WO2024046370A1 - Composés hétérocycliques utilisés en tant qu'inhibiteurs de kras, leur préparation et leur utilisation thérapeutique - Google Patents

Composés hétérocycliques utilisés en tant qu'inhibiteurs de kras, leur préparation et leur utilisation thérapeutique Download PDF

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WO2024046370A1
WO2024046370A1 PCT/CN2023/115860 CN2023115860W WO2024046370A1 WO 2024046370 A1 WO2024046370 A1 WO 2024046370A1 CN 2023115860 W CN2023115860 W CN 2023115860W WO 2024046370 A1 WO2024046370 A1 WO 2024046370A1
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alkyl
halogen
compound
substituted
cycloalkyl
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PCT/CN2023/115860
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Chinese (zh)
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田红旗
黄功超
高旭光
刘欢欢
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上海科州药物研发有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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 certain novel heterocyclic compounds or pharmaceutically acceptable salts thereof, which compounds can be used to treat or prevent cancers associated with H-ras, K-ras or N-ras inhibition.
  • the present invention also relates to pharmaceutical compositions comprising the compounds or pharmaceutically acceptable salts thereof, as well as intermediates for the preparation of the compounds, and the use of the compounds or pharmaceutically acceptable salts thereof in the treatment of H-ras , K-ras or N-ras methods to inhibit related cancers.
  • the ras gene is quite conserved in evolution and is widely found in various eukaryotes such as mammals, fruit flies, fungi, nematodes and yeast, suggesting that it has important physiological functions.
  • the mammalian ras gene family has three members, namely H-ras, K-ras, N-ras, among which the fourth exon of K-ras has two variants, A and B.
  • Various ras genes have similar structures and are composed of four exons distributed on a DNA of about 30 kb in length. Their encoded product is a protein with a relative molecular mass of 21,000, so it is called P21 protein.
  • H-ras is located on the short arm of human chromosome 11 (11p15.1 ⁇ p15.3), K-ras is located on the short arm of chromosome 12 (12p1.1 ⁇ pter), and N-ras is located on the short arm of chromosome 1.
  • the sequence encoding P21 of each ras gene is evenly distributed among the four exons, while the sequences and sizes of the introns are different. are very large, so the entire genes are also very different.
  • human K-ras is 35kb long, while N-ras is 3kb long.
  • K-ras can be spliced in two ways, but the content of the mRNA encoding K-ras-B is high. Except for K-ras-B, which contains 188 amino acids, the other two Ras proteins contain 189 amino acids.
  • Ras(P21) protein is located on the inside of the cell membrane and plays an important role in transmitting cell growth and differentiation signals. It is a guanosine triphosphate (GTP)-binding protein (a coupling factor for cell information transmission) that regulates information transmission through the mutual conversion of GTP and guanosine diphosphate (GDP).
  • GTP guanosine triphosphate
  • GDP guanosine diphosphate
  • P21 has strong affinity with GTP and GDP, and has weak GTPase activity. Under normal circumstances, the combination of P21 and GDP is in an inactive state. When extracellular growth and differentiation factors transmit signals to P21 on the inside of the cell membrane, the binding activity of P21 and GTP can be enhanced, making the combination of P21 and GTP into an activated state, and the signaling system is open. .
  • P21 has GTPase activity, it can hydrolyze GTP into GDP. After P21 and GDP combine, P21 is inactivated and the signaling system is shut down. Under normal circumstances, the GTPase activity of P21 is very weak. When combined with GTPase activating protein (GAP), its hydrolysis rate can increase 10,000 times, thereby inactivating P21. The combination of P21 and GDP can activate guanylate releasing protein (GNRP). GNRP causes P21 to release GDP to bind GTP. Therefore, through the mutual conversion of GTP and GDP, the opening and closing of the signaling system by P21 can be regulated to complete the growth and differentiation signal. Intracellular processes.
  • GAP GTPase activating protein
  • Ras gene mutations More than 1/5 of cancer patients are accompanied by Ras gene mutations. These mutations mostly occur at G12, G13 and Q61 residues. The mutations lead to the failure of GAP protein mediation and the Ras signal continues to be activated.
  • the RAS gene family is the most commonly mutated gene in human cancers. RAS mutations are present in 90% of pancreatic cancers, 45% of colon cancers, and 35% of lung cancers. Among the three Ras genes, Kirsten-RAS (KRAS) is the most frequently mutated subtype, with a proportion of up to 86%, and the other two subtypes of neuroblastoma-RAS (NRAS) and Harvey-RAS (HRAS) are mutated The rates are lower (11% and 3%).
  • KRAS proteins 33.4% have KRAS-G12D mutations, 22.8% have KRAS-G12V mutations, 12.4% have KRAS-G13D mutations, 11.3% have KRAS-G12C mutations, and 5.3% have KRAS-G12A and KRAS-G12S mutations, respectively. 4.4%.
  • the ones with the most mutations are HRAS-G13R (17.8%), HRAS-Q61R (14.0%) and HRAS-G12 (12.3%), and the least mutated ones are HRAS-G12S (4.9%).
  • the present invention designs and synthesizes a series of chemical molecules, which have strong biological activity of inhibiting ras, and provides a method for treating related cancers by inhibiting H-ras, K-ras or N-ras.
  • the present invention provides compounds capable of regulating KRAS, HRAS and/or NRAS protein mutations, including their stereoisomers, pharmaceutically acceptable salts, tautomers and prodrugs. Methods of using such compounds to treat different diseases or conditions, such as cancer, are also provided.
  • X 1 is selected from O, S, N and CR 4 ;
  • X 2 is selected from NR 4 , CR 4 and S(O) 0,1,2 R 4 ,
  • R 1 is selected from hydrogen, halogen, C 1-6 alkyl optionally substituted by halogen or hydroxyl or -NR 1a R 1b , CN, -OR 1a , -SR 1a , -NR 1a R 1b , -S(O) R 1a , -S(O) 2 R 1a , -C(O)R 1a , -C(O)OR 1a , -NR 1a C(O)R 1b , -C(O)NR 1a R 1b , -S (O) 2 N(R 1a R 1b ) 2 and 5- to 6-membered heteroaryl, wherein R 1a and R 1b are each independently hydrogen, C 1-6 alkyl, hydroxy C 1-6 alkyl, Halogenated C 1-6 alkyl and C 1-6 alkoxy C 1-6 alkyl-, C 3-6 cycloalkyl;
  • R 4 is selected from hydrogen, halogen, C 1-6 alkyl optionally substituted by halogen or hydroxyl, CN, -OR 4a , -SR 4a , -S(O)R 4a , -S(O) 2 R 4a , -C(O)R 4a , -C(O)OR 4a , -NR 4a C(O)R 4b , -C(O)NR 4a R 4b and -S(O) 2 N(R 4a R 4b ) 2 , where R 4a and R 4b are each independently hydrogen, C 1-6 alkyl, hydroxy C 1-6 alkyl, halo C 1-6 alkyl and C 1-6 alkoxy C 1-6 alkyl -;
  • L is a single bond, -O-, -S-, -NR La -, -O-(CR La R Lb ) t -, -S-(CR La R Lb ) t -, -NR c -(CR La R Lb ) t -, -(CR La R Lb ) t -O-, -(CR La R Lb ) t -S-, -(CR La R Lb ) t -NR Lc -, -C(O)-, - SO 2 -, -SO-, -C(O)-O-, -OC(O)-, -C(O)-NR Lc - or -N Lc C(O)-, where R La , R Lb and R Lc is each independently selected from hydrogen and C 1-6 alkyl, or R La and R Lb are attached to the same carbon atom and together with the attached carbon atom form a C 3 -C 6 cycl
  • R 2 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein said C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, aryl, heteroaryl and heterocyclyl are each independently unsubstituted or substituted by halogen, cyano, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl-, oxo, -OR 2a , -C (O) R 2a , -(CR 2a R 2b ) m -OC(O)NR 2c R 2d , -CO 2 R 2a , -CONR 2c R 2d , -NR 2c R 2d , C 3-8 cycloalkyl, C 3- 8
  • n 1 0, 1 or 2;
  • Q 1 , Q 2 and Q 3 are each independently N or CR 6 , M 1 and M 2 are each independently N or CR 7 , provided that at least one of Q 1 and M 1 is N;
  • R 6 and R 7 are each independently hydrogen, halogen, hydroxyl, cyano, nitro, C 1 - 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, Aryl, heteroaryl or heterocyclyl, -OR 6a , -C(O)R 6a , -CO 2 R 6a , -CONR 6a R 6b or -NR 6a R 6b , wherein said C 1-6 alkyl , C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, aryl, heteroaryl and heterocyclyl are each independently substituted by oxo, halogen, hydroxyl, C 1-4 alkoxy , C 1-4 alkyl, C 3-6 cycloalkyl, nitro, cyano and one or more substitutions of -NR d Re , where R 6a , R 6b , R 6c and R 6d
  • L is -O- CH2- or -O-.
  • L is -O-CH 2 -
  • R 2 is heterocyclyl, which is unsubstituted or substituted by halogen, C 1-6 alkyl, -OR 2a and -(CR 2a R 2b ) m -
  • halogen C 1-6 alkyl
  • R 2a is substituted by one or more
  • the heterocyclyl is unsubstituted or halogen, C 1 -6 alkyl and -OR 2a are substituted by one or more; more preferably the heterocyclyl is unsubstituted or substituted by one or two of halogen, methyl and methoxy.
  • L is -O-CH 2 -
  • R 2 is a 4- to 8-membered monocyclic heterocyclic ring member containing 1, 2, or 3 heteroatoms selected from oxygen, nitrogen, and sulfur as ring members.
  • L is -O- CH2-
  • R2 is a monocyclic heterocycle that is azetidinyl, pyrrolidinyl, or piperidinyl, said ring being unsubstituted or One or two halogen or C 1-6 alkyl substitutions.
  • L is -O- CH2-
  • R2 is a bicyclic heterocycle, which is octahydropentadiene, in which at least one carbon atom is replaced by a nitrogen atom, and the other carbon atoms are One is optionally replaced by an oxygen atom;
  • R 2 is tetrahydro-1H-pyrrolazinyl (such as tetrahydro-1H-pyrrolizin-7-yl Preferred are (2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl), tetrahydro-1H-furopyrrolyl (for example, tetrahydro-1H-furo[3,4- b]pyrrole-3a-yl Tetrahydro-1H-furo[3,4-c]pyrrole-3a-yl Tetrahydro-1H-furo[3,4-b]pyrrole-6a-yl ) and octahydrocycl
  • R 2 is azabicyclo[3.1.0]hexyl, such as 3-azabicyclo[3.1.0]hexyl (3-azabicyclo[3.1.0]hexane -1-yl), 2-azabicyclo[3.1.0]hexanyl (2-azabicyclo[3.1.0]hexan-1-yl), wherein the bicyclic heterocycle is unsubstituted or substituted by one or more of halogen, C 1-6 alkyl, -OR 2a and -(CR 2a R 2b ) m -OC(O)NR 2c R 2d , where each variable is as in formula (I) Definition;
  • the heterocyclyl group is unsubstituted or substituted by one or more of halogen, C
  • LR2 is
  • R in compounds of Formula (I) and (II) is
  • Monocyclic aryl or heteroaryl selected from phenyl, pyridyl, pyrimidinyl and pyrazinyl;
  • Bicyclic aryl or heteroaryl selected from naphthyl (such as naphthyl-1-yl, naphthyl-2-yl, naphthyl-3-yl, naphthyl-4-yl, naphthyl-5-yl, naphthyl-6 -yl, naphth-7-yl, naphth-8-yl), isoquinolinyl (such as isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-yl) 5-yl, isoquinol-6-yl, isoquinol-7-yl and isoquinol-8-yl), tetrahydroisoquinoline (e.g.
  • naphthyl such as naphthyl-1-yl, naphthyl-2-yl, naphthyl-3-yl, naphthyl-4-yl, naphthyl-5-yl, naphth
  • Tricyclic aryl or heteroaryl selected from
  • R 3 in the compounds of formulas (I) and (II) is naphth-1-yl (wherein R 3 serves as a naphthyl group and is attached to the parent structure at position 1), and the naphthalene-1-
  • R 3 in the compounds of formulas (I) and (II) is naphthyl-1-yl (wherein R 3 serves as a naphthyl group, and the position connected to the parent structure is the 1-position), and the naphthalene
  • R 3 in the compounds of formulas (I) and (II) is naphthyl-1-yl (wherein R 3 serves as a naphthyl group, and the position connected to the parent structure is the 1-position), and the naphthalene
  • the 3-position of the -1- group is unsubstituted or is substituted by -OH or -NH 2 , -OC(O)NR 8a R 8b , -OC(O)OR 8a , -OC(O)R 8a , OCH 2 OC( O) OR 8a is substituted, and at least one of the 7 and 8 positions of the naphth-1-yl group is substituted (for example, both the 7 and 8 positions of the naphthyl group are substituted, and the 7 position of the naphthyl group is substituted, or substituted at position 8 of the naphthyl group), the substituents are independently selected from halogen, C 1-6 alkyl optionally substituted by halogen, C
  • R in compounds of Formula (I) and (II) is
  • X is N or CR 8 , R 8 is preferably selected from hydrogen, fluorine, chlorine, hydroxyl, amino,
  • the compound of Formula (I) is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound of Formula (I) is as Formula (I-1-1)
  • R 7 is hydrogen, fluorine, chlorine, trifluoroethoxymethyl or cyclopropyloxy, and the remaining variables are as defined for formula (I).
  • L in LR 2 is -O-, and R 2 is tetrahydro-1H-pyrrolazinyl (e.g., tetrahydro-1H-pyrrolizin-7-yl Preferred is (2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a( 5H )-yl), wherein R 2 is unsubstituted or halogen, C 1-6 alkyl, -OR 2a and - One or more substitutions in (CR 2a R 2b ) m -OC(O)NR 2c R 2d .
  • LR2 is
  • R3 is
  • R 8 is selected from hydrogen, fluorine, chlorine, hydroxyl, amino,
  • compounds of Formula (I) are represented by Formulas (I-2), (I-3), (I-4), (I-5), and (I-6):
  • R 6 is hydrogen, fluorine, chlorine, or cyano, and the remaining variables are as defined for formula (I).
  • the compound of Formula (I) is as Formula (I-2-1)
  • L is -O-
  • R 2 is tetrahydro-1H-pyrrolizinyl (e.g., tetrahydro-1H-pyrrolizin-7-yl Preferred is (2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl), wherein R 2 is unsubstituted or halogen, C 1-6 alkyl, -OR 2a and - One or more substitutions in (CR 2a R 2b ) m -OC(O)NR 2c R 2d ;
  • R 6 is hydrogen, fluorine, chlorine or cyano
  • R 7 is hydrogen, fluorine, chlorine, trifluoroethoxymethyl or cyclopropyloxy
  • R3 is
  • R 8 is selected from hydrogen, fluorine, chlorine, hydroxyl, amino,
  • the substituents of Q 2 and Q 3 in the compound of formula (I) are connected to form a saturated, partially saturated 5-6 membered alicyclic or aromatic heterocyclic ring, such as formula (I-7), ( I-8), (I-9), (I-10), (I-11), (I-12), (I-13), (I-14), (I-15), (I- 16), (I-17) and (I-18) are shown:
  • LR 2 is preferably
  • the compound of formula (II) is represented by formula (II-1):
  • the compound of formula (II) is represented by formula (II-1-1):
  • the present invention relates to pharmaceutical compositions of compounds of formula (I) and (II) or pharmaceutically acceptable salts, prodrugs and solvates thereof.
  • Yet another aspect of the invention provides methods of treating disease conditions using compounds or pharmaceutical compositions of the invention, including but not limited to conditions associated with G12 KRAS, HRAS or NRAS mutations (eg, cancer). Cancers are pancreatic cancer, lung cancer, colorectal cancer, etc. mediated by G12S mutations.
  • the present invention relates to compounds of formula (I) and (II) which have good physical and chemical properties and safety and toxicity parameters, and can be used for the treatment of cancer and inflammation in mammals.
  • methods of inhibiting proliferation of a population of cells comprising contacting the population of cells with any one of a compound of structures (I) and (II).
  • compositions include any one (or more) of the aforementioned compounds and a pharmaceutically acceptable carrier.
  • pharmaceutical compositions are formulated for oral administration.
  • the pharmaceutical compositions are formulated for injection.
  • pharmaceutical compositions comprise a compound disclosed herein and another therapeutic agent (eg, an anti-cancer agent).
  • another therapeutic agent eg, an anti-cancer agent
  • Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, otic, nasal and topical administration.
  • parenteral delivery includes, by way of example only, intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.
  • prodrug refers to any derivative that can be converted in an organism into the corresponding active pharmaceutical compound.
  • Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to transform into the compounds of the present invention.
  • prodrugs can be converted to compounds of the invention by chemical or biochemical methods in the in vivo environment.
  • salts of acidic groups that may be present in the compounds of the invention (eg, but not limited to, potassium salts, sodium salts, magnesium salts, calcium salts, etc.) or Salts of basic groups (for example, but not limited to, formate, acetate, citrate, tartrate, methanesulfonate, malate or sulfate, hydrochloride, phosphate, nitrate, carbonates, etc.).
  • solvate refers to a complex molecular compound formed by solute molecules or ions in a solution attracting adjacent solvent molecules through intermolecular forces such as Coulomb force, van der Waals force, charge transfer force, and hydrogen bonding.
  • the solvent is water, i.e., the compounds of the invention form hydrates.
  • the compounds of the present invention may contain one or more step symmetry centers and may therefore give rise to enantiomers, diastereoisomers and other stereoisomeric forms, with respect to the absolute stereochemistry of the amino acids.
  • the configuration is defined as (R)- or (S)-, or as (D)- or (L)-configuration.
  • the present invention is intended to include all such possible isomers, as well as racemic and optically pure forms thereof.
  • Optically active (+) and (-), (R)- and (S)- or (D)- and (L)-isomers can be synthesized or prepared using chiral synthesis, or using conventional techniques such as chromatography and fractional crystallization) derived from analysis.
  • tautomer or “tautomeric form” means that at room temperature, isomers with different functional groups are in dynamic equilibrium and can quickly convert into each other. If tautomers are possible (eg in solution), a chemical equilibrium of tautomers can be achieved.
  • proton tautomers also called proton transfer tautomers
  • interconversions by proton migration such as keto-enol isomerization and imine-enol isomerization. Amine isomerization.
  • Valence bond isomers (valencetautomers) involve interconversion through the reorganization of some bonding electrons.
  • alkyl herein refers to a hydrocarbon group selected from linear saturated hydrocarbon groups and branched chain saturated hydrocarbon groups, which contains 1 to 18 (such as 1 to 12, further such as 1 to 10, further such as 1 to 8 or 1 to 6 or 1 to 4) carbon atoms.
  • alkyl groups containing 1 to 6 carbon atoms include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl (“n-Pr”), 2-propyl or isopropyl (“i-Pr”), 1-butyl or n-butyl (“n-Bu”), 2-methyl-1-propyl or isobutyl (“i-Bu”), 1-methylpropyl or sec-butyl (“s-Bu”), 1,1-dimethylethyl or tert-butyl (“t-Bu”), 1-pentyl, 2-pentyl, 3 -Pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2- Hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,
  • halogen herein refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
  • haloalkyl refers to an alkyl group in which one or more hydrogens are replaced by one or more halogen atoms such as fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
  • haloalkyl include haloC 1-8 alkyl, haloC 1-6 alkyl or haloC 1-4 alkyl, but are not limited to -CF 3 , -CH 2 Cl , -CH 2 CF 3 , -CCl 2 , CF 3 , etc.
  • alkenyl groups such as C 2-6 alkenyl include but are not limited to ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but- 1-alkenyl, but-2-enyl, but-3-enyl, but-1,3-dienyl, 2-methylbut-1,3-dienyl, hex-1-enyl, Hex-2-enyl, hex-3-enyl, hex-4-enyl and hex-1,3-dienyl.
  • alkynyl herein refers to a hydrocarbon group selected from linear hydrocarbon groups and branched chain hydrocarbon groups, which contains at least one C ⁇ C triple bond and 2 to 18 (such as 2 to 8, further such as 2 to 6) carbon atoms atom.
  • alkynyl groups such as C 2-6 alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butyl Alkynyl.
  • alkoxy refers to an alkyl group as defined above bonded to oxygen, represented by -O alkyl.
  • alkoxy groups such as C 1-6 alkoxy or C 1-4 alkoxy include but are not limited to methoxy, ethoxy, isopropoxy, propoxy, n-butoxy, tert-butoxy base, pentyloxy and hexyloxy, etc.
  • cycloalkyl refers to a hydrocarbyl group selected from saturated and partially unsaturated cyclic hydrocarbyl groups, including monocyclic and polycyclic (eg, bicyclic and tricyclic) groups.
  • a cycloalkyl group may contain 3 to 12 (eg, 3 to 10, further, 3 to 8, further, 3 to 6, 3 to 5, or 3 to 4) carbon atoms.
  • the cycloalkyl group may be selected from monocyclic groups containing from 3 to 12 (such as 3 to 10, further such as 3 to 8, 3 to 6) carbon atoms.
  • Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, Cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl , cyclodecanyl, cycloundecanyl and cyclododecanyl.
  • saturated monocyclic cycloalkyl groups such as C 3-8 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • cycloalkyl is a monocyclic ring containing 3 to 6 carbon atoms (abbreviated as C 3-6 cycloalkyl), which includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • bicyclic cycloalkyl groups include those having 7 to 12 ring atoms arranged in an arrangement selected from [4,4], [4,5], [5,5], [5,6] or [6,6 ] ring system, or a bridged bicyclic ring selected from the group consisting of bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane.
  • Other examples of bicyclic cycloalkyl groups include those arranged as a bicyclic ring selected from [5,6] and [6,6] ring systems, such as where wavy lines represent attachment points.
  • the ring may be saturated or have at least one double bond (ie, partially unsaturated), but not fully conjugated, and not aromatic, as aromatic is defined herein.
  • aryl used alone or in combination with other terms refers to a group selected from:
  • Bicyclic systems such as 7 to 12 membered bicyclic systems, in which at least one ring is carbocyclic and aromatic, such as naphthyl;
  • Tricyclic system such as a 10 to 15-membered tricyclic system, in which at least one ring is carbocyclic and aromatic, such as fluorenyl.
  • aromatic hydrocarbon ring and “aryl” are used interchangeably in this disclosure.
  • a monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (ie, C 5-10 aryl).
  • monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthracenyl, phenanthrenyl, and the like.
  • the aromatic hydrocarbon ring is a naphthalene ring (naphth-1-yl or naphth-2-yl) or benzene ring.
  • the aromatic hydrocarbon ring is a benzene ring.
  • heteroaryl refers to a group selected from:
  • at least one heteroatom such as 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, or in other embodiments 1 or 2 heteroatoms , these heteroatoms are selected from N, O and S (as one or more ring atoms), the remaining ring atoms are carbon, and at least one of the rings is aromatic and at least one heteroatom is present in the aromatic ring.
  • the heteroaryl group is a 5- to 6-membered heteroaryl group containing one nitrogen atom and 0 or 1 additional heteroatoms selected from N, O, and S, including but not limited to pyridyl, isoxazole base and oxazolyl group.
  • the total number of S and O atoms in a heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group is no greater than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is no greater than 1. When a heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. Nitrogen atoms in one or more rings of the heteroaryl group can be oxidized to form N-oxides.
  • a monocyclic or bicyclic aromatic heterocycle has 5, 6, 7, 8, 9, or 10 ring members, wherein 1, 2, 3, or 4 heteroatom ring members are independently selected from nitrogen ( N), sulfur (S) and oxygen (O), the remaining ring members are carbon.
  • a monocyclic or bicyclic aromatic heterocycle is a monocyclic or bicyclic ring containing 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O).
  • the monocyclic or bicyclic aromatic heterocycle is a 5- to 6-membered heteroaryl ring that is monocyclic and has 1 independently selected from nitrogen (N), sulfur (S), and oxygen (O) or 2 heteroatom ring members.
  • the monocyclic or bicyclic aromatic heterocycle is an 8 to 10 membered heteroaryl ring that is bicyclic and has 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen.
  • heteroaryl or monocyclic or bicyclic aromatic heterocycles include, but are not limited to (numbered from the attachment position designated priority 1) pyridyl (such as 2-pyridyl, 3-pyridyl or 4-pyridyl), pyridyl Phyllinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiazolyl Diazolyl (such as 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl or 1,3,4-thiadiazolyl), tetrazolyl, thienyl (such as thiophene-2 -yl, thiophen-3-yl), triazinyl, benzothienyl, furyl (furyl or furanyl), benzofuranyl, benzo
  • heterocyclic or “heterocycle” or “heterocyclyl” herein refers to a group selected from the group consisting of 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 membered monocyclic, bicyclic and tricyclic rings. Saturated rings and partially unsaturated rings containing at least one carbon atom and at least one heteroatom, such as 1 to 4 heteroatoms, further such as 1 to 3 heteroatoms or further such as 1 or 2 heteroatoms, these heteroatoms.
  • the atoms are selected from nitrogen (N), sulfur (S), oxygen (O), -SO- or -SO2 (as one or more ring atoms).
  • heterocyclyl is a 4, 5, 6, 7, or 8 membered monocyclic ring having at least one heteroatom selected from N, O, and S. In some preferred embodiments, heterocyclyl is a 4, 5, 6, 7 or 8 membered saturated monocyclic ring containing one nitrogen heteroatom. Exemplary heterocyclyl groups are azetidinyl, pyrrolidinyl, piperidinyl, azepanyl and azepanyl. In other embodiments, heterocyclyl is a 5, 6, 7 or 8 membered saturated monocyclic ring containing one nitrogen atom and a ring selected from -NH, -O-, -S-, -SO- or -SO2- 1 additional heteroatom.
  • heterocyclyl groups are morpholino, morpholinyl or piperazinyl rings.
  • heterocyclyl is a 7 to 12 membered saturated bicyclic ring containing one nitrogen atom and 0 or 1 or 2 selected from -NH, -O-, -S-, -SO- or -SO 2 - additional heteroatoms.
  • the heterocyclyl group is a bicyclic bridged ring or a spiro ring.
  • Heterocycle herein also refers to a 5 to 5- to 7-membered cycloalkyl group containing at least one heteroatom selected from N, O and S fused to a 5-, 6- and/or 7-membered cycloalkyl, carbocyclic aromatic ring or heteroaromatic ring. 7-membered heterocyclic ring, the prerequisite is that the entire ring structure is non-aromatic. Heterocycle is not heteroaryl as defined herein.
  • the heterocyclyl group is a 5- to 6-membered heterocyclyl group containing one nitrogen atom and 0 or 1 additional heteroatom selected from N, O, and S, including but not limited to pyrrolyl, dihydrogen Pyridine, morpholino, morpholinyl and tetrahydropyranyl.
  • heterocycles include, but are not limited to (numbered from the attachment position designated priority 1) 1-pyrrolidinyl, 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2,5-piperazinyl, pyranyl, morpholinyl, morpholino, 2-morpholinyl, 3-morpholinyl, oxiranyl, aziridinyl, thiethyl, azetidinyl, oxetanyl, thietanyl, 1,2-disulfide Heterocyclobutanyl, 1,3-dithietanyl, dihydropyridyl, tetrahydropyridyl, thiomorpholinyl, thioxacinyl, piperazinyl, homopiperazinyl, homopiperazinyl Aldyl,
  • Substituted heterocycles also include ring systems substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and 1,1-dioxo-1-thiomorpholinyl.
  • oxo moieties such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and 1,1-dioxo-1-thiomorpholinyl.
  • the heterocyclyl group is a nonaromatic fused bicyclic heterocyclyl group, such as the fused bicyclic heterocyclyl groups listed above; and, for example, the nonaromatic fused bicyclic heterocyclyl groups below.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable of.
  • oxygen it means that two hydrogen atoms are replaced.
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical achievability.
  • any variable e.g., R
  • its definition in each instance is independent.
  • said group may optionally be substituted by up to two R's, with independent options for R in each case.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • substituted with one or more groups includes, for example, 1 to 5 (such as 1 to 4, further such as 1, 2 or 3) substituents, provided that the valency permits.
  • heteroalkyl by itself or in combination with another term means a stable linear or branched alkyl group or other group consisting of a certain number of carbon atoms and at least one heteroatom, or heteroatom group. combination.
  • the heteroatoms are selected from B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatoms are optionally quaternized.
  • the heteroalkyl group is C 1 -C 6 heteroalkyl; in other embodiments, the heteroalkyl group is C 1 -C 3 heteroalkyl.
  • a heteroatom or heteroatom group may be located at any internal position of a heteroalkyl group, including the point at which the alkyl group is attached to the rest of the molecule, but the terms "alkoxy,”"alkylamino,” and “alkylthio” (or thioalkyl Oxygen) is a conventional expression referring to those alkyl groups connected to the rest of the molecule through an oxygen atom, an amino group, or a sulfur atom, respectively.
  • alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl and other moieties described herein may each independently be replaced by one or more groups selected from: Optional substitutions: hydroxyl, oxo, halogen, cyano, nitro, trifluoromethyl, azido, amino, carboxyl, thiol.
  • Suitable solvents commonly used in organic reactions can be used in the following reactions of each step of the preparation method of the present invention, such as, but not limited to: aliphatic and aromatic, optional hydrocarbons or halogenated hydrocarbons (such as pentane, hexane, Heptane, cyclohexane, petroleum ether, gasoline, volatile oils, benzene, toluene, xylene, methylene chloride, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene and o-dichlorobenzene), aliphatic and aromatic family, optional alcohols (such as methanol, ethanol, propanol, isopropyl alcohol, tert-butyl alcohol, ethylene glycol, etc.), ethers (such as diethyl ether and dibutyl ether, ethylene glycol dimethyl ether and diethylene glycol) Dimethyl ether, tetrahydrofuran and dioxane,
  • DCM dichloromethane
  • CHCl 3 represents chloroform
  • EA represents ethyl acetate
  • THF represents tetrahydrofuran
  • MeCN represents acetonitrile
  • MeOH represents methanol
  • EtOH represents ethanol
  • i-PrOH represents isopropyl Alcohol
  • PE represents petroleum ether
  • Toulene represents toluene
  • DMSO represents dimethyl sulfoxide
  • DMF represents N,N-dimethylformamide
  • DMA represents N,N-dimethylacetamide
  • CDCl 3 represents deuterated chloroform
  • D 2 O represents heavy water
  • (CD 3 ) 2 SO represents deuterated DMSO
  • CD 3 OD represents deuterated methanol
  • CuI represents cuprous iodide
  • DIPEA represents diisopropylethylamine
  • TEA represents triethylamine
  • K 2 CO 3 represents potassium carbonate
  • Cs 2 CO 3 represents ces
  • the crude compound 8-chloro-7-fluoronaphthalene-1-ol obtained in the previous step was synthesized into 5-chloro-6-fluoro-1,4-dihydro-1,4-epoxynaphthalene (4.3g, 21.98mmol) Dissolve in ethanol (10 ml) and concentrated hydrochloric acid (8 mL), heat to 80°C and stir for 4 hours. After the reaction is completed, cool to room temperature, dilute the reaction solution with water, extract with ethyl acetate, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, and concentrate to obtain a brown oil. Place the oil in the refrigerator for 24 hours.
  • Step 3 Synthesis of 4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotinic acid tert-butyl ester
  • Step 7 Synthesis of 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine
  • Step 8 Synthesis of 4-(benzyloxy)-5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine
  • Step 1 Synthesis of 7-chloro-8-fluoro-5-(2-hydroxyethyl)amino-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol
  • Step 2 Synthesis of 7-chloro-5-((2-chloroethyl)amino)-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol
  • Step 4 5-(8-chloro-7-fluoronanth-1-yl)-6-fluoro-8-(methylthio)-2,3-dihydroimidazo[1',2':1,2 Synthesis of ]pyrido[4,3-d]pyrimidin-10-ol:
  • Step 1 Synthesis of 7-chloro-8-fluoro-5-((4-methoxybenzyl)amino)-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol
  • Step 2 Synthesis of 4,7-dichloro-8-fluoro-N-(4-methoxybenzyl)-2-(methylthio)pyrido[4,3-d]pyrimidin-5-amine
  • Step 4 Synthesis of 5,10-dichloro-6-fluoro-8-(methylthio)imidazo[1',2':1,2]pyrido[4,3-d]pyrimidine
  • Step 5 10-(benzyloxy)-5-chloro-6-fluoro-8-(methylthio)imidazo[1',2':1,2]pyrido[4,3-d]pyrimidine synthesis
  • Step 8 Synthesis of compound 6-bromo-1,3-dichloro-5-fluoro-8,9-dihydro-7H-cyclopenta[f]quinazoline
  • Step 10 1-(benzyloxy)-6-bromo-5-fluoro-3-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy Synthesis of )-8,9-dihydro-7H-cyclopenta[f]quinazoline
  • Step 5 Synthesis of 7-bromo-5-(tert-butoxycarbonyl)amino)-6-fluorobenzo[d][1,3]dioxazole-4-carboxylic acid tert-butyl ester
  • Step 7 Synthesis of 4-bromo-5-fluoro-7-mercapto-[1,3]dioxano[4,5-f]quinazoline-9(8H)-one
  • reaction solution is diluted with water, extracted with ethyl acetate, the organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product which is directly used in the next step. (0.5g, yield: 68%).
  • Step 8 Synthesis of 4-bromo-5-fluoro-7-(methylthio)-[1,3]dioxazolo[4,5-f]quinazolin-9(8H)-one
  • Step 10 Synthesis of 9-(benzyloxy)-4-bromo-5-fluoro-7-(methylthio)-[1,3]dioxazolo[4,5-f]quinazoline
  • Step 11 9-(benzyloxy)-4-bromo-5-fluoro-7-(methylsulfinyl)-[1,3]dioxola[4,5-f]quinazoline synthesis
  • Step 12 9-(benzyloxy)-4-bromo-5-fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy Synthesis of )-[1,3]dioxola[4,5-f]quinazoline
  • Example 1 (1R,6R)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 7-(8-methyl-5,6,7,8-tetralin-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo [4.2.0]Synthesis of octane-7-one
  • Step 2 4-(benzyloxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy )Synthesis of pyrido[4,3-d]pyrimidines
  • Step 3 4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7- Synthesis of (8-methyl-5,6,7,8-tetralin-1-yl)pyrido[4,3-d]pyrimidine
  • Step 4 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrozine-7a(5H)-yl)methoxy)-7-(8-methyl-5, Synthesis of 6,7,8-tetralin-1-yl)pyrido[4,3-d]pyrimidin-4-ol
  • Step 5 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrozine-7a(5H)-yl)methoxy)-7-(8-methyl-5, Synthesis of 6,7,8-tetralin-1-yl)pyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate
  • Step 6 (1R,6R)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7 -(8-Methyl-5,6,7,8-tetralin-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[ 4.2.0] Synthesis of octane-7-one
  • Example 65 (1R,6R)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8 -Methyl-5,6,7,8-tetralin-1-yl)pyrido[4,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[4.2.0 ]Synthesis of oct-7-one
  • Examples 66-67 were prepared by applying the method of Example 65.
  • Example 68 (1R,6R)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8 -Methyl-5,6,7,8-tetralin-1-yl)-8-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl) -Synthesis of 8-oxo-3-azabicyclo[4.2.0]octane-7-one
  • Step 2 4-(benzyloxy)-7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy )Synthesis of pyrido[4,3-d]pyrimidines
  • Step 3 4-(benzyloxy)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7- (8-Methyl-5,6,7,8-Tetra Synthesis of Hydronaphth-1-yl)pyrido[4,3-d]pyrimidine
  • Step 4 4-(benzyloxy)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-yl)methoxy)-7-(8- Synthesis of methyl-5,6,7,8-tetralin-1-yl)-8-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidine
  • Step 5 2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8 -Synthesis of -tetralin-1-yl)-8-(2,2,2-trifluoroethoxy)pyridyl[4,3-d]pyrimidin-4-ol
  • Step 6 2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7,8 -Synthesis of tetralin-1-yl)-8-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate
  • Step 7 (1R,6R)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8- Methyl-5,6,7,8-tetralin-1-yl)-8-(2,2,2-trifluoroethoxy)pyridin[4,3-d]pyrimidin-4-yl)- Synthesis of 8-oxo-3-azabicyclo[4.2.0]octane-7-one
  • Example 79 (1R,6R)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8 -Methyl-5,6,7,8-tetralin-1-yl)pyrido[3,2-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[4.2.0 ]Synthesis of oct-7-one
  • Example 82 (1R,6R)-3-(2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8 -Methyl-5,6,7,8-tetralin-1-yl)pyrido[2,3-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[4.2.0 ]Synthesis of oct-7-one
  • Example 85 (1R,6R)-3-(6-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 7-(8-methyl-5,6,7,8-tetralin-1-yl)quinazolin-4-yl)-8-oxa-3-azabicyclo[4.2.0]octane -Synthesis of 7-ketone
  • Example 88 (1R,6R)-3-(6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy base)-7-(8-methyl-5,6,7,8-tetralin-1-yl)quinazolin-4-yl)-8-oxa-3-azabicyclo[4.2.0 ]Synthesis of octane-7-one
  • Examples 146-152 were prepared by applying the method of Example 145.
  • Example 153 (1R,6R)-3-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 7-(8-methyl-5,6,7,8-tetralin-1-yl)quinazolin-4-yl)-8-oxa-3-azabicyclo[4.2.0]octane -Synthesis of 7-ketone
  • Examples 154-214 were prepared by applying the method of Example 153.
  • Example 215 (1R,6R)-3-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methyl Oxygen)-7-(8-methyl-5,6,7,8-tetralin-1-yl)quinazolin-4-yl)-8-oxa-3-azabicyclo[4.2. 0] Synthesis of oct-7-one
  • Examples 216-246 were prepared by applying the method of Example 215.
  • Example 247 8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrozine-7a(5H)-yl)methoxy)-7-(8-methyl-5 ,6,7,8-tetralin-1-yl)-4-((1R,6R)-7-oxo-8-oxo-3-azabicyclo[4.2.0]octane-3- Synthesis of 1,6-naphthyridine-3-nitrile
  • Step 1 Synthesis of 2,7-dichloro-8-fluoro-4-(2,2,2-trifluoroethoxy)-1,6-naphthalene-3-carbonitrile
  • Step 2 7-Chloro-8-fluoro-2-fluorotetrahydro-1H-pyrrozin-7a-ylmethoxy-4-(2,2,2-trifluoroethoxy)-1,6-naphthalene Synthesis of pyridine-3-carbonitrile
  • Step 3 8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6 ,Synthesis of 7,8-tetralin-1-yl)-4-(2,2,2-trifluoroethoxy)-1,6-naphthyridin-3-carbonitrile
  • Step 4 8-fluoro-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrrozine-7a(5H)-ylmethoxy)-7-(8-methyl-5,6,7 ,8-tetralin-1-yl)-4-(1R,6R)-7-oxo-8-oxo-3-azabicyclo[4.2.0]octane-3-yl)-1, Synthesis of 6-naphthyridine-3-carbonitrile
  • Examples 248-253 were prepared by applying the method of Example 247.
  • Example 254 8-fluoro-2-((2R,7aS)-2-fluorotetrahydrofuran-1H-pyrrolizine-7a(5H)-yl)methoxy)-7-(8-methyl-5, 6,7,8-Tetralin-1-yl)-4-((1R,6R)-7-oxo-8-oxo-3-azabicyclo[4.2.0]octane-3-yl )Synthesis of quinoline-3-nitrile
  • Example 247 Following the synthesis of Example 247, using 7-bromo-2,4-dichloro-8-fluoroquinoline-3-nitrile as the starting material, a light yellow solid (239 mg) was obtained. LCMS[ESI,M+1]:599.
  • Examples 255-266 were prepared by applying the method of Example 254.
  • Example 267 6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydrofuran-1H-pyrrolizine-7a(5H)-yl)methoxy)-7-(8-methyl Base-5,6,7,8-tetralin-1-yl)-4-((1R,6R)-7-oxo-8-oxo-3-azabicyclo[4.2.0]octane -3-yl)quinoline-3-carbonitrile)
  • Example 247 Following the synthesis of Example 247, using 7-bromo-2,4-dichloro-6,8-difluoroquinoline-3-nitrile as the starting material, a light yellow solid (327 mg) was obtained. LCMS[ESI,M+1]:617.
  • Example 280 (1R,6R)-3-(3,8-difluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy )-7-(8-methyl-5,6,7,8-tetralin-1-yl)-1,6-naphthyridin-4-yl)-8-oxo-3-azabicyclo[ 4.2.0] Synthesis of octane-7-one
  • Step 1 Synthesis of compound 4-acetamido-6-chloro-5-fluoronicotinic acid:
  • Step 2 Synthesis of compound 4-acetamido-6-chloro-5-fluorobenzoic acid methyl ester:
  • Step 4 Synthesis of compound 7-chloro-8-fluoro-3-nitro-1,6-naphthyridine-2,4(1H,3H)-dione
  • Step 5 Synthesis of compound 2,4,7-trichloro-8-fluoro-3-nitro-1,6-naphthyridine:
  • Step 6 Synthesis of compound 4-(benzyloxy)-2,7-dichloro-8-fluoro-3-nitro-1,6-naphthyridine:
  • Step 7 Synthesis of compound 4-benzyloxy-7-chloro-8-fluoro-2-fluorotetrahydro-1H-pyrrozine-7a-ylmethoxy-3-nitro-1,6-naphthyridine:
  • Step 8 Synthesis of compound 4-benzyloxy-7-chloro-8-fluoro-2-fluorotetrahydro-1H-pyrrozin-7a-ylmethoxy-1,6-naphthyridin-3-amine
  • Step 9 Synthesis of compound 4-benzyloxy-7-chloro-3,8-difluoro-2-2-fluorotetrahydro-1H-pyrrozin-7a-ylmethoxy-1,6-naphthyridine:
  • Step 10 Compound 4-benzyloxy-3,8-difluoro-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a-yl)methoxy)-7-(8- Synthesis of methyl-5,6,8-tetralin-1-yl)-1,6-naphthyridine
  • Step 11 Compound 3,8-difluoro-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a-yl)methoxy)-7-(8-methyl-5,6 ,Synthesis of 7,8-tetralin-1-yl)-1,6-naphthalene-4-ol
  • Step 12 Compound 3-(3,8-difluoro-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a-yl)methoxy-7-(8-methyl-5 , Synthesis of 6,7,8-tetralin-1-yl)quinolin-4-yl)-8-oxa-3-azabicyclo[4.2.0]octane-7-one
  • Examples 281-291 were prepared by applying the method of Example 280.
  • Example 292 Compound 3-(3,6,8-trifluoro-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a-yl)methoxy)-7-(8- Synthesis of methyl-5,6,7,8-tetralin-1-yl)quinolin-4-yl)-8-oxa-3-azabicyclo[4.2.0]octane-7-one :
  • Example 280 Following the synthesis of Example 280, using 2-amino-4-bromo-3,5-difluorobenzoic acid as the starting material, a light yellow solid was obtained. (52mg). MS m/z:610.26[M+H]+
  • Example 313 Compound 3-(3,8-difluoro-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a-yl)methoxy-7-(8-methyl- Synthesis of 5,6,7,8-tetralin-1-yl)quinolin-4-yl)-8-oxa-3-azabicyclo[4.2.0]octane-7-one:
  • Example 280 Following the synthesis of Example 280, using 2-amino-4-bromo-3-fluorobenzoic acid as the starting material, a light yellow solid was obtained. (220mg). MS m/z:592.27[M+H] +
  • Examples 314-333 were prepared by applying the method of Example 313.
  • Example 334 (1R,6R)-3-(4-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-5-fluoro-7-(((2R,7aS)-2 -Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-[1,3]dioxola[4,5-f]quinazolin-9-yl)-8 -Synthesis of oxa-3-azabicyclo[4.2.0]octane-7-one:
  • Example 343 (1R,6R)-3-(6-(8-(1R,6R)-3-(4-(8-ethyl-7-fluoro-3-hydroxynaphthyl-1-yl)-5 -Fluoro-7-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrozin-7a(5H)-yl)methoxy)-8,9-dihydro-7H-cyclopenta[ Synthesis of f]quinazolin-1-yl)-8-oxa-3-azabicyclo[4.2.0]octane-7-one:
  • Example 349 (1R,6R)-3-(5-(8-chloro-7-fluoronaphthyl)-6-fluoro-8-((2R,7aS)-2-fluorotetrahydro- 1H-Pyrrozine-7a(5H)-yl)methoxy)-2,3-dihydroimidazo[1',2':1,2]pyrido[4,3-d]pyrimidin-10-yl Synthesis of )-8-oxa-3-azabicyclo[4.2.0]octane-7-one
  • Examples 368-373 were prepared by applying the method of Example 367.
  • Example 374 (1R,6R)-3-(2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8- Methyl-5,6,7,8-tetralin-1-yl)-5,6,7,8-tetrahydropyridin[3,4-d]pyrimidin-4-yl)-8-oxo- Synthesis of 3-azabicyclo[4.2.0]octane-7-one
  • Step 1 Synthesis of compound 1-(8-methyl-5,6,7,8-tetralin-1-yl)-3-oxopiperidine-4-carboxylic acid ethyl ester
  • Step 2 Compound 7-(8-methyl-5,6,7,8-tetrahydronaphthalene-1-yl)-2-methylthio-5,6,7,8-tetrahydropyrido[3, Synthesis of 4-d]pyrimidin-4-ol
  • Step 3 Compound 4-benzyloxy-7-(8-methyl-5,6,7,8-tetralin-1-yl)-2-methylthio-5,6,7,8-tetralin Synthesis of Hydropyrido[3,4-d]pyrimidines
  • Step 4 Compound 4-benzyloxy-7-(8-methyl-5,6,7,8-tetralin-1-yl)-2-(methylsulfinyl)-5,6,7 ,Synthesis of 8-tetrahydropyrido[3,4-d]pyrimidine
  • Step 5 Compound 4-benzyloxy-2-(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a-yl)methoxy)-7-(8-methyl-5,6, Synthesis of 7,8-tetralin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine
  • Step 6 Compound 2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(8-methyl-5,6,7, Synthesis of 8-tetralin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol
  • Step 7 Compound 2-fluorotetrahydro-1H-pyrrozine-7-methoxy-7-(8-methyl-5,7,7-tetralin-1-yl)-5,6,7, 8-Tetralin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[4.2. 0] Synthesis of octane-7-one
  • Example 404 Compound (1R,6R)-3-(2-((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-6-(3 -Hydroxy-1-naphthyl)-6,7-dihydro-5H-pyran[3,4-d]pyrimidin-4-yl)-8-oxo-3-azabicyclo[4.2.0]octane Synthesis of alkane-7-one
  • Example 412 Ethyl (4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-( ((1R,6R)-7-oxo-8-oxo-3-azabicyclo[4.2.0]oct-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-5- Synthesis of Methyl-5,6,7,8-tetralin-2-yl)carbonate
  • Step 1 Ethyl (4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-(( (1R,6R)-7-oxo-8-oxo-3-azabicyclo[4.2.0]oct-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-methyl Synthesis of base-5,6,7,8-tetralin-2-yl) carbonate, under cooling in an ice water bath, to (1R, 6R)-3-(8-fluoro-2-(((2R, 7aS) )-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-(3-hydroxy-8-methyl-5,6,7,8-tetralin-1 -yl)pyrido[4,3-d]pyrimidin-4-yl)-8-oxo-3
  • Examples 413-498 were prepared by applying the method of Example 412, and the acylating reagent was acid chloride or chloroformate.
  • Example 499 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((1R, 6R)-7-oxo-8-oxa-3-azabicyclo[4.2.0]octane-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-methyl -Synthesis of 5,6,7,8-tetrahydronaphthyl-2-yl(2-methoxyethyl)carbamate
  • Step 1 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-yl)methoxy)-4-((1R,6R )-7-oxo-8-oxa-3-azabicyclo[4.2.0]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-methyl- Synthesis of 5,6,7,8-tetrahydronaphthyl-2-yl(4-nitrophenyl)carbonate
  • reaction solution is diluted with water and extracted with ethyl acetate.
  • organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product which is used directly in the next step.
  • Step 2 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4-((1R,6R )-7-oxo-8-oxa-3-azabicyclo[4.2.0]octan-3-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-methyl- Synthesis of 5,6,7,8-tetrahydronaphthyl-2-yl(2-methoxyethyl)carbamate
  • Example 500 4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1-oxo) Generation-2-oxa-7-azaspiro[3.5]nonan-7-yl)pyrido[4,3-d]pyrimidin-7-yl)-5-methyl-5,6,7,8 -Synthesis of tetrahydronaphthyl-2-ylmethylcarbamate
  • Ba/F3 cells were cultured in RPMI 1640 supplemented with 10% heat-inactivated FBS and 10 ng/ml recombinant mouse IL-3. When the cell confluence reaches more than 80%, subculture is carried out.
  • MTT/MTS cell viability was detected by MTT/MTS.
  • the specific method is as follows: Equilibrate the 96-well plate to room temperature, add diluted CTG reagent (100 ⁇ l) (1:4 CTG reagent/PBS) to each well, place the plate on the orbital shaker for 30 minutes, and then use a multifunctional microplate reader (EnVision, PE) recorded chemiluminescence.
  • GraphPad Prism 8 software was used to create dose-response curves and calculate IC 50 .

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Abstract

La présente invention concerne des composés de formule (I) et de formule (II), ou des sels pharmaceutiquement acceptables, des promédicaments, des tautomères ou des stéréoisomères et des solvates de ceux-ci. Lesdits composés peuvent être utilisés pour le traitement de cancers et d'inflammations de mammifères. La présente invention concerne également des procédés de préparation des composés de formule (I) et de formule (II), ainsi que des compositions pharmaceutiques comprenant les composés.
PCT/CN2023/115860 2022-08-30 2023-08-30 Composés hétérocycliques utilisés en tant qu'inhibiteurs de kras, leur préparation et leur utilisation thérapeutique WO2024046370A1 (fr)

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WO2021219072A1 (fr) * 2020-04-30 2021-11-04 上海科州药物研发有限公司 Préparation et procédé d'application d'un composé hétérocyclique en tant qu'inhibiteur de kras
CN113999226A (zh) * 2020-12-22 2022-02-01 上海科州药物研发有限公司 作为kras抑制剂的杂环化合物的制备及其应用方法
WO2022221739A1 (fr) * 2021-04-16 2022-10-20 Merck Sharp & Dohme Corp. Inhibiteurs à petites molécules de mutant de kras g12d
TW202241869A (zh) * 2020-12-22 2022-11-01 大陸商上海科州藥物研發有限公司 作為ｋｒａｓ抑制劑的雜環化合物的製備及其應用方法
WO2022232331A1 (fr) * 2021-04-29 2022-11-03 Amgen Inc. Composés hétérocycliques et procédés d'utilisation
WO2023122662A1 (fr) * 2021-12-22 2023-06-29 The Regents Of The University Of California Inhibiteurs de liaison covalente des mutants g12s, g12d et/ou g12e de k-ras gtpase
WO2023150284A2 (fr) * 2022-02-03 2023-08-10 Mirati Therapeutics, Inc. Inhibiteurs de pan-kras de quinazoline

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CN113999226A (zh) * 2020-12-22 2022-02-01 上海科州药物研发有限公司 作为kras抑制剂的杂环化合物的制备及其应用方法
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WO2022221739A1 (fr) * 2021-04-16 2022-10-20 Merck Sharp & Dohme Corp. Inhibiteurs à petites molécules de mutant de kras g12d
WO2022232331A1 (fr) * 2021-04-29 2022-11-03 Amgen Inc. Composés hétérocycliques et procédés d'utilisation
WO2023122662A1 (fr) * 2021-12-22 2023-06-29 The Regents Of The University Of California Inhibiteurs de liaison covalente des mutants g12s, g12d et/ou g12e de k-ras gtpase
WO2023150284A2 (fr) * 2022-02-03 2023-08-10 Mirati Therapeutics, Inc. Inhibiteurs de pan-kras de quinazoline

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