WO2018233526A1 - 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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WO2018233526A1
WO2018233526A1 PCT/CN2018/091044 CN2018091044W WO2018233526A1 WO 2018233526 A1 WO2018233526 A1 WO 2018233526A1 CN 2018091044 W CN2018091044 W CN 2018091044W WO 2018233526 A1 WO2018233526 A1 WO 2018233526A1
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group
alkyl
cycloalkyl
membered
aryl
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PCT/CN2018/091044
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WO2018233526A9 (fr
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张鸣鸣
赵保卫
喻红平
陈椎
徐耀昌
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上海和誉生物医药科技有限公司
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Publication of WO2018233526A1 publication Critical patent/WO2018233526A1/fr
Publication of WO2018233526A9 publication Critical patent/WO2018233526A9/fr

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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 in particular relates to a CSF1R inhibitor and a preparation method and application thereof.
  • CSF1R The full name of CSF1R (cFMS) is a cell colony stimulating factor receptor.
  • CSF1R shares the same three types of growth hormone receptor family as cKIT, FLT3, and PDGFR-a&b.
  • the receptor is a membrane protein expressed on the surface of macrophages and monocytes, and its extracellular domain is capable of binding to macrophage colony-stimulating factor, and intracellular tyrosine kinase activates macrophages and downstream of monocytes.
  • Cell growth and reproduction signaling pathways including MAPK, PI3K and the like. Therefore, the CSF1R signaling pathway has an important influence on the development and differentiation of macrophages, monocytes, and the physiological functions of Tumor-Associated Macrophage (TAM).
  • TAM Tumor-Associated Macrophage
  • Tumor immunological checkpoint inhibitors are popular in the field of cancer treatment in recent years. These drugs can significantly inhibit tumor growth in clinical practice, and even some solid tumors completely disappear after treatment. However, clinical trials have shown that only about 30% of patients are able to respond to immunological checkpoint inhibitors such as PD-1/PD-L1. Due to the lack of relevant biomarkers, how to select a population of patients who may respond is also an unresolved issue. In addition, immunological checkpoint inhibitors produce immune system-related side effects in clinical practice, requiring experienced clinicians and medical institutions to successfully carry out treatment. Therefore, how to use immunological checkpoint inhibitors in combination with small molecule inhibitors to reduce toxic and side effects and improve the response rate of cancer patients is an urgent problem to be solved in the development of anti-tumor drugs.
  • TAM tumor-associated macrophages
  • MDSC bone marrow-derived suppressor cells
  • Small molecule kinase inhibitors are ubiquitous in selectivity issues, especially for other members of the same kinase family. Since the small molecule drugs in this patent may be used in combination with other immunological checkpoint inhibitors in future clinical trials, the inventors tried to improve the molecular structure to enhance the inhibition of CSF1R targets and other The selectivity of the kinase receptor increases the therapeutic window and reduces the likelihood of clinical side effects.
  • the inventors of the present application have extensively and intensively studied to develop a CSF1R inhibitor having the structure of the formula (I) and a preparation method and application thereof for the first time.
  • the compound of the invention has strong inhibitory effect on CSF1R kinase activity and can be widely applied to the preparation of drugs for treating cancer, tumor, autoimmune disease, metabolic disease or metastatic disease, especially for treating ovarian cancer, pancreatic cancer and prostate.
  • Drugs for cancer, breast cancer, cervical cancer, glioblastoma, multiple myeloma, metabolic diseases, neurodegenerative diseases, metastatic tumor sites or bone metastatic cancer are expected to be developed into a new generation of CSF1R inhibition. Drugs. On the basis of this, the present invention has been completed.
  • a first aspect of the invention provides a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • X is selected from -N(R 2 )- or -C(R 3 R 4 )-;
  • Z 1 , Z 2 , Z 3 are each independently selected from C(R 8 ) or N;
  • Z 4 , Z 5 , Z 6 , Z 7 are each independently selected from C(R 9 ) or N;
  • R 1 is selected from the group consisting of hydrogen, deuterium, hydroxy, 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, 3-10 membered heterocyclooxy, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered heteroaryl, 5- a 10-membered heteroaryloxy group or -NR 10 R 11 , the above group optionally further selected from one or more selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-8 alkyl, C 2 ⁇ 8 -alkenyl, C 2-8 alkynyl, halo-substituted C 1-8 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic, C 5-10 aryl, 5-10 membered Aryl, -C 0
  • R 2 is selected from the group consisting of hydrogen, hydrazine, 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, 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 together with a group directly attached thereto form a 3-10 membered heterocyclic group, which is optionally further further selected from one or more selected from the group consisting of hydrazine, halogen, cyano and 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 member Cyclic 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 Substituting a substituent of NR 16
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, hydrazine, halogen, cyano, nitro, azide, 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 heterocyclyl, 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 to which they are directly bonded form a C 3-10 cycloalkyl group or a 3-10 membered heterocyclic group, and the C 3-10 cycloalkane or 3-10 membered heterocyclic ring is optionally further One or more selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halogen substituted C 1-8 alkane , C 3-10 cycloalkyl, 3-10 membered heterocyclic, 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 , -
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, hydrazine, halogen, cyano, nitro, azide, 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 heterocyclyl, 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 the carbon atom to which they are directly bonded together form a carbonyl group, a C 3-10 cycloalkyl group or a 3-10 membered heterocyclic group, optionally a C 3-10 cycloalkane or a 3-10 membered heterocyclic ring.
  • R 7 is selected from the group consisting of hydrogen, hydrazine, 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, 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 10 and R 11 is independently selected from the group consisting of hydrogen, hydrazine, 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, 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 the group consisting of hydrogen, hydrazine, 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, 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 the group consisting of hydrogen, deuterium, hydroxy, C 1-8 alkyl, C 1-8 alkoxy, halo-substituted C 1-8 alkyl, halo-substituted C 1-8 alkoxy, C 2-8 Alkenyl, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic, 3-10 membered heterocyclooxy, C 5-10 aryl, C 5-10 aryl An oxy group, a 5-10 membered heteroaryl group, a 5-10 membered heteroaryloxy group or -NR 16 R 17 , the above group optionally further selected from one or more selected from the group consisting of hydrazine, halogen, hydroxy, carbonyl, C 1- 8- alkyl, C 1-8 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic, 3-10 membered heterocyclooxy,
  • Each R 14 is independently selected from the group consisting of hydrogen, deuterium, C 1-8 alkyl, C 2-8 alkenyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 5-10 aryl or 5- a 10-membered heteroaryl group, the above group optionally further selected from one or more selected from the group consisting of hydrazine, halogen, hydroxy, carbonyl, cyano, C 1-8 alkyl, C 1-8 alkoxy, C 3-10 ring Alkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic, 3-10 membered heterocyclooxy, C 5-10 aryl, C 5-10 aryloxy, 5-10 membered heteroaryl Substituted by a 5- to 10-membered heteroaryloxy group or a substituent of -NR 16 R 17 ;
  • Each R 15 is independently selected from the group consisting of hydrogen, deuterium, hydroxy, C 1-8 alkyl, C 1-8 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl a C 3-10 cycloalkoxy group, a 3-10 membered heterocyclic group, a 3-10 membered heterocyclic oxy group, a C 5-10 aryl group, a C 5-10 aryloxy group, a 5-10 membered heteroaryl group, a 5-10 membered heteroaryloxy group or -NR 16 R 17 , the above group optionally further selected from one or more selected from the group consisting of hydrazine, halogen, hydroxy, cyano, C 1-8 alkyl, C 1-8 alkoxy , C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic, 3-10 membered heterocyclooxy, C 5-10 aryl, C 5-10
  • Each R 16 and each R 17 are independently selected from the group consisting of hydrogen, hydrazine, hydroxy, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, 3-10 a heterocyclic group, a C 5-10 aryl group, a 5-10 membered heteroaryl group, a sulfonyl group, a methylsulfonyl group, an isopropylsulfonyl group, a cyclopropylsulfonyl group, a p-toluenesulfonyl group, an amino group, a monoalkylamino group, a dialkylamino group or a C 1-8 alkanoyl group, the above group optionally further selected from one or more selected from the group consisting of hydrazine, halogen, hydroxy, C 1-8 alkyl, C 1-8 alkoxy, C 3-10 Cycloalkyl, C 3
  • R 16 , R 17 and the directly attached nitrogen atom thereof together form a 5-10 membered heterocyclyl group, said group optionally further comprising one or more selected from the group consisting of hydrazine, halogen, hydroxy, C 1-8 alkyl, C 1-8 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkoxy, 3-10 membered heterocyclic, 3-10 membered heterocyclooxy, C 5-10 aryl, C Substituted with a substituent of 5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C1-8 alkanoyl;
  • Each r is independently 0, 1, or 2.
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo Substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 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 the carbon atom to which they are directly bonded together form a carbonyl group, a C 3-8 cycloalkyl group or a 3-8 membered heterocyclic group, optionally a C 3-10 cycloalkane or a 3-10 membered heterocyclic ring.
  • substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, a halogen substituted C 1- 4- alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 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 is substituted with a substituent.
  • substituents selected from deuterium, halogen, cyan
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, hydrazine, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, allyl, trifluoromethyl, cyclopropyl, cyclobutyl, 3- Oxetanyl, methoxy, trifluoromethoxy, methoxymethyl, methoxycarbonyl, acetoxy, amino, dimethylamino or acetylamino, or R 5 and R 6 directly attached thereto
  • the carbon atoms together form a carbonyl group, a cyclopropyl group or a cyclobutyl group, and the cyclopropyl or cyclobutyl group is optionally further further selected from one or more selected from the group consisting of hydrazine, fluorine, chlorine, methyl, ethyl, isopropyl, Allyl, trifluoromethyl, cyclopropyl, cyclobutyl, 3-
  • each of R 8 in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is independently selected from the group consisting of hydrogen, hydrazine, fluorine, chlorine, cyano, methyl, and B.
  • Base isopropyl, allyl, ethynyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, isopropoxy, methoxymethyl, trifluoromethyl, trifluoromethoxy , triterpene methyl or amino.
  • the compound of formula (I) has the structure of the compound 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 the group consisting of hydrogen, hydrazine, hydroxy, 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, 3-8 membered heterocyclooxy, C 5-8 aryl, C 5-8 aryloxy, 5-8 membered heteroaryl, 5- An 8-membered heteroaryloxy group or -NR 10 R 11 , the above group optionally further selected from one or more selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, 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, C 5-8 aryl, 5-8 membered Aryl, -C
  • R 2 is selected from the group consisting of hydrogen, hydrazine, 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, 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 together with a group directly attached thereto form a 3-8 membered heterocyclic group, which is optionally further further selected from one or more selected from the group consisting of hydrazine, halogen, cyano and 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 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 Substituting a substituent of
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo Substituted C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, 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 the carbon
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, hydrazine, fluorine, methyl, methoxy, trifluoromethoxy or methoxymethyl, or R 5 and R 6 together with the carbon atom to which they are directly attached Carbonyl, cyclopropyl or cyclobutyl;
  • R 8 is selected from the group consisting of hydrogen, hydrazine, 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 , r are as defined for the compound of formula (I).
  • the compound of the formula (I), the stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of -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 C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 5-8 aryl or 5-8 membered heteroaryl, and the above group is optionally further Or a plurality selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, 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, 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 - Substituted by a substitu
  • R 2 is selected from the group consisting of hydrogen, hydrazine, C 1-4 alkyl, C 3-8 cycloalkyl C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 5-8 aromatic Base or 5-8 membered heteroaryl;
  • R 1 and R 2 together with a group directly attached thereto form a 3-6 membered heterocyclic group, which is optionally further further selected from one or more selected from the group consisting of hydrazine, halogen, cyano and 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 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 Substituting a substituent of
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, hydrazine, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic, C 5-6 aryl or 5-6 membered heteroaryl. Or, R 3 and R 4 together with the carbon atom to which they are directly bonded form a C 3-6 cycloalkyl group or a 3-6 membered heterocyclic group;
  • R 5 and R 6 are each independently selected from the group consisting of hydrogen, hydrazine, fluorine, methyl, methoxy, trifluoromethoxy or methoxymethyl, or R 5 and R 6 together with the carbon atom to which they are directly attached Carbonyl, cyclopropyl or cyclobutyl;
  • R 8 is independently selected from the group consisting of hydrogen, hydrazine, fluorine, chlorine, cyano, methyl, ethyl or methoxy;
  • the compound of the formula (I), the stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the group consisting of -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 C 1-4 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 5-8 aryl or 5-8 membered heteroaryl, and the above group is optionally further Or a plurality selected from the group consisting of hydrazine, fluorine, chlorine, cyano, nitro, azide, hydroxy, methyl, ethyl, isopropyl, allyl, trifluoromethyl, cyclopropyl, cyclobutyl, Substitution of 3-oxetanyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, methoxymethyl, methoxycarbonyl, acetoxy, amino, dimethylamino or acetylamino Substituted by
  • R 2 is selected from the group consisting of hydrogen, hydrazine, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic or cyclopropylmethyl;
  • R 1 and R 2 together with a group directly attached thereto form a 4-6 membered heterocyclic group, which is optionally further further selected from one or more selected from the group consisting of hydrazine, halogen, cyano and nitro Substituted with a substituent of an azide group, a C 1-4 alkyl group, a vinyl group, an allyl group, an ethynyl group, a trifluoromethyl group, a cyclopropyl group or a methoxy group;
  • R 3 and R 4 are each independently selected from hydrogen, hydrazine or C 1-4 alkyl, or R 3 and R 4 together with the carbon atom to which they are directly bonded form a cyclopropyl or cyclobutyl group;
  • R 5 and R 6 are each independently selected from hydrogen, hydrazine, fluoro or methyl, or R 5 and R 6 together with the carbon atom to which they are directly bonded form a carbonyl group, a cyclopropyl group or a cyclobutyl group;
  • R 8 is independently selected from the group consisting of hydrogen, deuterium, methyl or ethyl
  • the compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof includes, but is not limited to, the following compounds:
  • a second aspect of the present invention provides a process for the preparation of a compound of the above formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the steps of: a compound of the formula (Ia) or an acid salt thereof and the formula (Ib) The compound is reacted to form a compound of formula (I) having the following reaction formula:
  • R is selected from the group consisting of isocyanato or acid chloride, and when X is selected from -C(R 3 R 4 )-, R is selected from a carboxyl group or an alkyl carboxylate. base;
  • a third aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the above formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention provides a compound of the above formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above for the preparation of a cancer, tumor, autoimmune disease, metabolic disease or metastasis Application in sexually transmitted diseases.
  • a compound of the above formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above is prepared for the treatment of ovarian cancer, pancreatic cancer, prostate cancer, breast cancer, cervix Use in cancer, glioblastoma, multiple myeloma, metabolic disease, neurodegenerative disease, metastasis of primary tumor sites, or bone metastatic cancer drugs.
  • a sixth aspect of the invention provides a compound of the above formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above for use in the treatment of cancer, tumor, autoimmune disease, metabolic disease Or a drug for metastatic disease.
  • a seventh aspect of the invention provides a compound of the above formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above for use in the treatment of 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 tumor, solid tumor, melanoma, mesothelioma, glioblastoma , osteosarcoma, multiple myeloma, hyperproliferative diseases, metabolic diseases, neurodegenerative diseases, metastasis of primary tumor sites, myeloproliferative diseases, leukemia, rheumatoid arthritis, rheumatoid arthritis, bone and joint Inflammation, multiple sclerosis, autoimmune nephritis, lupus, Crohn's disease, asthma, chronic obstructive pulmonary disease, osteoporosis, hypere
  • An eighth aspect of the invention provides a method of treating a cancer, a tumor, an autoimmune disease, a metabolic disease or a metastatic disease, comprising administering to a patient a compound of the above formula (I), a stereoisomer thereof or a pharmaceutically acceptable substance thereof Salt, or the aforementioned pharmaceutical composition.
  • a ninth aspect of the present invention provides a method for 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, stomach Intestinal stromal tumors, solid tumors, melanoma, mesothelioma, glioblastoma, osteosarcoma, multiple myeloma, hyperproliferative diseases, metabolic diseases, neurodegenerative diseases, primary tumor sites Metastasis, myeloproliferative diseases, leukemia, rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, multiple sclerosis, autoimmune nephritis, lupus, Crohn's disease, asthma, chronic obstructive pulmonary disease, osteoporosis Or a method for the treatment of hypereosinophilic syndrome, mastocytosis or mastocytoma, comprising administering to a patient
  • Alkyl means a straight-chain or branched-chain saturated aliphatic hydrocarbon group, for example, "C 1-8 alkyl” means a straight-chain alkyl group having from 1 to 8 carbon atoms and a branched 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-methylpropane 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethyl Butyl, 2-ethylbutyl, 2-methyl
  • 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, 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- Substituents of C 0-8 -N(R 16 R 17
  • Cycloalkyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, for example, "C 3-10 cycloalkyl” refers to a cycloalkyl group of 3 to 10 carbon atoms, which is divided into a single ring. a cycloalkyl, polycyclic cycloalkyl group, wherein:
  • Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, Cyclooctyl and the like.
  • Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.
  • “Spirocycloalkyl” refers to a polycyclic group that shares a carbon atom (called a spiro atom) between the monocyclic rings. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system.
  • the spirocycloalkyl group is divided into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group according to the number of common spiro atoms between the ring and the ring, and the spirocycloalkyl group includes, but is not limited to:
  • fused cycloalkyl refers to an all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but None of the rings have a fully conjugated ⁇ -electron system. Depending on the number of constituent rings, it may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl groups, and fused cycloalkyl groups include, but are not limited to:
  • Bridge cycloalkyl refers to an all-carbon polycyclic group in which two rings share two carbon atoms that are not directly bonded, which may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system . According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, and bridged cycloalkyl groups include but are not limited to:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group including, but not limited to, indanyl, tetrahydronaphthyl , benzocycloheptyl and the like.
  • the cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C.
  • Heterocyclyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer 0, 1, 2 a hetero atom, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • r is an integer 0, 1, 2 a hetero atom, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • r is an integer 0, 1, 2 a hetero atom, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • r is an integer 0, 1, 2 a hetero atom, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • 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.
  • “Spiroheterocyclyl” refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer) The heteroatoms of 0, 1, 2), and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system.
  • the spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspiroheterocyclic group depending on the number of shared spiro atoms between the ring and the ring.
  • Spiroheterocyclyl includes, but is not limited to:
  • “Fused heterocyclyl” refers to a polycyclic heterocyclic group in which each ring of the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bonds, but none
  • the ring has a fully conjugated pi-electron system in which one or more ring atoms are selected from the group consisting of nitrogen, oxygen or S(O) r (wherein r is an integer of 0, 1, 2) heteroatoms, the remaining ring atoms being carbon.
  • the bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl group may be classified according to the number of constituent rings, and the fused heterocyclic group includes but is not limited to:
  • Bridge heterocyclyl refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly bonded, and these may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system, One or more of the ring atoms are selected from the group consisting of nitrogen, oxygen or S(O) r (wherein r is an integer of 0, 1, 2) heteroatoms, and the remaining ring atoms are carbon.
  • the bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group may be classified according to the number of constituent rings, and the bridged heterocyclic group includes but is not limited to:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group including, but not limited to:
  • the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C.
  • Aryl means an all-carbon monocyclic or fused polycyclic (ie, a ring that shares a pair of adjacent carbon atoms) groups having a polycyclic ring of a conjugated ⁇ -electron system (ie, having a ring adjacent to a carbon atom) a group, for example, "C 5-10 aryl” means an all-carbon aryl group having 5 to 10 carbons, and "5-10 membered aryl group” means an all-carbon aryl group having 5 to 10 carbons, including It is not limited to phenyl and naphthyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, including but not limited to:
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-8.
  • Heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms including nitrogen, oxygen and a hetero atom of S(O)r (wherein r is an integer of 0, 1, 2), for example, 5-8 membered heteroaryl refers to a heteroaromatic system containing 5-8 ring atoms, and 5-10 membered heteroaryl refers to a heteroaromatic system containing 5-10 ring atoms, including but not limited to furyl, thiophene.
  • Base pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring including, but not limited to:
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C.
  • Alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example, C 2-8 alkenyl refers to a straight or branched chain containing from 2 to 8 carbons. Alkenyl. These include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like.
  • the alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-8.
  • Alkynyl means an alkyl radical as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, for example, C2-8 alkynyl refers to a straight or branched chain containing from 2 to 8 carbons. Alkynyl. These include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.
  • the alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-8.
  • Alkoxy means -O-(alkyl) wherein alkyl is as defined above, for example, "C 1-8 alkoxy” refers to an alkyloxy group containing from 1 to 8 carbons, including but not It is limited to methoxy, ethoxy, propoxy, butoxy and the like.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent, preferably one or more of the following groups, independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, 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, 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 a substituent of -C
  • Cycloalkoxy refers to and -O-(unsubstituted cycloalkyl), wherein cycloalkyl is as defined above, for example, “C 3-10 cycloalkoxy” refers to 3-10 carbons. Cycloalkyloxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
  • the cycloalkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, 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, 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 a substituent of
  • 3-10 membered heterocyclic oxy refers to -O-(unsubstituted 3-10 membered heterocyclic group) wherein 3-10 membered heterocyclic group is as defined above, 3-10 membered heterocyclic oxy group.
  • the substituent is preferably one or more of the following groups, independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halo substituted C 1-8 alkyl, 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 -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 Substituted by a group consisting of hydrazine, halogen, cyano,
  • C 5-10 aryloxy means both -O-(unsubstituted C 5-10 aryl) wherein the C 5-10 aryl group is as defined above, and the C 5-10 aryloxy group may be optionally Substituted or unsubstituted, when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, 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, C 5-10 aryl, 5-10 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 -
  • 5-10 membered heteroaryloxy means -O-(unsubstituted 5-10 membered heteroaryl) wherein 5-10 membered heteroaryl is as defined above, 5-10 membered heteroaryloxy It may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of hydrazine, halogen, cyano, nitro, azide, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halo substituted C 1-8 alkyl, 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 -OR 14 , -C 0-8 -C(O)OR 14 , -C 0-8 -C(O)R 15 , -C —
  • C 1-8 alkanoyl refers to a monovalent atomic group remaining after the C 1-8 alkyl acid has been removed from the hydroxy group, and is also generally referred to 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 a C 3-10 cycloalkyl substituted C 1-8 alkyl group, wherein C 3-8 cycloalkyl, C 1-8 alkyl is as defined above Said.
  • -C 0-8 -OR 14 means that the oxygen atom in -OR 14 is attached to a C 0-8 alkyl group, wherein the C 0 alkyl group means a bond, and the C 1-8 alkyl group is as defined above.
  • -C 0-8 -NR 16 R 17 means that the nitrogen atom in -NR 16 R 17 is bonded to a C 0-8 alkyl group, wherein the C 0 alkyl group means a bond, and the C 1-8 alkyl group is as defined above. Said.
  • Halo-substituted C 1-8 alkyl refers to a hydrogen on the alkyl group optionally substituted with a fluorine, chlorine, bromine or iodine atom, including 1 to 8 carbon alkyl groups, including but not limited to difluoromethyl, Chloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and the like.
  • the hydrogen on the "halo-substituted C 1-8 alkoxy" alkyl group is optionally a 1-8 carbon alkoxy group substituted with a fluorine, chlorine, bromine or iodine atom.
  • fluorine chlorine, bromine or iodine atom.
  • these include, but are not limited to, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, and the like.
  • Halogen means fluoro, chloro, bromo or iodo.
  • NaH means sodium hydride.
  • MeOH means methanol.
  • DCM means dichloromethane.
  • DMF means N,N-dimethylformamide.
  • DEAD means diethyl azodicarboxylate.
  • X-phos means 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl.
  • Dess-Martin oxidizing agent means (1,1,1-triacetoxy)-1,1-dihydro-1,2-phenyliodo-3(1H)-one.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but is not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • Substituted means that one or more hydrogen atoms in the group are each independently substituted with 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 will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond such as an olefin.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS).
  • NMR chemical shift ( ⁇ ) is given in parts per million (ppm).
  • NMR was measured using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ).
  • the internal standard was four.
  • Methyl silane (TMS) Methyl silane
  • LC-MS was determined by LC-MS using an Agilent 6120 mass spectrometer.
  • the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
  • the thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification for TLC is 0.15mm ⁇ 0.20mm, and the specification for separation and purification of thin layer chromatography is 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.
  • Second step preparation of tert-butyl (5-(hydroxymethyl)pyridin-2-yl)carbamate
  • Methyl 6-tert-butoxycarbonylaminonicotinate (3 g, 8.2 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL). Lithium aluminum hydride (576 mg, 15.2 mmol) was slowly added under ice bath. After the reaction mixture was further stirred under an ice bath for 6 hours, the reaction was quenched by careful addition of sodium sulfate decahydrate. The reaction mixture was filtered through celite, and then filtered and evaporated.
  • Second step Preparation of tert-butyl (5-formyl-6-methylpyridin-2-yl)carbamate
  • the third step preparation of N,N-dimethyl-1H-pyrrolo[2,3-b]pyridine-5-amine
  • 3-Bromo-2-methyl-6-nitropyridine (5 g, 23 mmol) was dissolved in 1,4-dioxane (30 mL), and then the mixture of bis-di-boric acid (7 g, 27.6 mmol). 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (1.88 g, 2.3 mmol) and potassium acetate (4.5 g, 46.1 mmol) and then evacuated at room temperature for nitrogen After 3 times, the mixture was heated to 90 ° C and stirred for 12 hours. Then, the mixture was cooled to room temperature with ethyl acetate and a water layer.
  • Second step Preparation of tert-butyl 3-(hydroxymethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate
  • tert-Butyl 3-formyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (5.0 g, 20.3 mmol) was dissolved in methanol (30 mL) and sodium borohydride (1.0 g, 24.4 mmol). The reaction was stirred at room temperature for 4 hours. The organic layer is then washed with water and saturated sodium chloride, then dried over anhydrous sodium sulfate, filtered, concentrated, and then purified. (5:1) to dichloromethane/methanol (3:1)] to give tert-butyl 3-(hydroxymethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (4.8 g, yield 95%). MS m/z (ESI): 495 [M+H] + .
  • Step 3 Preparation of tert-butyl 3-(bromomethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate
  • tert-Butyl 3-(hydroxymethyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (4.0 g, 16.1 mmol) was dissolved in dichloromethane (30 mL) at 0 ° C Phosphorus tribromide (10.8 g, 40.3 mmol) was added. The reaction was warmed to room temperature and stirred for 4 hours. The aqueous solution of sodium hydrogencarbonate was adjusted to make the pH of the reaction mixture to be basic. The organic layer was washed with water and saturated sodium chloride, and then dried over anhydrous sodium sulfate.
  • Step 5 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)
  • the third step preparation of 5-((tetrahydrofuran-2-yl)oxy)-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde
  • Step 4 Preparation of tert-butyl 3-formyl-5-((tetrahydrofuran-3-yl)oxy)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate
  • Step 5 Preparation of tert-butyl 3-(hydroxymethyl)-5-((tetrahydrofuran-3-yl)oxy)-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
  • Step 7 tert-Butyl 3-((6-amino-2-methylpyridin-3-yl)methyl)-5-((tetrahydrofuran-3-yl)oxo)-1H-pyrrolo[2 , 3-b]pyridine-1-carboxylate preparation
  • Second step Preparation of tert-butyl (5-(hydroxy(1H-pyrazolo[3,4-b]pyridin-3-yl)methyl)pyridin-2-yl)carbamate
  • 3-iodo-1H-pyrazolo[3,4-b]pyridine (700 mg, 2.86 mmol) was dissolved in tetrahydrofuran (5 mL), the reaction solution was cooled to ° C, and after nitrogen was applied, 2 M isopropyl magnesium chloride (5.72) was added. mL, 5.72 mmol). After stirring at 0 ° C for 30 minutes, tert-butyl (5-formylpyridin-2-yl)carbamate (630 mg, 2.86 mmol) was dissolved in tetrahydrofuran (5 mL) and the mixture was added dropwise to the mixture and the mixture was stirred at 0 ° C for 1 hour. .
  • tert-Butyl (5-(1H-pyrazolo[3,4-b]pyridine-3-carbonyl)pyridin-2-yl)carbamate (190 mg, 0.56 mmol) was dissolved in dichloromethane (5 mL) In the middle, trifluoroacetic acid (1 mL) was added, and the mixture was reacted at room temperature for 16 hours. The aqueous sodium hydrogencarbonate solution was adjusted to pH 8 and then diluted with methylene chloride (5 mL), washed successively (5 mL ⁇ 2) and brine (5 mL) and dried over anhydrous sodium sulfate.
  • 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 mixture was stirred at room temperature for 1 hour, then warmed to 75 ° C and stirring was continued for 1 hour. After the reaction solution was cooled, it was used in the next reaction without post-treatment.
  • Methyl 4,4-dimethyl-3-oxopentanoate (800 mg, 5.06 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). NaH (607 mg, 15.2 mmol) was slowly added and stirred at 0 ° C. After a minute, iodomethane (0.9 mL, 15.2 mmol) was added to the mixture and stirred at room temperature overnight. After completion of the reaction, it was quenched with a saturated aqueous solution of ammonium chloride (50 mL), and the organic phase was separated, and the aqueous phase was extracted with methyl tert-butyl ether (20 mL ⁇ 3).
  • the organic phase was combined and concentrated to about 20 mL When the solution is stopped, the concentration is stopped. Tetrahydrofuran (30 mL), water (40 mL) and lithium hydroxide monohydrate (1.0 g, 25.3 mmol) were added to the obtained mixture, and stirred at room temperature overnight. The tetrahydrofuran was removed under reduced pressure and the residual aqueous solution was extracted with methyl t-butyl ether (20mL). The aqueous phase was adjusted to pH 5-6, and then extracted with dichloromethane (20 mL ⁇ 3).
  • Examples 2 to 16 were prepared by referring to the synthesis method of Example 1:
  • nuclear magnetic data prepared by the above compounds 2 to 16 are listed as follows:
  • Examples 20 to 24 were prepared by referring to the synthesis method of Example 19:
  • nuclear magnetic data prepared by the above compounds 20 to 24 are listed as follows:
  • the present invention employs the CSF1R ADP-Glo assay to determine the properties of a compound against CSF1R inhibitory activity.
  • Compound-mediated inhibition was evaluated by inhibiting the production of ADP (produced by consumption of ATP) using the ADP-Glo kit (Promega, cat. No. V9101).
  • the specific experimental process is as follows:
  • the kinase reaction carried out in the present invention was carried out in a 384-well plate (Perkinelmer, cat. No. 6007290), and 3.95 nM of CSF1R, 500 ⁇ M of ATP and 0.2 mg/ml of polypeptide (Poly(Glu4, Try1), respectively. , Sigma, cat. No. P0275);
  • the final concentration of the compound was determined to be 40 ⁇ M, and was set to a concentration of 50 times, that is, 2 mM.
  • KIT/PDGFRA kinase was added to 1X kinase buffer to form a 2.5-fold enzyme solution.
  • the present invention employs (Cell Titer Glo (CTG) experiment) to evaluate the functional effects of compounds on cell proliferation.
  • M-NFS-60 mouse myeloid leukemia lymphocytes (Catalog No. CCBJ078) from the China Food and Drug Administration Institute in RPMI 1640 (Gibco, cat. No. 11875-119), 10% fetal bovine serum (Gibco, 10099) -141), human 10 ng/ml M-CSF macrophage colony stimulating factor (R&D, cat. No. MVN0915101) and cultured in an incubator at 37 ° C, 5% CO 2 .
  • CCG Cell Titer Glo
  • the dose-effect effect was evaluated by 3-fold serial dilution of the test compound
  • the present invention evaluates the functional effects of compounds on the proliferation of several cells by using the Cell Titer Glo (CTG) experiment, thereby observing the proliferative effect of the compounds on different cells to judge the selectivity of the cells.
  • CCG Cell Titer Glo
  • M07e human giant cell leukemia cells (Catalog No. CBP60791) from Nanjing Kezhen Biotechnology Co., Ltd. were used in RPMI1640 (Gibco, cat. No. 11875-119), 20% fetal bovine serum (Gibco, 10099-141).
  • human 10 ng/ml GM-CSF granulocyte macrophage colony-stimulating factor R&D, cat. No.
  • M07e human giant cell leukemia cells M07e human giant cell leukemia cells
  • the cells were inoculated into a tissue culture medium 96-well plate (Costar #3904) at 3500 cells/well/80 ⁇ L of fresh medium for 24 hours;
  • the dose effect was evaluated by 4-fold serial dilution of the test compound, starting at 18 ⁇ M;
  • the cells were inoculated into a tissue culture medium 96-well plate (Costar #3904) at 5000 cells/well/90 ⁇ L of fresh medium for 24 hours;
  • the dose effect was evaluated by 3-fold serial dilution of the test compound, starting at 18 ⁇ M;
  • the cells were inoculated into a tissue culture medium 96-well plate (Costar #3904) at 5000 cells/well/90 ⁇ L of fresh medium for 24 hours;
  • the dose effect was evaluated by 3-fold serial dilution of the test compound, starting at 18 ⁇ M;
  • the compounds of the present invention have a strong inhibitory effect on CSF1R kinase activity.
  • 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 which are highly expressed by CSF1R.
  • 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 clinical application requirements.

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 WO2018233526A1 (fr)

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WO2022063241A1 (fr) * 2020-09-25 2022-03-31 南京明德新药研发有限公司 Composés 1h-pyrrolo[2,3-c]pyridine et leur application
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WO2005116035A1 (fr) * 2004-05-27 2005-12-08 Pfizer Products Inc. Derives pyrrolopyrimidiniques convenant au traitement du cancer
CN102256493A (zh) * 2008-10-29 2011-11-23 迪赛孚尔制药有限公司 表现出抗癌活性和抗增殖活性的环丙烷酰胺及其类似物
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WO2022063241A1 (fr) * 2020-09-25 2022-03-31 南京明德新药研发有限公司 Composés 1h-pyrrolo[2,3-c]pyridine et leur application
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