WO2024072075A1 - Dérivé de pyrimidine ayant une activité inhibitrice de protéine kinase, et composition pharmaceutique thérapeutique le comprenant - Google Patents

Dérivé de pyrimidine ayant une activité inhibitrice de protéine kinase, et composition pharmaceutique thérapeutique le comprenant Download PDF

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WO2024072075A1
WO2024072075A1 PCT/KR2023/014982 KR2023014982W WO2024072075A1 WO 2024072075 A1 WO2024072075 A1 WO 2024072075A1 KR 2023014982 W KR2023014982 W KR 2023014982W WO 2024072075 A1 WO2024072075 A1 WO 2024072075A1
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amino
group
phenyl
compound
pyrimidin
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PCT/KR2023/014982
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Korean (ko)
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이구
천광우
임수민
심태보
산딥센굽타
김영훈
김남경
전은혜
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주식회사 테라펙스
연세대학교 산학협력단
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Publication of WO2024072075A1 publication Critical patent/WO2024072075A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system

Definitions

  • the present invention provides compounds selected from novel trisubstituted pyrimidine derivatives having protein kinase inhibitory activity, pharmaceutically acceptable salts thereof, hydrates thereof, or stereoisomers thereof, a method for producing the compounds, and active ingredients containing the compounds. It relates to a pharmaceutical composition for preventing, alleviating, or treating cancer diseases caused by abnormal cell growth, including.
  • Protein kinases are enzymes that catalyze the phosphorylation reaction that transfers the gamma-phosphate group of ATP to the hydroxy groups of tyrosine, serine, and threonine in proteins. They are responsible for cellular metabolism, gene expression, cell growth, differentiation, and cell division. It plays an important role in signal transmission. Protein kinases make up about 2% of the eukaryotic genome, and about 518 species exist in the human genome. Protein kinases are classified into tyrosine protein kinases, which phosphorylate tyrosine, and serine/threonine kinases, which phosphorylate serine and threonine.
  • tyrosine kinases which are divided into receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (NRTKs).
  • RTKs receptor tyrosine kinases
  • NRTKs non-receptor tyrosine kinases
  • Receptor tyrosine kinase is a membrane protein that has a domain that can accept growth factors on the cell surface and an active site that can phosphorylate tyrosine residues in the cytoplasm.
  • Protein kinases are molecular switches that must smoothly regulate the transition between active and inactive states within the cell. When abnormally regulated, intracellular signaling is excessively activated, leading to uncontrolled cell division and proliferation.
  • abnormal activation due to genetic mutation, amplification, and overexpression of protein kinases is associated with the development and progression of various tumors and plays a critical role in the growth and metastasis of cancer cells.
  • Lung cancer is a malignant tumor that occurs in the lungs, a respiratory organ. Depending on the size and shape of the cancer cells, it is divided into non-small cell lung cancer and small cell lung cancer. Non-small cell lung cancer accounts for 80% of all lung cancers. Non-small cell lung cancer can be cured through surgery if detected early, but 20 to 50% of patients who undergo surgery show recurrence, and metastasis to the brain, bones, liver, and other lungs is more common than other cancers.
  • EGFR epidermal growth factor receptor
  • 30 to 40% of non-small cell lung cancer patients in Asia and 10 to 15% in the United States and Europe have mutations in the EGFR gene, and 40 to 50% of Asian non-smoking female patients have EGFR mutations.
  • Mutations in the EGFR gene cause lung cancer regardless of smoking status.
  • 90% of all EGFR mutations are activating mutations that enable EGFR activation without epidermal growth factor (43% exon 19 deletion mutation, 41% L858R point mutation).
  • EGFR a transmembrane tyrosine kinase
  • Activated EGFR creates conditions that make it easy to bind to downstream molecules and phosphorylates them, leading to downstream pathways (RAS-mitogen-activated protein kinase (MAPK), phosphotidylinosititol 3-kinase (PI3-K)-Akt, phospholipase-C ⁇ (PLC ⁇ )).
  • MAPK mitogen-activated protein kinase
  • PI3-K phosphotidylinosititol 3-kinase
  • PLC ⁇ phospholipase-C ⁇
  • PLC protein kinase-C
  • STAT signal transducer and activator of transcription
  • first-generation EGFR tyrosine kinase inhibitors that can be administered orally, extend the survival period by 10 months compared to cytotoxic anticancer drugs, the existing standard anticancer treatment. Although superiority has been proven, T790M mutation occurs in 60% of patients due to resistance to first-generation inhibitors.
  • Gilotrif (afatinib, Gilotrif ® , Boehringer Ingelheim), a second-generation EGFR tyrosine kinase inhibitor capable of suppressing the T790M mutation, was released and demonstrated good clinical efficacy, but failed to secure a therapeutic window.
  • Second-generation inhibitors have relatively narrow indications as they are approved only as first-line treatment for locally advanced or metastatic non-small cell lung cancer with EGFR mutations.
  • Tagrisso (osimertinib, Targrisso ® , AstraZeneca), a third-generation EGFR tyrosine kinase inhibitor, introduced a michael acceptor capable of covalently binding to cysteine and was the first third-generation EGFR-targeted anticancer drug to receive FDA approval and be released, but was administered for about 10 months.
  • the patient developed acquired resistance to the C797S mutation.
  • the C797S mutation is a mutation in which the cysteine residue in the Tagrisso binding site is modified to serine, thereby disabling the covalent bond of Tagrisso.
  • Tagrisso can be used when the T790M mutation occurs after treatment with a first- or second-generation EGFR inhibitor
  • patients who develop resistance to Tagrisso have three mutations: EGFR activating mutation (exon 19 deletion or L858R), T790M, and C797S. have them all. Therefore, fourth-generation EGFR inhibitors are effective for triple mutations (exon 19 deletion/T790M/C797S or L858R/T790M/C797S) as well as double mutations (exon 19 deletion/C797S, L858R/C797S, exon 19 deletion/T790M or L858R/T790M).
  • Each activating mutation should also have adequate efficacy.
  • Lung cancer is a very fatal cancer that occurs in more than 20,000 people annually and has the highest mortality rate in Korea. In particular, if it metastasizes to other organs, the 5-year survival rate is very low at 8.9%.
  • the number of lung cancer patients in Korea is approximately 30,000, of which 30-40% are EGFR mutation positive.
  • EGFR mutations are also found in several cancer types, including glioblastoma (50%), triple-negative breast cancer (13% - 30%), and colon cancer (25% - 77%).
  • EGFR inhibitors are effective in a wide range of cancers, including lung cancer and head and neck cancer. Clinical trials are in progress.
  • the present inventors conducted research to develop a new material that can overcome the limitations of third-generation EGFR inhibitors and completed the present invention.
  • Patent Document 1 PCT Patent Publication WO/2018/230934/Al
  • Patent Document 2 US/2020/0207768/Al
  • Patent Document 3 Korean Patent Publication 10-2019-0114910
  • Patent Document 4 PCT Patent Publication WO/2019/112344/A1
  • Patent Document 5 PCT Patent Publication WO/2020/147702/A1
  • Non-patent Document 1 J. Med. Chem. 2018, 61, 4290-4300
  • Non-patent Document 2 J. Med. Chem. 2019, 62, 10272-10293
  • the purpose of the present invention is to provide a novel pyrimidine derivative compound that has protein kinase inhibitory activity.
  • another object of the present invention is to provide a pharmaceutical composition useful for the treatment, prevention and alleviation of cancer diseases containing a novel pyrimidine derivative compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof or a stereoisomer thereof as an active ingredient.
  • the purpose is to provide.
  • another object of the present invention is to provide a treatment for cancer diseases caused by EGFR mutations containing a novel pyrimidine derivative compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, or an isomer thereof as an active ingredient. It is for that purpose.
  • one aspect of the present invention seeks to provide a method for producing the above-mentioned novel compound.
  • one aspect of the present invention seeks to provide a new intermediate compound synthesized during the process of carrying out the above-described production method.
  • one aspect of the present invention provides a compound selected from pyrimidine derivative compounds represented by the following formula (1), pharmaceutically acceptable salts thereof, hydrates thereof, and stereoisomers thereof.
  • R 1 is hydrogen; hydroxyl group; halogen group; C 1 -C 13 alkyl group; C 3 -C 10 cycloalkyl group; -C(O)O-(C 1 -C 6 alkyl) group; or C 1 -C 6 alkoxy group;
  • R 2 is hydrogen; halogen group; C 1 -C 13 alkyl group; C 3 -C 10 cycloalkyl group; or amino group (-NR 8 R 9 ); ego,
  • R 3 and R 4 are each independently hydrogen; C 1 -C 13 alkyl group; or C 3 -C 10 cycloalkyl group; sulfide group (-SR 8 ); A sulfone group (-S(O) 2 R 8 ); or a phospiryl group (-P(O)R 8 R 9 ),
  • X 1 , X 2 and X 3 are each independently carbon or nitrogen
  • A is an amino group (-NR 8 R 9 ); C 6 -C 10 aryl group; C 3 -C 10 cycloalkyl group; Heteroaryl group of 3 to 10 atoms; Heterocyclyl group of 3 to 10 atoms; or a linear or branched heteroalkyl group of 3 to 15 atoms,
  • B is C 6 -C 10 aryl group; C 3 -C 10 cycloalkyl group; Heteroaryl group of 3 to 10 atoms; Or a heterocyclyl group of 3 to 10 atoms,
  • Each of R 11 is independently hydrogen; hydroxyl group; halogen group; -CF 3 ; C 1 -C 6 alkyl group substituted or unsubstituted with a hydroxy group or -SO 2 (C 1 -C 3 alkyl) group; C 1 -C 6 alkenyl group; C 1 -C 6 alkynyl group; C 1 -C 6 alkoxy group; C 3 -C 10 cycloalkyl group; -N(C 1 -C 6 alkyl group)(C 1 -C 6 alkyl group); C 6 -C 10 aryl group; Heteroaryl group of 3 to 10 atoms; A heterocyclyl group of 3 to 10 atoms;
  • a spiro compound can be created in which two rings of the C 3 -C 10 cycloalkyl group or 3 to 10-membered heterocyclyl group are connected by sharing one atom,
  • Another aspect of the present invention provides a pharmaceutical composition for preventing, improving, or treating diseases caused by EGFR protein kinase, containing the above compound as an active ingredient.
  • the disease caused by the EGFR protein kinase includes metabolic disease caused by the EGFR protein kinase; or tumor diseases caused by abnormal cell proliferation caused by EGFR protein kinase; Phosphorus, pharmaceutical compositions are provided.
  • the disease includes lung cancer, liver cancer, esophageal cancer, stomach cancer, colon cancer, small intestine cancer, pancreatic cancer, melanoma, breast cancer, oral cancer, brain tumor, thyroid cancer, parathyroid cancer, kidney cancer, cervical cancer, sarcoma, and prostate cancer. , urethral cancer, bladder cancer, testicular cancer, blood cancer, lymphoma, skin cancer, psoriasis, and fibroadenoma.
  • the active ingredient provides a pharmaceutical composition that prevents, improves, or treats the disease by inhibiting the activity of EGFR kinase or EGFR mutation.
  • the EGFR mutation may be the activity of del19, L858R, T790M, C797S, or a combination thereof.
  • a pharmaceutical composition in which the active ingredient can be administered in combination with a cytotoxic treatment agent.
  • a pharmaceutical composition in which the active ingredient and the cytotoxic treatment agent can be administered in combination at 10 to 1000 parts by weight of the cytotoxic treatment agent based on 100 parts by weight of the active ingredient.
  • the compound of the present invention has an excellent ability to inhibit the activity of EGFR protein kinase, it can be used as an active ingredient in a pharmaceutical composition for the prevention and treatment of diseases caused by abnormal cell growth and metabolism.
  • the compound according to the present invention is a disease caused by abnormal cell growth and metabolism, such as metabolic diseases such as diabetes and obesity, and endometrial cancer, bladder cancer, stomach cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreas cancer, and brain cancer.
  • metabolic diseases such as diabetes and obesity, and endometrial cancer
  • bladder cancer stomach cancer
  • lung cancer liver cancer
  • colon cancer small intestine cancer
  • pancreas cancer pancreas cancer
  • brain cancer bone cancer, melanoma, breast cancer, sclerosing adenoma, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, leukemia, multiple myeloma, blood cancer such as myelodysplastic syndrome, Hodgkin's disease and non-Hodgkin's disease.
  • lymphoma such as lymphoma or fibroadenoma.
  • the variable when a range is stated for a variable, the variable will be understood to include all values within the stated range, including the stated endpoints of the range.
  • the range “5 to 10” includes the values 5, 6, 7, 8, 9, and 10, as well as any subranges such as 6 to 10, 7 to 10, 6 to 9, 7 to 9, etc. It will be understood that it also includes any values between integers that fall within the scope of the stated range, such as 5.5, 6.5, 7.5, 5.5 to 8.5, and 6.5 to 9, etc.
  • the range “10% to 30%” includes values such as 10%, 11%, 12%, 13%, etc. and all integers up to and including 30%, as well as 10% to 15%, 12% to 12%, etc. It will be understood that it includes any subranges, such as 18%, 20% to 30%, etc., and any value between reasonable integers within the range of the stated range, such as 10.5%, 15.5%, 25.5%, etc.
  • the terms “individual(s)”, “subject(s)” and “patient(s)” refer to any mammal.
  • the mammal is a human.
  • the mammal is not a human. Neither term requires or is limited to situations characterized by supervision (e.g., full-time or intermittent) by a health care worker (e.g., physician, registered nurse, trainee nurse, physician assistant, handyman, or hospice worker). It doesn't work.
  • a health care worker e.g., physician, registered nurse, trainee nurse, physician assistant, handyman, or hospice worker. It doesn't work.
  • Treatment is an attempt made with the intention of preventing the lesions of a disease from developing or changing. Accordingly, “treatment” refers to both therapeutic and prophylactic treatment. Those that need to be treated include conditions in which the disease is to be prevented as well as those that already have the disease.
  • the therapeutic agent may mean directly reducing the pathology of the tumor cells or making the tumor cells more sensitive to treatment by other therapeutic agents, such as radiation and/or chemotherapy and/or immunotherapy. .
  • the terms “alleviation” or “cured” refer to signs approaching normalized values as measured by routine statistical tests.
  • An indication of approaching a normalized value herein is a value that differs by less than 50%, preferably by less than 25%, and more preferably a value that differs by less than 25% from the normalized value, for example, by a value obtained from a healthy patient or subject. It may be a value that differs by less than 10%, or, more preferably, a value that does not differ significantly from the normalized value.
  • Treatment of cancer means any one or more of the following effects; 1) Inhibition of tumor growth, including i) slowing or ii) complete growth arrest; 2) reduction in tumor cell number; 3) maintenance of tumor size; 4) reduction of tumor size; 5) Inhibition of tumor cell infiltration into peripheral organs, including i) reduction or ii) slowing or iii) complete prevention; 6) Inhibition of metastases, including i) reduction or ii) slowing or iii) complete prevention; 7) Enhancement of the anti-tumor immune response, which may result in i) maintaining tumor size or ii) reducing tumor size or iii) slowing tumor growth or iv) reducing, slowing or preventing invasion. increase.
  • an “effective amount” or “therapeutically effective amount” refers to a compound disclosed herein that alleviates to some extent the symptoms of the disease or condition being treated (e.g., cancer or inflammatory disease, periodontal disease, or soft tissue calcification). means a sufficient amount of In some embodiments, the result is 1) reduction and/or alleviation of signs, symptoms or causes of a disease, or 2) any other desirable alteration of a biological system in a clinical setting. In some embodiments, the appropriate “effective” amount in any individual case is determined using techniques such as dose escalation studies.
  • an “effective amount” is the amount of a compound disclosed in a monotherapy or combination therapy, i.e., when administered in one or more doses, compared to EGFR activity in an individual not treated with the compound, or before treatment with the compound, or Later, when compared to EGFR activity in the subject, reducing EGFR by about 20% (20% inhibition), at least about 30% (30% inhibition), at least about 40% (40% inhibition), or at least about 50% (50% inhibition).
  • the effective amount for inhibition is about 60% or more (60% inhibition), about 70% or more (70% inhibition), about 80% or more (80% inhibition), or about 90% or more (90% inhibition).
  • a “therapeutically effective amount” is the amount of a compound disclosed in monotherapy or combination therapy, i.e., when administered in one or more doses, compared to the tumor burden of a subject not treated with the compound, or treated with the compound.
  • increasing the subject's tumor burden by about 20%, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, or about 80% or more , which is an effective amount to reduce by about 90% or more.
  • tumor burden is the total mass of tumor tissue carried by a subject with cancer.
  • a “therapeutically effective amount” is the amount of a compound disclosed in monotherapy or combination therapy, i.e., the dose of radiation therapy required to observe tumor shrinkage in subjects not treated with the compound when administered in one or more doses. Compared to , the amount of radiotherapy required to observe tumor shrinkage in the object is about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%. This is an effective amount to reduce it by about 90% or more.
  • compositions such as vehicles, adjuvants, carriers or diluents are readily available to those skilled in the art.
  • Pharmaceutically acceptable auxiliary substances such as pH adjusters and buffers, tonicity adjusters, stabilizers, wetting agents, etc. are readily available to those skilled in the art.
  • compounds of the invention are formulated in an aqueous buffer.
  • Suitable aqueous buffers include, but are not limited to, acetate, succinate, citrate and phosphate buffers, varying in strength from 5mM to 1000mM.
  • the aqueous buffer includes reagents that provide an isotonic solution. These reagents include, but are not limited to, sodium chloride, sugars such as mannitol, dextrose, sucrose, etc.
  • the aqueous buffer further includes a nonionic surfactant such as polysorbate 20 or 80.
  • the formulation may further comprise a preservative.
  • Suitable preservatives include, but are not limited to, benzyl alcohol, phenol, chlorobutanol, benzalkonium chloride, etc.
  • the formulation is stored at about 4°C.
  • Preparations can also be lyophilized, and they usually contain a cryoprotectant such as sucrose, trehalose, lactose, maltose, mannitol, etc. Freeze-dried preparations can be stored for long periods of time even at room temperature.
  • the pharmaceutical composition may contain or consist essentially of a compound disclosed in the present invention, or a pharmaceutically acceptable salt thereof, an isomer thereof, or a tautomer thereof, and additionally the pharmaceutical composition may contain one or more additional active agents of interest.
  • a pharmaceutical composition that may include or consist essentially of. Any convenient active agent may be used in the present methods in conjunction with the compounds of the invention.
  • the compound of the invention and the immune checkpoint inhibitor, as well as the additional therapeutic agent as described herein for combination therapy may be administered orally, subcutaneously, intramuscularly, intranasally, parenterally, or by other routes.
  • a compound of the invention and a chemotherapy agent may be administered orally, subcutaneously, or intramuscularly. , can be administered intranasally, parenterally, or by other routes.
  • the compounds of the invention and the second active agent may be administered by the same or different routes of administration.
  • the therapeutic agent may be administered by any suitable means, including but not limited to oral, rectal, nasal, topical, vaginal, parenteral, intravenous, intranasal, or intratumoral injection into the affected organ.
  • the compounds of the present invention can be administered in unit dosage form and can be prepared by any method well known in the art. These methods include combining a compound of the invention with a pharmaceutically acceptable carrier or diluent that constitutes one of one or more accessory ingredients.
  • Pharmaceutically acceptable carriers are selected based on the chosen route of administration and standard pharmaceutical practice. Each carrier must be “pharmaceutically acceptable” in the sense that it is compatible with the other ingredients of the formulation and does not cause harm to the subject or patient. This carrier can be solid or liquid, and the type is generally chosen depending on the type of administration used.
  • suitable solid carriers include lactose, sucrose, gelatin, agar, and bulk powders.
  • suitable liquid carriers include water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, such as esters, emulsions, syrups or elixirs, suspensions and solutions reconstituted from non-effervescent granules and/or Contains suspensions.
  • These liquid carriers may contain, for example, suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, thickeners and melting agents.
  • One aspect of the present invention provides a compound selected from pyrimidine derivative compounds represented by the following formula (1), pharmaceutically acceptable salts thereof, hydrates thereof, and stereoisomers thereof.
  • R 1 is hydrogen; hydroxyl group; halogen group; C 1 -C 13 alkyl group; C 3 -C 10 cycloalkyl group; -C(O)O-(C 1 -C 6 alkyl) group; or C 1 -C 6 alkoxy group;
  • R 2 is hydrogen; halogen group; C 1 -C 13 alkyl group; C 3 -C 10 cycloalkyl group; or amino group (-NR 8 R 9 ); ego,
  • R 3 and R 4 are each independently hydrogen; C 1 -C 13 alkyl group; or C 3 -C 10 cycloalkyl group; sulfide group (-SR 8 ); A sulfone group (-S(O) 2 R 8 ); or a phospiryl group (-P(O)R 8 R 9 ),
  • X 1 , X 2 and X 3 are each independently carbon or nitrogen
  • A is an amino group (-NR 8 R 9 ); C 6 -C 10 aryl group; C 3 -C 10 cycloalkyl group; Heteroaryl group of 3 to 10 atoms; Heterocyclyl group of 3 to 10 atoms; or a linear or branched heteroalkyl group of 3 to 15 atoms,
  • B is C 6 -C 10 aryl group; C 3 -C 10 cycloalkyl group; Heteroaryl group of 3 to 10 atoms; Or a heterocyclyl group of 3 to 10 atoms,
  • Each of R 11 is independently hydrogen; hydroxyl group; halogen group; -CF 3 ; C 1 -C 6 alkyl group substituted or unsubstituted with a hydroxy group or -SO 2 (C 1 -C 3 alkyl) group; C 1 -C 6 alkenyl group; C 1 -C 6 alkynyl group; C 1 -C 6 alkoxy group; C 3 -C 10 cycloalkyl group; -N(C 1 -C 6 alkyl group)(C 1 -C 6 alkyl group); C 6 -C 10 aryl group; Heteroaryl group of 3 to 10 atoms; A heterocyclyl group of 3 to 10 atoms;
  • a spiro compound can be created in which two rings of the C 3 -C 10 cycloalkyl group or 3 to 10-membered heterocyclyl group are connected by sharing one atom,
  • the pharmaceutically acceptable salt of the pyrimidine compound represented by Formula 1 according to the present invention can be prepared by a method conventional in the art.
  • Pharmaceutically acceptable salts must have low toxicity to the human body and not adversely affect the biological activity and physicochemical properties of the parent compound.
  • Free acids that can be used to prepare pharmaceutically acceptable salts can be divided into inorganic acids and organic acids.
  • Inorganic acids may include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid, etc.
  • Organic acids include acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, oxalic acid, Benzoic acid, embonic acid, aspartic acid, glutamic acid, etc. can be used.
  • Organic bases that can be used to prepare organic base addition salts include tris(hydroxymethyl)methylamine and dicyclohexylamine.
  • Amino acids that can be used to produce amino acid addition bases are natural amino acids such as alanine and glycine.
  • the pyrimidine compound represented by Formula 1 includes all hydrates and solvates in addition to the pharmaceutically acceptable salts. Hydrates and solvates are obtained by dissolving the compound represented by Formula 1 in a water-miscible solvent such as methanol, ethanol, acetone, or 1,4-dioxane, and then crystallizing or recrystallizing after adding a free acid or free base. It can be. In such cases, solvates (especially hydrates) may be formed. Therefore, the compounds of the present invention include stoichiometric solvates, including hydrates, in addition to compounds containing various amounts of water that can be prepared by methods such as freeze-drying.
  • a water-miscible solvent such as methanol, ethanol, acetone, or 1,4-dioxane
  • alkyl refers to an aliphatic hydrocarbon radical.
  • the alkyl may be a “saturated alkyl” that does not contain an alkenyl or alkynyl moiety, or an “unsaturated alkyl” that contains at least one alkenyl or alkynyl moiety.
  • Alkenyl means a group containing at least one carbon-carbon double bond
  • alkynyl means a group containing at least one carbon-carbon triple bond.
  • Alkyls, when used alone or in combination, may each be cyclic, branched or straight-chain.
  • aryl' refers to a carbocyclic group containing 6 carbon atoms, which may be further fused with a second 5- or 6-membered carbocyclic group, which may be aromatic, saturated or unsaturated. It refers to an aromatic monocyclic group or a polycyclic group in which at least one ring is aromatic.
  • aryl may include, but are not limited to, phenyl, indanyl, 1-naphthyl, 2-naphthyl, tephrahydronaphthyl, etc.
  • Aryl can be connected to other groups at appropriate positions on the aromatic ring.
  • alkoxy' refers to an alkyl group (i.e. -O-alkyl) connected to another group through an oxygen atom.
  • the alkoxy group may be unsubstituted or substituted with one or more suitable substituents.
  • alkoxy groups include (C 1 -C 6 )alkoxy groups such as -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -O-2-methyl-1-propyl, -O -2-methyl-2-propyl, -O-2-methyl-1-butyl, -O-3-methyl-1-butyl, -O-2-methyl-3-butyl, -O-2,2-dimethyl -1-propyl, -O-2-methyl-1-pentyl, 3-O-methyl-1-pentyl, -O-4-methyl-1-pentyl, -O-2-methyl-2-pentyl, -O -3-methyl-2-pentyl, -O-4-methyl-2-pentyl, -O-2,2-dimethyl-1-butyl, -O-3,3-dimethyl-butyl, -O-2-ethyl Including, but not limited to
  • 'phenoxy' refers to a phenyl group (i.e. -O-aryl) connected to another group through an oxygen atom.
  • the phenoxy group is unsubstituted or may be substituted with one or more halogens; Alkyl group; It may be substituted with an aryl group and a heteroaryl group, but is not limited thereto.
  • amino group' refers to an alkyl group (i.e. -NH- or -N-alkyl) connected to another group through a nitrogen atom.
  • the amino group may be unsubstituted or substituted with one or more suitable substituents.
  • Examples of amino groups include (C1-C6) amino groups such as -NH-methyl, -NH-ethyl, -NH-propyl, -NH-isopropyl, -NH-2-methyl-1-propyl, -NH-2-methyl.
  • 'halogen group means fluorine, chlorine, bromine or iodine.
  • heterocyclyl group' refers to an aromatic or non-aromatic compound containing one or more heteroatoms selected from the group consisting of N, O, and S, unless otherwise specified.
  • the heterocyclyl group is dioxalanyl group, pyrrolyl group, oxazolyl group, thiazolyl group, imidazolyl group, oxadiazolyl group, thiadiazolyl group, triazolyl group, triazinyl group, and isothiazolyl group.
  • pyrrolidinyl group furyl group, It may include a morpholine group, a piperazinyl group, or a piperidinyl group, and more preferably, it may include a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, or a morpholine group, but is not limited thereto.
  • heteroaryl group' refers to a heteroaromatic compound or a fused bicyclic heteroaromatic compound containing one or more heteroatoms selected from the group consisting of N, O, and S.
  • the heteroaryl group is furyl group, thienyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, triazolyl group, tetrazolyl group, thiazolyl group, oxazolyl group, oxadiazolyl group, isoxazolyl group.
  • the term 'spiro compound' refers to a compound in which two rings of a cycloalkyl group and a heterocyclyl group are connected by sharing one atom.
  • the spiro compound may include a diazaspiro[5,5]undecane group and a diazaspiro[3,5]nonane group, but is not limited thereto.
  • R 1 is hydrogen; or halogen group; C 1 -C 3 alkyl group; C 3 -C 6 cycloalkyl group; or -C(O)O-(C 1 -C 3 alkyl) group;
  • R 2 is hydrogen; C 1 -C 3 alkyl group; Or an amino group (-NR 8 R 9 );
  • R 3 is hydrogen; or C 1 -C 3 alkyl group
  • R 4 is hydrogen; or C 1 -C 3 alkyl group
  • R 5 is hydrogen; hydroxyl group; halogen group; C 1 -C 3 alkyl group; or C 1 -C 3 alkoxy group;
  • R 6 is hydrogen; halogen group; C 1 -C 3 alkyl group; C 2 -C 3 alkenyl group; Or a heteroaryl group of 5 to 6 atoms,
  • R 7 is hydrogen; C 1 -C 3 alkyl group; Or an amino group (-NR 8 R 9 );
  • X 1 , X 2 and X 3 are each independently carbon or nitrogen
  • A is an amino group (-NR 8 R 9 ); Heteroaryl group of 3 to 10 atoms; Heterocyclyl group of 3 to 10 atoms; or a linear or branched heteroalkyl group of 3 to 15 atoms,
  • B is C 6 -C 10 aryl group; Heteroaryl group of 3 to 10 atoms; Or a heterocyclyl group of 3 to 10 atoms,
  • the C 1 -C 3 alkoxy group, C 1 -C 3 alkyl group, C 3 -C 6 cycloalkyl group, C 2 -C 3 alkenyl group or 5 to 6-membered heteroaryl group is hydrogen; hydroxyl group; halogen group; and an amino group (-NR 8 R 9 ); and may include one or more substituents selected from the group consisting of,
  • the 3 to 10 atom heteroaryl group and the 3 to 10 atom heterocyclyl group may include one or more heteroatoms selected from the group consisting of N, O, and S,
  • Each of R 11 is independently hydrogen; hydroxyl group; halogen group; -CF 3 ; C 1 -C 6 alkyl group substituted or unsubstituted with a hydroxy group or -SO 2 (C 1 -C 3 alkyl) group; C 1 -C 6 alkenyl group; C 1 -C 6 alkynyl group; C 1 -C 6 alkoxy group; C 3 -C 10 cycloalkyl group; -N(C 1 -C 6 alkyl group)(C 1 -C 6 alkyl group); C 6 -C 10 aryl group; Heteroaryl group of 3 to 10 atoms; A heterocyclyl group of 3 to 10 atoms;
  • a spiro compound can be created in which two rings of the C 3 -C 10 cycloalkyl group or 3 to 10-membered heterocyclyl group are connected by sharing one atom,
  • pyrimidine derivative compounds represented by Formula 1 pharmaceutically acceptable salts thereof, hydrates thereof, and stereoisomers thereof.
  • R 1 is hydrogen; halogen group; -CF 3 ; or -C(O)O-(C 1 -C 3 alkyl) group;
  • R 2 is hydrogen; or C 1 -C 3 alkyl group
  • R 3 is hydrogen; or C 1 -C 3 alkyl group
  • R 4 is hydrogen
  • R 5 is hydrogen; halogen group; or C 1 -C 6 alkoxy group
  • R 6 is hydrogen; halogen group; C 1 -C 3 alkyl group; ethylene group; or 1-methyl-1 H -pyrazol-4-yl group,
  • R 7 is hydrogen; or -NH 2 ;
  • X 1 , X 2 and X 3 are each independently carbon
  • pyrimidine derivative compounds represented by Formula 1 pharmaceutically acceptable salts thereof, hydrates thereof, and stereoisomers thereof.
  • pyrimidine derivative compounds represented by Formula 1 pharmaceutically acceptable salts thereof, hydrates thereof, and stereoisomers thereof.
  • the above B is ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; and It is any one selected from the group consisting of ;,
  • R 10 is a sulfonamide group (-NR 8 S(O) 2 R 9 ); Or a phospiryl group (-P(O)R 8 R 9 );
  • R 8 and R 9 are each independently hydrogen; C 1 -C 6 alkyl group; or C 3 -C 6 cycloalkyl group;
  • pyrimidine derivative compounds represented by Formula 1 pharmaceutically acceptable salts thereof, hydrates thereof, and stereoisomers thereof.
  • R 1 is hydrogen; halogen group; -CF 3 ; or -C(O)O-(C 1 -C 3 alkyl) group;
  • R 2 is hydrogen
  • R 3 is hydrogen; or C 1 -C 3 alkyl group
  • R 4 is hydrogen
  • R 5 is hydrogen; halogen group; or C 1 -C 6 alkoxy group
  • R 6 is hydrogen; halogen group; C 1 -C 3 alkyl group; ethylene group; or 1-methyl-1 H -pyrazol-4-yl group,
  • R 7 is hydrogen; or -NH 2 ;
  • X 1 , X 2 and X 3 are each independently carbon
  • B is ; ; ; ; ; ; ;and ; It is any one selected from the group consisting of,
  • R 10 is a sulfonamide group (-NR 8 S(O) 2 R 9 ); Or a phospiryl group (-P(O)R 8 R 9 );
  • R 8 and R 9 are each independently hydrogen; C 1 -C 6 alkyl group; or C 3 -C 6 cycloalkyl group;
  • pyrimidine derivative compounds represented by Formula 1 pharmaceutically acceptable salts thereof, hydrates thereof, and stereoisomers thereof.
  • the compound is a pyrimidine derivative compound represented by Formula 1, a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein the compound is any one selected from the group consisting of Compound Nos. 1 to 101 below. and stereoisomers thereof:
  • the pharmaceutically acceptable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, and selected from the group consisting of delic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid.
  • Another aspect of the present invention provides a pharmaceutical composition for preventing, alleviating or treating cancer, which contains a compound according to any one aspect of the present invention as an active ingredient.
  • a pharmaceutical composition for preventing, alleviating or treating cancer wherein the cancer is caused by an EGFR mutation.
  • the pharmaceutical composition provides a pharmaceutical composition for preventing, alleviating or treating cancer, applied to patients with EGFR mutations.
  • a pharmaceutical composition for preventing, alleviating, or treating cancer wherein the cancer is at least one selected from the group consisting of glioblastoma, triple-negative breast cancer, colon cancer, lung cancer, and head and neck cancer.
  • a pharmaceutical composition for preventing, alleviating or treating cancer, wherein the cancer is lung cancer.
  • the pharmaceutical composition is administered to a patient carrying a triple mutation of exon 19 deletion/T790M/C797S or a triple mutation of L858R/T790M/C797S, which are EGFR-related mutations, for the prevention and alleviation of cancer.
  • a pharmaceutical composition for treatment is provided.
  • the pharmaceutical composition is a pharmaceutical for preventing, alleviating or treating cancer, characterized in that it is administered to a patient carrying an EGFR-related mutation, exon 19 deletion/T790M double mutation or L858R/T790M double mutation.
  • a composition is provided.
  • the pharmaceutical composition provides a pharmaceutical composition for preventing, alleviating or treating cancer, which is characterized in that it is administered to a patient carrying an EGFR-related mutation, exon 19 deletion mutation or L858R mutation.
  • the pharmaceutical composition may be applied to laboratory animals such as mice, rabbits, rats, guinea pigs, or hamsters, or primates including humans, but is not limited thereto, and is preferably applied to primates including humans, and more preferably to humans.
  • treatment refers to alleviation or improvement of symptoms, reduction of the extent of the disease, delay or alleviation of disease progression, improvement, alleviation or stabilization of the disease state, partial or complete recovery, extension of survival and other beneficial treatment results, etc. It can be used in a meaning that includes all of the following.
  • cancer refers to breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, urinary tract cancer, esophageal cancer, laryngeal cancer, glioblastoma, stomach cancer, skin cancer, keratoacanthoma, lung cancer, squamous cell carcinoma, large cell carcinoma, Small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, gonocarcinoma, follicular adenocarcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer and biliary duct cancer, kidney cancer, myeloid disease, lymphoid Disease, Hodg
  • the content of the active ingredient, the compound represented by Formula 1, its pharmaceutically acceptable salt, or hydrate may be appropriately adjusted according to the selection of a person skilled in the art.
  • the pharmaceutical composition contains the compound represented by Formula 1, a pharmaceutically acceptable salt, or hydrate thereof in an amount of 0.1 to 10% by weight, more preferably 0.5 to 5% by weight, based on the total weight of the entire composition. It can be included.
  • the compound represented by Formula 1, its pharmaceutically acceptable salt, or hydrate may be included alone in the pharmaceutical composition, or may be included together with other pharmaceutically acceptable carriers, excipients, diluents, or auxiliary ingredients.
  • Examples of the pharmaceutically acceptable carriers, excipients or diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • the pharmaceutical composition includes conventional fillers, extenders, binders, disintegrants, anti-coagulants, lubricants, wetting agents, pH adjusters, nutrients, vitamins, electrolytes, alginic acid and its salts, pectic acid and its salts, protective chloride, and glycerin. , flavorings, emulsifiers, or preservatives may be additionally included.
  • the compound of Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention can enhance the therapeutic effect of an anticancer agent by co-administering it with other anticancer agents for treating cancer or tumors.
  • the pharmaceutical composition can be administered either orally or parenterally, and for example, it can be administered through various routes including orally, transdermally, subcutaneously, intravenously, or intramuscularly.
  • the formulation of the composition may vary depending on the method of use, and may be formulated using methods well known in the art to provide rapid, sustained, or delayed release of the active ingredient after administration to a mammal. It can be.
  • solid preparations for oral administration include tablets, pills, soft or hard capsules, pills, powders, and granules, and these preparations include one or more It can be prepared by mixing excipients, such as starch, calcium carbonate, sucrose or lactose, and gelatin.
  • lubricants such as magnesium stearate and talc may also be used.
  • Liquid preparations for oral use include suspensions, oral solutions, emulsions, and syrups.
  • simple diluents such as water and liquid paraffin, they contain various excipients, such as wetting agents, Sweeteners, aromatics, preservatives, etc. may be included.
  • forms for parenteral administration include CREAM, LOTIONS, OINTMENTS, PLASTERS, LIQUIDS AND SOULTIONS, AEROSOLS, FRUIDEXTRACTS, and elixirs.
  • It may be in the form of (ELIXIR), INFUSIONS, SACHET, PATCH, or INJECTIONS, and if it is an injectable formulation, it may preferably be in the form of an isotonic aqueous solution or suspension. .
  • the pharmaceutical composition may further contain auxiliaries such as sterilants, preservatives, stabilizers, wetting agents or emulsification accelerators, salts and/or buffers for adjusting osmotic pressure, and other therapeutically useful substances, and may be subject to conventional mixing and granulation.
  • auxiliaries such as sterilants, preservatives, stabilizers, wetting agents or emulsification accelerators, salts and/or buffers for adjusting osmotic pressure, and other therapeutically useful substances, and may be subject to conventional mixing and granulation.
  • auxiliaries such as sterilants, preservatives, stabilizers, wetting agents or emulsification accelerators, salts and/or buffers for adjusting osmotic pressure, and other therapeutically useful substances, and may be subject to conventional mixing and granulation.
  • it can be formulated according to a coating method, and in addition, it can be formulated using a suitable method known in the art.
  • the dosage of the pharmaceutical composition can be determined considering the administration method, the age and gender of the recipient, the severity and condition of the patient, the absorption of the active ingredient in the body, the inactivation rate, and the drug used in combination, and can be administered once or several times. It can be administered in divided doses.
  • an active ingredient of a pharmaceutical composition it is preferably administered orally or parenterally to mammals, including humans, in an amount of 0.001 to 100 mg/kg body weight, preferably 0.01 to 35 mg/kg body weight, once a day or in divided doses. It can be administered by the old route.
  • Another embodiment of the present invention provides a method of treating cancer, comprising administering a therapeutically effective amount of a compound represented by Formula 1 below, a pharmaceutically acceptable salt, or hydrate thereof.
  • the treatment method may further include the step of identifying patients in need of prevention or treatment of the cancer before the administration step.
  • “Therapeutically effective amount” of the present invention refers to the amount of an active ingredient for mammals that is effective in preventing or treating cancer, and the therapeutically effective amount refers to the type of disease, the severity of the disease, the active ingredient and other ingredients contained in the composition. It can be adjusted according to various factors, including the type and content, type of dosage form and patient's age, weight, general health condition, gender and diet, administration time, administration route and blood clearance of the composition, treatment period, and concurrently used drugs. However, preferably, as described above, it is administered by oral or parenteral route, once a day or divided in an amount of 0.001 to 100 mg/kg body weight per day, preferably 0.01 to 35 mg/kg body weight. can do.
  • the present invention is characterized by a method for producing a compound represented by the following formula (1).
  • R 1 is hydrogen; hydroxyl group; halogen group; C 1 -C 13 alkyl group; C 3 -C 10 cycloalkyl group; -C(O)O-(C 1 -C 6 alkyl) group; or C 1 -C 6 alkoxy group;
  • R 2 is hydrogen; halogen group; C 1 -C 13 alkyl group; C 3 -C 10 cycloalkyl group; or amino group (-NR 8 R 9 ); ego,
  • R 3 and R 4 are each independently hydrogen; C 1 -C 13 alkyl group; or C 3 -C 10 cycloalkyl group; sulfide group (-SR 8 ); Sulfonic group (-S(O) 2 R 8 ); Or a phospiryl group (-P(O)R 8 R 9 ),
  • X 1 , X 2 and X 3 are each independently carbon or nitrogen
  • A is an amino group (-NR 8 R 9 ); C 6 -C 10 aryl group; C 3 -C 10 cycloalkyl group; Heteroaryl group of 3 to 10 atoms; Heterocyclyl group of 3 to 10 atoms; or a linear or branched heteroalkyl group of 3 to 15 atoms,
  • B is C 6 -C 10 aryl group; C 3 -C 10 cycloalkyl group; Heteroaryl group of 3 to 10 atoms; Or a heterocyclyl group of 3 to 10 atoms,
  • Each of R 11 is independently hydrogen; hydroxyl group; halogen group; -CF 3 ; C 1 -C 6 alkyl group substituted or unsubstituted with a hydroxy group or -SO 2 (C 1 -C 3 alkyl) group; C 1 -C 6 alkenyl group; C 1 -C 6 alkynyl group; C 1 -C 6 alkoxy group; C 3 -C 10 cycloalkyl group; -N(C 1 -C 6 alkyl group)(C 1 -C 6 alkyl group); C 6 -C 10 aryl group; Heteroaryl group of 3 to 10 atoms; A heterocyclyl group of 3 to 10 atoms;
  • a spiro compound can be created in which two rings of the C 3 -C 10 cycloalkyl group or 3 to 10-membered heterocyclyl group are connected by sharing one atom,
  • the present invention combines a commercially available pyrimidine compound represented by Formula 2 and an amine represented by Formula 3 to prepare a pyrimidine compound represented by Formula 1 below. It includes the process of
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X 1 , X 2 , X 3 , A and B are as defined in Formula 1 above.
  • Chemical Formula 4 can be obtained by combining a commercially available pyrimidine compound (Formula 2) with a commercially available Chemical Formula 3. It involves stirring at a temperature of 60°C, and at this time, the reaction solvent usually includes tetrahydrofuran, dioxane, N,N -dimethylformamide, N,N -dimethylsulfoxide, 2-butanol, 2-pentanol, etc. Organic solvents can be used.
  • the prepared formula 4 is reacted at room temperature in a solvent such as N,N -dimethylformamide under basic conditions such as sodium hydride using commercially available methane iodide to obtain formula 6 in which a sulfone group or methyl group is substituted. You can get it.
  • Formula 1 can be obtained by stirring the prepared amines represented by Formula 4 or Formula 6 and Formula 5 at 120°C in the presence of a 1.25 M hydrochloric acid methanol solution and acetic acid.
  • Reaction Scheme 2 is a reaction scheme for preparing the amine intermediate of Chemical Formula 5,
  • Chemical Formula 8 can be obtained by combining a commercially available nitro compound represented by Chemical Formula 7 with A.
  • Formula 8 can be obtained by stirring iron and ammonia chloride in a mixed solvent of tetrahydrofuran, methanol, and water at 85°C to reduce the nitro group to an amino group to obtain Formula 5.
  • the present invention provides a pharmaceutical composition containing a pyrimidine compound represented by Formula 1 above, a pharmaceutically acceptable salt thereof, a solvate thereof, a hydrate thereof, or an optical isomer thereof as an active ingredient.
  • the compound of the present invention Since the compound of the present invention has an excellent ability to inhibit the activity of EGFR protein kinase, it can be used as an active ingredient in a pharmaceutical composition for the prevention and treatment of diseases caused by abnormal cell metabolism and sugar metabolism. Therefore, the compound according to the present invention is a disease caused by abnormal cell metabolism and sugar metabolism, such as metabolic diseases such as diabetes and obesity, and endometrial cancer, bladder cancer, stomach cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreas cancer, and brain cancer.
  • metabolic diseases such as diabetes and obesity, and endometrial cancer, bladder cancer, stomach cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreas cancer, and brain cancer.
  • lymphoma such as lymphoma or fibroadenoma.
  • the present invention provides a pharmaceutical composition containing the pyrimidine compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a solvate thereof, and a hydrate thereof as active ingredients, and a pharmaceutical composition for treating diseases caused by abnormal cell metabolism and sugar metabolism. It features preventive and therapeutic agents.
  • the pharmaceutical composition of the present invention contains as an active ingredient at least one selected from the pyrimidine compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a solvate thereof, and a hydrate thereof, and includes a conventional non-toxic pharmaceutical agent.
  • a pharmaceutically acceptable salt thereof such as sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate thereof, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bi
  • Excipients that can be used in the pharmaceutical composition of the present invention may include sweeteners, binders, solubilizers, solubilizing agents, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances, etc.
  • Examples include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterine, magnesium stearate, magnesium aluminum silicate, starch, gelatin, gum tragacanth, arginic acid, sodium.
  • Examples include alginate, methylcellulose, sodium carboxymethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, and vanilla flavor.
  • the administered dose of the compound according to the present invention to the human body may vary depending on the patient's age, weight, gender, form of administration, health condition, and degree of disease, and is generally 0.01 kg based on an adult patient weighing 70 kg. ⁇ 1,000 mg/day, and can be administered in divided doses once or several times a day at certain time intervals, depending on the judgment of the doctor or pharmacist.
  • 6-Nitro-2,3-dihydrobenzofuran-5-amine (1 eq.) was dissolved in dichloromethane (0.3 M), triethylamine (4 eq.) was added at 0 °C, and methanesulfonyl chloride was added. MsCl (3 eq.) was added slowly. The mixture was stirred at room temperature for 30 minutes, and when the reaction was complete, the reaction mixture was diluted with hexane and stirred for an additional 15 minutes. The resulting yellow solid was filtered under reduced pressure to obtain the title compound.
  • step 1) The compound prepared in step 1) was dissolved in tetrahydrofuran:4 N NaOH solution (1:1, 0.2 M) and stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was distilled under reduced pressure and the pH was adjusted to 5-6 with 1 N HCl solution at 0 °C. The resulting yellow solid was filtered under reduced pressure to obtain the title compound.
  • the compound (1 eq.) prepared in step 3) was diluted in isopropyl alcohol (0.3 M) and 2,4,5-trichloropyrimidine (2 eq.) and sodium bicarbonate (4 eq.) were added. It was stirred under nitrogen atmosphere at 65°C for 40 hours.
  • Step 2) N -(6-((5-bromo-2-((5-bromo-2-methoxy-4-(4-morpholinopiperidin-1-yl)phenyl)amino)pyrimidine -4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide
  • Example 16 N-(6-((2-((5-bromo-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)-5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide
  • Step 4) N -(6-((2-((5-bromo-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Preparation of amino)-5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)- N -methylmethanesulfonamide
  • Example 17 N-(6-((2-((5-bromo-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl )Amino)-5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide
  • Step 2) N -(6-((2-((5-bromo-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Preparation of amino)-5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)- N -methylmethanesulfonamide
  • Example 19 N-(6-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5 -vinylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide
  • Example 22 N-(5-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidine-1- yl)phenyl)amino)pyrimidin-4 -yl)amino)-2,3-dihydrobenzofuran-6-yl)methanesulfonamide
  • step 1 The compound (4.5 mmol) prepared in step 1) was diluted in 9 ml ethanol, then concentrated hydrochloric acid (20 mmol) was added, and the mixture was stirred at 80°C for 3 hours. When the reaction was complete, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water to obtain 800 mg (yield: 99%) of the title compound.
  • Example 40 N-(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidine-1 -yl)phenyl)amino)pyrimidin-4 -yl)amino)benzofuran-5-yl)-N-methylmethanesulfonamide
  • step 1) The compound prepared in step 1) (1.52 mmol) and 2.8 g (2.74 mmol) of 5-bromo-2,4-dichloropyrimidine were diluted in 3 ml of isopropyl alcohol and mixed with N,N -diisopropylethylamine 3.8. ml (3.04 mmol) was added and stirred at 60°C for 12 hours.
  • ml 3.04 mmol
  • the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water.
  • the obtained residue was separated by column chromatography (50% ethyl acetate / hexane) to obtain 450 mg of the title compound (yield: 68%).
  • step 2 The compound prepared in step 2) (1.42 mmol) and 5-bromo-2,4-dichloropyrimidine (2.56 mmol) were diluted in 2 ml of isopropyl alcohol and added to N,N -diisopropylethylamine (2.84 mmol). ) was added and stirred at 60°C for 12 hours. When the reaction was complete, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water. The obtained residue was separated by column chromatography (50% ethyl acetate/hexane) to obtain 420 mg (yield: 74%) of the title compound.
  • Step 3 (6-((5-bromo-2-((2-methoxy-5-(1-methyl-1 H -pyrazol-4-yl)-4-(4-(4-methylpipe Razin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) -2,3-dihydrobenzofuran-5-yl)
  • dimethylphosphine oxide ((5-bromo-2-((2-methoxy-5-(1-methyl-1 H -pyrazol-4-yl)-4-(4-(4-methylpipe Razin-1-yl) piperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) -2,3-dihydrobenzofuran-5-yl)
  • 6-Fluoro-7-nitroquinoxaline (18.1 mmol) was diluted in 36 ml of acetonitrile, potassium carbonate (36.2 mmol) and methanesulfonamide (21.7 mmol) were added, and the mixture was stirred at 90°C for 24 hours.
  • the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water.
  • the obtained residue was separated by column chromatography (50% ethyl acetate/hexane) to obtain 3.0 g of the title compound (yield: 62%).
  • N -(6-nitroquinoxalin-5-yl)methanesulfonamide (1.87 mmol) was diluted in dimethylformamide, potassium carbonate (3.74 mmol) and methyl iodide (2.24 mmol) were added, and stirred at room temperature for 3 hours. I ordered it.
  • the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water. The obtained residue was separated by column chromatography (50% ethyl acetate/hexane) to obtain 400 mg of the title compound (yield: 76%).
  • step 1) The compound prepared in step 1) (1.08 mmol) and 5-bromo-2,4-dichloropyrimidine (1.94 mmol) were diluted in 2 ml of isopropyl alcohol and added to N,N -diisopropylethylamine (2.16 mmol). ) was added and stirred at 60°C for 12 hours.
  • the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water.
  • the obtained residue was separated by column chromatography (50% ethyl acetate/hexane) to obtain 400 mg of the title compound (yield: 84%).
  • Step 2) N -(6-((5-fluoro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidine-1- Preparation of yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)- N -methylmethanesulfonamide
  • Example 56 N-(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidine-1 -yl)phenyl)amino)pyrimidin-4-yl)amino)benzo[d][1,3]dioxol-5-yl)-N-methylmethanesulfonamide
  • Benzo[d][1,3]dioxol-5-amine (1 eq.) was dissolved in dichloromethane (0.3 M), triethylamine (4 eq.) was added at 0°C, and methanesulfonyl chloride MsCl ( 3 eq.) was added slowly. The mixture was stirred at room temperature for 30 minutes, and when the reaction was complete, the reaction mixture was diluted with hexane and stirred for an additional 15 minutes. The resulting yellow solid was filtered under reduced pressure and then concentrated. The reaction mixture was dissolved in tetrahydrofuran:4 N NaOH solution (1:1, 0.2 M) and stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was distilled under reduced pressure and the pH was adjusted to 5-6 with 1 N HCl solution at 0 °C. The resulting yellow solid was filtered under reduced pressure to obtain the title compound.
  • step 1 The compound (1.0 eq.) prepared in step 1) was dissolved in dichloroethane (0.5 M), iron(III) nitrate hydrate (1.2 eq.) was added, and the mixture was stirred at 50° C. for 1 hour. The mixture was diluted with hexane and stirred for an additional 15 minutes. The resulting yellow solid was filtered under reduced pressure to obtain the title compound.
  • the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water.
  • the reaction mixture was washed with dichloromethane through a filter filled with Celite, filtered under reduced pressure, and concentrated to obtain the title compound.
  • Example 61 N-(5-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidine-1 -yl)phenyl)amino)pyrimidin-4-yl)amino)benzo[d][1,3]dioxol-4-yl)-N-methylmethanesulfonamide
  • Step 1) N -(5-((5-bromo-2-chloropyrimidin-4-yl)amino)benzo[ d ][1,3]dioxol-4-yl)- N -methylmethanesulfonamide manufacture of
  • the title compound was obtained by performing the same process as step 1) to step 4) of Example 56 using benzo[ d ][1,3]dioxol-4-amine.
  • Step 2) N -(5-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidine-1- Preparation of 1) phenyl) amino) pyrimidin-4-yl) amino) benzo [ d ] [1,3] dioxol-4-yl) - N - methylmethanesulfonamide
  • Example 65 N-(6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidine-1- yl)phenyl)amino)pyrimidin-4-yl)amino)benzo[d][1,3]dioxol-5-yl)-N-methylmethanesulfonamide
  • Example 56 The compound (1 eq.) prepared in step 3) of Example 56 was diluted in isopropyl alcohol (0.3 M) and mixed with 2,4,5-trichloropyrimidine (2 eq.) and N , N -diiso Propylethylamine (2 eq.) was added and stirred at 65°C for 40 hours under a nitrogen atmosphere.
  • Step 2) N -(6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl ) Phenyl) amino) pyrimidin-4-yl) amino) benzo [ d ] [1,3] dioxol-5-yl) - N - Preparation of methylmethanesulfonamide
  • Example 68 N-(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidine-1 -yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-7-yl)-N-methylmethanesulfonamide
  • Step 2) N -(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidine-1- Preparation of yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-7-yl)- N -methylmethanesulfonamide
  • Example 71 N-(5-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidine-1 -yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-4-yl)-N-methylmethanesulfonamide
  • Step 2) N -(5-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidine-1- Preparation of yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-4-yl)- N -methylmethanesulfonamide
  • Example 74 N-(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidine-1 -yl)phenyl)amino)pyrimidin-4-yl)amino)benzo[d][1,3]dioxol-5-yl)methanesulfonamide
  • Example 77 N-(6-((2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide
  • Step 2) N -(6-((2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino )-5-(trifluoromethyl)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)- N -preparation of methylmethanesulfonamide
  • Example 82 N-(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidine-1 -yl)phenyl)amino)pyrimidin-4-yl)amino)benzo[d]thiazol-5-yl)-N-methylmethanesulfonamide
  • Step 2) N -(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidine-1- Preparation of yl)phenyl)amino)pyrimidin-4-yl)amino)benzo[d]thiazol-5-yl)-N-methylmethanesulfonamide
  • Example 87 N-(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidine-1 -yl)phenyl)amino)pyrimidin-4 -yl)(methyl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide
  • step 1) of Example 17 was diluted in dimethylformamide (0.5 M), sodium hydride (1.2 eq.) and methyl iodide (1.2 eq.) were added, and then stirred at room temperature for 3 hours.
  • the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water.
  • the obtained residue was separated by column chromatography (50% ethyl acetate/hexane) to obtain the title compound (yield: 58%).
  • Step 2) N-(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidine-1- yl)phenyl)amino)pyrimidin-4-yl)(methyl)amino)-2,3-dihydrobenzofuran-5-yl)-N-methylmethanesulfonamide
  • 6-Nitro-2,3-dihydrobenzofuran-5-amine (1 eq.) was dissolved in dichloromethane (0.3 M), triethylamine (4 eq.) was added at 0 °C, and methanesulfonyl chloride was added. Cyclopropanesulfonyl chloride (3 eq.) was added slowly. The mixture was stirred at room temperature for 30 minutes, and when the reaction was complete, the reaction mixture was diluted with hexane and stirred for an additional 15 minutes. The resulting yellow solid was filtered under reduced pressure, dissolved in tetrahydrofuran:4 N NaOH solution (1:1, 0.2 M), and stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was distilled under reduced pressure and the pH was adjusted to 5-6 with 1 N HCl solution at 0 °C. The resulting yellow solid was filtered under reduced pressure to obtain the title compound.
  • the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water.
  • the reaction mixture was washed with dichloromethane through a filter filled with Celite, filtered under reduced pressure, and concentrated to obtain the title compound.
  • Step 4) N -(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidine-1- Preparation of yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)- N -methylcyclopropanesulfonamide
  • Example 94 N-(7-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidine-1 -yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-N-methylmethanesulfonamide
  • Step 2) N -(7-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidine-1- Preparation of 1) phenyl) amino) pyrimidin-4-yl) amino) -2,3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) - N -methylmethanesulfonamide
  • Example 98 Isopropyl 2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-4- ((5-(N-methylmethylsulfonamido)-2,3-dihydrobenzofuran-6-yl)amino)pyrimidine-5-carboxylate
  • Step 1) Preparation of isopropyl 2-chloro-4-((5-( N -methylmethylsulfonamido)-2,3-dihydrobenzofuran-6-yl)amino)pyrimidine-5-carboxylate
  • Example 16 The title compound was obtained by performing the same process as step 3) of Example 16 using isopropyl 2,4-dichloropyrimidine-5-carboxylate.
  • Step 2) Isopropyl 2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-4-( Preparation of (5-( N -methylmethylsulfonamido)-2,3-dihydrobenzofuran-6-yl)amino)pyrimidine-5-carboxylate
  • Example Compounds structure Compound name MS [M+H]+ One N -(6-((2-((5-bromo-2-methoxy-4-(4-morpholinopiperidin-1-yl)phenyl)amino)-5-chloropyrimidin-4-yl )Amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide 708 2 N -(6-((5-bromo-2-((5-bromo-2-methoxy-4-(4-morpholinopiperidin-1-yl)phenyl)amino)pyrimidine-4- yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide 752 3 N -(6-((2-((5-bromo-2-methoxy-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-chloro Py
  • the new compound represented by Formula 1 according to the present invention can be formulated in various forms depending on the purpose.
  • the following is an example of several formulation methods containing the compound represented by Formula 1 as an active ingredient according to the present invention, and the present invention is not limited thereto.
  • Formulation Example 2 Tablets (wet granulation)
  • the active ingredient After 5.0 mg of the active ingredient was sieved, it was mixed with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. The mixture was mixed into solid No. 1 using a suitable device. Filled into 5 gelatin capsules.
  • An injection was prepared by containing 100 mg of the active ingredient, as well as 180 mg of mannitol, 26 mg of Na 2 HPO 4 ⁇ 12H 2 O, and 2974 mg of distilled water.
  • the compounds obtained in Examples 1 to 152 were EGFR-wt, del19/T790M/C797S/ (EGFR-DTC), L858R/T790M/C797S (EGFR-LTC), del19/C797S/ (EGFR-DC) , L858R/C797S (EGFR-LC), del19/T790M (EGFR-DT), and L858R/T790M (EGFR-LT)
  • the purpose was to confirm the growth inhibition ability of Ba/F3 cells expressing variants.
  • Partneal Ba/F3 cell line is a cell in which no EGFR mutation has been introduced. Specifically, 100,000 cells/1 ml of cell lines expressing each variant were placed in 100 ⁇ l of a 96 well plate. Prepare 2 mM compound by serial dilution in 10 points, 1/4 each. After 4 hours, 0.5 ⁇ l (0.5% DMSO) of the compound was added and cultured for 72 hours at 37°C with 5% CO2. After culturing, the number of living cells was measured using the Celltiter glo assay kit (Promega), and the 50% growth inhibition value (GI50, ⁇ M) of each compound was measured. The results are summarized and shown in Table 2.
  • the pyrimidine compound represented by Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention exhibits inhibitory activity against EGFR protein kinase, and thus abnormal cell metabolism and abnormal cell metabolism caused by EGFR protein kinase.
  • Diseases caused by sugar metabolism include, for example, metabolic diseases such as diabetes and obesity, and endometrial cancer, bladder cancer, stomach cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenoma, A group consisting of head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, leukemia, multiple myeloma, blood cancer such as myelodysplastic syndrome, lymphoma such as Hodgkin's disease and non-Hodgkin's lymphoma, or fibroadenoma. It is useful as a preventive and therapeutic agent for tumor diseases selected from.
  • metabolic diseases such as diabetes and obesity, and endometrial cancer, bladder cancer, stomach cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast

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Abstract

La présente invention concerne une composition pharmaceutique pour la prévention et le traitement de cancers, y compris le cancer du poumon, provoqué par une croissance cellulaire anormale, la composition contenant, en tant que principes actifs, un nouveau dérivé de pyrimidine trisubstitué ayant une activité inhibitrice vis-à-vis des protéines kinases comprenant l'EGFR, et un sel pharmaceutiquement acceptable de celui-ci. Le nouveau composé selon la présente invention a une excellente activité inhibitrice vis-à-vis des protéines kinases. En particulier, le nouveau composé selon la présente invention a un excellent effet inhibiteur sur divers mutants EGFR résistants aux médicaments (mutants EGFR comprenant l'exon 19 déletion-T790M-C797S-EGFR, L858R-T790M-C797S-EGFR, exon 19 déletion-C797S-EGFR, L858R-C797S-EGFR, exon 19 déletion-T790M-EGFR, L858R-T790M-EGFR, 19 déletion-EGFR et L858R-EGFR), et est utile en tant qu'agent pour prévenir et traiter des cancers provoqués par les mutants EGFR.
PCT/KR2023/014982 2022-09-30 2023-09-27 Dérivé de pyrimidine ayant une activité inhibitrice de protéine kinase, et composition pharmaceutique thérapeutique le comprenant WO2024072075A1 (fr)

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