[go: up one dir, main page]

WO2024244972A1 - Dérivé d'amide aromatique, son procédé de préparation et son utilisation - Google Patents

Dérivé d'amide aromatique, son procédé de préparation et son utilisation Download PDF

Info

Publication number
WO2024244972A1
WO2024244972A1 PCT/CN2024/093281 CN2024093281W WO2024244972A1 WO 2024244972 A1 WO2024244972 A1 WO 2024244972A1 CN 2024093281 W CN2024093281 W CN 2024093281W WO 2024244972 A1 WO2024244972 A1 WO 2024244972A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
alkylene
alkyl
cancer
halogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2024/093281
Other languages
English (en)
Chinese (zh)
Inventor
仇宗兴
彭记磊
汪泽峰
曹海
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zhejiang Hisun Pharmaceutical Co Ltd
Shanghai Aryl Pharmtech Co Ltd
Original Assignee
Zhejiang Hisun Pharmaceutical Co Ltd
Shanghai Aryl Pharmtech Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zhejiang Hisun Pharmaceutical Co Ltd, Shanghai Aryl Pharmtech Co Ltd filed Critical Zhejiang Hisun Pharmaceutical Co Ltd
Publication of WO2024244972A1 publication Critical patent/WO2024244972A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/38—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles

Definitions

  • the present invention relates to an aromatic amide derivative, a preparation method thereof, a pharmaceutical composition containing the derivative, and use of the derivative as a therapeutic agent, in particular as a KIF18A inhibitor.
  • Kinesin molecules are motor proteins that use microtubules as tracks and play an important role in organelle migration, tissue and organ development, signal transduction, mitosis, meiosis and other processes.
  • Various microtubule-associated proteins (MAPs) of the kinesin-8 family regulate the dynamic instability of microtubules by affecting the polymerization and depolymerization of microtubules.
  • KIF18A is a member of the kinesin-8 family. It can move toward the positive pole using microtubules as tracks and tends to bind to longer microtubules. Its activity is length-dependent and affects the length of the spindle, which can ensure the timely and smooth completion of the alignment of sister chromosomes. Its functions in different species are very similar and conservative.
  • KIF18A is a molecular motor protein that moves toward the positive end of microtubules using microtubules as tracks. It regulates the midplate assembly of chromosomes by affecting the dynamic instability of microtubule ends and functions during mitosis. In late mitosis, the protein is ubiquitinated and degraded to ensure the precise separation of chromosomes during mitosis and promote the smooth completion of mitosis and cytokinesis. In early mitosis, the localization of KIF18A at the positive end of microtubules close to the kinetochore is a necessary condition for its function. The localization depends not only on the motor activity of its N-terminus, but also on the tail domain with microtubule binding ability.
  • KIF18A is also subject to reversible protein phosphorylation/dephosphorylation modification, but there is still a lack of systematic research on how the post-translational modification of this protein regulates the function of KIF18A.
  • Estrogen receptor ER ⁇ can bind to KIF18A and promote its transcription, but it is still unclear whether KIF18A is also regulated by other transcription factors. Therefore, the research on the gene transcription regulation mechanism of KIF18A needs to be deepened. During meiosis, cells lacking KIF18A will be unable to complete meiosis, which will lead to sperm formation disorders and testicular dysplasia in male animals.
  • KIF18A protein is highly expressed in a variety of cancers, including but not limited to hepatocellular carcinoma, glioblastoma, colon cancer, breast cancer, lung cancer, bile duct cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, cervical cancer, ovarian cancer, synovial sarcoma, rhabdomyosarcoma, etc., which indicates that KIF18A is closely related to the occurrence and development of tumors and can become a target for molecular diagnosis and treatment of a variety of tumors.
  • the expression of KIF18A is related to the development of clinical colorectal cancer.
  • KIF18A can induce Akt phosphorylation, and knocking out KIF18A in mice can significantly promote cell apoptosis. It is speculated that KIF18A can promote the occurrence and development of colorectal cancer by activating the PI3K-Akt signaling pathway. KIF18A is also highly expressed in human breast cancer cells, and its overexpression is related to the grade, migration and prognosis of breast tumors. Studies on breast cancer cells have found that overexpression of KIF18A can lead to the formation of multinucleated cells, while low expression can significantly reduce the proliferation ability of cells both in vivo and in vitro.
  • KIF18A is upregulated at both the transcriptional and translational levels in lung adenocarcinoma, and abnormal expression of KIF18A is associated with clinical pathological malignancy.
  • KIF18 gene mutations can be observed in lung adenocarcinoma, and its expression is also affected by the DNA copy number. Regulation, KIF18A gene knockout can inhibit the proliferation of lung adenocarcinoma cells in vivo and in vitro, induce apoptosis and G2/M phase arrest.
  • the genes highly expressed at the same time as KIF18A are concentrated in the cell cycle signaling pathway, so in-depth research on the mechanism of action of KIF18A in tumors is of great clinical significance.
  • the present invention provides an aromatic amide derivative represented by general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
  • Ring A is selected from 5- to 10-membered aryl or 5- to 6-membered heteroaryl
  • Y 1 , Y 2 and Y 3 are each independently selected from CR d or a N atom, and at most two atoms among Y 1 , Y 2 and Y 3 are N atoms at the same time;
  • R d is selected from hydrogen, halogen, hydroxy, cyano, alkyl or alkoxy, wherein the alkyl or alkoxy is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy;
  • G is selected from 5-10 membered aryl, 5-10 membered heteroaryl or 6-14 membered fused ring, wherein the aryl, heteroaryl or fused ring is optionally further substituted with one or more R 4 ;
  • two R 4 and the same carbon atom to which they are attached form a -C(O)-;
  • L1 is selected from a bond, -C 1-6 alkylene-, -C 0-4 alkylene-NR c S( ⁇ O)( ⁇ NH)-C 0-4 alkylene-, -C 0-4 alkylene- SC 0-4 alkylene-, -C 0-4 alkylene-S( ⁇ O)-C 0-4 alkylene-, -C 0-4 alkylene-SO 2 -C 0-4 alkylene-, -C 0-4 alkylene-S( ⁇ O)( ⁇ NH)-C 0-4 alkylene-, -C 0-4 alkylene-NR c SO 2 -C 0-4 alkylene-, -C 0-4 alkylene-SO 2 NR c -C 0-4 alkylene- , -C 0-4 alkylene-OC 0-4 alkylene-, -C 0-4 alkylene-NR c -C 0-4 alkylene- , -C 0-4 alkylene
  • R c is selected from a hydrogen atom or an alkyl group
  • R2 are the same or different and are independently selected from halogen, hydroxy, cyano, alkyl, cycloalkyl or alkoxy; wherein the alkyl, cycloalkyl or alkoxy is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy;
  • L 2 is selected from in represents the connection site between the group and G in the general formula (I); Indicates that the group and the general formula (I) The attachment site of
  • R 3 are each independently selected from a hydrogen atom or an alkyl group, wherein the alkyl group is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano or alkoxy; R 3 is preferably a hydrogen atom;
  • R 8 , R 9 and R 10 are each independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted with one or more substituents selected from a hydroxyl group, a halogen group, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group;
  • n 0, 1 or 2;
  • r is independently 0, 1 or 2.
  • a preferred embodiment of the present invention is a compound of general formula (I) or its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, which is a compound of general formula (II) or its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof:
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from CR a , C(O), NR b or N atom;
  • X5 is selected from C atoms or N atoms; and at most three atoms among X1 , X2 , X3 , X4 , and X5 are N atoms at the same time;
  • R a are each independently selected from hydrogen, halogen, hydroxy, cyano, alkyl or alkoxy; wherein the alkyl or alkoxy is optionally further substituted by one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy;
  • R b are each independently selected from a hydrogen atom or an alkyl group
  • Ring A, Y 1 , Y 2 , Y 3 , L 1 , L 2 , R 1 , R 2 , R 4 and m are as defined in the general formula (I).
  • a preferred embodiment of the present invention is a compound of general formula (I) or its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, which is a compound of general formula (III), (IV) or (V) or its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof:
  • Ring B is independently selected from a 3- to 10-membered heterocyclic group, a 3- to 10-membered cycloalkyl group, a 5- to 6-membered aryl group, or a 5- to 6-membered heteroaryl group;
  • X 6 and X 7 are each independently selected from CR a , C(O), NR b or N atom;
  • X 8 , X 9 , and X 10 are each independently selected from CR a , C(O), NR b or a N atom, and at most two atoms among X 8 , X 9 , and X 10 are N atoms at the same time;
  • X 11 , X 12 , and X 13 are each independently selected from CR a , C(O), NR b or a N atom, and at most two atoms among X 11 , X 12 , and X 13 are N atoms at the same time;
  • R a are each independently selected from hydrogen, halogen, hydroxy, cyano, alkyl or alkoxy; wherein the alkyl or alkoxy is optionally further substituted by one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy;
  • R b are each independently selected from a hydrogen atom or an alkyl group
  • n is each independently selected from 0, 1, 2, 3 or 4;
  • Ring A, Y 1 , Y 2 , Y 3 , L 1 , L 2 , R 1 , R 2 , R 4 and m are as defined in the general formula (I).
  • a preferred embodiment of the present invention is a compound of formula (I), (II), (III), (IV) or (V) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein Y 1 , Y 2 and Y 3 are each independently selected to be CH.
  • a preferred embodiment of the present invention is a compound of general formula (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein Selected from the following groups:
  • R aa , R bb , R cc , R dd , R ee , R ff , R gg , R hh , R ii , R jj , R kk , R mm , R nn , R oo , R pp , R qq , R rr are the same or different and are each independently selected from a hydrogen atom, a halogen, a hydroxyl group, a cyano group, a methyl group or a methoxy group;
  • R aaa is selected from a hydrogen atom or a methyl group.
  • a preferred embodiment of the present invention is a compound of formula (III), (IV) or (V) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 and X 13 are each independently selected to be CH.
  • a preferred embodiment of the present invention is a compound of formula (III), (IV) or (V) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein Ring B is independently selected from the following groups:
  • a preferred embodiment of the present invention is a compound of formula (I), (II), (III), (IV) or (V) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein ring A is phenyl.
  • a preferred embodiment of the present invention is a compound of formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein R2 are the same or different and are independently selected from halogen, hydroxyl, cyano, C1 - C3 alkyl, C1 - C3 haloalkyl, cyclopropyl or methoxy.
  • a preferred embodiment of the present invention is a compound of formula (I), (II), (III), (IV) or (V) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein:
  • L is selected from a bond, -NR c -C 0-4 alkylene-, -NR c SO 2 -C 0-4 alkylene-, -SO 2 NR c -C 0-4 alkylene-, -NR c SO 2 NR c -, -S( ⁇ O)( ⁇ NH)-, -NR c S( ⁇ O)( ⁇ NH)-, -C 1-4 alkylene-, -S( ⁇ O)-, -O-, -C( ⁇ O)-, -C( ⁇ O)NR c -C 0-4 alkylene-, -C 0-4 alkylene-SO 2 -C 0-4 alkylene-, -C ⁇ N(OH)- or -NR c -C( ⁇ O)-, wherein said -C 0-4 alkylene- or -C 1-4 alkylene- is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano,
  • R c are each independently selected from a hydrogen atom or a methyl group.
  • a preferred embodiment of the present invention is a compound of formula (I), (II), (III), (IV) or (V) or a stereoisomer , a tautomer or a pharmaceutically acceptable salt thereof, wherein L1 is selected from a bond, -NHSO2CH2CH2- , -SO2NHCH2CH2- , -SO2- , -CH 2 SO 2 -, -NHSO 2 -, -SO 2 NH-, -NHC(CH 3 ) 2 CH2-, -C(O)NHCH 2 CH 2 -, -C(O)NHC(CH 3 ) 2 CH2-, -C(O)N(CH 3 )CH 2 CH 2 -, -CH(CH 3 )(OH)CH 2 -, -NHSO 2 CH(CH3)CH 2 -, -SO 2 NHC(CH3) 2 CH 2 -, -C(O)NH-, -NHCH 2 CH 2 or -CH 2 SO 2 CH 2 CH 2
  • a preferred embodiment of the present invention is a compound of formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein R1 is selected from a hydrogen atom, a hydroxyl group, an alkyl group, a heterocyclic group, a cycloalkyl group or a heteroaryl group, wherein the alkyl group, the heterocyclic group, the cycloalkyl group or the heteroaryl group is optionally further substituted by one or more substituents selected from a hydroxyl group or an alkyl group.
  • a preferred embodiment of the present invention is a compound of formula (I), (II), (III), (IV) or (V) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein for
  • a preferred embodiment of the present invention is a compound of formula (I), (II), (III), (IV) or (V) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein L 2 is selected from in represents the connection site between the group and G in the general formula (I); The group represented by The attachment site of
  • R3 is a hydrogen atom.
  • a preferred embodiment of the present invention is a compound of formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein R4 is selected from halogen, alkyl, alkoxy, cycloalkyl or heterocyclic group; wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally further substituted by one or more halogens;
  • two R 4 groups and the same carbon atom to which they are attached form a -C(O)-.
  • R4 is halogen, methyl, difluoromethyl, trifluoromethyl, methoxy
  • two R 4 groups and the same carbon atom to which they are attached form a -C(O)-.
  • the compound described by the general formula is selected from:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective dose of a compound of formula (I), (II), (III), (IV) or (V) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.
  • the present invention provides a use of a compound of general formula (I), (II), (III), (IV) or (V) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof in the preparation of a KIF18A inhibitor.
  • the present invention also provides a use of a compound of formula (I), (II), (III), (IV) or (V) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof in the preparation of a medicament for treating a disease mediated by KIF18A, wherein the disease mediated by KIF18A is preferably cancer; wherein the disease mediated by KIF18A is selected from hepatocellular carcinoma, glioblastoma, colon cancer, breast cancer, lung cancer, bile duct cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, cervical cancer, ovarian cancer, synovial sarcoma, rhabdomyosarcoma, colorectal cancer and lung adenocarcinoma.
  • the present invention further provides a use of a compound of general formula (III), (IV) or (V) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof in the preparation of a drug for treating cancer.
  • the present invention provides a compound described by general formula (III), (IV) or (V) or its stereoisomer, tautomer or pharmaceutically acceptable salt, or its pharmaceutical composition for use in preparing a drug for treating hepatocellular carcinoma, glioblastoma, colon cancer, breast cancer, lung cancer, bile duct cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, cervical cancer, ovarian cancer, synovial sarcoma, rhabdomyosarcoma, colorectal cancer and lung adenocarcinoma.
  • Alkyl when used as a group or a part of a group refers to a straight or branched aliphatic hydrocarbon group including C1 - C20 . Preferably, it is C1 - C10 alkyl, and more preferably C1 - C6 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-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc.
  • Alkyl can be substituted or unsubstituted.
  • C ⁇ - ⁇ alkylene refers to an aliphatic hydrocarbon group containing a minimum of ⁇ and a maximum of ⁇ carbon atoms in a branched or linear relationship, having 2 residues derived from the same carbon atom or two different carbon atoms of a parent alkane by removing two hydrogen atoms, wherein ⁇ and ⁇ represent integers, the designation of C 0 alkylene represents a direct bond, and examples of C 1-6 alkylene include, but are not limited to, methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene, 1,4-butylene, and the like.
  • C ⁇ - ⁇ alkylene may be substituted or unsubstituted.
  • Cycloalkyl refers to a non-aromatic cyclic alkyl group in which one or more of the atoms forming the ring is a carbon atom, including monocyclic, Polycyclic, fused, bridged and spirocyclic, preferably with 5 to 7 membered monocyclic or 7 to 10 membered bicyclic or tricyclic.
  • Examples of “cycloalkyl” include, but are not limited to, cyclopropyl, cyclopentyl, cyclobutyl. Cycloalkyl may be substituted or unsubstituted.
  • “Spirocycloalkyl” refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and one carbon atom (called spiro atom) shared between the monocyclic rings, containing one or more double bonds in the ring, but no ring has a completely conjugated ⁇ -electron aromatic system. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members.
  • the spirocycloalkyl is divided into single spiro, double spiro or multiple spirocycloalkyl, preferably single spiro and double spirocycloalkyl, preferably 4/5 members, 4/6 members, 5/5 members or 5/6 members.
  • 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, all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms, one or more rings may contain one or more double bonds, but no ring has a completely conjugated ⁇ -electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl.
  • 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, decahydronaphthyl or tetradecahydrophenanthryl.
  • “Bridged cycloalkyl” refers to a 5-18 membered, all-carbon polycyclic group containing two or more cyclic structures, sharing two carbon atoms that are not directly connected to each other, one or more rings may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron aromatic system, preferably 6-12 members, more preferably 7-10 members. Preferably 6-14 members, more preferably 7-10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl include, but are not limited to: (1s, 4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s, 5s)-bicycloo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r, 5r)-bicyclo[3.3.2]decyl.
  • Heterocyclyl “heterocycloalkyl”, “heterocycle” or “heterocyclic” are used interchangeably in this application and refer to non-aromatic heterocyclic groups, wherein one or more of the atoms forming the ring are selected from nitrogen, oxygen or S(O) t (wherein t is selected from 0, 1 or 2) heteroatoms, including monocyclic, polycyclic, fused, bridged and spirocyclic rings. Preferably, it has a 5-7-membered monocyclic ring or a 7-10-membered bicyclic or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur.
  • heterocyclyl examples include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazinyl, hexahydropyrimidine,
  • the heterocyclic group may be substituted or unsubstituted.
  • “Spiro heterocyclic group” refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and one atom shared between the monocyclic rings, containing one or more double bonds in the ring, but no ring has a completely conjugated ⁇ -electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) t (wherein t is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon.
  • it is 6 to 14 members, more preferably 7 to 10 members.
  • the spiro alkyl group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. More preferably, it is a 4-member/4-member, 4-member/5-member, 4-member/6-member, 5-member/5-member or 5-member/6-member single spiral heterocyclic group.
  • spiroheterocyclyl include, but are not limited to, 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl,
  • “Fused heterocyclic group” refers to an all-carbon polycyclic group containing two or more cyclic structures that share a pair of atoms with each other, one or more rings may contain one or more double bonds, but no ring has a completely conjugated ⁇ -electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) t (where t is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon.
  • it is 6 to 14 members, more preferably 7 to 10 members.
  • the number of constituent rings it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group.
  • fused heterocyclic group 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 5-14-membered, 5-18-membered, polycyclic group containing two or more cyclic structures, sharing two atoms that are not directly connected to each other, one or more rings may contain one or more double bonds, but no ring has a completely conjugated ⁇ -electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) t (wherein t is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon.
  • it is 6 to 14 members, more preferably 7 to 10 members.
  • bridged heterocyclic group include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 2-azabicyclo[3.3.2]decyl.
  • Aryl refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be connected together in a fused manner.
  • aryl includes monocyclic or bicyclic aromatic groups, such as phenyl, naphthyl, and tetrahydronaphthyl aromatic groups.
  • the aryl group is a C 6 -C 10 aromatic group, more preferably, the aryl group is phenyl and naphthyl, and most preferably, it is naphthyl.
  • the aryl group may be substituted or unsubstituted.
  • Heteroaryl refers to an aromatic 5- to 6-membered monocyclic 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, furanyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoind
  • a heteroaryl group can be substituted or unsubstituted.
  • “Fused ring” refers to a polycyclic group in which two or more cyclic structures share a pair of atoms, wherein at least one ring has a completely conjugated ⁇ -electron aromatic system, and at the same time, one or more rings may contain one or more double bonds, but at least one ring does not have a completely conjugated ⁇ -electron aromatic system, wherein the ring atoms are selected from 0, one or more heteroatoms selected from nitrogen, oxygen or S(O) r (wherein r 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 and a monocyclic heterocyclic group or a monocyclic cycloalkyl. Preferably, it is 6 to 14 yuan, and 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 is as defined herein.
  • C 1 -C 6 alkoxy is preferred, and examples thereof include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.
  • Niro refers to a -NO2 radical.
  • Hydrophilicity refers to an -OH group.
  • Halogen refers to fluorine, chlorine, bromine and iodine.
  • Amino refers to -NH2 .
  • Cyano refers to -CN.
  • Benzyl refers to -CH2 -phenyl.
  • Carboxy refers to -C(O)OH.
  • Carboxylate refers to -C(O)O-alkyl or -C(O)O-cycloalkyl, wherein alkyl and cycloalkyl are as defined above.
  • Hydroalkyl refers to an alkyl group substituted with a hydroxy group wherein alkyl is as defined above.
  • Aminoalkyl refers to an alkyl group substituted with an amino group, wherein alkyl is as defined above.
  • Haloalkyl refers to an alkyl group substituted with a halogen, wherein alkyl is as defined above.
  • Haloalkoxy refers to an alkoxy group substituted with a halogen group, wherein alkoxy is as defined above.
  • DMSO dimethyl sulfoxide
  • BOC refers to tert-butoxycarbonyl
  • THP refers to 2-tetrahydropyranyl
  • TFA trifluoroacetic acid
  • Ts refers to p-toluenesulfonyl.
  • leaving group is an atom or functional group that detaches from a larger molecule in a chemical reaction. It is a term used in nucleophilic substitution reactions and elimination reactions. In nucleophilic substitution reactions, the reactant attacked by the nucleophile is called a substrate, and the atom or atomic group that breaks away from the substrate molecule with a pair of electrons is called a 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.
  • the reason is that when the pKa of its conjugate acid is smaller, the corresponding The leaving group does not need to be combined with other atoms, and the tendency to exist in the form of anion (or neutral leaving group) is enhanced.
  • Common leaving groups include but are not limited to halogen, mesyl, -OTs or -OH.
  • Substituted means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.
  • R9 , R10 and R11 are each independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted with one or more substituents selected from a hydroxyl group, a halogen group, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group;
  • r is selected from 0, 1 or 2;
  • the compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers and geometric (conformational) isomers and mixtures thereof, such as racemic mixtures All of them are within the scope of the present invention.
  • structures depicted herein also encompass all isomeric (e.g., diastereoisomers, enantiomers, and atropisomers and geometric (conformational) isomeric forms of such structures; for example, R and S configurations at various asymmetric centers, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, individual stereoisomers as well as enantiomeric mixtures, diastereomeric mixtures, and geometric (conformational) isomeric mixtures of the compounds of the invention are within the scope of the invention.
  • “Pharmaceutically acceptable salts” refer to salts of the above compounds that can retain their original biological activity and are suitable for medical use.
  • Pharmaceutically acceptable salts of the compounds represented by general formula (I) may be metal salts or amine salts formed with suitable acids.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.
  • the present invention adopts the following technical scheme:
  • the present invention provides a method for preparing a compound of general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, the method comprising:
  • Compound (IA) reacts with compound (IB) to obtain compound (IC), and compound (IC) reacts with compound (ID) to produce compound (I).
  • L 2 is selected from R 3 is a hydrogen atom
  • Y represents hydroxyl or chlorine
  • W 1 represents fluorine, chlorine, bromine or iodine
  • Ring A, G, Y 1 , Y 2 , Y 3 , L 1 , R 1 , R 2 , R 4 and m are as defined in the general formula (I).
  • Compound (IA) undergoes a condensation reaction with compound (IIA) to obtain a compound of general formula (IIB), compound (IIB) reacts with compound (IIC) for coupling reaction to obtain a compound of general formula (IC), and compound (IC) reacts with compound (ID) to generate compound (I).
  • L 2 is selected from R 3 is a hydrogen atom
  • Y represents hydroxyl or chlorine
  • W 1 represents fluorine, chlorine, bromine or iodine
  • W 2 represents bromine or iodine
  • Ring A, G, Y 1 , Y 2 , Y 3 , L 1 , R 1 , R 2 , R 4 and m are as defined in the general formula (I).
  • the mass spectrum is obtained by LC/MS, 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 silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.
  • CD 3 OD deuterated methanol.
  • Argon atmosphere means that the reaction bottle is connected to an argon balloon with a capacity of about 1L.
  • the solution in the reaction refers to an aqueous solution.
  • the compound is purified by silica gel column chromatography and reverse phase column chromatography, wherein the eluent system is selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane: ethyl acetate; D: trifluoroacetic acid aqueous solution and acetonitrile system.
  • the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or alkaline reagents, such as acetic acid or triethylamine, can also be added for adjustment.
  • the reaction of the raw materials was complete and the product was generated according to mass spectrometry.
  • the reaction solution was concentrated to dryness under reduced pressure to obtain 2-(4-cyclopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 1c (13.00 g), which was directly used in the next reaction.
  • the reaction of the raw materials was complete and the product was generated according to mass spectrometry.
  • the reaction solution was diluted with water (150 mL) and extracted with ethyl acetate (60 mL ⁇ 2).
  • the combined organic phase was washed with a saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the residue was separated and purified by silica gel column chromatography (eluent: System A) to give 5-bromo-4'-cyclopropyl-[1,1'-biphenyl]-2-carboxylic acid methyl ester 1e (3.30 g) with a yield of 81.08%.
  • methyl 4-bromo-2-iodobenzoate 1d 500 mg, 1.47 mmol
  • (4-(difluoromethyl)phenyl)boronic acid 2a (252 mg, 1.47 mmol, commercially available) were added to 1,4-dioxane (10 mL) and water (4 mL), followed by potassium carbonate (405 mg, 2.93 mmol) and tetrakis(triphenylphosphine)palladium (169 mg, 0.147 mmol), nitrogen was replaced three times, and the reaction was carried out at 50°C for 18 hours.
  • 5-bromo-4'-(difluoromethyl)-[1,1'-biphenyl]-2-carboxylic acid methyl ester 2b 70.0 mg, 0.205 mmol was added to a mixed solution of tetrahydrofuran (1 mL), methanol (1 mL) and water (1 mL), followed by lithium hydroxide monohydrate (17.2 mg, 0.410 mmol), and reacted at 60°C for 18 hours. The mixture was concentrated to dryness under reduced pressure to give 5-bromo-4'-(difluoromethyl)-[1,1'-biphenyl]-2-carboxylic acid 2c (50 mg) with a yield of 74.49%.
  • 5-bromo-4'-(difluoromethyl)-[1,1'-biphenyl]-2-carboxylic acid 2c (50.0 mg, 0.153 mmol) and 3-(4,4-difluoropiperidin-1-yl)aniline 1 g (35.7 mg, 0.168 mmol) were added to N,N-dimethylformamide (1 mL), followed by (7- Azabenzotriazole-1-oxy)tripyrrolphosphonium hexafluorophosphate (159 mg, 0.305 mmol) and N,N-diisopropylethylamine (59.3 mg, 0.459 mmol) were added, replaced with nitrogen three times, and reacted at 70°C for 18 hours.
  • 2-iodo-1-methoxy-4-nitrobenzene 3a (5.00 g, 17.92 mmol, commercially available) was dissolved in 1,4-dioxane (50 mL) solution, and cesium carbonate (11.68 g, 35.84 mmol), 4,4-difluoropiperidine hydrochloride 3b (3.39 g, 21.50 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (1.71 g, 3.58 mmol) and palladium acetate (402.30 mg, 1.79 mmol) were added in sequence. After nitrogen replacement three times, the reaction was carried out at 100 ° C for 18 hours.
  • the reaction of the raw materials was complete and the product was generated by mass spectrometry.
  • the reaction solution was diluted with water (250 mL) and extracted with ethyl acetate (100 mL ⁇ 2).
  • the combined organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the residue was separated and purified by silica gel column chromatography (eluent: System A) to give 4,4-difluoro-1-(2-methoxy-5-nitrophenyl)piperidine 3c (4.60 g) with a yield of 94.3%.
  • reaction solution was concentrated to dryness under reduced pressure, and the mixture was dissolved in a mixed solvent of methanol (40 mL) and hydrochloric acid (8 mL), stirred at room temperature for 1 hour, and the reaction solution was concentrated to dryness under reduced pressure to obtain 3-(4,4-difluoropiperidin-1-yl)-4-methoxyaniline 3d (4.80 g), which was directly used in the next step.
  • 3-(4,4-difluoropiperidin-1-yl)-4-methoxyaniline 3d (1.00 g, 4.13 mmol) was dissolved in N,N-dimethylformamide (10 mL) solution, and N,N-diisopropylethylamine (2.67 g, 20.64 mmol), 4-bromo-2-iodobenzoic acid 3e (1.35 g, 4.13 mmol, commercially available), (7-azabenzotriazole-1-oxy)tripyrrolylphosphonium hexafluorophosphate (3.23 g, 6.19 mmol) were added in sequence. After three replacements. The reaction was carried out at 25°C for 18 hours.
  • the reaction was carried out at 100°C for 3 hours.
  • the reaction of the raw materials was complete by mass spectrometry, and the reaction solution was poured into water (80 mL) and extracted with ethyl acetate (30 mL ⁇ 2).
  • the combined organic phase was washed with a saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the reaction was carried out at 100 ° C for 3 hours to obtain a black suspension.
  • the reaction of the raw materials was complete by mass spectrometry, and the reaction solution was poured into water (100 mL) and extracted with ethyl acetate (40 mL ⁇ 2).
  • the combined organic phase was washed with a saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • reaction solution was filtered and concentrated under reduced pressure.
  • residue was separated and purified by silica gel column chromatography (eluent: System A) to give 5-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide 5b (30.0 mg) with a yield of 29%.
  • reaction solution was filtered and concentrated under reduced pressure.
  • residue was separated and purified by silica gel column chromatography (eluent: System A) to give 5-bromo-4'-(difluoromethyl)-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-[1,1'-biphenyl]-2-carboxamide 6b (30.0 mg) with a yield of 30%.
  • 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride 164 mg, 0.226 mmol
  • potassium acetate 666 mg, 6.79 mmol
  • 1-bromo-4-(1,1-difluoroethyl)benzene 7a 500 mg, 2.26 mmol, commercially available
  • biboronic acid pinacol ester 747 mg, 2.94 mmol
  • 1,4-dioxane 10 mL
  • Ammonium chloride (559.35 mg, 10.55 mmol) and iron powder (589.38 mg, 10.55 mmol) were added to a mixed solution of 4,4-difluoro-1-(5-nitro-2,3-dihydrobenzofuran-7-yl)piperidine 8c (300 mg, 1.06 mmol) in water (20 mL) and ethanol (20 mL), and the mixture was heated to 80°C and stirred for 2 hours. After the reaction was complete, the mixture was filtered, ethyl acetate (30 mL) was added to the filtrate, and the layers were separated.
  • aqueous phase was extracted with ethyl acetate (30 mL ⁇ 2), and the organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrobenzofuran-5-amine 8d (220 mg) with a yield of 81.98%.
  • ethylsulfonyl chloride 8f (1.34 g, 10.43 mmol, commercially available), 4-amino-2-bromo-benzoic acid methyl ester 8e (2 g, 8.69 mmol, commercially available) and triethylamine (2.64 g, 26.08 mmol) were added to dichloromethane (30 mL) and stirred at room temperature for 16 hours.
  • the reaction solution was put into water, extracted with ethyl acetate (20 mL ⁇ 3), and the combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • methyl 2-bromo-4-(ethylsulfonylamino)benzoate 8g 600mg, 1.86mmol
  • 4-trifluoromethylphenylboronic acid 8h 530mg, 2.79mmol
  • tetrakis(triphenylphosphine)palladium 215mg, 0.186mmol
  • potassium carbonate 772mg, 5.59mmol
  • the reaction solution was put into water, extracted with ethyl acetate (20mL ⁇ 3), and the combined organic phase was washed with saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the crude product was purified by silica gel chromatography (eluent: A system) to obtain 5-(ethylsulfonylamino)-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide 8i (660mg) with a yield of 91.69%.
  • benzotriazol-1-yl-oxytripyrrolidinophosphine hexafluorophosphate (418 mg, 803.54 ⁇ mol), 5-(ethyl sulfonyl)-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxylic acid 8j (200 mg, 0.54 mmol) and N,N-diisopropylethylamine (207 mg, 1.61 mmol) were added to N,N-dimethylformamide (3 mL), stirred at room temperature for 10 minutes, 7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrobenzofuran-5-amine 8d (163 mg, 0.64 mmol) was added thereto, heated at 65°C and stirred for 2 hours.
  • Example 10 was prepared, and the specific structure and structural characterization are as follows:
  • Test Example 1 Determination of the inhibitory effect of the compounds of the present invention on OVCAR-3 cell proliferation
  • OVCAR-3 cells (containing the TP53 R248Q mutation) were purchased from the Cell Resource Center of the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and cultured in RPMI 1640 medium containing 10% fetal bovine serum, 100 U penicillin, and 100 ⁇ g/mL streptomycin. Cell viability was measured by The assay was performed using the Luminescent Cell Viability Assay Kit (Promega, Catalog No. G7573).
  • test compound was first dissolved in DMSO to prepare a 10mM stock solution, and then diluted with culture medium to prepare the test sample, and the final concentration of the compound ranged from 1000nM to 0.015nM.
  • Cells in the logarithmic growth phase were inoculated into a 96-well cell culture plate at a density of 1000 cells per well, cultured overnight in a 37°C, 5% CO2 incubator, and then the test compound was added and continued to be cultured for 72 hours.
  • the compound of the present invention has a good inhibitory effect on the proliferation of OVCAR-3 cells with IC 50 ⁇ 100nM.
  • AMG 650 prepared according to Example 4 of the patent publication WO2020132648A1 is as follows:
  • Test Example 2 Determination of the inhibitory effect of the compounds of the present invention on HT-29 cell proliferation
  • HT-29 cells (containing the TP53R273H mutation) were purchased from the Cell Resource Center of the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and cultured in McCoy's 5A medium containing 10% fetal bovine serum, 100 U penicillin, and 100 ⁇ g/mL streptomycin. Cell viability was measured by The assay was performed using the Luminescent Cell Viability Assay Kit (Promega, Catalog No. G7573).
  • test compound was first dissolved in DMSO to prepare a 10mM stock solution, and then diluted with the aforementioned McCoy's 5A medium to prepare the test sample, and the final concentration of the compound ranged from 1000nM to 0.015nM.
  • Cells in the logarithmic growth phase were seeded into a 96-well cell culture plate at a density of 1000 cells per well, cultured overnight in a 37°C, 5% CO 2 incubator, and then the test compound was added and continued to be cultured for 120 hours.
  • the compounds of the present invention have a good inhibitory effect on HT-29 cell proliferation with IC 50 ⁇ 100nM.
  • Test Example 3 Test of the Inhibition of KIF18A Enzyme Activity by the Compounds of the Invention
  • the following method is used to determine the degree of inhibition of the compound of the present invention on the recombinant human KIF18A enzyme activity under in vitro conditions.
  • This method uses the ADP-Glo TM Kinase Assay kit (Cat. No. V9102) from Promega.
  • ADP-Glo TM Kinase Assay kit Cat. No. V9102
  • the kit instructions please refer to the kit instructions.
  • test compound was first dissolved in DMSO to prepare a stock solution, and then gradiently diluted using reaction buffer A (15mM Tris, pH 7.5, 10mM MgCl2 , 0.01% Pluronic F-68).
  • reaction buffer A 15mM Tris, pH 7.5, 10mM MgCl2 , 0.01% Pluronic F-68.
  • the final concentration range of the test compound in the reaction system was 10000nM to 0.15nM
  • reaction buffer B (15mM Tris, pH7.5, 10mM MgCl2 , 0.01% Pluronic F-68, 37.5 ⁇ g/ml tubulin, 1.25 ⁇ M paclitaxel) was used to prepare KIF18A protein and ATP working solutions.
  • the reaction was carried out in a 384-well microplate.
  • test compound and recombinant human KIF18A protein were added to the wells and incubated at room temperature for 20 minutes.
  • ATP solution from ADP-Glo TM Kinase Assay kit component V915A, final concentration 60 ⁇ M
  • 5 ⁇ L ADP-Glo Reagent was added to the reaction system and incubated at room temperature for 50 minutes.
  • 10 ⁇ L Kinase Detection Reagent was added to the reaction system and incubated at room temperature for 30 minutes.
  • the chemiluminescence intensity of each well was measured in the luminescence mode of the microplate reader.
  • the percentage inhibition rate of the compound at each concentration was calculated by comparing the luminescence intensity value with the control group (0.1% DMSO), and the IC 50 value of the compound was obtained by nonlinear regression analysis of the compound concentration logarithm-inhibition rate using GraphPad Prism 5 software, as shown in Table 3.
  • the compounds of the present invention have a significant inhibitory effect on KIF18A enzyme activity with an IC 50 of ⁇ 200 nM.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un dérivé d'amide aromatique, son procédé de préparation et une utilisation d'une composition pharmaceutique contenant le dérivé en médecine. Spécifiquement, l'invention concerne un dérivé d'amide aromatique représenté par la formule générale (I), son procédé de préparation et un sel pharmaceutiquement acceptable de celui-ci, et une utilisation du dérivé et du sel en tant qu'agents thérapeutiques, en particulier des inhibiteurs de KIF18A ; la définition de chaque substituant dans la formule générale (I) étant la même que celle indiquée dans la description.
PCT/CN2024/093281 2023-05-30 2024-05-15 Dérivé d'amide aromatique, son procédé de préparation et son utilisation Pending WO2024244972A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202310623576 2023-05-30
CN202310623576.2 2023-05-30

Publications (1)

Publication Number Publication Date
WO2024244972A1 true WO2024244972A1 (fr) 2024-12-05

Family

ID=93656625

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2024/093281 Pending WO2024244972A1 (fr) 2023-05-30 2024-05-15 Dérivé d'amide aromatique, son procédé de préparation et son utilisation

Country Status (1)

Country Link
WO (1) WO2024244972A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12391709B2 (en) 2022-08-18 2025-08-19 Accent Therapeutics, Inc. Inhibitors of KIF18A and uses thereof
WO2025232650A1 (fr) * 2024-05-07 2025-11-13 南京同诺康医药科技有限公司 Inhibiteur de kif18a ainsi que son procédé de préparation et son utilisation

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011014888A1 (fr) * 2009-07-31 2011-02-03 Selexagen Therapeutics Inhibiteurs inédits de la voie de signalisation hedgehog
CN106794161A (zh) * 2014-03-26 2017-05-31 默沙东公司 TrkA激酶抑制剂、组合物及其方法
CN114401953A (zh) * 2019-08-02 2022-04-26 美国安进公司 Kif18a抑制剂
US20220289724A1 (en) * 2019-08-02 2022-09-15 Amgen Inc. Kif18a inhibitors
WO2022268230A1 (fr) * 2021-06-25 2022-12-29 杭州英创医药科技有限公司 Composé destiné à être utilisé en tant qu'inhibiteur de kif18a
WO2023088441A1 (fr) * 2021-11-19 2023-05-25 微境生物医药科技(上海)有限公司 Inhibiteur de kif18a

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011014888A1 (fr) * 2009-07-31 2011-02-03 Selexagen Therapeutics Inhibiteurs inédits de la voie de signalisation hedgehog
CN106794161A (zh) * 2014-03-26 2017-05-31 默沙东公司 TrkA激酶抑制剂、组合物及其方法
CN114401953A (zh) * 2019-08-02 2022-04-26 美国安进公司 Kif18a抑制剂
US20220289724A1 (en) * 2019-08-02 2022-09-15 Amgen Inc. Kif18a inhibitors
WO2022268230A1 (fr) * 2021-06-25 2022-12-29 杭州英创医药科技有限公司 Composé destiné à être utilisé en tant qu'inhibiteur de kif18a
WO2023088441A1 (fr) * 2021-11-19 2023-05-25 微境生物医药科技(上海)有限公司 Inhibiteur de kif18a

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12391709B2 (en) 2022-08-18 2025-08-19 Accent Therapeutics, Inc. Inhibitors of KIF18A and uses thereof
WO2025232650A1 (fr) * 2024-05-07 2025-11-13 南京同诺康医药科技有限公司 Inhibiteur de kif18a ainsi que son procédé de préparation et son utilisation

Similar Documents

Publication Publication Date Title
CN112110918B (zh) 螺环取代的嘧啶并环类化合物，其制法与医药上的用途
CN108699055B (zh) 用作抗癌药物的杂环化合物
WO2023274383A1 (fr) Inhibiteur de kras g12d et son utilisation
CN117980298A (zh) 作为kif18a抑制剂的化合物
WO2020064002A1 (fr) Composé d'isoindoline, procédé de préparation, composition pharmaceutique et utilisation associée
WO2019037678A1 (fr) Dérivé de pyrazolo[3,4-d]pyrimidin-3-one, composition pharmaceutique et utilisation associée
CN118005656B (zh) Kras g12c突变蛋白嘧啶并噻喃二酮类抑制剂的制备及其应用
WO2024244972A1 (fr) Dérivé d'amide aromatique, son procédé de préparation et son utilisation
WO2016011979A1 (fr) Dérivé 7h-pyrrolo[2,3-d]pyrimidine 2,4-disubstituté, procédé de préparation et utilisation médicinale de ce dernier
CN106749233A (zh) 一类磺酰胺衍生物及其应用
CN116514846A (zh) 杂环类衍生物、其制备方法及其医药上的用途
WO2024149189A1 (fr) Dérivé d'amide aromatique, son procédé de préparation et son utilisation
WO2024146593A1 (fr) Dérivé d'amide aromatique, son procédé de préparation et son utilisation médicale
WO2022170947A1 (fr) Dérivés de tétrahydronaphtyridine utilisés en tant qu'inhibiteurs de g12c mutants kras, leur procédé de préparation et leur utilisation
WO2022227987A1 (fr) Dérivé hétérocyclique, son procédé de préparation et son utilisation
WO2022206724A1 (fr) Dérivé hétérocyclique, son procédé de préparation et son utilisation
WO2024125488A1 (fr) Dérivé d'amide aromatique, son procédé de préparation et son utilisation pharmaceutique
WO2024078569A1 (fr) Dérivé d'amide aromatique, son procédé de préparation et son utilisation
WO2024188086A1 (fr) Dérivé d'amide aromatique, son procédé de préparation et son utilisation
CN114907385A (zh) 氮杂芳基化合物、其制备方法及应用
WO2025021003A1 (fr) Dérivé d'amide aromatique, son procédé de préparation et son utilisation
WO2024235073A1 (fr) Dérivé d'amide aromatique, son procédé de préparation et son utilisation en médecine
WO2020114519A1 (fr) Composé hétérocyclique à titre d'inhibiteur de la voie double cdk-hdac
WO2024099386A1 (fr) Composé bicyclique fusionné
CN113896669B (zh) 雌激素受体调节剂及其用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24814172

Country of ref document: EP

Kind code of ref document: A1