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WO2023246837A1 - Classe de composés ayant une structure cyclique pyrimido à six chaînons, compositions pharmaceutiques les comprenant et leur utilisation - Google Patents

Classe de composés ayant une structure cyclique pyrimido à six chaînons, compositions pharmaceutiques les comprenant et leur utilisation Download PDF

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WO2023246837A1
WO2023246837A1 PCT/CN2023/101588 CN2023101588W WO2023246837A1 WO 2023246837 A1 WO2023246837 A1 WO 2023246837A1 CN 2023101588 W CN2023101588 W CN 2023101588W WO 2023246837 A1 WO2023246837 A1 WO 2023246837A1
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substituted
unsubstituted
group
substituents
alkyl
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PCT/CN2023/101588
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Chinese (zh)
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李东升
刘财路
蔡亚磊
杨茂志
屠汪洋
于冰
谢晴
张毅翔
李乐平
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上海海和药物研究开发股份有限公司
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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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to a class of compounds having a pyrimido six-membered ring structure, their stereoisomers, racemates, geometric isomers, tautomers, prodrugs, hydrates, solvates or their Pharmaceutically acceptable salts, and pharmaceutical compositions containing them, which have SOS1 inhibitor activity.
  • RAS proteins include KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), HRAS (neuroblastoma RAS viral oncogene homolog) and NRAS (Harvey murine sarcoma virus oncogene), of which KRAS has two alternatively spliced isomers KRAS4A and KRAS4B.
  • RAS protein is mainly distributed on the inside of the cell membrane, and membrane localization is a key step in activating RAS.
  • RAS protein requires prenylation and palmitoylation of its C terminus, but due to the lack of palmitoylation site, the membrane localization of KRAS4B relies on the electrostatic interaction between the polybasic region composed of lysine and the plasma membrane.
  • RAS protein belongs to the small GTPase family and exists in cells in a GTP-binding or GDP-binding manner. The activation of RAS protein requires its transition from a GDP-bound state to a GTP-bound state.
  • GEFs guanine nucleotide exchange factors
  • SOS1 Syn of Sevenless 1
  • RAS activation will promote the activation of downstream effector molecules RAF, PI3K (Phosphoinositide 3-kinase) and RalGDS (Ral guanine nucleotide dissociation stimulator) to affect cell proliferation, growth, metabolism, migration, angiogenesis and other biological processes (Rodriguez-Viciana and McCormick, 2005; Young et al., 2009).
  • RAS proteins have intrinsic hydrolytic activity that converts GTP into GDP.
  • GTPase activating proteins can increase its hydrolysis rate to inactivate RAS.
  • GAPs and GEFs strictly regulate the inactivation and activation of RAS protein, but when the RAS protein is mutated, the regulatory mechanism is dysregulated.
  • RAS mutations in tumor cells mainly occur at positions G12, G13 and Q61. Mutations at these sites weaken endogenous and GAPs-mediated hydrolysis activities. Mutations at G13 and Q61 also increase the GTP exchange rate mediated by GEFs (Simanshu et al., 2017; Smith et al., 2013).
  • the SOS1 protein has two important motifs, the RAS exchanger motif (REM) and the CDC25 homology domain, which are the allosteric binding site and the catalytic binding site respectively.
  • REM RAS exchanger motif
  • CDC25 binds RAS-GDP to promote the exchange of GDP and GTP
  • REM binds RAS-GTP to further increase the catalytic activity of SOS1 (Freedman et al., 2006; Pierre et al., 2011).
  • SOS1 plays a key role in KRAS mutant tumors. Knocking down SOS1 will reduce the proliferation and viability of KRAS mutant tumor cells, but has no effect on KRAS wild-type cells (Jeng et al., 2012).
  • SOS1 plays an important role in activating the RAS signaling pathway. After activation of tyrosine kinase receptor RTKs, SHP2 is activated, binding to the adapter protein Grb2, promoting the formation of a complex between Grb2 and SOS1 and activating SOS1, thereby activating the RAS protein (Baltanas et al., 2020).
  • SOS1 mutations exist in tumor cells, such as embryonal rhabdomyosarcoma, lung adenocarcinoma, etc. (Denayer et al., 2010), while SOS1 is highly expressed in bladder cancer and prostate cancer (Timofeeva et al., 2009; Watanabe et al. ,2000). In addition, SOS1 is also present in Noonan syndrome (NS), cardio-facio-cutaneous syndrome (CFC), hereditary gingival fibromatosis and related syndromes. mutation (Pierre et al., 2011).
  • SOS2 the homolog of SOS1 also acts as a GEF to activate RAS proteins, and there is functional redundancy between the two.
  • Knocking out SOS1 in mice results in embryonic lethality (Qian et al., 2000), while conditional knocking out of SOS1 in adult mice is viable (Baltanas et al., 2013).
  • knocking out SOS2 in mice has no obvious phenotype (Esteban et al., 2000). If both SOS1 and SOS2 are knocked out in adult mice, the mice die quickly (Baltanas et al., 2013). Selective inhibition of individual SOS isoforms, such as SOS1, may be more effective in treating SOS1-RAS-activated diseases.
  • Inhibiting the SOS1 catalytic site from binding to RAS can prevent SOS1-mediated RAS-GTP production and inhibit the RAS signaling pathway.
  • RAS-dependent tumors such compounds can theoretically disrupt the combination of RAS and SOS, inhibit the phosphorylation of cellular ERK, and have anti-tumor effects.
  • Compounds that inhibit the interaction between SOS1 and RAS can inhibit RAS activity and can be used to treat head and neck cancer, lung cancer, mediastinal tumors, gastrointestinal tumors, prostate cancer, testicular cancer, gynecological tumors, breast cancer, kidney and bladder cancer, and endocrine system tumors.
  • soft tissue sarcoma soft tissue sarcoma, osteosarcoma, rhabdoid tumor, mesothelioma, skin cancer, peripheral nervous system tumors, central nervous system tumors, lymphoma, leukemia, unknown primary cancer, Noonan syndrome, cardiofaciocutaneous syndrome, Hereditary gingival fibromatosis and its associated syndromes.
  • the invention provides a compound of formula (I), its enantiomers, diastereomers, racemates, prodrugs, hydrates, solvates or pharmaceutically acceptable salts thereof:
  • ring A represents a C 6-10 aryl group, a 5-10 membered heteroaryl group or a 4-10 membered saturated or unsaturated heterocyclyl group; in particular, ring A is a phenyl group;
  • n is an integer from 0 to 5;
  • R 1 is selected from hydrogen, halogen, hydroxyl, unsubstituted or substituted C 1-6 alkyl, unsubstituted or substituted C 3-6 cycloalkyl, unsubstituted or substituted 4-10 membered saturated or unsaturated heterocycle group, unsubstituted or substituted C 1-6 alkoxy, -CN, -COOH, -CONH 2 , -CONH-C 1-6 alkyl, amino, -NH-C 1-6 alkyl; in particular, R 1 is selected from hydrogen, halogen, hydroxyl, unsubstituted or substituted C 1-4 alkyl, unsubstituted or substituted C 3-6 cycloalkyl, unsubstituted or substituted C 1-4 alkoxy, -CN , -COOH, amino; preferably, R 1 is selected from hydrogen, halogen, hydroxyl, -CN, methyl, ethyl, methoxy, ethoxy, amino,
  • R 2 is hydrogen, unsubstituted or substituted C 1-6 alkyl, or unsubstituted or substituted C 3-6 cycloalkyl; in particular, R 2 is methyl or ethyl;
  • R 4 is hydrogen, unsubstituted or substituted C 1-10 alkyl, unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C 3- 6- cycloalkyl, unsubstituted or substituted 4-10-membered saturated or unsaturated heterocyclyl, unsubstituted or substituted 5-10-membered heteroaryl and 4-10-membered heterocyclyl, halogen, -CN, -COOH , -OR 5 , -NH-R 5 , -CONH-R 5 , -NHCO-R 5 , -SO 2 -R 5 , or -SO 2 NH-R 5 ; preferably, R 4 is selected from unsubstituted or substituted C 1-10 alkyl, unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted 5-6 membered heteroaryl
  • R 5 is selected from hydrogen, unsubstituted or substituted C 1-10 alkyl, unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C 3 -6 cycloalkyl, unsubstituted or substituted 4-10 membered saturated or unsaturated heterocyclyl;
  • substitution in R 1 , R 2 , R 4 and R 5 means substitution with one or more substituents from the following group A.
  • the substituents in group A include: unsubstituted or one of the substituents in group B.
  • One or more substituted C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, hydroxyl, halogen, cyano, amino, carboxyl, oxo group ( O), -NH-C 1-6 alkyl, -NH-C 3-6 cycloalkyl, unsubstituted or C 6-10 aryl substituted with one or more substituents of Group B, unsubstituted or substituted by Group B 5-10 membered heteroaryl substituted by one or more substituents, C 3-6 cycloalkyl unsubstituted or substituted by one or more substituents of Group B, unsubstituted or substituted by Group B One or more substituted 4-10-membered saturated or unsaturated hetero
  • R2 is methyl or ethyl.
  • Ring A is phenyl
  • n is 1, 2 or 3; preferably, n is 1 or 2;
  • Each R 3 is independently selected from: substituted or unsubstituted C 1-4 alkyl, substituted or unsubstituted C 2-4 alkynyl, substituted Or unsubstituted 4-6 membered saturated or unsaturated heterocyclic group, halogen, cyano group and amino group; the substitution refers to being substituted by one or more substituents selected from halogen, hydroxyl, cyano group and amino group ;Other substituents are as defined above.
  • each R 3 is independently selected from: halogen, cyano, C 1-2 alkyl, halo C 1-2 alkyl; preferably, each R 3 is independently methyl, F , CN, CHF 2 or CF 3 ; more preferably, each R 3 is independently F or CHF 2 .
  • R 1 is hydrogen, halogen, hydroxyl, unsubstituted or substituted C 1-4 alkyl, unsubstituted or substituted C 3-6 cycloalkyl, unsubstituted or substituted C 1-4 alkyl Oxygen, -CN, -COOH, or amino; the substitution means substitution with one or more selected from hydroxyl, halogen, cyano, and amino; preferably, R 1 is hydrogen, halogen, hydroxyl, -CN, methyl, ethyl, methoxy, ethoxy, amino, or cyclopropyl; more preferably, R 1 is hydrogen, halogen, -CN, methyl, methoxy, or cyclopropyl; Other substituents are as defined above.
  • R 4 is selected from unsubstituted or substituted C 1-10 alkyl, unsubstituted or substituted C 6-10 aryl, unsubstituted or substituted 5-6 membered heteroaryl, unsubstituted or substituted C 3-6 cycloalkyl, unsubstituted or substituted 4-10 membered heterocyclyl;
  • the 5-6 membered heteroaryl group is selected from: Preferably, the 5-6 membered heteroaryl group is selected from:
  • the 4-10 membered heterocyclic group is selected from: Preferably, the 4-10 membered heterocyclic group is selected from
  • R 4 means that it is substituted by one or more of the following substituents of Group A.
  • the substituents of Group A include: C 1 which is unsubstituted or substituted by one or more of the substituents of Group B. -6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, hydroxyl, halogen, cyano, amino, carboxyl, -C(O)-R 6 , -C(O)-NH-R 6 ; R 6 is selected from hydrogen, unsubstituted or C 1-10 alkyl substituted by one or more of the substituents of Group B, unsubstituted or substituted by one or more of the substituents of Group B C 3-6 cycloalkyl;
  • Group B substituents include: C 1-6 alkyl, C 1-6 alkoxy, hydroxyl, halogen, cyano, amino, carboxyl.
  • R 4 is selected from C 1-10 alkyl which is unsubstituted or substituted by m substituents R 7 and the following structure:
  • n 1, 2 or 3;
  • R 7 and R 8 are each independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, which is unsubstituted or substituted by one or more of the substituents in Group B. group, hydroxyl, halogen, cyano, amino, carboxyl, -C(O)-R 9 ;
  • R 9 is selected from hydrogen, unsubstituted or C 1-10 alkane substituted by one or more of the substituents in Group B group, unsubstituted or C 3-6 cycloalkyl substituted by one or more of the substituents in Group B;
  • Group B substituents include: C 1-6 alkyl, C 1-6 alkoxy, hydroxyl , halogen, cyano, amino, carboxyl;
  • n 1 or 2;
  • R 7 is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, hydroxyl , halogen, which is unsubstituted or substituted by one or more of the substituents of Group B.
  • Group B substituents include: hydroxyl, halogen, cyano group, amino group;
  • R 8 is selected from H, C 1-6 alkyl, C 1-6 alkoxy, -C(O)-R 9 ;
  • R 9 is selected from C 1-6 alkyl, C 3-6 cycloalkyl;
  • n 1 or 2;
  • R 7 is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, hydroxyl , halogen, which is unsubstituted or substituted by one or more of the substituents of Group B.
  • Group B substituents include: hydroxyl, halogen, cyano group, amino group;
  • R 8 is selected from H, methyl, ethyl, methoxy, ethoxy, -C(O)-R 9 ;
  • R 9 is selected from methyl, ethyl, cyclopropyl;
  • R 4 is selected from C 1-6 alkyl substituted by hydroxyl and/or C 3-6 cycloalkyl and the following structure:
  • R 7 and R 7 ' are selected from H, hydroxyl, amino, methyl, ethyl, methoxy, hydroxymethyl, hydroxyethyl, and R 8 is selected from H, methyl, ethyl, methoxy, -C(O)-R 9 ; R 9 is selected from methyl, ethyl, and cyclopropyl;
  • R 1 is methyl, methoxy or cyclopropanyl.
  • R 3 is F, CHF 2 , CF 3 or CN.
  • the compound of formula (I) is represented by the following formula III:
  • R 4 is defined as above respectively.
  • the compound of formula (I) is selected from the following compounds:
  • Another aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising:
  • Another aspect of the present invention provides the compound of formula (I), its enantiomers, diastereomers, racemates, prodrugs, hydrates, solvates or pharmaceutically acceptable compounds thereof. Acceptable salts, or the use of said pharmaceutical composition in the preparation of SOS1 inhibitors.
  • Another aspect of the present invention provides the compound of formula (I), its enantiomers, diastereomers, racemates, prodrugs, hydrates, solvates or pharmaceutically acceptable compounds thereof.
  • the diseases related to SOS1 mutation, activity or expression include head and neck cancer, lung cancer, mediastinal tumors, gastrointestinal tumors, prostate cancer, testicular cancer, gynecological tumors, breast cancer, kidney and bladder cancer, endocrine system tumors, Soft tissue sarcoma, osteosarcoma, rhabdoid tumor, mesothelioma, skin cancer, peripheral nervous system tumors, central nervous system tumors, lymphoma, leukemia, unknown primary cancer, Noonan syndrome, cardiofaciocutaneous syndrome, genetic Gingival fibromatosis and its related syndromes.
  • the compound of the present application exhibits significantly excellent KRAS-G12C/SOS1 interaction inhibitory activity. Therefore, it has the potential to be an SOS1 inhibitor and can be developed into a therapeutic drug for diseases related to this.
  • the group valency has a wavy line when, for example, , the wavy line indicates the point of attachment of the group to the rest of the molecule.
  • the halogen is F, Cl, Br or I.
  • C 1-6 means having 1, 2, 3, 4, 5 or 6 carbon atoms
  • C 1-8 means having 1, 2, 3, 4, 5, 6 , 7 or 8 carbon atoms, and so on.
  • 3- to 8-membered heterocyclyl refers to a heterocyclic group with 3-8 ring atoms, and so on, “4- to 10-membered heterocyclyl” and so on.
  • alkyl refers to a saturated linear or branched hydrocarbon moiety.
  • C 1-10 alkyl refers to a linear or branched alkyl group having 1 to 10 carbon atoms, without limitation. Specifically include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl, etc.; preferably methyl, ethyl, propyl, isopropyl base, butyl, isobutyl, sec-butyl and tert-butyl.
  • the C 1-10 alkyl group is preferably a C 1-6 alkyl group, and more preferably a C 1-4 alkyl group.
  • alkoxy means an -O-(C 1-6 alkyl) group.
  • C 1-6 alkoxy refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including without limitation methoxy, ethoxy, propoxy, iso Propoxy and butoxy etc.
  • alkenyl refers to a linear or branched chain hydrocarbon moiety containing at least one double bond.
  • C 2-6 alkenyl refers to a hydrocarbon group having 2 to 6 carbon atoms and containing one double bond.
  • Straight-chain or branched alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, and the like.
  • cycloalkyl refers to a saturated cyclic hydrocarbon moiety.
  • C 3-8 cycloalkyl refers to a cyclic alkyl group with 3 to 8 carbon atoms in the ring, without limitation. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclodecyl, etc.
  • aryl refers to a carbocyclic hydrocarbon group consisting of one ring or more, such as two fused rings, at least one of which is an aromatic ring.
  • aryl groups include, but are not limited to, phenyl, naphthyl, and the like.
  • heterocyclyl refers to a cyclic group containing at least one carbon atom and at least one (such as 1-3) cyclic heteroatoms selected from N, O, and S, specifically as used in this application.
  • R is hydrogen, C 1-4 alkyl or nitrogen protecting group (for example, benzyloxycarbonyl, p-methoxybenzylcarbonyl, tert-butoxycarbonyl, acetyl , benzoyl, benzyl, p-methoxy-
  • Heterocyclyl includes monocyclic, bridged, spiro and other bicyclic structures, such as 3- to 8-membered heterocyclyl, 3- to 6-membered heterocyclyl, etc.; such as tetrahydrofuranyl, pyrrolidinyl, oxyheterocycle Butyl, oxanyl, azetidinyl, oxiranyl, aziridinyl, thietanyl, 1,2-dithietanyl, 1,3-di Thietanyl, azepanyl, oxetanyl, etc.
  • the term "5- to -10-membered heteroaryl” refers to a monomer having 5 to 10 ring atoms, such as 5, 6 or 7 ring atoms (ie, 5- to 7-membered heteroaryl).
  • a cyclic or bicyclic or fused polycyclic cyclic aromatic hydrocarbon group which contains at least one (such as 1-3) ring heteroatoms independently selected from N, O and S (such as N) in the ring, and the remaining ring atoms Is a carbon atom; such as imidazolyl, pyridyl, pyrrolyl, thiazolyl, furyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, pyrimidinyl, 1,2,4-triazolyl, etc. ; Preferred is a five-membered heteroaryl group, such as imidazolyl, isoxazolyl, and 1,2,4-triazolyl.
  • Bicyclic heteroaryl groups include, for example, benzoxazolyl, imidazopyridyl, triazolopyridyl, benzofuryl, pyrazolopyrimidinyl, benzodioxolyl, indolyl , quinolyl, isoquinolyl, etc.
  • the substitution is mono-substitution or poly-substitution
  • the poly-substitution is disubstitution, tri-substitution, tetra-substitution or penta-substitution.
  • the disubstituted means having two substituents, and so on. In the case of polysubstitution, the substituents may be the same as or different from each other.
  • the pharmaceutically acceptable salt described in the present invention may be a salt formed by an anion and a positively charged group on the compound of formula (I).
  • Suitable anions are chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, tosylate, tartrate, fumarate Acid, glutamate, glucuronate, lactate, glutarate or maleate.
  • salts can be formed from cations with negatively charged groups on compounds of formula I. Suitable cations include sodium, potassium, magnesium, calcium and ammonium ions, such as tetramethylammonium.
  • “pharmaceutically acceptable salts” refer to salts formed by the compound of formula (I) with an acid selected from the following group: hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, Sulfuric acid, nitric acid, methanesulfonic acid, sulfamic acid, salicylic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, citric acid, acetic acid, lactic acid, tartaric acid, succinic acid, wood sorrel Acid, pyruvic acid, malic acid, glutamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, malonic acid, fumaric acid, propionic acid, oxalic acid, trifluoroacetic acid, stealic acid,
  • “Therapeutically effective amount” refers to the amount of active ingredient sufficient to significantly improve the condition without causing serious side effects.
  • pharmaceutical compositions typically contain 1-2000 mg active ingredient/dose, more preferably, 10-200 mg active ingredient/dose.
  • the "dose” is a tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gel substances that are suitable for human use and must be of sufficient purity and low enough toxicity. "Compatibility” here refers to the ability of each component of the composition to be blended with the active ingredients of the present invention and with each other without significantly reducing the efficacy of the active ingredients.
  • Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearin acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • talc such as sodium carb
  • the administration mode of the active ingredients or pharmaceutical compositions of the present invention is not particularly limited.
  • Representative administration modes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), etc.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • the compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions may contain, in addition to the active ingredient, suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances and the like.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances and the like.
  • compositions for parenteral injection may contain physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the compounds of the present invention can be administered alone or in combination with other therapeutic drugs (such as anti-tumor drugs).
  • a therapeutically effective dose of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, and the dosage when administered is a pharmaceutically effective dosage.
  • a mammal such as a human
  • the daily dose is usually 1 to 2000 mg, preferably 20 to 500 mg.
  • the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the skill of a skilled physician.
  • the compound of general formula (I) of the present invention can be synthesized through the following synthetic route.
  • the synthetic route described below the information involved such as solvents, acids, bases, coupling catalysts and ligands are based on existing organic chemistry knowledge and famous reactions.
  • the present invention relates to the synthesis of a class of chiral amine intermediates, and its main synthesis route is as shown in Synthesis Route 1:
  • the R 3 -substituted aromatic bromide (I-a) and the tin reagent are cleaved through Stille coupling reaction under acidic conditions to obtain the compound (I-d).
  • the Weinreb amide (I-c) can be obtained through the condensation reaction of R3 - substituted aromatic carboxylic acid (I-b) and dimethylhydroxylamine hydrochloride, and then reacted with Grignard reagent to obtain the corresponding ketone (I-d ).
  • Ketone (I-d) reacts with (S)-(-)-tert-butylsulfenamide to generate the corresponding ketimine (I-e), which is stereoselectively reduced to obtain (I-f) .
  • the sulfinyl group is removed in a hydrogen chloride system to obtain the intermediate chiral amine hydrochloride (I-g).
  • the carboxylic acid reacts with a sulfuric acid methanol system or trimethylsilyl diazomethane to obtain the methyl esterification product (II-c).
  • reduction reaction such as catalytic hydrogenation, iron powder/dilute hydrochloric acid system, the nitro group is reduced to obtain the amino compound (II-d).
  • This compound is halogenated, such as using NCS, to obtain R1 is methoxy and 6-position is chlorinated.
  • 2-chloro-5-amino-4-pyridinecarboxylic acid (II-e) can also be used as the starting material, esterified to obtain the methyl ester (II-f), and then halogenated with NBS to obtain a dihalo-substituted pyridine compound. (II-g).
  • the above halide and the corresponding boron reagent such as trimethylcyclotriboroxane and cyclopropylboronic acid, are coupled under the catalysis of palladium reagent to obtain compounds (II-h) with different types of R 1 substituents, such as methyl , cyclopropyl compounds.
  • the multi-substituted pyridine compound (II-h) and formamidine acetate are cyclized to obtain the pyrimidopyridine ring compound (II-i).
  • This compound and the chiral amino compound (II-g) prepared in the synthetic route 1 undergo a condensation reaction to obtain Amino-substituted compound (II-j).
  • Chlorine-containing compound (II-j) undergoes a coupling reaction, such as Suzuki, Buchwald, Stille, etc., to introduce compound (I) with R 4 substituent.
  • the R 4 group also involves the introduction of some functional groups, which are specifically explained in subsequent examples.
  • Diethylamine sulfur trifluoride DAST; 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate: HATU; dioxane : dixoane; dichloromethane: DCM; N,N-dimethylformamide: DMF; petroleum ether: PE; ethyl acetate: EA.
  • Step 1 Add compound Int-1-a (100g, 0.49mol) and dichloromethane 1L) into a dry 3L round-bottomed flask. The solution was cooled to 0°C, and DAST (120g, 0.17mol) was added dropwise under nitrogen protection. After the addition, the mixture was raised to room temperature and reacted for 16 hours. The reaction solution was poured into ice water, extracted with EA (500mL Bromo-3-(difluoromethyl)-2-fluorobenzene Int-1-b (90g, light yellow oil), yield: 82%.
  • EA 500mL Bromo-3-(difluoromethyl)-2-fluorobenzene Int-1-b (90g, light yellow oil), yield: 82%.
  • Step 2 Add compound Int-1-b (90g, 0.40mol), tributyl (1-ethoxyvinyl) stannane (173g, 0.48mol) and anhydrous to a dry 2L single-neck round-bottomed flask in sequence.
  • Dioxane 900 mL
  • triethylamine 101 g, 1.0 mol
  • bis(triphenylphosphine) palladium (II) chloride 2.8 g, 4.0 mmol
  • Step 3 Add compound Int-1-c (100g, crude product) and anhydrous dioxane (200mL) into a dry 1L single-neck round-bottom flask in sequence.
  • the solution was cooled to 0°C, and dilute hydrochloric acid (200 mL, 0.40 mol, 2 M) was added dropwise under nitrogen protection. After the dropwise addition, the mixture was raised to room temperature and reacted for 12 hours.
  • the reaction solution was poured into water, and the filtrate was extracted with dichloromethane (300mL 1) Obtain 1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-one Int-1-d (53g, light yellow oil), yield: 50% in two steps.
  • Step 4 Add compound Int-1-d (17g, 90mmol), (S)-2-methylpropane-2-sulfinamide (16g, 0.14mol) and anhydrous to a dry 1L single-neck round-bottomed flask in sequence.
  • Step 5 In a dry 1L three-necked flask, add dichloro(p-methylcumyl)ruthenium(II) dimer (1.4g, 2.3mmol), (1S,2R)-1-amino-2, 3-Dihydro-1H-inden-2-ol (0.70g, 4.5mmol), 4A molecular sieve (50g) and isopropanol (100mL) were stirred and reacted at 90°C for 20 minutes under argon protection.
  • reaction temperature was cooled to 40°C, a solution of compound Int-1-e (13g, 45mmol) in isopropyl alcohol (450mL) and a solution of potassium tert-butoxide in isopropyl alcohol (113mL, 11mmol, 0.1M) were added in sequence, and reaction was carried out at 40°C 2 Hour.
  • the reaction solution was concentrated, saturated brine (100 mL) was added to the residue, and extracted with EA (100 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate.
  • Step 6 Add compound Int-1-f (12.5g, 43mmol) and anhydrous dioxane (100mL) into a dry 1L single-neck round-bottom flask in sequence.
  • the solution was cooled to 0°C, and dilute hydrochloric acid dioxane solution (50 mL, 0.20 mol, 4 M) was added dropwise under nitrogen protection. After the dropwise addition, the mixture was raised to room temperature and stirred for 12 hours.
  • the reaction solution was concentrated, methyl tert-butyl ether (200 mL) was added to the residue, and stirred for 2 hours.
  • the precipitated product was filtered and dried to obtain (R)-1-(3-(difluoromethyl)-2-fluorophenyl).
  • Step 1 Add compound Int-2-a (100g, 465mmol), dry DMF (1.5L) and HATU (195g, 512mmol) into a dry 3L three-necked flask. After stirring at room temperature for 30 minutes, add methoxymethyl. Amine hydrochloride (69g, 512mmol) and N,N-diisopropylethylamine (180g, 1.4mol) were stirred at room temperature for 3 hours.
  • Step 2 Add compound Int-2-b (20g, 77mmol) and anhydrous tetrahydrofuran to a dry 1L three-necked bottle. (300 mL), cooled to 0°C in an ice bath, methylmagnesium bromide (51 mL, 154 mmol, 3.0 M) was added dropwise, and the reaction was slowly raised to room temperature and stirred for 3 hours.
  • methylmagnesium bromide 51 mL, 154 mmol, 3.0 M
  • Step 3 Add compound Int-2-c (9.3g, 47mmol), anhydrous tetrahydrofuran (250mL), (R)-(+)-tert-butylsulfenamide (6.4g, 52mmol) and titanium tetraethoxide (50g, 218mmol), stirred and reacted at 80°C for 12 hours under argon protection.
  • Step 4 Add dichloro(p-methylcumyl)ruthenium(II) dimer (0.73g, 1.2mmol) and (1S,2R)-1-amino-2,3 in sequence to a 500mL three-necked flask. -Dihydro-1H-inden-2-ol (0.35g, 2.4mmol), 4A molecular sieve (29g) and isopropyl alcohol (60mL), under argon protection, react at 90°C for 20 minutes, the system changes from yellow to deep red .
  • Step 5 Add compound Int-2-e (6.1g, 19mmol) and dioxane (50mL) into a dry 250mL single-mouth bottle, cool to 0°C in an ice bath, and add hydrochloric acid/1,4 dioxane dropwise. (25 mL, 100 mmol, 4 M) solution, stirred at room temperature for 12 hours. The reaction solution was concentrated, PE (200 mL) was added to the crude product, stirred for 12 hours, filtered, and dried to obtain (R)-1-(3-bromo-2-methylphenyl)ethane-1-amine hydrochloride Int- 2-f (4.8g, dark gray solid), yield: 100%.
  • Step 6 Add compound Int-2-f (6.5g, 30mmol), di-tert-butyl dicarbonate (1.3g, 33mmol), and N,N-diisopropylethylamine (12g) into a dry 250mL single-mouth bottle in sequence. ,31mmol) and anhydrous dichloromethane (150mL), stir at room temperature for 3 hours.
  • Step 7 Add compound Int-2-g (7.1g, 23mmol) and zinc cyanide into a dry 250mL single-mouth bottle (3.2g, 27mmol), tetrakis triphenylphosphine palladium (2.6g, 2.3mmol) and anhydrous DMF (100mL), stir and react at 110°C for 3 hours under argon protection. Dilute with water (150 mL), extract with EA (200 mL ⁇ 3), combine the organic phases, wash with saturated brine (100 mL ⁇ 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue obtained is subjected to silica gel column chromatography.
  • Step 8 Add compound Int-2-h (5.0g, 16mmol) and dioxane (50mL) to a dry 250mL single-mouth bottle, cool to 0°C in an ice bath, and add hydrochloric acid/1,4 dioxane dropwise. (25mL, 100mmol, 4M) solution, warmed to room temperature and stirred for 15 hours. The reaction solution was concentrated, methyl tert-butyl ether (200 mL) was added, stirred for 12 hours, filtered, and dried to obtain (R)-3-(1-aminoethyl)-2-toluonitrile hydrochloride Int-2 (3.0 g , white solid), yield: 80%.
  • Step 2 Dissolve compound A-1-b (9.0g, 48.1mmol) and N-bromosuccinimide (10.3g, 57.8mmol) in 150mL DMF, and stir at 85°C for 16 hours under nitrogen protection. .
  • the reaction solution was extracted with EA, the organic phase was collected and dried over anhydrous sodium sulfate, then cold water was added to the organic phase at 0°C, filtered and the precipitated product was collected to obtain compound A-1-c (13g, brown solid). Yield: 100%.
  • LCMS(ESI): m/z 265[M+H] + .
  • Step 5 Dissolve compound A-1-e (250mg, 1.3mmol) and compound Int-1 (226mg, 1.4mmol) in an eggplant-shaped flask filled with 10mL DMF, then add PyBOP (733mg, 1.4mmol), N,N-diisopropylethylamine (3.3g, 25.6mmol) was stirred at 50°C for 10 hours under nitrogen protection.
  • the reaction solution was extracted with EA, the organic phase was collected and dried over anhydrous sodium sulfate, the organic phase was filtered and concentrated under reduced pressure. The residue was purified by normal phase column chromatography to obtain compound A-1-f (180 mg, yellow solid), yield: 39%.
  • LCMS (ESI): m/z 367.1[M+H] + .
  • Step 6 Dissolve compound A-1-f (180 mg, 0.14 mmol) and N-Boc-piperazine (275 mg, 1.5 mmol) in a 3 mL dioxane sealed tube, and add cesium carbonate ( 482 mg, 1.5 mmol), Binap (60 mg, 0.1 mmol) and NHC-Pd (34 mg, 0.05 mmol), stirred at 110°C for 8 hours under nitrogen protection.
  • the reaction solution was extracted with EA, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was preparatively purified to obtain compound A-1-g (80 mg, yellow solid), yield: 32%.
  • LCMS (ESI): m/z 517.2[M+H] + .
  • Step 7 Dissolve compound A-1-g (80 mg, 0.16 mmol) in 3 mL of methylene chloride, add trifluoroacetic acid (1 mL) to the reaction system, and stir at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound A-1-h (60 mg, yellow oil), yield: 94%.
  • LCMS (ESI): m/z 417.2[M+H] + .
  • Step 2 Add HCl (5 mL, 2.0 N, aq.) to a solution of compound A-10-b (200 mg, 0.50 mmol) in dioxane (10 mL), and react at room temperature for 4 hours. Adjust the pH to 6 with sodium hydroxide solution (2.0N), extract with EA, filter and concentrate under reduced pressure. The residue (crude product A-10-c) is directly used in the next reaction.
  • LCMS(ESI): m/z 375.1[M+H] + .
  • Step 3 Slowly add methylmagnesium bromide (0.32 mL, 0.32 mmol) into a solution of compound A-10-c (60 mg, 0.16 mmol) in THF (3 mL), and react at room temperature overnight. Quenched with saturated ammonium chloride solution, then extracted with ethyl acetate, filtered and concentrated under reduced pressure, the residue was purified by reverse phase preparative purification to obtain A-10 (11.0 mg, yield: 17%).
  • Step 2 Add compound A-11-a (40 mg, 0.09 mmol), palladium on carbon (0.02 mmol) and 10 mL methanol to a single-mouth bottle, stir at room temperature overnight under a hydrogen atmosphere, and perform reverse preparative purification to obtain the target compound A-11 (20 mg ), white solid, yield: 50%.
  • LCMS (ESI): m/z 458.2[M+H] + .
  • Step 1 Dissolve compound A-12 (80 mg, 0.17 mmol) in 10 mL dichloromethane, cool the dry ice-EA system to low temperature, and add DAST (1.2 eq). After the addition is completed, the mixture is naturally raised to room temperature and stirred overnight. The reaction was quenched with ammonium chloride, dichloromethane-water system was added, and the layers were separated. The organic phase was collected, dried over anhydrous magnesium sulfate, and concentrated to obtain crude compound A-13-a, which was directly used in the next step.
  • Step 2 Add the crude compound A-13-a to the sealed tube, dissolve it in 5 mL of methanol, and then slowly add 20 mg of sodium methoxide. Sealed, react at 70°C for 2 hours. Add a small amount of water to quench. The reaction system was prepared by reverse phase to obtain the target compound A-13 (13.2 mg) as a white solid. The two-step yield: 16%.
  • LCMS (ESI): m/z 488.1[M+H] + .
  • Step 1 Add compound A-13-a (50 mg, 0.11 mmol), 1 mL ammonia water, and dioxane 2 into the sealed tube. mL. Seal and react at 100°C for 2 hours. The reaction solution was prepared by reverse phase to obtain target compound A-14 (8.3 mg) as a white solid, yield: 16%.
  • LCMS (ESI): m/z 473.1[M+H] + .
  • Step 1 Dissolve compound A-1-f (50mg, 0.14mmol) and compound A-22-a (71.7mg, 0.68mmol) into 1,4-dioxane (2mL) in a sealed tube, and then Add NHC-Pd (7.5mg), BINAP (8.5mg, 0.014mmol) and Cs 2 CO 3 (134.0 mg, 0.41 mmol), reacted at 110°C for 8 hours under nitrogen protection.
  • reaction solution was extracted with saturated ammonium chloride solution and EA, the organic phase was backwashed with saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by neutral reversed phase preparation to obtain compound A-22 (28.0 mg, Light yellow solid), yield: 45.5%.
  • LCMS (ESI): m/z 452.0[M+H] + .
  • Step 1 Add compound A-1-f (50 mg, 0.14 mmol), 1,4-dioxane (5 mL), A-35-a (58 mg, 0.68 mmol), and cesium carbonate in sequence to a dry sealed tube. (137 mg, 0.41 mmol), NHC-Pd (9.3 mg, 0.01 mmol), BINAP (8.5 mg, 0.01 mmol); stir overnight at 110°C under nitrogen protection. Cool, quench the reaction solution with ammonium chloride solution, add EA for extraction, backwash the organic phase with saturated brine, dry over sodium sulfate, and concentrate under reduced pressure. The residue is purified by flash column chromatography to obtain white solid A-35 (21.6 mg, yield: 41%).
  • Test Example 1 Detection of the Inhibitory Effect of Compounds on KRAS-G12C/SOS1
  • IC 50 represents the inhibitory ability of the compound on KRAS-G12C/SOS1. The lower the IC 50 value, the stronger its inhibitory ability.
  • BI-3406 was used as a positive control compound.
  • KRASG12C/SOS Binding kit (Cisbio, cat. 63ADK000CB16PEG); DMSO (Sigma, cat. D8418-1L); 384-well white plate (PerkinElmer, cat. 6007290)
  • the concentration of the test compound is 5000nM, dilute it into a 100% DMSO solution of 200 times the final concentration in a 384-well plate, and dilute the compound 3 times to 10 concentrations.
  • Inhibition% (Max signal-Compound signal)/(Max signal-Min signal) ⁇ 100; where Min signal is the mean value of the negative control wells and Max signal is the mean value of the positive control wells.
  • a in IC 50 means IC 50 ⁇ 200nM
  • B means 200nM ⁇ IC 50 ⁇ 2000nM
  • C means 2000nM ⁇ IC 50 ⁇ 5000nM
  • D means IC 50 > 5000nM.

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Abstract

La présente invention concerne une classe de composés ayant une structure cyclique pyrimido à six chaînons, des compositions pharmaceutiques les comprenant, et leur utilisation. Les composés ont une structure représentée par la formule (I) ci-dessous. Des expériences prouvent que les composés selon la présente invention ont une excellente activité inhibitrice contre l'interaction KRAS-G12C/SOS1. Par conséquent, les composés de formule I ont le potentiel d'être un inhibiteur de SOS1 et peuvent être développés en un médicament pour le traitement de maladies associées à celui-ci.
PCT/CN2023/101588 2022-06-22 2023-06-21 Classe de composés ayant une structure cyclique pyrimido à six chaînons, compositions pharmaceutiques les comprenant et leur utilisation WO2023246837A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105793254A (zh) * 2012-11-29 2016-07-20 默克专利有限公司 氮杂喹唑啉羧酰胺衍生物
WO2021074227A1 (fr) * 2019-10-15 2021-04-22 Bayer Aktiengesellschaft 2-méthyl-aza-quinazolines
WO2021083936A1 (fr) * 2019-11-01 2021-05-06 Syngenta Crop Protection Ag Composés hétéroaromatiques bicycliques fusionnés à action pesticide
WO2021228028A1 (fr) * 2020-05-09 2021-11-18 正大天晴药业集团股份有限公司 Inhibiteur de sos1 contenant du phosphore
CN114685488A (zh) * 2020-12-31 2022-07-01 南京圣和药业股份有限公司 作为sos1抑制剂的化合物及其应用
CN115785088A (zh) * 2021-09-09 2023-03-14 南京圣和药业股份有限公司 作为sos1抑制剂的化合物及其应用
WO2023067546A1 (fr) * 2021-10-21 2023-04-27 Satyarx Pharma Innovations Pvt Ltd Nouveaux dérivés bicycliques hétéroaryles utilisés en tant qu'inhibiteurs de l'interaction protéine-protéine sos1 : kras

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105793254A (zh) * 2012-11-29 2016-07-20 默克专利有限公司 氮杂喹唑啉羧酰胺衍生物
WO2021074227A1 (fr) * 2019-10-15 2021-04-22 Bayer Aktiengesellschaft 2-méthyl-aza-quinazolines
WO2021083936A1 (fr) * 2019-11-01 2021-05-06 Syngenta Crop Protection Ag Composés hétéroaromatiques bicycliques fusionnés à action pesticide
WO2021228028A1 (fr) * 2020-05-09 2021-11-18 正大天晴药业集团股份有限公司 Inhibiteur de sos1 contenant du phosphore
CN114685488A (zh) * 2020-12-31 2022-07-01 南京圣和药业股份有限公司 作为sos1抑制剂的化合物及其应用
CN115785088A (zh) * 2021-09-09 2023-03-14 南京圣和药业股份有限公司 作为sos1抑制剂的化合物及其应用
WO2023067546A1 (fr) * 2021-10-21 2023-04-27 Satyarx Pharma Innovations Pvt Ltd Nouveaux dérivés bicycliques hétéroaryles utilisés en tant qu'inhibiteurs de l'interaction protéine-protéine sos1 : kras

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