Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—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
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
• • 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
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • 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
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • 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
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
  • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Definitions

• the present invention belongs to the field of medicine, and specifically relates to TAM family kinases/ and CSF1R kinase inhibitor compounds represented by the general formula (I), pharmaceutically acceptable salts, esters, stereoisomers, tautomers and the same thereof Pharmaceutical compositions, pharmaceutical preparations and their use.
• the compounds of the invention selectively inhibit the tyrosine kinase TAM family/and CSF1R kinase and are useful in the treatment of diseases mediated by abnormal expression of the TAM family kinase/and CSF1R kinase receptors and/or their ligands.
• the TAM family includes three members, Axl, Mer, and Tyro-3, which comprise an extracellular domain, a transmembrane domain, and a conserved intracellular kinase domain.
• the extracellular domain consists of two immunoglobulin-like domains that link two type III fibronectin repeat units.
• the conserved amino acid sequence KW(I/L)A(I/L)ES of its intracellular kinase domain is a structural feature unique to the TAM family.
• the family has a common ligand-growth inhibition specific protein 6 (Gas6) that binds to all TAM receptors but differs in binding strength.
• Axl othernames UFO, Ark, Tyro-7, JTK1
• Mer othernames c-Mer, Mertk, Eyk, Nyk, Tyro-12
• Tyro-3 aka Sky, Byk, Rse, Dtk, etc.
• Gas6 and ProS are abnormally expressed in various solid tumors such as lung cancer, gastric cancer and liver cancer, and various hematomas such as AML, ALL and CML, and have poor prognosis, disease progression, tumor metastasis and tumor resistance. Has a strong correlation (Douglas K, Nature reviews, 2014).
• Axl as a tyrosine kinase, has been shown to be one of the causes of EGFR inhibitor resistance in NSCLC and is closely related to the metastasis of various solid tumors.
• the drug developed as a target also confirmed that inhibition of Axl can delay the drug resistance of EGFR inhibitors and tumor metastasis (T. Jimbo, Annals of Oncology, 2017; Sacha J. Holland, American Association for Cancer Research, 2010).
• Axl, Mer, Tryo-3 and TAM ligands also play a major role in the direction of immune tumors.
• Inhibition of the TAM family and its ligands can reverse the tumor's immunosuppressive environment and enhance the immune system by promoting the polarization of macrophages to M1 macrophages, increasing the activation and function of effector T cells, and enhancing the anti-tumor activity of NK cells.
• Ability to kill tumor cells Yamamoto, IL-12, IL-12, IL-12, IL-12, IL-12, IL-12, IL-12, etc.
• the development of such inhibitors can have strong inhibition and treatment effects on various physical and hematological tumors induced by the family, such as lung cancer, liver cancer, breast cancer, glioma, melanoma, AML, ALL, CML, etc. .
• TAM family receptors and ligands can regulate vascular smooth muscle homeostasis, platelet aggregation, thrombus stabilization, erythropoiesis, oligodendrocyte survival, osteoclast function, phagocytosis of apoptotic cells, inflammation , a number of physiological functions such as innate immunity. Therefore, TAM family inhibitors can also be used for endometriosis, vascular disease/injury, psoriasis, visual defects/lesions (macular degeneration, diabetes and premature birth), kidney diseases caused by disorders of the TAM family signaling pathway, Treatment of rheumatoid arthritis, osteoporosis and other related diseases.
• CSF1R Cold Stimulating Factor 1 Receptor
• c-FMS Cold-Simulating Factor 1 Receptor
• FMS FMS
• FIM2 MCSF
• CD115 CD115
• CSF1R Colony Stimulating Factor 1 Receptor
• PDGFR and KIT belong to the class III receptor tyrosine kinase (RTK) family.
• CSF-1R is only expressed on the surface of monocyte lines, such as macrophages.
• CSF1R ligands include colony stimulating factor 1 (CSF-1, macrophage colony-stimulating factor, nicknamed M-CSF) and interleukin-34 (IL-34, Interleukin-34).
• CSF-1 affects the various cellular functions of monocyte cell lines by binding to CSF1R, and IL-34 can firmly bind CSF-1R to promote the survival, proliferation and differentiation of monocyte cell lines. They constitute the CSF-1/IL-34/CSF-1R pathway.
• CSF-1 and CSF1R form a signal axis to promote the growth of macrophages in the body, while regulating the normal development and homeostasis of tissues and organs, and the imbalance of the body's steady state will lead to more Such diseases as inflammation, immune system diseases, tumors and the like.
• macrophages have the potential to kill tumor cells
• TAMs tumor-associated macrophages
• TAMs tumor-associated macrophages
• MDSCs myeloid-derived suppressor cells
• MDSCs myeloid-derived suppressor cells
• CSF-1/CSF1R Increased expression of CSF-1/CSF1R has been found in various tumors such as breast cancer, ovarian cancer, colorectal cancer, prostate cancer, lung cancer, and Hodgkin's lymphoma (O'Brien J, Am J Pathol, 2010).
• Overexpression of CSF-1/CSF-1R is associated with tumor malignancy and poor prognosis.
• High expression of CSF1R was detected in CSF-1-induced fibroblasts and epithelial cells, and tumors were eventually formed in nude mice, indicating that the CSF-1/CSF1R axis promotes tumor cell proliferation and survival in tumorigenesis. And play an important role in development.
• CSF1R plays a role in osteolytic bone destruction (Ohno, Mol.
• CSF-1/IL-34/CSF-1R signaling pathway can alleviate the immunosuppressive effect of tumors and enhance the activity of the immune system, thereby inhibiting the development and metastasis of tumors. It has also been reported that CSF-1R inhibitors can be significantly reduced. Tumors, such as glioblastoma, and other tumor volumes reduce tumor invasiveness and proliferation (Pyonteck Stephanie M, Nature Medicine, 2013). In summary, inhibition of the CFS1R pathway has become one of the main therapeutic targets for cancer.
• TAM and CSF1R inhibitors can improve the immunosuppressive environment of tumors and enhance the ability of the immune system to kill tumor cells. However, based on the complexity of tumor pathogenesis, if they can simultaneously target these two targets, they can exert their immunotherapy for tumors. double effect.
• CSF1R inhibitors are more commonly used in combination with PD-1, and no inhibitors targeting TAM/ and CSF1R have been marketed.
• the present invention provides a novel inhibitor compound and pharmaceutically acceptable salts, esters, stereoisomers, tautomers thereof (hereinafter sometimes referred to as compounds of the present invention).
• the compounds of the invention have an inhibitory effect on TAM family kinases.
• the compounds of the invention may also target CSF1R kinase and have an inhibitory effect on CSF1R kinase.
• the compounds of the invention are useful for the treatment and/or prevention of diseases mediated by aberrant expression of TAM family kinase receptors and/or their ligands.
• the compounds of the present invention are useful for the treatment and/or prevention of diseases mediated by abnormal expression of TAM family kinases/and CSF1R kinase receptors and/or their ligands.
• the compound of the present invention reverses the immunosuppression in the tumor microenvironment by inhibiting the TAM family kinase/CSF1R kinase, inhibits the growth, migration, and/or drug resistance of the tumor, and exerts the tumor immune effect and the antitumor effect.
• the present invention provides the following technical solutions.
• W is selected from hydrogen or a C 1-6 alkyl group optionally substituted with a substituent
• R represents a group represented by the following formula (a), (b) or (c),
• the ring A portion represents a 6-10 membered aromatic ring, a 5-6 membered heteroaryl ring having 1-3 hetero atoms selected from NR b , O and S or has a NR b , O selected from And a 5-6 membered heterocyclic ring of 1-4 heteroatoms in S;
• Q is each independently selected from a hydrogen atom, a cyano group, a hydroxyl group, a thiol group, a halogen atom, a carboxyl group, a nitro group, -NR b R c , -C(O)R d , -C(O)OR d , -C(O NR b R c , -OC(O)NR b R c , -NR b C(O)OR d , -NR b C(O)R d , -SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d , a C 1-6 alkyl group optionally substituted by a substituent, a C 1-6 alkoxy group optionally substituted by a substituent, a C 2-8 olefin optionally substituted with a substituent a C 2-8 alkynyl group optionally substituted with a substitu
• q is an integer from 0-4;
• X 4 and X 5 are each independently selected from CR a or N;
• Cy 1 is selected from optionally substituted with one or more substituted with R 1 is 3-12 membered heterocyclic group and optionally substituted with one or more substituted with R 1 is 3-12 membered cycloalkyl group
• R 1 is independently selected from: a hydrogen atom, a cyano Base, hydroxyl group, mercapto group, halogen atom, carboxyl group, nitro group, -NR b R c , -C(O)R d , -C(O)OR d , -C(O)NR b R c , -OC(O NR b R c , -NR b C(O)OR d , -NR b C(O)R d , -SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d , any a C 1-6 alkyl group substituted with a substituent, a C 1-6 alkoxy group optional
• CY 2 is selected from optionally substituted with one or more R 2 is 6-14 membered aryl 2 and optionally substituted by one or more R 5-10 membered heteroaryl group
• R 2 is independently selected from: a hydrogen atom, a cyano group , hydroxy, fluorenyl, halogen atom, carboxyl group, nitro group, -NR b R c , -C(O)R d , -C(O)OR d , -C(O)NR b R c , -OC(O) NR b R c , -NR b C(O)OR d , -NR b C(O)R d , -SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d , optional a C 1-6 alkyl group substituted with a substituent, a C 1-6 alkoxy group optionally substituted with a substituent,
• R 3 is substituted 6-14 membered aromatic radical
• R 3 is independently selected from a hydrogen atom, a cyano group, a hydroxyl group, a mercapto group, a halogen atom, a carboxyl group, a nitro group , -NR b R c , -C(O)R d , -C(O)OR d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O) OR d , -NR b C(O)R d , -SO 2 -NR b R c , -SO 2 R d
• CY 4 is selected from optionally substituted with one or more R 4 substituted 3-12 membered cycloalkyl, optionally substituted by one or more R 4 3-14 membered heterocyclyl, optionally substituted with one or more of R 4 5-14 membered heteroaryl and optionally substituted with one or more R 4 is 6-14 membered aryl, R 4 is independently selected from a hydrogen atom, a cyano group, a hydroxyl group, a mercapto group, a halogen atom, a carboxyl group, a nitro group, -NR b R c , -C(O)R d , -C(O)OR d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O)OR d , -NR b C(O)R d , -SO 2 -NR b R c , -SO 2 R d
• L is selected from -NR b -, -O-, -S-, -(CR a R a ) m -, a 3-12 membered cycloalkyl group optionally substituted by a substituent, 3 optionally substituted by a substituent a 14-membered heterocyclic group, a 5-14 membered heteroaryl group optionally substituted with a substituent, and a 6-14 membered aromatic group optionally substituted with a substituent selected from an integer of 0 to 3;
• R a is absent or, at each occurrence, independently selected from a hydrogen atom, a cyano group, a hydroxyl group, a thiol group, a halogen atom, a carboxyl group, a nitro group, -NR b R c , -C(O)R d , C(O)OR d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O)OR d , -NR b C(O)R d , -SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d , a C 1-6 alkyl group optionally substituted with a substituent, a C 1-6 alkoxy group optionally substituted with a substituent, A C 2-8 alkenyl group substituted with a substituent, a C 2-8 alkynyl group optionally substitute
• R b , R c , R d or each are absent or, at each occurrence, independently selected from a hydrogen atom, a hydroxyl group, a thiol group, a C 1-6 alkyl group optionally substituted by a substituent, optionally substituted a substituted C 1-6 alkoxy group, a C 1-6 alkyl-R' optionally substituted with a substituent, a C 1-6 alkoxy group -R', -O optionally substituted by a substituent -R', -C(O)-R', -SO 2 -R', a 3-12 membered cycloalkyl group optionally substituted by a substituent, a 3-12 membered cycloalkenyl group optionally substituted by a substituent, a 3-12 membered heterocyclic group optionally substituted by a substituent, a 6-14 membered aryl group optionally substituted by a substituent, a 5-10 membered heteroary
• R' is selected from a 3-12 membered cycloalkyl group optionally substituted by a substituent, a 3-12 membered cycloalkenyl group optionally substituted by a substituent, a 3-12 membered heterocyclic group optionally substituted by a substituent, or a 6-14 membered aryl group substituted with a substituent and a 5-10 membered heteroaryl group optionally substituted with a substituent;
• substituents in the "optionally substituted with a substituent" are each independently selected from the group consisting of: a hydroxyl group, a thiol group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group.
• a C 1-6 alkyl group a C 1-6 alkoxy group, a C 1-6 alkyl C 1-6 alkoxy group, a C 1-6 alkoxy C 1-6 alkoxy group, a C 1-6 alkane Amino group, (C 1-6 alkyl) 2 amino group, C 1-6 alkyl ester group, C 1-6 alkylaminocarbonyl group, (C 1-6 alkyl) 2 aminocarbonyl group, C 1-6 alkyl group Carbonyl group, C 1-6 alkylcarbonyloxy group, C 1-6 alkylcarbonylamino group, C 1-6 alkylsulfonylamino group, halogenated C 1-6 alkyl group, halogenated C 1-6 alkoxy group, C 1-6 alkylsulfonyl, C 1-6 alkylthio, 3-12 membered cycloalkyl, 6-14 membered aryl, 3-12 membered heterocyclic group, 5-10 membered heteroaryl and oxygen
• Cy 1 when carrying two carbonyl groups, Cy 1 represents optionally substituted with one or more substituted with R 1 is selected from the group comprising O, S, S (O) , S (O) in 21 a 3-12 membered heterocyclic group of 3 groups, and the Cy 3 -L moiety does not form an aryloxy moiety;
• Cy 1 represents a group optionally substituted by one or more R 1 and is selected from O, S, S(O), a 3-12 membered heterocyclic group of 1-3 groups in S(O) 2 ;
• Cy 1 represents a group optionally substituted by one or more R 1 and is selected from O, S. a 3-12 membered heterocyclic group of 1-3 groups in S(O), S(O) 2 , and Cy 2 represents a 6-14 membered aryl group optionally substituted by one or more R 2 ;
• n is an integer from 0-4.
• W is selected from hydrogen or a C 1-6 alkyl group optionally substituted with a substituent
• R represents a group represented by the following formula (a),
• the ring A portion represents a 6-10 membered aromatic ring, a 5-6 membered heteroaryl ring having 1-3 hetero atoms selected from NR b , O and S or has a NR b , O selected from And a 5-6 membered heterocyclic ring of 1-4 heteroatoms in S;
• Q is each independently selected from a hydrogen atom, a cyano group, a hydroxyl group, a thiol group, a halogen atom, a carboxyl group, a nitro group, -NR b R c , -C(O)R d , -C(O)OR d , -C(O NR b R c , -OC(O)NR b R c , -NR b C(O)OR d , -NR b C(O)R d , -SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d , a C 1-6 alkyl group optionally substituted by a substituent, a C 1-6 alkoxy group optionally substituted by a substituent, a C 2-8 olefin optionally substituted with a substituent a C 2-8 alkynyl group optionally substituted with a substitu
• q is an integer from 0-4;
• Cy 1 is selected from optionally substituted with one or more substituted with R 1 is 3-12 membered heterocyclic group and optionally substituted with one or more substituted with R 1 is 3-12 membered cycloalkyl group
• R 1 is independently selected from: a hydrogen atom, a cyano Base, hydroxyl group, mercapto group, halogen atom, carboxyl group, nitro group, -NR b R c , -C(O)R d , -C(O)OR d , -C(O)NR b R c , -OC(O NR b R c , -NR b C(O)OR d , -NR b C(O)R d , -SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d , any a C 1-6 alkyl group substituted with a substituent, a C 1-6 alkoxy group optional
• R 3 is substituted 6-14 membered aromatic radical
• R 3 is independently selected from a hydrogen atom, a cyano group, a hydroxyl group, a mercapto group, a halogen atom, a carboxyl group, a nitro group , -NR b R c , -C(O)R d , -C(O)OR d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O) OR d , -NR b C(O)R d , -SO 2 -NR b R c , -SO 2 R d
• CY 4 is selected from optionally substituted with one or more R 4 substituted 3-12 membered cycloalkyl, optionally substituted by one or more R 4 3-14 membered heterocyclyl, optionally substituted with one or more of R 4 5-14 membered heteroaryl and optionally substituted with one or more R 4 is 6-14 membered aryl, R 4 is independently selected from a hydrogen atom, a cyano group, a hydroxyl group, a mercapto group, a halogen atom, a carboxyl group, a nitro group, -NR b R c , -C(O)R d , -C(O)OR d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O)OR d , -NR b C(O)R d , -SO 2 -NR b R c , -SO 2 R d
• L is selected from -NR b -, -O-, -S-, -(CR a R a ) m -, a 3-12 membered cycloalkyl group optionally substituted by a substituent, 3 optionally substituted by a substituent a 14-membered heterocyclic group, a 5-14 membered heteroaryl group optionally substituted with a substituent, and a 6-14 membered aromatic group optionally substituted with a substituent selected from an integer of 0 to 3;
• R a is absent or, at each occurrence, independently selected from a hydrogen atom, a cyano group, a hydroxyl group, a thiol group, a halogen atom, a carboxyl group, a nitro group, -NR b R c , -C(O)R d , C(O)OR d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O)OR d , -NR b C(O)R d , -SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d , a C 1-6 alkyl group optionally substituted with a substituent, a C 1-6 alkoxy group optionally substituted with a substituent, A C 2-8 alkenyl group substituted with a substituent, a C 2-8 alkynyl group optionally substitute
• R b , R c , R d or each are absent or, at each occurrence, independently selected from a hydrogen atom, a hydroxyl group, a thiol group, a C 1-6 alkyl group optionally substituted by a substituent, optionally substituted a substituted C 1-6 alkoxy group, a C 1-6 alkyl-R' optionally substituted with a substituent, a C 1-6 alkoxy group -R', -O optionally substituted by a substituent -R', -C(O)-R', -SO 2 -R', a 3-12 membered cycloalkyl group optionally substituted by a substituent, a 3-12 membered cycloalkenyl group optionally substituted by a substituent, a 3-12 membered heterocyclic group optionally substituted by a substituent, a 6-14 membered aryl group optionally substituted by a substituent, a 5-10 membered heteroary
• R' is selected from a 3-12 membered cycloalkyl group optionally substituted by a substituent, a 3-12 membered cycloalkenyl group optionally substituted by a substituent, a 3-12 membered heterocyclic group optionally substituted by a substituent, or a 6-14 membered aryl group substituted with a substituent and a 5-10 membered heteroaryl group optionally substituted with a substituent;
• substituents in the "optionally substituted with a substituent" are each independently selected from the group consisting of: a hydroxyl group, a thiol group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group.
• a C 1-6 alkyl group a C 1-6 alkoxy group, a C 1-6 alkyl C 1-6 alkoxy group, a C 1-6 alkoxy C 1-6 alkoxy group, a C 1-6 alkane Amino group, (C 1-6 alkyl) 2 amino group, C 1-6 alkyl ester group, C 1-6 alkylaminocarbonyl group, (C 1-6 alkyl) 2 aminocarbonyl group, C 1-6 alkyl group Carbonyl group, C 1-6 alkylcarbonyloxy group, C 1-6 alkylcarbonylamino group, C 1-6 alkylsulfonylamino group, halogenated C 1-6 alkyl group, halogenated C 1-6 alkoxy group, C 1-6 alkylsulfonyl, C 1-6 alkylthio, 3-12 membered cycloalkyl, 6-14 membered aryl, 3-12 membered heterocyclic group, 5-10 membered heteroaryl and oxygen
• n is an integer from 0-4.
• Cy 1 represents a 3-12 membered heterocyclic group optionally substituted by one or more R 1
• the ring A moiety represents a 6-10 membered aromatic ring or has a selected from the group consisting of NR b , O and S A 5-6 membered heteroaryl ring of 1-4 heteroatoms.
• Cy 1 represents 1-3 groups selected from O, NR b , S, S(O), S(O) 2 optionally substituted by one or more R 1 A 3-12 membered heterocyclic group, and a ring A moiety represents a 6-10 membered aromatic ring.
• the ring A moiety represents a benzene ring, a furan ring, a thiophene ring, a pyrrole ring, an oxazole ring, an isoxazole ring, a thiazole ring, an isothiazole ring, a pyrazole ring, a thiazole ring, an imidazole.
• Q is each independently selected from the group consisting of a hydrogen atom, a cyano group, a hydroxyl group, a thiol group, a halogen atom, a carboxyl group, a nitro group, -NR b R c , -C(O)R d , -C ( O) OR d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O)OR d , -NR b C(O)R d , -SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d , C 1-6 alkyl optionally substituted by a substituent, C 1-6 alkoxy optionally substituted by a substituent, optionally C 1-6 alkyl-R' substituted by a substituent, -C 1-6 alkoxy-R', -
• X 7 represents CR a R a .
• X 7 represents CR a R a
• X 7 has a double bond between adjacent C atoms.
• q is 0, 1, 2 or 3.
• W is selected from hydrogen or a C 1-6 alkyl group optionally substituted with a substituent
• R represents a group represented by the following formula (b) or formula (c),
• q 0, 1, 2 or 3;
• X 4 and X 5 are each independently selected from CR a or N;
• Cy 1 is selected from optionally substituted with one or more substituted with R 1 is 3-12 membered heterocyclic group and optionally substituted with one or more substituted with R 1 is 3-12 membered cycloalkyl group
• R 1 is independently selected from: a hydrogen atom, a cyano Base, hydroxyl group, mercapto group, halogen atom, carboxyl group, nitro group, -NR b R c , -C(O)R d , -C(O)OR d , -C(O)NR b R c , -OC(O NR b R c , -NR b C(O)OR d , -NR b C(O)R d , -SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d , any a C 1-6 alkyl group substituted with a substituent, a C 1-6 alkoxy group optional
• CY 2 is selected from optionally substituted with one or more R 2 is 6-14 membered aryl 2 and optionally substituted by one or more R 5-10 membered heteroaryl group
• R 2 is independently selected from: a hydrogen atom, a cyano group , hydroxy, fluorenyl, halogen atom, carboxyl group, nitro group, -NR b R c , -C(O)R d , -C(O)OR d , -C(O)NR b R c , -OC(O) NR b R c , -NR b C(O)OR d , -NR b C(O)R d , -SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d , optional a C 1-6 alkyl group substituted with a substituent, a C 1-6 alkoxy group optionally substituted with a substituent,
• R 3 is substituted 6-14 membered aromatic radical
• R 3 is independently selected from a hydrogen atom, a cyano group, a hydroxyl group, a mercapto group, a halogen atom, a carboxyl group, a nitro group , -NR b R c , -C(O)R d , -C(O)OR d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O) OR d , -NR b C(O)R d , -SO 2 -NR b R c , -SO 2 R d
• CY 4 is selected from optionally substituted with one or more R 4 substituted 3-12 membered cycloalkyl, optionally substituted by one or more R 4 3-14 membered heterocyclyl, optionally substituted with one or more of R 4 5-14 membered heteroaryl and optionally substituted with one or more R 4 is 6-14 membered aryl, R 4 is independently selected from a hydrogen atom, a cyano group, a hydroxyl group, a mercapto group, a halogen atom, a carboxyl group, a nitro group, -NR b R c , -C(O)R d , -C(O)OR d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O)OR d , -NR b C(O)R d , -SO 2 -NR b R c , -SO 2 R d
• L is selected from -NR b -, -O-, -S-, -(CR a R a ) m -, a 3-12 membered cycloalkyl group optionally substituted by a substituent, 3 optionally substituted by a substituent a 14-membered heterocyclic group, a 5-14 membered heteroaryl group optionally substituted with a substituent, and a 6-14 membered aromatic group optionally substituted with a substituent, m being an integer selected from 0 to 3;
• R a is absent or, at each occurrence, independently selected from a hydrogen atom, a cyano group, a hydroxyl group, a thiol group, a halogen atom, a carboxyl group, a nitro group, -NR b R c , -C(O)R d , C(O)OR d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O)OR d , -NR b C(O)R d , -SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d , a C 1-6 alkyl group optionally substituted with a substituent, a C 1-6 alkoxy group optionally substituted with a substituent, A C 2-8 alkenyl group substituted with a substituent, a C 2-8 alkynyl group optionally substitute
• R b , R c , R d or each are absent or, at each occurrence, independently selected from a hydrogen atom, a hydroxyl group, a thiol group, a C 1-6 alkyl group optionally substituted by a substituent, optionally substituted a substituted C 1-6 alkoxy group, a C 1-6 alkyl-R' optionally substituted with a substituent, a C 1-6 alkoxy group -R', -O optionally substituted by a substituent -R', -C(O)-R', -SO 2 -R', a 3-12 membered cycloalkyl group optionally substituted by a substituent, a 3-12 membered cycloalkenyl group optionally substituted by a substituent, a 3-12 membered heterocyclic group optionally substituted by a substituent, a 6-14 membered aryl group optionally substituted with a substituent, and a 5-10 membered hetero
• R' is selected from a 3-12 membered cycloalkyl group optionally substituted by a substituent, a 3-12 membered cycloalkenyl group optionally substituted by a substituent, a 3-12 membered heterocyclic group optionally substituted by a substituent, or a 6-14 membered aryl group substituted with a substituent and a 5-10 membered heteroaryl group optionally substituted with a substituent;
• substituents in the "optionally substituted with a substituent" are each independently selected from the group consisting of: a hydroxyl group, a thiol group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group.
• a C 1-6 alkyl group a C 1-6 alkoxy group, a C 1-6 alkyl C 1-6 alkoxy group, a C 1-6 alkoxy C 1-6 alkoxy group, a C 1-6 alkane Amino group, (C 1-6 alkyl) 2 amino group, C 1-6 alkyl ester group, C 1-6 alkylaminocarbonyl group, (C 1-6 alkyl) 2 aminocarbonyl group, C 1-6 alkyl group Carbonyl group, C 1-6 alkylcarbonyloxy group, C 1-6 alkylcarbonylamino group, C 1-6 alkylsulfonylamino group, halogenated C 1-6 alkyl group, halogenated C 1-6 alkoxy group, C 1-6 alkylsulfonyl, C 1-6 alkylthio, 3-12 membered cycloalkyl, 6-14 membered aryl, 3-12 membered heterocyclic group, 5-10 membered heteroaryl group and
• Cy 1 when carrying two carbonyl groups, Cy 1 represents optionally substituted with one or more substituted with R 1 is selected from the group comprising O, S, S (O) , S (O) in 21 a 3-12 membered heterocyclic group of 3 groups, and the Cy 3 -L moiety does not form an aryloxy moiety;
• Cy 1 represents a group optionally substituted by one or more R 1 and is selected from O, S, S(O), a 3-12 membered heterocyclic group of 1-3 groups in S(O) 2 ;
• Cy 1 represents a group optionally substituted by one or more R 1 and is selected from O, S. a 3-12 membered heterocyclic group of 1-3 groups in S(O), S(O) 2 , and Cy 2 represents a 6-14 membered aryl group optionally substituted by one or more R 2 ;
• n is an integer from 0-4.
• At least one double bond is present in the ring of formula (b).
• At least one double bond is present in the ring of formula (c).
• Cy 1 means optionally One or more R 1 substituted 3-12 membered heterocyclic groups containing 1-3 groups selected from O, S, S(O), S(O) 2 , and Cy 2 represents optionally more than one R 2 Substituted 6-14 membered aryl, and L does not represent a heteroaryl group.
• Cy 1 represents optionally more than one R. 1 substituted 3-12 membered heterocyclic group containing 1 to 3 groups selected from O, S, S(O), S(O) 2 , and Cy 2 represents 6 optionally substituted by one or more R 2 -14 yuan aryl.
• Cy 1 represents a group optionally substituted by one or more R 1 and is selected from the group consisting of O, S, S(O), S(O) 2 a 3-12 membered heterocyclic group of 1-3 groups.
• a compound of the formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof having the structure represented by the formula (II) ,
• q 0, 1, 2 or 3;
• X 4 and X 5 are each independently selected from CR a or N.
• q 0, 1, 2 or 3;
• q 0, 1, 2 or 3;
• Cy ⁇ 1> is selected from a 4-10 membered heterocyclyl optionally substituted with one or more R ⁇ 1> .
• Cy ⁇ 1> is selected from a 3-10 membered cycloalkyl group optionally substituted with one or more R ⁇ 1> .
• R 1 is each independently selected from the group consisting of: a hydrogen atom, a cyano group, a hydroxyl group, a thiol group, a halogen atom, a carboxyl group, a nitro group, -NR b R c , -C(O)R d , C(O)OR d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O)OR d , -NR b C(O)R d , -SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d , a C 1-6 alkyl group optionally substituted with a substituent, a C 1-6 alkoxy group optionally substituted with a substituent, A C 2-8 alkenyl group substituted with a substituent, a C 2-8 alkynyl
• Cy ⁇ 1> is selected from a 4-8 membered heterocyclyl optionally substituted with one or more R ⁇ 1> .
• the heterocyclic group of Cy 1 contains 1-3 groups selected from the group consisting of O, NR b , S, S(O), and S(O) 2 .
• Cy 2 is selected from a 6-10 membered aryl group optionally substituted with more than one R 2 .
• Cy 2 is selected from a 5-6 membered heteroaryl optionally substituted with more than one R 2 .
• R 2 is each independently selected from the group consisting of: a hydrogen atom, a cyano group, a hydroxyl group, a thiol group, a halogen atom, a carboxyl group, a nitro group, -NR b R c , -C(O)R d , C(O)OR d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O)OR d , -NR b C(O)R d , -SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d , a C 1-6 alkyl group optionally substituted with a substituent, a C 1-6 alkoxy group optionally substituted with a substituent, A C 2-8 alkenyl group substituted with a substituent, a C 2-8 alkynyl
• the heteroaryl group of Cy 2 contains 1-3 groups selected from the group consisting of O, NR b , S, S(O), S(O) 2 .
• Cy 2 is selected from phenyl or naphthyl optionally substituted by more than one R 2 .
• Cy 3 is selected from a 3-8 membered cycloalkyl group optionally substituted with more than one R 3 .
• Cy 3 is selected from a 3-6 membered cycloalkyl group optionally substituted with more than one R 3 .
• Cy 3 is selected from a 5-6 membered heteroaryl group optionally substituted with more than one R 3 .
• Cy 3 is selected from a 6-10 membered aromatic group optionally substituted with more than one R 3 .
• Cy 3 is selected from phenyl or naphthyl optionally substituted by more than one R 3 .
• R 3 are each independently selected from the group consisting of a hydrogen atom, a cyano group, a hydroxyl group, a thiol group, a halogen atom, a carboxyl group, a nitro group, -NR b R c , -C(O)R d , -C (O)OR d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O)OR d , -NR b C(O)R d , -SO 2 - NR b R c , -SO 2 R d , -NR b SO 2 R d , C 1-6 alkyl group optionally substituted by a substituent, C 1-6 alkoxy group optionally substituted by a substituent, optionally C 2-8 alkenyl substituted by a substituent, C 2-8 alkynyl optionally substituted
• the heteroaryl group of Cy 3 contains 1-3 atoms selected from O, NR b , S.
• Cy 4 is selected from a 5-10 membered heteroaryl optionally substituted with more than one R 4 .
• Cy 4 is selected from a 9-10 membered heteroaryl optionally substituted with more than one R 4 .
• Cy 4 is selected from a 6-10 membered aryl group optionally substituted with more than one R 4 .
• Cy 4 is selected from phenyl or naphthyl optionally substituted by more than one R 4 .
• R 4 is each independently selected from the group consisting of a hydrogen atom, a cyano group, a hydroxyl group, a thiol group, a halogen atom, a carboxyl group, a nitro group, -NR b R c , -C(O)R d , -C (O)OR d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O)OR d , -NR b C(O)R d , -SO 2 - NR b R c , -SO 2 R d , -NR b SO 2 R d , C 1-6 alkyl group optionally substituted by a substituent, C 1-6 alkoxy group optionally substituted by a substituent, optionally C 2-8 alkenyl substituted by a substituent, C 2-8 alkynyl optionally substituted
• two R 4 may form a 5-14 membered cyclic group with the attached atom.
• two R 4 may form a 5-10 membered cyclic group with the attached atom.
• two R 4 may form a 5-6 membered cyclic group with the attached atom.
• two R 4 may form a 5-6 membered oxygen-containing cyclic group with the attached atom.
• the heteroaryl group of Cy 4 contains from 1 to 4 atoms selected from O, NR b , S.
• L is selected from the group consisting of -NR b -, -O-, -S-, and a 5-10 membered heteroaryl group optionally substituted with a substituent.
• L is heteroaryl selected from the group comprising O, NR b, S 1-4 atoms.
• R a is absent or, at each occurrence, each independently selected from the group consisting of a hydrogen atom, a cyano group, a hydroxyl group, a thiol group, a halogen atom, a carboxyl group, a nitro group, a —NR b R c , -C(O)R d , -C(O)OR d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O)OR d , -NR b C (O)R d , -SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d , a C 1-6 alkyl group optionally substituted by a substituent, optionally substituted by a substituent C 1-6 alkoxy, C 2-8 alkenyl optionally substituted by a substituent, C
• R b , R c , R d or each are absent or, at each occurrence, C 1 each independently selected from a hydrogen atom, a hydroxyl group, a thiol group, optionally substituted with a substituent -6 alkyl, optionally substituted with C 1-6 alkoxy, - optionally substituted C 1-6 alkyl group substituted by -R ', - optionally substituted with a C 1-6 alkoxy-R', -O-R', -C(O)-R', -SO 2 -R', a 3-8 membered cycloalkyl group optionally substituted by a substituent, optionally substituted with a substituent a 3-8 membered cycloalkenyl group, a 3-10 membered heterocyclic group optionally substituted by a substituent, a 6-10 membered aryl group optionally substituted by a substituent, a 5-6 membered heterocyclic optionally
• R' is selected from a 3-8 membered cycloalkyl group optionally substituted by a substituent, a 3-8 membered cycloalkenyl group optionally substituted by a substituent, optionally substituted with a substituent.
• R' is selected from a 4-6 membered cycloalkyl group optionally substituted by a substituent, a 4-6 membered cycloalkenyl group optionally substituted by a substituent, optionally substituted with a substituent.
• the substituents in the "optionally substituted by a substituent" are each independently selected from the group consisting of: a hydroxyl group, a thiol group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, a C 1-6 alkyl group.
• the substituents in the "optionally substituted with a substituent" are each independently selected from the group consisting of: a hydroxyl group, a thiol group, an amino group, a carboxyl group, a cyano group, a nitro group, a halogen atom, and a C 1-4 alkyl group.
• n 0, 1, 2 or 3.
• X 1 is N
• X 2 is CR a
• X 1 is CR a
• X 2 is N
• X 2 is CR a
• X 1 is CR a
• X 2 is CR a
• the ring in the group represented by the formula (b) is represented by any one of the following formulas, wherein Represents a single or double bond,
• the ring in the group represented by the formula (c) is represented by any one of the following formulas, wherein Represents a single or double bond,
• X 4 is selected from C or N, and X 5 is selected from C.
• X 2 is CR a or NR b .
• Cy ⁇ 1> is selected from a 4-6 membered heterocyclyl optionally substituted with one or more R ⁇ 1> .
• Cy 1 is selected from the group consisting of 1-3 groups selected from O, NR b , S, S(O), S(O) 2 optionally substituted by more than one R 1 4-6 membered heterocyclic group.
• Cy 2 is selected from optionally substituted by one or more R 2 phenyl or naphthyl, optionally substituted by one or more R 2 pyridinyl.
• Cy 3 is optionally substituted by more than one R 3
• the group shown, in the formula, Represents a single bond or a double bond
• Y 2 , Y 3 , Y 6 , and Y 7 are each independently selected from CR a R a or NR b .
• At least one of Y 2 , Y 3 , Y 6 , Y 7 is NR b .
• Cy 3 is optionally substituted by more than one R 3
• the groups shown, Y 2 , Y 3 , Y 6 , Y 7 are each independently selected from CH or N, and at least one is N.
• Cy 3 is selected from cyclohexyl optionally substituted with more than one R 3 .
• Cy 3 is selected from thienyl groups optionally substituted with more than one R 3 .
• Cy 4 is optionally substituted by more than one R 4
• the group shown, in the formula, Representing a single bond or a double bond, Y 4 and Y 5 are each independently selected from CR a R a or NR b , and at least one is NR b , and ring B is a benzene ring, a naphthalene ring or a 5-10 membered heteroaryl ring.
• Cy 4 is optionally substituted by more than one R 4
• the groups shown, Y 4 and Y 5 are each independently selected from C or N, and at least one is N.
• Ring B is a benzene ring or a 5-6 membered heteroaryl ring containing from 1 to 3 atoms selected from the group consisting of NR b , O, and S.
• Cy 1 is selected from the group consisting of the following groups optionally substituted by more than one R 1 :
• Cy 2 is selected from the group consisting of the following: optionally substituted by more than one R 2 :
• Cy 3 is selected from the group consisting of the following: optionally substituted by more than one R 3 :
• Cy 4 is selected from the group consisting of the following: optionally substituted by more than one R 4 :
• Cy 1 is selected from the group consisting of the following groups optionally substituted by more than one R 1 :
• Cy 2 is selected from the group consisting of the following: optionally substituted by more than one R 2 :
• Cy 3 is selected from the group consisting of the following: optionally substituted by more than one R 3 :
• Cy 3 is selected from the group consisting of the following: optionally substituted by more than one R 3 : * The end is connected to N, and the end is connected to L.
• Cy 4 is selected from the group consisting of the following: optionally substituted by more than one R 4 :
• Cy 1 represents a 3-12 membered heterocyclic group optionally substituted by one or more R 1
• Cy 2 represents a 6-14 membered aryl group optionally substituted with one or more R 2 .
• R 1 in Cy 1 is each independently selected from the group consisting of a hydrogen atom, a hydroxyl group, a thiol group, a halogen atom, a carboxyl group, a nitro group, -NR b R c , -C(O)R d , -C(O)OR d , -C(O)NR b R c , -NR b C(O)R d , a C 1-6 alkyl group optionally substituted by a substituent, and C optionally substituted by a substituent 1-6 alkoxy group.
• R 1 is each independently selected from the group consisting of a hydrogen atom, a hydroxyl group, a thiol group, a halogen atom, a C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, an amino C 1-6 alkyl group, Halogenated C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy.
• R 1 is each independently selected from the group consisting of a hydrogen atom, a hydroxyl group, a fluorine, a chlorine, a bromine, and a C 1-4 alkyl group.
• R 2 in Cy 2 is each independently selected from the group consisting of a hydrogen atom, a hydroxyl group, a thiol group, a halogen atom, a carboxyl group, a nitro group, -NR b R c , -C(O)R d , -C(O)OR d , -C(O)NR b R c , -NR b C(O)R d , a C 1-6 alkyl group optionally substituted by a substituent, and C optionally substituted by a substituent 1-6 alkoxy group.
• R 2 is each independently selected from the group consisting of a hydrogen atom, a hydroxyl group, a thiol group, a halogen atom, a C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, an amino C 1-6 alkyl group, Halogenated C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy.
• R 2 is each independently selected from the group consisting of a hydrogen atom, a hydroxyl group, a fluorine, a chlorine, a bromine, and a C 1-4 alkyl group.
• R 3 in Cy 3 is each independently selected from a hydrogen atom, a hydroxyl group, a thiol group, a halogen atom, a carboxyl group, a nitro group, -NR b R c , -C(O)R d , C(O)OR d , -C(O)NR b R c , -NR b C(O)R d , a C 1-6 alkyl group optionally substituted by a substituent, and C 1 optionally substituted by a substituent -6 alkoxy.
• R 3 is each independently selected from the group consisting of a hydrogen atom, a hydroxyl group, a thiol group, a halogen atom, a C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, an amino C 1-6 alkyl group, Halogenated C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy.
• R 3 is each independently selected from the group consisting of a hydrogen atom, a hydroxyl group, a fluorine, a chlorine, a bromine, and a C 1-4 alkyl group.
• R 4 in Cy 4 is each independently selected from a hydrogen atom, a hydroxyl group, a thiol group, a halogen atom, a carboxyl group, a nitro group, -NR b R c , -C(O)R d , C(O)OR d , -C(O)NR b R c , -NR b C(O)R d , a C 1-6 alkyl group optionally substituted by a substituent, and C 1 optionally substituted by a substituent -6 alkoxy, or two R 4 may form a 5-6 membered cyclic group with the attached atom.
• R 4 is each independently selected from the group consisting of a hydrogen atom, a hydroxyl group, a thiol group, a halogen atom, a C 1-6 alkyl group, a hydroxy C 1-6 alkyl group, an amino C 1-6 alkyl group, and a halogen.
• C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkyl C 1-6 Alkoxy, C 1-6 alkoxy C 1-6 alkoxy, or both R 4 may form a 5-6 membered oxygen-containing cyclic group with the attached atom.
• R 4 is selected from the group consisting of a hydrogen atom, a hydroxyl group, a thiol group, a halogen atom, a C 1-4 alkyl group, a halogenated C 1-4 alkyl group, a C 1-4 alkoxy group, C 1- 4 alkoxy C 1-4 alkyl, C 1-4 alkyl C 1-4 alkoxy, C 1-4 alkoxy C 1-4 alkoxy, halogenated C 1-4 alkoxy.
• two R 4 may form a 5-6 membered oxygen-containing cyclic group with the attached atom.
• L is selected from the group consisting of -NR b -, -O-, -S-, and a 5-10 membered heteroaryl group optionally substituted with a substituent.
• L is selected from -O -, - S-, and optionally containing substituents selected from NR b, O, S atoms 1-3 5-6 membered heteroaryl Group.
• L is -O-.
• L represents an optionally substituted pyridyl group.
• R a is absent or, at each occurrence, each independently selected from the group consisting of a hydrogen atom, a cyano group, a hydroxyl group, a thiol group, a halogen atom, a carboxyl group, a nitro group, a C 1-6 alkyl group , C 1-6 alkoxy, halogenated C 1-6 alkyl.
• R a is absent, or at each occurrence, is independently selected from hydrogen atoms, C 1-6 alkyl, C 1-6 alkoxy.
• R b , R c , R d or each are absent or, at each occurrence, each independently selected from the group consisting of a hydrogen atom, a cyano group, a hydroxyl group, a thiol group, a halogen atom, a carboxyl group, and a nitrate a group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a halogenated C 1-6 alkyl group.
• R b , R c , R d or each are absent or, at each occurrence, each independently selected from a hydrogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group base.
• Y 1 is selected from the group consisting of O, S, S(O), S(O) 2 ;
• Cy 2 is selected from the group consisting of phenyl and 5-6 membered heteroaryl
• Y 2 and Y 3 are independently selected from C or N, and at least one is N;
• Cy 4 is The groups shown, Y 4 and Y 5 are independently selected from C or N, and at least one is N, and ring B is a benzene ring or a 5-6 membered heteroaryl ring;
• R 1 is selected from the group consisting of hydrogen atom, hydroxyl group, mercapto group, halogen atom, carboxyl group, nitro group, -NR b R c , -C(O)R d , -C(O)OR d , -C(O)NR b R c , -NR b C(O)R d , C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy Base, halogenated C 1-6 alkoxy;
• R 2 is selected from the group consisting of hydrogen atom, hydroxyl group, mercapto group, halogen atom, carboxyl group, nitro group, -NR b R c , -C(O)R d , -C(O)OR d , -C(O)NR b R c , -NR b C(O)R d , C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy Base, halogenated C 1-6 alkoxy;
• R 3 is selected from the group consisting of: a hydrogen atom, a hydroxyl group, a fluorenyl group, a halogen atom, a carboxyl group, a nitro group, -NR b R c , -C(O)R d , -C(O)OR d , -C(O)NR b R c , -NR b C(O)R d , C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy Base, halogenated C 1-6 alkoxy;
• R 4 is selected from the group consisting of hydrogen atom, hydroxyl group, mercapto group, halogen atom, carboxyl group, nitro group, -NR b R c , -C(O)R d , -C(O)OR d , -C(O)NR b R c , -NR b C(O)R d , C 1-6 alkyl, hydroxy C 1-6 alkyl, amino C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy , halogenated C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkyl C 1-6 alkoxy, C 1-6 alkoxy C 1- 6 alkoxy, or two R 4 may form a 5-6 membered oxygen-containing cyclic group with the attached atom;
• L is selected from -NR b -, -O-, -S-;
• R a is absent or, at each occurrence, each independently selected from a hydrogen atom, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group;
• R b , R c , R d or each absent, or each occurrence, each independently selected from a hydrogen atom, a C 1-6 alkyl group;
• n is an integer from 0 to 2;
• q represents an integer from 0 to 2;
• t 1 , t 2 , t 3 , t 4 are each independently selected from an integer of 0-5;
• p 1 and p 2 are each independently selected from an integer of 0-2.
• a compound of the formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof having the structure represented by the formula (VI) ,
• X 1 is N
• X 2 is CR a
• X 1 is CR a
• X 2 is N
• X 2 is CR a
• X 1 is CR a
• X 2 is CR a
• X 1 is N
• X 2 is CR a
• X 1 is CR a
• X 2 is N
• X 2 is CR a
• X 1 is CR a
• X 2 is CR a
• Cy 2 represents a 6-14 membered aryl group optionally substituted by more than one R 2
• Cy 1 represents optionally The above R 1 substituted 3-12 membered heterocyclic group containing 1-3 groups selected from O, S, S(O), S(O) 2 , and the Cy 3 -L moiety does not form aryl oxygen Base part.
• Cy 1 represents a group selected to be optionally substituted by one or more R 1 A 3-12 membered heterocyclic group of 1-3 groups in O, S, S(O), and S(O) 2 .
• Cy 1 represents a moiety selected to be optionally substituted by one or more R 1 A 3-12 membered heterocyclic group of 1-3 groups in O, S, S(O), and S(O) 2 .
• Cy 1 represents an optional group optionally substituted by one or more R 1 a 3-12 membered heterocyclic group of 1-3 groups from O, S, S(O), S(O) 2
• Cy 2 represents a 6-14 membered aryl group optionally substituted by one or more R 2 And L does not represent a heteroaryl group.
• Cy 1 represents an optional group optionally substituted by one or more R 1 a 3-12 membered heterocyclic group of 1-3 groups from O, S, S(O), S(O) 2
• Cy 2 represents a 6-14 membered aryl group optionally substituted by one or more R 2 .
• the structure of the compound of the invention does not have the direct attachment of two carbonyl groups.
• Ring A is selected from the group consisting of phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl.
• Q is selected from the group consisting of hydrogen, cyano, hydroxy, halogen, carboxyl, nitro, -NR b R c , -C(O)R d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O)OR d , -NR b C(O)R d , -SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d , C 1-6 alkyl, hydroxy C 1-6 alkyl, cyano C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkylamino C 1-6 alkyl, halogen C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, C 1-6 alkoxy C 1- 6 alkoxy, C 2-8 alken
• Cy 1 is selected from a 3-12 membered heterocyclic group optionally substituted by one to a plurality of R 1 , and R 1 is selected from the group consisting of hydrogen, cyano, hydroxy, halogen, carboxyl, nitro, -NR b R c , -C(O)R d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O)OR d , -NR b C(O R d , -SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d , C 1-6 alkyl, hydroxy C 1-6 alkyl, cyano C 1-6 alkyl , amino C 1-6 alkyl, C 1-6 alkylamino C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C
• Cy 2 is selected from 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-14 optionally substituted with one to more R 2 a aryl group, a 5-10 membered heteroaryl group, and R 2 is selected from the group consisting of hydrogen, cyano, hydroxy, halogen, carboxyl, nitro, -NR b R c , -C(O)R d , -C(O) NR b R c , -OC(O)NR b R c , -NR b C(O)OR d , -NR b C(O)R d , -SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d , C 1-6 alkyl, hydroxy C 1-6 alkyl, cyano C 1-6 alkyl, amino C 1-6 alkyl
• Cy 3 is selected from 3-12 membered cycloalkyl, 3-14 membered heterocyclyl, 5-10 membered heteroaryl, optionally substituted by one to more R 3 , 6-14 a aryl group
• R 3 is selected from the group consisting of hydrogen, cyano, hydroxy, halogen, carboxyl, nitro, -NR b R c , -C(O)R d , -C(O)NR b R c , -OC(O NR b R c , -NR b C(O)OR d , -NR b C(O)R d , -SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d , C 1-6 alkyl, hydroxy C 1-6 alkyl, cyano C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkylamino C 1-6 alkyl,
• Cy 4 is selected from a 3-14 membered heterocyclic group, a 5-14 membered heteroaryl group optionally substituted by one to a plurality of R 4 , and R 4 is selected from the group consisting of hydrogen, cyano, hydroxy, Halogen, carboxyl, nitro, -NR b R c , -C(O)R d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O)OR d -NR b C(O)R d , -SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d , C 1-6 alkyl, hydroxy C 1-6 alkyl, cyanide a C 1-6 alkyl group, an amino C 1-6 alkyl group, a C 1-6 alkylamino C 1-6 alkyl group, a halogenated
• R a is absent or, at each occurrence, independently selected from the group consisting of hydrogen, cyano, hydroxy, halogen, carboxyl, nitro, -NR b R c , -C(O) R d , -C(O)NR b R c , -OC(O)NR b R c , -NR b C(O)OR d , -NR b C(O)R d , -SO 2 -NR b R c , -SO 2 R d , -NR b SO 2 R d , C 1-6 alkyl, hydroxy C 1-6 alkyl, cyano C 1-6 alkyl, amino C 1-6 alkyl, C 1 -6 alkylamino C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 alkoxy C 1-6 Alkyl, C 1-6 alkoxy
• R b , R c are absent or, at each occurrence, independently selected from the group consisting of hydrogen, hydroxy, -C(O)R d , -C(O)NR b R c , -SO 2 -NR b R c , -SO 2 R d , C 1-6 alkyl, hydroxy C 1-6 alkyl, cyano C 1-6 alkyl, amino C 1-6 alkyl, C 1- 6 alkylamino C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, -C 1-6 alkyl-R', -C(O) -R', -SO 2 -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl, R' is a 3-12 membered cyclo
• R d is absent or, at each occurrence, independently selected from the group consisting of hydrogen, -NR b R c , -NR b C(O)OR d , -NR b C(O) R d , -NR b SO 2 R d , C 1-6 alkyl, hydroxy C 1-6 alkyl, cyano C 1-6 alkyl, amino C 1-6 alkyl, C 1-6 alkylamino C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 alkoxy C 1-6 alkyl, C 1 -6 alkoxy C 1-6 alkoxy, -C 1-6 alkyl-R', -C 1-6 alkoxy-R', -O-R', -NR b C(O)- R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membere
• the present invention also provides a pharmaceutical composition
• a pharmaceutical composition comprising the compound represented by any one of the above formula (I), formula (II), formula (III), formula (IV), formula (V) and formula (VI), At least one of a pharmaceutically acceptable salt, ester, stereoisomer, tautomeric pharmaceutical composition thereof.
• the present invention also provides a compound comprising the above formula (I), formula (II), formula (III), formula (IV), formula (V) and formula (VI) or a pharmaceutically acceptable salt thereof
• the present invention also provides a compound comprising the above formula (I), formula (II), formula (III), formula (IV), formula (V) and formula (VI) or a pharmaceutically acceptable salt thereof
• the aforementioned pharmaceutical composition or dosage form may further comprise one or more second therapeutically active agents.
• a compound comprising any one of the above formula (I), formula (II), formula (III), formula (IV), formula (V) and formula (VI) or A pharmaceutical composition of a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof, which may optionally contain at least one second therapeutically active agent.
• the second therapeutically active agent is at least one selected from the group consisting of an antimetabolite, a growth factor inhibitor, a silk classification inhibitor, an antitumor hormone, and an alkylating agent.
• an antimetabolite a growth factor inhibitor
• a silk classification inhibitor an antitumor hormone
• an alkylating agent an alkylating agent.
• the pharmaceutical composition or dosage form can be administered by any suitable means known in the art, for example, by oral administration, parenterally (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal). Internal, intrathecal and epidural), transdermal, rectal, nasal, transpulmonary, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal administration, etc. / or treated patients or subjects.
• oral administration parenterally (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal). Internal, intrathecal and epidural), transdermal, rectal, nasal, transpulmonary, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal administration, etc. / or treated patients or subjects.
• the pharmaceutical composition or dosage form can be prepared into a conventional solid preparation, such as a tablet, a capsule, a pill, a granule, etc.; or an oral liquid preparation, such as an oral solution, orally. Suspensions, syrups, and the like.
• a suitable filler, a binder, a disintegrant, a lubricant, or the like may be added.
• the pharmaceutical composition can be prepared as an injection, a sterile powder for injection, and a concentrated solution for injection.
• the injection When the injection is prepared, it can be produced by a conventional method in the prior art, and when the injection is placed, an additional agent may be added, or a suitable additive may be added depending on the nature of the drug.
• the pharmaceutical composition For rectal administration, can be formulated as a suppository or the like.
• the pharmaceutical composition For pulmonary administration, can be formulated as an inhalant or a spray.
• the compound of any one of the above formula (I), formula (II), formula (III), formula (IV), formula (V) and formula (VI) or a pharmaceutical thereof is provided Acceptable salts, esters, stereoisomers, tautomers, pharmaceutical compositions of the above, above dosage forms for use in the preparation of a therapeutic and/or prophylactic mediated by aberrant expression of a TAM family kinase receptor and/or its ligand
• the disease mediated by the abnormal expression of the TAM family kinase receptor and/or its ligand includes at least one of the following diseases: tumor, tumor immunity, endometriosis, blood vessel Diseases/injuries, psoriasis, visual defects/lesions (macular degeneration, diabetes and premature birth), kidney disease, rheumatoid arthritis, osteoporosis and other related diseases.
• the disease mediated by abnormal expression of the TAM family kinase receptor and/or its ligand includes at least one of the following diseases: tumor, tumor immunity, endometriosis, vascular disease/injury, psoriasis, vision Defects/lesions (caused by macular degeneration, diabetes and premature birth), kidney disease, rheumatoid arthritis, osteoporosis and other related diseases.
• the compound of any one of the above formula (I), formula (II), formula (III), formula (IV), formula (V) and formula (VI) or a pharmaceutical thereof is provided Acceptable salts, esters, stereoisomers, tautomers, pharmaceutical compositions of the above, above dosage forms for the preparation and/or prevention of abnormalities by TAM family kinases/and CSF1R kinase receptors and/or their ligands
• Use of a drug for expressing a mediated disease includes at least one of the following diseases: tumor, tumor immunity Endometriosis, vascular disease/injury, psoriasis, visual defects/lesions (macular degeneration, diabetes and premature birth), kidney disease, rheumatoid arthritis, osteoporosis and other related diseases.
• Mediated diseases, diseases mediated by abnormal expression of the TAM family kinases/and CSF1R kinase receptors and/or their ligands include at least one of the following diseases: tumors, tumor immunity, endometriosis, Vascular diseases/injuries, psoriasis, visual defects/lesions (macular degeneration, diabetes and premature labor, etc.), kidney diseases, rheumatoid arthritis, osteoporosis and other related diseases.
• the tumor includes sarcoma, lymphoma and cancer, and specifically may be lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, breast ductal carcinoma, Head and neck cancer, endometrial cancer, uterine body cancer, rectal cancer, liver cancer, kidney cancer, renal pelvic cancer, esophageal cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female reproductive system cancer, carcinoma in situ, Lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, pharyngeal cancer, multiple myeloma, leukemia, non-Hodgkin's lymphoma, Colonic villus adenoma, melanoma, cell tumor and sarcoma.
• lung cancer squamous cell carcinoma, bladder cancer, gastric cancer, ovarian
• the compounds of the invention have an inhibitory effect on TAM family kinases.
• the compounds of the invention may also target CSF1R kinase and have an inhibitory effect on CSF1R kinase.
• the compounds of the invention are useful for the treatment and/or prevention of diseases mediated by aberrant expression of TAM family kinase receptors and/or their ligands.
• the compounds of the present invention are useful for the treatment and/or prevention of diseases mediated by abnormal expression of TAM family kinases/and CSF1R kinase receptors and/or their ligands.
• the compound of the present invention reverses the immunosuppression in the tumor microenvironment by inhibiting the TAM family kinase and CSF1R kinase, inhibits the growth, migration, and/or drug resistance of the tumor, and exerts the tumor immune effect and the antitumor effect.
• the compound of the present invention has a long half-life in vivo and excellent metabolic stability in vivo, and therefore the compound of the present invention can improve the therapeutic effect of the drug, reduce the burden of administration of the patient, and improve patient compliance.
• hydrocarbons or hydrocarbon derivative groups of more than 3 carbon atoms such as propyl, propoxy, butyl, unless otherwise explicitly defined, or the meaning is beyond the understanding of those skilled in the art
• butane, butene, butenyl, hexane, etc. have the same meaning as when the prefix is "positive" when the prefix is "positive”.
• propyl is generally understood to be n-propyl
• butyl is generally understood to be n-butyl unless otherwise specified.
• the "hair- emitting group” group and b represent an integer of 1 or more, and the expression a ⁇ b) means that a "group” has ab carbon atoms, for example, a C 1-4 alkyl group, that is, a carbon atom.
• the alkyl group, C 1-4 alkoxy C 1-4 alkyl group means a group in which an alkoxy group having 1 to 4 carbon atoms is bonded to an alkyl group having 1 to 4 carbon atoms.
• base and “group” mean a monovalent group or a divalent or higher group which conforms to a valence as required, for example, a "cycloalkyl group (also expressed as a cycloalkyl group) table includes therefrom.
• a monovalent group obtained by one hydrogen atom also includes a divalent or higher group obtained by removing one hydrogen atom from the same carbon atom or two or more different carbon atoms.
• cycloalkyl is used as When it is a terminal group, it is naturally a monovalent group, and when the cycloalkyl group is a linking group in the structure, it is a divalent or higher group.
• halogen atom as used in the present invention means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. It is preferably a fluorine atom, a chlorine atom or a bromine atom.
• halo means that one or more hydrogens on any carbon atom of the substituent may be substituted by one or more of the same or different halogens.
• Halogen is as defined above.
• C 1-6 alkyl group as used in the present invention means a linear or branched alkyl group derived by removing one or more hydrogen atoms from an alkane moiety having 1 to 6 carbon atoms, and for example, a methyl group is exemplified.
• C 1-4 alkyl group means the above examples containing from 1 to 4 carbon atoms.
• C 1-6 alkylamino group "(C 1-6 alkyl) 2 amino group", “C 1-6 alkyl ester group”, “C 1-6 alkylaminocarbonyl group”, “C 1-6 alkylcarbonyl”, “C 1-6 alkylcarbonyloxy”, “C 1-6 alkylsulfonylamino”, “C 1-6 alkylsulfonyl", “C 1-6”
• a group containing a "C 1-6 alkyl group” such as an alkylthio group means that each of the C 1-6 alkyl groups is -NH 2 , -CO-NH 2 -, -CO-O-, -CO-, - A group formed by the attachment of a corresponding group such as SO 2 NH 2 -, -SO 2 -, -S-.
• C 1-6 alkyl group may each be combined with -NH 2 , -CO-NH 2 -, -CO-O-, -CO-, -SO 2 NH 2 -, - A group formed by the attachment of a corresponding group such as SO 2 -, -S-, or the like.
• the "C 2-8 alkenyl group” as used in the present invention means a linear or branched olefin group derived by removing one or more hydrogen atoms from an olefin moiety having 2 to 8 carbon atoms containing at least one carbon-carbon double bond.
• a vinyl group, a 1-propenyl group, a 2-propenyl group, a 1-butenyl group, a 2-butenyl group, a 1,3-butadien-1-yl group, a 1-penten-3-yl group can be cited.
• the "C 2-8 alkenyl group” contains a carbon-carbon double bond.
• the "C 2-8 alkynyl group” as used in the present invention means a linear or branched alkyne derived by removing one or more hydrogen atoms from an alkyne moiety having 2 to 8 carbon atoms containing at least one carbon-carbon triple bond.
• the hydrocarbon group may, for example, be ethynyl, propynyl, 2-butyn-1-yl, 2-pentyn-1-yl, 3-pentyn-1-yl, 4-methyl-2-pentyne- 1-Based, 2-hexyn-1-yl, 2-hexyn-2-yl, 3-hexyn-1-yl, 3-hexyn-2-yl and the like.
• the "C 2-8 alkynyl group” contains a carbon-carbon oxime bond.
• C 1-6 alkoxy refers to the present invention as hereinbefore defined “C 1-6 alkyl” through an oxygen atom to the parent moiety is connected, i.e., "C 1-6 alkyl -O- Examples of the group include a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, a t-butoxy group, a n-pentyloxy group, a neopentyloxy group, a n-hexyloxy group, and the like.
• the "C 1-4 alkoxy group” refers to the above-mentioned example having 1 to 4 carbon atoms, that is, a "C 1-4 alkyl-O-" group.
• the "halogenated C 1-6 alkoxy group", “C 1-6 alkoxy C 1-6 alkoxy group”, “C 1-6 alkyl C 1-6 alkoxy” oxygen of the present invention means that at least one halogen atom, a C 1-6 alkoxy group, a C 1-6 alkyl group or the like respectively independently substitutes a C 1-6 alkoxy group. a group formed by at least one hydrogen atom on the group.
• the "fused ring” as used in the present invention means a polycyclic ring structure formed by joining two, two or more cyclic structures in a snail, a snail, or a bridge.
• the parallel ring refers to a fused ring structure formed by two or more ring structures sharing two adjacent ring atoms with each other (ie, sharing one bond).
• the bridged ring refers to a fused ring structure formed by two or more ring structures sharing two non-adjacent ring atoms with each other.
• the spiro ring refers to a fused ring structure formed by two or more ring structures sharing one ring atom with each other.
• cycloalkyl or “cycloalkyl” alkane as used herein is generally referred to as “cycloalkyl” alkane, and refers to a monovalent group derived from a cycloalkane or (as needed) a divalent or higher. Group.
• the cycloalkane includes a monocyclic cycloalkane or a fused ring cycloalkane and may have 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms.
• a certain cycloalkyl group includes all monocyclic, fused rings (including fused in the form of a snail, a snail, or a bridge) which may be formed.
• the cycloalkyl group may be a monovalent group of 3 to 12 members or (as needed) a divalent or higher group, and may be a monovalent group of 3 to 10 members or a divalent or higher group (as needed) a 3-8 membered monovalent group or (as needed) a divalent or higher group, a 3-6 membered monovalent group or (as needed) a divalent or higher group, 4-6 members A monovalent group or (as needed) a divalent or higher group.
• the monocyclic cycloalkyl group (monovalent or divalent or higher) may be a 3-12 membered cycloalkyl group, a 3-10 membered cycloalkyl group, a 3-8 membered cycloalkyl group, a 3-6 membered cycloalkyl group, or 4- 6-membered cycloalkyl.
• Examples thereof include, but are not limited to, cyclopropyl, cyclobutane, cyclopentyl, cyclohexane, cycloheptyl, cyclooctyl, cyclopentane-1,3-diyl, cyclohexane -1,4-diyl, cycloheptane-1,4-diyl and the like.
• the fused ring cycloalkyl (monovalent or divalent or higher) includes a cyclocycloalkyl group, a bridged cycloalkyl group, a spirocycloalkyl group.
• the (monovalent or divalent or higher) cyclocycloalkyl group may be a 6-11 membered cyclocycloalkyl group, a 7-10 membered cyclocycloalkyl group, and representative examples thereof include, but are not limited to, by a bicyclo ring [3.1. 1] heptane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] decane, bicyclo [3.3.1] decane and bicyclo [4.2.1] decane derived A monovalent group or a divalent or higher group obtained.
• cycloalkenyl group as used in the present invention means a group having at least one double bond in the group of the above cycloalkyl group. It may have 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring-forming carbon atoms. Unless otherwise specified, a certain cycloalkenyl group includes all monocyclic, fused rings (including fused in the form of a snail, a snail, or a bridge) which may be formed.
• the cycloalkenyl group may be a 3-12 membered cycloalkenyl group, a 3-8 membered cycloalkenyl group, a 4-6 membered cycloalkenyl group, a 7-11 membered spirocycloalkenyl group, a 7-11 membered cycloalkenyl group, and 6-11. Yuanqiao cycloalkenyl and the like.
• Examples of the cycloalkenyl group include a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a 1,4-cyclohexadien-1-yl group, a cycloheptenyl group, and a 1,4-cycloheptadiene-1. a group, a cyclooctyl group, a 1,5-cyclooctadien-1-yl group, etc., but is not limited thereto.
• Cycloalkyl and “cycloalkenyl” may also be a monovalent group obtained by removing a hydrogen atom from a 7-12 membered spiro ring or a 7-11 membered spiro ring, or from the same carbon atom or as needed.
• Cycloalkyl and “cycloalkenyl” may also be a monovalent group derived by removing a hydrogen atom from a 6-12 membered bridged ring or a 7-11 membered bridged ring, or from the same carbon atom or as needed. A divalent or higher group obtained by removing two or more hydrogen atoms from different carbon atoms. Examples of the bridge ring include, but are not limited to:
• the "heterocycle” as used in the present invention includes at least one selected from the group consisting of O, S, and N in the ring (may be 1-5, 1-4, 1-3, 1-2, or 1) a heteroatom as a non-aromatic cyclic hydrocarbon of a ring-forming atom. It may be a heterocyclic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring-forming atoms. There may optionally be at least one double bond in the ring.
• the heterocyclic ring of the present invention may be a single ring system or a fused ring system (fused in the form of a snail, a snail, or a bridge).
• heterocyclic ring examples include pyrroline, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, tetrahydropyran, dihydropyridine, dihydropyridazine, dioxane, and thiophene ring.
• a monocyclic heterocyclic ring such as cyclopentane, tetrahydrofuran, tetrahydropyran, tetrahydrothiazole or tetrahydroisothiazole; indoline, isoindoline, benzopyran, benzodioxane, A fused heterocyclic ring such as tetrahydroquinoline, benzo[d]oxazole-2(3H)-one, tetrahydrobenzothiophene or the like.
• 6-12-membered spiro heterocycle 7-11-membered spiroheterocycle, 6-12-membered saturated spiro ring, 7-membered saturated spiroheterocycle, 6-12-membered bridged heterocycle, and 7 -11 yuan bridge heterocycle, 6-12 yuan saturated bridge ring, 7-8 yuan saturated bridge ring.
• heterocyclic group or “heterocyclic group” ring hereinafter referred to as “heterocyclic group” ring means a monovalent or divalent or higher group derived from the above “heterocyclic ring".
• the "heterocyclic group” of the present invention may also be that at least one ring carbon atom of the above cycloalkyl or cycloalkenyl group is selected from O, S, S(O), S(O) 2 , N.
• the non-aromatic monovalent or divalent or higher cyclic group substituted with at least one hetero atom is preferably replaced by from 1 to 4 hetero atoms.
• heterocyclic group may be a group having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring-forming atoms. It may be a 3-14 membered heterocyclic group, a 3-12 membered heterocyclic group, a 3-10 membered heterocyclic group, a 4-10 membered heterocyclic group, a 3-8 membered heterocyclic group, and a 4-8 membered heterocyclic group. 4-6 membered heterocyclic group.
• heterocyclyl includes monovalent or (as needed) divalent or higher monocyclic heterocyclic radical systems or monovalent or (as desired) divalent or higher polycyclic heterocyclic radical systems (also known as thick Ring system), including saturated, partially saturated heterocyclic groups, but excluding aromatic rings. Unless otherwise specified, all single rings, fused rings (including fused in the form of snails, snails, bridges), saturated, partially saturated, which may be formed, are included.
• the monovalent or (as needed) divalent or higher monoheterocyclic group may be a 3-14 membered heterocyclic group, a 3-12 membered heterocyclic group, a 3-10 membered heterocyclic group, a 4-10 membered heterocyclic group, 3-8 membered heterocyclic group, 4-8 membered heterocyclic group, 4-6 membered heterocyclic group.
• it may be a 3-14 membered oxygen-containing heterocyclic group, a 3-14 membered nitrogen-containing heterocyclic group, a 3-12 membered oxygen-containing heterocyclic group, a 3-12 membered sulfur-containing heterocyclic group, and a 3-12 member-containing A sulfone group (S(O) 2 )heterocyclic group, a 3-12 membered sulfoxide group (S(O)) heterocyclic group or the like.
• heterocyclyl examples include, but are not limited to, aziridine, oxacyclopropane, thietyl, azetidinyl, oxetanyl, thietane, Tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, 1,2-thiazolidinyl, 1, 3-thiazolidinyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, piperidinyl, piperazinyl, morpholinyl, 1,4-dioxanyl, 1, 4-oxathiolanyl, 4,5-dihydroisoxazolyl, 4,5-dihydrooxazolyl, 2,5-dihydrooxazolyl, 2,
• a monovalent or (as needed) divalent or higher fused heterocyclic ring includes a heterocyclic group, a spiroheterocyclyl group, a bridged heterocyclic group which may be saturated, partially saturated or unsaturated, but not aromatic .
• the fused heterocyclic group may be a heterocyclic group fused to a 6-14 membered aryl group, a 3-12 membered cycloalkyl group, a 3-12 membered cycloalkenyl group, a 3-14 membered heterocyclic group or a 3-14 membered heteroaryl group.
• a heterocyclic group derived from pyridine A heterocyclic group derived from pyridine.
• the heterocyclic group may be 6-12 members and a cyclic group, a 7-10 membered ring group, a 6-10 membered ring group, a 6-12 membered saturated ring group, and representative examples include, but are not limited to: 3-azabicyclo[3.1.0]hexane, 3,6-diazabicyclo[3.2.0]heptyl, 3,8-diazabicyclo[4.2.0]octyl, 3, 7-diazabicyclo[4.2.0]octyl, octahydropyrrolo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3, 4-b][1,4]oxazinyl, octahydro-1H-pyrrolo[3,4-c]pyridyl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydro Benzofuran
• the spiroheterocyclyl group may be a monovalent group obtained by removing one hydrogen atom from a 6-12 membered spiroheterocycle, a 7-11 membered spiroheterocycle, a 6-12 membered saturated spiro ring, and a 7-membered saturated spiroheterocycle.
• a group, or a divalent or higher group obtained by removing two or more hydrogen atoms from the same carbon atom or a different carbon atom as needed, and examples of the spiroheterocycle include, but are not limited to:
• the bridged heterocyclic group may be a monovalent value obtained by removing a hydrogen atom from a 6-12-membered bridged heterocyclic ring, a 7-11-membered bridged heterocyclic ring, a 6-12-membered saturated bridged ring, and a 7-8-membered saturated bridged ring.
• a group, or a divalent or higher group obtained by removing two or more hydrogen atoms from the same carbon atom or a different carbon atom as needed, and examples of the bridged heterocyclic ring include, but are not limited to:
• aromatic ring as used in the present invention means a carbocyclic hydrocarbon having an aromatic character. It may be a 6-14 membered aromatic ring or a 6-10 membered aromatic ring. Specifically, the 6-membered aromatic ring is a benzene ring, the 10-membered aromatic ring is a naphthalene ring, and the 14-membered aromatic ring is an anthracene ring or a phenanthrene ring.
• aryl or aromatic group” group as used in the present invention is hereinafter referred to as "aryl” group, and means a monovalent group derived from an aromatic carbocyclic hydrocarbon or a divalent or higher amount as needed. Group. It includes a 6-14 membered aryl group and a 6-10 membered aryl group.
• the 6-14 membered aryl group is, for example, a phenyl group, a naphthyl group, a phenanthryl group or a fluorenyl group
• a 6-10 membered aryl group such as phenyl or naphthyl. When it is a divalent group, a phenylene group, a naphthylene group, etc. are mentioned.
• heteroaromatic ring as used in the present invention means at least one (may be 1-5, 1-4, 1-3, 1-2 or 1) which is selected from the group consisting of O, S, and N.
• An atom has a aromatic cyclic hydrocarbon as a ring-forming atom. It may be a 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 membered heteroaryl ring.
• the heteroaromatic ring of the present invention may be a single ring system or a fused ring system (fused in the form of a snail, a snail, or a bridge).
• pyrrole pyrazine
• pyrazole indole
• tetrazole furan
• thiophene pyridine
• imidazole triazole
• tetrazole triazine
• pyridazine pyrimidine
• pyrazine isoxazole
• thiazole pyrrole, pyrazine, pyrazole, indole, tetrazole, furan, thiophene
• pyridine imidazole
• triazole tetrazole
• triazine pyridazine
• pyrimidine pyrazine
• isoxazole and thiazole.
• a monocyclic heteroaryl ring such as isothiazole, thiadiazole, oxazole or oxadiazole; and examples thereof include isoindole, carbazole, hydrazine, isoindoline, quinoline, isoquinoline, anthracene Porphyrin, 2,3-naphthyridine, quinazoline, naphthyridine, quinoxaline, anthracene, pteridine, benzimidazole, benzisoxazole, benzoxazole, benzoxazole, benzoxazole, benzo Isothiazole, benzothiazole, benzothiadiazole, benzofuran, isobenzofuran, benzothiophene, benzotriazole, imidazopyridine, triazolopyridine, imidazothiazole, pyrazine and pyridazine, A fused heteroaryl ring such as benzimidazoline
• heteroaryl or “heteroaryl group” aryl as used in the present invention is hereinafter referred to as “heteroaryl” aryl means a monovalent or higher group derived from the above “heteroaryl ring".
• the "heteroaryl group” of the present invention may further have a ring-constituting atomic number of at least one hetero atom selected from O, S, and N of 5, 6, 7, 8, 9, 10, 11, An aromatic cyclic hydrocarbon group of 12, 13 or 14. That is, it may be a 5-14 membered heteroaryl group, a 5-10 membered heteroaryl group, or a 5-6 membered heteroaryl group.
• the heteroaryl group may have 1, 2, 3, 4 or 5 hetero atoms as ring-forming atoms. Further, the heteroaryl group also includes a case where a carbon atom or a sulfur atom is substituted by oxo or nitrogen, for example, a carbon atom is replaced by C(O), and a sulfur atom is replaced by S(O) or S(O) 2 .
• the heteroaryl group includes a monoheteroaryl group and a fused heteroaryl group, and unless otherwise specified, a certain heteroaryl group includes all monocyclic, fused ring, wholly aromatic, partially aromatic forms which may be formed.
• the monoheteroaryl group may be a 5-6 membered heteroaryl group, examples of which include, but are not limited to, furyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridyl, Pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thienyl, triazolyl and triazinyl.
• a fused heteroaryl group refers to a group formed by condensing a monocyclic heteroaryl ring to a phenyl group, a cycloalkenyl group, a heteroaryl group, a cycloalkyl group, or a heterocyclic group, and the fused heteroaryl group may be It is a 8-14 membered heteroaryl group, a 9-10 membered heteroaryl group, and examples include, but are not limited to, benzimidazolyl, benzofuranyl, benzothienyl, benzooxadiazolyl, benzothiazide Azyl, benzothiazolyl, porphyrin, 5,6-dihydroquinolin-2-yl, 5,6-dihydroisoquinolin-1-yl, furopyridinyl, oxazolyl, anthracene Base, isodecyl, isoquinolyl, naphthyridinyl, flu
• the "membered cyclic group of the invention” as used in the present invention means a group having 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring-forming atoms, which may be the present invention
• the above cycloalkyl group, cycloalkenyl group, heterocyclic group, aromatic ring group, and heteroaryl group have 5 to 14 ring-forming atoms. Specifically, it may be a 5-10 membered cyclic group or a 5-6 membered cyclic group.
• Examples thereof include, but are not limited to, pyrroline, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, tetrahydropyran, dihydropyridine, dihydropyridazine, dioxane, thiophene, Cyclopentane sulfide, tetrahydrofuran, tetrahydropyran, tetrahydrothiazole, tetrahydroisothiazole, pyrrole, pyrazine, pyrazole, indole, tetrazole, furan, thiophene, pyridine, imidazole, triazole, tetrazole, three A group derived from a derivative such as a azine, a pyridazine, a pyrimidine, a pyrazine, an isoxazole, a thiazole, an isothiazole, a thi
• At least one as used in the present invention means the number of substituents from 1 to all chemically replaceable positions of the group to be substituted, preferably 1 to 6, more preferably 1 to 5, more preferably 1 - 4, more preferably 1-3, more preferably 1-2 or 1.
• the ester according to the invention means a pharmaceutically acceptable ester formed by the compound of the invention, more particularly a formate, acetate, propionate, butyrate, acrylate of the compound of the invention and An ester such as ethyl succinate, but is not limited thereto.
• the "pharmaceutically acceptable salt” as used in the present invention means a pharmaceutically acceptable acid or base addition salt or a solvate thereof.
• Such pharmaceutically acceptable salts include salts of the following acids: hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfurous acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid. Hydroiodic acid, alkanoic acid (such as acetic acid, HOOC-(CH 2 ) n -COOH (where n is 0 to 4)), and the like.
• Salts of bases sodium salts, potassium salts, calcium salts, ammonium salts, and the like.
• a variety of non-toxic pharmaceutically acceptable addition salts are known to those skilled in the art.
• the hydrogen atom, fluorine atom, carbon atom, nitrogen atom, oxygen atom, sulfur atom and the like in the present invention also include their respective radioisotopes or stable isotopes.
• the "tumor” of the present invention includes sarcoma, lymphoma and cancer, and specifically includes lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, breast ductal carcinoma, head and neck cancer, and intrauterine Membrane cancer, uterine body cancer, rectal cancer, liver cancer, kidney cancer, renal pelvic cancer, esophageal cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female reproductive system cancer, carcinoma in situ, lymphoma, nerve fiber Tumor, bone, skin, brain, colon, testicular, gastrointestinal stromal, oral, pharyngeal, multiple myeloma, leukemia, non-Hodgkin's lymphoma, large intestine villus adenoma, Melanoma, cell tumor and sarcoma.
• invention and B means A alone, or both A and B.
• family kinase/and CSF1R kinase is meant “refers to” “family kinase” alone or both “independent or family kinase” and “CSF1R kinase.”
• stereoisomers of the compounds of the formulae (I), (II), (III), (IV), (V) and (VI) of the present invention mean when the formulae (I), (II), (III), When the (IV), (V) and (VI) compounds have an asymmetric carbon atom, an enantiomer is produced; when the compound has a carbon-carbon double bond or a cyclic structure, a cis-trans isomer is produced, all of which (I) Enantiomers, diastereomers, racemic isomers, geometric isomers, epimers, and mixtures thereof of the compounds are included within the scope of the invention.
• the definition of a compound of the invention includes all possible stereoisomers and mixtures thereof.
• racemic form includes racemic forms and isolated optical isomers having the indicated activities.
• the racemic form can be resolved by physical methods such as fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography.
• Individual optical isomers can be obtained from the racemate by conventional methods, such as salt formation with an optically active acid followed by crystallization.
• the "tautomer" of the compounds of the formulae (I), (II), (III), (IV), (V) and (VI) of the present invention means when the formula (I), (II), (III)
• the functional group isomers in which the atom of (IV), (V) and (VI) rapidly moves at two positions is called a tautomer; when the hydrogen group at the ⁇ position of the functional group containing a carbonyl group is in ⁇ On carbon, a keto tautomer is produced; when the hydrogen at the alpha position of the functional group containing a carbonyl group is on the oxygen of the carbonyl group, an alcoholic tautomer is produced.
• the pharmaceutical composition of the present invention comprises at least one of the compounds of the formulae I, II, III, IV, V and VI, pharmaceutically acceptable salts, esters, stereoisomers and tautomers thereof.
• the pharmaceutical composition of the present invention comprises a compound of Formulas I, II, III, IV, V and VI, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof and optionally Or a variety of pharmaceutically acceptable carriers.
• compositions of the present invention may be administered by any suitable means known in the art, for example, orally, parenterally (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural).
• parenterally including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural.
• the pharmaceutical composition of the present invention can be formulated into a conventional solid preparation such as a tablet, a capsule, a pill, a granule or the like; or an oral liquid preparation such as an oral solution, an oral suspension, a syrup or the like.
• a suitable excipient, diluent, sweetener, solubilizer, lubricant, binder, tablet disintegrating agent, stabilizer, preservative or encapsulating material may be added or A variety of substances.
• the pharmaceutical composition can be prepared as an injection, a sterile powder for injection, and a concentrated solution for injection.
• the injection When the injection is prepared, it can be produced by a conventional method in the prior art, and when the injection is placed, an additional agent may be added, or a suitable additive may be added depending on the nature of the drug.
• the pharmaceutical composition For rectal administration, the pharmaceutical composition can be formulated as a suppository or the like.
• the pharmaceutical composition can be formulated as an inhalant or a spray.
• Suitable solid carriers in the present invention include, but are not limited to, for example, cellulose, glucose, lactose, mannitol, magnesium stearate, magnesium carbonate, sodium carbonate, sodium saccharin, sucrose, dextrin, talc, starch, pectin, gelatin.
• Suitable liquid carriers include, but are not limited to, water, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, and the like), vegetable oils, glycerides, and mixtures thereof.
• compositions of the invention are generally known.
• the preparation of the pharmaceutical compositions of the present invention in a known manner includes conventional methods of mixing, granulating, tableting, coating, dissolving or lyophilizing.
• the pharmaceutical preparation is preferably in unit dosage form.
• the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient.
• the unit dosage form can be packaged in a package containing discrete quantities of the preparation, such as a packaged tablet, a capsule, or a powder in a vial or ampule.
• the dosage of the drug to be administered depends on various factors including the age, weight and condition of the patient and the route of administration. The precise dose administered is determined based on the judgment of the treating physician. Typical dosages for administration of the active compound may be, for example, from about 0.01 to about 100 mg per day, from about 0.05 to about 75 mg per day, from about 0.1 to about 50 mg per day, or from about 5 to about 10 mg per day. The desired dose will also depend on the particular compound employed, the severity of the disease, the route of administration, the weight and condition of the patient, and the judgment of the treating physician.
• reaction conditions are not indicated in the examples, and are carried out according to the conventional conditions or the conditions recommended by the manufacturer.
• the reagents or instruments used are not indicated by the manufacturer, and are conventional products which are commercially available.
• NBS N-bromosuccinimide
• AIBN azobisisobutyronitrile
• Pd(PPh 3 ) 2 Cl 2 bis(triphenylphosphine)dichloropalladium
• PE petroleum ether
• HATU 2-(7-azobenzotriazole)-tetramethylurea hexafluorophosphate
• DIPEA/DIEA N,N-diisopropylethylamine
• DEC Dichloroethane
• Step 3 Synthesis of 3-oxo-4-(p-tolyl)butyric acid ethyl ester
• Step 4 Synthesis of ethyl 4-oxo-5-(p-tolyl)-1,4-dihydropyridine-3-carboxylate
• Step 5 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-(p-tolyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester synthesis
• Step 6 Synthesis of 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-(p-tolyl)-1,4-dihydropyridine-3-carboxylic acid
• 6-Bromopyridin-3-ol (1.74 g, 10.0 mmol, 1.0 eq)
• 4-chloro-6,7-dimethoxybenzopyridine (2.24 g, 10.0 mmol, 1.0 eq)
• 4-dimethyl Aminopyridine (3.67 g, 30.0 mmol, 3.0 eq) was dissolved in toluene (50 mL) and was taken to 100 ° C for 16 hours.
• ,6,7-dimethoxyquinoline (1.70 g, yield: 47%)
• Step 3 N-(5-((6,7-Dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-4-oxo-1-((tetrahydro-2H-pyridyl) Synthesis of m--4-yl)methyl)-5-(p-tolyl)-1,4-dihydropyridine-3-carboxamide
• Step 2 Synthesis of 2-diazo-3-oxo-4-(p-tolyl)butyric acid ethyl ester
• Step 3 Synthesis of 2-indolyl-3-oxo-4-(p-tolyl)butyric acid ethyl ester
• Step 4 Synthesis of 2-(1-ethoxy-1,3-dioxo-4-(p-tolyl)but-2-enyl)indole-1-carboxylic acid tert-butyl ester
• Step 5 Synthesis of 4-oxo-5-(p-tolyl)-1,4-dihydropyridazine-3-carboxylic acid ethyl ester hydrochloride
• Step 1 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-(p-tolyl)-1,4-dihydropyridazine-3-carboxylic acid B Ester synthesis
• Step 2 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-(p-tolyl)-1,4-dihydropyridazine-3-carboxylic acid synthesis
• Step 1 Synthesis of ethyl 4-oxo-1-(tetrahydro-2H-pyran-4-yl)-5-(p-tolyl)-1,4-dihydropyridazine-3-carboxylate
• Step 2 Synthesis of 4-oxo-1-(tetrahydro-2H-pyran-4-yl)-5-(p-tolyl)-1,4-dihydropyridazine-3-carboxylic acid
• Step 3 Synthesis of 3-oxo-4-(p-tolyl)butyric acid ethyl ester
• Step 4 Synthesis of ethyl 5-(dimethylamino)-2-((dimethylamino)methylene)-3-oxo-4-(p-tolyl)pent-4-enoate
• Step 5 Synthesis of ethyl 4-oxo-1-(tetrahydro-2H-pyran-4-yl)-5-(p-tolyl)-1,4-dihydropyridine-3-carboxylate
• Step 6 Synthesis of 4-oxo-1-(tetrahydro-2H-pyran-4-yl)-5-(p-tolyl)-1,4-dihydropyridine-3-carboxylic acid
• reaction solution was concentrated under reduced pressure to remove tetrahydrofuran, and the pH was adjusted to 4 to 5, and a large amount of solid was precipitated, filtered, filtered, ethyl acetate (3.0 mL), and filtered, and filtered to give a white solid product (1.6 g, Step yield: 55%).
• Step 1 Synthesis of tert-butyl (5-hydroxypyrimidin-2-yl)carbamate
• tert-Butyl (5-hydroxypyrimidin-2-yl)carbamate (4.4 g, 20.8 mmol, 1.0 eq) was dissolved in diphenyl ether (70 mL) and 4-chloro-6,7-dimethoxyquine was added.
• the porphyrin (5.6 g, 24.9 mmol, 1.2 eq) and 4-dimethylaminopyridine (5.0 g, 41.6 mmol, 2.0 eq) was stirred overnight at 140 °C.
• the reaction was completely monitored by TLC. After cooling to room temperature, the mixture was poured into petroleum ether (200 mL) to precipitate a solid, which was filtered and dried to give product (2.4 g, yield: 32.2%).
• Step 1 4-oxo-1-((tetrahydro-2H-thiopyran-4-yl)methyl)-5-(p-tolyl)-1,4-dihydropyridazine-3-carboxylic acid B Ester synthesis
• Step 2 4-oxo-1-((tetrahydro-2H-thiopyran-4-yl)methyl)-5-(p-tolyl)-1,4-dihydropyridazine-3-carboxylic acid synthesis
• Step 3 N-(5-((6,7-Dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-4-oxo-1-((tetrahydro-2H-thio) Synthesis of m--4-yl)methyl)-5-(p-tolyl)-1,4-dihydropyridazine-3-carboxamide
• Step 1 Synthesis of ethyl 5-(dimethylamino)-2-((dimethylamino)methylene)-3-oxo-4-(p-tolyl)pentan-4-enoate
• Step 3 Synthesis of 4-oxo-1-((tetrahydro-2H-thiopyran-4-yl)methyl)-5-(p-tolyl)-1,4-dihydropyridine-3-carboxylic acid
• Step 4 N-(5-((6,7-Dimethoxyquinolin-4-yl)oxy)pyrimidin-2-yl)-4-oxo-1-((tetrahydro-2H-thio) Synthesis of m--4-yl)methyl)-5-(p-tolyl)-1,4-dihydropyridine-3-carboxamide
• Step 1 N-(5-((6,7-Dimethoxyquinolin-4-yl)oxy)pyrimidin-2-yl)-4-oxo-1-((tetrahydro-2H-thio) Synthesis of m--4-yl)methyl)-5-(p-tolyl)-1,4-dihydropyridazine-3-carboxamide
• Step 3 N-(6-((6,7-Dimethoxyquinolin-4-yl)oxy)pyridazin-3-yl)-4-oxo-1-((tetrahydro-2H-) Synthesis of pyran-4-yl)methyl)-5-(p-tolyl)-1,4-dihydropyridine-3-carboxamide
• Step 1 Synthesis of ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate
• Step 2 Synthesis of ethyl 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydroquinoline-3-carboxylate
• Step 4 N-(5-((6,7-Dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-4-oxo-1-((tetrahydro-2H-pyridyl) Synthesis of m--4-yl)methyl)-1,4-dihydroquinoline-3-carboxamide
• Step 1 N-(5-((6,7-Dimethoxyquinolin-4-yl)oxy)pyrimidin-2-yl)-5-(4-fluorophenyl)-4-oxo- Synthesis of 1-(tetrahydro-2H-pyran-4-yl)-1,4-dihydropyridine-3-carboxamide
• Step 2 N-(5-((6,7-Dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-1-(4-fluorophenyl)-2-oxo- Synthesis of 5-((tetrahydro-2H-pyran-4-yl)methyl)-1,2-dihydropyridine-3-carboxamide
• Step 2 Synthesis of 2-diazo-4-(4-fluorophenyl)-3-oxobutanoic acid ethyl ester
• Step 3 Synthesis of ethyl 4-(4-fluorophenyl)-2-ylidene-3-oxobutanoate
• Step 4 Synthesis of tert-butyl 2-(1-ethoxy-4-(4-fluorophenyl)-1,3-dioxobutan-2-yl)indole-1-carboxylate
• Step 5 Synthesis of ethyl 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridazine-3-carboxylate
• Step 6 Ethyl 5-(4-fluorophenyl)-4-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,4-dihydropyridazine-3-carboxylate synthesis
• Step 7 Synthesis of 5-(4-fluorophenyl)-4-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,4-dihydropyridazine-3-carboxylic acid
• Step 8 N-(5-((6,7-Dimethoxyquinolin-4-yl)oxy)pyrimidin-2-yl)-5-(4-fluorophenyl)-4-oxo- Synthesis of 1-(tetrahydro-2H-pyran-4-yl)-1,4-dihydropyridazine-3-carboxamide
• Step 1 N-(5-((6,7-Dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-5-(4-fluorophenyl)-4-oxo- Synthesis of 1-(tetrahydro-2H-pyran-4-yl)-1,4-dihydropyridazine-3-carboxamide
• Step 1 N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-2-oxo-1-((tetrahydro-2H) Synthesis of pyran-4-yl)methyl)-5-(p-tolyl)-1,2-dihydropyridine-3-carboxamide:
• Step 1 N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-6-oxo-1–((tetrahydro-2H) Synthesis of pyran-4-yl)methyl)-5-(p-tolyl)-1,6-dihydropyridine-3-carboxamide
• Step 1 N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-2,4-dioxo-1-((four Synthesis of Hydrogen-2H-pyran-4-yl)methyl)-3-(p-tolyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 3 Synthesis of 2,4-dioxo-3-(p-tolyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ethyl ester
• Step 5 2,4-Dioxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-3-(p-tolyl)-1,2,3,4-tetrahydropyrimidine -5-formic acid synthesis
• Step 1 Synthesis of methyl 5-bromo-6-oxo-1,6-dihydropyridine-3-carboxylate
• Step 2 Synthesis of methyl 5-bromo-6-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,6-dihydropyridine-3-carboxylate
• Step 3 6-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-(p-tolyl)-1,6-dihydropyridine-3-carboxylic acid methyl ester synthesis
• Step 4 Synthesis of 6-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-(p-tolyl)-1,6-dihydropyridine-3-carboxylic acid
• 6-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-(p-tolyl)-1,6-dihydropyridine-3-carboxylic acid methyl ester (1.7 g , 5 mmol, 1 eq) was dissolved in a mixed solution of THF / water / MeOH (1:1:1) (20mL), NaOH (2.0 g, 50 mmol, 10 eq) was added and allowed to react at room temperature for 3 hours.
• Step 1 Synthesis of methyl 5-bromo-2-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,2-dihydropyridine-3-carboxylate
• Step 3 Synthesis of 3-(4-aminophenyl)-5-(3,4-dimethoxyphenyl)pyridin-2-amine:
• Step 3 N-(5-((6,7-Dimethoxyquinolin-4-yl)oxy)thiophen-2-yl)-4-oxo-1-((tetrahydro-2H-pyridyl) Synthesis of m--4-yl)methyl)-5-(p-tolyl)-1,4-dihydropyridine-3-carboxamide
• Step 1 1-((1,1-dioxotetrahydro-2H-thiopyran-4-yl)methyl)-4-oxo-5-(p-tolyl)-1,4-dihydropyridine Synthesis of methyl-3-carboxylate
• reaction solution was concentrated under reduced pressure, water (1.5 mL) was added, and the pH was adjusted to 3 to 4 with hydrochloric acid (1 mol/L), filtered, and the filter cake was dried at 40 ° C to obtain a product (110.0 mg, yield: 90.9%) .
• Step 3 N-(5-((6,7-Dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-1-((1,1-dioxotetrahydro-2H) Synthesis of -thiam-4-yl)methyl)-4-oxo-5-(p-tolyl)-1,4-dihydropyridine-3-carboxamide
• Step 1 N-(5-((6,7-Dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-1-((1-oxotetrahydro-2H-thiopyran) Synthesis of 4-yl)methyl)-4-oxo-5-(p-tolyl)-1,4-dihydropyridine-3-carboxamide
• Step 3 Synthesis of 4-oxo-1-((tetrahydro-2H-thiopyran-4-yl)methyl)-5-(p-tolyl)-1,4-dihydropyridine-3-carboxylic acid
• Step 4 N-(5-((6,7-Dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-4-oxo-1-((tetrahydro-2H-thio) Synthesis of m--4-yl)methyl)-5-(p-tolyl)-1,4-dihydropyridine-3-carboxamide
• 2-Bromo-4-chloro-6,7-dimethoxyquinoline (4.4 g, 14.6 mmol), p-methoxybenzylamine (2.0 g, 14.6 mmol), potassium t-butoxide (1.64 g, 14.6) Methyl), dppf (161.03 mg, 0.292 mmol) and tetrakis(triphenylphosphine)palladium (168.9 mg, 0.146 mmol) were added to tetrahydrofuran (45 mL) and toluene (45 mL). .
• Step 4 Synthesis of 4-((6-bromopyridin-3-yl)oxy)-6,7-dimethoxy-N-(4-methoxybenzyl)quinolin-2-amine
• Step 5 Synthesis of 4-((6-aminopyridin-3-yl)oxy)-6,7-dimethoxy-N-(4-methoxybenzyl)quinolin-2-amine
• Step 6 N-(5-((6,7-Dimethoxy-2-((4-methoxybenzyl)amino)quinolin-4-yl)oxy)pyridin-2-yl)- Synthesis of 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-(p-tolyl)-1,4-dihydropyridine-3-carboxamide
• Step 7 N-(5-((2-Amino-6,7-dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-4-oxo-1-((tetrahydro) Synthesis of -2H-pyran-4-yl)methyl)-5-(p-tolyl)-1,4-dihydropyridine-3-carboxamide
• Step 1 N-(5-((6,7-Dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-2-oxo-1-((tetrahydro-2H-pyridyl) Synthesis of m--4-yl)methyl)-5-(p-tolyl)-1,2-dihydropyridine-3-carboxamide
• Step 1 Synthesis of 5-bromo-2-chloronicotinic acid ethyl ester
• Step 2 Synthesis of 5-bromo-2-ethoxyotinic acid ethyl ester
• Step 3 Synthesis of 2-ethoxy-5-methylnicotinic acid ethyl ester
• Step 4 Synthesis of 5-(bromomethyl)-2-ethoxyotinic acid ethyl ester
• Step 6 Synthesis of 2-ethoxy-5-((tetrahydro-4H-pyran-4-ylidene)methyl)nicotinic acid ethyl ester
• Step 7 Synthesis of 2-ethoxy-5-((tetrahydro-2H-pyran-4-yl)methyl)nicotinic acid ethyl ester
• Step 8 Synthesis of ethyl 2-oxo-5-((tetrahydro-2H-pyran-4-yl)methyl)-1,2-dihydropyridine-3-carboxylate
• Step 10 Synthesis of 2-oxo-5-((tetrahydro-2H-pyran-4-yl)methyl)-1-(p-tolyl)-1,2-dihydropyridine-3-carboxylic acid
• Step 11 N-(5-((6,7-Dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-2-oxo-5-((tetrahydro-2H-pyridyl) Synthesis of m--4-yl)methyl)-1-(p-tolyl)-1,2-dihydropyridine-3-carboxamide
• Step 1 Synthesis of ethyl 5-(4-fluorophenyl)-4-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,4-dihydropyridine-3-carboxylate
• Step 2 Synthesis of 5-(4-fluorophenyl)-4-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,4-dihydropyridine-3-carboxylic acid
• Step 3 N-(5-((6,7-Dimethoxyquinolin-4-yl)oxy)pyridin-2-yl)-5-(4-fluorophenyl)-4-oxo- Synthesis of 1-(tetrahydro-2H-pyran-4-yl)-1,4-dihydropyridine-3-carboxamide
• Step 3 N-(5-((6,7-Dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-4-oxo-1-(tetrahydro-2H-pyridyl) Synthesis of m--4-yl)-5-p-tolyl-1,4-dihydropyridazine-3-carboxamide
• Step 4 N-(5-([1,3]dioxol[4,5-g]quinolin-8-yloxy)pyridin-2-yl)-4-oxo-1 Synthesis of (tetrahydro-2H-pyran-4-yl)-5-(p-tolyl)-1,4-dihydropyridazine-3-carboxamide
• Step 3 Synthesis of 9-((6-bromopyridin-3-yl)oxy)-2,3-dihydro[1,4]dioxan[2,3-g]quinoline
• Step 4 5-((2,3-Dihydro-[1,4]dioxan[2,3-g]quinolin-9-yl)oxy)pyridin-2-amine synthesis
• Step 5 N-(5-((2,3-Dihydro-[1,4]dioxan[2,3-g]quinolin-9-yl)oxy)pyridine-2 Synthesis of 4-yl-1-(tetrahydro-2H-pyran-4-yl)-5-(p-tolyl)-1,4-dihydropyridazine-3-carboxamide
• Step 4 N-((cis)-4-((6,7-dimethoxyquinolin-4-yl)oxy)cyclohexyl)-4-oxo-1-((tetrahydro-2H) -pyran-4-yl)methyl)-5-(p-tolyl)-1,4-dihydropyridine-3-carboxamide and N-((trans)-4-((6,7-di) Methoxyquinolin-4-yl)oxy)cyclohexyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-5-(p-tolyl)- Synthesis of 1,4-dihydropyridine-3-carboxamide
• Test substance The structure and preparation of the compound of the present invention are as described above.
• the compound was dissolved in 100% DMSO to prepare a stock solution with a maximum concentration of 500 ⁇ M.
• the compound stock solution was diluted to a final concentration of the compound of 500, 150, 50, 15, 5, 1.5, 0.5, 0.15, 0.05 ⁇ M to become a compound working solution (50 ⁇ ).
• the Axl(h) enzyme was dissolved in 8 mM MOPS (pH 7.0), 0.2 mM EDTA, 250 ⁇ M KKSRGDYMTM QIG to prepare an enzyme solution having a final concentration of 1.7 nM.
• the enzymatic reaction was activated by using 10 mM magnesium acetate, 10 ⁇ M [ ⁇ - 33 P]-ATP to form a Mg/ATP mixture.
• the Mer(h) enzyme was dissolved in 8 mM MOPS (pH 7.0), 0.2 mM EDTA, 30 mM NaCl, 250 ⁇ M GGMEDIYFEFMGGKKK to prepare an enzyme solution having a final concentration of 3.1 nM.
• the enzymatic reaction was activated by using 10 mM magnesium acetate, 10 ⁇ M [ ⁇ - 33 P]-ATP to form a Mg/ATP mixture.
• the Tyro3(h) enzyme was dissolved in 8 mM MOPS (pH 7.0), 0.2 mM EDTA, 1 mM MnCl 2 , 250 ⁇ M KVEKIGEGTYGVVYK to prepare an enzyme solution having a final concentration of 38 nM.
• the enzymatic reaction was activated by using 10 mM magnesium acetate, 10 ⁇ M [ ⁇ - 33 P]-ATP to form a Mg/ATP mixture.
• the CSF1R enzyme was dissolved in 8 mM MOPS (pH 7.0), 0.2 mM EDTA, 250 ⁇ M KKSRGDYMTM QIG to prepare an enzyme solution having a final concentration of 64 nM.
• the enzymatic reaction was activated by using 10 mM magnesium acetate, 10 ⁇ M [ ⁇ - 33 P]-ATP to form a Mg/ATP mixture.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Rheumatology (AREA)
• Physical Education & Sports Medicine (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Epidemiology (AREA)
• Dermatology (AREA)
• Ophthalmology & Optometry (AREA)
• Pain & Pain Management (AREA)
• Endocrinology (AREA)
• Reproductive Health (AREA)
• Immunology (AREA)
• Urology & Nephrology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Plural Heterocyclic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Pyridine Compounds (AREA)

Priority Applications (3)

Applications Claiming Priority (6)

Publications (2)

Family

ID=67274177

Family Applications (1)

Country Status (5)

Cited By (3)

Families Citing this family (8)

Citations (4)

Family Cites Families (4)

• 2019
  • 2019-01-17 US US15/733,382 patent/US20210177828A1/en not_active Abandoned
  • 2019-01-17 EP EP19741754.6A patent/EP3741752A4/en not_active Withdrawn
  • 2019-01-17 JP JP2020539206A patent/JP7282397B2/ja active Active
  • 2019-01-17 WO PCT/CN2019/072083 patent/WO2019141202A1/zh not_active Ceased
  • 2019-01-17 CN CN201910046133.5A patent/CN110041316B/zh active Active

Patent Citations (4)

Non-Patent Citations (8)

Also Published As

Similar Documents

Legal Events