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WO2023280280A1 - Composé à cycle fusionné agissant en tant qu'inhibiteur de kras g12d - Google Patents

Composé à cycle fusionné agissant en tant qu'inhibiteur de kras g12d Download PDF

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Publication number
WO2023280280A1
WO2023280280A1 PCT/CN2022/104439 CN2022104439W WO2023280280A1 WO 2023280280 A1 WO2023280280 A1 WO 2023280280A1 CN 2022104439 W CN2022104439 W CN 2022104439W WO 2023280280 A1 WO2023280280 A1 WO 2023280280A1
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Prior art keywords
alkyl
compound
independently
pharmaceutically acceptable
general formula
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PCT/CN2022/104439
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English (en)
Chinese (zh)
Inventor
谢雨礼
吴应鸣
钱立晖
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微境生物医药科技(上海)有限公司
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Priority to CN202280047839.3A priority Critical patent/CN117751116A/zh
Publication of WO2023280280A1 publication Critical patent/WO2023280280A1/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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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
    • C07D471/04—Ortho-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
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of medicinal chemistry, and more specifically, relates to a class of fused-ring compounds with KRas G12D protein inhibitory effect, a preparation method thereof, and the use of such compounds for preparing, treating, regulating or preventing related diseases mediated by KRas G12D. Application in the medicine of disease.
  • KRas (Kirsten Rat Sarcoma 2 Viral Oncogene Homolog) is a class of GTPases and a member of the oncogene Ras family.
  • Kras protein has a GDP-bound form (inactive form) and a GTP-bound form (activated form), and these two forms of KRas protein will be transformed into each other to transduce the activation signals of various upstream tyrosine kinases to downstream effector proteins to regulate a series of important physiological functions, such as cell proliferation.
  • KRas G12D mutation is the most common KRas mutation.
  • pancreatic ductal carcinoma patients have been characterized by pancreatic ductal carcinoma patients, 13.3% of colon adenocarcinoma patients, 10.1% of rectal adenocarcinoma patients, 4.1% of non-small cell lung cancer patients and 1.7% of small cell lung cancer patients have KRas G12D mutation.
  • KRas The important role of KRas in carcinogenesis and the discovery of common KRas mutations in numerous tumors make KRas a very attractive target. Although a large number of studies have attempted to find KRas inhibitors in the past 30 years, except for KRas G12C irreversible inhibitors that have observed efficacy in clinical trials, so far no other KRas inhibitors have shown outstanding efficacy and safety in clinical trials.
  • KRas G12D small molecule inhibitors have important clinical value for the treatment of tumors with KRas G12D mutations.
  • the present invention provides a compound represented by general formula (1) or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
  • Y is 0 or NR 5 ;
  • Ring A is phenyl, (5-7 membered) heteroaryl, (C5-C7) cycloalkyl or (5-7 membered) heterocycloalkyl;
  • Each R is independently -H, halogen, (C1 - C3) alkyl, (C1-C3) haloalkyl, (C1-C3) haloalkoxy, (C6-C14) aryl or (5-14 member ) heteroaryl, wherein the (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) haloalkoxy, (C6-C14) aryl or (5-14 member) heteroaryl can each independently be optionally substituted by 1, 2, 3 or 4 R 6 ;
  • Each R3 is independently -H, halogen, -OH, (C1-C3) alkyl, (C1-C3) alkyl substituted with hydroxy, (C1-C3) haloalkyl, (C1-C3) alkoxy , (5-7 membered) heteroaryl, -CN, -SO 2 F, NHC(O)R 8 , -N(R 5 ) 2 , -CH 2 OC(O)N(R 5 ) 2 , -CH 2 NHC(O)OR 7 , -CH 2 NHC(O)N(R 5 ) 2 , -CH 2 NHC(O)R 7 , -CH 2 NHS(O) 2 R 7 , -CH 2 OC(O)R 8 , -OC(O)N(R 5 ) 2 , -OC(O)NH(CH 2 ) m OR 7 , -OC(O) NH(CH 2 ) m O(CH 2 ) n R 8 ,
  • Q is a chemical bond or O
  • Ring B is (C5-C7) cycloalkyl, phenyl, (5-7 member) heteroaryl or (5-7 member) heterocycloalkyl;
  • Each R 4 is independently -H, -D, halogen, R 9 , -OH, -(CH 2 ) n OR 9 , -(CH 2 ) n NR 9 R 10 , -OR 9 , -NR 9 R 10 , -CN, -C(O)NR 9 R 10 , -NR 10 C(O)R 9 , -NR 10 S(O) 2 R 9 , -S(O) p R 9 , -S(O) 2 NR 9 R 10 , (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl or (C3-C9) cycloalkyl, wherein ( C1-C6) Alkyl, (C1-C6) Haloalkyl, (C2-C6) Alkenyl, (C2-C6) Alkynyl or (C3-C9) Cycloalkyl can be independently optionally replaced
  • each R is independently -H or (C1 - C3) alkyl
  • Each R is independently (C1 - C6) alkyl, (C1-C6) haloalkyl or (C1-C3) alkoxy;
  • Each R is independently ( 5-7 membered) heterocycloalkyl, (5-7 membered) heteroaryl or phenyl, wherein the (5-7 membered) heterocycloalkyl, (5-7 membered )heteroaryl or phenyl can be independently optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -OH, -CN, -C(O)H, -(CH 2 ) n OR 7 and -(CH 2 ) n N(R 7 ) 2 ;
  • R 9 and R 10 are each independently -H, (C1-C6) alkyl or (C3-C7) cycloalkyl, or R 9 and R 10 on the same nitrogen atom and the N atom they are connected to can jointly Constitutes a (3-7 membered) heterocycloalkyl group, which can be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, (C1-C3) alkyl, (C3- C5) cycloalkyl or (C1-C3) alkoxy; and
  • p is an integer of 0, 1 or 2
  • r is an integer of 1, 2, 3 or 4
  • s is an integer of 0, 1, 2, 3 or 4
  • t is an integer of 0, 1, 2, 3 or 4
  • n is an integer of 0, 1, 2 or 3
  • m is an integer of 1, 2 or 3.
  • Y is O, NH or NCH 3 .
  • ring A is phenyl, 6-membered heteroaryl, cyclohexyl or (5-6-membered) heterocycloalkyl.
  • ring A is: The end marked with * is connected to a nitrogen atom.
  • each R 2 is independently -H, -F, -Cl, -Br, -I, (C1-C3) alkyl, (C1- C3) haloalkyl, (C1-C3) haloalkoxy, (C6-C14) aryl or (5-14) heteroaryl, wherein the (C1-C3) alkyl, (C1-C3) haloalkyl , (C1-C3) haloalkoxy, (C6-C14) aryl or (5-14 member) heteroaryl can be independently optionally substituted by 1, 2, 3 or 4 of the following groups: -H, - F, -Cl, -Br, -I, -OH, -CN, -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , - SCH 3
  • each R 3 is independently -H, -OH, -F, -Cl, -Br, -I, (C1-C3) alkyl, Hydroxy-substituted (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy, (5-6) heteroaryl, -CN, NHC(O)R 8 , -N(R 5 ) 2 , -CH 2 OC(O)N(R 5 ) 2 , -CH 2 NHC(O)OR 7 , -CH 2 NHC(O)N(R 5 ) 2 , -CH 2 NHC(O)R 7 , -CH 2 NHS(O) 2 R 7 , -CH 2 OC(O)R 8 , -OC(O)N(R 5 ) 2 , -OC(O )NH(CH 2 ) m OR 7 , -OC(O)NH(CH 2 )
  • each R 3 is independently: -H, -OH, -F, -Cl, -Br, -I, -CN, -SO 2 F , -OCH 3 , -CF 3 ,
  • ring B is (C5-C6) cycloalkyl, phenyl, (5-6 membered) heteroaryl or (5-6 membered) heterocyclic alkyl.
  • ring B is:
  • the end marked with * is connected to a nitrogen atom.
  • each R 4 is independently -H, -D, -F, -Cl, -Br, -I, -OH, -CH 2 OR 9 , -CH 2 NR 9 R 10 , -OR 9 , -NR 9 R 10 , -CN, -C(O)NR 9 R 10 , -NR 10 C(O)R 9 , -NR 10 S(O) 2 R 9 , -SR 9 , -S(O) 2 R 9 , -S(O) 2 NR 9 R 10 , (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl , (C2-C4) alkynyl or (C3-C6) cycloalkyl, wherein said (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) Alkynyl or (C3-C6) cyclo
  • each R 4 is independently: -H, -D, -F, -Cl, -Br, -I, -OH, -CH 2 OCH 3. -CH 2 N(CH 3 ) 2 , -OCH 3 , -OCF 3 , -N(CH 3 ) 2 , -CN, -C(O)NH 2 , -C(O)NH(CH 3 ), -C(O)N(CH 3 ) 2 , -NHC(O)CH 3 , -N(CH 3 )-C(O)CH 3 , -NHS(O) 2 CH 3 , -NCH 3 S(O) 2 CH 3 , -SCH 3 , -S(O) 2 CH 3 and -S(O) 2 NH 2 , -S(O) 2 NH(CH 3 ), -S(O) 2 N(CH 3 ) 2 , Or when two R 4 are connected on the same
  • R 1 , R 2 , R 3 , R 4 , Y, B, r, s and t are as defined above and exemplified in the examples.
  • the general formula (1) has the structure shown in the general formula (2a)-general formula (2d):
  • R 1 , R 2 , R 3 , R 4 , Y, r, s and t are as defined above and exemplified in the examples.
  • the compound of general formula (1) has one of the following structures:
  • Another object of the present invention is to provide a pharmaceutical composition, which contains a pharmaceutically acceptable carrier, diluent and/or excipient, and the compound of general formula (1) of the present invention, or its various isomers, Various crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used as active ingredients.
  • Another object of the present invention provides the compound represented by the general formula (1) of the present invention, or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the above-mentioned pharmaceutical composition Application in the preparation of medicines for treating, regulating or preventing diseases related to KRas G12D; said diseases are preferably cancers, and said cancers are hematological cancers and solid tumors.
  • Another object of the present invention is also to provide a method for treating, regulating or preventing related diseases mediated by KRas G12D, comprising administering to a subject a therapeutically effective amount of a compound represented by general formula (1) of the present invention, or its Each isomer, each crystal form, a pharmaceutically acceptable salt, hydrate or solvate or the above pharmaceutical composition; the disease is preferably cancer, and the cancer is blood cancer and solid tumor.
  • the compounds of general formula (1) described above can be synthesized using standard synthetic techniques or known techniques combined with methods herein. In addition, solvents, temperatures and other reaction conditions mentioned herein may vary. Starting materials for the synthesis of compounds can be obtained synthetically or from commercial sources. The compounds described herein and other related compounds having various substituents can be synthesized using well known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed., Vols. A and B (Plenum 2000, 2001), methods in Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3rd Ed., (Wiley 1999). The general methods of compound preparation can be varied by using appropriate reagents and conditions to introduce different groups into the formulas provided herein.
  • the compounds described herein are according to methods well known in the art.
  • the conditions of the method such as reactants, solvent, base, amount of the compound used, reaction temperature, time required for the reaction, etc., are not limited to those explained below.
  • the compound of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in the specification or known in the art. Such a combination can be easily performed by those skilled in the art to which the present invention belongs.
  • the present invention also provides a method for preparing the compound represented by the general formula (1), wherein the compound of the general formula (1) can be prepared by the following general reaction scheme 1 or general reaction scheme 2:
  • Embodiments of compounds of general formula (1) can be prepared according to general reaction scheme 1, wherein R 1 , R 2 , R 3 , R 4 , Y and ring B are as defined above, H represents hydrogen, N represents nitrogen, and S represents sulfur , O represents oxygen, and X represents nitrogen or carbon.
  • R 1 , R 2 , R 3 , R 4 , Y and ring B are as defined above, H represents hydrogen, N represents nitrogen, and S represents sulfur , O represents oxygen, and X represents nitrogen or carbon.
  • R 1 , R 2 , R 3 , R 4 , Y and ring B are as defined above
  • H represents hydrogen
  • N represents nitrogen
  • S sulfur
  • O oxygen
  • X represents nitrogen or carbon
  • Compound 1-6 reacts under acidic conditions to generate 1-7, compound 1-7 reacts with compound 1-8 to generate compound 1-9, compound 1-9 reacts with POCl 3 to generate compound 1-10, compound 1- Compound 1-12 is produced by substitution reaction between 10 and compound 1-11, compound 1-14 is produced by substitution reaction between compound 1-12 and compound 1-13, and compound 1-14 is deprotected under acidic conditions to produce 1-15.
  • Embodiments of compounds of general formula (1) can be prepared according to general reaction scheme 2, wherein R 1 , R 2 , R 3 , R 4 , Y and ring B are as defined above, H represents hydrogen, N represents nitrogen, and S represents sulfur , O represents oxygen.
  • R 1 , R 2 , R 3 , R 4 , Y and ring B are as defined above, H represents hydrogen, N represents nitrogen, and S represents sulfur , O represents oxygen.
  • compounds 2-1 and 2-2 undergo a substitution reaction under basic conditions to generate compound 2-3
  • compound 2-3 and 2-4 undergo a substitution reaction to generate compound 2-5, compound 2- 5.
  • Compound 2-6 reacts with compound 2-7 or 2-8 to generate compound 2-9.
  • Compound 2-9 deprotects under acidic conditions. Generate 2-10.
  • “Pharmaceutically acceptable” here refers to a substance, such as a carrier or diluent, that does not abolish the biological activity or properties of the compound, and that is relatively nontoxic, e.g., does not cause unwanted biological effects or Interact in a harmful manner with any of its components.
  • the term "pharmaceutically acceptable salt” refers to a form of a compound which does not cause significant irritation to the organism to which it is administered and which does not abolish the biological activity and properties of the compound.
  • the pharmaceutically acceptable salt is obtained by reacting the compound of general formula (1) with an acid, such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid and other inorganic acids, formic acid, acetic acid , propionic acid, oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and other organic acids and acidic amino acids such as aspartic acid and glutamic acid.
  • an acid such as hydrochloric acid, hydrobromic acid, hydro
  • references to pharmaceutically acceptable salts are understood to include solvent added forms or crystalline forms, especially solvates or polymorphs.
  • Solvates contain stoichiometric or non-stoichiometric solvents and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol.
  • Solvates of compounds of general formula (1) are conveniently prepared or formed according to the methods described herein.
  • the hydrate of the compound of general formula (1) is conveniently prepared by recrystallization from a mixed solvent of water/organic solvent, and the organic solvent used includes but not limited to tetrahydrofuran, acetone, ethanol or methanol.
  • the compounds mentioned herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for purposes of the compounds and methods provided herein.
  • compounds of general formula (1) are prepared in different forms including, but not limited to, amorphous, pulverized and nano-particle sized forms.
  • the compound of the general formula (1) includes crystalline forms and may also be regarded as polymorphic forms.
  • Polymorphs include different lattice arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction spectra, infrared spectra, melting points, densities, hardness, crystal forms, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystal form to predominate.
  • the compounds of general formula (1) may have chiral centers and/or axial chirality and thus exist as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single non- Enantiomeric forms, and cis-trans isomeric forms occur.
  • Each chiral center or axial chirality will independently give rise to two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
  • compounds can be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C).
  • radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C).
  • heavy hydrogen can be used to replace hydrogen atoms to form deuterated compounds.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Stability, enhanced curative effect, extended drug half-life in vivo and other advantages. All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are encompassed within the scope of the invention.
  • alkyl means a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 6 carbon atoms. Lower alkyl groups having 1 to 4 carbon atoms are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl. As used herein, “alkyl” includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted with one or more halogens.
  • Preferred alkyl groups are selected from CH3 , CH3CH2 , CF3 , CHF2 , CF3CH2 , CF3 ( CH3 ) CH , iPr , nPr , iBu , nBu or tBu .
  • alkylene refers to a divalent alkyl group as defined above.
  • alkylene groups include, but are not limited to, methylene and ethylene.
  • alkenyl refers to an unsaturated aliphatic hydrocarbon group containing carbon-carbon double bonds, including straight or branched chain groups of 1 to 14 carbon atoms. Lower alkenyl groups having 1 to 4 carbon atoms, such as vinyl, 1-propenyl, 1-butenyl or 2-methylpropenyl, are preferred.
  • alkynyl refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including straight and branched chain groups of 1 to 14 carbon atoms.
  • cycloalkyl means a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), and if the carbocyclic ring contains at least one double bond, then a partially unsaturated cycloalkyl group may be referred to as "cycloalkyl". alkenyl", or if the carbocyclic ring contains at least one triple bond, a partially unsaturated cycloalkyl group may be referred to as a "cycloalkynyl”. Cycloalkyl groups can include monocyclic or polycyclic (eg, having 2, 3 or 4 fused rings) groups and spirocycles. In some embodiments, cycloalkyl groups are monocyclic.
  • cycloalkyls are monocyclic or bicyclic. Ring-forming carbon atoms of cycloalkyl groups can be optionally oxidized to form oxo or sulfide groups. Cycloalkyl also includes cycloalkylene. In some embodiments, cycloalkyl groups contain 0, 1, or 2 double bonds. In some embodiments, the cycloalkyl contains 1 or 2 double bonds (partially unsaturated cycloalkyl). In some embodiments, cycloalkyl groups can be fused with aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups.
  • cycloalkyl groups can be fused with aryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl and heterocycloalkyl groups. In some embodiments, a cycloalkyl group can be fused with an aryl group and a cycloalkyl group.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl , norpinenyl, norcarpanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexyl, etc.
  • alkoxy means an alkyl group bonded to the remainder of the molecule through an ether oxygen atom.
  • Representative alkoxy groups are alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxyl.
  • alkoxy includes unsubstituted and substituted alkoxy, especially alkoxy substituted with one or more halogens.
  • Preferred alkoxy groups are selected from OCH 3 , OCF 3 , CHF 2 O, CF 3 CH 2 O, i- PrO, n- PrO, i- BuO, n- BuO or t- BuO.
  • aryl refers to a hydrocarbon aromatic group, aryl is monocyclic or polycyclic, eg a monocyclic aryl ring fused with one or more carbocyclic aromatic groups.
  • aryl groups include, but are not limited to, phenyl, naphthyl, and phenanthrenyl.
  • aryloxy refers to an aryl group bonded to the rest of the molecule through an ether oxygen atom.
  • Examples of aryloxy include, but are not limited to, phenoxy and naphthyloxy.
  • arylene refers to a divalent aryl group as defined above.
  • arylene groups include, but are not limited to, phenylene, naphthylene, and phenanthrenylene.
  • heteroaryl refers to an aromatic group containing one or more heteroatoms (O, S or N), and the heteroaryl is monocyclic or polycyclic.
  • a monocyclic heteroaryl ring is fused with one or more carbocyclic aromatic groups or other monocyclic heterocycloalkyl groups.
  • heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolyl, furyl, thienyl, Isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, benzene Pyridyl, pyrrolopyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, 1H- Pyrrolo[2,3-b]pyridyl,
  • heteroarylene refers to a divalent heteroaryl group as defined above.
  • heterocycloalkyl means a non-aromatic ring or ring system which may optionally contain as part of the ring structure one or more alkenylene groups having at least one group independently selected from boron, phosphorus, , nitrogen, sulfur, oxygen, and phosphorus heteroatom ring members.
  • a partially unsaturated heterocycloalkyl group may be referred to as a "heterocycloalkenyl” if the heterocycloalkyl group contains at least one double bond, or a partially unsaturated heterocycloalkyl group if the heterocycloalkyl group contains at least one triple bond. may be referred to as a "heterocycloalkynyl".
  • Heterocycloalkyl groups can include monocyclic, bicyclic, spiro, or polycyclic (eg, having two fused or bridged rings) ring systems.
  • heterocycloalkyl is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen.
  • the ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group can be optionally oxidized to form oxo or sulfide groups or other oxidized linkages (e.g., C(O), S(O), C(S), or S(O) 2, N-oxide, etc.), or the nitrogen atom can be quaternized.
  • a heterocycloalkyl group can be attached via a ring-forming carbon atom or a ring-forming heteroatom.
  • heterocycloalkyl groups contain 0 to 3 double bonds.
  • heterocycloalkyl groups contain 0 to 2 double bonds.
  • moieties having one or more aromatic rings fused to (i.e., sharing a bond with) the heterocycloalkyl ring such as piperidine, morpholine, azepine or Benzo derivatives such as thienyl.
  • a heterocycloalkyl group containing a fused aromatic ring may be attached via any ring-forming atom, including ring-forming atoms of a fused aromatic ring.
  • heterocycloalkyl include, but are not limited to, azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa -9-Azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrole Alkyl, quinyl, tetrahydrofuryl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolyl, tropane, 4,5,6,7-tetrahydrothiazolo[5,4 -c]pyridyl, 4,5
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • halo or halogen substitution
  • appearing before the group name means that the group is partially or fully halogenated, that is, substituted by F, Cl, Br or I in any combination, preferably Substituted by F or Cl.
  • the substituent "-O-CH 2 -O-" means that two oxygen atoms in the substituent are connected to two adjacent carbon atoms of heterocycloalkyl, aryl or heteroaryl, such as:
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a single bond.
  • membered ring includes any ring structure.
  • member is meant to indicate the number of skeletal atoms that make up the ring.
  • cyclohexyl, pyridyl, pyranyl, and thienyl are six-membered rings
  • cyclopentyl, pyrrolyl, furyl, and thienyl are five-membered rings.
  • fragment refers to a specific portion or functional group of a molecule. Chemical fragments are generally considered to be chemical entities contained in or attached to molecules.
  • keys with wedge-shaped solid lines and dotted wedge keys Indicates the absolute configuration of a stereocenter, with a straight solid-line bond and straight dashed keys Indicates the relative configuration of the stereocenter, with a wavy line Indicates wedge-shaped solid-line bond or dotted wedge key or with tilde Indicates a straight solid line key or straight dotted key
  • acceptable means that a formulation ingredient or active ingredient does not have an undue adverse effect on health for the general purpose of treatment.
  • treatment includes alleviating, suppressing or improving the symptoms or conditions of a disease; inhibiting the development of complications; improving or preventing the underlying metabolic syndrome; inhibiting the development of diseases or symptoms, Such as controlling the development of a disease or condition; alleviating a disease or a symptom; causing a disease or a symptom to regress; alleviating a complication caused by a disease or a symptom, or preventing or treating a symptom caused by a disease or a symptom.
  • a certain compound or pharmaceutical composition after administration, can improve a certain disease, symptom or situation, especially improve its severity, delay the onset, slow down the progression of the disease, or reduce the duration of the disease. Circumstances that may be attributable to or related to the administration, whether fixed or episodic, continuous or intermittent.
  • Active ingredient refers to the compound represented by the general formula (1), and the pharmaceutically acceptable inorganic or organic salts of the compound of the general formula (1).
  • the compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality) and thus exist as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single non- Enantiomers occur in the form of enantiomers.
  • the asymmetric centers that can exist depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently give rise to two optical isomers and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • composition a compound or composition capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.
  • administered, administering, or administration means direct administration of the compound or composition, or administration of a prodrug, derivative, or analog of the active compound Wait.
  • the compound of general formula (1) or the pharmaceutical composition provided by the present invention can generally be used to inhibit KRas G12D protein, and therefore can be used to treat one or more diseases related to the activity of KRas G12D protein. Therefore, in certain embodiments, the present invention provides a method for treating a KRas G12D protein-mediated disorder, the method comprising administering a compound of the present invention, or a pharmaceutically acceptable composition thereof, to a patient in need thereof. step.
  • a method for treating cancer comprising administering an effective amount of any of the aforementioned pharmaceutical compositions comprising the compound of general structural formula (1) to an individual in need thereof.
  • the cancer is mediated by the KRas G12D protein.
  • the cancer is blood cancer and solid tumors, including but not limited to leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial cancer, prostate cancer, liver cancer, ovarian cancer , head and neck cancer, stomach cancer, mesothelioma or all cancer metastases.
  • the compounds of the present invention and their pharmaceutically acceptable salts can be made into various preparations, which contain the compounds of the present invention or their pharmaceutically acceptable salts and pharmaceutically acceptable excipients or carriers within the range of safe and effective amounts .
  • safe and effective amount means: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects.
  • the safe and effective dose of the compound is determined according to the specific conditions such as the age, condition, and course of treatment of the subject to be treated.
  • “Pharmaceutically acceptable excipient or carrier” means: one or more compatible solid or liquid filler or gel substances, which are suitable for human use and must be of sufficient purity and low enough toxicity .
  • “Compatibility” herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound.
  • Examples of pharmaceutically acceptable excipients or carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
  • cellulose and derivatives thereof such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as stearic acid, magnesium stearate
  • calcium sulfate such as soybean oil, sesam
  • the compounds of the present invention When the compounds of the present invention are administered, they can be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea, or
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • coatings and shell materials such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • Examples of usable embedding components are polymeric substances and waxy substances.
  • the active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.
  • 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, isopropanol, 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, etc.
  • inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and
  • compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain 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 comprise 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 vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for topical administration of a compound of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required, if necessary.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily
  • the dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
  • 1 H-NMR was recorded by a Varian Mercury 400 nuclear magnetic resonance apparatus, and the chemical shifts were expressed in ⁇ (ppm); the silica gel used for separation was 200-300 mesh, and the ratio of the eluent was volume ratio.
  • the present invention adopts the following abbreviations: Ac 2 O stands for acetic anhydride; (Boc) 2 O stands for di-tert-butyl dicarbonate; CDCl 3 stands for deuterated chloroform; CO stands for carbon monoxide; Cs 2 CO 3 stands for cesium carbonate; CsF stands for Cesium fluoride; EtOAc represents ethyl acetate; Hexane represents n-hexane; HPLC represents high performance liquid chromatography; MeCN or CH 3 CN represents acetonitrile; DCM represents dichloromethane; DIPEA represents diisopropylethylamine; Dioxane represents 1, 4-dioxane; DMF stands for N,N-dimethylformamide; DMAP stands for 4-(dimethylamino)pyridine; DMSO stands for dimethyl sulfoxide; Dichloro(p-cymene)ruthenium(II) dimer stands for di Chloro(p-cymen
  • Int_A-1-1 hydrochloride (31g, 178.13mmol) was dissolved in water (500mL), and NaHCO 3 (37.41g, 445.34mmol) was added at room temperature, and after stirring for 30 minutes, acetic anhydride (20.00g , 195.95mmol, 18.35mL), the reaction solution was stirred at room temperature for another 4 hours, and a white solid precipitated out. LC-MS detection showed that the reaction was complete. Filtration gave a filter cake, which was washed with water (50 mL X 2) and dried to give the crude product. The crude product was slurried with MTBE (300ml) at room temperature for 30 minutes, filtered to obtain a filter cake and dried to obtain a white solid (18g, yield: 56.3%).
  • Int_A-1-4 (10g, 44.00mmol) was dissolved in 10% hydrochloric acid (320.88g, 880.06mmol, 314.59mL), and the mixture was heated to 80°C for 3 hours. LC-MS detection showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product can be directly used in the next reaction (8g, yield: 95.9%).
  • Int_A-1-5 (8g, 52.23mmol) and Pd/C (3g, 5.22mmol, 10%purity) were dissolved in ethanol (200mL), and the mixture was hydrogenated at 15psi for 16 hours. LC-MS detection showed that the reaction completely. Filtrate was obtained by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product can be directly used in the next reaction (8g, yield: 98.7%).
  • Int_A-1-6 (7g, 45.10mmol) was dissolved in methanol (200mL), and SOCl 2 (10.73g, 90.21mmol, 6.54mL) was slowly added dropwise at 20°C, and the reaction solution was stirred at room temperature for 16 hours, LC- MS detection showed complete reaction.
  • the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product can be directly used in the next reaction (8g, yield: 105%).
  • Int_A-1-8 (9.1g, 33.79mmol) was dissolved in THF (160mL), LiHMDS (1M, 54.06mL) was slowly added dropwise at -60°C, and the reaction solution was stirred at -60°C for 1 hour, and then added to the reaction Int_A-1-9 (7.98g, 50.68mmol, 4.99mL) was added to the solution, and the reaction solution was stirred at -60°C for 1 hour, then raised to room temperature for 2 hours, and LC-MS detection showed that the reaction was complete.
  • Int_A-1-12 (2.3g, 10.99mmol) was dissolved in THF (50mL), LiAlH4 (834mg, 21.98mmol) was added at 0°C, and the reaction solution was stirred at room temperature for 2 hours. LC-MS detection showed that the reaction was complete .
  • 10 ⁇ H2O ⁇ Na2SO4 (20 g) was added to the reaction solution at 0° C. and the mixture was raised to room temperature and stirred for half an hour. The reaction solution was filtered to obtain a filtrate, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • the crude product was suspended in dichloromethane (10 mL), filtered again to obtain a filtrate, and the filtrate was concentrated under reduced pressure to obtain a yellow oil (1.5 g, yield: 75.3%).
  • Int_A-2-1 hydrochloride (75g, 430.97mmol) was dissolved in water (1000mL), and NaHCO 3 (90.51g, 1.08mol) was added at room temperature, and after stirring for 30 minutes, acetic anhydride (48.40g , 474.07mmol, 44.40mL), the reaction solution was stirred at room temperature for another 4 hours, and a white solid precipitated out. LC-MS detection showed that the reaction was complete. Filtration gave a filter cake, which was washed with water (50 mL X 2) and dried to give the crude product. The crude product was slurried with MTBE (500ml) at room temperature for 30 minutes, filtered to obtain a filter cake and dried to obtain a white solid (40g, yield: 51.7%).
  • MTBE 500ml
  • Int_A-2-2 25g, 182.19mmol, 26.57mL
  • Int_A-2-3 39.27g, 218.62mmol
  • acetonitrile 300mL
  • DIPEA 23.55g, 182.19mmol, 31.73 mL
  • 3 mL of water was added to the reaction solution and stirring was continued for 3 hours.
  • the reaction solution was concentrated under reduced pressure to obtain a crude product.
  • Int_A-2-4 (25g, 110.01mmol) was dissolved in 10% hydrochloric acid (401.10g, 1.10mol, 393.23mL), and the mixture was heated to 80°C for 3 hours. LC-MS detection showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product can be directly used in the next reaction (18g, crude product).
  • Int_A-2-5 (15g, 97.93mmol) and Pd/C (1.5g, 10%purity) were dissolved in ethanol (40mL), and the mixture was hydrogenated under 15psi pressure for 16 hours. LC-MS detection showed that the reaction was complete. The filtrate was obtained by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product can be directly used in the next reaction (15g, crude product).
  • Int_A-2-6 (15g, 96.65mmol) was dissolved in methanol (200mL), and SOCl 2 (23.00g, 193.31mmol, 14.02mL) was slowly added dropwise at 20°C, and the reaction solution was stirred at room temperature for 16 hours, LC- MS detection showed complete reaction. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product can be directly used in the next reaction (16g, crude product).
  • Int_A-2-8 (16g, 59.41mmol) was dissolved in THF (300mL), and LiHMDS (1M, 89.11mL) was slowly added dropwise at -60°C, and the reaction solution was stirred at -60°C for 1 hour, and then added to the reaction solution Int_A-2-9 (14.03g, 89.11mmol, 8.77mL) was added, and the reaction solution was stirred at -60°C for 1 hour, then raised to room temperature for 2 hours, and LC-MS detection showed that the reaction was complete.
  • Int_A-2-11 (12g, 48.83mmol) was dissolved in methanol (200mL), K 2 CO 3 (20.25g, 146.49mmol) was added at room temperature, and the reaction solution was stirred at room temperature for 16 hours. LC-MS detection showed that the reaction completely.
  • the reaction solution was filtered to obtain a filtrate, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • Int_A-2-12 (7g, 33.45mmol) was dissolved in THF (150mL), LiAlH4 (2.54g, 66.89mmol) was added at 0°C, and the reaction solution was stirred at room temperature for 2 hours. LC-MS detection showed that the reaction was complete .
  • 10 ⁇ H2O ⁇ Na2SO4 50 g was added to the reaction solution at 0° C. and the mixture was raised to room temperature and stirred for half an hour.
  • the reaction solution was filtered to obtain a filtrate, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • the crude product was suspended in dichloromethane (10 mL), filtered again to obtain a filtrate, and the filtrate was concentrated under reduced pressure to obtain a yellow oil (5 g, yield: 82.5%).
  • Int_B-1-5 (115g, 222.5mmol), Int_B-1-6 (113g, 445mmol), Pd(dppf)Cl2 ( 16.3g , 23mmol) and potassium acetate (76g, 0.78mol) were dissolved in toluene ( 800 mL), the reaction solution was reacted at 110° C. for 3 hours under nitrogen protection, and LC-MS detection showed that the reaction was complete.
  • Int_2-2 (0.95g, 3.85mmol) was dissolved in dichloromethane (6mL), and TFA (3mL) was slowly added dropwise at a temperature lower than 10°C. The reaction solution was reacted at room temperature for 6 hours, and LC-MS detection showed that the reaction was complete . The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product can be directly used in the next reaction (564mg, yield: 100%).
  • Int_2-7 (10g, 21mmol) was dissolved in methanol (100mL), and ammonia in methanol solution (10mL, 20%purity) was slowly added dropwise to the solution, and the reaction solution was reacted at room temperature for 1 hour, and LC-MS detection showed that the reaction was complete .
  • the reaction solution was concentrated under reduced pressure to obtain a crude product.
  • the crude product was slurried in MTBE to obtain the product (3.9 g, yield: 86.7%).
  • Int_2-8 (2g, 9.3mmol) was dissolved in toluene (10mL), and phosphorus oxychloride (4.3g, 27.8mmol, 2.6mL) and DIPEA (3.6g, 27.8mmol, 4.85 mL), the reaction solution was heated to 110° C. for 5 hours, and LC-MS detection showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product can be directly used in the next reaction (2.1g, yield: 89.7%).
  • Int_2-9 (1.0g, 3.961mmol) was dissolved in DCM (25mL), DIPEA (2.6g, 19.81mmol) was added, and DCM of Int_2-10 (841mg, 3.961mmol) was added dropwise at -40°C under nitrogen protection ( 10mL) solution, after dripping, the reaction solution was reacted at -40°C for 0.5 hours, LC-MS detection showed that the reaction was complete, 50mL water was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (50mL X 3), and the organic phase was extracted with saturated Washed with brine and dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure to obtain a crude product, which was directly used in the next reaction (1.65 g, 97.1%).
  • Int_2-13 (30mg, 0.033mmol) was dissolved in DMF (2mL), cesium fluoride (50mg, 0.33mmol) was added, and the reaction solution was reacted at room temperature under nitrogen protection for 2 hours. LC-MS detection showed that the reaction was complete. 10mL of water was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (10mL ⁇ 3), the organic phase was washed with saturated brine and dried with anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure to obtain a crude product, and the crude product was subjected to reverse phase HPLC A yellow solid product (20 mg, yield: 79.1%) was prepared.
  • Int_2-14 (20mg, 0.026mmol) was dissolved in methanol (1mL), cooled to -5°C in an ice bath, and 4M dioxane hydrochloride solution (2mL) was slowly added dropwise to the reaction solution. After the addition was complete, the reaction solution was The reaction was kept at -5°C for 2 hours, and LC-MS detection showed that the reaction was complete.
  • the reaction solution was adjusted to pH 7-8 with saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate (10mL ⁇ 3), the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain crude
  • the crude product was prepared by reverse phase HPLC to give the product as a yellow solid (5 mg, 31.6%).
  • Int_3-3 (28mg, 0.0366mmol) was dissolved in methanol (1.5mL), cooled to -5°C in an ice bath, and 4M dioxane hydrochloride solution (3mL) was slowly added dropwise to the reaction solution. After the addition was complete, the reaction The solution was kept at -5°C for 2 hours, and LC-MS detection showed that the reaction was complete.
  • the reaction solution was adjusted to pH 7-8 with saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate (10mL ⁇ 3), the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain crude
  • the crude product was prepared by reverse phase HPLC to give the product as a yellow solid (7 mg, 31.8%).
  • the target compound 1 and compounds 4-348 in Table 1 can be obtained by using the above synthesis method and using different raw materials.
  • the human pancreatic cancer cell line Aspc-1 carrying the KRAS-G12D mutation was suspended in RPMI1640 medium containing fetal bovine serum, planted in a 96-well ultra-low adsorption plate (Corning 7007), and the number of cells per well was 2500. Incubate for 1 day at 37°C in an incubator with 5% CO 2 gas.
  • +++ means IC 50 less than or equal to 500nM
  • N.D means activity not determined

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Abstract

La présente invention concerne un composé à cycle fusionné qui agit en tant qu'inhibiteur de KRas G12D, en particulier, la présente invention concerne un composé représenté par la formule générale (1) et un procédé de préparation de celui-ci, ainsi qu'une utilisation du composé représenté par la formule générale (1) et des isomères, des formes cristallines, un sel pharmaceutiquement acceptable, un hydrate ou un solvate de celui-ci en tant qu'inhibiteur de KRas G12D. Le composé et les isomères, les formes cristallines, le sel pharmaceutiquement acceptable, l'hydrate ou le solvate de celui-ci peuvent être utilisés pour préparer un médicament pour le traitement ou la prévention de maladies associées médiées par KRas G12D.
PCT/CN2022/104439 2021-07-07 2022-07-07 Composé à cycle fusionné agissant en tant qu'inhibiteur de kras g12d WO2023280280A1 (fr)

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WO2023198078A1 (fr) * 2022-04-11 2023-10-19 杭州英创医药科技有限公司 Composés polycycliques en tant qu'inhibiteurs de kras g12d
WO2023240263A1 (fr) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Inhibiteurs de ras macrocycliques
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WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024211663A1 (fr) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Composés macrocycliques condensés en tant qu'inhibiteurs de ras
WO2024211712A1 (fr) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Composés macrocycliques condensés en tant qu'inhibiteurs de ras
WO2024216048A1 (fr) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Formes cristallines d'inhibiteurs de ras, compositions les contenant et leurs procédés d'utilisation
WO2024216016A1 (fr) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Formes cristallines d'un inhibiteur de ras
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WO2019099524A1 (fr) * 2017-11-15 2019-05-23 Mirati Therapeutics, Inc. Inhibiteurs de kras g12c
WO2021041671A1 (fr) * 2019-08-29 2021-03-04 Mirati Therapeutics, Inc. Inhibiteurs de kras g12d
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WO2019099524A1 (fr) * 2017-11-15 2019-05-23 Mirati Therapeutics, Inc. Inhibiteurs de kras g12c
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Cited By (11)

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Publication number Priority date Publication date Assignee Title
WO2023138583A1 (fr) * 2022-01-21 2023-07-27 上海湃隆生物科技有限公司 Composé hétérocyclique, composition pharmaceutique et utilisation associée
US11912723B2 (en) 2022-02-09 2024-02-27 Quanta Therapeutics, Inc. KRAS modulators and uses thereof
WO2023172940A1 (fr) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Méthodes de traitement du cancer du poumon réfractaire immunitaire
WO2023198078A1 (fr) * 2022-04-11 2023-10-19 杭州英创医药科技有限公司 Composés polycycliques en tant qu'inhibiteurs de kras g12d
WO2023240263A1 (fr) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Inhibiteurs de ras macrocycliques
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024211663A1 (fr) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Composés macrocycliques condensés en tant qu'inhibiteurs de ras
WO2024211712A1 (fr) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Composés macrocycliques condensés en tant qu'inhibiteurs de ras
WO2024216048A1 (fr) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Formes cristallines d'inhibiteurs de ras, compositions les contenant et leurs procédés d'utilisation
WO2024216016A1 (fr) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Formes cristallines d'un inhibiteur de ras
US12145947B2 (en) 2023-11-07 2024-11-19 Quanta Therapeutics, Inc. Pyrimidine based modulators and uses thereof

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