WO2018233526A9 - Inhibiteur de csf1r, son procédé de préparation et son utilisation - Google Patents

Inhibiteur de csf1r, son procédé de préparation et son utilisation Download PDF

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WO2018233526A9
WO2018233526A9 PCT/CN2018/091044 CN2018091044W WO2018233526A9 WO 2018233526 A9 WO2018233526 A9 WO 2018233526A9 CN 2018091044 W CN2018091044 W CN 2018091044W WO 2018233526 A9 WO2018233526 A9 WO 2018233526A9
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group
alkyl
deuterium
cycloalkyl
membered heterocyclic
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WO2018233526A1 (fr
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张鸣鸣
赵保卫
喻红平
陈椎
徐耀昌
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Abbisko Therapeutics Co Ltd
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Abbisko Therapeutics Co Ltd
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N55/00—Biocides, pest repellants or attractants, or plant growth regulators, containing organic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen and sulfur
    • A01N55/02—Biocides, pest repellants or attractants, or plant growth regulators, containing organic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen and sulfur containing metal atoms
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • 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
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of drug synthesis, and specifically relates to a CSF1R inhibitor and a preparation method and application thereof.
  • CSF1R stands for cell colony stimulating factor receptor.
  • CSF1R, cKIT, FLT3, and PDGFR-a&b belong to the three growth hormone receptor families.
  • the receptor is a membrane protein expressed on the surface of macrophages and monocytes. Its extracellular segment can bind to macrophage colony stimulating factor, and the intracellular segment tyrosine kinase can activate the downstream of macrophages and monocytes.
  • Tumor immune checkpoint inhibitors have become popular in the field of tumor treatment in recent years. This type of drugs can significantly inhibit tumor growth in clinical practice, and even some solid tumors completely disappear after treatment. However, clinical trial results have shown that only about 30% of patients can respond to immune checkpoint inhibitors such as PD-1/PD-L1. Due to the lack of relevant biomarkers, how to select patients who may respond is also an unresolved problem. In addition, immune checkpoint inhibitors can produce immune system-related side effects in clinical practice, requiring experienced clinicians and medical institutions to successfully carry out treatment. Therefore, how to use immune checkpoint inhibitors in combination with small molecule inhibitors to reduce side effects and increase the response rate of tumor patients is an urgent problem in the development of anti-tumor drugs.
  • TAM tumor-associated macrophages
  • MDSC bone marrow-derived suppressor cells
  • Small molecule kinase inhibitors generally have selectivity problems, especially for other members of the same kinase family. Since the small molecule drugs in this patent may be used in combination with other immune checkpoint inhibitors in future clinical trials, the inventors have tried to optimize the molecular structure to improve the inhibitory effect of CSF1R targets and other The selectivity of kinase receptors increases the therapeutic window and reduces the possibility of clinical side effects.
  • the series of compounds of the present invention have a strong inhibitory effect on CSF1R kinase activity, and can be widely used in the preparation of drugs for the treatment of cancer, tumors, autoimmune diseases, metabolic diseases or metastatic diseases, especially for the treatment of ovarian cancer, pancreatic cancer, and prostate cancer.
  • Drugs for cancer, breast cancer, cervical cancer, glioblastoma, multiple myeloma, metabolic diseases, neurodegenerative diseases, metastasis of primary tumor sites, or bone metastasis cancer are expected to be developed into a new generation of CSF1R inhibition Drugs. On this basis, the present invention has been completed.
  • the first aspect of the present invention provides a compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt:
  • X is selected from -N(R 2 )- or -C(R 3 R 4 )-;
  • Z 1 , Z 2 , and Z 3 are each independently selected from C(R 8 ) or N;
  • Z 4 , Z 5 , Z 6 , and Z 7 are each independently selected from C(R 9 ) or N;
  • R 1 is selected from hydrogen, deuterium, hydroxyl, C 1-8 alkyl, C 1-8 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic oxy group, C 5-10 aryl group, C 5-10 aryloxy group, 5-10 membered heteroaryl group, 5- 10-membered heteroaryloxy or -NR 10 R 11 , the above groups are optionally further selected by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-8 alkyl, C 2- 8 -alkenyl, C 2-8 alkynyl, halogen-substituted C 1-8 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl, 5-10 membered hetero Aryl, -C 0-8 -S(
  • R 2 is selected from hydrogen, deuterium, C 1-8 alkyl, C 3-10 cycloalkyl, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 ring Alkyl, 3-10 membered heterocyclic group, C 5-10 aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 13 , -C 0-8 -OR 14 ,- C 0-8 -C(O)OR 14 , -C 0-8 -C(O)OR 14 , -C 0-8 -C(O)R 15 , -C 0-8 -OC(O)R 15 , -C 0-8 -NR 16 R 17 ,- C 0-8 -C(O)NR 16 R 17 or -C 0-8 -N(R 16 )-C(O)R 15 ;
  • R 1 and R 2 and their directly connected groups together form a 3-10 membered heterocyclic group, and the 3-10 membered heterocyclic group is optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro , Azido, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogen substituted C 1-8 alkyl, C 3-10 cycloalkyl, 3-10 membered hetero Cyclic, C 5-10 aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 13 , -C 0-8 -OR 14 , -C 0-8 -C(O )OR 14 , -C 0-8 -C(O)R 15 , -C 0-8 -OC(O)R 15 , -C 0-8 -NR 16 R 17 , -C 0-8 -C(O ) NR 16 R 17 or -
  • R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogen Substituted C 1-8 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 13 , -C 0-8 -OR 14 , -C 0-8 -C(O)OR 14 , -C 0-8 -C(O)R 15 , -C 0-8 -OC(O)R 15 , -C 0-8 -NR 16 R 1 7 , -C 0-8 -C(O)NR 16 R 17 or -C 0-8 -N(R 16 )-C(O)R 15 , or,
  • R 3 and R 4 together with the carbon atom directly connected to it form a C 3-10 cycloalkyl group or a 3-10 membered heterocyclic group.
  • the C 3-10 cycloalkane or 3-10 membered heterocyclic group is optionally further One or more selected from deuterium, halogen, cyano, nitro, azido, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogen substituted C 1-8 alkane Group, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 13 , -C 0-8 -8 -OR 14 , -C 0-8 -C(O)OR 14 , -C 0-8 -C(O)R 15 , -C 0-8 -OC(O)R 15 , -C 0-8 -NR 16
  • R 5 and R 6 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogen Substituted C 1-8 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 13 , -C 0-8 -OR 14 , -C 0-8 -C(O)OR 14 , -C 0-8 -C(O)R 15 , -C 0-8 -OC(O)R 15 , -C 0-8 -NR 16 R 1 7 , -C 0-8 -C(O)NR 16 R 17 or -C 0-8 -N(R 16 )-C(O)R 15 , or,
  • R 5 , R 6 and their directly connected carbon atoms together form a carbonyl group, a C 3-10 cycloalkyl group or a 3-10 membered heterocyclic group, the C 3-10 cycloalkane or a 3-10 membered heterocyclic group optionally Further substituted by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogen substituted C 1- 8 alkyl group, C 3-10 cycloalkyl group, 3-10 membered heterocyclic group, C 5-10 aryl group, 5-10 membered heteroaryl group, -C 0-8 -OR 14 , -C 0-8 -C(O)OR 14 , -C 0-8 -C(O)R 15 , -C 0-8 -OC(O)R 15 , -
  • R 7 is selected from hydrogen, deuterium, C 1-8 alkyl, C 3-10 cycloalkyl, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 ring Alkyl, 3-10 membered heterocyclic group, C 5-10 aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 13 , -C 0-8 -OR 14 ,- C 0-8 -C(O)OR 14 , -C 0-8 -C(O)OR 14 , -C 0-8 -C(O)R 15 , -C 0-8 -OC(O)R 15 , -C 0-8 -NR 16 R 17 ,- C 0-8 -C(O)NR 16 R 17 or -C 0-8 -N(R 16 )-C(O)R 15 ;
  • Each R 10 and R 11 is independently selected from hydrogen, deuterium, C 1-8 alkyl, C 3-10 cycloalkyl, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 13 , -C 0-8 -OR 14 , -C 0-8 -C(O)OR 14 , -C 0-8 -C(O)R 15 , -C 0-8 -OC(O)R 15 , -C 0-8 -NR 16 R 17 , -C 0-8 -C(O)NR 16 R 17 or -C 0-8 -N(R 16 )-C(O)R 15 ;
  • Each R 12 is independently selected from hydrogen, deuterium, C 1-8 alkyl, C 3-10 cycloalkyl, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3- 10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 13 , -C 0-8 -OR 14 , -C 0-8 -C(O)OR 14 , -C 0-8 -C(O)R 15 , -C 0-8 -OC(O)R 15 , -C 0-8 -NR 16 R 17 , -C 0-8 -C(O)NR 16 R 17 or -C 0-8 -N(R 16 )-C(O)R 15 ;
  • Each R 13 is independently selected from hydrogen, deuterium, hydroxyl, C 1-8 alkyl, C 1-8 alkoxy, halogen substituted C 1-8 alkyl, halogen substituted C 1-8 alkoxy, C 2-8 Alkenyl, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic oxy group, C 5-10 aryl, C 5-10 aryl Oxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or -NR 16 R 17 , the above-mentioned groups are optionally further selected from deuterium, halogen, hydroxyl, carbonyl, C 1- 8 alkyl, C 1-8 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic oxy group, C 5-10 Substituted by aryl, C 5-10 aryloxy
  • Each R 14 is independently selected from hydrogen, deuterium, C 1-8 alkyl, C 2-8 alkenyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl or 5- 10-membered heteroaryl group, the above-mentioned groups are optionally further selected by one or more selected from deuterium, halogen, hydroxyl, carbonyl, cyano, C 1-8 alkyl, C 1-8 alkoxy, C 3-10 ring Alkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic oxy group, C 5-10 aryl group, C 5-10 aryloxy group, 5-10 membered heteroaryl Group, 5-10 membered heteroaryloxy group or -NR 16 R 17 substituent;
  • Each R 15 is independently selected from hydrogen, deuterium, hydroxyl, C 1-8 alkyl, C 1-8 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl , C 3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic oxy group, C 5-10 aryl group, C 5-10 aryloxy group, 5-10 membered heteroaryl group, 5-10 membered heteroaryloxy group or -NR 16 R 17 , the above groups are optionally further selected by one or more selected from deuterium, halogen, hydroxy, cyano, C 1-8 alkyl, C 1-8 alkoxy Group, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic oxy group, C 5-10 aryl group, C 5-10 aryloxy group , 5-10 membered heteroaryl, 5-10 membere
  • Each R 16 and each R 17 are independently selected from hydrogen, deuterium, hydroxyl, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, 3-10 Membered heterocyclic group, C 5-10 aryl, 5-10 membered heteroaryl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino, monoalkylamino, Dialkylamino or C 1-8 alkanoyl, the above groups are optionally further selected by one or more selected from deuterium, halogen, hydroxyl, C 1-8 alkyl, C 1-8 alkoxy, C 3-10 Cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclic oxy, C 5-10 aryl, C 5-10
  • R 16 , R 17 and their directly connected nitrogen atoms together form a 5-10 membered heterocyclic group.
  • the above-mentioned groups are optionally further selected from deuterium, halogen, hydroxyl, C 1-8 alkyl, C 1-8 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic group, 3-10 membered heterocyclic oxy, C 5-10 aryl, C Substituted by substituents of 5-10 aryloxy, 5-10 heteroaryl, 5-10 heteroaryloxy, amino, monoalkylamino, dialkylamino or C 1-8 alkanoyl;
  • Each r is independently 0, 1, or 2.
  • Y in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof is selected from -C(R 5 R 6 )-;
  • R 5 and R 6 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, -C 0- 4 -S (O) r R 13 , -C 0-4 -OR 14 , -C 0-4 -C(O)OR 14 , -C 0-4 -C(O)R 15 , -C 0-4 -OC(O)R 15 , -C 0-4 -NR 16 R 17 , -C 0-4 -C(O)NR 16 R 17 or -C 0-4 -N(R 16 )-C(O)R 15 , or,
  • R 5 , R 6 and their directly connected carbon atoms together form a carbonyl group, a C 3-8 cycloalkyl group or a 3-8 membered heterocyclic group, and the C 3-10 cycloalkane or 3-10 membered heterocyclic group is optional Further substituted by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1- 4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 13 ,- C 0-4 -OR 14 , -C 0-4 -C(O)OR 14 , -C 0-4 -C(O)R 15 , -C 0-4 -OC(O)R 15 , -C 0
  • Y in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof is selected from -C(R 5 R 6 )-;
  • R 5 and R 6 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, allyl, trifluoromethyl, cyclopropyl, cyclobutyl, 3- Oxetanyl, methoxy, trifluoromethoxy, methoxymethyl, methoxycarbonyl, acetoxy, amino, dimethylamino or acetamido, or R 5 and R 6 and their directly connected
  • the carbon atoms together form a carbonyl group, a cyclopropyl group or a cyclobutyl group, and the cyclopropyl group or the cyclobutyl group is optionally further selected from deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, Allyl, trifluoromethyl, cyclopropyl, cyclobutyl, 3-oxetanyl, methoxy, trifluoromethoxy, me
  • each R 8 in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl Group, isopropyl, allyl, ethynyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, isopropoxy, methoxymethyl, trifluoromethyl, trifluoromethoxy , Tri-deuterium methyl or amino.
  • the compound of formula (I) has the following compound structure of formula (II):
  • X is selected from -N(R 2 )- or -C(R 3 R 4 )-; Y is selected from -C(R 5 R 6 )-;
  • R 1 is selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclic group, 3-8 membered heterocyclic oxy group, C 5-8 aryl group, C 5-8 aryloxy group, 5-8 membered heteroaryl group, 5- 8-membered heteroaryloxy or -NR 10 R 11 , the above-mentioned groups are optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2- 4 -alkenyl, C 2-4 alkynyl, halogen-substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 5-8 aryl, 5-8 membered hetero Aryl, -C
  • R 2 is selected from hydrogen, deuterium, C 1-4 alkyl, C 3-8 cycloalkyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 ring Alkyl, 3-8 membered heterocyclic group, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 13 , -C 0-4 -OR 14 ,- C 0-4 -C(O)OR 14 , -C 0-4 -C(O)OR 14 , -C 0-4 -C(O)R 15 , -C 0-4 -OC(O)R 15 , -C 0-4 -NR 16 R 17 ,- C 0-4 -C(O)NR 16 R 17 or -C 0-4 -N(R 16 )-C(O)R 15 ;
  • R 1 and R 2 and their directly connected groups together form a 3-8 membered heterocyclic group, and the 3-8 membered heterocyclic group is optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro , Azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered hetero Cyclic group, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 13 , -C 0-4 -OR 14 , -C 0-4 -C(O )OR 14 , -C 0-4 -C(O)R 15 , -C 0-4 -OC(O)R 15 , -C 0-4 -NR 16 R 17 , -C 0-4 -C(O ) NR 16 R 17 or
  • R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 5-8 aryl, 5-8 membered heteroaryl, -C 0- 4 -S (O) r R 13 , -C 0-4 -OR 14 , -C 0-4 -C(O)OR 14 , -C 0-4 -C(O)R 15 , -C 0-4 -OC(O)R 15 , -C 0-4 -NR 16 R 17 , -C 0-4 -C(O)NR 16 R 17 or -C 0-4 -N(R 16 )-C(O)R 15 , or, R 3 Together with R 4 and its directly connected carbon atom to form a
  • R 5 and R 6 are each independently selected from hydrogen, deuterium, fluorine, methyl, methoxy, trifluoromethoxy or methoxymethyl, or, R 5 and R 6 together with the directly connected carbon atom form Carbonyl, cyclopropyl or cyclobutyl;
  • R 8 is selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl or methoxy;
  • Z 4 , Z 6 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 17 , and r are as defined for the compound of formula (I).
  • X in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof is selected from -N(R 2 )- or -C(R 3 R 4 )-; Y is selected from -C(R 5 R 6 )-; Z 4 is selected from CH or N; Z 6 is selected from C(R 9 ) or N;
  • R 1 is selected from a C 1-4 alkyl group, a C 3-8 cycloalkyl group, a 3-8 membered heterocyclic group, a C 5-8 aryl group or a 5-8 membered heteroaryl group. Or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl , C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 13 , -C 0- 4 -OR 14 , -C 0-4 -C(O)OR 14 , -C 0-4 -C(O)R 15 , -C 0-4 -OC(O)R 15 , -C 0-4- NR 16 R 17 , -C
  • R 2 is selected from hydrogen, deuterium, C 1-4 alkyl, C 3-8 cycloalkyl, C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic group, C 5-8 aromatic Group or 5-8 membered heteroaryl group;
  • R 1 and R 2 and their directly connected groups together form a 3-6 membered heterocyclic group, and the 3-6 membered heterocyclic group is optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro , Azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered hetero Cyclic group, C 5-8 aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 13 , -C 0-4 -OR 14 , -C 0-4 -C(O )OR 14 , -C 0-4 -C(O)R 15 , -C 0-4 -OC(O)R 15 , -C 0-4 -NR 16 R 17 , -C 0-4 -C(O ) NR 16 R 17 or
  • R 3 and R 4 are each independently selected from hydrogen, deuterium, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 5-6 aryl or 5-6 membered heteroaryl Group, or, R 3 and R 4 together with the carbon atom to which they are directly connected form a C 3-6 cycloalkyl group or a 3-6 membered heterocyclic group;
  • R 5 and R 6 are each independently selected from hydrogen, deuterium, fluorine, methyl, methoxy, trifluoromethoxy or methoxymethyl, or, R 5 and R 6 together with the directly connected carbon atom form Carbonyl, cyclopropyl or cyclobutyl;
  • R 8 is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl or methoxy;
  • X in the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof is selected from -N(R 2 )- or -C(R 3 R 4 )-; Y is selected from -C(R 5 R 6 )-; Z 4 is selected from CH or N; Z 6 is selected from C(R 9 ) or N;
  • R 1 is selected from a C 1-4 alkyl group, a C 3-8 cycloalkyl group, a 3-8 membered heterocyclic group, a C 5-8 aryl group or a 5-8 membered heteroaryl group. Or more selected from deuterium, fluorine, chlorine, cyano, nitro, azido, hydroxyl, methyl, ethyl, isopropyl, allyl, trifluoromethyl, cyclopropyl, cyclobutyl, Substitution of 3-oxetanyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, methoxymethyl, methoxycarbonyl, acetoxy, amino, dimethylamino or acetamino Substituted by
  • R 2 is selected from hydrogen, deuterium, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group or cyclopropylmethyl;
  • R 1 and R 2 and their directly connected groups together form a 4-6 membered heterocyclic group, and the 4-6 membered heterocyclic group is optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro , Azido, C 1-4 alkyl, vinyl, allyl, ethynyl, trifluoromethyl, cyclopropyl or methoxy substituents;
  • R 3 and R 4 are each independently selected from hydrogen, deuterium or C 1-4 alkyl, or, R 3 and R 4 together with the carbon atom directly connected to it form a cyclopropyl or cyclobutyl;
  • R 5 and R 6 are each independently selected from hydrogen, deuterium, fluorine or methyl, or, R 5 and R 6 and the carbon atom to which they are directly connected together form a carbonyl, cyclopropyl or cyclobutyl;
  • R 8 is independently selected from hydrogen, deuterium, methyl or ethyl
  • the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof include but are not limited to the following compounds:
  • the second aspect of the present invention provides a method for preparing the aforementioned compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, comprising the following steps: a compound of formula (Ia) or its acid salt and formula (Ib) The compound reacts to produce a compound of formula (I), the reaction formula is as follows:
  • R is selected from isocyanate group or acid chloride group
  • R is selected from carboxyl group or alkyl carboxylate base
  • R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and r are as defined for the compound of formula (I).
  • the third aspect of the present invention provides a pharmaceutical composition, which comprises the aforementioned compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.
  • the fourth aspect of the present invention provides a compound of the aforementioned formula (I), its stereoisomer or its pharmaceutically acceptable salt, or the aforementioned pharmaceutical composition for preparing and treating cancer, tumor, autoimmune disease, metabolic disease or metastasis Application in drugs for sexual diseases.
  • the fifth aspect of the present invention provides a compound of the aforementioned formula (I), its stereoisomer or its pharmaceutically acceptable salt, or the aforementioned pharmaceutical composition for preparing and treating ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, Kidney cancer, liver cancer, cervical cancer, bone metastatic cancer, papillary thyroid cancer, non-small cell lung cancer, colon cancer, gastrointestinal stromal tumors, solid tumors, melanoma, mesothelioma, glioblastoma, bone Tumor, multiple myeloma, hyperproliferative disease, metabolic disease, neurodegenerative disease, metastasis of primary tumor site, myeloproliferative disease, leukemia, rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, Multiple sclerosis, autoimmune nephritis, lupus, Crohn's disease, asthma, chronic obstructive pulmonary disease, osteoporosis, hypereosinophilic
  • a compound of the aforementioned formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical composition for preparing and treating ovarian cancer, pancreatic cancer, prostate cancer, breast cancer, and cervical cancer.
  • the sixth aspect of the present invention provides a compound of the aforementioned formula (I), its stereoisomer or its pharmaceutically acceptable salt, or the aforementioned pharmaceutical composition, which is used for the treatment of cancer, tumor, autoimmune disease, and metabolic disease Or drugs for metastatic disease.
  • the seventh aspect of the present invention provides a compound of the aforementioned formula (I), its stereoisomer or its pharmaceutically acceptable salt, or the aforementioned pharmaceutical composition, which is used for the treatment of ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, and breast cancer.
  • the eighth aspect of the present invention provides a method for treating cancer, tumor, autoimmune disease, metabolic disease or metastatic disease, which comprises administering the aforementioned compound of formula (I), its stereoisomer or its pharmaceutically acceptable Salt, or the aforementioned pharmaceutical composition.
  • the ninth aspect of the present invention provides a treatment for ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, breast cancer, kidney cancer, liver cancer, cervical cancer, bone metastatic cancer, papillary thyroid cancer, non-small cell lung cancer, colon cancer, and stomach cancer.
  • Intestinal stromal tumors solid tumors, melanoma, mesothelioma, glioblastoma, osteosarcoma, multiple myeloma, hyperproliferative diseases, metabolic diseases, neurodegenerative diseases, primary tumor sites Metastasis, myeloproliferative disease, leukemia, rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, multiple sclerosis, autoimmune nephritis, lupus, Crohn's disease, asthma, chronic obstructive pulmonary disease, osteoporosis
  • a method for dysfunction, hypereosinophilic syndrome, mastocytosis or mast cell leukemia comprising administering to a patient the aforementioned compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, or the aforementioned pharmaceutical composition .
  • Alkyl refers to a linear or branched saturated aliphatic hydrocarbon group, for example, "C 1-8 alkyl” refers to a straight chain alkyl group including 1 to 8 carbon atoms and a branched chain alkyl group, including but 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 Group, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl Butyl, 2-ethylbuty
  • Alkyl group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more groups independently selected from deuterium, halogen, cyano, nitro, azido group, C 1 -8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogen substituted C 1-8 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 13 , -C 0-8 -OR 14 , -C 0-8 -C(O)OR 14 , -C 0 -8 -C(O)R 15 , -C 0-8 -OC(O)R 15 , -C 0-8 -NR 16 R 17 , -C 0-8 -C(O)NR 16 R 17 or- C 0-8 -N(R 16 )-C(O)
  • Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • C 3-10 cycloalkyl refers to a cycloalkyl group containing 3 to 10 carbon atoms, divided into monocyclic Cycloalkyl, polycyclic cycloalkyl, of which:
  • Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, Cyclooctyl and others.
  • Polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls.
  • “Spirocycloalkyl” refers to polycyclic groups that share one carbon atom (called spiro atom) between single rings. These can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system. According to the number of shared spiro atoms between rings, spirocycloalkyls are classified into single spirocycloalkyls, dispirocycloalkyls or polyspirocycloalkyls. Spirocycloalkyls include but are not limited to:
  • “Fused cycloalkyl” refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system. One or more of the rings may contain one or more double bonds, but No ring has a completely conjugated ⁇ -electron system. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl. Condensed cycloalkyl includes but is not limited to:
  • Bridged cycloalkyl refers to all-carbon polycyclic groups in which any two rings share two carbon atoms that are not directly connected. These can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system . According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls. Bridged cycloalkyls include but are not limited to:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, including but not limited to indanyl and tetrahydronaphthyl , Benzocycloheptanyl, etc.
  • Cycloalkyl groups may be optionally substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogen-substituted C 1-8 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5- 10 aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 13 , -C 0-8 -OR 14 , -C 0-8 -C(O)OR 14 , -C 0-8 -C(O)R 15 , -C 0-8 -OC(O)R 15 , -C 0-8 -NR 16 R 17 , -C 0-8 -C(O)NR 16 R 17 or -C 0-8 -N
  • Heterocyclic group refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which one or more ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer of 0, 1, 2 ), but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • r is an integer of 0, 1, 2
  • “5-10 membered heterocyclic group” refers to a cyclic group containing 5 to 10 ring atoms
  • 3-10 membered heterocyclic group refers to a cyclic group containing 3 to 10 ring atoms.
  • Monocyclic heterocyclic groups include but are not limited to pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • “Spiroheterocyclic group” refers to a polycyclic heterocyclic group sharing one atom (called a spiro atom) between single rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer 0, 1, 2) heteroatoms, the rest of the ring atoms are carbon. These can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system.
  • the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group.
  • Spiro heterocyclic groups include but are not limited to:
  • “Fused heterocyclic group” refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system.
  • One or more rings may contain one or more double bonds, but none of them
  • the ring has a fully conjugated ⁇ -electron system, where one or more ring atoms are selected from nitrogen, oxygen, or S(O) r (where r is an integer of 0, 1, 2) heteroatoms, and the remaining ring atoms are carbon.
  • the fused heterocyclic groups include but are not limited to:
  • Bridged heterocyclic group refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. These can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system, One or more of the ring atoms are selected from nitrogen, oxygen or S(O) r (wherein r is an integer of 0, 1, 2) heteroatoms, and the remaining ring atoms are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups. Bridged heterocyclic groups include but are not limited to:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclyl, including but not limited to:
  • the heterocyclic group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogen-substituted C 1-8 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5- 10 aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 13 , -C 0-8 -OR 14 , -C 0-8 -C(O)OR 14 , -C 0-8 -C(O)R 15 , -C 0-8 -OC(O)R 15 , -C 0-8 -NR 16 R 17 , -C 0-8 -C(O)NR 16 R 17 or -C 0-8 -N(R
  • Aryl refers to an all-carbon monocyclic or fused polycyclic (that is, a ring that shares adjacent pairs of carbon atoms), a polycyclic ring with a conjugated ⁇ -electron system (that is, a ring with adjacent pairs of carbon atoms). ) Group, for example, “C 5-10 aryl” refers to an all-carbon aryl group containing 5-10 carbons, and “5-10 membered aryl” refers to an all-carbon aryl group containing 5-10 carbons, including but It is not limited to phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, including but not limited to:
  • Aryl groups may be substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogen-substituted C 1-8 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl , 5-10 membered heteroaryl, -C 0-8 -S(O) r R 13 , -C 0-8 -OR 14 , -C 0-8 -C(O)OR 14 , -C 0-8 -C(O)R 15 , -C 0-8 -OC(O)R 15 , -C 0-8 -NR 16 R 17 , -C 0-8 -C(O)NR 16 R 17 or -C 0 -8 -N(R 16
  • Heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms including nitrogen, oxygen and S(O)r (where r is an integer of 0, 1, 2) heteroatoms, for example, 5-8 membered heteroaryl refers to a heteroaromatic system containing 5-8 ring atoms, 5-10 membered heteroaryl refers to a heteroaromatic system containing 5-10 ring atoms, including but not limited to furyl, thiophene Group, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, including but not limited to:
  • Heteroaryl groups may be optionally substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogen-substituted C 1-8 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5- 10 aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 13 , -C 0-8 -OR 14 , -C 0-8 -C(O)OR 14 , -C 0-8 -C(O)R 15 , -C 0-8 -OC(O)R 15 , -C 0-8 -NR 16 R 17 , -C 0-8 -C(O)NR 16 R 17 or -C 0-8 -N
  • Alkenyl refers to an alkyl group as defined above composed of at least two carbon atoms and at least one carbon-carbon double bond.
  • C 2-8 alkenyl refers to a straight chain or branched chain containing 2-8 carbons. Alkenyl. Including but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl and the like.
  • the alkenyl group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogen-substituted C 1-8 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl , 5-10 membered heteroaryl, -C 0-8 -S(O) r R 13 , -C 0-8 -OR 14 , -C 0-8 -C(O)OR 14 , -C 0-8 -C(O)R 15 , -C 0-8 -OC(O)R 15 , -C 0-8 -NR 16 R 17 , -C 0-8 -C(O)NR 16 R 17 or -C 0 -8 -N(
  • Alkynyl refers to an alkyl group as defined above composed of at least two carbon atoms and at least one carbon-carbon triple bond.
  • C 2-8 alkynyl refers to a straight or branched chain containing 2-8 carbons Alkynyl. Including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl and the like.
  • the alkynyl group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogen-substituted C 1-8 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl , 5-10 membered heteroaryl, -C 0-8 -S(O) r R 13 , -C 0-8 -OR 14 , -C 0-8 -C(O)OR 14 , -C 0-8 -C(O)R 15 , -C 0-8 -OC(O)R 15 , -C 0-8 -NR 16 R 17 , -C 0-8 -C(O)NR 16 R 17 or -C 0 -8 -N
  • Alkoxy refers to -O-(alkyl), where the definition of alkyl is as described above, for example, "C 1-8 alkoxy” refers to an alkyloxy group containing 1-8 carbons, including but not Limited to methoxy, ethoxy, propoxy, butoxy, etc.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogen substituted C 1-8 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5 -10 aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 13 , -C 0-8 -OR 14 , -C 0-8 -C(O)OR 14 ,- C 0-8 -C(O)R 15 , -C 0-8 -OC(O)R 15 , -C 0-8 -NR 16 R 17 , -C 0-8 -C(O)NR 16 R 17 Or -C 0-8 -N(R 16 )-
  • Cycloalkoxy refers to and -O- (unsubstituted cycloalkyl), where the definition of cycloalkyl is as described above, for example, “C 3-10 cycloalkoxy” refers to those containing 3-10 carbons Cycloalkyloxy includes but is not limited to cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
  • the cycloalkoxy group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogen substituted C 1-8 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5 -10 aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 13 , -C 0-8 -OR 14 , -C 0-8 -C(O)OR 14 ,- C 0-8 -C(O)R 15 , -C 0-8 -OC(O)R 15 , -C 0-8 -NR 16 R 17 , -C 0-8 -C(O)NR 16 R 17 Or -C 0-8 -N(R 16
  • 3-10 membered heterocyclic oxy group refers to and -O- (unsubstituted 3-10 membered heterocyclic group), wherein the definition of 3-10 membered heterocyclic group is as described above, 3-10 membered heterocyclic oxy group Can be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogen-substituted C 1-8 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl , 5-10 membered heteroaryl, -C 0-8 -S(O) r R 13 , -C 0-8 -OR 14 , -C 0-8 -C(O)OR 14 , -C 0-8 -C(O)R 15 , -C 0-8 -OC(O)R 15 , -C 0-8 -NR 16 R 17 , -C 0-8 -C(O)NR 16 R 17 or -C 0 -8 -N(R 16 )-C(O)R 15 substituents.
  • groups independently selected from
  • C 5-10 aryloxy refers to and -O- (unsubstituted C 5-10 aryl), wherein the definition of C 5-10 aryl is as described above, and C 5-10 aryloxy may optionally be Substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogen substituted C 1-8 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl, 5-10 Yuan heteroaryl, -C 0-8 -S(O) r R 13 , -C 0-8 -OR 14 , -C 0-8 -C(O)OR 14 , -C 0-8 -C(O)OR 14 , -C 0-8 -C(O )R 15 , -C 0-8 -OC(O)R 15 , -C 0-8 -NR 16 R 17 , -C 0-8 -C(O)NR 16 R 17 or -C 0-8 -N (R 16 )-C(O)R
  • 5-10 membered heteroaryloxy group refers to and -O- (unsubstituted 5-10 membered heteroaryl group), wherein 5-10 membered heteroaryl group is defined as above, 5-10 membered heteroaryloxy group Can be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, independently selected from deuterium, halogen, cyano, nitro, azido, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogen-substituted C 1-8 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 5-10 aryl , 5-10 membered heteroaryl, -C 0-8 -S(O) r R 13 , -C 0-8 -OR 14 , -C 0-8 -C(O)OR 14 , -C 0-8 -C(O)R 15 , -C 0-8 -OC(O)R 15 , -C 0-8 -NR 16 R 17 , -C 0-8 -C(O)NR 16 R 17 or -C 0 -8 -N(R 16 )-C(O)R 15 substituents.
  • groups independently selected from
  • C 1-8 Alkanoyl refers to the monovalent atomic group remaining after removing the hydroxyl group of C 1-8 alkyl acid, and is usually expressed as "C 0-7 -C(O)-", for example, “C 1 -C (O)-” means acetyl; “C 2 -C(O)-” means propionyl; “C 3 -C(O)-” means butyryl or isobutyryl.
  • C 3-10 cycloalkyl C 1-8 alkyl refers to C 3-10 cycloalkyl substituted C 1-8 alkyl, wherein C 3-8 cycloalkyl and C 1-8 alkyl are as defined above Said.
  • Halogen substituted C 1-8 alkyl refers to a 1-8 carbon alkyl group optionally substituted by fluorine, chlorine, bromine, or iodine on the hydrogen on the alkyl group, including but not limited to difluoromethyl, difluoromethyl, Chloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, etc.
  • Halogen-substituted C 1-8 alkoxy The hydrogen on the alkyl group is optionally substituted by fluorine, chlorine, bromine, or iodine atoms with 1-8 carbon alkoxy groups. Including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, etc.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • NaH means sodium hydride.
  • MeOH means methanol.
  • DCM means dichloromethane.
  • DMF means N,N-dimethylformamide.
  • DEAD means diethyl azodicarboxylate.
  • X-phos means 2-bicyclohexylphosphine-2',4',6'-triisopropylbiphenyl.
  • Dess-Martin oxidant refers to (1,1,1-triacetoxy)-1,1-dihydro-1,2-phenyliodoyl-3(1H)-one.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may but need not be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group .
  • Substituted means that one or more of the hydrogen atoms in the group are independently replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an olefin).
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, and other components such as physiological/pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredients and thus the biological activity.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid mass spectrometry (LC-MS).
  • NMR chemical shift ( ⁇ ) is given in units of parts per million (ppm).
  • the NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), and the internal standard was four Methylsilane (TMS).
  • the liquid mass spectrometry LC-MS is measured with Agilent 6120 mass spectrometer.
  • HPLC determination uses Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150 ⁇ 4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 ⁇ 4.6mm chromatographic column).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specification used for TLC is 0.15mm ⁇ 0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized by using or following methods known in the art.
  • Step 2 Preparation of tert-butyl (5-formyl-6-methylpyridin-2-yl) carbamate
  • reaction solution was diluted with ethyl acetate, washed with water and saturated sodium chloride solution once, dried with anhydrous sodium sulfate, evaporated under reduced pressure to remove the solvent, and the crude product was separated by silica gel column chromatography to obtain (4-methylpiperazin-1-yl) (1H-pyrrolo[2,3-b]pyridin-5-yl)methanone (147 mg, yield 60%). MS m/z (ESI): 245 [M+H] + .
  • the first step tert-butyl (5-(hydroxy(1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)pyridin-2-yl)carbamate and tert-butyl( Preparation of 5-(Methoxy(1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)pyridin-2-yl)carbamate
  • Step 1 Preparation of tert-butyl 3-formyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate
  • Step 2 Preparation of tert-butyl 3-(hydroxymethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate
  • the third step preparation of tert-butyl 3-(bromomethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate
  • the fifth step 5-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-6-methylpyridin-2-amine (26) and tert-butyl 3-(( Preparation of 6-amino-2-methylpyridin-3-yl)methyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (27)
  • Step 1 Preparation of 6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine
  • the 5-bromo-6-picoline-2-amine (1.0g, 5.37mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2' -Bis (1,3,2-dioxaborolane) (2.0g, 8.06mmol), potassium acetate (1.6g, 16.11mmol) and 1,1'-bisdiphenylphosphine ferrocene palladium dichloride (438mg, 0.537mmol) was dissolved in 1,4-dioxane (10mL), protected by nitrogen, and reacted at 110°C for 16 hours.
  • the third step Preparation of 5-((tetrahydrofuran-2-yl)oxo)-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde
  • Step 4 Preparation of tert-butyl 3-formyl-5-((tetrahydrofuran-3-yl)oxo)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate
  • Step 5 Preparation of tert-butyl 3-(hydroxymethyl)-5-((tetrahydrofuran-3-yl)oxo)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate
  • Step 6 Preparation of tert-butyl 3-(bromomethyl)-5-((tetrahydrofuran-3-yl)oxo)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate
  • the seventh step tert-butyl 3-((6-amino-2-methylpyridin-3-yl)methyl)-5-((tetrahydrofuran-3-yl)oxo)-1H-pyrrolo[2 ,3-b) Preparation of pyridine-1-carboxylate
  • Step 2 Preparation of tert-butyl (5-(hydroxy(1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)pyridin-2-yl)carbamate
  • Trimethylacetamide (101 mg, 1 mmol) was dissolved in 1,2-dichloroethane (5 mL), and oxalyl chloride (121 mg, 0.95 mmol) was slowly added dropwise. The mixed solution was stirred at room temperature for 1 hour, and then heated to 75° C. to continue stirring for 1 hour. After the reaction liquid is cooled, no post-treatment is required and it is directly used in the next reaction.
  • Examples 2-16 were prepared by referring to the synthesis method of Example 1:
  • the first step tert-butyl 3-((6-(3,3-dimethyl-2-carbonylpyrrolidine-1-carboamido)-2-methylpyridin-3-yl)methan
  • Triphosgene (94mg, 0.316mmol) was dissolved in dichloromethane (2mL), and 3,3-dimethylpyrrolidin-2-one (53mg, 0.472mmol) and pyridine (112mg, 1.4mmol) were added under ice bath.
  • Examples 20-24 were prepared by referring to the synthesis method of Example 19:
  • nuclear magnetic data obtained from the preparation of the compounds 20-24 in the above examples are listed as follows:
  • the present invention uses the CSF1R ADP-Glo assay to determine the characteristics of the compound's inhibitory activity on CSF1R.
  • the compound-mediated inhibitory effect was achieved by inhibiting the production of ADP (generated by consuming ATP), using the ADP-Glo kit (Promega, cat. No. V9101) to evaluate the activity of the compound.
  • the specific experiment process is as follows:
  • the kinase reaction carried out in the present invention is carried out in a 384-well plate (Perkinelmer, cat. No. 6007290), with 3.95 nM CSF1R, 500 ⁇ M ATP and 0.2 mg/ml polypeptide (Poly (Glu4, Try1) , Sigma, cat. No. P0275);
  • 1.1 1x kinase buffer 50mM HEPES, pH 7.5, 0.0015% Brij-35.
  • the final detection concentration of the compound is 40 ⁇ M, and it is configured to a 50-fold concentration, that is, 2 mM.
  • the present invention uses (Cell Titer Glo (CTG) test) to evaluate the functional effects of compounds on cell proliferation.
  • CCG Cell Titer Glo
  • M-NFS-60 mouse myeloid leukemia lymphocytes catalog number CCBJ078
  • RPMI1640 Gibco, cat. No. 11875-119
  • 10% fetal bovine serum Gibco, 10099
  • human 10ng/ml M-CSF macrophage colony stimulating factor R&D, cat. No. MVN0915101
  • ATP is an indicator of living cell metabolism
  • CTG Promega, #G7573
  • reagent is a homogeneous detection method to detect the number of living cells in culture by quantitatively measuring ATP. Therefore, the compound-mediated inhibition of cell proliferation/survival is evaluated by quantifying the ATP content in the cell.
  • the specific experimental process is as follows:
  • the present invention uses the Cell Titer Glo (CTG) experiment to evaluate the functional effects of the compounds on the proliferation of several cells, thereby observing the proliferation effects of the compounds on different cells to determine the strength of its selectivity.
  • CCG Cell Titer Glo
  • the experiment used M07e human giant cell leukemia cells (catalog number CBP60791) from Nanjing Kebai Biotechnology Co., Ltd., in RPMI1640 (Gibco, cat. No. 11875-119), 20% fetal bovine serum (Gibco, 10099-141).
  • GM-CSF granulocyte macrophage colony stimulating factor (R&D, cat.No.215-GM-010) and cultured in an incubator at 37°C and 5% CO 2 ; kasumi- 1 Human acute myeloid leukemia cells (Cat. No. CBP60524), under the conditions of RPMI1640 (Gibco, cat. No. 11875-119), 20% fetal bovine serum (Gibco, 10099-141) and 37°C and 5% CO 2 Culture in an incubator; NCI-H1703 human non-small cell lung cancer squamous cell carcinoma cells (catalog number CBP60115), in RPMI1640 (Gibco, cat. No.
  • NCI-H1703 human non-small cell lung cancer squamous cell Two), NCI-H1703 human non-small cell lung cancer squamous cell:
  • MV-4-11 human acute monocytic leukemia cells Three), MV-4-11 human acute monocytic leukemia cells:
  • the series of compounds of the present invention have a strong inhibitory effect on CSF1R kinase activity. From the cell activity data of the compounds in the specific examples, the series of compounds of the present invention have a strong inhibitory effect on the proliferation activity of M-NFS-60 mouse myeloid leukemia lymphocytes with high expression of CSF1R. In addition, from the above experimental results, the series of compounds of the present invention have strong selectivity for KIT, FLT3, and PDGFRA, and are expected to be developed into a new generation of highly selective CSF1R inhibitors to meet the needs of clinical applications.

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Abstract

L'invention concerne un inhibiteur de CSF1R de formule I et plus particulièrment ses composés, son stéréo-isomère et son sel pharmaceutiquement acceptable de formule I. L'inhibiteur permet de traiter le cancer, les maladies auto-immunes, les maladies métaboliques ou les métastases.
PCT/CN2018/091044 2017-06-19 2018-06-13 Inhibiteur de csf1r, son procédé de préparation et son utilisation Ceased WO2018233526A1 (fr)

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