WO2023030215A1 - Dérivé de pyridopyrimidone, son procédé de préparation et son utilisation - Google Patents

Dérivé de pyridopyrimidone, son procédé de préparation et son utilisation Download PDF

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WO2023030215A1
WO2023030215A1 PCT/CN2022/115377 CN2022115377W WO2023030215A1 WO 2023030215 A1 WO2023030215 A1 WO 2023030215A1 CN 2022115377 W CN2022115377 W CN 2022115377W WO 2023030215 A1 WO2023030215 A1 WO 2023030215A1
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cycloalkyl
alkyl
aryl
heteroaryl
ethyl
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PCT/CN2022/115377
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English (en)
Chinese (zh)
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仇宗兴
沈卫超
曹海
汪泽峰
陈友喜
叶成
钱文建
陈磊
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浙江海正药业股份有限公司
上海昂睿医药技术有限公司
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Priority to CN202280051065.1A priority Critical patent/CN117730080A/zh
Publication of WO2023030215A1 publication Critical patent/WO2023030215A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—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
    • 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 present invention relates to a substituted pyridopyrimidinone derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and its use as a therapeutic agent, especially as an SOS1 inhibitor.
  • RAS genes are widely found in various eukaryotic organisms such as mammals, fruit flies, fungi, nematodes and yeasts, and have important physiological functions in various life systems.
  • the mammalian RAS gene family has three members, namely H- RAS, K-RAS and N-RAS, each RAS gene has a similar structure, and all of them are composed of four exons, which are distributed on the DNA with a total length of about 30 kb.
  • Their encoded products are monomeric globular proteins with a relative molecular mass of 21kDa.
  • the activation and inactivation state of RAS protein has a significant impact on the life processes such as cell growth, differentiation, proliferation and apoptosis.
  • This protein is a membrane-bound guanine nucleotide-binding protein with weak GTPase activity and regulates RAS through GTPase-activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs) in normal physiological activities
  • GAPs GTPase-activating proteins
  • GEFs guanine nucleotide exchange factors
  • the active state when the RAS protein combines with GTP to form RAS-GTP, it is the active state, and the GTPase activating protein can dephosphorylate RAS-GTP into RAS-GDP, and then inactivate it; the inactivated RAS-GDP is in the guanine Under the action of nucleotide exchange factors, it is transformed into active RAS-GTP, thereby activating a series of downstream pathways such as RAF/MER/ERK and PI3K/AKT/mTOR.
  • the RAS gene is also closely related to various human diseases, especially in cancer.
  • RAS is a frequently mutated oncogene, and the KRAS subtype gene mutation accounts for 86% of the total number of RAS gene mutations, and about 90% of pancreatic cancers. 30%-40% of colon cancer and 15-20% of lung cancer have different degrees of KRAS gene mutation.
  • this target has always been the focus of drug research and development workers. Since the announcement of the clinical results of AMG-510, which directly acts on the KRAS-G12C target, research on KRAS inhibitors has set off a wave of upsurge at home and abroad.
  • SOS Seon of sevenless homolog
  • hSOS1 and hSOS2 SOS homologues
  • hSOS1 and hSOS2 SOS homologues
  • hSOS1 and hSOS2 SOS homologues
  • hSOS1 and hSOS2 SOS homologues
  • the hSOS1 protein is 150kDa in size and is a multi-structural protein domain consisting of 1333 amino acids, including an N-terminal protein domain (HD), multiple homology domains, a helical linker (HL), a RAS exchange sequence (REM) and a rich Proline C-terminal domain.
  • HD N-terminal protein domain
  • HL helical linker
  • REM RAS exchange sequence
  • RAS protein on hSOS1 There are two binding sites for RAS protein on hSOS1, namely the catalytic site and the allosteric site.
  • the catalytic site binds to the RAS protein on the RAS-GDP complex to promote the exchange of guanine nucleotides
  • the allosteric site binds
  • the RAS protein on the RAS-GTP complex further enhances the catalytic effect, and then participates in and activates the signal transduction of RAS family proteins.
  • Studies have shown that inhibition of SOS1 can not only completely inhibit the RAS-RAF-MEK-ERK pathway in wild-type KRAS cells, but also lead to a 50% reduction in phospho-ERK activity in mutant KRAS cell lines.
  • the inhibition of SOS1 can also reduce the activity of RAS, thereby treating various cancers caused by RAS gene mutation or RAS protein overactivation, including pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma tumor, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer , chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, kidney cancer and sarcoma.
  • pancreatic cancer lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma tumor, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, u
  • the present invention provides a substituted pyridopyrimidinone compound represented by general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
  • Ring A is selected from C 6 -C 10 aryl, 5-10 membered heteroaryl or 9-10 membered fused rings;
  • L is selected from a single bond or (CR a R b ) p ;
  • R a and R b are each independently selected from hydrogen, hydroxyl, halogen, alkyl, alkoxy, and cycloalkyl, and the alkyl, alkoxy, and cycloalkyl are optionally further selected from one or more Substituents of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl;
  • R a and R b form a C 3 -C 6 cycloalkyl group or a 3-6 membered heterocyclic group together with the atoms they are connected to, wherein the 3-6 membered heterocyclic group contains one or more N, O or S, and the C 3 -C 6 cycloalkyl or 3-6 membered heterocyclic group is optionally further selected from one or more groups selected from hydroxyl, halogen, nitro, cyano, alkyl, alkane Oxygen, haloalkyl, haloalkoxy, hydroxyalkyl substituents are substituted;
  • R A is selected from C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocyclic group, C 6 -C 10 aryl or 5-10 membered heteroaryl;
  • R 3 is selected from halogen, cyano, C 3 -C 10 cycloalkyl or -OR 7 ;
  • R 4 is selected from C 1 -C 4 alkyl, halogen, cyano, alkoxy, C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl or 3-6 membered heterocyclic group, preferably C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl;
  • R is selected from methyl or deuterated methyl
  • R 6 is selected from a hydrogen atom or a deuterium atom
  • R 10 , R 11 and R 12 are each independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclyl group, an aryl group or a heteroaryl group; , aryl or heteroaryl are optionally further replaced by one or more selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , carboxyl or carboxylate substituents;
  • each r is independently selected from 0, 1 or 2;
  • p is selected from 1 or 2;
  • n is selected from 0, 1, 2 or 3.
  • a compound represented by general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or its Stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
  • R 1 , R 2 , R 3 , R 4 , L and m are as defined in general formula (I).
  • a compound represented by general formula (II) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof is a compound represented by general formula (III) or its Stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
  • R c is selected from C 1 -C 4 alkyl, deuterated C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl;
  • R 1 , R 2 , R 4 , L and m are as described in the general formula (II).
  • a compound represented by general formula (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof is a compound represented by general formula (IV) or its Stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
  • Ring B is selected from C 3 -C 10 cycloalkyl, 3-12 membered heterocyclic group, C 6 -C 10 aryl, 5-10 membered heteroaryl;
  • n is selected from 0, 1 or 2;
  • R 1 , R 4 , R 7 -R 9 , R c , L, r and m are as described in the general formula (III).
  • a compound described in general formula (I), (II), (III) or (IV) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof wherein R 1 are the same or different, each independently selected from halogen or haloalkyl, preferably from fluorine, trifluoromethyl or difluoromethyl.
  • Ring B is selected from C 3 -C 6 cycloalkyl or 3-6 membered heterocyclyl
  • R d is selected from alkyl or haloalkyl.
  • a preferred version of the present invention a compound described in general formula (III) or (IV) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R c is selected from methyl, deuterium substituted methyl or cyclopropyl.
  • the compound described in general formula (I) is selected from:
  • the present invention provides a pharmaceutical composition, which contains an effective dose of the compound described in general formula (I), (II), (III) or (IV) or its stereoisomer, Tautomers or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, excipients or combinations thereof.
  • the present invention provides a compound described in general formula (I), (II), (III) or (IV) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical combination thereof
  • SOS1 inhibitor a compound described in general formula (I), (II), (III) or (IV) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical combination thereof.
  • the present invention also provides a compound described in general formula (I), (II), (III) or (IV) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or its drug
  • hereditary diseases wherein the diseases mediated by SOS1 are preferably pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute Myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian carcinoma, prostate cancer, glioblastoma, renal carcinoma, and sarcoma.
  • the diseases mediated by SOS1 are preferably pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute Myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer,
  • the present invention further provides a compound described in general formula (I), (II), (III) or (IV) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or its drug Use of the composition in the preparation of medicines for treating RAS family protein signaling pathway-dependent cancers, cancers caused by SOS1 mutations or hereditary diseases caused by SOS1 mutations.
  • the present invention provides a compound described in general formula (I), (II), (III) or (IV) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical combination thereof
  • a compound described in general formula (I), (II), (III) or (IV) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical combination thereof In the preparation of drugs for the treatment of pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer , cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, kidney cancer And the purposes in the
  • Alkyl when used as a group or a part of a group refers to a C 1 -C 20 straight chain or branched aliphatic hydrocarbon group. It is preferably C 1 -C 10 alkyl, more preferably C 1 -C 6 alkyl.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-di Methylpropyl, 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-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl wait.
  • Alkyl groups can be substituted or unsubstituted.
  • Cycloalkyl refers to saturated or partially saturated monocyclic, fused, bridged and spiro carbocyclic rings. It is preferably a C 3 -C 12 cycloalkyl group, more preferably a C 3 -C 8 cycloalkyl group, and most preferably a C 3 -C 6 cycloalkyl group.
  • Examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyl Alkenyl, cyclooctyl, etc., preferably cyclopropyl, cyclohexenyl. Cycloalkyl groups can be substituted or unsubstituted.
  • “Spirocycloalkyl” refers to a polycyclic group with 5 to 18 members, two or more ring structures, and a single carbon atom shared between the single rings (called a spiro atom).
  • the ring may contain 1 or An aromatic system with multiple double bonds but none of the rings has fully conjugated ⁇ electrons. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spiro cycloalkyl group is divided into single spiro, double spiro or polyspiro cycloalkyl, preferably single spiro and double spiro cycloalkyl, 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: spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.
  • “Fused cycloalkyl” refers to a 5 to 18-membered, full-carbon polycyclic group containing two or more ring structures sharing a pair of carbon atoms with each other, and one or more rings may contain one or more double bonds, Aromatic systems where none of the rings have fully conjugated pi-electrons, preferably 6 to 12, more preferably 7 to 10 membered. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl groups.
  • fused cycloalkyl include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, Decalinyl or tetrahydrophenanthrenyl.
  • “Bridged cycloalkyl” refers to a 5- to 18-membered, full-carbon polycyclic group that contains two or more ring structures and shares two carbon atoms that are not directly connected to each other.
  • One or more rings may contain one or more Aromatic systems with multiple double bonds but none of the rings having fully conjugated pi electrons are preferably 6 to 12 membered, more preferably 7 to 10 membered. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bis Cyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)-bicyclo[3.3.2]decyl.
  • Heterocyclyl “heterocyclic” or “heterocyclic” are used interchangeably in this application and all refer to non-aromatic heterocyclic groups in which one or more atoms forming the ring are heteroatoms, such as oxygen, Nitrogen, sulfur atoms, etc., including monocyclic, polycyclic, condensed, bridged and spiro rings.
  • Examples of “monocyclic heterocyclyl” include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, Linyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-onyl, piperazinyl, hexahydropyrimidinyl,
  • Monocyclic heterocyclyl groups may be substituted or unsubstituted.
  • “Spiroheterocyclic group” refers to a polycyclic group with 5 to 18 members, two or more ring structures, and one atom shared between the single rings.
  • the ring may contain one or more double bonds, but Aromatic systems in which none of the rings have fully conjugated ⁇ -electrons, in which one or more ring atoms are selected from nitrogen, oxygen or heteroatoms of S(O) n (where n is selected from 0, 1 or 2), and the remaining ring atoms for carbon.
  • the spirocycloalkyl group can be divided into single spiroheterocyclyl, double spiroheterocyclyl or polyspiroheterocyclyl, preferably single spiroheterocyclyl and double 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 monospiro heterocyclic group.
  • spiroheterocyclyl include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[4.4]nonyl, Spiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl,
  • a spiroheterocyclyl can be substituted or unsubstituted.
  • “Fused heterocyclic group” refers to a polycyclic group containing two or more ring structures that share a pair of atoms with each other, one or more rings may contain one or more double bonds, but none of the rings has complete conjugation
  • An aromatic system of ⁇ electrons wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) n (wherein n is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • 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: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1. 0]hexyl, octahydrobenzo[b][1,4]dioxine.
  • “Bridged heterocyclic group” refers to a polycyclic group with 5 to 14 members, 5 to 18 members, containing two or more ring structures, sharing two atoms that are not directly connected to each other, and one or more rings can be Aromatic systems containing one or more double bonds, but none of the rings have fully conjugated ⁇ -electrons, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) n (where n is selected from 0, 1 or 2), the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclyl include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 2-azabicyclo[2.2.2]octyl, cyclo[3.3.2]decyl,
  • Bridged heterocyclyl groups can be substituted or unsubstituted.
  • Aryl means a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion.
  • aryl includes monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferred aryl groups are C 6 -C 10 aryl groups, more preferred aryl groups are phenyl and naphthyl, most preferably phenyl.
  • Aryl groups can be substituted or unsubstituted.
  • Heteroaryl refers to an aromatic 5 to 6 membered monocyclic ring or 8 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, furyl, 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 Dioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoin
  • Heteroaryl groups can be substituted or unsubstituted.
  • “Fused ring” refers to a polycyclic group in which two or more ring structures share a pair of atoms with each other, one or more rings may contain one or more double bonds, but at least one ring does not have complete conjugation At the same time, at least one ring has an aromatic system with fully conjugated ⁇ electrons, wherein 0, one or more ring atoms are selected from nitrogen, oxygen or S(O) n (wherein n is selected from 0 , 1 or 2), and the remaining ring atoms are carbon.
  • the fused ring preferably includes a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl group and a monocyclic heterocyclic group or a monocyclic cycloalkyl group. Preferably it is 7 to 14 yuan, more preferably 8 to 10 yuan. Examples of "fused rings" include, but are not limited to:
  • Alkoxy refers to a group of (alkyl-O-). Wherein, alkyl refers to relevant definitions herein. C 1 -C 6 alkoxy is preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.
  • Hydroalkyl refers to a hydroxy-substituted alkyl group.
  • Haloalkyl means an alkyl group substituted with a halogen.
  • Haldroxy means an -OH group.
  • Halogen refers to fluorine, chlorine, bromine and iodine.
  • Amino refers to -NH2 .
  • Cyano refers to -CN.
  • Niro refers to -NO2 .
  • Benzyl means -CH2 -phenyl.
  • DMSO dimethylsulfoxide
  • leaving group an atom or functional group that is separated from a larger molecule in a chemical reaction, is a term used in nucleophilic substitution reactions and elimination reactions.
  • the reactant attacked by the nucleophile is called the substrate, and the atom or atomic group that breaks off with a pair of electrons from the substrate molecule is called the leaving group.
  • Groups that are easy to accept electrons and have strong ability to bear negative charges are good leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to detach from other molecules.
  • Common leaving groups include, but are not limited to, halogens, methanesulfonyl, -OTs, or -OH.
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
  • substitution or “substituted” in this specification, unless otherwise specified, means that a group can be substituted by one or more substituents.
  • “Pharmaceutically acceptable salt” refers to certain salts of the above compounds that can maintain their original biological activity and are suitable for medical use.
  • the pharmaceutically acceptable salt of the compound represented by the general formula (I) may be a metal salt or an amine salt with a suitable acid.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiologically acceptable carriers and excipients. Forming agent.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • the present invention provides a preparation method of a compound of general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, said method comprising:
  • the compound of the general formula (IA) reacts with the compound of the general formula (IB) to obtain the compound of the general formula (IC); the compound of the general formula (IC) undergoes an intramolecular cyclization reaction under heating conditions to obtain the compound of the general formula (I);
  • Ring A, R 1 -R 4 and m are as defined in general formula (I).
  • the mass spectrum is measured by LC/MS instrument, and the ionization method can be ESI or APCI.
  • the thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.2mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm. ⁇ 0.5mm.
  • CD 3 OD deuterated methanol.
  • the nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon with a volume of about 1 L.
  • the solution in the reaction refers to an aqueous solution.
  • the compound was purified by silica gel column chromatography eluent system and thin layer chromatography; wherein the eluent system was selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: two Chloromethane and ethyl acetate system; the volume ratio of the solvent varies according to the polarity of the compound, and can also be adjusted by adding a small amount of acidic or alkaline reagents, such as acetic acid or triethylamine.
  • A petroleum ether and ethyl acetate system
  • B dichloromethane and methanol system
  • C two Chloromethane and ethyl acetate system
  • the volume ratio of the solvent varies according to the polarity of the compound, and can also be adjusted by adding a small amount of acidic or alkaline reagents, such as acetic acid or triethylamine.
  • reaction solution was adjusted to neutrality with aqueous sodium bicarbonate solution, extracted with ethyl acetate (15mL ⁇ 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was analyzed by thin-layer chromatography.
  • reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (eluent: A system) to obtain (R)-2-(6-((1-(3-(di Fluoromethyl)-2-fluorophenyl)ethyl)amino)-5-(1,3-dioxolan-2-yl)-2-methoxypyrimidin-4-yl)ethyl acetate 13a( 410 mg, 900.25 ⁇ mol), yield: 90.19%.
  • (R)-2-(6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-5-(1,3-dioxolane -2-yl)-2-methoxypyrimidin-4-yl) lithium acetate 15a (57 mg, 127.42 ⁇ mol) was added to dimethyl sulfoxide (3 mL), followed by the addition of morpholin-4-amine 6a (19.52 mg ,191.13 ⁇ mol), triethylamine (38.68mg, 382.27 ⁇ mol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (72.67 mg, 191.13 ⁇ mol), stirred at room temperature for 1 hour.
  • N-chlorosuccinimide (9.05 mg, 67.75 ⁇ mol) was slowly added to (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl) Amino)-2-methoxy-6-morpholinopyrido[4,3-d]pyrimidin-7(6H)-one 15c (29mg, 64.53 ⁇ mol) in acetonitrile (2mL) solution, stirred at room temperature for 1 hour .
  • reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (eluent: A system) to obtain 2-(6-(((R)-1-(3-(di Fluoromethyl)-2-fluorophenyl)ethyl)amino)-5-(1,3-dioxolan-2-yl)-2-(methoxy-d 3 )pyrimidin-4-yl) Ethyl propionate 20a (120 mg, 253.98 ⁇ mol), yield 50.15%.
  • Test example 1 the test that the compound of the present invention blocks the combination of SOS1 and KRAS G12C protein
  • the following method is used to determine the ability of the compound of the present invention to block the interaction between SOS1 and KRAS G12C protein under in vitro conditions.
  • This method uses the KRAS-G12C/SOS1 BINDING ASSAY KITS kit (Cat. No. 63ADK000CB16PEG) from Cisbio.
  • Kit instructions for detailed experimental operations, please refer to the kit instructions.
  • the experimental procedure is briefly described as follows: use diluent buffer (Product No. 62DLBDDF) to prepare Tag1-SOS1 and Tag2-KRAS-G12C proteins at a working solution concentration of 5X for later use.
  • the test compound was dissolved in DMSO to prepare a 10 mM stock solution, and then diluted with diluent buffer for use.
  • Table 1 Compounds of the present invention block the activity table of SOS1 binding to KRAS G12C protein
  • the compound of the present invention has a strong blocking effect on the interaction between SOS1 and KRAS G12C protein, IC 50 ⁇ 200nM, and the preferred compound IC 50 ⁇ 100nM.
  • Test example 2 compound of the present invention is to OCI-AML5 cell proliferation inhibitory assay
  • OCI-AML5 cells containing the SOS1N233Y mutation
  • MEM ⁇ medium containing 10% fetal bovine serum, 100 U penicillin and 100 ⁇ g/mL streptomycin.
  • cell viability through Luminescent Cell Viability Assay Kit was used for determination.
  • test compound is first dissolved in DMSO to prepare a 10mM stock solution, and then diluted with medium to prepare a test sample.
  • concentration of the compound ranges from 10000nM to 0.15nM .
  • Cells in the logarithmic growth phase were seeded into 96-well cell culture plates at a density of 1000 cells per well, cultured overnight at 37°C in a 5% CO2 incubator, and then continued to culture for 120 hours after adding the test compound.
  • the compound of the present invention has a good inhibitory effect on the proliferation of OCI-AML5 cells.
  • Test example 3 the assay of compound of the present invention to p-ERK1/2 inhibitory activity in DLD-1 cell
  • the following method is used to determine the inhibitory activity of the compounds of the present invention on p-ERK1/2 in DLD-1 cells.
  • This method uses the Advanced phospho-ERK1/2 (Thr202/tyr204) kit (Cat. No. 64AERPEH) from Cisbio, and the detailed experimental operation can refer to the kit instruction manual.
  • DLD-1 cells (containing the KRAS G13D mutation) were purchased from the Cell Resource Center, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.
  • DLD-1 cells were cultured in RPMI 1640 complete medium containing 10% fetal bovine serum, 100 U penicillin, 100 ⁇ g/mL streptomycin and 1 mM Sodium Pyruvate. DLD-1 cells were plated in 96-well plates at a rate of 30,000 per well, the medium was complete medium, and cultured overnight at 37° C. in a 5% CO 2 incubator.
  • test compound was dissolved in DMSO to prepare a 10mM stock solution, then diluted with RPMI 1640 basal medium, and 90uL of RPMI 1640 basal medium containing the corresponding concentration of the test compound was added to each well, and the final concentration of the test compound in the reaction system was The concentration range is 10000nM-0.15nM, and cultured in a cell incubator for 3 hours and 40 minutes. Subsequently, 10 uL of hEGF prepared with RPMI 1640 basal medium (purchased from Roche, product number 11376454001) was added to make the final concentration 5 nM, and cultured in an incubator for 20 minutes.
  • the compound of the present invention has a better inhibitory effect on ERK phosphorylation in DLD-1 cells.
  • Test example 4 compound of the present invention is to NCI-H358 cell proliferation inhibitory assay
  • NCI-H358 cells containing KRAS G12C mutation
  • RPMI 1640 medium containing 10% fetal bovine serum, 100U penicillin, 100 ⁇ g/mL streptomycin and 1mM Sodium Pyruvate middle.
  • cell viability through 3D Cell Viability Assay kit was used for determination.
  • the experimental method is operated according to the steps of the kit instructions, which are briefly described as follows: the test compound is first dissolved in DMSO to prepare a 10mM stock solution, and then diluted with medium to prepare a test sample. The final concentration of the compound ranges from 10000nM to 0.15nM . Cells in the logarithmic growth phase were seeded into an ultra-low adsorption 384-well cell culture plate (PerkinElmer, #3830) at a density of 2000 cells per well, and the test compound was added and cultured for 120 hours.
  • the test compound is first dissolved in DMSO to prepare a 10mM stock solution, and then diluted with medium to prepare a test sample. The final concentration of the compound ranges from 10000nM to 0.15nM .
  • Cells in the logarithmic growth phase were seeded into an ultra-low adsorption 384-well cell culture plate (PerkinElmer, #3830) at a density of 2000 cells per well, and the test compound was added and culture
  • the compound of the present invention has a good inhibitory effect on the proliferation of H358 cells.
  • the LC-MS/MS method is used to determine the compound of the present invention administered intravenously or intragastrically to the mice, and to measure the drug concentration in plasma at different times, and to study the pharmacokinetics of the compound of the present invention in mice. dynamic characteristics.
  • Embodiment 6 compound
  • ICR mice 27 males, 33.8-39.4 g, were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.
  • ICR mice 9 in a single group, were administered intravenously (administration dose 1 mg/kg, administration volume 5 mL/kg) and intragastric administration (administration dose 10 mg/kg, administration volume 5 mL/kg) respectively after fasting overnight.
  • Volume 10mL/kg and intragastric administration administration dose 100mg/kg, administration volume 10mL/kg), take food 4 hours after administration.
  • LC-MS/MS was used to determine the content of the compounds to be tested in mouse plasma after intravenous injection and intragastric administration of different compounds.
  • mice pharmacokinetic parameters of the compounds of the present invention are shown in the table below.
  • Example 6 of the present invention has good pharmacokinetic absorption, high bioavailability, and good pharmacokinetic properties.
  • Test example 6 the pharmacokinetic research of compound of the present invention beagle dog
  • the LC-MS/MS method was used to determine the compound of Example 6 of the present invention by intragastric administration to the Beagle dogs, and the drug concentration in plasma at different times was measured to study the effect of the compound of the present invention on Beagle dogs. pharmacokinetic characteristics.
  • Embodiment 6 compound
  • Beagle dogs, male, n 3, 14 months old, were purchased from Beijing Masi Biotechnology Co., Ltd.
  • the blood samples were stored in wet ice, and the plasma was centrifuged within 30 minutes after sampling (centrifugation conditions: 1530 g, 10 minutes).
  • the collected upper layer plasma was stored at -40 ⁇ -20°C before analysis.
  • LC-MS/MS was used to determine the content of the compound to be tested in the plasma of dogs after the compound was given intragastrically.
  • Example 6 of the present invention has good pharmacokinetic absorption in dogs and has good pharmacokinetic properties.

Abstract

La présente invention concerne un dérivé de pyridopyrimidone substitué, son procédé de préparation et l'utilisation d'une composition pharmaceutique le contenant dans des médicaments. Plus précisément, la présente invention concerne un dérivé de pyridopyrimidone substitué tel que représenté par la formule générale (I), et son procédé de préparation et un sel pharmaceutiquement acceptable de celui-ci, et l'utilisation de celui-ci en tant qu'agent thérapeutique, en particulier en tant qu'inhibiteur de SOS1, la définition de chaque substituant dans la formule générale (I) étant la même que celle dans la description.
PCT/CN2022/115377 2021-08-30 2022-08-29 Dérivé de pyridopyrimidone, son procédé de préparation et son utilisation WO2023030215A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019122129A1 (fr) * 2017-12-21 2019-06-27 Boehringer Ingelheim International Gmbh Nouvelles pyridopyrimidinones à substitution benzylamino et dérivés à utiliser en tant qu'inhibiteurs de sos1
CN113200981A (zh) * 2021-02-10 2021-08-03 杭州英创医药科技有限公司 作为sos1抑制剂的杂环化合物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019122129A1 (fr) * 2017-12-21 2019-06-27 Boehringer Ingelheim International Gmbh Nouvelles pyridopyrimidinones à substitution benzylamino et dérivés à utiliser en tant qu'inhibiteurs de sos1
CN113200981A (zh) * 2021-02-10 2021-08-03 杭州英创医药科技有限公司 作为sos1抑制剂的杂环化合物

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