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WO2022152313A1 - Dérivé de pyrimidine et son application pharmaceutique - Google Patents

Dérivé de pyrimidine et son application pharmaceutique Download PDF

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Publication number
WO2022152313A1
WO2022152313A1 PCT/CN2022/072530 CN2022072530W WO2022152313A1 WO 2022152313 A1 WO2022152313 A1 WO 2022152313A1 CN 2022072530 W CN2022072530 W CN 2022072530W WO 2022152313 A1 WO2022152313 A1 WO 2022152313A1
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Prior art keywords
mixture
compound
pharmaceutically acceptable
stereoisomer
tautomer
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PCT/CN2022/072530
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English (en)
Chinese (zh)
Inventor
张靖
魏用刚
尹杰
杨科
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Chengdu Baiyu Pharmaceutical Co Ltd
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Chengdu Baiyu Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • This application relates to pyrimidine derivatives and their use in medicine.
  • the RAS gene is one of the important human proto-oncogenes and plays a key role in regulating cell signal transduction and the occurrence and development of tumors; it is also the most frequently mutated oncogene in human cancers, and the RAS gene is present in about 30% of cancers. mutation.
  • the human RAS superprotein family contains three genes (KRAS, NRAS, and HRAS, respectively) that encode four proteins (KRAS-4A, KRAS-4B, NRAS, and HRAS).
  • KRAS is the most common subtype in the RAS family and the most easily mutated gene; 86% of RAS mutations are KRAS mutations, 86-96% of pancreatic cancer, 40-54% of colorectal cancer and 20-37% of KRAS gene mutations can be detected in lung cancers of 2000, and KRAS mutations are also found in cancers such as cholangiocarcinoma, cervical cancer, bladder cancer, liver cancer, and breast cancer (Kessler et al., 2019).
  • KARS proteins belong to the small GTPase family of proteins. Under normal physiological conditions, KRAS proteins regulate signaling pathways by transitioning between inactive (binding to GDP) and activated (binding to GTP) states (Downward, 2003): when KRAS binds to guanosine diphosphate (GDP) Inactive state; active state can activate downstream signaling pathways when combined with guanosine triphosphate (GTP).
  • GDP guanosine diphosphate
  • GTP guanosine triphosphate
  • GEFs guanine nucleotide exchange factors
  • GAPs GTPase activating/accelerating proteins
  • KRAS has a stronger binding ability to GDP, so KRAS in cells is generally inactive; when KRAS is activated by binding to GTP, it can be promoted through multiple downstream signaling pathways such as MAPK, PI3K, and Ral-GEFs. Cell survival, proliferation and cytokine release, etc. (Liu et al., 2019).
  • KRAS When KRAS is mutated or its conformation changes, its GTP hydrolysis activity decreases, its binding stability to GDP increases, and its interaction with GAP is blocked, so that KRAS protein is in a long-term activated state, and by stimulating a large number of downstream cell signals, it continues to promote cell growth and growth. Divide, eventually leading to cancer. Current studies have shown that the most common mutation of KRAS is single-point mutations at codons 12, 13 and 61, of which codon 12 mutations account for about 82% of KRAS mutations.
  • KRAS mutant cells In addition to KRAS gene alterations that directly lead to tumorigenesis, KRAS mutant cells also have a wide range of effects on the microenvironment that causes tumor progression through paracrine action, which can promote the secretion of various cytokines, chemokines and growth factors to fibroblasts and immune cells. It also affects the tumor microenvironment, and can also remodel and reprogram stromal cells.
  • KRAS inhibitors have been carried out in recent decades, and it was generally believed that this target is difficult to be drugged. The main reasons are as follows: (1) The affinity of KRAS protein to guanosine phosphate (GDP or GTP) is as low as picomolar (pM) ), the concentration of guanosine phosphate in cells can reach the millimolar (mM) level, which makes it difficult for general drugs (analogs of guanosine phosphate) to compete with KRAS proteins (Waters & Der, 2018); (2) KRAS The guanosine phosphate binding site of the protein also lacks a region suitable for the binding of other small molecule compounds.
  • small-molecule compounds can inhibit tumors with KRAS-G12C mutation. Because the 12th codon of KRAS protein is close to the nucleoside binding domain and catalytic center of the protein, after cysteine mutation at this site, small molecule compounds can affect KRAS through irreversible covalent binding to cysteine The function of the protein, and the small molecule compound is more inclined to bind to the KRAS-GDP protein, which reduces the affinity of GTP to the protein (Lito, Solomon, Li, Hansen, & Rosen, 2016).
  • ARS-853 an early developed small-molecule compound targeting KRAS-G12C tumors, showed good activity in vitro and effectively inhibited the conversion of GDP and GTP, but lacked in vivo activity (Patricelli et al., 2016). Subsequently, the structure was further optimized to obtain ARS-1620, which showed good pharmacological activity against KRAS-G12C tumor cells in vitro and in vivo, but had no significant effect on other KRAS mutant cells (Janes et al., 2018). At present, a variety of KRAS inhibitor drugs have entered the stage of clinical research, but according to the data published so far, the clinical efficacy in tumor patients still needs to be further improved. Therefore, there is still a need to develop a new generation of efficient and safe KRAS-G12C mutation inhibitors to better meet clinical needs.
  • One of the objectives of one or more embodiments of the present application is to provide novel pyrimidine derivatives, pharmaceutical compositions thereof, and their preparation for KRAS G12C inhibitors.
  • One or more embodiments of the present application provide compounds of general formula (I) or stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers thereof Isomers, or mixtures thereof, or solvates, metabolites, co-crystals, prodrugs, or pharmaceutically acceptable salts thereof:
  • R 1 is H, halogen or C 3-8 cycloalkyl
  • X is N or CR 3 ;
  • R 2 and R 3 are each independently H or halogen
  • Y is N or CR 4 ;
  • R 4 and R 5 are each independently H, hydroxy, halogen, amino, trifluoromethyl or C 1-6 alkyl;
  • R4 and R5 together with the carbon atom to which they are attached form a 4- or 5 -membered cycloalkyl or heterocycloalkyl containing 1 or 2 selected from N and O A heteroatom, the 4- or 5-membered cycloalkyl or heterocycloalkyl is optionally substituted with 1 or 2 C 1-6 alkyl groups;
  • n 1, 2, 3 or 4;
  • R 6 and R 7 are each independently C 1-6 alkyl or halogen
  • L is O or N atom
  • R 8 is C 3-8 cycloalkyl or C 3-8 heterocycloalkyl containing 1 to 4 heteroatoms selected from N and O, R 8 is optionally 1 or 2 C 1-6 alkyl substitutions;
  • n 0 or 1.
  • R 1 is selected from H, halogen or cyclopropyl
  • X is selected from N or CR 3 ;
  • R 2 and R 3 are each independently H or halogen
  • L is selected from O or N atoms
  • R 8 is selected from C 3-8 heterocycloalkyl containing 1 to 4 (eg 1, 2, 3 or 4) heteroatoms selected from N or O, R 8 optionally substituted with 1 or 2 C 1-6 alkyl;
  • n 0 or 1.
  • the halogen is F.
  • the C 1-6 alkyl group is methyl
  • R1 is H.
  • R 2 is halogen
  • R3 is halogen
  • R 4 is halo or C 1-6 alkyl, and R 5 is hydroxy.
  • R4 and R5 are taken together with the carbon atom to which they are attached to form a 4- or 5 -membered heterocycloalkyl group containing 2 N heteroatoms, so The 4- or 5-membered heterocycloalkyl is optionally substituted with 1 C 1-6 alkyl.
  • m is 2.
  • L is O.
  • R8 is C5-6 heterocycloalkyl containing 1 or 2 heteroatoms selected from N and O, and R8 is optionally Substituted with 1 C 1-6 alkyl.
  • n is one.
  • One or more embodiments of the present application provide compounds or stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, or the same thereof A mixture, or a solvate, metabolite, co-crystal, prodrug or pharmaceutically acceptable salt thereof, said compound being:
  • One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer thereof , or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug or pharmaceutically acceptable salt thereof, or use of a composition of the present application in the manufacture of a medicament for the treatment or prevention of cancer or tumor.
  • the cancer is pancreatic cancer, colorectal cancer, lung cancer, bile duct cancer, cervical cancer, bladder cancer, liver cancer, or breast cancer.
  • One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer thereof , or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug or pharmaceutically acceptable salt thereof, or use of a composition of the present application in the preparation of a KRAS G12C inhibitor.
  • One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer thereof , or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or use of a composition of the present application in the manufacture of a composition for the treatment or prophylaxis of a disease associated with KRAS G12C.
  • One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer thereof , or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or a composition of the present application, as a medicament.
  • One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer thereof , or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or a composition of the present application, for use in the treatment or prevention of cancer or tumor.
  • the cancer is pancreatic cancer, colorectal cancer, lung cancer, bile duct cancer, cervical cancer, bladder cancer, liver cancer, or breast cancer.
  • One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer thereof , or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or a composition of the present application, as a KRAS G12C inhibitor.
  • One or more embodiments of the present application provide a compound of the present application or a stereoisomer, tautomer, meso, racemate, enantiomer, diastereomer thereof , or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or a composition of the present application, for use in the treatment or prophylaxis of a disease associated with KRAS G12C.
  • One or more embodiments of the present application provide a method of treating or preventing cancer or tumor comprising administering to a subject in need thereof a compound of the present application or a stereoisomer, tautomer, mesomer thereof , racemates, enantiomers, diastereomers, or mixtures thereof, or solvates, metabolites, co-crystals, prodrugs, or pharmaceutically acceptable salts thereof, or compositions of the present application .
  • the cancer is pancreatic cancer, colorectal cancer, lung cancer, bile duct cancer, cervical cancer, bladder cancer, liver cancer, or breast cancer.
  • One or more embodiments of the present application provide a method of treating or preventing a disease associated with KRAS G12C, comprising administering to a subject in need thereof a compound of the present application or a stereoisomer, tautomer, endoisomer thereof A racemate, racemate, enantiomer, diastereomer, or a mixture thereof, or a solvate, metabolite, co-crystal, prodrug, or pharmaceutically acceptable salt thereof, or the present application Compositions.
  • One or more embodiments of the present application provide methods of inhibiting KRAS G12C, comprising administering to a subject in need thereof a compound of the present application, or a stereoisomer, tautomer, meso, racemic, or stereoisomer thereof Rotors, enantiomers, diastereomers, or mixtures thereof, or solvates, metabolites, co-crystals, prodrugs, or pharmaceutically acceptable salts thereof, or compositions of the present application.
  • the disease associated with KRAS G12C is cancer or tumor.
  • the disease associated with KRAS G12C is pancreatic cancer, colorectal cancer, lung cancer, bile duct cancer, cervical cancer, bladder cancer, liver cancer, or breast cancer.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention all include their isotopic conditions, and the carbons involved in the groups and compounds of the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, wherein isotopes of carbon include 12 C, 13 C and 14 C, and isotopes of hydrogen include protium (H), deuterium (D, Also known as heavy hydrogen), tritium (T, also known as super-heavy hydrogen), the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, and the isotopes of nitrogen include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
  • isotopes of carbon include 12 C, 13 C
  • Alkyl refers to a straight or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably 1 to 8 (eg 1, 2, 3, 4, 5, 6, 7, 8) carbon atoms , more preferably an alkyl group of 1 to 6 carbon atoms, further preferably an alkyl group of 1 to 4 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched chain isomers thereof; when the alkyl group is substituted, it can be optionally further substituted by one or more substituents.
  • Alkoxy refers to a group formed by substituting at least one carbon atom in an alkyl group with an oxygen atom.
  • Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyl oxy and cyclobutoxy.
  • the definition of alkyl is the same as the definition of "alkyl" described above.
  • Alkenyl means a straight chain consisting of 2 to 20 carbon atoms containing 1 to 10 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon-carbon double bonds Chain or branched unsaturated aliphatic hydrocarbon groups, preferably alkenyl groups of 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 2 to 12 An alkenyl group of 8 carbon atoms, more preferably an alkenyl group of 2 to 6 carbon atoms.
  • Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, Hexen-3-yl, hepten-2-yl, hepten-3-yl, hepten-4-yl, octen-3-yl, nonen-3-yl, decen-4-yl and undecen-yl Alken-3-yl.
  • the alkenyl group may be optionally further substituted with one or more substituents.
  • Alkynyl means a carbon-carbon triple bond containing 1 to 10 (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon-carbon triple bonds, consisting of 2 to 20 carbon atoms Linear or branched unsaturated aliphatic hydrocarbon groups, preferably alkynyl groups of 2 to 12 (eg 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms, more preferably 2 An alkynyl group of to 8 carbon atoms, more preferably an alkynyl group of 2 to 6 carbon atoms.
  • Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethyl butyn-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyn-4- yl, octyn-3-yl, nonyn-3-yl, decyn-4-yl, undecyn-3-yl, dodecyn-4-yl.
  • the alkynyl group may optionally be further substituted with one or more substituents.
  • Aryl means a substituted or unsubstituted aromatic ring, which may be a 5- to 8-membered (eg, 5, 6, 7, 8) , 8, 9, 10, 11, 12 membered) bicyclic ring or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, which may be a bridged ring or a spiro ring, non-limiting implementation Examples include phenyl, naphthyl. The aryl group may optionally be further substituted with one or more substituents.
  • Heteroaryl refers to a substituted or unsubstituted aromatic ring, which may be a 3 to 8 membered (eg 3, 4, 5, 6, 7, 8 membered) monocyclic, 5 to 12 membered (eg 6, 7, 8, 9, 10, 11, 12 membered) bicyclic ring or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 6 (eg 1, 2, 3, 4, 5, 6) heteroatoms selected from N, O or S, preferably 5- to 8-membered heteroaryl, 1 to 4 (eg 1, 2) optionally substituted in the ring of heteroaryl , 3, 4) N, S can be oxidized into various oxidation states.
  • N, S can be oxidized into various oxidation states.
  • Heteroaryl groups can be attached to heteroatoms or carbon atoms, and heteroaryl groups can be bridged or spirocyclic, non-limiting examples include cyclopyridyl, furyl, thienyl, pyranyl, pyrrolyl, pyrimidinyl, Pyrazinyl, pyridazinyl, imidazolyl, piperidinylbenzimidazolyl, benzopyridyl, pyrrolopyridyl. Heteroaryl groups are optionally further substituted with one or more substituents.
  • Carbocyclyl or “carbocycle” refers to a saturated or unsaturated aromatic or non-aromatic ring. When aromatic, it is as defined above for “aryl”; when non-aromatic, it may be 3 to 10 membered (eg 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic ring, 4 to 12 membered (eg 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) (membered) tricyclic ring system, which can be bridged or spiro, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2 -Alkenyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclo
  • Heterocyclyl or “heterocycle” refers to a saturated or unsaturated aromatic heterocycle or a non-aromatic heterocycle, and when it is an aromatic heterocycle, its definition is the same as the definition of "heteroaryl” above; when When it is a non-aromatic heterocycle, it can be a 3- to 10-membered (eg 3, 4, 5, 6, 7, 8, 9, 10-membered) monocyclic, 4- to 12-membered (eg 7, 8, 9, 10, 11, 12 membered) bicyclic ring or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring system, and contains 1 to 4 (eg 1, 2, 3, 4) heteroatoms selected from N, O or S, preferably a 3- to 8-membered heterocyclic group.
  • 1- to 10-membered eg 3, 4, 5, 6, 7, 8, 9, 10-membered
  • 4- to 12-membered eg 7, 8, 9, 10, 11, 12 membered
  • bicyclic ring or 10 to 15 membere
  • Optionally substituted 1 to 4 (eg 1, 2, 3, 4) N, S in the ring of “heterocyclyl” or “heterocycle” can be oxidized to various oxidation states; “heterocyclyl” or A “heterocycle” can be attached to a heteroatom or a carbon atom; a “heterocyclyl” or “heterocycle” can be a bridged ring or a spirocyclic ring.
  • heterocyclyl or “heterocycle” include oxiranyl, glycidyl, azetidinyl, oxetanyl, azetidinyl, thietanyl , 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, oxepanyl, thiepanyl, oxygen Azazelyl, diazepine, thiazepinyl, pyridyl, piperidinyl, homopiperidinyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyridyl Azinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl
  • Cycloalkyl refers to a saturated cyclic hydrocarbon group, the ring of which may be 3 to 10 membered (eg 3, 4, 5, 6, 7, 8, 9, 10 membered) monocyclic, 4 to 12 membered (eg 4 , 5, 6, 7, 8, 9, 10, 11, 12 yuan) double ring or 10 to 20 yuan (such as 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 yuan) and more
  • the ring carbon atoms are preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms.
  • Non-limiting examples of "cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexyl Alkenyl, cycloheptenyl, 1,5-cyclooctadienyl, 1,4-cyclohexadienyl and cycloheptatrienyl and the like. When cycloalkyl is substituted, it may be optionally further substituted with one or more substituents.
  • Heterocycloalkyl refers to a substituted or unsubstituted saturated non-aromatic ring group, which may be a (eg 4, 5, 6, 7, 8, 9, 10, 11, 12 membered) bicyclic or 10 to 15 membered (eg 10, 11, 12, 13, 14, 15 membered) tricyclic ring systems, including 1, 2 or 3 heteroatoms selected from N, O or S, preferably a 3- to 8-membered heterocyclic group.
  • heterocycloalkyl can be oxidized to various oxidation states; “heterocycloalkyl” can be attached to a heteroatom or carbon atom; “heterocycloalkyl” Alkyl” can be bridged or spiro.
  • heterocycloalkyl include oxiranyl, azetidinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxetanyl Oxolanyl, 1,3-dioxanyl, azepanyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, tetrahydrofuranyl , tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxa Tricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl.
  • Halogens include F, Cl, Br and I.
  • “Pharmaceutically acceptable salt” or “a pharmaceutically acceptable salt thereof” means that a compound of the present invention retains the biological effectiveness and properties of a free acid or free base that is treated with a non-toxic inorganic base or Organic bases, said free bases are salts obtained by reacting with non-toxic inorganic or organic acids.
  • “Pharmaceutical composition” refers to a mixture of one or more of the compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof and other chemical components, wherein “other chemical components” refers to pharmaceutically acceptable Accepted carriers, excipients and/or one or more other therapeutic agents.
  • Carrier refers to a material that is not appreciably irritating to the organism and that does not abrogate the biological activity and properties of the administered compound.
  • Excipient refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound.
  • Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binding agents agent and disintegrant.
  • a “prodrug” refers to a compound of the present invention that can be metabolized in vivo into a biologically active compound.
  • the prodrugs of the present invention are prepared by modifying the amino or carboxyl groups in the compounds of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound.
  • the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.
  • Co-crystal refers to a crystal formed by the combination of an active pharmaceutical ingredient (API) and a co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, wherein the pure states of API and CCF are both at room temperature solid, and there is a fixed stoichiometric ratio between the components.
  • a co-crystal is a multicomponent crystal that includes both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between neutral solids and salts or solvates.
  • Steps refer to isomers resulting from different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
  • heterocyclyl optionally substituted with an alkyl group means that the alkyl group may, but need not, be present, and the description includes instances where the heterocyclyl group is substituted with an alkyl group, as well as where the heterocyclyl group is not substituted with an alkyl group happening.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • HPLC assay was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 ⁇ 4.6 mm, 3.5 ⁇ M).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm-0.20mm, and the specification used for TLC separation and purification products is 0.4mm -0.5mm.
  • reaction solution was concentrated under reduced pressure to obtain a crude product which was dissolved in tetrahydrofuran (200 mL), and triethylamine (88 g, 682 mmol) and 2-tert-butoxycarbonyl-2,7-diazaspiro[3.5]nonane were slowly added dropwise at 0°C alkane (16.98 g, 75.0 mmol), and reacted at room temperature for 2 hours.
  • Water 200 mL
  • ethyl acetate 50 mL x 3
  • the organic phases were combined, concentrated, and separated by column chromatography to obtain 1c (yellow solid, 20 g, yield 56%).
  • compound 2 (white solid, 30 mg, yield 16%) was prepared under medium pressure.
  • compound 3 (white solid, 40 mg, yield 22%) was prepared under medium pressure.
  • compound 4 was prepared (white solid, 45 mg, yield 21%).
  • IC50 refers to the concentration of the compound at which the activity of KRAS is inhibited by 50%.
  • DMEM Dulbecco's modified eagle medium
  • FBS fetal bovine serum
  • NBT Nitrotetrazolium blue.
  • reaction temperature is room temperature
  • most suitable reaction temperature at room temperature is 20°C-30°C.
  • test compound was prepared into a 10 mM stock solution, doubling dilution (1:5) with growth medium, diluted 8-10 concentration gradients (initial concentration 10 ⁇ M), and added with 96 containing the upper layer of agarose-cells well (50 ⁇ L/well); set solvent control wells; each concentration was replicated twice, placed in a carbon dioxide incubator for 10-14 days.

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  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un dérivé de pyrimidine et une application pharmaceutique de celui-ci. La formule structurale du dérivé de pyrimidine est la suivante :
PCT/CN2022/072530 2021-01-18 2022-01-18 Dérivé de pyrimidine et son application pharmaceutique Ceased WO2022152313A1 (fr)

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WO2019150305A1 (fr) * 2018-02-01 2019-08-08 Pfizer Inc. Dérivés de quinazoline et de pyridopyrimidine substitués utiles en tant qu'agents anticancéreux
CN110267957A (zh) * 2017-02-02 2019-09-20 安斯泰来制药株式会社 喹唑啉化合物
CN111499634A (zh) * 2019-01-31 2020-08-07 贝达药业股份有限公司 一种喹唑啉化合物及其在医药上的应用
WO2020177629A1 (fr) * 2019-03-01 2020-09-10 劲方医药科技(上海)有限公司 Composé cyclique fusionné à une pyrimidine spiro-substitué, son procédé de préparation et son utilisation médicale
WO2020216190A1 (fr) * 2019-04-22 2020-10-29 贝达药业股份有限公司 Composé quinazoline et son application pharmaceutique
CN112110918A (zh) * 2019-06-21 2020-12-22 劲方医药科技(上海)有限公司 螺环取代的嘧啶并环类化合物，其制法与医药上的用途
WO2021031952A1 (fr) * 2019-08-16 2021-02-25 劲方医药科技(上海)有限公司 Composé de pyrimidine cyclique à six chaînons substitué par oxygène, son procédé de préparation et son utilisation médicale
WO2021190467A1 (fr) * 2020-03-25 2021-09-30 微境生物医药科技(上海)有限公司 Composé de quinazoline contenant un cycle spiro

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107849022A (zh) * 2015-04-10 2018-03-27 亚瑞克西斯制药公司 取代的喹唑啉化合物和其使用方法
CN108779097A (zh) * 2015-11-16 2018-11-09 亚瑞克西斯制药公司 包含取代的杂环基的2-取代的喹唑啉化合物及其使用方法
CN110267957A (zh) * 2017-02-02 2019-09-20 安斯泰来制药株式会社 喹唑啉化合物
WO2019150305A1 (fr) * 2018-02-01 2019-08-08 Pfizer Inc. Dérivés de quinazoline et de pyridopyrimidine substitués utiles en tant qu'agents anticancéreux
CN111499634A (zh) * 2019-01-31 2020-08-07 贝达药业股份有限公司 一种喹唑啉化合物及其在医药上的应用
WO2020177629A1 (fr) * 2019-03-01 2020-09-10 劲方医药科技(上海)有限公司 Composé cyclique fusionné à une pyrimidine spiro-substitué, son procédé de préparation et son utilisation médicale
WO2020216190A1 (fr) * 2019-04-22 2020-10-29 贝达药业股份有限公司 Composé quinazoline et son application pharmaceutique
CN112110918A (zh) * 2019-06-21 2020-12-22 劲方医药科技(上海)有限公司 螺环取代的嘧啶并环类化合物，其制法与医药上的用途
WO2021031952A1 (fr) * 2019-08-16 2021-02-25 劲方医药科技(上海)有限公司 Composé de pyrimidine cyclique à six chaînons substitué par oxygène, son procédé de préparation et son utilisation médicale
WO2021190467A1 (fr) * 2020-03-25 2021-09-30 微境生物医药科技(上海)有限公司 Composé de quinazoline contenant un cycle spiro

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