WO2022170947A1 - Dérivés de tétrahydronaphtyridine utilisés en tant qu'inhibiteurs de g12c mutants kras, leur procédé de préparation et leur utilisation - Google Patents

Dérivés de tétrahydronaphtyridine utilisés en tant qu'inhibiteurs de g12c mutants kras, leur procédé de préparation et leur utilisation Download PDF

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WO2022170947A1
WO2022170947A1 PCT/CN2022/073358 CN2022073358W WO2022170947A1 WO 2022170947 A1 WO2022170947 A1 WO 2022170947A1 CN 2022073358 W CN2022073358 W CN 2022073358W WO 2022170947 A1 WO2022170947 A1 WO 2022170947A1
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membered
heterocyclyl
heterocyclic group
cycloalkyl
alkyl
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PCT/CN2022/073358
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English (en)
Chinese (zh)
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郑苏欣
谢成英
郑明月
陆晓杰
乔刚
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苏州阿尔脉生物科技有限公司
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Priority to CN202280007411.6A priority Critical patent/CN116600808B/zh
Publication of WO2022170947A1 publication Critical patent/WO2022170947A1/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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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

Definitions

  • the invention belongs to the technical field of KRAS mutant G12C inhibitors, in particular to a tetrahydronaphthyridine derivative as a KRAS mutant G12C inhibitor, a preparation method and application thereof.
  • the RAS gene is the first discovered human tumor gene.
  • RAS proteins are activated by binding to GTP under the catalysis of guanine nucleotide exchange factor (GEF), while GTPase activating proteins (GAPs) catalyze the hydrolysis of RAS-bound GTP into a GDP-terminating active state to inhibit RAS activity.
  • GEF guanine nucleotide exchange factor
  • GAPs GTPase activating proteins
  • RAS proteins By cycling between active (GTP-bound) and inactive (GDP-bound) states, RAS proteins transduce upstream signals received from a variety of tyrosine kinases to downstream effectors to regulate cell proliferation, survival, migration, and processes such as apoptosis. Because RAS proteins are central to the axis of many important cellular signaling networks, and these signals are associated with multiple tumor markers, overactive RAS signaling may ultimately lead to tumorigenesis.
  • KRAS mutations are most common in KRAS (85%), while NRAS (12%) and HRAS (3%) are less common, and KRAS mutations are common in pancreatic cancer, colorectal cancer, lung cancer, gallbladder cancer, And thyroid cancer, etc.
  • the abnormal expression of KRAS accounts for up to 20% of all cancers, and 80% of KRAS mutations are missense mutations of a single amino acid substitution at codon 12.
  • KRAS G12C mutation accounts for 12% of all KRAS mutations, but it has a higher proportion in lung cancer, especially non-small cell lung cancer (14%).
  • Mutations in oncogenes, such as EGFR, ALK, and BRAF are mutually exclusive, suggesting that KRAS mutations are unique in lung cancer and that they may serve as an important indicator of tumor prognosis.
  • KRAS G12C mutant Due to the protein structure of KRAS without obvious binding sites, after more than 30 years of research efforts by scientists, there is still no KRAS inhibitor with sufficient safety and efficacy in clinical practice. In recent years, breakthroughs in the study of covalent inhibitors of KRAS mutants have made it possible to target KRAS mutants through allosteric sites.
  • the small molecule covalently bound to the cysteine replaced by the missense mutation is more likely to bind to the GDP-binding KRAS protein to reduce the affinity of GTP to KRAS, while preventing GEF from catalyzing the replacement of GDP by GTP, Locking the KRAS G12C mutant in an inactive state.
  • the object of the present invention is to provide a tetrahydronaphthyridine derivative, a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof as a KRAS mutant G12C inhibitor isomers in order to screen out compounds with excellent properties in terms of efficacy, safety and selectivity as KRAS mutant G12C inhibitors.
  • Another object of the present invention is to provide a method for the preparation of the derivatives, their pharmaceutically acceptable salts, their tautomers or their stereoisomers.
  • the present invention provides a tetrahydronaphthyridine derivative, a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof, wherein the structure of the tetrahydronaphthyridine derivative is as follows Formula (I) shows:
  • R 1 is selected from H or F
  • R 2 is selected from 6-12-membered aryl or 5-12-membered heteroaryl, wherein said aryl or heteroaryl is optionally substituted by 1-4 R c ;
  • R c is selected from halogen, hydroxy, C1-C3 alkyl, C1-C3 alkenyl, -NR a R b , cyano, C1-C3 alkoxy, C3-C7 cycloalkyl or 3-8 membered heterocycle group, wherein said alkyl, alkenyl, cycloalkyl, R a , R b or heterocyclyl is optionally substituted with 1-3 R c1 ;
  • R a and R b are each independently selected from H, C1-C3 alkyl, C3-C7 cycloalkyl or 4-7 membered heterocyclyl, or R a and R b together with the atoms to which they are attached may further form 4-7 membered heterocyclic group;
  • R c1 is selected from halogen, hydroxy, -NR a R b , cyano, C1-C3 alkyl or C1-C3 alkoxy.
  • L 1 is selected from bond, O, S, NH or NCH 3 ;
  • R 3 is selected from C1-C3 alkyl, C1-C3 alkenyl, C3-C7 cycloalkyl, 3-8-membered heterocyclic group, 4-10-membered fused heterocyclic group, 5-10-membered bridged heterocyclic group cyclic group, 5-10-membered spiro heterocyclic group, 6-12-membered aryl group or 5-12-membered heteroaryl group, wherein the alkyl group, alkenyl group, cycloalkyl group, heterocyclic group, fused heterocyclic group Cyclyl, bridged heterocyclyl, spiroheterocyclyl, aryl or heteroaryl may be optionally substituted with 1-4 R c2 .
  • R c2 is selected from halogen, hydroxyl, C1-C3 alkyl, C1-C3 alkenyl, -NR a R b , cyano, C1-C3 alkoxy, C3-C7 cycloalkyl, 3-8 membered heterocyclyl , 4-10-membered fused heterocyclic group, 5-10-membered bridged heterocyclic group, 5-10-membered spiro heterocyclic group, -C(O)R c1 , -C(O)NR a R b , - NR a C(O)R b , 6-12-membered aryl group or 5-12-membered heteroaryl group, wherein the alkyl, alkenyl, cycloalkyl, heterocyclyl, fused heterocyclyl, bridge Heterocyclyl, spiroheterocyclyl, R a , R b , aryl or heteroaryl optionally substitute
  • L 2 is selected from C3-C8 cycloalkyl, C5-C10 spirocycloalkyl, C4-C10 fused cycloalkyl, C5-C10 bridged cycloalkyl, 3-8-membered heterocyclyl, 5-10-membered Condensed heterocyclic group, 5-10-membered bridged heterocyclic group, 5-10-membered spiro heterocyclic group, 6-12-membered aryl group, 5-12-membered heteroaryl group, wherein the cycloalkyl, spirocycloalkyl, fused cycloalkyl, bridged cycloalkyl, heterocyclyl, fused heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, aryl, heteroaryl optionally surrounded by 1-4 R c replaced;
  • R 4 is selected from -C(O)R d or -S(O) 2 R d ;
  • R d is selected from C2-C4 alkenyl or C2-C4 alkynyl, wherein the alkenyl and alkynyl can be optionally further substituted by 1-3 R d1 ;
  • R d1 is selected from halogen, cyano, C1-C3 alkyl, C3-C7 cycloalkyl or 4-7 membered heterocyclyl, wherein said alkyl, cycloalkyl or heterocyclyl is optionally replaced by 1- 3 R c substitutions;
  • heteroatoms in the heterocyclic group and the heteroaryl group in the formula (I) are 1-4 and are selected from one or more of oxygen, nitrogen and sulfur.
  • R e1 , R e2 or R e3 are independently selected from H, halogen, cyano, C1-C3 alkyl, C3-C7 cycloalkyl or 4-7 membered heterocyclic group, and the above-mentioned alkyl, ring Alkyl or heterocyclyl is optionally substituted with 1-3 halogens, C1-C3 alkyl, C3-C7 cycloalkyl, 4-7 membered heterocyclyl, hydroxy or amino;
  • heteroatoms in the heterocyclic group are 1-3 one or more selected from oxygen, nitrogen and sulfur;
  • R 2 is selected from 6-12-membered aryl or 5-12-membered heteroaryl, wherein said aryl or heteroaryl is optionally substituted by 1-4 R; wherein, R c is selected from halogen, hydroxy, C1-C3 alkyl, C1-C3 alkenyl, -NR a R b , cyano, C1-C3 alkoxy, C3-C7 cycloalkyl or 3-8 membered heterocycle group, wherein said alkyl, alkenyl, cycloalkyl, R a , R b or heterocyclyl is optionally substituted with 1-3 R c1 ;
  • R c1 is selected from halogen, hydroxyl, -NR a R b , cyano, C1-C3 alkyl or C1-C3 alkoxy;
  • R 3 is selected from C1-C3 alkyl, C1-C3 alkenyl, C3-C7 cycloalkyl, 3-8 membered heterocyclyl, 4-10 membered fused heterocyclyl, 5-10 membered heterocyclyl Bridged heterocyclyl with 5-10 members, spiro heterocyclyl with 5-10 members, aryl with 6-12 members or heteroaryl with 5-12 members, wherein the alkyl, alkenyl, cycloalkyl, heterocycle base, fused heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, aryl or heteroaryl may be optionally substituted with 1-4 R c2 ;
  • R c2 is selected from halogen, hydroxyl, C1-C3 alkyl, C1-C3 alkenyl, -NR a R b , cyano, C1-C3 alkoxy, C3-C7 cycloalkyl, 3-8 membered heterocyclyl , 4-10-membered fused heterocyclic group, 5-10-membered bridged heterocyclic group, 5-10-membered spiro heterocyclic group, -C(O)R c1 , -C(O)NR a R b , - NR a C(O)R b , 6-12-membered aryl group or 5-12-membered heteroaryl group, wherein the alkyl, alkenyl, cycloalkyl, heterocyclyl, fused heterocyclyl, bridge Heterocyclyl, spiroheterocyclyl, R a , R b , aryl or heteroaryl optionally substitute
  • R a and R b are each independently selected from H, C1-C3 alkyl, C3-C7 cycloalkyl or 4-7 membered heterocyclyl, or R a and R b together with the atoms to which they are attached may further form 4-7 membered heterocyclic group;
  • R 3 is a 4-8-membered heterocyclic group optionally substituted by 1-4 R c 2
  • R c 2 when the R c 2 is 2-4, the R c 2 are the same or different;
  • the heterocyclic group contains 1-2 heteroatoms
  • the heteroatom of the heterocyclic group is nitrogen and/or oxygen;
  • R 3 is a 4-8 membered heterocyclic group optionally substituted by 1-4 R c2
  • the heteroatoms of the heterocyclic group are two, the two hetero atoms are the same or different.
  • R 1 , R 3 , R e1 , R e2 , R e3 and L 1 have the same limited range as above;
  • R is selected from C1-C3 alkyl, C1-C3 alkenyl, C3-C7 cycloalkyl, 3-8 membered heterocyclyl, 4-10 membered fused Heterocyclyl, 5-10-membered bridged heterocyclyl, 5-10-membered spiro heterocyclyl, 6-12-membered aryl or 5-12-membered heteroaryl, wherein the alkyl, alkenyl , cycloalkyl, heterocyclyl, fused heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, 6-12 membered aryl or 5-12 membered heteroaryl can be optionally replaced by 1-4 R replaced by c2 ;
  • R c2 is selected from halogen, hydroxyl, C1-C3 alkyl, C1-C3 alkenyl, -NR a R b , cyano, C1-C3 alkoxy, C3-C7 cycloalkyl, 3-8 membered heterocyclyl , 4-10-membered fused heterocyclic group, 5-10-membered bridged heterocyclic group, 5-10-membered spiro heterocyclic group, -C(O)R c1 , -C(O)NR a R b , - NR a C(O)R b , 6-12-membered aryl group or 5-12-membered heteroaryl group, wherein the alkyl, alkenyl, cycloalkyl, heterocyclyl, fused heterocyclyl, bridge Heterocyclyl, spiroheterocyclyl, R a , R b , aryl or heteroaryl optionally substitute
  • R c1 is selected from halogen, hydroxyl, -NR a R b , cyano, C1-C3 alkyl or C1-C3 alkoxy;
  • R a and R b are each independently selected from H, C1-C3 alkyl, C3-C7 cycloalkyl or 4-7 membered heterocyclyl, or R a and R b together with the atoms to which they are attached may further form 4-7 membered heterocyclic group;
  • R 3 is a 4-8-membered heterocyclic group optionally substituted by 1-4 R c 2
  • R c 2 when the R c 2 is 2-4, the R c 2 are the same or different;
  • the heterocyclic group contains 1-2 heteroatoms
  • the heteroatom of the heterocyclic group is nitrogen and/or oxygen;
  • R 3 is a 4-8 membered heterocyclic group optionally substituted by 1-4 R c2
  • the heteroatoms of the heterocyclic group are two, the two hetero atoms are the same or different.
  • R 3 , R e1 , R e2 , R e3 and L 1 have the same limited range as above;
  • R is selected from C1-C3 alkyl, C1-C3 alkenyl, C3-C7 cycloalkyl, 3-8 membered heterocyclyl, 4-10 membered fused Heterocyclyl, 5-10-membered bridged heterocyclyl, 5-10-membered spiro heterocyclyl, 6-12-membered aryl or 5-12-membered heteroaryl, wherein the alkyl, alkenyl , cycloalkyl, heterocyclyl, fused heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, 6-12 membered aryl or 5-12 membered heteroaryl can be optionally replaced by 1-4 R replaced by c2 ;
  • R c2 is selected from halogen, hydroxyl, C1-C3 alkyl, C1-C3 alkenyl, -NR a R b , cyano, C1-C3 alkoxy, C3-C7 cycloalkyl, 3-8 membered heterocyclyl , 4-10-membered fused heterocyclic group, 5-10-membered bridged heterocyclic group, 5-10-membered spiro heterocyclic group, -C(O)R c1 , -C(O)NR a R b , - NR a C(O)R b , 6-12-membered aryl group or 5-12-membered heteroaryl group, wherein the alkyl, alkenyl, cycloalkyl, heterocyclyl, fused heterocyclyl, bridge Heterocyclyl, spiroheterocyclyl, R a , R b , aryl or heteroaryl optionally substitute
  • R c1 is selected from halogen, hydroxyl, NR a R b , cyano, C1-C3 alkyl or C1-C3 alkoxy;
  • R a and R b are each independently selected from H, C1-C3 alkyl, C3-C7 cycloalkyl or 4-7 membered heterocyclyl, or R a and R b together with the atoms to which they are attached may further form 4-7 membered heterocyclic group;
  • R 3 is a 4-8-membered heterocyclic group optionally substituted by 1-4 R c 2
  • R c 2 when the R c 2 is 2-4, the R c 2 are the same or different;
  • the heterocyclic group contains 1-2 heteroatoms
  • the heteroatom of the heterocyclic group is nitrogen and/or oxygen;
  • R 3 is a 4-8 membered heterocyclic group optionally substituted by 1-4 R c2
  • the heteroatoms of the heterocyclic group are two, the two hetero atoms are the same or different.
  • tetrahydronaphthyridine derivatives are selected from any one of the following structures:
  • the present invention provides a preparation method of the tetrahydronaphthyridine derivatives, pharmaceutically acceptable salts thereof, tautomers or stereoisomers thereof as described in the first aspect, which are selected from From the following schemes:
  • the preparation method of the compound described in the general formula (I) of the present invention or its stereoisomer, tautomer or its pharmaceutically acceptable salt comprises the following steps:
  • the compound of general formula (I-1) is reacted with ammonia methanol to obtain the compound of general formula (I-2);
  • the compound of the general formula (I-2) and the compound of the general formula (I-3) are subjected to condensation reaction in the presence of a basic reagent and a condensing agent to obtain the compound of the general formula (I-4);
  • the compound of the general formula (I-8) is reacted with the compound of the general formula (I-9) to obtain the compound of the general formula (I-A).
  • PG is Boc or Cbz;
  • X is halogen, preferably bromine;
  • R 1 , R 3 , L 1 , L 2 have the same limited ranges as above;
  • R 1 is preferably cyano;
  • L 1 is preferably O.
  • the compound of the general formula (I-12) is de-esterified to obtain the compound of the general formula (I-13) under acidic conditions;
  • the compound of the general formula (I-13) is halogenated at the 2-position under basic conditions to obtain the compound of the general formula (I-14);
  • the compound of the general formula (I-16) and the compound of the general formula (I-7) are subjected to Mitsunobu reaction to obtain the compound of the general formula (I-17);
  • the compound of the general formula (I-17) and the compound of the general formula (I-9) are subjected to Buchwald reaction under basic conditions, in the presence of a metal catalyst and a ligand, to obtain the compound of the general formula (I-18) ;
  • the compound of the general formula (I-18) is subjected to a reduction reaction to obtain the compound of the general formula (I-A).
  • X is halogen, preferably bromine; R 1 , R 3 , L 1 , L 2 have the same limited ranges as above; R 1 is preferably fluorine; L 1 is preferably O.
  • the compound of the general formula (I-2) is protected by a protective group under acid conditions to obtain the compound of the general formula (I-19);
  • the compound of the general formula (I-19) is reacted with methyl malonate under basic conditions to obtain the compound of the general formula (I-20);
  • the fifth step the compound of the general formula (I-22) and the compound of the general formula (I-9) obtain the compound of the general formula (I-23) under basic conditions;
  • the compound of the general formula (I-23) is de-esterified and the protecting group is obtained to obtain the compound of the general formula (I-24);
  • the compound of general formula (I-25) and the compound of general formula (I-7) are subjected to Mitsunobu reaction to obtain the compound of general formula (I-A).
  • PG and PG 1 are protecting groups; PG is preferably Boc or Cbz; PG 1 is preferably PMB; X is halogen or OTs, preferably bromine; R 1 , R 3 and L 1 , L 2 have the same definitions as above range; R 1 is preferably hydrogen; L 1 is preferably O.
  • the compound of the general formula (I-A) and the compound of the general formula (I-B) are subjected to Buchwald reaction under basic conditions, in the presence of a metal catalyst and a ligand, to obtain the compound of the general formula (I-C);
  • R 1 , R 2 , R 3 , R 4 , L 1 , L 2 have the same limited range as the general formula (I);
  • X is halogen or OTs, preferably bromine.
  • the reagent for providing alkaline conditions is selected from organic bases or inorganic bases, and the organic bases are triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylamine
  • the organic bases are triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylamine
  • the inorganic bases are sodium hydride, potassium phosphate, sodium carbonate,
  • potassium acetate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate and lithium hydroxide sodium hydride, potassium phosphate, sodium carbonate, potassium acetate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate and lithium hydroxide;
  • the reagent for providing acidic conditions is one or more of hydrogen chloride, hydrogen chloride solution in 1,4-dioxane, hydrogen chloride solution in methanol, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid and phosphoric acid kind;
  • the metal catalyst is palladium/carbon, Raney nickel, tetrakis-triphenylphosphine palladium, palladium dichloride, palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride ( Pd(dppf)Cl 2 ), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, bistriphenylphosphonium palladium dichloride (Pd(PPh) 3 ) one or more of Cl 2 ) and tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 );
  • the ligands are 2-dicyclohexylphosphine-2,6'-dimethoxybiphenyl (SPhos), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (XantPhos), 2- Dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (XPhos), 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl (DavePhos), 1, One or more of 1'-bis(diphenylphosphino)ferrocene (Dppf) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (BINAP), preferably 1,1 '-Binaphthalene-2,2'-bisdiphenylphosphine (BINAP);
  • the reducing agent is one or more of sodium borohydride, potassium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium aluminum tetrahydrogen;
  • the oxidant is one or more of potassium permanganate, manganese dioxide, potassium dichromate, sodium dichromate and potassium osmate;
  • the above reaction is preferably carried out in a solvent, and the solvent used is N,N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, 1,4-dioxane, water, tetrahydrofuran, dichloromethane, One or more of 1,2-dichloroethane, methanol, ethanol, toluene, petroleum ether, ethyl acetate, n-hexane and acetone.
  • the solvent used is N,N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, 1,4-dioxane, water, tetrahydrofuran, dichloromethane, One or more of 1,2-dichloroethane, methanol, ethanol, toluene, petroleum ether, ethyl acetate, n-hexane and acetone.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned tetrahydronaphthyridine derivatives, pharmaceutically acceptable salts thereof, tautomers or stereoisomers thereof body;
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier and/or excipient.
  • pharmaceutically acceptable carrier is a pharmaceutically acceptable solvent, suspending agent or excipient for delivering the active substance of the present invention or a physiologically acceptable salt thereof to animals or humans.
  • the carrier can be liquid or solid.
  • the pharmaceutical composition contains a safe and effective amount (such as 0.001-99.9 parts by weight, more preferably 0.01-99 parts by weight, more preferably 0.1-90 parts by weight) of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient, wherein the total weight of the composition is 100 parts by weight.
  • a safe and effective amount such as 0.001-99.9 parts by weight, more preferably 0.01-99 parts by weight, more preferably 0.1-90 parts by weight
  • a pharmaceutically acceptable carrier or excipient wherein the total weight of the composition is 100 parts by weight.
  • the pharmaceutical composition of the present invention contains 0.001-99.9 wt %, more preferably 0.01-99 wt %, more preferably 0.1-90 wt % of the total weight of the compound represented by formula (I) or its pharmacy an acceptable salt; and a pharmaceutically acceptable carrier or excipient, wherein the total weight of the composition is 100% by weight.
  • the preferred ratio of the compound of formula (I) to a pharmaceutically acceptable carrier, excipient or sustained-release agent is that formula (I) as an active ingredient accounts for more than 65% of the total weight, and the rest accounts for The total weight ratio is 0.5-40%, or more preferably 1-20%, or more preferably 1-10%.
  • the unit dose of each dose comprises 0.05mg-500mg, preferably 0.5mg-200mg, more preferably 0.1mg-100mg of the compound of formula (I), enantiomer, external Racemates, pharmaceutically acceptable salts or mixtures thereof.
  • the amount of the active ingredients can generally be the conventional amount or lower in the prior art.
  • compositions of the present invention may be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, etc., wherein the compound of formula (I) may be present in a suitable solid or liquid carrier or diluent middle.
  • the pharmaceutical compositions of the present invention may also be stored in a suitable sterile device for injection or instillation.
  • the pharmaceutical composition may also contain odorants, flavoring agents, and the like.
  • the compound of formula (I) or the pharmaceutical composition comprising the compound of formula (I) of the present invention can be clinically used in mammals (including humans) through oral, nasal, skin, lung or gastrointestinal routes of administration.
  • the preferred route of administration is oral.
  • the preferred daily dose is 0.5 mg to 200 mg/kg body weight, taken in one or divided doses. Regardless of the method of administration, the optimal dose for an individual should depend on the specific treatment. It is common to start with a small dose and gradually increase the dose until the most suitable dose is found.
  • the effective dose of active ingredient employed may vary with the compound employed, the mode of administration, and the severity of the disease to be treated. Generally, however, satisfactory results are obtained when the compounds of the present invention are administered in doses of about 1-300 mg/kg of animal body weight per day, preferably in 1-3 divided doses per day, or in sustained release form Dosing. For most large mammals, the total daily dose is about 5-1000 mg, preferably about 10-500 mg.
  • Dosage forms suitable for oral administration contain about 1-200 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen can be adjusted to provide optimal therapeutic response. For example, several divided doses may be administered daily, or the dose may be proportionally reduced, as dictated by the exigencies of the therapeutic situation.
  • the compounds or pharmaceutically acceptable salts and compositions thereof can be administered orally as well as intravenously, intramuscularly or subcutaneously.
  • the preferred pharmaceutical compositions are solid compositions, especially tablets and solid- or liquid-filled capsules. Oral administration of the pharmaceutical composition is preferred.
  • Solid carriers include: starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include: sterile water, polyethylene glycols, nonionic surfactants and edible oils (eg corn oil, peanut oil and sesame oil) as appropriate to the characteristics of the active ingredient and the particular mode of administration desired.
  • Adjuvants commonly used in the preparation of pharmaceutical compositions may also advantageously be included, such as flavors, colors, preservatives and antioxidants such as vitamin E, vitamin C, BHT and BHA.
  • the active compounds or pharmaceutically acceptable salts thereof and compositions thereof may also be administered parenterally or intraperitoneally.
  • Solutions or suspensions of these active compounds can also be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquids, polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, these forms must be sterile and must be fluid for easy syringe expelling. It must be stable under the conditions of manufacture and storage and must be resistant to the contaminating influence of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, alcohol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • the compound represented by formula (I) or its pharmaceutically acceptable salt and its composition can also be administered in combination with other active ingredients or drugs for treating or preventing chronic pain diseases.
  • other active ingredients or drugs for treating or preventing chronic pain diseases.
  • two or more drugs are administered in combination, they generally have better effects than when the two drugs are administered separately.
  • the present invention provides a tetrahydronaphthyridine derivative as described in the first aspect, a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof, or a tetrahydronaphthyridine derivative as described in the third aspect.
  • a pharmaceutically acceptable salt thereof a tautomer or a stereoisomer thereof, or a tetrahydronaphthyridine derivative as described in the third aspect.
  • the cancers described therein are, but are not limited to, astrocytic carcinoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, pancreatic cancer, Lung cancer, oral cancer, ovarian cancer, prostate cancer, thyroid cancer, sarcoma, kidney cancer and bile duct cancer; preferably lung cancer, pancreatic cancer or colorectal cancer.
  • the present invention provides a tetrahydronaphthyridine derivative as described in the first aspect, a pharmaceutically acceptable salt thereof, a tautomer or a stereoisomer thereof or as described in the third aspect Application of the pharmaceutical composition in the preparation of KRAS mutant G12C inhibitor.
  • the present invention provides a method for treating and/or preventing cancer, comprising administering to a human a therapeutically effective amount of the tetrahydronaphthyridine derivative as described in the first aspect, a pharmaceutically acceptable A salt, a tautomer or a stereoisomer thereof or a pharmaceutical composition as described in the third aspect.
  • Alkyl refers to a saturated aliphatic hydrocarbon group comprising 1-20 carbon atoms, or 1-10 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms , or a saturated linear or branched monovalent hydrocarbon group of 1-2 carbon atoms, wherein the alkyl group may be independently optionally substituted by one or more substituents described herein.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1 ,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2 - Dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-di Methylbutyl etc. Alkyl groups can be optionally substituted or unsubstituted.
  • Alkenyl refers to a linear or branched monovalent hydrocarbon group of 2-12 carbon atoms, or 2-8 carbon atoms, or 2-6 carbon atoms, or 2-4 carbon atoms, wherein at least one CC is sp 2 double bond, wherein the alkenyl group can be independently optionally substituted by one or more substituents described in the present invention, specific examples of which include, but are not limited to, vinyl, allyl and alkene Butyl and so on. Alkenyl groups can be optionally substituted or unsubstituted.
  • Cycloalkyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring comprising 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl , cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. Cycloalkyl groups can be optionally substituted or unsubstituted.
  • “Spirocycloalkyl” refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and the single rings share one carbon atom (called spiro atom) with each other, and the ring contains one or more aromatic systems with double bonds but none of the rings have fully conjugated pi electrons.
  • spiro atom carbon atom
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • spirocycloalkyl groups are divided into mono-spiro, double-spiro or poly-spirocycloalkyl groups, preferably mono-spiro and double-spirocycloalkyl groups, preferably 4-membered/5-membered, 4-membered Yuan/6 Yuan, 5 Yuan/5 Yuan or 5 Yuan/6 Yuan.
  • spirocycloalkyl include, but are not limited to:
  • “Fused cycloalkyl” refers to a 5- to 18-membered all-carbon polycyclic group containing two or more cyclic structures that share a pair of carbon atoms with each other, and one or more rings may contain one or more double bonds, But none of the rings have an aromatic system with fully conjugated pi electrons, preferably 6 to 12 membered, more preferably 7 to 10 membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl.
  • Non-limiting examples of "fused cycloalkyl” include, but are not limited to:
  • “Bridged cycloalkyl” refers to an all-carbon polycyclic group of 5 to 18 members, containing two or more cyclic structures, sharing two carbon atoms that are not directly connected to each other, and one or more rings may contain one or more Aromatic systems in which multiple double bonds, but none of the rings have fully conjugated pi electrons, are preferably 6 to 12 membered, more preferably 7 to 10 membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • Non-limiting examples of "bridged cycloalkyl” include, but are not limited to:
  • the cycloalkyl ring can be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring connected to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthalene base, benzocycloheptyl, etc.
  • Heterocyclyl “heterocycle” or “heterocyclic” are used interchangeably in this application, and are used interchangeably in this application, and all refer to a saturated or partially unsaturated monocyclic ring containing 3-12 ring atoms , bicyclic or tricyclic non-aromatic heterocyclic groups, wherein at least one ring atom atom is a heteroatom, such as oxygen, nitrogen, sulfur atom and the like. It preferably has a 5- to 7-membered monocyclic ring or a 7- to 10-membered bi- or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur.
  • heterocyclyl examples include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidine base, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and Piperazinyl.
  • the heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl.
  • Heterocyclyl groups can be optionally substituted or unsubstituted.
  • spiroheterocyclyls are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl, preferably mono-spiroheterocyclyl and bis-spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl group.
  • spiroheterocyclyl include, but are not limited to:
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
  • fused heterocyclyl include, but are not limited to:
  • bridged heterocyclyl include, but are not limited to:
  • Aryl refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion.
  • aryl includes aromatic groups such as phenyl, naphthyl, tetrahydronaphthyl. Preferred aryl groups are C6 - C10 aryl groups, more preferred aryl groups are phenyl and naphthyl, and most preferred are phenyl groups.
  • Aryl groups can be substituted or unsubstituted.
  • the "aryl” can be fused with a heteroaryl, a heterocyclyl or a cycloalkyl, wherein the parent structure is linked together by an aryl ring, non-limiting examples include but are not limited to:
  • Heteroaryl refers to an aromatic 5- to 6-membered monocyclic or 9- to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen, and/or sulfur.
  • heteroaryl include, but are not limited to, furanyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl , oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo-diazolyl Oxolyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindo
  • Heteroaryl groups can be optionally substituted or unsubstituted.
  • the heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples include but are not limited to:
  • Alkoxy refers to a group (alkyl-O-). Wherein, alkyl is as defined herein. Ci - C6 alkoxy groups are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.
  • Haloalkyl refers to an alkyl group having one or more halogen substituents, wherein the alkyl group has the meaning as described herein.
  • haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, 1,1-dichloroethyl, 1,2-dichloropropyl, and the like.
  • Halogen means fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.
  • Amino refers to -NH2 .
  • Cyano refers to -CN.
  • Niro refers to -NO2 .
  • Benzyl refers to -CH2 -phenyl.
  • Carboxyl refers to -C(O)OH.
  • Alcohol refers to -C(O) CH3 or Ac.
  • Carboxylate means -C(O)O(alkyl) or (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, are substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • the compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including, but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute the part.
  • Diastereomers can be separated into individual diastereomers by methods such as chromatography, crystallization, distillation or sublimation on the basis of their physicochemical differences.
  • Enantiomers can be separated by converting a chiral mixture into a diastereomeric mixture by reaction with an appropriate optically active compound such as a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride , the diastereomers are separated, and the individual diastereomers are converted to the corresponding pure enantiomers.
  • the intermediates and compounds of the present invention may also exist in different tautomeric forms, and all such forms are included within the scope of the present invention.
  • optically active compounds that is, they have the ability to rotate the plane of plane-polarized light.
  • the prefixes D, L or R, S are used to denote the absolute configuration of the chiral center of the molecule.
  • the prefixes d, l or (+), (-) are used to designate the sign of the plane-polarized light rotation of the compound, (-) or l means that the compound is levorotatory, and the prefix (+) or d means that the compound is dextrorotatory.
  • the atoms or groups of atoms of these stereoisomers are connected to each other in the same order, but their steric structures are different.
  • a specific stereoisomer may be an enantiomer, and a mixture of isomers is often referred to as an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can result in no stereoselectivity or stereospecificity during chemical reactions.
  • the terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomers, devoid of optical activity.
  • Tautomer or "tautomeric form” means that isomers of structures of different energies can be interconverted through a low energy barrier.
  • proton tautomers ie, prototropic tautomers
  • Valence (valence) tautomers include interconversions that recombine bond electrons.
  • the structural formulas described herein include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers): such as R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Accordingly, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers, or geometric isomers thereof are within the scope of the present invention.
  • “Pharmaceutically acceptable salts” refer to salts of the compounds of the present invention which are safe and effective when used in humans or animals.
  • the salts of the compounds can be obtained by using a sufficient amount of base or acid in neat solution or in a suitable inert solution to obtain the corresponding addition salts.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts, etc.
  • Pharmaceutically acceptable acid addition salts include inorganic acid salts and organic acid salts, and the inorganic and organic acids include Hydrochloric acid, hydrobromic acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, acetic acid, maleic acid, malonic acid, succinic acid, rice butenedioic acid, Phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, and methanesulfonic acid, among others (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977)).
  • the invention provides a KRAS mutant G12C inhibitor with a new structure, and the test results show that the tetrahydronaphthyridine derivative exhibits excellent KRAS mutant G12C inhibitory activity, and at the same time exhibits excellent safety and selectivity, It can be used to prepare medicines for treating cancer, especially lung cancer, colorectal cancer or pancreatic cancer.
  • Fig. 1 is a graph showing the effect of the compounds of the present invention on the KRAS/ERK1/2 signal transduction pathway of KRAS G12C mutant MIAPaCa-2 pancreatic cells.
  • Figure 2 is a graph showing the in vivo antitumor effect of the compounds of the present invention on KRAS G12C mutant MIAPaCa-2 pancreatic xenograft tumor nude mice model.
  • Figure 3 is a graph showing the effect of the compounds of the present invention on the body weight of mice in a nude mouse model of KRAS G12C mutant MIAPaCa-2 pancreatic xenograft tumor.
  • the mass spectrum was measured by LC/MS, and the ionization mode was ESI.
  • HPLC model Agilent 1260, Thermo Fisher U3000; Column model: Waters xbrige C18 (4.6*150mm, 3.5 ⁇ m); Mobile phase: A: ACN, B: Water (0.1% H 3 PO 4 ); Flow rate: 1.0mL/min; Gradient: 5%A for 1min, increase to 20%A within 4min, increase to 80%A within 8min, 80%A for 2min, back to 5%A within 0.1min; Wavelength: 220nm; Column oven: 35°C.
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.2mm-0.3mm, and the specification used for TLC separation and purification products is 0.4mm -0.5mm.
  • HATU 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.
  • reaction temperature is room temperature, which is 20°C-30°C.
  • the monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of the column chromatography used for purifying the compound or the developing solvent system of the thin layer chromatography method includes: A: Petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: n-hexane: ethyl acetate; the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or basic reagent can also be added Adjustments such as acetic acid or triethylamine, etc.
  • TLC thin layer chromatography
  • Methyl 3-amino-4-pyridinecarboxylate IN-2a 1.0 g, 6.57 mmol
  • monoethyl malonate 1.0 g, 7.88 mmol
  • pyridine 1.6 g, 19.71 mmol
  • ethyl acetate 20 mL
  • 1-propyl phosphoric anhydride 6.4 g, 10.06 mmol, 50% N,N-dimethylformamide solution
  • reaction solution was quenched with water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound IN-2b (1.3 g, yield 74%).
  • the sixth step 4-bromo-3-fluoro-1,7 naphthyridin-2-ol IN-2
  • reaction solution was quenched by adding saturated aqueous ammonium chloride solution (1.0 L), extracted with ethyl acetate (1.5 L), the organic phases were combined, washed with saturated brine (1.0 L), dried over anhydrous sodium sulfate, concentrated, and the crude product was filtered through a silica gel column Analysis and purification gave the title compound IN-4b (303.0 g, 65% yield) as a yellow solid.
  • reaction solution was concentrated to (4.0 L), quenched by adding saturated aqueous ammonium chloride solution (3 L), extracted with ethyl acetate (2.0 L), the organic phases were combined, washed with saturated brine (3 L), and concentrated to obtain the title compound IN- 4c (140.0 g, 54% yield).
  • reaction solution was filtered, water (2.5L) and dichloromethane (2.5L) were added to the filtrate, the layers were separated, the aqueous phase was extracted with dichloromethane (2.0L), the organic phases were combined, washed with saturated brine (2.5L), and anhydrous sulfuric acid It was dried over sodium, concentrated, and the crude product was purified by silica gel column chromatography to give the title compound IN-4d (68.6 g, 49% yield) as a brown oil.
  • the sixth step ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol and ((2S,7aR)-2-fluorotetrahydro-1H-pyrrolizine- 7a(5H)-yl)methanol mixture IN-4
  • the ninth step 2-((S)-1-acryloyl-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl) Methoxy)-5,6,7,8-tetrahydro-1,7-naphthyridin-4-yl)piperazin-2-yl)acetonitrile 3
  • reaction solution was quenched by adding a small amount of water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 4 (4.0 mg, yield 10%) .
  • the first step 1- (tert-butyl)2-(3-chloropropyl)pyrrolidine-1,2-dicarboxylic acid 2-methyl ester 5b
  • Boc-proline methyl ester 5a (5.0 g, 21.81 mmol) was dissolved in dry tetrahydrofuran (20 mL), and under nitrogen protection, the temperature was lowered to -65 °C, and bistrimethylsilylamine was slowly added to a constant pressure dropping funnel Lithium (32 mL, 32 mmol, 1M tetrahydrofuran solution), after adding -65 ° C for 1 hour, slowly adding 1-bromo-3-chloropropane (17 g, 109.2 mmol), slowly warming to room temperature after the addition and reacting for 2 hours, TLC Shows that the reaction is complete.
  • reaction solution was poured into water, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to obtain the title compound 5b (5.1 g, yield 80%) as a yellow liquid.
  • Lithium aluminum hydride (595 mg, 15.6 mmol) was dispersed in dry tetrahydrofuran (30 mL), cooled to 0 °C, and a solution of 6b-1 (1.7 g, 7.8 mmol) in tetrahydrofuran (15 mL) was added dropwise under nitrogen protection. After completion, the temperature was raised to 50° C. to react for 2 hours, and the reaction of the raw materials was monitored by TLC.
  • reaction solution was cooled to room temperature, quenched by adding water (0.6 mL), 15% sodium hydroxide solution (0.6 mL) and water (1.8 mL) successively, filtered, and the filtrate was concentrated to give the title compound 6c-1 (1.0 g, crude product), used directly in the next step.
  • the third step 4-bromo-3-fluoro-2-(((3R,4R)-4-methoxy-1-methylpyrrolidin-3-yl)oxy)-1,7-naphthyridine 6d
  • reaction solution was cooled to room temperature, diluted with water (5 mL), extracted with ethyl acetate (10 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the title compound 8c as a pale yellow solid ( 30 mg, crude product), used directly in the next step.
  • the reaction solution was adjusted to pH 8 with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (5 mL), the organic phases were combined, concentrated to remove about half of the dichloromethane, extracted with 1N dilute hydrochloric acid (5 mL), the aqueous phases were combined, and the aqueous phase was washed with sodium carbonate
  • the first step 4-bromo-3-fluoro-2-((tetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-1,7-naphthyridine 9a
  • Human pancreatic cancer MIAPaCa-2 cells (CRL-1420) used in the present invention were purchased from American Type Culture Collection (ATCC). Cells were grown in DMEM medium containing 2.5% horse serum, 10% fetal bovine serum, and 1% dual antibodies at 37°C in a 5% CO 2 environment.
  • the inhibitory effect of compounds on the proliferation of MIAPaCa-2 cells cultured in vitro was determined by the following methods:
  • the compounds of the examples of the present invention can inhibit the proliferation of MIAPaCa-2 cells, and the activity of compound 5 is comparable to that of MRTX849.
  • MIAPaCa-2 cells in good logarithmic growth phase were seeded into a six-well plate at 1*10 6 cells/well, and cultured overnight at 37° C. and 5% CO 2 .
  • Protein sample preparation trypsin digestion, collect cells, centrifuge at 500g for 5 minutes, discard the supernatant, wash 3 times with PBS, and use 1 ⁇ SDS gel loading buffer (50mM Tris-HCl (pH 6.8), 100mM DTT, 2% SDS, 10% glycerol, 0.1% bromophenol blue) 100 ⁇ L of lysed cells. Cell lysates were denatured by heating at 100°C for 10 minutes.
  • 1 ⁇ SDS gel loading buffer 50mM Tris-HCl (pH 6.8), 100mM DTT, 2% SDS, 10% glycerol, 0.1% bromophenol blue
  • Compound 5 in the examples of the present invention has a significant inhibitory effect on the phosphorylation of ERK1/2 in MIAPaCa-2 cells, and the inhibitory activity is concentration gradient dependent, and the activity is roughly equivalent to MRTX849.
  • Compound 5 and MRTX849 were administered intravenously at a dose of 5 mg/kg.
  • the mice tested were 7-8 week old ICR male mice.
  • the sampling time points were 0.083h, 0.5h, 1h, 2h, and the sampling tissues were plasma, brain, lung, colorectum, pancreas, gallbladder and bile duct.
  • the specific operation process is as follows:
  • Blood was collected from the mouse heart, thoroughly mixed, placed on ice, and centrifuged within 30 min to separate the plasma (4°C, 8000 rpm for 5 min), and the plasma was stored at -80°C until measurement.
  • the brain, lung, colorectum, pancreas, gallbladder and bile duct were collected from mice on ice, perfused with normal saline, rinsed, blotted dry with filter paper, and finally stored at -80°C until measurement.
  • Blood, brain, lung, colorectum, pancreas, gallbladder and bile duct were collected from blank animals without administration of carbon dioxide after euthanasia, as blank matrix.
  • Euthanasia The experimental animals were euthanized by inhaling excess CO2 after the experiment.
  • the blood-brain drug concentration was measured at different time points, and the pharmacokinetic software WinNonlin was used to fit and calculate the metabolic parameters of the sample, such as the area under the drug-time curve (AUC), peak concentration (Cmax), time to peak (Tmax), half-life ( T1/2) and other parameters.
  • AUC area under the drug-time curve
  • Cmax peak concentration
  • Tmax time to peak
  • T1/2 half-life
  • the present invention is to illustrate a class of tetrahydronaphthyridine derivatives as KRAS mutant G12C inhibitors of the present invention, the preparation method and the application thereof through the above-mentioned examples, but the present invention is not limited to the above-mentioned examples. , that is, it does not mean that the present invention must rely on the above-mentioned embodiments to be implemented.
  • Those skilled in the art should understand that any improvement of the present invention, the equivalent replacement of each raw material of the product of the present invention, the addition of auxiliary components, the selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

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Abstract

La présente invention relève du domaine technique des inhibiteurs de G12C mutants de KRAS, et concerne en particulier des dérivés de tétrahydronaphtyridine utilisés en tant qu'inhibiteurs de G12C mutants de KRAS, leur procédé de préparation et leur utilisation. Plus particulièrement, la structure de chaque dérivé de tétrahydronaphtyridine est telle que représentée dans la formule (I). L'invention concerne en outre un nouveau dérivé de tétrahydronaphtyridine, ayant des effets significatifs d'inhibition de l'activité G12C KRAS et de traitement du cancer, le cancer étant de préférence un cancer du poumon, un cancer colorectal, ou un cancer du pancréas.
PCT/CN2022/073358 2021-02-09 2022-01-24 Dérivés de tétrahydronaphtyridine utilisés en tant qu'inhibiteurs de g12c mutants kras, leur procédé de préparation et leur utilisation WO2022170947A1 (fr)

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