WO2022194066A1 - Inhibiteur de kras g12d et ses applications en médecine - Google Patents

Inhibiteur de kras g12d et ses applications en médecine Download PDF

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Publication number
WO2022194066A1
WO2022194066A1 PCT/CN2022/080545 CN2022080545W WO2022194066A1 WO 2022194066 A1 WO2022194066 A1 WO 2022194066A1 CN 2022080545 W CN2022080545 W CN 2022080545W WO 2022194066 A1 WO2022194066 A1 WO 2022194066A1
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Prior art keywords
compound
alkylene
cycloalkyl
alkyl
substituted
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PCT/CN2022/080545
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English (en)
Chinese (zh)
Inventor
吴颢
陈小平
路渊
徐人奇
黄传龙
何将旗
王维
李波燕
湛波
张运来
王冬
王国建
赵志昌
张洪波
周晓
兰宏
王家炳
丁列明
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贝达药业股份有限公司
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Priority to CN202280018826.3A priority Critical patent/CN116964058A/zh
Publication of WO2022194066A1 publication Critical patent/WO2022194066A1/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
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a novel compound having KRAS inhibitory activity, especially KRAS G12D inhibitory activity.
  • the present invention also relates to methods for the preparation of these compounds and pharmaceutical compositions containing them.
  • RAS is the gene with the highest mutation rate in human tumors, about 20-30% of all tumors have RAS mutations, about 98% of pancreatic cancer, 52% of colon cancer, 43% of multiple myeloma, And 32% of lung adenocarcinomas have RAS gene mutations.
  • the most common mutation of RAS is point mutation, which often occurs at codons 12, 13, and 61, of which codon 12 is the most common mutation, such as G12C, G12D or G12V.
  • KRAS G12C inhibitors AMG510 (WO2018217651A1) and MRTX849 (WO2019099524A1) have entered the late clinical stage; MIRATI is leading the way in the development of G12D inhibitors (WO2021041671A1).
  • the present invention provides a compound represented by general formula (I), its tautomer, deuterated substance or pharmaceutically acceptable salt:
  • Ring A is selected from C 3-6 cycloalkyl or 3-6 membered heterocyclyl
  • L 1 is selected from -O-(CH 2 ) 0-3 , -S-(CH 2 ) 0-3 , -NH-(CH 2 ) 0-3 or C 1-3 alkylene;
  • L 2 is selected from a bond or a C 1-3 alkylene group
  • R 1 is independently selected from H, halogen, alkyl, alkoxy, haloalkyl, hydroxy, and hydroxyalkyl;
  • R 2 is selected from C 3-14 cycloalkyl, 3-14-membered heterocyclyl, C 6-14 aryl and 5-14-membered heteroaryl, the C 3-14 cycloalkyl, 3-14-membered heteroaryl Cyclic, C 6-14 aryl and 5-14 membered heteroaryl are optionally further 1-4 selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl , cyano, amino, nitro, hydroxyl, C 1-6 hydroxyalkyl, -C 0-3 alkylene-N(R a ) 2 , cycloalkyl, heterocortyl, aryl and heteroaryl Substituents are substituted, and the R a is independently selected from H or C 1-6 alkyl;
  • R 3 is selected from H, halogen, C 1-6 alkyl or -OR 2a , and R 2a is selected from C 1-6 alkyl, C 3-8 cycloalkyl or haloalkyl;
  • R4 is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further substituted with one or more R3a ;
  • R 5 is selected from H, amino, substituted amino, C 1-6 alkyl, substituted C 1-6 alkyl, halogen, C 2-6 alkenyl, substituted C 2-6 alkenyl, C 3-6 cycloalkyl or substituted C 3-6 cycloalkyl;
  • R 6 is selected from H, halogen or C 1-6 alkyl
  • n is selected from 0, 1, 2, 3 or 4.
  • ring A in formula (I) is selected from C 3-6 cycloalkyl; preferably cyclopropyl;
  • L 1 in formula (I) is selected from -O-(CH 2 ) 0-3 , -NH-(CH 2 ) 0-3 or C 1-3 alkylene; preferably -O- (CH 2 ) 0-3 ;
  • L in formula (I) is selected from C 1-3 alkylene
  • R 1 in formula (I) is selected from H, halogen or alkyl; preferably H;
  • R 2 in formula (I) is selected from C 3-14 cycloalkyl or 3-14 membered heterocyclyl; the C 3-14 cycloalkyl or 3-14 membered heterocyclyl is optionally is further selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, cyano, amino, nitro, hydroxyl, C 1-6 hydroxyalkyl, -C 0-3 alkylene-N(R a ) 2 , cycloalkyl, heteroalkyi, aryl and heteroaryl substituents, the R a is independently selected from H or C 1-6 alkyl;
  • R in formula (I) is selected from
  • R 3 in formula (I) is selected from H, halogen or -OR 2a , and R 2a is selected from C 1-6 alkyl, C 3-8 cycloalkyl or haloalkyl;
  • R4 in formula (I) is selected from aryl or heteroaryl, optionally further substituted with one or more R3a ; said R3a is independently selected from H, hydroxy, cyano, halogen, nitro, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 haloalkyl, substituted or unsubstituted C 2-6 alkenyl or substituted or unsubstituted Substituted C 2-6 alkynyl;
  • R in formula (I) is selected from
  • R 5 in formula (I) is selected from H, C 1-6 alkyl, cyclopropyl, halogen, C 1-6 haloalkyl, C 2-6 alkenyl.
  • R 6 in formula (I) is selected from H.
  • the compound of formula (I) is selected from formula (IA):
  • L 1 is selected from -O-(CH 2 ) 0-3 ;
  • L 2 is selected from C 1-3 alkylene
  • R 2 , R 3 , R 4 , R 5 and R 6 are the same as those shown in formula (I).
  • the compound represented by formula (I) is selected from:
  • the present invention also provides a pharmaceutical composition, characterized in that, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound represented by formula (I) and at least one pharmaceutically acceptable adjuvant.
  • the present invention further provides a pharmaceutical composition, characterized in that the therapeutically effective amount of at least one compound represented by formula (I) and a pharmaceutically acceptable auxiliary material are in a mass percentage of 0.0001:1-10.
  • the present invention provides the application of the compound represented by the structural formula (I) or the pharmaceutical composition in the preparation of medicine.
  • the application is in the preparation of a drug for treating and/or preventing cancer.
  • the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophagus Carcinoma, melanoma, colorectal cancer, hepatoma, head and neck tumor, hepatocholangiocarcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, Schwann cell tumor, lung squamous cell Carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
  • the present invention also provides a method for treating and/or preventing a disease, comprising administering a therapeutically effective amount of at least any compound represented by structural formula (I) or a pharmaceutical composition containing the same to a treatment subject.
  • the present invention also provides a method for treating cancer, comprising administering a therapeutically effective amount of at least any compound represented by the structural formula (I) or a pharmaceutical composition containing the same to a treatment subject.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • alkyl includes linear or branched monovalent saturated hydrocarbon groups.
  • alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2 -pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc.
  • “ 1-8 " in “base 1-8 alkyl” refers to a group containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms arranged in straight or branched chain form group.
  • C 1-3 alkylene refers to methylene, 1,2-ethylene, 1,3-propylene or 1,2-isopropylene.
  • Alkoxy refers to the oxyether form of the aforementioned straight or branched chain alkyl groups, ie, -O-alkyl.
  • compositions comprising "a” pharmaceutically acceptable excipient can be interpreted to mean that the composition includes “one or more” pharmaceutically acceptable excipients.
  • aryl in the present invention, unless otherwise specified, refers to an unsubstituted or substituted mono- or fused-ring aromatic group comprising atoms of a carbocyclic ring.
  • the aryl group is a 6- to 14-membered monocyclic or polycyclic aromatic ring group.
  • Preferred are phenyl and naphthyl. Most preferred is phenyl.
  • the aryl ring can be fused to a heteroaryl, heterocyclyl, or cycloalkyl, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples including, but not limited to, benzocyclopentyl.
  • heterocyclyl in the present invention, unless otherwise specified, refers to an unsubstituted or substituted 3-14 membered stable ring consisting of carbon atoms and 1-3 heteroatoms selected from N, O or S. system, which is a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 14 carbon atoms, wherein nitrogen or sulfur heteroatoms can be selectively oxidized, and nitrogen heteroatoms can be selectively Quaternized.
  • the heterocyclyl group can be attached to any heteroatom or carbon atom to form a stable structure.
  • heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone and tetrahydro oxadiazolyl.
  • the heterocyclyl group can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl group.
  • heteroaryl in the present invention, unless otherwise specified, refers to an unsubstituted or substituted stable 5- or 6-membered monocyclic aromatic ring system or an unsubstituted or substituted 9-14 membered benzo-fused
  • Heteroaryl groups can be attached to any heteroatom or carbon atom to form a stable structure.
  • heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl Azinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiazolyl, benzene thiadiazolyl, benzotriazolyl adenine, quinolinyl or isoquinolinyl.
  • the heteroaryl group can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring.
  • cycloalkyl refers to a cyclic saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent having 3 to 14 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl .
  • the cycloalkyl group can be fused to an aryl, heterocyclyl or heteroaryl ring, wherein the ring attached to the parent structure is a cycloalkyl group.
  • substituted refers to the replacement of one or more hydrogen atoms in a group with the same or a different substituent, respectively.
  • the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy group, isobutoxy, tert-butoxy, -SCH 3 , -SC 2 H 5 , carboxaldehyde, -C(OCH 3 ), cyano, nitro, -CF 3 , -OCF 3 , amino, dimethyl amino, methylthio, sulfonyl and acetyl groups.
  • substituted alkyl groups include, but are not limited to, 2,3-dihydroxypropyl, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl , phenylmethyl, dioxinylmethyl and piperazinylmethyl.
  • substituted alkoxy groups include, but are not limited to, 2-hydroxyethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2-methoxyethoxy, 2-aminoethoxy, 2,3-dihydroxypropoxy, cyclopropylmethoxy, aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3- Hydroxypropoxy.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
  • the compound represented by formula (I) will be used as a medicine, it is preferable to use a certain purity, for example, at least 60% pure, more suitably at least 75% pure, particularly suitably at least 98% pure (% by weight) Compare).
  • Prodrugs of the compounds of the present invention are included within the scope of the present invention.
  • the prodrugs refer to functional derivatives that are readily converted into the desired compound in vivo.
  • any pharmaceutically acceptable salt, ester, salt of ester or other derivative of a compound of the present application which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present application or a pharmaceutically active metabolite thereof or Residues.
  • the compounds of the present invention may contain one or more asymmetric centers and may thereby give rise to diastereomers and optical isomers.
  • the present invention includes all possible diastereomers and racemic mixtures thereof, substantially pure resolved enantiomers thereof, all possible geometric isomers and pharmaceutically acceptable salts thereof.
  • the present invention includes any possible tautomer and pharmaceutically acceptable salts thereof, and mixtures thereof.
  • substitution of compounds of formula (I) with heavier isotopes may provide certain therapeutic advantages due to greater metabolic stability, eg increased in vivo half-life or reduced dosage requirements.
  • the present invention includes any possible solvates and polymorphs.
  • the type of solvent that forms the solvate is not particularly limited as long as the solvent is pharmaceutically acceptable.
  • water, ethanol, propanol, acetone and similar solvents can be used.
  • composition refers to a product comprising a specified amount of each of the specified ingredients, as well as any product produced directly or indirectly from a combination of the specified amounts of each of the specified ingredients. Accordingly, pharmaceutical compositions containing the compounds of the present invention as active ingredients and methods of preparing the compounds of the present invention are also part of the present invention.
  • some of the crystalline forms of the compounds may exist as polymorphs, and such polymorphs are included in the present invention.
  • some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also within the scope of this invention.
  • the pharmaceutical composition provided by the present invention comprises a compound represented by formula (I) (or a pharmaceutically acceptable salt thereof) as an active component, a pharmaceutically acceptable excipient and other optional therapeutic components or Accessories.
  • the pharmaceutical compositions of the present invention include oral, rectal, topical and Pharmaceutical compositions for parenteral (including subcutaneous, intramuscular, intravenous) administration.
  • the pharmaceutical compositions of the present invention may conveniently be presented in unit dosage form and prepared by any of the methods of preparation well known in the art of pharmacy.
  • the first step introduce substituents through substitution reaction under basic conditions such as cesium carbonate to obtain compound 1-2, wherein L can be O, S or NL a ;
  • Step II Under the action of a Pa catalyst such as X-Phos Pd G2, a substituent R 4 is introduced through a Suzuki coupling reaction to obtain compound I-3;
  • Step III Compound I-3 is deprotected under acidic conditions such as trifluoroacetic acid to obtain the target product I.
  • CDI carbonyldiimidazole
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • DABCO triethylenediamine
  • DIEA N,N-diisopropylethylamine
  • Dioxane Dioxane
  • TBS-Cl tert-butyldimethylsilyl chloride
  • NBS N-bromosuccinimide
  • Tf 2 O trifluoromethanesulfonic anhydride
  • HOAc glacial acetic acid
  • POCl 3 phosphorus oxychloride
  • TFA trifluoroacetic acid
  • LiAlH 4 lithium aluminum hydride
  • TBAF tetrabutylammonium fluoride
  • LiHMDS Lithium Bistrimethylsilylamide
  • X-Phos Pd G2 Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1, 1'-biphenyl)]palladium(II);
  • Pre-HPLC preparation of high performance liquid phase
  • 2,2,2-Trichloroethane-1,1-diol (66.4 g) and Na 2 SO 4 (503.4 g) were dissolved in water (560 mL) and then heated to 55°C.
  • the resulting mixture was stirred at 90°C for 3 hours and a yellow precipitate formed.
  • the mixture was cooled to room temperature.
  • the solid was collected by filtration, rinsed with water, and air-dried to give the product as a tan solid (47 g, 99% yield), compound M1-3.
  • the compound ethynyltriisopropylsilane (20 g) was dissolved in acetone (500 mL), NBS (21.08 g) was added, and silver nitrate (1.86 g) was added, and the reaction was carried out at room temperature for 12 hours.
  • the reaction solution was concentrated, water (500 mL) was added thereto, extracted with petroleum ether (3 ⁇ 500 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain compound M3-1 (28 g, yield 93%).
  • Example 1 Compound 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-((1-( Synthesis of (S)-2-methylpyrrolidin-1-yl)methyl)cyclopropyl)methoxy)quinazolin-7-yl)naphthalen-2-ol
  • compound 1-2 (129.16 mg) was added to compound M1 (300.00 mg), DABCO (14.27 mg), Cs 2 CO 3 (621.57 mg) in DMF (6.00 mL) solution, and the reaction was stirred at room temperature for 14 h.
  • Example 65 Compound 4-(2-((1-((7-azabicyclo[2.2.1]hept-7-yl)methyl)cyclopropyl)methoxy)-4-((1R, Synthesis of 5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoroquinazolin-7-yl)-5-ethynylnaphthalen-2-ol
  • intermediate M2 500 mg was dissolved in DMF (5 mL), NaH (340 mg) was added in portions, and the mixture was stirred at room temperature for 30 min.
  • the above solution was added dropwise to a solution of intermediate M1 (1.01 g, 2.15 mmol) in DMF (5 mL) at 0° C., and stirred at room temperature for 2-4 h after the addition.
  • the reaction solution was poured into 20 mL of saturated ammonium chloride, and EA (20 mL) was added for extraction twice. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated.
  • ESI-MS m/z 616 [M+H] + .
  • Two KRas-G12D mutant tumor cells AGS ( CRL- 1739TM ) or Panc 04.03 ( CRL-2555 TM ) was plated in a 96-well plate at a cell density of 5 ⁇ 10 4 /well, and cultured overnight in a cell incubator. After the cells adhered, the compounds to be tested were added to the 96-well plate according to the final concentration of 10000nM, 3333nM, 1111nM, 370.4nM, 123.4nM, 41.15nM, 13.72nM, 4.57nM, 1.52nM, 0.51nM, 0.1% DMSO, and cultured.
  • the lysis buffer (50 ⁇ L) in the MSD (Meso Scale Discovery) electrochemiluminescence immunoassay kit was used to extract the protein lysate of each treated cell sample in the 96-well plate, and the protein lysate was quantified by BCA method.
  • lysis buffer to dilute the protein sample concentration to 0.1 ⁇ g/ ⁇ L.
  • p-ERK% value ((2 ⁇ phosphorylation signal value)/(phosphorylation signal value+total signal value)) ⁇ 100
  • Inhibition percentage (Maximum value - Measured value) / (Maximum value - Blank) ⁇ 100
  • Curve fitting was performed using GraphPad Prism software and IC50 values were obtained.
  • KRas-G12D mutant tumor cells AGS ( CRL-1739 TM ) was plated in a low-adsorption 96-well plate at a cell density of 1 ⁇ 10 3 /well, and cultured in a cell incubator overnight. After the cells adhered, the compounds to be tested were added to the 96-well plate according to the final concentration of 20000, 6666.67, 2222.22, 740.74, 246.91, 82.30, 27.43, 9.14, 3.05, 0 nM (the final concentration of DMSO was 0.5%), and incubated at 37°C After 96 hours, 50 ⁇ L of Cell-titer GLO working solution was added to each well, shaken and mixed, and incubated at room temperature for 10 min. The Luminescence luminescence value was read on a multi-function microplate reader, and the luminescence value data was calculated and converted into inhibition percentage. And according to the following formula, calculate the percentage of inhibition of cell proliferation:
  • Inhibition percentage (Maximum value - Measured value) / (Maximum value - Blank) ⁇ 100
  • Curve fitting was performed using GraphPad Prism software and IC50 values were obtained.
  • KRas-WT tumor cells NCI-H1975 ( CRL-5908 TM ) was plated in a low-adsorption 96-well plate at a cell density of 1 ⁇ 10 3 /well, and placed in a cell incubator for overnight culture.
  • the compounds to be tested were added to the 96-well plate according to the final concentration of 20000, 6666.67, 2222.22, 740.74, 246.91, 82.30, 27.43, 9.14, 3.05, 0 nM (the final concentration of DMSO was 0.5%), and incubated at 37°C After 96 hours, 50 ⁇ L of Cell-titer GLO working solution was added to each well, shaken and mixed, and incubated at room temperature for 10 min. The Luminescence luminescence value was read on a multi-function microplate reader, and the luminescence value data was calculated and converted into inhibition percentage. And according to the following formula, calculate the percentage of inhibition of cell proliferation:
  • Inhibition percentage (Maximum value-Measured value)/(Maximum value-Blank) ⁇ 100
  • Curve fitting was performed using GraphPad Prism software and IC50 values were obtained.
  • the compounds of the present invention have good selectivity. And the selectivity between compounds 2/50 and 65/51 is higher than 10 times, indicating that R 3 in general formula (I) is optionally substituted by 1-2 R 3a When X is alkynyl or halogen, it has better selectivity.

Abstract

L'invention concerne un composé ayant une activité de modulation de KRAS G12D, un procédé de préparation de celui-ci, et une composition pharmaceutique le comprenant.
PCT/CN2022/080545 2021-03-15 2022-03-14 Inhibiteur de kras g12d et ses applications en médecine WO2022194066A1 (fr)

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Cited By (3)

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Publication number Priority date Publication date Assignee Title
CN115181106A (zh) * 2021-04-07 2022-10-14 药雅科技(上海)有限公司 喹唑啉类krasg12d突变蛋白抑制剂的制备及其应用
WO2023114733A1 (fr) * 2021-12-13 2023-06-22 Quanta Therapeutics, Inc. Modulateurs de kras et leurs utilisations
US11912723B2 (en) 2022-02-09 2024-02-27 Quanta Therapeutics, Inc. KRAS modulators and uses thereof

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