 2,7-diazaspiro[4.4]nonanediyl.
• spiroheterocycloalkylene may be a divalent group of the above-mentioned “spiroheterocycloalkyl” in which the nitrogen atom or carbon atom constituting the ring has another bond.
• spiroheterocycloalkylene is a saturated 7- to 9-membered spiroheterocycloalkylene containing 1 to 2 nitrogen atoms, such as 2,6-diazaspiro[3.3]heptanediyl, 2,6-Diazaspiro[3.4]octanediyl, 2,7-Diazaspiro[3.5]nonanediyl, 2,7-Diazaspiro[4.4]nonanediyl, 2-Azaspiro[3.3]heptanediyl, 2-Azaspiro[3.4]octanediyl, 6- They are azaspiro[3.4]octanediyl, 2-azaspiro[3.5]nonanediyl, 7-azaspiro[3.5]nonanediyl, 2-azaspiro[4.4]nonanediyl, and 7-azaspiro[
• heterocycle is an aromatic heterocycle containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring constituent atoms.
• a “5-membered heterocycle” is a 5-membered heterocycle containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring constituent atoms.
• a certain embodiment of the "5-membered heterocycle” is a pyrazole ring, an imidazole ring, a triazole ring, a tetrazole ring, an oxazole ring, an isoxazole ring, a thiazole ring, an isothiazole ring, an oxadiazole ring, or a thiadiazole ring; is a pyrazole ring, imidazole ring, triazole ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring, oxadiazole ring or thiadiazole ring.
• a “6-membered heterocycle” is a 6-membered heterocycle containing 1-3 nitrogen atoms as ring constituent atoms.
• a certain embodiment of the "6-membered heterocycle” is a 6-membered heterocycle containing 1 to 3 nitrogen atoms as ring constituent atoms, and some embodiments include a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, or a triazine ring. It is a ring.
• “5-6 membered heterocycle” is a 5-membered heterocycle or a 6-membered heterocycle. In one embodiment, the "5-6 membered heterocycle” is a 5-membered heterocycle, and in another embodiment, it is a 6-membered heterocycle.
• Heteroaryl is a 5- to 6-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring constituent atoms.
• a 5-membered heteroaryl containing 1-4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as a ring-constituting atom or a 6-membered ring containing 1-3 nitrogen atoms as a ring-constituting atom.
• ring heteroaryl It is a membered ring heteroaryl, and in some embodiments it is a 5-membered ring heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring constituent atoms, and in some embodiments, A 6-membered heteroaryl containing 1 to 3 nitrogen atoms as ring constituent atoms, and in certain embodiments, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, Pyrazinyl, pyridazinyl or triazinyl, in some embodiments pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, is
• Heteroarylene is a divalent group in which two different carbon atoms and/or nitrogen atoms constituting the ring among the “heteroaryl” have bonding hands.
• a certain embodiment of “heteroarylene” includes a 5-membered heteroarylene containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring constituent atoms, or a 5-membered heteroarylene containing 1-4 nitrogen atoms as ring constituent atoms.
• it is a 6-membered heteroarylene containing 1 to 3 nitrogen atoms as ring constituent atoms, and in some embodiments, it is pyrazolediyl, imidazolediyl, triazolediyl, tetrazoldiyl, oxazolediyl, isoxazole.
• pyrazolediyl isothiazolediyl, oxadiazolediyl, thiadiazolediyl, pyridinediyl, pyrimidinediyl, pyrazinediyl, pyridazinediyl or triazinediyl, and in certain embodiments, pyrazolediyl, imidazolediyl, triazolediyl, tetrazolediyl, Oxazolediyl, isoxazolediyl, thiazolediyl, isothiazolediyl, oxadiazolediyl, thiadiazolediyl, and in certain embodiments, pyridinediyl, pyrimidinediyl, pyrazinediyl, pyridazinediyl or triazinediyl.
• 4- to 8-membered saturated heterocycle is a 4- to 8-membered saturated heterocycle containing 1 to 2 heteroatoms selected from the group consisting of oxygen, sulfur, and nitrogen as ring constituent atoms, It may contain a partially unsaturated bond, it may have a bridge, it may form a spiro ring, and the sulfur atom contained in the heterocycle may be oxidized. .
• substituents allowed in "optionally substituted heteroarylene”, “optionally substituted phenylene”, and “optionally substituted heteroaryl” include C 1-3 alkyl, - O(C 1-3 alkyl), halogen, OH, and in some embodiments, C 1-3 alkyl, -O(C 1-3 alkyl), halogen, and in some embodiments, C 1-3 It is alkyl, in some embodiments it is methyl, in some embodiments it is ethyl, in some embodiments it is halogen, in some embodiments it is F.
• the substituents allowed in "optionally substituted oxazolyl" are C 1-3 alkyl, in some embodiments methyl or isopropyl, in some embodiments methyl, and in some embodiments is isopropyl.
• 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.
• EUB is a group capable of binding to E3 ubiquitin ligase.
• the group is capable of binding to one E3 ubiquitin ligase selected from the group consisting of cereblon, IAP, MDM2, DCAF11, DCAF15, DCAF16, BIRC2, KEAP1, RNF4, RNF114, FEM1B, and AhR.
• it is a group capable of binding to cereblon, IAP, or MDM2.
• it is a group capable of binding to cereblon.
• GDB is a group that has the ability to bind to G12D mutant KRAS protein, and is limited to the example compounds described in the following documents.
• the "G12D 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 aspartic acid.
• G12D mutation KRAS refers to KRAS having the above-mentioned "G12D 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.
• G12D mutant KRAS positive pancreatic cancer is G12D mutant KRAS positive pancreatic cancer.
• this is pancreatic cancer in which the KRAS G12D mutation occurs, and the positive rate for G12D-mutated KRAS is high.
• G12D mutant KRAS-positive pancreatic ductal carcinoma is G12D mutant KRAS-positive pancreatic ductal adenocarcinoma.
• Z N1 is a group of 1 selected from the group consisting of the following formulas (Z N1 -1) to (Z N1 -15) ( *LGZ indicates the bond with LG Z or Linker, R Z1' is the same or different and is optionally substituted C 1-6 alkyl, halogen, cyano, -OH, -O-(optionally substituted C 1-6 alkyl), -S-( (optionally substituted C 1-6 alkyl), -NH- (optionally substituted C 1-6 alkyl) or -N- (optionally substituted C 1-6 alkyl) 2 , n' is an integer of 0-2, R Z2' , R Z3' and R Z4' are the same or different and are H or optionally substituted C 1-6 alkyl, and ring B1' is a benzene ring or a 6-membered heterocycle, where R Z1' and - *LGN form a bond with the carbon atoms constituting ring B1'.)
• Z N2 is a group selected from the group consisting of the following formulas (Z N2 -1) to (Z N2 -15) ( *LGZ indicates the bonding part with LG Z or Linker, R Z1' is the same or different and is optionally substituted C 1-6 alkyl, halogen, cyano, -OH, -O-(optionally substituted C 1-6 alkyl), -S-( (optionally substituted C 1-6 alkyl), -NH- (optionally substituted C 1-6 alkyl) or -N- (optionally substituted C 1-6 alkyl) 2 , n' is an integer of 0-2, R Z2' and R Z3' are the same or different and are H or optionally substituted C 1-6 alkyl, and ring B1' is a benzene ring. or a 6-membered heterocycle, where R Z1' and - *LGN form a bond with the carbon atom constituting ring B1'.)
• Z C is a group selected from the group consisting of the following formulas (Z C -16) to (Z C -27) ( *LGZ indicates the bonding part with LG Z or Linker, and R Z1' is the same or different and is optionally substituted C 1-6 alkyl, halogen, cyano, -OH, -O-(optionally substituted C 1-6 alkyl), -S-( (optionally substituted C 1-6 alkyl), -NH- (optionally substituted C 1-6 alkyl) or -N- (optionally substituted C 1-6 alkyl) 2 , n' is an integer of 0-2, R Z2' , R Z4' and R Z5' are the same or different and are H or optionally substituted C 1-6 alkyl, and M' is , bond, -O-, -S-, -N(R M' )- or optionally substituted C 1-3 alkylene, and R M' is H or optionally substituted C 1- 3 alkyl
• A is CR A or N, A compound or a salt thereof, wherein R A is H, optionally substituted C 1-3 alkyl, or cyano.
• a compound or a salt thereof, wherein A is CH or N.
• a compound or a salt thereof, wherein A is CH.
• Q is CR Q or N, A compound or a salt thereof, wherein R Q is H, halogen, optionally substituted C 1-3 alkyl, C 3-6 cycloalkyl, or vinyl.
• Q is CR Q , A compound or a salt thereof, wherein R Q is C 3-6 cycloalkyl.
• Q is CR Q , A compound or a salt thereof, wherein R Q is cyclopropyl.
• (3-1) A compound or a salt thereof, wherein E is CH or N.
• (3-2) A compound or a salt thereof, wherein E is CH.
• R 1 is optionally substituted with one or two groups selected from the group consisting of optionally substituted C 1-3 alkyl, cyano, OH, and halogen, or 1 group selected from the group consisting of the following formula (II), formula (III) and formula (IV), A compound or a salt thereof, wherein R 1a , R 1b and R 1c are the same or different and are H, optionally substituted C 1-3 alkyl, vinyl or halogen.
• R 1 is the following formula (II), A compound or a salt thereof, wherein R 1a and R 1c are the same or different from each other and are C 1-3 alkyl or halogen.
• R 1 is the following formula (II), A compound or a salt thereof, wherein R 1a is halogen and R 1c is C 1-3 alkyl.
• R 1 is the following formula (II-2).
• R 2 is -V 1 -V 2 or W
• V 1 is a bond, -CH 2 -, -O-, -S- or -N(R V1 )-
• R V1 is H or optionally substituted C 1-3 alkyl
• V 2 is the following formula (V) or formula (VI)
• W is the following formula (VII), (VII-2) or a 7- to 9-membered bridged heterocycloalkyl containing 1-2 nitrogen atoms
• R 2a is the same or different from each other and is OH, OCH 3 , F, or optionally substituted C 1-3 alkyl
• R 2a is an azetidine ring represented by formula (V), or an azetidine ring represented by formula (VI).
• R 2 is -V 1 -V 2 or W
• V 1 is a bond, -CH 2 -, -O-, -S- or -N(R V1 )-
• R V1 is C 1-3 alkyl optionally substituted with one group selected from the group consisting of C 3-6 cycloalkyl, halogen and -OH
• V 2 is the following formula (V-2) or (VI-2)
• W is selected from the group consisting of the following formulas (VII-3), (VII-4), (VIII), (IX), (X), (XI), (XII), (XIII) and (XIV);
• R 2 is -V 1 -V 2 or W, V 1 is a bond, -O- or -N(R V1 )-, R V1 is C 1-3 alkyl, V 2 is the following formula (VI-2), A compound or a salt thereof, wherein W is the following formula (XII).
• R 2 is -V 1 -V 2 or W, V 1 is -O- or -N(CH 3 )-, V 2 is the following formula (VI-2), A compound or a salt thereof, wherein W is the following formula (XII).
• R 2 is -V 1 -V 2 or W, V 1 is -O-, V 2 is the following formula (VI-2), A compound or a salt thereof, wherein W is the following formula (XII).
• R 2 is -V 1 -V 2 or W, V 1 is a bond, -CH 2 -, -O-, -S- or -N(R V1 )-, R V1 is C 1-3 alkyl optionally substituted with one group selected from the group consisting of C 3-6 cycloalkyl, halogen and -OH, V 2 is the following formula (V-2) or (VI-2), A compound or a salt thereof, wherein W is one group selected from the group consisting of the following formulas (VII-4), (XI) and (XII).
• R 2 is -V 1 -V 2 or W, V 1 is -O- or -N(R V1 )-, R V1 is C 1-3 alkyl, V 2 is the following formula (V-2) or (VI-2), A compound or a salt thereof, wherein W is one group selected from the group consisting of the following formulas (VII-4), (XI) and (XII).
• R 2 is -V 1 -V 2 or W, V 1 is -O- or -N(CH 3 )-, V 2 is the following formula (VI-2), A compound or a salt thereof, wherein W is the following formula (VII-4) or (XII).
• R 3 is optionally substituted C 1-6 alkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl.
• R 3 is from the group consisting of -O-(C 1-6 alkyl), -S-(C 1-6 alkyl), -N-(C 1-6 alkyl) 2 and heterocycloalkyl A compound or a salt thereof which is C 1-6 alkyl optionally substituted with one selected group or heterocycloalkyl optionally substituted.
• (6-5) A compound or a salt thereof, wherein R 3 is n-propyl optionally substituted with -OCH 3 or tetrahydropyranyl.
• X is a bond, -CH 2 -, -O-, -S-, or -NR 4X -, A compound or a salt thereof, wherein R 4X is H or optionally substituted C 1-3 alkyl.
• X is -O- or -NR 4X -, A compound or a salt thereof, wherein R 4X is C 1-3 alkyl.
• (7-3) A compound or a salt thereof, wherein X is -O-.
• Y 1 is -O-(optionally substituted C 1-3 alkylene)- *Y2 , -S-(optionally substituted C 1-3 alkylene)- *Y2 , - SO 2 -(Optionally substituted C 1-3 alkylene)- *Y2 , -NR Y -(optionally substituted C 1-3 alkylene)- *Y2 , -(optionally substituted C 1-3 alkylene)-O- *Y2 , -(optionally substituted C 1-3 alkylene)-S- *Y2 , -(optionally substituted C 1-3 alkylene)-SO 2 - * Y2 or -(optionally substituted C 1-3 alkylene)-NR Y - *Y2 ( *Y2 indicates the bonding part with Y 2 ), A compound or a salt thereof, wherein R Y is H or optionally substituted C 1-3 alkyl.
• Y 1 is -O-(C 1-3 alkylene)- *Y2 or -(C 1-3 alkylene)-O- *Y2 ( *Y2 indicates the bond with Y 2 ), compound or its salt.
• (8-3) A compound or a salt thereof, in which Y 1 is -O-(C 1-3 alkylene)- *Y2 ( *Y2 indicates a bond with Y 2 ).
• (8-4) A compound or a salt thereof, in which Y 1 is -O-(methylene)- *Y2 ( *Y2 indicates a bond with Y 2 ).
• (9-1) A compound or a salt thereof, wherein Y 2 is a bond, optionally substituted phenylene, or optionally substituted heteroarylene.
• (9-2) A compound or a salt thereof, wherein Y 2 is phenylene or pyridinediyl.
• (9-3) A compound or a salt thereof, wherein Y 2 is phenylene optionally substituted with fluorine.
• (9-4) A compound or a salt thereof, wherein Y 2 is phenylene.
• (9-5) A compound or a salt thereof, wherein Y 2 is optionally substituted phenylene or pyridinediyl.
• Linker is a group that chemically bonds Y 2 and EUB.
• Linker has the following formulas (L-1), (L-2), (L-3), (L-4), (L-5), (L-6) and (L-7) ) is one group selected from the group consisting of
• C in the formulas (L-1), (L-2), (L-3), (L-4), (L-5), (L-6) and (L-7)
• O forms a bond with Y 2
• L' is -O-, -(C 1-3 alkylene)-NH-, -N(CH 3 )(C 1-3 alkylene)-, piperazinediyl or -(C 1-3 alkylene)-piperazinediyl can be,
• L'' is a bond, C 1-3 alkylene, or -(C 1-3 alkylene)-O-,
• R L2 is H or C 1-3 alkyl.
• EUB is a group capable of binding to an E3 ubiquitin ligase selected from the group consisting of cereblon, IAP, MDM2, DCAF11, DCAF15, DCAF16, BIRC2, KEAP1, RNF4, RNF114, FEM1B and AhR.
• a compound or its salt A compound or a salt thereof, in which EUB is a group capable of binding to cereblon.
• EUB is the following formula (XV), G is CR G or N, R G is H or C 1-6 alkyl, Z is the following formula (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z- 8), (Z-9), (Z-10), (Z-11), (Z-12), (Z-13), (Z-14), (Z-15), (Z-16) , (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22) and (Z-23) 1 is the basis of
• ring B1 and ring B2 are Forms
• EUB is a group having the ability to bind to cereblon
• the group having the ability to bind to cereblon is the following formula (XV)
• G is CR G or N
• R G is H or C 1-6 alkyl
• Z is the following formula (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z- 8), (Z-9), (Z-10), (Z-11), (Z-12), (Z-13), (Z-14), (Z-15), (Z-16) , (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22) and (Z-23) 1 is the basis of
• EUB is the following formula (XV), G is CH or N, Z is the following formula (Z-1), (Z-4), (Z-5), (Z-11), (Z-14), (Z-15), (Z-16), (Z- 18), (Z-19), (Z-20), (Z-22) and (Z-23),
• the relevant formulas (Z-1), (Z-4), (Z-5), (Z-11), (Z-14), (Z-15), (Z-16), (Z- 18), Ring B1 and Ring B2 in (Z-19), (Z-20), (Z-22) and (Z-23) form a bond with Linker
• G is N
• Z consists of formulas (Z-16), (Z-18), (Z-19), (Z-20), (Z-22) and (Z-23) is a group of 1 selected from the group
• R Z1 is C 1-6 alkyl or halogen
• n is an integer of 0 or 1
• R Z2 and R Z4 are the same or different from each other and are H or C 1-6 alkyl
• M is a bond or
• EUB is the following formula (XV), G is CH or N, Z is the following formula (Z-1), (Z-5), (Z-11), (Z-14), (Z-15), (Z-16), (Z-20), (Z- 22) and (Z-23), Here, the formulas (Z-1), (Z-5), (Z-11), (Z-14), (Z-15), (Z-16), (Z-20), (Z- Ring B1 and Ring B2 in 22) and (Z-23) form a bond with Linker,
• G is N
• Z is a group of 1 selected from the group consisting of formulas (Z-16), (Z-20), (Z-22) and (Z-23)
• R Z1 is C 1-3 alkyl or halogen
• n is an integer from 0-1
• R Z2 is C 1-3 alkyl
• M is a bond or C 1-3 alkylene
• Ring B1 is a benzene ring or a pyridine ring
• R Z1 and Linker form a bond with a carbon atom constitu
• EUB is the following formula (XV), G is CH or N, Z is the following formula (Z-1A), (Z-1B), (Z-5A), (Z-5B), (Z-14A), (Z-14B), (Z-14C), (Z- 15A), (Z-16A), (Z-16B), (Z-16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (Z-23B) , (Z-23C), (Z-23D), (Z-23E) and (Z-23F),
• EUB is the following formula (XV), G is CH, Z is the following formula (Z-1A), (Z-1B), (Z-5A), (Z-5B), (Z-14A), (Z-14B), (Z-14C) and (Z- 15A) is a group selected from the group consisting of Here, the formulas (Z-1A), (Z-1B), (Z-5A), (Z-5B), (Z-14A), (Z-14B), (Z-14C) and (Z- A compound or a salt thereof in which the benzene ring or 6-membered heterocycle in 15A) forms a bond with Linker.
• EUB is the following formula (XV), G is CH or N, Z is a group selected from the group consisting of the following formulas (Z-1A), (Z-14B), (Z-15A), (Z-16A) and (Z-22A), Here, the benzene ring or 6-membered heterocycle in the formulas (Z-1A), (Z-14B), (Z-15A), (Z-16A) and (Z-22A) forms a bond with the Linker. , However, when G is N, Z is (Z-16A) or (Z-22A), a compound or a salt thereof.
• EUB is the following formula (XV), G is CR G or N, R G is H or C 1-6 alkyl, Z is the following formula (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z- 8), (Z-9), (Z-10), (Z-11), (Z-12), (Z-13), (Z-14), (Z-15), (Z-16) , (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22), (Z-23), (Z-24), ( 1 group selected from the group consisting of Z-25), (Z-26) and (Z-27),
• EUB is the following formula (XV), G is CH or N, Z is the following formula (Z-1A), (Z-1B), (Z-5A), (Z-5B), (Z-14A), (Z-14B), (Z-14C), (Z- 15A), (Z-16A), (Z-16B), (Z-16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (Z-23B) , (Z-23C), (Z-23D), (Z-23E), (Z-23F) and (Z-24A),
• (12) A compound or a salt thereof that is a mutually consistent combination of two or more of the embodiments described in (1-1) to (11-10) above. Examples include, but are not limited to, the following combinations. (12-1) A compound of formula (I) or a salt thereof.
• A is CR A or N
• R A is H, optionally substituted C 1-3 alkyl or cyano
• Q is CR Q or N
• R Q is H, halogen, optionally substituted C 1-3 alkyl, C 3-6 cycloalkyl, or vinyl
• E is CH or N, Naphthyl, in which R 1 is optionally substituted with one or two groups selected from the group consisting of optionally substituted C 1-3 alkyl, cyano, OH, and halogen, or the following formula (II) , one group selected from the group consisting of formula (III) and formula (IV), R 1a , R 1b and R 1c are the same or different from each other and are H, optionally substituted C 1-3 alkyl, vinyl or halogen;
• R 2 is -V 1 -V 2 or W
• V 1 is a bond, -CH 2 -, -O-, -S- or -N(R V1 )-
• m is an integer from 0-2
• R 3 is optionally substituted C 1-6 alkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl
• X is a bond, -CH2- , -O-, -S-, or -NR4X-
• R 4X is H or optionally substituted C 1-3 alkyl
• Y 1 is -O-(optionally substituted C 1-3 alkylene)- *Y2
• -SO 2 (substituted C 1-3 alkylene which may be substituted)- *Y2 , -NR Y -(C 1-3 alkylene which may be substituted)- *Y2 ,
• EUB is the following formula (XV), G is CR G or N, R G is H or C 1-6 alkyl, Z is the following formula (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z- 8), (Z-9), (Z-10), (Z-11), (Z-12), (Z-13), (Z-14), (Z-15), (Z-16) , (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22) and (Z-23) 1 is the basis of Here, the relevant formulas (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z- 8), (Z-9), (Z-10), (Z-11), (Z-12), (Z-13), (Z-14), (Z-15), (Z-16) , (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22) and (Z-23) 1 is the basis of Here, the relevant formulas (Z-1), (
• EUB is the following formula (XV), G is CH or N, Z is the following formula (Z-1), (Z-4), (Z-5), (Z-11), (Z-14), (Z-15), (Z-16), (Z- 18), (Z-19), (Z-20), (Z-22) and (Z-23),
• the relevant formulas (Z-1), (Z-4), (Z-5), (Z-11), (Z-14), (Z-15), (Z-16), (Z- 18), Ring B1 and Ring B2 in (Z-19), (Z-20), (Z-22) and (Z-23) form a bond with Linker
• G is N
• Z consists of formulas (Z-16), (Z-18), (Z-19), (Z-20), (Z-22) and (Z-23) is a group of 1 selected from the group
• R Z1 is C 1-6 alkyl or halogen
• n is an integer of 0 or 1
• R Z2 and R Z4 are the same or different from each other and are H or C 1-6 alkyl
• M is a bond or
• A is CH or N
• Q is CR Q
• R Q is C 3-6 cycloalkyl
• E is CH
• R 1 is the following formula (II)
• R 1a and R 1c are the same or different from each other and are C 1-3 alkyl or halogen
• R 2 is -V 1 -V 2 or W
• V 1 is a bond, -CH 2 -, -O-, -S- or -N(R V1 )-
• R V1 is C 1-3 alkyl optionally substituted with one group selected from the group consisting of C 3-6 cycloalkyl, halogen and -OH
• V 2 is the following formula (V-2) or (VI-2)
• W is selected from the group consisting of the following formulas (VII-3), (VII-4), (VIII), (IX), (X), (XI), (XII), (XIII) and (XIV); is the basis of 1, 1, wherein R 3 is selected from the group consisting
• Q is CR Q , R Q is cyclopropyl, R 1 is the following formula (II-2), R 2 is -V 1 -V 2 or W, V 1 is -O- or -N(CH 3 )-, V 2 is the following formula (VI-2), W is the following formula (XII) R 3 is C 1-3 alkyl, tetrahydrofuranyl or tetrahydropyranyl, which may be substituted with -OCH 3 or tetrahydrofuranyl, Y 1 is -O-(methylene)- *Y2 ( *Y2 indicates the bond with Y 2 ),
• the Linker is one selected from the group consisting of the following formulas (L-1), (L-2), (L-3), (L-4), (L-5), and (L-7).
• L' is -O-, -(C 1-3 alkylene)-NH-, -N(CH 3 )(C 1-3 alkylene)-, piperazinediyl or -(C 1-3 alkylene)-piperazinediyl can be, L'' is a bond, C 1-3 alkylene or -(C 1-3 alkylene)-O-, R L2 is H or C 1-3 alkyl, EUB is the following formula (XV), G is CH or N, Z is the following formula (Z-1A), (Z-1B), (Z-5A), (Z-5B), (Z-14A), (Z-14B), (Z-14C), (Z- 15A), (Z-16A), (Z-16B), (Z-16C), (Z-16D), (Z-20A), (Z-22A), (Z-23
• (12-8) (1-2), (2-3), (3-2), (4-4), (5-5), (6-5), (7-3), (8 -4), (9-4), (10-7), and (11-8), a compound of formula (I) or a salt thereof.
• (12-9) (1-2), (2-2), (3-2), (4-3), (5-2), (6-3), (7-2), (8 -2), (9-3), (10-5), and (11-4), a compound of formula (I) or a salt thereof.
• (12-10) (1-2), (2-2), (3-2), (4-2), (5-6), (6-2), (7-2), (8 -2), (9-2), (10-2), and (11-4), a compound of formula (I) or a salt thereof.
• R 2 is -V 1 -V 2 or W
• V 1 is -O-
• V 2 is the following formula (VI-2)
• W is the following formula (XII)
• R 3 is n-propyl optionally substituted with -OCH 3 or tetrahydropyranyl
• Linker is the following formula (L-5A) or (L-7A)
• EUB is the following formula (XV)
• G is CH or N
• Z is a group selected from the group consisting of the following formulas (Z-1A), (Z-14B), (Z-15A), (Z-16A) and (Z-22A)
• the benzene ring or 6-membered heterocycle in the formulas (Z-1A), (Z-14B), (Z-15A), (Z-16A) and (Z-22A) forms a bond with the Linker.
• EUB is the following formula (XV), G is CR G or N, R G is H or C 1-6 alkyl, Z is the following formula (Z-1), (Z-2), (Z-3), (Z-4), (Z-5), (Z-6), (Z-7), (Z- 8), (Z-9), (Z-10), (Z-11), (Z-12), (Z-13), (Z-14), (Z-15), (Z-16) , (Z-17), (Z-18), (Z-19), (Z-20), (Z-21), (Z-22), (Z-23), (Z-24), ( 1 group selected from the group consisting of Z-25), (Z-26) and (Z-27),
• A is CH or N
• Q is CR Q
• R Q is cyclopropyl
• R 1 is the following formula (II-2)
• R 2 is -V 1 -V 2 or W
• V 1 is -O- or -N(CH 3 )-
• V 2 is the following formula (VI-2)
• W is the following formula (VII-4) or (XII)
• R 3 is C 1-3 alkyl, tetrahydrofuranyl or tetrahydropyranyl, which may be substituted with -OCH 3 or tetrahydrofuranyl
• X is -O-
• Y 1 is -O-(methylene)- *Y2 ( *Y2 indicates the bond with Y 2 )
• Y 2 is phenylene Linker is one group selected from the group consisting of the following formulas (L-1), (L-2), (L-3), (L-4), (L-5) and (L-7).
• L' is -O-, -(C 1-3 alkylene)-NH-, -N(CH 3 )(C 1-3 alkylene)-, piperazinediyl or -(C 1-3 alkylene)-piperazinediyl can be, L'' is a bond, C 1-3 alkylene or -(C 1-3 alkylene)-O-, R L2 is H or C 1-3 alkyl, EUB is the following formula (XV), G is CH or N, Z is the following formula (Z-1A), (Z-1B), (Z-5A), (Z-5B), (Z-14A), (Z-14B), (Z-14C), (Z- 15A), (Z-16A), (Z-16B), (Z-16C), (Z-16D), (Z-20A), (Z-22A), (Z-23A), (
• a compound of formula (XXI) or a salt thereof in the present invention is shown below.
• (21-1) A compound of formula (XXI) or a salt thereof.
• A is CR A or N
• R A is H, optionally substituted C 1-3 alkyl or cyano
• Q is CR Q or N
• R Q is H, halogen, optionally substituted C 1-3 alkyl, C 3-6 cycloalkyl, or vinyl
• m is an integer from 0-2
• R 3P is optionally substituted C 1-6 alkylene, optionally substituted heterocycloalkylene, or optionally substituted heteroarylene
• X is a bond, -CH2- , -O-, -S-, or -NR4X-
• R 4X is H or optionally substituted C 1-3 alkyl
• Y 1 is -O-(optionally substituted C 1-3 alkylene)- *Y2
• -SO 2 (substituted C 1-3 alkylene which may be substituted)- *Y2 , -NR Y -(C 1-3 alkylene which may be substituted)- *Y2 ,
• Linker is a group that chemically connects R 3P and EUB
• EUB is a group capable of binding to one E3 ubiquitin ligase selected from the group consisting of cereblon, IAP, MDM2, DCAF11, DCAF15, DCAF16, BIRC2, KEAP1, RNF4, RNF114, FEM1B, and AhR.
• A is CH or N
• Q is CR Q
• R Q is C 3-6 cycloalkyl
• E is CH
• R 1 is the following formula (II)
• R 1a is halogen
• R 1c is C 1-3 alkyl
• R 2 is -V 1 -V 2 or W
• V 1 is a bond, -O- or -N(R V1 )-
• R V1 is C 1-3 alkyl
• V 2 is the following formula (VI-2)
• W is the following formula (XII), C 1-6 alkylene, oxetanediyl, tetrahydrofurandiyl, in which R 3P may be substituted with one group selected from the group consisting of -O(C 1-6 alkyl), oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl or tetrahydropyrandiyl
• R 5 is H or the following formula (XXIV
• Y 2 is phenylene
• Linker is -(L 1 -L 2 -L 3 -L 4 )-
• L 2 is piperidinediyl optionally substituted with C 1-3 alkyl, piperadinediyl optionally substituted with C 1-3 alkyl, pyrrolidinediyl optionally substituted with C 1-3 alkyl, bridged piperazinediyl or 2,6-diazaspiro[3.4]octanediyl
• L 3 is a bond, -N(R L3 )-, C 1-3 alkylene or piperazine diyl
• L 4 is a bond, -N(R L4 )-, -O-, piperazinediyl or C 1-3 alkylene
• R L3 is H or C 1-3 alkyl
• R L4 is H or C 1-3 alkyl
• EUB is a group having the ability to bind to cereblon, and
• A is CH or N
• Q is CR Q
• R Q is cyclopropyl
• E is CH
• R 1 is the following formula (II-2)
• R 2 is -V 1 -V 2 or W
• V 1 is -O- or -N(CH 3 )-
• V 2 is the following formula (VI-2)
• W is the following formula (XII)
• R 3P is C 1-6 alkylene optionally substituted with -O(C 1-3 alkyl)
• R 5 is H
• X is -O-
• Y 1 is -O-(methylene)- *Y2 ( *Y2 indicates the bond with Y 2 )
• Y 2 is phenylene
• Linker is from the group consisting of the following formulas (L-1), (L-2), (L-3), (L-4), (L-5), (L-6) and (L-7).
• L' is -O-, -(C 1-3 alkylene)-NH-, -N(CH 3 )(C 1-3 alkylene)-, piperazinediyl or -(C 1-3 alkylene)-piperazinediyl can be, L'' is a bond, C 1-3 alkylene, or -(C 1-3 alkylene)-O-, R L2 is H or C 1-3 alkyl, EUB is a group having the ability to bind to cereblon, and the group having the ability to bind to cereblon is the following formula (XV), G is CH or N, Z is the following formula (Z-1A), (Z-1B), (Z-5A), (Z-5B), (Z-14A), (Z-14B), (Z-14C), (XV), G is CH or N, Z is the following formula (Z-1A), (Z-1B), (Z-5A), (Z-5B), (Z-14A), (Z-14B), (Z-14C), (XV)
• a compound of formula (XXII) or a salt thereof in the present invention is shown below.
• A is CR A or N
• R A is H, optionally substituted C 1-3 alkyl or cyano
• Q is CR Q or N
• R Q is H, halogen, optionally substituted C 1-3 alkyl, C 3-6 cycloalkyl, or vinyl
• E is CH or N, Naphthylene or the following formula (II - 22A ), formula (II-22B), formula (II-22C), formula (III-22A), formula (III-22B), formula (III-22C) and formula (III-22D) is the basis of 1, R 1a , R 1b and R 1c are the same or different from each other and are H, optionally substituted C 1-3 alkyl, vinyl or halogen;
• R 2 is -V 1 -V 2 or W, V 1 is a bond, -CH 2
• m is an integer from 0-2
• R 3 is optionally substituted C 1-6 alkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl
• X is a bond, -CH2- , -O-, -S-, or -NR4X-
• R 4X is H or optionally substituted C 1-3 alkyl
• Y 1 is -O-(optionally substituted C 1-3 alkylene)- *Y2
• -SO 2 (substituted C 1-3 alkylene which may be substituted)- *Y2 , -NR Y -(C 1-3 alkylene which may be substituted)- *Y2 ,
• Linker is a group that chemically connects R 1P and EUB
• EUB is a group capable of binding to one E3 ubiquitin ligase selected from the group consisting of cereblon, IAP, MDM2, DCAF11, DCAF15, DCAF16, BIRC2, KEAP1, RNF4, RNF114, FEM1B, and AhR.
• A is CH or N
• Q is CR Q
• R Q is C 3-6 cycloalkyl
• E is CH, Naphthylene or the following formula (II- 22A ), formula (II-22B) and formula (II-22C)
• R 1a is halogen
• R 1c is C 1-3 alkyl
• R 2 is -V 1 -V 2 or W
• V 1 is a bond, -O- or -N(R V1 )-
• R V1 is C 1-3 alkyl
• V 2 is the following formula (VI-2)
• W is the following formula (XII)
• R 3 is optionally substituted C 1-6 alkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl
• R 5 is H or the following formula (XXIV), (XXV), (XXVI), (XXVII), (XVIII), (XXIX), (XXX), (XXXI), (XXII
• Y 2 is phenylene
• Linker is -(L 1 -L 2 -L 3 -L 4 )-
• L 2 is piperidinediyl optionally substituted with C 1-3 alkyl, piperadinediyl optionally substituted with C 1-3 alkyl, pyrrolidinediyl optionally substituted with C 1-3 alkyl, bridged piperazinediyl or 2,6-diazaspiro[3.4]octanediyl
• L 3 is a bond, -N(R L3 )-, C 1-3 alkylene or piperazine diyl
• L 4 is a bond, -N(R L4 )-, -O-, piperazinediyl or C 1-3 alkylene
• R L3 is H or C 1-3 alkyl
• R L4 is H or C 1-3 alkyl
• EUB is a group having the ability to bind to cereblon, and
• A is CH or N
• Q is CR Q
• R Q is cyclopropyl
• E is CH, Naphthylene or the following formula (II - 22A ), formula (II-22B) and formula (II-22C)
• R 1a is F
• R 1c is methyl
• R 2 is -V 1 -V 2 or W
• V 1 is -O- or -N(CH 3 )-
• V 2 is the following formula (VI-2)
• W is the following formula (XII)
• R 3 is C 1-3 alkyl, tetrahydrofuranyl or tetrahydropyranyl, which may be substituted with -OCH 3 or tetrahydrofuranyl
• R 5 is H
• X is -O-
• Y 1 is -O-(methylene)- *Y2 ( *Y2 indicates the bond with Y 2 )
• Y 2 is phenylene
• Linker is from the group consist
• L' is -O-, -(C 1-3 alkylene)-NH-, -N(CH 3 )(C 1-3 alkylene)-, piperazinediyl or -(C 1-3 alkylene)-piperazinediyl can be, L'' is a bond, C 1-3 alkylene, or -(C 1-3 alkylene)-O-, R L2 is H or C 1-3 alkyl, EUB is a group having the ability to bind to cereblon, and the group having the ability to bind to cereblon is the following formula (XV), G is CH or N, Z is the following formula (Z-1A), (Z-1B), (Z-5A), (Z-5B), (Z-14A), (Z-14B), (Z-14C), (XV), G is CH or N, Z is the following formula (Z-1A), (Z-1B), (Z-5A), (Z-5B), (Z-14A), (Z-14B), (Z-14C), (XV)
• (23-1) A compound of formula (XXIII) or a salt thereof in the present invention.
• GDB is a group that has the ability to bind to G12D mutant KRAS protein
• -Linker - EUB is one group selected from the group consisting of the following formulas (LE-1) to (LE-37).
• GDB is a group that has the ability to bind to G12D mutant KRAS protein
• -Linker - EUB is one group selected from the group consisting of the following formula (LE-5), formula (LE-8), formula (LE-10), formula (LE-20) or (LE-23).
• GDB is a group that has the ability to bind to G12D mutant KRAS protein
• -Linker - EUB is the compound described in (23-2), which is the following formula (LE-10), or a salt thereof.
• (23-4) A compound of formula (XXIII) or a salt thereof.
• GDB is a group that has the ability to bind to G12D mutant KRAS protein
• -Linker - EUB is one group selected from the group consisting of the following formulas (LE-1) to (LE-40).
• (23-5) GDB is a group that has the ability to bind to G12D mutant KRAS protein
• -Linker - EUB is one group selected from the group consisting of the following formula (LE-5), formula (LE-8), formula (LE-10), formula (LE-15) or (LE-23).
• the compounds of formula (I), formula (XXI), formula (XXII) or formula (XXIII) may exist as tautomers or geometric isomers depending on the type of substituent.
• the compound of formula (I), formula (XXI), formula (XXII) or formula (XXIII) may be described herein only in one form of isomer, the present invention It also includes isomers, separated isomers, and mixtures thereof.
• the compounds of formula (I), formula (XXI), formula (XXII), or formula (XXIII) may have asymmetric carbon atoms or axial asymmetry, and diastereomers based on this may exist. .
• the present invention also encompasses separated diastereomers of compounds of formula (I), formula (XXI), formula (XXII) or formula (XXIII), or mixtures thereof.
• the present invention also includes pharmaceutically acceptable prodrugs of the compounds represented by formula (I), formula (XXI), formula (XXII), or formula (XXIII).
• 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. Examples of groups that form prodrugs include Prog. Med., 1985, 5, p.2157-2161, "Drug Development", Vol. 7, Molecular Design, Hirokawa Shoten, 1990, p.163-198. Examples include the groups described in .
• the salt of the compound of formula (I), formula (XXI), formula (XXII) or formula (XXIII) is a pharmaceutically acceptable salt of the compound of formula (I), and the types of substituents are may form acid addition salts or salts with bases.
• 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.
• 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 also encompasses various hydrates, solvates, and crystalline polymorphs of the compound of formula (I), formula (XXI), formula (XXII), or formula (XXIII) and its salts. .
• the present invention also provides compounds of formula (I), formula (XXI), formula (XXII) or formula (XXIII) labeled with one or more pharmaceutically acceptable radioactive or non-radioactive isotopes; Includes all salts.
• 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.
• a desired compound can be obtained by introducing the protecting group and carrying out the reaction, and then removing the protecting group as necessary.
• prodrugs of compounds of formula (I), formula (XXI), formula (XXII), or formula (XXIII) can be prepared by introducing or obtaining a specific group at the stage from raw materials to intermediates, similar to the above-mentioned protecting groups. It can be produced by further reacting using the compound of formula (I), formula (XXI), formula (XXII) or formula (XXIII) obtained.
• the reaction can be carried out by applying conventional methods such as esterification, amidation, dehydration, etc. known to those skilled in the art.
• DMF N,N-dimethylformamide
• DMAc N,N-dimethylacetamide
• THF tetrahydrofuran
• MeCN acetonitrile
• MeOH methanol
• EtOH ethanol
• iPrOH isopropyl alcohol
• tBuOH tert-butyl alcohol
• 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(diphenylphos) fino)ferrocene]palladium(II) dichloride/dichloromethane adduct
• Pd/C palladium on carbon
• PyBOP (benzotriazol
• This production method is the first method for producing the compound of formula (I) or a salt thereof.
• PG 1 -R 11 is a group in which PG 1 , which is a protecting group, is bonded to NH or OH contained in R 1
• PG 2 -R 21 is a group in which NH or OH contained in R 2 is a protecting group
• It is a group to which PG 2 is bonded.
• the compound of formula (I) can be obtained by subjecting compound (1) to deprotection reaction conditions under acidic conditions.
• protecting groups that can be deprotected under acidic conditions include tert-butoxycarbonyl group, triphenylmethyl group, tetrahydro-2H-pyran-2-yl group, methoxymethyl group, dimethylmethanediyl group, -butylsulfinyl group, etc.
• This reaction is carried out using the same equivalent or excess equivalent of a deprotecting reagent as the compound (1), in a solvent inert to the reaction, and stirring under cooling to heating under reflux, usually for 0.1 hour to 5 days.
• deprotection reagents used here include, but are not limited to, hydrogen chloride (DOX solution), trifluoroacetic acid, methanesulfonic acid, phosphoric acid, p-toluenesulfonic acid, Examples include acids such as trifluoromethanesulfonic acid, and mixtures thereof.
• solvents used here include, but are not limited to, alcohols such as MeOH and EtOH, halogenated hydrocarbons such as dichloromethane, 1,2-dichloromethane, and chloroform, diethyl ether, THF, DOX, dimethoxyethane, etc. ethers, DMF, DMSO, MeCN, TfOH or water, and mixtures thereof.
• deprotection can also be performed by catalytic hydrogenation reaction or basic conditions.
• protecting groups that can be deprotected by catalytic hydrogenation 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.
• protecting groups include tert-butyl(dimethyl)silyl group, (trimethylsilyl)ethoxymethyl group, and the like.
• protecting groups that can be deprotected under basic conditions include acetyl group, trifluoroacetyl group, benzoyl group, and the like. Furthermore, protecting groups that can be deprotected under different deprotection conditions are selected as PG1 and PG2, and deprotection can be carried out stepwise. 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, 2014)." In addition, when compound (1), which is a raw material, has axial asymmetry, the present reaction may be performed using a stereoisomer obtained by once separating compound (1).
• This production method is the second method for producing the salt of the compound of formula (I).
• the compound of formula (I) or its salt is isolated as a free form by subjecting compound (1) to deprotection reaction conditions under acidic conditions and then treating it under basic conditions, and then subjecting it to deprotection reaction conditions under acidic conditions. It can be obtained by attaching it to
• examples of protecting groups that can be deprotected under acidic conditions include tert-butoxycarbonyl group, triphenylmethyl group, tetrahydro-2H-pyran-2-yl group, methoxymethyl group, dimethylmethanediyl group, -butylsulfinyl group, etc.
• reaction the same equivalent or excess equivalent of a deprotecting reagent as that of compound (1) is used, and the reaction is stirred in a solvent inert to the reaction under cooling to heating under reflux, usually for 0.1 hour to 5 days, and then mixed with a basic aqueous solution. After treatment, it is isolated as a free form. Thereafter, using the same equivalent or excess equivalent of the acidic reagent, the reaction is stirred in a solvent inert to the reaction under cooling to heating under reflux, usually for 0.1 hour to 5 days.
• deprotection reagents used here include, but are not limited to, hydrogen chloride (DOX solution), trifluoroacetic acid, methanesulfonic acid, phosphoric acid, p-toluenesulfonic acid, Examples include acids such as trifluoromethanesulfonic acid, and mixtures thereof.
• solvents used here include, but are not limited to, alcohols such as MeOH and EtOH, halogenated hydrocarbons such as dichloromethane, 1,2-dichloromethane, and chloroform, diethyl ether, THF, DOX, dimethoxyethane, etc. ethers, DMF, DMSO, MeCN, TfOH or water, and mixtures thereof.
• Examples of acidic reagents used here include acids such as hydrogen chloride (DOX solution), phosphoric acid, and p-toluenesulfonic acid.
• Examples of the basic aqueous solution used here include, but are not particularly limited to, a sodium hydrogen carbonate aqueous solution and the like.
• deprotection can also be performed by catalytic hydrogenation reaction or basic conditions.
• Examples of protecting groups that can be deprotected by catalytic hydrogenation 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.
• protecting groups include tert-butyl(dimethyl)silyl group, (trimethylsilyl)ethoxymethyl group, and the like.
• protecting groups that can be deprotected under basic conditions include acetyl group, trifluoroacetyl group, benzoyl group, and the like.
• protecting groups that can be deprotected under different deprotection conditions are selected as PG1 and PG2, and deprotection can be carried out stepwise. As references for this reaction, for example, the following can be referred to. P.G.M. Wuts and T.W.
• This production method is a method for producing compound (1)-1 included in compound (1), which is a raw material for the first production method and the second production method.
• L 2A is piperidinediyl optionally substituted with C 1-3 alkyl, piperadinediyl optionally substituted with C 1-3 alkyl, pyrrolidine optionally substituted with C 1-3 alkyl) diyl, bridged piperazinediyl or 2,6-diazaspiro[3.4]octanediyl, and R LG represents a C 1-12 alkyl group. The same applies hereinafter)
• This step is a step in which compound (3) is obtained by subjecting compound (2) to hydrolysis conditions.
• This reaction is carried out using the same equivalent or excess equivalent of a hydrolysis reagent as the compound (2), in a solvent inert to the reaction, and stirring under cooling to heating under reflux, usually for 1 hour to 5 days.
• a hydrolysis reagent used here include, but are not particularly limited to, an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, an aqueous lithium hydroxide solution, a trimethyltin hydroxide, and the like.
• solvents include, but are not limited to, alcohols such as methanol, ethanol, and n-propanol, ether solvents such as tetrahydrofuran, diethyl ether, and 1,4-dioxane, dichloromethane, 1,2-dichloroethane, and chloroform.
• alcohols such as methanol, ethanol, and n-propanol
• ether solvents such as tetrahydrofuran, diethyl ether, and 1,4-dioxane, dichloromethane, 1,2-dichloroethane, and chloroform.
• examples include halogenated hydrocarbons, acetonitrile, water, and mixtures thereof.
• This step is a step in which compound (1)-1 is obtained by subjecting compound (3) and compound (4) to condensation reaction conditions.
• Compound (3) and Compound (4) are used in the same equivalent amount or an excess equivalent amount of one of them, a condensing agent and a base are added to the mixture, and the reaction is carried out in a solvent inert to the reaction at room temperature, usually for 1 hour. This is done by stirring for 1 day.
• Examples of the condensing agent used here include, but are not limited to, HATU, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or its hydrochloride, dicyclohexylcarbodiimide, and 1,1'-carbonyldiimide.
• Examples include imidazole, COMU, PyBOP, and the like.
• Examples of the base include, but are not particularly limited to, organic bases such as triethylamine, N,N-diisopropylethylamine, and pyridine, and inorganic bases such as potassium carbonate, sodium carbonate, and cesium carbonate.
• solvents include, but are not limited to, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, or chloroform, ether solvents such as tetrahydrofuran, diethyl ether, and 1,4-dioxane, methanol, ethanol, n- Examples include alcohols such as propanol, N,N-dimethylformamide, and mixtures thereof.
• This production method is the first method for producing compound (2)-1 contained in compound (2), which is the raw material of raw material production method 1.
• PG 3 is an OH protecting group
• LG 1 is a leaving group
• BLG is 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 trifluoroboric acid group.
• Indicates a base hereinafter sometimes referred to as a boronic acid group, etc.
• Examples of the leaving group shown here include Cl, Br, methanesulfonyloxy group, p-toluenesulfonyloxy group, etc. Below: similar
• This step is a method for producing compound (7) by an ipsosubstitution reaction between compound (5)-1 and compound (6)-1.
• This reaction uses the same equivalent amount of compound (5)-1 and compound (6)-1 or an excess equivalent amount of one of them, and heats the mixture under cooling in a solvent inert to the reaction or without a solvent. Stirring is carried out under reflux, preferably at 0°C to 120°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.
• compound (7) can be produced by subjecting a compound obtained by a Mizorogi-Heck reaction between compound (5)-1 and compound (6)-1 to catalytic hydrogenation reaction. [Literature] Chem. Rev., 2003, 103, p.2945-2964
• This step is a method for producing compound (9) by an ipsosubstitution reaction between compound (7) and compound (8).
• the reaction conditions are the same as in the first step of raw material production method 2.
• compound (9) can be produced by Negishi coupling of a compound obtained by converting the hydrogen atom of compound (8) into a halogen and compound (7). [Literature] ACC. Chem. Res., 1982, 15, p.340-348
• This step is a method for producing compound (10)-1 by an ipsosubstitution reaction between compound (9) and PG 3 -OH.
• PG 3 -OH used here include benzyl alcohol, p-methoxybenzyl alcohol and 1-phenylethanol.
• the reaction conditions are the same as in the first step of raw material production method 2.
• 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, barium hydroxide, and cesium carbonate.
• Palladium catalysts include tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride/dichloromethane adduct, ( 1E,4E)-1,5-diphenylpent-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, mesyl[(tri-t-butylphosphine)-2-(2 -aminobiphenyl)]palladium(II) and the like.
• Dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine, 1,1'-bis It is advantageous for the reaction to proceed smoothly in the presence of a ligand such as (diphenylphosphino)ferrocene, butyldi-1-adamantylphosphine, or di(adamantan-1-yl)(butyl)phosphine.
• a ligand such as (diphenylphosphino)ferrocene, butyldi-1-adamantylphosphine, or di(adamantan-1-yl)(butyl)phosphine.
• This step is a method for producing compound (13) by a Suzuki-Miyaura coupling reaction between compound (11) and compound (12).
• the reaction conditions are the same as in the fourth step of raw material production method 2.
• Compound (13) may have axial asymmetry and may be obtained as a mixture of stereoisomers ; Each stereoisomer can be isolated by dividing the compound obtained by attaching the compound (for example, compound (14)) using a conventional separation operation, such as ODS column chromatography or silica gel column chromatography. .
• This step is a method for producing compound (14) by deprotecting compound (13) by catalytic hydrogenation reaction.
• compound (13) 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, under cooling to heating, preferably under heating.
• a metal catalyst a palladium catalyst such as Pd/C or palladium black, a platinum catalyst such as a platinum plate or platinum oxide, or a nickel catalyst such as reduced nickel or Raney nickel can be used.
• a base may be used to suppress its deprotection.
• the base used here include, but are not particularly limited to, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, and the like.
• Compound (14) may have axial asymmetry and can be obtained as a mixture of stereoisomers, but it can be obtained by subjecting compound (14) or compound (14) in which PG 1 is a protecting group to a deprotection reaction.
• Each stereoisomer can be isolated by subjecting the obtained compound to a conventional separation operation, for example, using ODS column chromatography or silica gel column chromatography.
• the following can be referred to. Edited by the Chemical Society of Japan, "Experimental Chemistry Course", 5th edition, Volume 13, Maruzen, 2004.
• This step is a method for producing compound (2)-1 by reacting compound (14) and compound (15).
• This reaction uses the same equivalent amount of compound (14) and compound (15) or an excess equivalent amount of one of them, and the mixture thereof is heated under cooling to reflux in the presence of a base in a solvent inert to the reaction, preferably.
• 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 (2)-1 may have axial chirality and can be obtained as a mixture of stereoisomers.
• compound (2)-1 in which PG 1 is a protecting group, or a compound obtained by subjecting compound (2)-1 to a deprotection reaction is subjected to a conventional separation operation such as ODS column chromatography or silica gel column chromatography.
• the respective stereoisomers can be isolated by performing a resolution using the method described above.
• compound (15) in which LG 1 is a sulfonyloxy group can be produced by sulfonylating a compound in which the moiety corresponding to LG 1 is a hydroxy group in the presence of a base.
• a base examples include, but are not particularly limited to, TEA, DIPEA, pyridine, tetramethylethylenediamine, and the like.
• This step is a method for producing compound (16) by an ipsosubstitution reaction between compound (7) and R LG -SH.
• R LG -SH used here include C 1-12 alkylthiols, such as ethanethiol, dodecanethiol.
• the reaction conditions are the same as in the first step of raw material production method 2.
• This step is a method for producing compound (17)-1 by an ipsosubstitution reaction between compound (16) and PG 3 -OH.
• PG 3 -OH used here include benzyl alcohol, p-methoxybenzyl alcohol and 1-phenylethanol.
• the reaction conditions are the same as in the first step of raw material production method 2.
• This step is a method for producing compound (19) by a Suzuki-Miyaura coupling reaction between compound (18) and compound (12).
• the reaction conditions are the same as in the fourth step of raw material production method 2.
• Compound (19) may have axial asymmetry and may be obtained as a mixture of stereoisomers, but compound (19) can be obtained by ordinary resolution procedures such as ODS column chromatography or silica gel column chromatography.
• the respective stereoisomers can be isolated by performing a resolution using the method described above.
• the stereoisomer of compound (19) can also be isolated by deprotecting compound (19), isolating the stereoisomer, and then protecting it again with a protecting group. Examples of protecting groups for reprotection include tetrahydro-2H-pyran-2-yl group and the like.
• This step is a method for producing compound (20) through an oxidation reaction of compound (19).
• This reaction is carried out by adding the compound (19) in an inert solvent to the reaction, under cooling to heating, preferably at -20°C to 80°C, usually for 0.1 hour to 3 days, with an equivalent or excess amount of an oxidizing agent.
• oxidation using m-chloroperbenzoic acid, perbenzoic acid, peracetic acid, sodium hypochlorite, or hydrogen peroxide is preferably used.
• solvents include aromatic hydrocarbons such as benzene and toluene, ethers such as THF, halogenated hydrocarbons such as chloroform and 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.
• This step is a method for producing compound (13) by an ipsosubstitution reaction between compound (20) and compound (8).
• the reaction conditions are the same as in the first step of raw material production method 2.
• compound (13) 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 (14) by deprotecting compound (13) by catalytic hydrogenation reaction.
• the reaction conditions are the same as those in the sixth step of raw material production method 2.
• Compound (14) may have axial asymmetry and may be obtained as a mixture of stereoisomers, but compound (14) may be obtained by ordinary resolution procedures such as ODS column chromatography or silica gel column chromatography. Each stereoisomer can be isolated by performing resolution using .
• This step is a method for producing compound (2)-1 by reacting compound (14) and compound (15).
• the reaction conditions are the same as those in the seventh step of raw material production method 2.
• Compound (2)-1 may have axial asymmetry and may be obtained as a mixture of stereoisomers, but compound (2)-1 can be obtained by ordinary resolution procedures such as ODS column chromatography or Each stereoisomer can be isolated by separation using silica gel column chromatography. Furthermore, the stereoisomer of compound (2)-1 can also be isolated by deprotecting compound (2)-1, isolating the stereoisomer, and then protecting it again with a protecting group. Examples of protecting groups for reprotection include tetrahydro-2H-pyran-2-yl group.
• This production method is the third method for producing compound (2)-1 contained in compound (2), which is the raw material of raw material production method 1.
• This step is a method for producing compound (21) by deprotecting compound (20) by catalytic hydrogenation reaction.
• the reaction conditions are the same as those in the sixth step of raw material production method 2.
• Compound (21) may have axial asymmetry and may be obtained as a mixture of stereoisomers, but compound (21) may be obtained by ordinary resolution procedures such as ODS column chromatography or silica gel column chromatography. Each stereoisomer can be isolated by performing resolution using .
• This step is a method for producing compound (22) through an alkylation reaction between compound (21) and compound (15).
• the reaction conditions are the same as in the seventh step of raw material production method 2.
• Compound (22) may have axial asymmetry and may be obtained as a mixture of stereoisomers, but compound (22) may be obtained by ordinary resolution procedures such as ODS column chromatography or silica gel column chromatography.
• Each stereoisomer can be isolated by performing resolution using .
• the stereoisomer of compound (22) can also be isolated by deprotecting compound (22), isolating the stereoisomer, and then protecting it again with a protecting group. Examples of protecting groups for reprotection include tetrahydro-2H-pyran-2-yl group and the like.
• This step is a method for producing compound (2)-1 by an ipsosubstitution reaction between compound (22) and compound (8).
• the reaction conditions are the same as in the first step of raw material production method 2.
• Compound (2)-1 may have axial asymmetry and can be obtained as a mixture of stereoisomers, but it can be obtained by subjecting compound (2)-1 or compound (2)-1 to a deprotection reaction.
• Each stereoisomer can be isolated by performing a conventional separation operation, for example, using ODS column chromatography or silica gel column chromatography.
• the reaction conditions for the deprotection reaction used here are the same as the steps described in Production Method 1.
• This step is a method for producing compound (23) by hydrolyzing compound (5)-1.
• Compound (5)-1 and the hydrolysis reagent are used in the same equivalent amount or an excess equivalent amount of one of them is used, and the reaction is carried out by stirring in a solvent inert to the reaction under cooling to heating under reflux, usually for 0.1 hour to 5 days. be exposed.
• the solvent used here include, but are not particularly limited to, alcohols such as methanol and ethanol, acetone, DMF, and THF. Further, a mixed solvent of the above solvent and water may be suitable for the reaction.
• hydrolysis reagent examples include, but are not particularly limited to, aqueous sodium hydroxide solution, aqueous potassium hydroxide solution, sodium hydroxide, potassium hydroxide, lithium hydroxide, 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 (24) by protecting the hydroxyl group of compound (23) with a tert-butyl group.
• This reaction is carried out using the same equivalent amount of compound (23) and the tert-butyl protecting reagent or an excess equivalent amount of one of them, and stirring in a solvent inert to the reaction under cooling to heating under reflux, usually for 0.1 hour to 5 days. be exposed.
• 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 limited to, isobutene, 2-tert-butyl-1,3-diisopropylisourea, and the like.
• compound (24) can be produced by a dehydration condensation reaction between compound (23) 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 (25) by an ipsosubstitution reaction between compound (24) and R LG -SH.
• the reaction conditions are the same as in the first step of raw material production method 2.
• This step is a method for producing compound (26) by an ipsosubstitution reaction between compound (25) and PG 3 -OH.
• the reaction conditions are the same as in the first step of raw material production method 2.
• This step is a method for producing compound (27) by a Suzuki-Miyaura coupling reaction between compound (26) and a boronic acid derivative comprising an R Q -boronic acid group or the like.
• the reaction conditions are the same as in the fourth step of raw material production method 2.
• Compound (27) (where R Q is hydrogen) can be produced by deiodination reaction of compound (26) using a Pd catalyst and a reducing agent. [Literature] J. Org. Chem., 1977, 42, p.3491-3494 Tetrahedron Letters 2013, 54, 5207-5210
• This step is a method for producing compound (28) by a Suzuki-Miyaura coupling reaction between compound (27) and compound (12).
• the reaction conditions are the same as in the fourth step of raw material production method 2.
• compound (28) may have axial asymmetry and may be obtained as a mixture of stereoisomers, but compound (28) may be obtained by ordinary resolution procedures such as ODS column chromatography or silica gel column chromatography.
• Each stereoisomer can be isolated by performing resolution using .
• the stereoisomer of compound (28) can also be isolated by deprotecting compound (28), isolating the stereoisomer, and then protecting it again with a protecting group. Examples of protecting groups for reprotection include tetrahydro-2H-pyran-2-yl group.
• This step is a method for producing compound (29) by oxidation reaction of compound (28).
• the reaction conditions are the same as in the fifth step of raw material production method 3.
• 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.
• This step is a method for producing compound (30) by ipsosubstitution reaction of compound (29) and compound (8).
• the reaction conditions are the same as in the first step of raw material production method 2.
• This step is a method for producing compound (31) by deprotecting compound (30) by catalytic hydrogenation reaction.
• the reaction conditions are the same as those in the sixth step of raw material production method 2.
• Compound (31) may have axial asymmetry and may be obtained as a mixture of stereoisomers, but compound (31) may be obtained by ordinary resolution procedures such as ODS column chromatography or silica gel column chromatography. Each stereoisomer can be isolated by performing resolution using .
• This step is a method for producing compound (32) through an alkylation reaction of compound (31) and compound (15).
• the reaction conditions are the same as those in the seventh step of raw material production method 2.
• compound (32) may have axial asymmetry and may be obtained as a mixture of stereoisomers, but compound (32) may be obtained by ordinary resolution procedures such as ODS column chromatography or silica gel column chromatography.
• Each stereoisomer can be isolated by performing resolution using .
• the stereoisomer of compound (32) can also be isolated by deprotecting compound (32), isolating the stereoisomer, and then protecting it again with a protecting group.
• This step is a method for producing compound (33) by subjecting compound (32) to a deprotection reaction.
• the reaction conditions are the same as the steps described in the first production method.
• deprotecting compound (33) it can be protected again with a protecting group.
• protecting groups for reprotection include tetrahydro-2H-pyran-2-yl group.
• the series of operations of deprotection and reprotection with a protecting group as described above may be performed as a one-step reaction.
• This step is a method for producing compound (2)-2 by reacting compound (33) and compound (6)-1.
• This reaction uses the same equivalent amount of compound (33) and compound (6)-1 or an excess equivalent amount of one of them, and the mixture is heated in the presence of a condensing agent in a solvent inert to the reaction, from cooling to heating.
• the mixture is stirred, 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 benzene and toluene, ethers such as THF and DOX, halogenated hydrocarbons such as chloroform and dichloromethane, alcohols such as methanol and ethanol, and DMF.
• condensing agents include PyBOP, HATU, CDI, 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.
• organic base such as TEA, DIPEA, or NMM
• inorganic base such as potassium carbonate, sodium carbonate, or cesium carbonate
• This production method is a method for producing compound (13)-1, which is included in compound (13), which is an intermediate in raw material production method 2.
• This step is a method for producing compound (34) by subjecting compound (30) to a deprotection reaction.
• the reaction conditions are the same as the steps described in the first production method.
• deprotecting compound (34) it can be protected again with a protecting group.
• protecting groups for reprotection include tetrahydro-2H-pyran-2-yl group and the like.
• the series of operations of deprotection and reprotection with a protecting group as described above may be performed as a one-step reaction.
• This step is a method for producing compound (13)-1 by reacting compound (34) and compound (6)-1.
• the reaction conditions are the same as in the twelfth step of raw material production method 5.
• This production method is a method for producing compound (30), which is a raw material in Raw Material Production Method 6.
• This step is a method for producing compound (37) by an ipsosubstitution reaction between compound (24) and compound (8).
• the reaction conditions are the same as in the first step of raw material production method 2.
• This step is a method for producing compound (38) by an ipsosubstitution reaction between compound (37) and PG 3 -OH.
• the reaction conditions are the same as in the first step of raw material production method 2.
• This step is a method for producing compound (39) by a Suzuki-Miyaura coupling reaction between compound (38) and a boronic acid derivative comprising an R Q -boronic acid group or the like.
• the reaction conditions are the same as those in the fourth step of raw material production method 2.
• Compound (39) (where R Q is hydrogen) can be produced by dehalogenating compound (38) using a Pd catalyst and a reducing agent. [Literature] J. Org. Chem., 1977, 42, p.3491-3494 Tetrahedron Letters 2013, 54, 5207-5210
• This step is a method for producing compound (30) by a Suzuki-Miyaura coupling reaction between compound (39) and compound (15).
• the reaction conditions are the same as in the fourth step of raw material production method 2.
• compound (30) may have axial asymmetry and may be obtained as a mixture of stereoisomers, but compound (30) may be obtained by ordinary resolution procedures such as ODS column chromatography or silica gel column chromatography.
• Each stereoisomer can be isolated by performing resolution using .
• the stereoisomer of compound (30) can also be isolated by deprotecting compound (30), isolating the stereoisomer, and then protecting it again with a protecting group.
• This production method is a method for producing compound (17)-2, which is included in compound (17), which is an intermediate in raw material production method 3.
• This step is a method for producing compound (5)-2 by chlorination reaction of compound (40).
• the compound (40) and the chlorinating agent are used in the same equivalent amount or one is used in an excess equivalent amount, and the mixture is heated under cooling to reflux, preferably in a solvent inert to the reaction or without a solvent. This is carried out by heating and stirring at 60° C. under reflux, usually for 0.1 hour to 5 days.
• the solvent used here include, but are not particularly limited to, aromatic hydrocarbons such as toluene, ethers such as THF and DOX, halogenated hydrocarbons such as dichloromethane, DMF, DMAc, and the like.
• chlorinating agents examples include phosphorus oxychloride, thionyl chloride, 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 in order for the reaction to proceed smoothly.
• organic base such as TEA, DIPEA or NMM
• This step is a method for producing compound (41) by an ipsosubstitution reaction between compound (5)-2 and R LG -SH.
• the reaction conditions are the same as in the first step of raw material production method 2.
• This step is a method for producing compound (42) by an ipsosubstitution reaction between compound (41) and PG 3 -OH.
• the reaction conditions are the same as in the first step of raw material production method 2.
• This step is a method for producing compound (17)-2 through an ipsosubstitution reaction between compound (42) and compound (6)-1.
• the reaction conditions are the same as in the first step of raw material production method 2.
• This production method is a method for producing compound (10)-2.
• This step is a method for producing compound (43) by an ipsosubstitution reaction between compound (5)-2 and compound (8).
• the reaction conditions are the same as in the first step of raw material production method 2.
• compound (43) can be produced by Negishi coupling of a compound obtained by converting the hydrogen atom of compound (8) into a halogen and compound (5)-2.
• This step is a method for producing compound (44) by an ipsosubstitution reaction between compound (43) and PG 3 -OH.
• the reaction conditions are the same as in the first step of raw material production method 2.
• This step is a method for producing compound (10)-2 by an ipsosubstitution reaction between compound (44) and compound (6)-1.
• the reaction conditions are the same as in the first step of raw material production method 2.
• This production method is a method for producing compound (4)-1 included in compound (4), which is an intermediate of raw material production method 1.
• L 2B represents piperazinediyl, bridged piperazinediyl, or 2,6-diazaspiro[3.4]octanediyl which may be substituted with C 1-3 alkyl
• PG E3 and PG L2 are protecting groups for NH.
• LG Z is a leaving group
• BLG is 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, etc.)
• Compound (4)-1 can also be produced by the same reaction for a compound in which the PG E3 moiety of compound (45) is H.
• leaving groups shown here Examples include Cl, Br, methanesulfonyloxy group, p-toluenesulfonyloxy group, etc. (the same applies hereinafter)
• This step is a step in which compound (47) is obtained by subjecting compound (45) and compound (46) to Suzuki-Miyaura coupling reaction conditions.
• the reaction conditions are the same as in the fourth step of raw material production method 2.
• This step is a step in which a 1,2-diol compound is obtained by subjecting the compound (47) to oxidation reaction conditions.
• the compound (47), an oxidizing agent, and an excess equivalent of a reoxidizing agent are used, and the mixture is stirred in a solvent inert to the reaction at room temperature from ice-cooling, usually for 1 hour to 2 days. It will be done.
• the oxidizing agent used here include, but are not particularly limited to, osmium (VIII) tetroxide, PI osmium (VIII) oxide, osmium (VIII) oxide in PEM polymer microcapsules, and the like.
• the reoxidizing agent used here includes, but is not particularly limited to, NMO, trimethylamine oxide, tBuOOH, K 3 Fe(CN) 6 and the like.
• Solvents used here include, but are not particularly limited to, ether solvents such as tetrahydrofuran, diethyl ether, and 1,4-dioxane, halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform, tBuOH, acetone, acetonitrile, toluene, and water. and mixtures thereof are used.
• Step-1B This step is a step of obtaining compound (48) by subjecting the compound obtained in the above (second step-1A) to oxidative cleavage reaction conditions.
• the same equivalent or excess equivalent of the oxidizing agent as the compound obtained in (Second Step-1A) is used in a solvent inert to the reaction, under ice cooling to room temperature, usually for 1 hour to 2 days. This is done by stirring.
• the oxidizing agent used here include, but are not particularly limited to, sodium periodate, periodic acid, and the like.
• solvents used here include, but are not limited to, ether solvents such as tetrahydrofuran, diethyl ether, and 1,4-dioxane, acetonitrile, water, halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform, and mixtures thereof. is used. Further, the above (second step-1A) and (second step-1B) can also be carried out as a one-step reaction. [Literature] J. Org. Chem. 1956, 21, 4, 478-479
• This step is a step of obtaining compound (48) by subjecting compound (47) to oxidation reaction conditions.
• This step is a method for obtaining compound (48), which is different from the second step-1A and the second step-1B.
• the compound (47) is stirred in an ozone atmosphere in a solvent inert to the reaction at room temperature from ice cooling, usually for 1 hour to 1 day, and then treated with a reducing agent.
• the reducing agent used here include, but are not limited to, dimethyl sulfide, triphenylphosphine, metallic zinc, and the like.
• the solvent used here is not particularly limited, but includes alcoholic solvents such as methanol and ethanol, halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform, ethyl acetate, and mixtures thereof.
• This step is a step in which compound (4)-1' is obtained by subjecting compound (48) and compound (49) to reductive amination reaction conditions.
• Compound (48) and Compound (49) are used in the same equivalent amount or an excess equivalent amount of one of them, and the reaction is usually carried out 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 done by stirring for an hour to 5 days.
• a reducing agent and acetic acid in a solvent inert to the reaction, from ice-cooling to room temperature. This is done by stirring for an hour to 5 days.
• 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 includes halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform, ether solvents such as tetrahydrofuran, diethyl ether, and 1,4-dioxane, alcohol solvents such as methanol and ethanol, or acetonitrile. etc. are used.
• halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform
• ether solvents such as tetrahydrofuran, diethyl ether, and 1,4-dioxane
• alcohol solvents such as methanol and ethanol, or acetonitrile. etc.
• This step is a step in which compound (4)-1 is obtained by subjecting (4)-1' to deprotection conditions.
• the reaction conditions are the same as in the first production method.
• This step is a step in which compound (45)-1' is obtained by subjecting compound (50) and compound (51) to alkylation reaction conditions.
• compound (50) and compound (51) are used in the same equivalent amount or an excess equivalent amount of one of them, and the reaction is carried out in the presence of a base in a solvent inert to the reaction, under ice cooling or under heating to reflux, usually for 1 hour. This is done by stirring for 1 day.
• a base include, but are not particularly limited to, sodium hydride, tBuOK, LHMDS, NHMDS, potassium carbonate, cesium carbonate, and the like.
• the solvent used here is not particularly limited, but ether solvents such as tetrahydrofuran, diethyl ether, and 1,4-dioxane, DMF, MeCN, and the like are used.
• compound (45)-1' can be obtained by subjecting the obtained compound to deprotection reaction conditions following the reaction.
• the reaction conditions are the same as in the first production method.
• This step is a step in which compound (45)-1 is obtained by subjecting (45)-1' to deprotection conditions.
• the reaction conditions are the same as in the first production method.
• This step is a step in which compound (45)-2' is obtained by subjecting compound (52) and compound (53) to coupling reaction conditions using a copper catalyst.
• compound (52) and compound (53) are used in the same equivalent amount or one is used in an excess equivalent amount, and a copper catalyst, a ligand, and a base are used. This is done by stirring for 1 hour to 5 days.
• the copper catalyst used here include, but are not particularly limited to, copper (I) iodide, copper (I) chloride, copper (I) oxide, and the like.
• the ligand used here include, but are not particularly limited to, DMEDA, trans-N,N'-dimethylcyclohexane-1,2'diamine, and the like.
• Examples of the base used here include, but are not particularly limited to, organic bases such as diisopropylethylamine and triethylamine, and inorganic bases such as potassium carbonate, cesium carbonate, sodium carbonate, and tripotassium phosphate.
• examples of solvents used here include, but are not limited to, ether solvents such as tetrahydrofuran and 1,4-dioxane, alcohol solvents such as methanol and ethanol, dimethyl sulfoxide, N,N-dimethylformamide, water, etc. can be mentioned. Further, heating the mixture by microwave irradiation may be advantageous in making the reaction proceed smoothly.
• This step is a step in which compound (45)-2 is obtained by subjecting (45)-2' to deprotection conditions.
• the reaction conditions are the same as in the first production method.
• This production method is a method for producing compound (4)-2 contained in compound (4), which is an intermediate of raw material production method 1.
• a compound in which the PG E3 moiety of compound (51) is H can also be produced by a similar reaction to a compound in which the PG E3 moiety of compound (4)-2' is H. The same applies hereinafter)
• This step is a step in which compound (55) is obtained by subjecting compound (54) and compound (50) to Suzuki-Miyaura coupling reaction conditions.
• the reaction conditions are the same as in the fourth step of raw material production method 2.
• This step is a step in which compound (4)-2' is obtained by subjecting compound (55) and compound (51) to alkylation reaction conditions.
• the reaction conditions are the same as in the first step of raw material production method 11.
• This step is a step in which compound (4)-2 is obtained by subjecting (4)-2' to deprotection conditions.
• the reaction conditions are the same as in the first production method.
• This production method is a method for producing compound (4)-3 included in compound (4), which is an intermediate of raw material production method 1.
• LG Z represents a leaving group. Examples of the leaving group shown here include Cl, Br, methanesulfonyloxy group, p-toluenesulfonyloxy group, etc. The same applies hereinafter)
• This step is a step in which compound (57) is obtained by subjecting compound (54) and compound (56) to Suzuki-Miyaura coupling reaction conditions.
• the reaction conditions are the same as in the fourth step of raw material production method 2.
• This step is a step in which compound (4)-3' is obtained by subjecting compound (57) and compound (53) to coupling reaction conditions using a copper catalyst.
• the reaction conditions are the same as in the first step of raw material production method 12.
• This step is a step in which compound (4)-3 is obtained by subjecting (4)-3' to deprotection conditions.
• the reaction conditions are the same as in the first production method.
• This production method is a method for producing compound (4)-1 included in compound (4), which is an intermediate of raw material production method 1.
• compound (4)-1 can also be produced by the same reaction for a compound in which the PG E3 moiety of compound (45) is H. The same applies hereinafter)
• This step is a step in which compound (4)-1' is obtained by subjecting compound (54) and compound (45) to Suzuki-Miyaura coupling reaction conditions.
• the reaction conditions are the same as in the fourth step of raw material production method 2.
• This step is a step in which compound (4)-1 is obtained by subjecting (4)-1' to deprotection conditions.
• the reaction conditions are the same as in the first production method.
• This production method is a method for producing compound (4)-5 contained in compound (4), which is an intermediate of raw material production method 1.
• LG Z3 represents a leaving group. Examples of the leaving group shown here include Cl, Br, methanesulfonyloxy group, p-toluenesulfonyloxy group, etc. The same applies hereinafter)
• This step is a step in which compound (60) is obtained by subjecting compound (58) and compound (59) to cyclization reaction conditions.
• Compound (58) and Compound (59) are used in the same equivalent amount or in an excess equivalent amount of one of them, in the presence of a base, in a solvent inert to the reaction, under ice cooling to heating under reflux, usually for 1 hour to 5 days. This is done by stirring.
• the base used here include, but are not particularly limited to, organic bases such as triethylamine and N,N'-diisopropylethylamine, and inorganic bases such as potassium carbonate and cesium carbonate.
• the solvent used here include, but are not particularly limited to, ether solvents such as tetrahydrofuran and 1,4-dioxane, N,N-dimethylformamide, and the like.
• This step is a step in which compound (61) is obtained by subjecting compound (60) and compound (54) to Suzuki-Miyaura coupling reaction conditions.
• the reaction conditions are the same as in the fourth step of raw material production method 2.
• This step is a step in which compound (4)-5' is obtained by subjecting compound (61) to cyclization reaction conditions.
• the reaction conditions are the same as in the third step of Raw Material Production Method 17.
• This step is a step in which compound (4)-5 is obtained by subjecting compound (4)-5' to deprotection conditions.
• the reaction conditions are the same as in the first production method.
• This production method is a method for producing compound (4)-6.
• Linker is -(-L 2 -L 3 -L 4 )-, and L 2 is piperidinediyl optionally substituted with C 1-3 alkyl, piperazinediyl optionally substituted with C 1-3 alkyl, pyrrolidinediyl optionally substituted with C 1-3 alkyl, 3,8-diazabicyclo[3.2.1]octanediyl or 2,6-diazaspiro[3.4]octanediyl, and L 3 is a bond, -N(R L3 )-, C 1-3 alkylene or piperazine diyl, and L 4 is a bond, -N(R L4 )-, -O-, piperazine diyl or C 1-3
• This step is a step in which compound (64) is obtained by subjecting compound (62) and compound (63) to Michael addition reaction conditions. This reaction is carried out by using equivalent amounts of compound (62) and compound (63) or an excess equivalent amount of one of them, and stirring in the presence of a base and an excess amount of an acid reagent under heating to reflux from room temperature for usually 1 to 5 days. be exposed.
• a base include, but are not particularly limited to, organic bases such as 1,8-diazabicyclo[5.4.0]undec-7ene and N,N'-diisopropylethylamine.
• the acidic reagent used here include, but are not limited to, lactic acid, trifluoroacetic acid, acetic acid, and the like.
• This step is a step in which compound (65) is obtained by subjecting compound (64) to ureation reaction conditions.
• This reaction is carried out by stirring in the presence of compound (64), a ureation reagent, an acid, in a solvent inert to the reaction or in the absence of a solvent, under heating to reflux from room temperature, usually for 1 to 5 days.
• a ureation reagent used here include, but are not particularly limited to, sodium cyanate, potassium cyanate, and the like.
• acids used here include, but are not limited to, acetic acid, hydrochloric acid, trifluoroacetic acid, and the like.
• solvents used here include, but are not particularly limited to, halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform, ether solvents such as tetrahydrofuran and 1,4-dioxane, acetic acid, toluene, water, and mixtures thereof. is used.
• This step is a step in which compound (4)-6' is obtained by subjecting compound (65) to cyclization reaction conditions. This reaction is carried out by stirring compound (65) in the presence of a base in a solvent inert to the reaction under ice-cooling to heating under reflux, usually for 1 hour to 5 days.
• a base include, but are not particularly limited to, Triton B, potassium trimethylsilanolate, sodium ethoxide, and the like.
• the solvent used here include, but are not particularly limited to, ether solvents such as tetrahydrofuran and 1,4-dioxane, N,N-dimethylformamide, and acetonitrile.
• This step is a step in which compound (4)-6 is obtained by subjecting compound (4)-6' to deprotection conditions.
• the reaction conditions are the same as in the first production method.
• This production method is a method for producing compound (67).
• compound (67) in place of compound (4) described in raw material production method 1, some compounds contained in the compound of formula (1) can be synthesized.
• L 1 is optionally substituted with C 1-3 alkyl, piperidinediyl, optionally substituted with C 1-3 alkyl, or C 1-3 alkyl
• pyrrolidinediyl 3,8-diazabicyclo[3.2.1]octanediyl or 2,6-diazaspiro[3.4]octanediyl
• L 2 is a bond, -N(R L3 )-, C 1-3 alkylene or piperazine diyl
• L 3 is a bond, -N(R L4 )-, -O-, piperazine diyl or C 1-3 alkylene
• R L3 is H or C 1-3 alkyl
• R L4 is , H or C 1-3 alkyl
• This step is a step of obtaining compound (67') by subjecting compound (66) and compound (65) to ipso reaction conditions.
• the reaction conditions are the same as in the first step of raw material production method 2.
• Compound (67') can also be produced by subjecting it to coupling reaction conditions using a copper catalyst.
• the reaction conditions are the same as in the first step of raw material production method 12.
• Compound (67') can also be produced by subjecting it to carbon-nitrogen bond forming reaction conditions.
• compound (66) and compound (65) are used in the same equivalent amount or an excess equivalent amount of one of them, a metal catalyst, a ligand, and a base are added to the mixture, and the mixture is heated to 80°C in a solvent inert to the reaction.
• metal reagent catalyst used here include, but are not limited to, palladium(II) acetate, tris(dibenzylideneacetone)dipalladium, [1,1'bis(diphenylphosphino)ferrocene]palladium(II).
• metal reagent catalyst used here include, but are not limited to, palladium(II) acetate, tris(dibenzylideneacetone)dipalladium, [1,1'bis(diphenylphosphino)ferrocene]palladium(II).
• Examples include dichloride, [1,1'bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct, and the like.
• the ligand include, but are not limited to, Xantphos, Ruphos, Xphos, BINAP, and the like.
• Examples of the base include, but are not particularly limited to, inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, and sodium tert-butoxide, and organic bases such as triethylamine and N,N-diisopropylethylamine.
• examples of the solvent include, but are not limited to, 1,4-dioxane, toluene, N,N-dimethylformamide, and mixtures thereof.
• this reaction may be performed under microwave irradiation.
• Compound (67') can also be produced by subjecting it to alkylation reaction conditions. The reaction conditions are the same as in the first step of raw material production method 2.
• This step is a step in which compound (67) is obtained by subjecting compound (67') to deprotection conditions.
• the reaction conditions are the same as in the first production method.
• This production method is a method for producing compound (1)-2 contained in compound (1), which is a raw material of the first production method.
• L 1A and L 4A are optionally substituted heterocycloalkylene, optionally substituted heteroarylene, saturated 7- to 9-membered spiroheterocycloalkylene containing 1-2 nitrogen atoms
• L 3A is C 1 Piperidinediyl optionally substituted with -3 alkyl, piperadinediyl optionally substituted with C 1-3 alkyl, pyrrolidinediyl optionally substituted with C 1-3 alkyl, bridged piperadinediyl or 2,6 -Indicates diazaspiro[3.4]octanediyl (hereinafter the same)
• This step is a method for producing compound (69) through an alkylation reaction of compound (14) and compound (68).
• the reaction conditions are the same as in the seventh step of raw material production method 2.
• This step is a step in which compound (70) is obtained by subjecting compound (69) to hydrolysis conditions.
• the reaction conditions are the same as in the first step of raw material production method 1.
• This step is a step in which compound (1)-2 is obtained by subjecting compound (70) and compound (71) to condensation reaction conditions.
• the reaction conditions are the same as in the second step of raw material production method 1.
• This step is a step in which compound (73) is obtained by subjecting compound (72) and compound (51) to nucleophilic substitution reaction conditions.
• the reaction conditions are the same as in the first step of raw material production method 11.
• This step is a step in which compound (74) is obtained by subjecting compound (73) to deprotection conditions.
• the reaction conditions are the same as in the first production method.
• This production method is a method for producing compound (2)-3 included in (2), which is the raw material of production method 1.
• This step is a method for producing compound (77) by reacting compound (75) and compound (76).
• compound (75) is converted to the corresponding enolate under acidic conditions using an orthoester such as trimethyl orthoformate, and then an equivalent amount of compound (76) or an excess amount of one of the two is added, and the mixture is left unused in the reaction.
• This is carried out by stirring in an active solvent under heating under reflux, preferably at 60° C. and under heating under reflux, usually for 0.1 hour to 5 days.
• the solvent used here include, but are not particularly limited to, aromatic hydrocarbons such as toluene, ethers such as THF and DOX, DMF, DMAc, and the like.
• This step is a method for producing compound (78) from compound (77).
• This reaction is carried out by stirring compound (77) in a solvent inert to the reaction under heating under reflux, preferably under heating under reflux from 150°C for usually 0.1 hour to 5 days.
• solvent used here include, but are not particularly limited to, NMP and the like.
• This step is a method for producing compound (79) from compound (78).
• the compound (78) and the brominating agent are used in equal amounts or an excess amount of one of them is used, and the mixture thereof is heated under cooling to reflux, preferably in a solvent inert to the reaction or without a solvent. This is carried out by stirring at room temperature, usually for 0.1 hour to 5 days.
• the solvent used here include, but are not particularly limited to, aromatic hydrocarbons such as toluene, ethers such as THF and DOX, halogenated hydrocarbons such as dichloromethane, DMF, and the like.
• brominating agents include N-bromosuccinimide, N-bromosaccharin, 1,3-dibromo-5,5-dimethylhydantoin, dibromoisocyanuric acid, and the like.
• This step is a method for producing compound (80) from compound (79).
• the reaction conditions are the same as in the first step of raw material production method 8.
• This step is a method for producing compound (81) by an ipsosubstitution reaction between compound (80) and compound (6)-1.
• the reaction conditions are the same as in the first step of raw material production method 2.
• This step is a method for producing compound (82) by an ipsosubstitution reaction between compound (81) and compound (8)-1.
• the reaction conditions are the same as in the first step of raw material production method 2.
• This step is a method for producing compound (82) by an ipsosubstitution reaction between compound (82) and PG 3 -OH.
• PG 3 -OH used here include benzyl alcohol, p-methoxybenzyl alcohol and 1-phenylethanol.
• the reaction conditions are the same as in the first step of raw material production method 2.
• This step is a method for producing compound (84) by a Suzuki-Miyaura coupling reaction between compound (83) and compound (12), which is a boronic acid derivative.
• the reaction conditions are the same as in the fourth step of raw material production method 2.
• compound (84) 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 separation using ODS column chromatography or silica gel column chromatography. Isomers can be isolated.
• PG 1 may be converted to another protecting group so that it can be deprotected under conditions different from the protecting group PG 2 introduced later.
• the reaction conditions for the deprotection reaction used here are the same as the steps described in Production Method 1.
• Examples of protecting groups for PG 1 that are subsequently converted include tetrahydro-2H-pyran-2-yl groups and the like.
• 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.
• This step is a method for producing compound (85) by deprotecting compound (84) by catalytic hydrogenation reaction.
• the reaction conditions are the same as those in the sixth step of raw material production method 2.
• This step is a method for producing compound (2)-3 by reacting compound (85) and compound (15).
• the reaction conditions are the same as those in the seventh step of raw material production method 2.
• This production method is a method for producing compound (4)-7 included in compound (4), which is an intermediate of raw material production method 1.
• This step is a method for producing compound (87) from compound (86).
• the reaction conditions are the same as in the first step of raw material production method 17.
• This step is a method for producing compound (88) from compound (87).
• This reaction is carried out in the presence of compound (87), triphosgene, and a base in a solvent inert to the reaction at room temperature by adding an ammonia reagent and stirring for usually 1 to 5 days.
• An example of the ammonia reagent used here is, but is not particularly limited to, an ammonia methanol solution or the like.
• Examples of the base used here include, but are not particularly limited to, organic bases such as pyridine, triethylamine, and N,N-diisopropylethylamine.
• the solvent used here include, but are not particularly limited to, halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform.
• This step is a method for producing compound (89) from compound (88).
• the reaction conditions are the same as in the third step of Raw Material Production Method 17.
• This step is a step in which compound (90) is obtained by subjecting compound (89) and compound (54) to Suzuki-Miyaura coupling reaction conditions.
• the reaction conditions are the same as in the fourth step of raw material production method 2.
• This step is a step in which compound (4)-7 is obtained by subjecting compound (90) to deprotection conditions.
• the reaction conditions are the same as in the first production method.
• This production method is a method for producing compound (45)-3 included in compound (45), which is the raw material of Raw Material Production Method 10.
• This step is a step in which compound (45)-3 is obtained by subjecting compound (92) and compound (53) to coupling reaction conditions using a copper catalyst.
• the reaction conditions are the same as in the first step of raw material production method 12.
• the compounds of formula (I), formula (XXI), formula (XXII) or formula (XXIII) may be present as free compounds, salts, hydrates, solvates or crystalline polymorphs thereof, or in amorphous solid form. It is isolated and purified as a substance.
• a salt of a compound of formula (I), formula (XXI), formula (XXII) or formula (XXIII) can also be produced by subjecting it to a conventional salt-forming reaction. Isolation and purification are performed by applying conventional chemical operations such as extraction, fractional crystallization, and various fractional chromatography.
• Various isomers can be produced by selecting appropriate starting compounds, or can be separated by utilizing differences in physicochemical properties between isomers.
• optical isomers can be obtained by general optical resolution methods for racemates (e.g., fractional crystallization leading to diastereomeric salts with optically active bases or acids, chromatography using chiral columns, etc.). , and can also be produced from suitable optically active raw material compounds.
• compounds of formula (I), formula (XXI), formula (XXII), or formula (XXIII) or their intermediates may have axial asymmetry and can be obtained as a mixture of stereoisomers, but they can be obtained by normal resolution.
• Each stereoisomer can be isolated by a separation operation using, for example, octadecylsilyl (ODS) column chromatography or silica gel column chromatography.
• Test Example 1 Evaluation of KRAS degrading effect on human G12D mutant KRAS-positive pancreatic cancer line AsPC-1 (CRL-1682; ATCC) The KRAS degrading effect of the test compound was evaluated by measuring the KRAS G12D expression level by Cell ELISA. 20 ⁇ L of AsPC-1 cells were seeded in a 384-well plate (Greiner bio-one) at 2.0 ⁇ 10 4 cells per well. Cell culture was carried out at 37° C. in the presence of 5% CO 2 using RPMI1640 (Sigma-Aldrich) medium containing 10% fetal bovine serum (Cytiva).
• test compound (10 points ranging from final concentration 10 ⁇ M to 0.3 nM) and DMSO (Fujifilm Wako Pure Chemical Industries, Ltd.), the solvent for the test compound as a negative control, were diluted 500 times with fresh medium, and 20 ⁇ L of each was diluted 500 times with fresh medium. After addition to the wells, the cells were cultured overnight. The next day, the culture supernatant was removed, 20 ⁇ L of 4% paraformaldehyde phosphate buffer (Fujifilm Wako Pure Chemical Industries, Ltd.) was added to each well, and the cells were fixed by standing at room temperature for 30 minutes.
• DMSO Flujifilm Wako Pure Chemical Industries, Ltd.
• Donkey anti-Mouse IgG H&L (IRDye 680RD) (Li-COR Biosciences) and Goat anti-Rabbit IgG H&L (IRDye 800CW) (Li-COR Biosciences) 1,000x. 15 ⁇ L of the diluted solution was added to each well. A solution obtained by diluting Donkey anti-Mouse IgG H&L (IRDye 680RD) (Li-COR Biosciences) 1,000 times with a blocking solution as a secondary antibody was added to the positive control wells.
• the 50% decomposition value (DC 50 ) of the amount of KRAS is calculated as Sigmoid- Calculated using Emax model nonlinear regression analysis.
• the results for several test compounds of formula (I) are shown in the table below. For compounds whose calculated 50% decomposition value exceeds the concentration within the evaluation range, the decomposition rate at the highest evaluation concentration (10 ⁇ M) is shown.
• Ex represents an example number. Further, the DC 50 of Ex 13, 15, and 16 was calculated using the molecular weight as the tetrahydrochloride, and the DC 50 of Ex 14 was calculated using the molecular weight as the trihydrochloride.
• Test Example 2 Evaluation of ERK phosphorylation inhibitory effect on human G12D mutant KRAS-positive pancreatic cancer line AsPC-1.
• the ERK phosphorylation inhibitory effect of the test compound was evaluated by measuring by ELISA.
• AsPC-1 cells were seeded at 20 ⁇ L/well in a 384-well plate at 2.0 ⁇ 10 4 cells per well.
• Cell culture conditions were RPMI1640 medium containing 10% fetal bovine serum at 37°C in the presence of 5% CO2 .
• test compound (10 points ranging from final concentration 10 ⁇ M to 0.3 nM), trametinib (MEK inhibitor) at a final concentration of 1 ⁇ M as a positive control, and DMSO, the solvent for the test compound as a negative control, were mixed at 500x with fresh medium. After diluting and adding 20 ⁇ L to each well, the mixture was cultured overnight. Immediately after culturing, 30 ⁇ L of 30% glyoxal solution (40% glyoxal [Nacalai Tesque] diluted with PBS) was added to each well, and the cells were fixed by standing at room temperature for 120 minutes. Thereafter, the supernatant was removed by centrifuging the plate (a centrifugal dehydrator was used.
• 30% glyoxal solution 40% glyoxal [Nacalai Tesque] diluted with PBS
• the supernatant was removed in the same manner below), and 20 ⁇ L of PBS containing 0.1% Triton X-100 was added to each well. After standing at room temperature for 10 minutes, the supernatant was removed and the same operation was repeated. Next, 20 ⁇ L of PBS containing 0.5% SDS was added to each well, and after standing at room temperature for 30 minutes, the supernatant was removed. Subsequently, 20 ⁇ L of blocking solution (Intercept Blocking Buffer) was added to each well and left at room temperature for 1 hour.
• PBS containing 0.1% Triton X-100 was added to each well. After standing at room temperature for 10 minutes, the supernatant was removed and the same operation was repeated. Next, 20 ⁇ L of PBS containing 0.5% SDS was added to each well, and after standing at room temperature for 30 minutes, the supernatant was removed. Subsequently, 20 ⁇ L of blocking solution (Intercept Blocking Buffer) was added to each well and left at room temperature for 1 hour.
• the signal value when DMSO was added was set as 100%, and the signal value when 1 ⁇ M trametinib was added was set as 0%, 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 compounds whose calculated 50% inhibition rate exceeds the concentration within the evaluation range, the inhibition rate at the highest evaluation concentration (10 ⁇ M) is shown.
• Ex represents an example number. Further, the IC 50 of Ex 13, 15, and 16 was calculated using the molecular weight as the tetrahydrochloride, and the IC 50 of Ex 14 was calculated using the molecular weight as the trihydrochloride.
• Test Example 3 Evaluation of anchorage-independent cell growth inhibitory effect on human G12D mutant KRAS-positive pancreatic cancer line AsPC-1
• the anchorage-independent cell growth inhibitory effect of the test compound was evaluated by three-dimensional spheroid culture. AsPC-1 cells were seeded at 20 ⁇ L (or 36 ⁇ L)/well at 5 ⁇ 10 2 cells per well in a low cell adsorption U-bottom 384-well plate (PrimeSurface: Sumitomo Bakelite). Cell culture conditions were RPMI1640 medium containing 10% fetal bovine serum at 37°C in the presence of 5% CO2 .
• test compound (10 points or 6 points with a final concentration ranging from 10 ⁇ M to 0.3 nM) and DMSO, the solvent for the test compound as a negative control, were diluted 500 times (or 100 times) with fresh medium, and 20 ⁇ L (or 4 ⁇ L) was added to each well. After culturing at 37° C. in the presence of 5% CO 2 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 set as 100%, and the signal value in the medium alone in the absence of cells was set as 0%, 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 compounds whose calculated 50% inhibition rate exceeds the concentration within the evaluation range, the inhibition rate at the highest evaluation concentration (10 ⁇ M) is shown.
• Ex represents the example number. Further, the IC 50 of Ex 13, 15, and 16 was calculated using the molecular weight as the tetrahydrochloride, and the IC 50 of Ex 14 was calculated using the molecular weight as the trihydrochloride.
• PK-59 tumor-bearing mice PK-59 cells (RIKEN BioResearch Center, RCB1901) were cultured using RPMI1640 medium containing 10% fetal bovine serum. Cultured at 37°C in the presence of % CO2 . PK-59 cells were collected and suspended in PBS, and an equal volume of Matrigel (Becton Dickinson) was added to prepare a cell suspension of 1.0 to 2.0 x 10 cells/mL to 4 to 5 week old male nudes.
• Matrigel Becton Dickinson
• the compounds were ethanol (Fujifilm Wako Pure Chemical Industries), 5% glucose solution (Otsuka Pharmaceutical), 1M hydrochloric acid (Kanto Chemical), 50% (2-hydroxypropyl)- ⁇ -cyclodextrin (HP- ⁇ CD) aqueous solution (ROQUETTE), HCO-40 (Nikko Chemicals) and 1M aqueous sodium hydroxide solution (Kanto Chemical) were dissolved in a solvent at a liquid volume ratio of 4:84.4:1.1:1:9:0.5.
• the test compound dissolved in each solvent or the vehicle was administered into the tail vein. Administration was performed twice, once a week. Tumor diameter and body weight measurements were performed twice a week. The following formula was used to calculate the tumor volume.
• [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 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 2 weeks after the first administration 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 results for several test compounds of formula (I) are shown in the table below.
• Test Example 5 Evaluation of inhibitory effect on KRAS G12D/SOS/c-Raf complex formation Using human recombinant KRAS G12D, SOS and c-Raf proteins, time-resolved fluorescence-fluorescence This was investigated using the resonance energy transfer (TR-FRET) method.
• Transfer assay buffer 50 mM HEPES [Jena], 150 mM NaCl [Nacalai Tesque], 5 mM MgCl 2 [Thermo Fisher Scientific], 0.05% Tween 20 [Sigma-Aldrich] to a 384-well plate (Corning)).
• Biotinylated AviTag-KRAS G12D (amino acid region 1-185, GDP) (2.5 ⁇ L; 400 nM) dissolved in 40,000 nM to 40 nM was added in a volume of 2.5 ⁇ L. This was supplemented with c-Raf (amino acid region 51-131) GST (2.5 ⁇ L; 130 nM) containing Son of Sevenless (SOS) (amino acid region 564-1049, 2.5 ⁇ L; 1.3 ⁇ M) and GTP (Sigma-Aldrich; 2 ⁇ M). ) was added and allowed to stand at room temperature for 1 hour.
• compositions containing one or more compounds of formula (I), formula (XXI), formula (XXII) or formula (XXIII) or salts thereof as active ingredients are commonly used in the art. It can be prepared by a commonly used method using excipients, ie, pharmaceutical excipients, pharmaceutical carriers, and the like. Administration can be by oral administration using tablets, pills, capsules, granules, powders, liquids, etc., or parenterally via intraarticular, intravenous, intramuscular injections, transmucosal agents, inhalants, etc. It may be a form.
• compositions for oral administration are used as solid compositions for oral administration.
• one or more active ingredients are mixed with at least one inert excipient.
• the compositions may contain inert additives such as lubricants, disintegrants, stabilizers and solubilizing agents in a conventional manner. 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 ethanol.
• 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 appropriate 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. Administer in separate doses or in 2 to 4 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. In addition, as a transmucosal agent, administer approximately 0.001 to 100 mg/kg per body weight in once to multiple divided doses per day. The dosage is appropriately determined on a case-by-case basis, taking into consideration symptoms, age, gender, etc.
• 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), formula (XXI), formula (XXII) or formula (XXIII) is a compound of formula (I), formula (XXI), formula (XXII) or formula (XXIII), It can be used in combination with various therapeutic or prophylactic agents for diseases thought to be associated with the disease.
• the combination may be administered simultaneously or separately, sequentially, or at desired time intervals.
• Co-administration formulations may be combined or separately formulated.
• 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.
• Amorphous solid forms as described herein include both forms that exhibit no peaks in the powder X-ray diffraction (XRD) pattern and forms that have low crystallinity.
• XRD powder X-ray diffraction
• XRD was performed using Empyrean, tube: Cu, tube current: 40 mA, tube voltage: 45 kV, step width: 0.013°, wavelength: 1.5418 ⁇ , measurement diffraction angle range (2 ⁇ ): 2.5 to 40°. Measure. Due to the nature of the data in powder X-ray diffraction patterns, the crystal lattice spacing and overall pattern are important in determining the identity of the crystal, and the error range of the diffraction angle (2 ⁇ (°)) in powder X-ray diffraction is important. is usually ⁇ 0.2°, but the diffraction angle and diffraction intensity may vary somewhat depending on the direction of crystal growth, particle size, and measurement conditions, so they should not be interpreted strictly.
• reaction solution After adding ice, saturated aqueous sodium thiosulfate solution, and saturated aqueous sodium bicarbonate solution and stirring at room temperature for about 20 minutes, the reaction solution was diluted with CH 2 Cl 2 and separated. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
• aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. Insoluble matter was filtered off and concentrated under reduced pressure.
• Production example 11 4-[( ⁇ (7M)-4-tert-butoxy-6-cyclopropyl-7-[6-fluoro-5-methyl-2-(triphenylmethyl)-2H-indazol-4-yl]-2- 3,4-dihydro-2H-pyran (2.7 mL) and 4-methylbenzene-1-sulfonic acid monohydrate (270 mg) were added thereto, and the mixture was stirred at 60°C for 2 hours.
• the mixture was stirred at room temperature for 2 hours under an argon atmosphere. Ice and saturated aqueous ammonium chloride solution were poured into the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate.
• Production example 17 A mixture of 7-bromo-2,4-dichloro-8-fluoro-6-iodoquinazoline (100 g), DOX (1000 mL), and THF (500 mL) was cooled on ice, then DIPEA (240 mL), (1S ,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl (48 g) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
• the obtained solid was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 7-bromo-4-chloro-2-(ethylsulfanyl)-8-fluoro-6-iodoquinoline (5.76 g) as a solid.
• Ta silica gel column chromatography
• Production example 24 A mixture prepared by adding tBuOK (1.59 g) to a solution of tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (2.7 g) in DMAc (20 mL) under an argon atmosphere and stirring at room temperature for 10 minutes. was added to a mixture of 7-bromo-4-chloro-2-(ethylsulfanyl)-6-iodo-8-[(1S)-1-phenylethoxy]quinoline (6.46 g) and DMAc (40 mL) under ice cooling. and stirred at the same temperature for 30 minutes.
• a saturated aqueous ammonium chloride solution, ice and ethyl acetate were added and stirred to separate the layers.
• the aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
• Production example 38 5-chloro-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100 mg), potassium ⁇ [4-(tert-butoxycarbonyl)piperazin-1-yl ]methyl ⁇ tri(fluoro)boranide (333 mg), palladium(II) acetate (12 mg), dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine (45 mg) ), cesium carbonate (532 mg), DOX (2 mL), and water (0.4 mL) were mixed under an argon atmosphere and reacted at 130°C for 1 hour under microwave irradiation.
• Production example 40 1-[(4-bromo-3-fluorophenyl)methyl]-3-[(4-methoxyphenyl)methyl]-1,3-diazinan-2,4-dione (100 mg), potassium ⁇ [(3S) -4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl]methyl ⁇ tri(fluoro)boranide (150 mg), cesium carbonate (240 mg), water (0.4 mL) and DOX (depleted by argon bubbling).
• reaction solution was concentrated, and the residue was purified by silica gel column chromatography (CHCl 3 /MeOH) to obtain (2S)-4- ⁇ [3-(2,4-dioxo-1,3-diazinan-1-yl)- Tert-butyl 1-methyl-1H-indazol-5-yl]methyl ⁇ -2-methylpiperazine-1-carboxylate (1.09 g) was obtained as a solid.
• Production example 48 1-[6-(hydroxymethyl)-2-methyl-2H-indazol-3-yl]-3-[(4-methoxyphenyl)methyl]-1,3-diazinan-2,4-dione (320 mg) 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3-(1H)-one (470 mg) was added to a solution of CH 2 Cl 2 (10 mL) at room temperature. The mixture was added and stirred for 1 hour. A 5% aqueous sodium thiosulfate solution and a saturated aqueous sodium bicarbonate solution were added to the reaction solution, stirred for a while, and then extracted with CHCl 3 .
• reaction solution was concentrated under reduced pressure, and the residue was purified by ODS column chromatography (0.1% formic acid in MeCN/0.1% formic acid in water).
• a saturated aqueous sodium bicarbonate solution was added to the fraction containing the target product, and the mixture was extracted four times with CHCl 3 /iPrOH (4/1).
• the combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated to give 1-(2-methyl-6- ⁇ [(3S)-3-methylpiperazin-1-yl]methyl ⁇ -2H-indazole-3 -yl)-1,3-diazinan-2,4-dione (50 mg) was obtained as a solid.
• reaction mixture was ice-cooled again, and separately, tBuOK (295 mg) was added to a mixture of (methoxymethyl)triphenylphosphonium chloride (900 mg) and THF (7 mL) under ice-cooling, and the mixture was stirred for 10 minutes.
• the suspension obtained in step 2 was added and then stirred at room temperature for 30 minutes.
• a saturated aqueous ammonium chloride solution and water were added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
• 6-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triphenylmethyl)-2H-indazole (1.6 g) was added, and the mixture was further stirred at 50°C for 15 minutes. The mixture was cooled to room temperature, ethyl acetate and water were added, insoluble matter was removed by filtration through Celite (registered trademark), and the two layers of the filtrate were separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate.
• Celite® was added and filtered, washing with ethyl acetate and CHCl3 .
• Toluene (approximately 20 mL) was added to the filtrate and concentrated under reduced pressure.
• MeOH 80 mL
• 10% Pd/C 52% water content, 1.4 g were added to the resulting solid, and the mixture was concentrated under a hydrogen atmosphere at normal pressure. and stirred at room temperature for 3 hours.
• Celite® was added and filtered, washing with ethyl acetate and CHCl3 .
• Production example 80 4-[( ⁇ (7M)-4-[(1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-cyclopropyl-7 -[6-fluoro-5-methyl-1-(oxan-2-yl)-1H-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-8-yl ⁇ oxy)methyl ]benzoic acid (70 mg), 5-[(3,8-diazabicyclo[3.2.1]octan-3-yl)methyl]-2-(2,6-dioxopiperidin-3-yl)-1H-iso DIPEA (60 ⁇ L) and HATU (45 mg) were added to a mixture of indole-1,3(2H)-dione n-hydrochloride (45 mg) and DMF (1 mL) under ice cooling, and the mixture was stirred at
• Production example 83 A mixture prepared by adding tBuOK (1.39 g) to a solution of (1S)-1-phenylethan-1-ol (1.56 mL) in dehydrated THF (40 mL) under an argon atmosphere and stirring at room temperature for 30 minutes was -Bromo-4-chloro-2-(ethylsulfanyl)-8-fluoro-6-iodoquinoline (5.5 g) and dehydrated THF (40 mL) was added dropwise over 20 minutes under ice-cooling, and at the same temperature. Stir for 10 minutes.
• a mixture prepared by adding tBuOK (415 mg) to a solution of (1S)-1-phenylethan-1-ol (0.45 mL) in dehydrated THF (10 mL) under an argon atmosphere and stirring for 10 minutes at room temperature was prepared separately. It was slowly added dropwise to the above reaction mixture under ice cooling, and the mixture was stirred at the same temperature for 10 minutes.
• a saturated aqueous ammonium chloride solution, ice and ethyl acetate were added to separate the layers. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate.
• Production example 227 A mixture of phenyl (2E)-2-benzylidenehydrazine-1-carboxylate (200 mg), 5-bromo-2-iodoaniline (373 mg), DABCO (281 mg) and benzotrifluoride (9 mL) was heated at 100°C. The mixture was stirred for 12 hours. After cooling, the reaction solution was concentrated under reduced pressure. DMSO (8 mL), copper(I) iodide (24 mg) and 1,10-phenanthroline (46 mg) were added to the residue, and the mixture was stirred at 100°C for 5 hours.
• Production example 228 1-[(E)-Benzylideneamino]-5-bromo-1,3-dihydro-2H-benzimidazol-2-one (450 mg, including impurities) obtained in Production Example 227, potassium carbonate (576 mg) ) and DMF (8 mL) was added methyl iodide (0.195 mL), and the mixture was stirred at room temperature for 4 hours. The mixture was diluted with ethyl acetate and washed with water. The two layers were separated, the aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure.
• Production example 236 Add concentrated sulfuric acid (500 ⁇ L) to a mixture of methyl 3-cyclopropyl-3-oxopropanoate (17 mL) and trimethyl orthoformate (20 mL) under ice cooling, and stir at room temperature under an argon atmosphere overnight. did. The reaction solution was concentrated and dried at room temperature under reduced pressure for 4 hours. 5-aminopyrimidine-2,4(1H,3H)-dione (11.4 g) and DMAc (300 mL) were added to the residue at room temperature, and the mixture was stirred at 110°C overnight under an argon atmosphere.
• Example 8 (1S,4S)-5- ⁇ (7M)-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-[(oxan-4-yl)oxy]quinazolin-4-yl ⁇ -2,5-diazabicyclo[2.2.1]heptane- Trifluoroacetic acid (1.2 mL) was added to a mixture of tert-butyl 2-carboxylate (300 mg) and CH 2 Cl 2 (2 mL) under ice cooling, and the mixture was stirred at room temperature for 2 hours.
• Example 12 (3S)-3-( ⁇ 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-2-(triphenyl tert - butyl)-2H-indazol-4-yl]-2-[(2S)-2-methoxypropoxy]quinolin-4-yl ⁇ oxy)pyrrolidine-1-carboxylate (74 mg) in CH2Cl2 (1 mL) solution was added trifluoroacetic acid (400 ⁇ L) under ice cooling, and the mixture was stirred at room temperature for 1 hour.
• trifluoroacetic acid 400 ⁇ L
• Example 16 (1S,4S)-5- ⁇ (7M)-6-cyclopropyl-8-( ⁇ 4-[(2S)-4- ⁇ [3-(2,4-dioxo-1,3-diazinane-1- yl)-1-methyl-1H-indazol-6-yl]methyl ⁇ -2-methylpiperazine-1-carbonyl]phenyl ⁇ methoxy)-7-[6-fluoro-5-methyl-1-(oxane-2- tert-butyl)-1H-indazol-4-yl]-2-[(oxan-4-yl)oxy]quinazolin-4-yl ⁇ -2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (164 mg) in CH 2 Cl 2 (3 mL) was added trifluoroacetic acid (1 mL) under ice cooling, and the mixture was stirred at room temperature for 4 hours.
• the obtained aqueous solution was added dropwise to stirring EtOH (15 mL) under ice-cooling, and the mixture was stirred at room temperature for 4 hours.
• the precipitated solid was collected by filtration, washed with EtOH, and dried under reduced pressure to obtain the phosphate salt (649 mg) as a solid.
• Water (1.5 mL) was added to the obtained solid and stirred at room temperature for 15 minutes to completely dissolve it.
• the obtained aqueous solution was added dropwise to stirring EtOH (15 mL) under ice-cooling, and the mixture was stirred at room temperature for 4 hours.
• the obtained aqueous solution was added dropwise to stirring EtOH (15 mL) under ice-cooling, and the mixture was stirred at room temperature for 4 hours.
• the precipitated solid was collected by filtration, washed with EtOH, and dried under reduced pressure to obtain the phosphate salt (543 mg) as a solid.
• Water (1.5 mL) was added to the obtained solid, and the mixture was stirred at room temperature for 15 minutes to completely dissolve.
• the obtained aqueous solution was added dropwise to stirring EtOH (15 mL) under ice-cooling, and the mixture was stirred at room temperature for 4 hours.
• a compound with "**" in the chemical structural formula indicates a mixture of geometric isomers of double bonds.
• n HCl n Hydrochloride
• n TfOH n trifluoromethanesulfonate
• Compounds with example numbers indicate monotrifluoromethanesulfonate to trifluoromethanesulfonate
• n H 3 PO 4 n phosphate (example numbers and production example numbers are attached).
• compounds having any of the following structures are shown. These compounds can also be produced by the typical production methods shown above, the production methods of Production Examples and Examples, a combination of these production methods, or methods obvious to those skilled in the art. Furthermore, these compounds are expected to have an excellent effect of inducing the degradation of G12D mutant KRAS protein and/or be useful as G12D mutant KRAS inhibitors, and can be used in pharmaceutical compositions, for example, pharmaceutical compositions for treating pancreatic cancer. It can be used as an active ingredient.
• the compound of the present invention or a salt thereof has an excellent effect of inducing the degradation of G12D mutant KRAS protein and/or is useful as a G12D mutant KRAS inhibitor, and is an active ingredient of a pharmaceutical composition, for example, a pharmaceutical composition for treating pancreatic cancer. It can be used as

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• 2023
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