WO2022199635A1 - Dérivés de benzylaminoquinazoline - Google Patents

Dérivés de benzylaminoquinazoline Download PDF

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Publication number
WO2022199635A1
WO2022199635A1 PCT/CN2022/082591 CN2022082591W WO2022199635A1 WO 2022199635 A1 WO2022199635 A1 WO 2022199635A1 CN 2022082591 W CN2022082591 W CN 2022082591W WO 2022199635 A1 WO2022199635 A1 WO 2022199635A1
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compound
mmol
added
pharmaceutically acceptable
acceptable salt
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PCT/CN2022/082591
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English (en)
Chinese (zh)
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吴凌云
展震
赵乐乐
代天资
孙建军
周建光
李不鱼
葛广存
李秋
胡国平
黎健
陈曙辉
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南京明德新药研发有限公司
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Publication of WO2022199635A1 publication Critical patent/WO2022199635A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings

Definitions

  • the present invention relates to a class of benzylaminoquinazoline derivatives and a preparation method thereof, in particular to a compound represented by formula (II) and a pharmaceutically acceptable salt thereof.
  • RAS protein is a 21kDa guanosine-binding protein located on the cell membrane with guanosine triphosphate hydrolase (GTPase) activity.
  • the RAS family includes KRAS, NRAS and HRAS, and the mutation rate in human cancers is as high as 20% to 30%.
  • the RAS pathway has a binary molecular switch controlled by GDP/GTP cycling: cycling between an active GTP-bound state (GTP-RAS) and an inactive GDP-bound state (GDP-RAS). In the absence of a stimulus signal, this switch state transitions very slowly (Hunter et al., Mol. Cancer Res., 2015, 13(9):1325-1335).
  • RAS-GDP When RAS-GDP binds to guanosine exchange factors (GEFs) such as SOS1, it will rapidly release GDP and combine with a high concentration of intracellular GTP into the "on" state, activating a series of downstream signaling pathways, including: MEK/ ERK, PI3K/AKT/mTOR, RalGDS, etc.
  • GAPs GTPase activating proteins
  • the GTPase activity of RAS increases thousands of times, the GTP bound to it is hydrolyzed into GDP, and RAS re-enters the “off” state of GDP binding, thus completing a complete cycle (Simanshu DK et al., Cell, 2017, 170:17–33). This cycle has important regulatory functions in cells and is closely related to cell proliferation, survival, metabolism, migration, immunity and growth.
  • Oncogenic RAS mutations inhibit both intrinsic GTPase activity and GAP-activated GTPase activity, keeping the RAS cycle in the "on" state of RAS-GTP, leading to continuous activation of downstream signaling pathways that lead to cancer.
  • KRAS mutations account for about 19% of lung cancers, about 71% of pancreatic cancers, and about 35% of colorectal cancers (Andrew et al., Cancer Cell, 2014, 25:272-281). Therefore, inhibition of KRAS mutants and abnormal activation of downstream pathways has become one of the hot targets for the treatment of cancer.
  • SOS1 (Son of Sevenless 1) is a GEF that regulates the GDP/GTP cycle of the RAS protein.
  • Small molecule SOS1 inhibitors that bind to the catalytic site can block the binding of SOS1 to RAS proteins and reduce RAS-GTP levels. Such inhibitors can effectively reduce the abnormal activation of RAS downstream signaling pathways (such as ERK phosphorylation) in cancer cells, thus playing a therapeutic role in cancer.
  • RAS downstream signaling pathways such as ERK phosphorylation
  • AMG-510 is a potent, orally bioavailable, selective KRAS G12C covalent inhibitor developed by Amgen for the treatment of locally advanced or metastatic non-small cell lung cancer harboring a KRAS G12C mutation. Its structure is as follows:
  • the present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
  • E is selected from -(CH 2 CH 2 O) m -;
  • E 1 is selected from -(CR 7 R 8 ) v -;
  • E 2 is selected from -(CH 2 CH 2 O) w -;
  • the heterocycloalkenyl groups are each independently optionally substituted with 1, 2, 3 or 4 R e ;
  • R 3 is selected from H, F, Cl, Br, I and C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted with 1, 2, 3 or 4 R b ;
  • R 4 is selected from C 1-4 alkyl and C 1-4 haloalkyl, wherein said C 1-4 alkyl and C 1-4 haloalkyl are each independently optionally surrounded by 1, 2, 3 or 4 R c replace;
  • R 5 is selected from H, F, Cl, Br, I, -NH 2 , C 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkylamino, wherein the C 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkylamino are each independently optionally substituted with 1, 2, 3 or 4 R d ;
  • R 6 is selected from H, F, Cl, Br, I, -OH, -NH 2 and -CN;
  • R 2 , R 6 and the carbon atoms to which they are attached together form
  • R 7 is selected from H, D, F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-4 alkyl and C 1-4 alkoxy, wherein said C 1-4 alkyl and C 1-4 alkoxy are each independently optionally substituted with 1, 2, or 3 R f ;
  • R 8 is selected from H, D, F, Cl, Br, I, -OH, -NH 2 and -CN;
  • two R7 on adjacent carbon atoms and the carbon atom to which they are attached together form a 4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 R g substitutions;
  • R 9 are each independently selected from H, F, Cl, Br, I, -OH, -NH 2 and -CN;
  • R 10 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-3 alkylamino;
  • the two R 9 and the carbon atoms to which they are attached are taken together to form a 4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 R;
  • R a is independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy and 3-6 membered heterocycloalkyl, wherein The C 1-4 alkyl, C 1-4 alkoxy and 3-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3 or 4 R;
  • R b is independently selected from F, Cl, Br, I, -OH , -NH and -CN;
  • R c is independently selected from F, Cl, Br, I, -OH , -NH and -CN;
  • R d are independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
  • R e is each independently selected from F, Cl, Br, I, -OH, -NH2 , -CN and -N( CH3 ) 2 ;
  • R f is independently selected from D, F, Cl, Br, I, -OH , -NH and -CN;
  • R is independently selected from F, Cl, Br, I, -OH, -NH2 , -CN and
  • n is selected from 0 or 1;
  • v is selected from 2, 3 or 4;
  • w is selected from 0 or 1;
  • hetero means 1, 2, 3 or 4, respectively A heteroatom or heteroatom group independently selected from -O-, -NH-, -S- and -N-.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • n 0 or 1
  • the heterocycloalkenyl groups are each independently optionally substituted with 1, 2, 3 or 4 R e ;
  • R 3 is selected from H, F, Cl, Br, I and C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted with 1, 2, 3 or 4 R b ;
  • R 4 is selected from C 1-4 alkyl and C 1-4 haloalkyl, wherein said C 1-4 alkyl and C 1-4 haloalkyl are each independently optionally surrounded by 1, 2, 3 or 4 R c replace;
  • R 5 is selected from H, F, Cl, Br, I, -NH 2 , C 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkylamino, wherein the C 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkylamino are each independently optionally substituted with 1, 2, 3 or 4 R d ;
  • R a is independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy and 3-6 membered heterocycloalkyl, wherein The C 1-4 alkyl, C 1-4 alkoxy and 3-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3 or 4 R;
  • R b is independently selected from F, Cl, Br, I, -OH , -NH and -CN;
  • R c is independently selected from F, Cl, Br, I, -OH , -NH and -CN;
  • R d are independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
  • Re is independently selected from F, Cl, Br, I, -OH , -NH and -CN;
  • R is independently selected from F, Cl, Br, I, -OH , -NH and -CN;
  • Hetero in the 3-6-membered heterocycloalkyl, 5-6-membered heterocycloalkyl and 5-6-membered heterocycloalkenyl means 1, 2, 3 or 4 are independently selected from -O-, -NH-, -S- and -N- heteroatoms or heteroatomic groups.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • n 0 or 1
  • R 1 is selected from H, F, Cl, Br and -NH 2 ;
  • R 3 is selected from H, F, Cl, Br, I and C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted with 1, 2, 3 or 4 R b ;
  • R 4 is selected from C 1-4 alkyl and C 1-4 haloalkyl, wherein said C 1-4 alkyl and C 1-4 haloalkyl are each independently optionally surrounded by 1, 2, 3 or 4 R c replace;
  • R 5 is selected from H, F, Cl, Br, I, -NH 2 , C 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkylamino, wherein the C 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkylamino are each independently optionally substituted with 1, 2, 3 or 4 R d ;
  • R a is independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN and 3-6 membered heterocycloalkyl, wherein the 3-6 membered heterocycloalkyl is selected from 1, 2 , 3 or 4 R substitutions;
  • R b is independently selected from F, Cl, Br, I, -OH , -NH and -CN;
  • R c is independently selected from F, Cl, Br, I, -OH , -NH and -CN;
  • R d are independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
  • R is independently selected from F, Cl, Br, I, -OH , -NH and -CN;
  • Hetero in the 3-6 membered heterocycloalkyl represents 1, 2, 3 or 4 heteroatoms or heteroatomic groups independently selected from -O-, -NH-, -S- and -N-.
  • the above compound has the structure represented by formula (II-1) or (II-2):
  • E, E 1 , E 2 , R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in the present invention.
  • n, R 1 , R 2 , R 3 , R 4 and R 5 are as defined in the present invention.
  • the above R a are independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN, -C 1-3 alkoxy and 5-membered heterocycloalkyl, wherein The -C 1-3 alkoxy and 5-membered heterocycloalkyl groups are each independently optionally substituted with 1, 2, 3 or 4 R, and other variables are as defined in the present invention.
  • the above R a are independently selected from F, Cl, Br, -OH, -NH 2 , -CN, -C 1-3 alkoxy, tetrahydrofuranyl and pyrrolidinyl, wherein the -C 1-3 alkoxy, tetrahydrofuranyl and pyrrolidinyl are each independently optionally substituted with 1, 2, 3 or 4 R, other variables are as defined herein.
  • R a are independently selected from F, Cl, Br, -OH, -NH 2 , -CN, -OCH 3 , wherein -OCH 3 , Each independently is optionally substituted with 1, 2, 3 or 4 R, other variables are as defined herein.
  • R a are independently selected from F, -OH, -OCH 3 ,
  • R a are independently selected from F, -OH, -OCH 3 , and Other variables are as defined in the present invention.
  • R a are independently selected from F, -OH and Other variables are as defined in the present invention.
  • R b , R c , and R d are each independently selected from F, and other variables are as defined in the present invention.
  • R e are independently selected from -OH, -NH 2 and -N(CH 3 ) 2 , and other variables are as defined in the present invention.
  • R e are independently selected from -OH, and other variables are as defined in the present invention.
  • R f are independently selected from D and F, and other variables are as defined in the present invention.
  • R f are independently selected from D, and other variables are as defined in the present invention.
  • R 1 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, -CH 3 , wherein -CH 3 , Each independently is optionally substituted with 1, 2, 3 or 4 R e , R e and other variables as defined herein.
  • R 1 is selected from H, -NH 2 , -CN, Re and other variables are as defined in the present invention.
  • R 1 is selected from H, -NH 2 , -CN, Other variables are as defined in the present invention.
  • R 1 is selected from H and -NH 2 , and other variables are as defined in the present invention.
  • R 2 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-4 alkyl and 5-membered heteroaryl, wherein the C 1 -4- alkyl and 5-membered heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 R a , R a and other variables as defined herein.
  • the above R 2 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, -CH 3 , -CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 and imidazolyl, wherein the -CH 3 , -CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 and and imidazolyl are each independently optionally substituted with 1, 2, 3 or 4 R a , R a and other variables are as defined in the present invention.
  • R 2 is selected from H, F, -CN, -CH 3 , -CH 2 CH 3 and -CH 2 CH(CH 3 ) 2 , wherein -CH 3 , -CH 2 CH 3 and -CH2CH( CH3 ) 2 are each independently optionally substituted with 1, 2 , 3 or 4 R a , R a and other variables as defined herein.
  • R 2 is selected from H, F, -CN, -CH 3 , -CH 2 CH 3 and -CH 2 CH(CH 3 ) 2 , wherein -CH 3 , -CH 2 CH 3 and -CH2CH( CH3 ) 2 are optionally substituted with 1, 2 or 3 R a , R a and other variables as defined herein.
  • R 2 is selected from H, F, -CN, Ra and other variables are as defined in the present invention.
  • R 2 is selected from H, F, -CN, Ra and other variables are as defined in the present invention.
  • R 2 is selected from H, F, -CN, -CHF 2 , -CF 3 , Other variables are as defined in the present invention.
  • R 2 is selected from H, F, -CN, -CHF 2 , -CF 3 , Other variables are as defined in the present invention.
  • R 2 is selected from H, F, -CN, -CF 3 , Other variables are as defined in the present invention.
  • R 3 is selected from H, F and -CH 3 , and other variables are as defined in the present invention.
  • R 3 is selected from H and F, and other variables are as defined in the present invention.
  • R 4 is selected from -CH 3 , and other variables are as defined in the present invention.
  • R 5 is selected from H, F, Cl and Br, and other variables are as defined in the present invention.
  • R 5 is selected from H, and other variables are as defined in the present invention.
  • R 6 is selected from H, and other variables are as defined in the present invention.
  • R 7 is selected from H, D, F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-3 alkoxy, wherein the C 1-3 alkoxy Oxygen is optionally substituted with 1, 2, or 3 Rf , Rf and other variables as defined herein.
  • R 7 is selected from H, D, F, Cl, Br, I and -OCH 3 , wherein the -OCH 3 is optionally substituted by 1, 2, or 3 R f , R f and other variables as defined herein.
  • R 7 is selected from H, D, F, -OCH 3 and -OCD 3 , and other variables are as defined in the present invention.
  • R 8 is selected from H, D, F, Cl and Br, and other variables are as defined in the present invention.
  • R 9 is selected from H, and other variables are as defined in the present invention.
  • R 10 is selected from H and -NHCH 3 , and other variables are as defined in the present invention.
  • the two R 7 on the above adjacent carbon atoms and the carbon atoms to which they are attached together form a 5-membered heterocycloalkyl, wherein the 5-membered heterocycloalkyl is optionally composed of 1, 2, 3 or 4 Rg substitutions, Rg and other variables are as defined herein.
  • the two R 7 on the above adjacent carbon atoms form together with the carbon atom to which they are attached.
  • the Optionally substituted with 1, 2, 3 or 4 Rg , Rg and other variables are as defined herein.
  • the two R 7 on the above adjacent carbon atoms form together with the carbon atom to which they are attached.
  • Other variables are as defined in the present invention.
  • the above two R 9 and the carbon atoms to which they are attached together form a 5-membered heterocycloalkyl, wherein the 5-membered heterocycloalkyl is optionally surrounded by 1, 2, 3 or 4 R h Substitution, Rh and other variables are as defined herein.
  • the above two R 9 and the carbon atoms to which they are attached together form wherein the Optionally substituted with 1, 2, 3 or 4 R h , R h and other variables as defined herein.
  • the above-mentioned compound has the structure represented by formula (II-3), (II-4) or (II-5):
  • n is selected from 0 and 1;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined in the present invention.
  • the above-mentioned compound has the structure represented by formula (II-3A), (II-3B), (II-4A), (II-4B), (II-5A) or (II-5B):
  • n is selected from 0 and 1;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined in the present invention.
  • the above-mentioned compound has the structure represented by formula (II-6), (II-7), (II-8) or (II-9):
  • n is selected from 0 and 1;
  • Ring A is selected from 4-6 membered heterocycloalkyl
  • R 1 , R 2 , R 3 , R 7 , R 8 , R 9 , R 10 and R g are as defined in the present invention.
  • the above-mentioned ring A is selected from 5-membered heterocycloalkyl, and other variables are as defined in the present invention.
  • the above-mentioned compounds have formulae (II-6A), (II-6B), (II-7A), (II-7B), (II-8A), (II-8B), (II- 9A) or the structure shown in (II-9B):
  • n is selected from 0 and 1;
  • Ring A is selected from 4-6 membered heterocycloalkyl
  • R 1 , R 2 , R 3 , R 7 , R 8 , R 9 , R 10 and R g are as defined in the present invention.
  • n, R 1 , R 2 and R 3 are as defined in the present invention.
  • n, R 1 , R 2 and R 3 are as defined in the present invention.
  • the present invention also provides a compound of the following formula or a pharmaceutically acceptable salt thereof,
  • the present invention also provides a compound of the following formula or a pharmaceutically acceptable salt thereof,
  • the present invention also provides the use of the above-mentioned compounds or their pharmaceutically acceptable salts in the preparation of medicaments for treating KRAS mutant solid tumor diseases.
  • the compound of the present invention has good KRAS(G12C)-SOS1 binding inhibitory activity, and has significant inhibitory activity on the proliferation of KRAS(G12C) mutant H358 cells and DLD-1 cells p-ERK, thereby obtaining excellent tumor growth inhibitory activity. active.
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue , without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids; also include salts of amino acids such as arginine, etc. , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • enantiomers or “optical isomers” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomer or “geometric isomer” result from the inability to rotate freely due to double bonds or single bonds to ring carbon atoms.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.
  • tautomer or “tautomeric form” refers to isomers of different functional groups that are in dynamic equilibrium and are rapidly interconverted at room temperature.
  • a chemical equilibrium of tautomers can be achieved if tautomers are possible (eg, in solution).
  • proton tautomers also called prototropic tautomers
  • prototropic tautomers include interconversions by migration of protons, such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence tautomers include interconversions by recombination of some bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in one enantiomer” refer to one of the isomers or pairs
  • the enantiomer content is less than 100%, and the isomer or enantiomer content is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
  • isomeric excess or “enantiomeric excess” refer to the difference between two isomers or relative percentages of two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80% .
  • Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
  • the diastereoisomers were resolved and the pure enantiomers recovered.
  • separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • deuterated drugs can be formed by replacing hydrogen with deuterium, and the bonds formed by deuterium and carbon are stronger than those formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable.
  • oxygen it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with up to two Rs, with independent options for R in each case.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • substituents When a substituent is vacant, it means that the substituent does not exist. For example, when X in A-X is vacant, it means that the structure is actually A. When the listed substituents do not indicate through which atom it is attached to the substituted group, such substituents may be bonded through any of its atoms, for example, pyridyl as a substituent may be through any one of the pyridine ring The carbon atom is attached to the substituted group.
  • the direction of attachment is arbitrary, for example,
  • the linking group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right. It is also possible to connect ring A and ring B in the opposite direction to the reading order from left to right.
  • Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • any one or more sites in the group can be linked to other groups by chemical bonds.
  • connection method of the chemical bond is not located, and there is an H atom at the linkable site, when the chemical bond is connected, the number of H atoms at the site will be correspondingly reduced with the number of chemical bonds connected to the corresponding valence. the group.
  • the chemical bond connecting the site to other groups can be represented by straight solid line bonds straight dotted key or wavy lines express.
  • a straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in this group;
  • the straight dashed bond in the group indicates that it is connected to other groups through the two ends of the nitrogen atom in the group;
  • the wavy lines in the phenyl group indicate connections to other groups through the 1 and 2 carbon atoms in the phenyl group.
  • C 1-4 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms.
  • the C 1-4 alkyl includes C 1-2 , C 1-3 and C 2-3 alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine).
  • Examples of C 1-4 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , s-butyl and t-butyl) and so on.
  • C 1-3 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (eg methyl), divalent (eg methylene) or multivalent (eg methine) .
  • Examples of C1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C1-4alkoxy refers to those alkyl groups containing 1 to 4 carbon atoms attached to the remainder of the molecule through an oxygen atom.
  • the C 1-4 alkoxy group includes C 1-3 , C 1-2 , C 2-4 , C 4 and C 3 alkoxy and the like.
  • Examples of C 1-6 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy) oxy, s-butoxy and t-butoxy) and the like.
  • C1-3alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy and the like.
  • Examples of C 1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • C 1-4 alkylamino refers to those alkyl groups containing 1 to 4 carbon atoms attached to the remainder of the molecule through an amino group.
  • the C 1-4 alkylamino includes C 1-3 , C 1-2 , C 2-4 , C 4 , C 3 and C 2 alkylamino and the like.
  • C 1-4 alkylamino examples include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -N(CH 2 CH 3 )( CH2CH3 ) , -NHCH2CH2CH3 , -NHCH2 ( CH3 ) 2 , -NHCH2CH2CH2CH3 , etc.
  • halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
  • C 1-4 haloalkyl refers to monohaloalkyl and polyhaloalkyl groups containing 1 to 4 carbon atoms.
  • the C 1-4 haloalkyl includes C 1-4 , C 1-3 , C 1-2 , C 3-4 , C 2-4 , C 2-3 , C 4 , C 3 , C 2 and C 1 haloalkyl, etc.
  • Examples of C 1-4 haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, pentachloroethyl, 3-bromopropyl, 4 - Chlorobutyl etc.
  • C 3-6 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which are monocyclic and bicyclic ring systems, said C 3-6 cycloalkyl including C 3-5 , C 4-5 and C 5-6 cycloalkyl and the like; it may be monovalent, divalent or polyvalent.
  • Examples of C3-6 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule.
  • the 3-6 membered heterocycloalkyl includes 4-6 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl and the like.
  • Examples of 3-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxiranyl, thioethane, azetidinyl, oxetanyl, thietanyl, Pyrrolidine, pyrazolidine, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydrofuranyl Hydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), Linyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithi
  • a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule.
  • the 4-6 membered heterocycloalkyl includes 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl and the like.
  • 4-6 membered heterocycloalkyl examples include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- piperidinyl and 3-piperidyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl,
  • a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule.
  • the 5-6 membered heterocycloalkyl includes 5- and 6-membered heterocycloalkyl.
  • 5-6 membered heterocycloalkyl examples include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.) , tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1 -piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazole Alkyl, 1,2-oxazinyl, 1,2-thiazinyl or hex
  • a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule.
  • 5-membered heterocycloalkyl examples include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.) or tetrahydrofuran base (including tetrahydrofuran-2-yl, etc.) and the like.
  • bicyclic ring systems include spiro, paracyclic and bridged rings, any ring of this system is non-aromatic.
  • a heteroatom may occupy the position of attachment of the heterocycloalkenyl to the rest of the molecule.
  • the 5-6 membered heterocyclenyl includes 5-membered and 6-membered heterocyclenyl and the like. Examples of 5-6 membered heterocycloalkenyl include but are not limited to
  • bicyclic ring systems include spiro, paracyclic and bridged rings, any ring of this system is non-aromatic.
  • a heteroatom may occupy the position at which the heterocycloalkenyl is attached to the rest of the molecule. Examples of 5-6 membered heterocycloalkenyl include but are not limited to
  • the terms “5-6 membered heteroaryl ring” and “5-6 membered heteroaryl” are used interchangeably in the present invention, and the term “5-6 membered heteroaryl” means from 5 to 6 ring atoms It is composed of a monocyclic group with a conjugated ⁇ electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , p is 1 or 2).
  • a 5-6 membered heteroaryl group can be attached to the remainder of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl groups include 5- and 6-membered heteroaryl groups.
  • Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4
  • the terms “5-membered heteroaryl ring” and “5-membered heteroaryl” can be used interchangeably in the present invention, and the term “5-membered heteroaryl” refers to a 5-membered ring atom having a conjugated ⁇ -electron system The monocyclic group of which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , p is 1 or 2).
  • a 5-6 membered heteroaryl group can be attached to the remainder of the molecule through a heteroatom or a carbon atom.
  • the 5-membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.) etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazole) base, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2, 4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl,
  • Cn-n+m or Cn - Cn+m includes any particular instance of n to n+ m carbons, eg C1-12 includes C1 , C2 , C3, C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range from n to n+ m , eg C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; in the same way, n yuan to n +m-membered means that the number of atoms in the ring is from n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membere
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, a nucleophilic substitution reaction).
  • a substitution reaction eg, a nucleophilic substitution reaction
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy, such as acetoxy, trifluoroacetoxy, and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl groups, such as alkanoyl groups (eg, acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); Arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS), 2-(trimethylsilyl (TMS),
  • hydroxy protecting group refers to a protecting group suitable for preventing hydroxyl side reactions.
  • Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (eg acetyl); arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and tert-butyl
  • acyl groups such as alkanoyl (eg acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenyl
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuK ⁇ radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • SXRD single crystal X-ray diffraction method
  • the cultured single crystal is collected by Bruker D8 venture diffractometer
  • the light source is CuK ⁇ radiation
  • the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • the volumes used in the present invention are commercially available.
  • Alloc stands for allyloxycarbonyl
  • SEM stands for trimethylsilylethoxymethyl
  • OTs stands for 4-toluenesulfonyl
  • Boc stands for tert-butoxycarbonyl
  • DCM stands for dichloromethane
  • DIEA represents N,N-diisopropylethylamine
  • MeI represents methyl iodide
  • PE represents petroleum ether
  • EA represents ethyl acetate
  • THF represents tetrahydrofuran
  • EtOH represents ethanol
  • MeOH represents methanol
  • Boc 2 O represents di-tert-butyl dicarbonate ;
  • NH 4 Cl for ammonium chloride
  • T 3 P for 1-propylphosphoric acid tricyclic anhydride
  • Pd/C for palladium/carbon catalyst
  • TMSN 3 for azidotrimethylsilane
  • NCS for N-chlorobutanedi Imide
  • HBr hydrobromic acid
  • the present invention will be described in detail by the following examples, but it does not mean any unfavorable limitation of the present invention.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the invention.
  • compound A-3 (15.2 g, 89.5 mmol) was dissolved in acetonitrile (100 mL), triethylamine (14.6 g, 144 mmol) and magnesium chloride (9.33 g, 98.0 mmol) were added successively at 0 °C, and at 15 °C The reaction was stirred for 2 hours. After cooling to 0 °C, a solution of compound A-2 (10.8 g, 42.6 mmol) in acetonitrile (50 mL) was added dropwise, and the reaction was stirred at 15 °C for 12 hours.
  • compound 3-1 (1.00 g, 5.00 mmol) was dissolved in toluene (2 mL), and then compound 3-2 (3.61 g, 10.0 mmol) and bistriphenylphosphine palladium dichloride (351 mg, 0.50 mmol) were added. mmol), and the reaction was stirred at 120 °C for 12 h. Saturated potassium fluoride solution (10 mL) was added to the reaction solution, extracted with ethyl acetate (5 mL ⁇ 2), filtered, and concentrated under reduced pressure to obtain compound 3-3.
  • the concentrated residue was separated and purified by preparative high performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150mm ⁇ 40mm ⁇ 4 ⁇ m; mobile phase: 0.05% aqueous hydrochloric acid solution-acetonitrile; gradient: acetonitrile: 28%-58%, 9min) to obtain The hydrochloride salt of compound 4.
  • compound 5-5 (441 mg, 1.56 mmol) was dissolved in toluene (5 mL), and compound 3-2 (1.87 g, 5.19 mmol) and bistriphenylphosphonium palladium dichloride (109 mg, 0.16 mmol) were added. , the reaction solution was stirred at 120 ° C for 12 hours. Saturated potassium fluoride solution (20 mL) was added to quench, and extracted with ethyl acetate (15 mL ⁇ 2). Filter and concentrate under reduced pressure to obtain compound 5-6.
  • Compound 5 was separated and purified by high performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150mm ⁇ 40mm ⁇ 4 ⁇ m; mobile phase: 0.05% aqueous hydrochloric acid solution-acetonitrile; gradient: acetonitrile: 28%-58%, 9min) to obtain the salt of compound 5 acid salt.
  • Compound 5 was subjected to SFC (chromatographic column: Chiralcel AD-3 150mm ⁇ 4.6mm ⁇ 3 ⁇ m; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%), measure ee value.
  • compound 6-5 (1.35 g, 4.87 mmol) was dissolved in toluene (10 mL), 3-2 (586 g, 16.2 mmol) and bistriphenylphosphonium palladium dichloride (342 mg, 0.49 mmol) were added, The reaction solution was stirred and reacted at 120°C for 12 hours. Saturated potassium fluoride solution (20 mL) was added to quench the reaction and extracted with ethyl acetate (15 mL ⁇ 2). Filter and concentrate under reduced pressure to obtain compound 6-6.
  • reaction solution was separated and purified by preparative high performance liquid chromatography (chromatographic column: Xtimate C18 150mm ⁇ 40mm ⁇ 5 ⁇ m; mobile phase: 0.05% aqueous hydrochloric acid solution-acetonitrile; gradient: acetonitrile: 17%-41%, 10min) to obtain the salt of compound 8 acid salt.
  • compound 1-8 (784 mg, 1.37 mmol) was dissolved in dimethyl sulfoxide (5 mL), 9-4 (500 mg, 1.64 mmol) and N,N-diisopropylethylamine (1.77 g g, 13.7 mmol), the reaction solution was stirred at 90 °C for 12 hours.
  • compound 9-5 (60.0 mg, 108 ⁇ mol) was dissolved in dimethyl sulfoxide (1 mL), compound 9-6 (93.9 mg, 1.08 mmol), cuprous iodide (10.3 mg, 53.9 ⁇ mol) were added. , potassium carbonate (29.8mg, 216 ⁇ mol) and L-proline (12.4mg, 108 ⁇ mol), the reaction solution was stirred at 120 ° C for 12 hours.
  • reaction solution was separated and purified by preparative high performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150mm ⁇ 30mm ⁇ 4 ⁇ m; mobile phase: 0.05% aqueous hydrochloric acid-acetonitrile; gradient: acetonitrile: 26%-56%, 9min) to obtain compound 9. Hydrochloride.
  • compound 11-1 (344 mg, 970 ⁇ mol) was dissolved in toluene (5 mL), 3-2 (701 mg, 1.94 mmol) and bistriphenylphosphonium palladium dichloride (68.1 mg, 97.0 ⁇ mol) were added, The reaction solution was stirred and reacted at 120°C for 7 hours. Saturated potassium fluoride solution (5 mL) was added to quench, and it was extracted with ethyl acetate (5 mL ⁇ 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 11-2.
  • compound 9-5 120 mg, 216 ⁇ mol was dissolved in N,N-dimethylformamide (5 mL), zinc cyanide (50.1 mg, 431 ⁇ mol), 2-dicyclohexylphosphorus-2,4 were added. , 6-triisopropylbiphenyl (20.6 mg, 43.1 ⁇ mol), tris(dibenzylideneacetone)dipalladium (19.7 mg, 21.6 ⁇ mol), and the reaction was stirred at 90° C. for 6 hours.
  • reaction solution was filtered, ethyl acetate (20 mL) was added to the filtrate, the organic phase was washed with saturated brine (50 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and the residue after concentration under reduced pressure was separated and purified by high performance liquid chromatography (chromatographic column: Phenomenex Genimi NX C18 150 ⁇ 40 mm ⁇ 5 ⁇ m; mobile phase: 0.05% aqueous hydrochloric acid solution-acetonitrile; gradient: acetonitrile 15%-45%, 10 min) to obtain the hydrochloride salt of compound 13.
  • SFC chromatographic column: Chiralcel IC-3 100mm ⁇ 4.6mm ⁇ 3 ⁇ m; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%
  • compound 14-1 (3.00 g, 14.8 mmol) was dissolved in anhydrous dichloromethane (30 mL), and diethylaminosulfur trifluoride (3.57 g, 22.2 mmol) was added dropwise at 0 °C, and the reaction solution was Stir at 25°C for 12 hours, add ice water (20 mL) to the reaction solution, extract with dichloromethane (20 mL ⁇ 1), wash the organic phase with saturated brine (20 mL ⁇ 1), dry over anhydrous sodium sulfate, filter , concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1 ⁇ 10/1, V/V) to obtain compound 14-2.
  • compound 14-2 (3.10 g, 13.8 mmol) was dissolved in dry toluene (50 mL), tributyl (1-ethoxyethylene) tin (9.95 g, 27.6 mmol) was added, and bistris Phenylphosphine palladium dichloride (967 mg, 1.38 mmol), the reaction solution was stirred at 110 ° C for 12 hours, a saturated aqueous potassium fluoride solution (200 mL) was added to the reaction solution, extracted with ethyl acetate (200 mL ⁇ 1), the organic The phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 14-3.
  • compound 14-4 (1.85 g, 9.83 mmol) was dissolved in dry tetrahydrofuran (50 mL), tetraethyl titanate (8.97 g, 39.3 mmol) and compound A-6 (2.38 g, 19.7 mmol) were added , the reaction solution was stirred at 72 °C for 36 hours, cooled to 0 °C, and saturated aqueous ammonium chloride solution (20 mL) was added dropwise, then ethyl acetate (20 mL) was added, filtered, and the filter cake was washed with ethyl acetate (10 mL), and the organic phase was washed with ethyl acetate (10 mL).
  • the hydrochloride salt of compound 13 (20.0 mg, 39.8 ⁇ mol) was dissolved in anhydrous tetrahydrofuran (5 mL), a solution of methylmagnesium bromide in tetrahydrofuran (3 M, 66.3 ⁇ L) was added dropwise to the reaction solution, and the solution was stirred for 30 minutes. After minutes, tetraisopropyl titanate (11.8 ⁇ L, 39.8 ⁇ mol) was added, and the reaction was stirred at 25° C. for 12 hours.
  • 1,2-Dibromoethane (10.9uL, 144 ⁇ mol) was dissolved in N,N-dimethylformamide (3mL), zinc powder (118mg, 1.80mmol,) was added, and the reaction was stirred at 70°C for 10 minutes . After cooling to 20°C, trimethylchlorosilane (18.3uL, 144 ⁇ mol) was added dropwise, and the reaction was stirred for 50 minutes. A solution of compound 17-1 (76.3 mg, 270 ⁇ mol, ) in N,N-dimethylformamide (3 mL) was added dropwise, and the reaction was stirred at 40° C. for 1 hour.
  • Compound 17 was obtained by preparative high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX 80mm ⁇ 30mm ⁇ 3 ⁇ m; mobile phase: 10mM aqueous ammonium bicarbonate solution-acetonitrile; gradient: acetonitrile 30%-90%, 9min).
  • compound 22-4 (580 mg, 904 ⁇ mol) was dissolved in dioxane/water solution (4:1, 1.25 mL), 22-5 (191 mg, 603 ⁇ mol), [1,1′-bis( Diphenylphosphino)ferrocene]palladium dichloride (44.1 mg, 60.2 ⁇ mol) and sodium carbonate (128 mg, 1.21 mmol).
  • the reaction solution was stirred and reacted at 100°C for 12 hours.
  • the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol, 1/0-10/1, V/V) to obtain compound 22-6.
  • MS-ESI calculated [M+H] + 645, found 645.
  • compound 27-3 (700 mg, 1.80 mmol) was dissolved in toluene (10 mL), compound 3-2 (1.57 g, 4.35 mmol) and bistriphenylphosphonium palladium dichloride (126 mg, 180 ⁇ mol) were added ), the reaction solution was stirred at 120 °C for 12 hours. Saturated potassium fluoride solution (5 mL) was added to quench, and it was extracted with ethyl acetate (5 mL ⁇ 2). Filter and concentrate under reduced pressure to get the crude product which can be directly used in the next step.
  • the hydrochloride salt of compound 33 (50 mg, 99.3 ⁇ mol) was dissolved in dichloromethane (2 mL), acetic anhydride (20.3 mg, 199 ⁇ mol) and triethylamine (27.7 ⁇ l, 199 ⁇ mol) were added, and the reaction was stirred at 25° C. 6 Hour. Filtration, the residue after the filtrate was concentrated under reduced pressure was separated and purified by preparative high performance liquid chromatography (chromatographic column: Xtimate C18 150mm ⁇ 40mm ⁇ 5 ⁇ m; mobile phase: 0.05% aqueous hydrochloric acid solution-acetonitrile; gradient: acetonitrile: 15%-45%, 10 min) to obtain the hydrochloride salt of compound 34.
  • compound 35-1 (6.00 g, 23.3 mmol) was dissolved in dry toluene (100 mL), compound 3-2 (12.6 g, 34.9 mmol) was added, and bistriphenylphosphine palladium dichloride ( 1.63 g, 2.33 mmol), the reaction solution was stirred at 120 ° C for 12 hours, and after cooling to room temperature, a saturated aqueous potassium fluoride solution (100 mL) was added to the reaction solution, extracted with ethyl acetate (100 mL ⁇ 2), and the organic phase was Dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain crude compound 35-2, which is directly used in the next step.
  • compound 36-1 (5.00 g, 25.5 mmol) was dissolved in dry toluene (50 mL), compound 3-2 (10.2 g, 28.3 mmol) was added, and bistriphenylphosphine palladium dichloride ( 1.79 g, 2.55 mmol), the reaction solution was stirred at 120 °C for 12 hours, and after cooling to room temperature, saturated aqueous potassium fluoride solution (50 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL ⁇ 2), and the organic phase was Dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain crude compound 36-2, which is directly used in the next step.
  • Small molecule compounds bind to the catalytic site of SOS1 and inhibit the binding of SOS1 to KRAS(G12C).
  • SOS1 When the binding of fluorescently labeled SOS1 protein to fluorescently labeled KRAS(G12C) protein is inhibited, the emitted fluorescence changes.
  • fluorescence changes By detecting fluorescence changes, the ability of small molecules to prevent SOS1 from binding to KRAS(G12C) can be tested.
  • a homogeneous time-resolved fluorescence (HTRF) binding assay was used to examine the ability of the compounds of the present invention to inhibit the mutual binding of SOS1 and KRAS(G12C).
  • HTRF time-resolved fluorescence
  • KRAS (G12C) protein was expressed and purified by Wuhan Pujian Biotechnology Co., Ltd., SOS1 exchange domin (564-1049) protein (H ⁇ man recombinant) was purchased from Cytoskeleton, Mab Anti 6HIS-XL665 and Mab Anti GST-E ⁇ cryptate were purchased from Cisbio.
  • the multi-plate reader Nivo5 was purchased from PerkinElmer.
  • 1X buffer preparation Hepes: 5mM; NaCl: 150mM; EDTA: 10mM; Igepal: 0.0025%; KF: 100mM; DTT: 1mM; BSA: 005%;
  • the compounds to be tested were diluted 5-fold with DMSO to the 8th concentration, that is, from 1 mM to 0.064 ⁇ M.
  • the IC 50 value can be obtained by curve fitting with four parameters (log(inhibitor) vs.response in GraphPad Prism --Variable slope mode).
  • Table 1 shows the results of the inhibitory activity of the compounds of the present invention on the binding of KRAS(G12C) and SOS1.
  • test compound IC50 (nM) Compound 1 hydrochloride 21.45 Compound 5 hydrochloride 12.56 Compound 6 hydrochloride 52.94 Compound 11 37.63 The hydrochloride salt of compound 14 35.13 Compound 18 hydrochloride 56.85 Compound 20 9.50 Compound 25 128.30 Compound 26 21.47 Compound 29 17.10 Compound 31 28.82 Compound 34 105.7 Compound 35 60.78
  • the compound of the present invention has a significant inhibitory effect on the combination of KRAS(G12C) and SOS1.
  • KRAS(G12C) mutant H358 cells the KRAS signaling pathway is abnormally activated.
  • Small molecule SOS1 inhibitors reduce the GEF activity and the ratio of activated RAS-GTP by inhibiting the binding of SOS1 to RAS protein. Further down-regulate the phosphorylation level of MEK/ERK pathway downstream of RAS to achieve the effect of inhibiting cell proliferation. Small molecules were co-cultured with H358 cells in 3D space, and then the cell readout indirectly reflected the proliferation inhibitory activity of SOS1 inhibitors on H358 cells.
  • RPMI1640 medium fetal bovine serum, penicillin/streptomycin antibiotics were purchased from Vicente, and low melting point agarose was purchased from Sigma. Almar blue reagent was purchased from Invitrogen.
  • the NCI-H358 cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd. Nivo Multilabel Analyzer (PerkinElmer).
  • the H358 cells were seeded in a 96-well U-shaped plate, and the low-melting point agarose was first made into a 2% stock solution.
  • the agarose stock solution was first heated in a microwave oven to completely melt it, and then the agarose was placed in a 42°C water bath. Sugar remains liquid.
  • the gel was added to the serum-containing medium to prepare a gel concentration of 0.6% as the bottom gel, and 50 ⁇ L per well was spread into a 96-well U-shaped plate.
  • After the bottom gel has solidified add 2% gel to the cell-containing medium to prepare a cell-containing top gel with a gel concentration of 0.4%, and the cell density is 4 ⁇ 10 4 cells/ml.
  • 75 ⁇ l was added to the 96-well U-shaped plate with the bottom gel, and the cell density was 3000 cells per well. After the supernatant gel was solidified, the cell plate was placed in a carbon dioxide incubator for overnight incubation.
  • the compound to be tested was diluted 3-fold to the ninth concentration, that is, from 6mM to 0.9 ⁇ M, and a double-well experiment was set up. For example, add 198 ⁇ L of medium to the middle plate, and then transfer 2 ⁇ L of the compound diluted in each well to the first middle plate according to the corresponding position, then add 100 ⁇ L of medium to the second middle plate, and take the first middle plate. Add 100 ⁇ L of the mixed compound, and transfer 40 ⁇ L per well to the cell plate after mixing. Compound concentrations transferred to cell plates ranged from 30 [mu]M to 4.5 nM. The cell plates were placed in a carbon dioxide incubator for an additional 7 days.
  • the IC 50 value can be obtained by curve fitting with four parameters ("log(inhibitor) vs. response--Variable slope" mode).
  • test compound IC50 (nM) Compound 1 hydrochloride 140
  • the compounds of the present invention can inhibit the proliferation of H358 cells under 3D conditions.
  • DLD-1 cells were purchased from Nanjing Kebai; 1640 medium was purchased from Biological Industries; fetal bovine serum was purchased from Biosera; Advanced Phospho-ERK1/2 (THR202/TYR204) KIT was purchased from Cisbio.
  • the composition of Advanced Phospho-ERK1/2 (THR202/TYR204) KIT is shown in Table 3.
  • DLD-1 cells were seeded in a transparent 96-well cell culture plate, 80 ⁇ L of cell suspension per well, each well containing 8000 DLD-1 cells, the cell plate was placed in a carbon dioxide incubator, and incubated overnight at 37°C;
  • the compounds to be tested were diluted with 100% DMSO to 2 mM as the first concentration, and then 5-fold diluted with a pipette to the eighth concentration, ie, from 2 mM to 0.026 [mu]M.
  • Phospho-ERK1/2 Eu Cryptate antibody and Phospho-ERK1/2 d2 antibody were diluted 20-fold with Detection buffer;
  • the IC 50 value can be obtained by curve fitting with four parameters (log(inhibitor) vs.response in GraphPad Prism --Variable slope mode).
  • Table 4 shows the test results of the inhibitory effect of the compounds of the present invention on p-ERK.
  • Min well negative control well reads 0.5% DMSO cell well cell lysate
  • test compound IC50 (nM) Compound 1 hydrochloride 140.5 Compound 5 hydrochloride 54.5 Compound 6 hydrochloride 112.1 The hydrochloride salt of compound 14 119.5 Compound 16 227.6
  • the compound of the present invention has inhibitory effect on the proliferation of p-ERK in DLD-1 cells.
  • CD-1 mice male, 7-9 weeks old, Beijing Weitonglihua
  • the pharmacokinetic characteristics of the compounds in rodents after intravenous bolus injection and oral administration were tested according to the standard protocol.
  • the candidate compounds were formulated into clear solutions and administered to mice by a single intravenous injection and oral administration.
  • the vehicle for intravenous injection and oral administration is a mixed solvent of 5% dimethyl sulfoxide, 5% polyethylene glycol-15 hydroxystearate and 10% water.
  • Four male CD-1 mice were used in this project, two mice were administered intravenously at a dose of 10 mg/kg, and the 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration were collected.
  • Plasma samples were given oral gavage at a dose of 50 mg/kg, and the plasma samples were collected at 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after administration. Centrifuge at x g for 10 minutes, separate the supernatant to obtain the plasma sample, add 20 times the volume of acetonitrile solution containing internal standard to precipitate the protein, stir at 12,000 x g for 15 minutes, centrifuge at 4°C to take 50 ⁇ L of the supernatant and transfer it to a 96-well plate for secondary centrifugation to take the supernatant for Quantitative analysis of blood drug concentration by LC-MS/MS analysis method, and calculation of pharmacokinetic parameters, such as peak concentration (C max ), clearance rate (CL), half-life (T 1/2 ), tissue distribution (Vdss) , area under the drug-time curve (AUC 0-last ), bioavailability (F) and so on.
  • C max peak concentration
  • CL clearance rate
  • T 1/2 half-life
  • Vdss tissue
  • the compound of the present invention has good pharmacokinetic properties, including good oral bioavailability, oral exposure, half-life and clearance rate.
  • Human pancreatic cancer cells (Miapaca2) were cultured in an adherent monolayer in vitro, and the culture conditions were DMEM medium plus 10% fetal bovine serum, 37 °C, 5% CO 2 incubator. Routine digestion with trypsin-EDTA was performed two to three times a week. When the cell saturation is 80%–90% and the number reaches the requirement, the cells are harvested, counted, and seeded.
  • Balb/c nude mice female, 6-7 weeks old, were purchased from Shanghai Sipple-Bike Laboratory Animal Co., Ltd.
  • Miapaca2 cells were subcutaneously inoculated into the right back of each mouse, and the group administration started when the average tumor volume reached 118 mm 3 .
  • the tumor-inhibitory efficacy of the test compounds was evaluated by using TGI (%).
  • TGI (%) reflects the tumor growth inhibition rate.
  • TGI(%) [1-(average tumor volume at the end of administration in a certain treatment group-average tumor volume at the beginning of administration in this treatment group)/(average tumor volume at the end of treatment in the solvent control group-average at the beginning of treatment in the solvent control group tumor volume)] ⁇ 100%.

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Abstract

L'invention concerne des dérivés de benzylaminoquinazoline et leur procédé de préparation, spécifiquement le composé tel que représenté par la formule (II) et un sel pharmaceutiquement acceptable de celui-ci, pour une utilisation dans la préparation d'un médicament pour le traitement de tumeurs solides mutantes de KRAS.
PCT/CN2022/082591 2021-03-25 2022-03-23 Dérivés de benzylaminoquinazoline WO2022199635A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023207991A1 (fr) * 2022-04-29 2023-11-02 南京明德新药研发有限公司 Composé de quinazoline fusionné et son utilisation

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Publication number Priority date Publication date Assignee Title
CN102775356A (zh) * 2011-05-13 2012-11-14 江苏恒谊药业有限公司 4-氨基喹唑啉衍生物及其应用
WO2018172250A1 (fr) * 2017-03-21 2018-09-27 Bayer Pharma Aktiengesellschaft 2-méthyl-quinazolines
CN110167928A (zh) * 2016-12-22 2019-08-23 勃林格殷格翰国际有限公司 作为sos1抑制剂的新型经苄基氨基取代的喹唑啉和衍生物
WO2019201848A1 (fr) * 2018-04-18 2019-10-24 Bayer Pharma Aktiengesellschaft 2-méthyl-aza-quinazolines
CN113677350A (zh) * 2019-02-01 2021-11-19 里兰斯坦福初级大学理事会 Enpp1抑制剂和调节免疫反应的方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102775356A (zh) * 2011-05-13 2012-11-14 江苏恒谊药业有限公司 4-氨基喹唑啉衍生物及其应用
CN110167928A (zh) * 2016-12-22 2019-08-23 勃林格殷格翰国际有限公司 作为sos1抑制剂的新型经苄基氨基取代的喹唑啉和衍生物
WO2018172250A1 (fr) * 2017-03-21 2018-09-27 Bayer Pharma Aktiengesellschaft 2-méthyl-quinazolines
WO2019201848A1 (fr) * 2018-04-18 2019-10-24 Bayer Pharma Aktiengesellschaft 2-méthyl-aza-quinazolines
CN113677350A (zh) * 2019-02-01 2021-11-19 里兰斯坦福初级大学理事会 Enpp1抑制剂和调节免疫反应的方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023207991A1 (fr) * 2022-04-29 2023-11-02 南京明德新药研发有限公司 Composé de quinazoline fusionné et son utilisation

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