WO2020182188A1 - Composé hétéroaryle substitué, composition correspondante et utilisations associées - Google Patents

Composé hétéroaryle substitué, composition correspondante et utilisations associées Download PDF

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Publication number
WO2020182188A1
WO2020182188A1 PCT/CN2020/078990 CN2020078990W WO2020182188A1 WO 2020182188 A1 WO2020182188 A1 WO 2020182188A1 CN 2020078990 W CN2020078990 W CN 2020078990W WO 2020182188 A1 WO2020182188 A1 WO 2020182188A1
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alkyl
cycloalkyl
heteroaryl
aryl
heterocyclyl
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PCT/CN2020/078990
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English (en)
Chinese (zh)
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习宁
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习峰
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Priority claimed from CN202010157262.4A external-priority patent/CN111689991B/zh
Application filed by 习峰 filed Critical 习峰
Publication of WO2020182188A1 publication Critical patent/WO2020182188A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of medicine, and specifically relates to a new class of substituted heteroaryl compounds, their pharmaceutically acceptable salts, and pharmaceutical compositions containing the compounds, and the use of the compounds and the pharmaceutical compositions in preparing and treating mammals
  • drugs for proliferative diseases, autoimmune diseases, allergic diseases, inflammatory diseases, transplant rejection, cancer or other diseases More specifically, the compounds of the present invention can modulate the activities of the TAM kinase family (including Axl, Mer and Tyro-3), and the Trk kinase family (tropomyosin receptor kinases, including TrkA, TrkB, and TrkC), etc. , And then regulate the signal transduction inside and outside the cell.
  • the protein kinase family includes a large class of structurally related enzymes that control various signal transduction processes in cells and catalyze the phosphorylation of target protein substrates.
  • Many diseases are related to abnormal cellular responses triggered by protein kinase-mediated events. These diseases include benign and malignant proliferative diseases, diseases caused by inappropriate activation of the immune system, allograft rejection, graft-versus-host diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological diseases And neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease and hormone-related diseases. Accordingly, the medical field has developed effective protein kinase inhibitors for treating diseases.
  • kinases can be divided into multiple families by phosphorylated substrates (eg, protein-tyrosine, protein-serine/threonine, lipid, etc.). Tyrosine phosphorylation is one of the central events that regulate various biological processes such as cell proliferation, migration, differentiation and survival. Multiple families of receptor and non-receptor tyrosine kinases control the tyrosine groups that catalyze the transfer of phosphoric acid from ATP to specific cellular protein targets.
  • phosphorylated substrates eg, protein-tyrosine, protein-serine/threonine, lipid, etc.
  • Tyrosine phosphorylation is one of the central events that regulate various biological processes such as cell proliferation, migration, differentiation and survival.
  • Multiple families of receptor and non-receptor tyrosine kinases control the tyrosine groups that catalyze the transfer of phosphoric acid from ATP to specific cellular protein targets.
  • kinases in the protein kinase family include, but are not limited to, Aurora, Axl, abl, Akt, bcr-abl, Blk, Brk, Btk, c-Met, c-src, c-fms, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRafl, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Flt-3, Fak, fes, FGFRl, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, Fyn, AXL, IGF-1R, INS-R, KDR, Lck, Lyn, MEK, Mer, p38, PDGFR, PIK, PKC, PYK2, ros, Tie, Tie-2, TRK, Yes, Tyro3 and Zap70, etc. (Robin
  • Cancer and other hyperproliferative diseases is characterized by uncontrolled cell proliferation. Compared with normal tissues, the activity of many protein kinases is increased in human tumors, and this increased activity may be due to many factors, including increased kinase levels, mutations in the expression of co-activators or inhibitory proteins.
  • Axl is a receptor tyrosine kinase (ligand: growth inhibition specific protein 6, Gas6), which is unique in that it has two tandem immunoglobulin-like repeat units and two adhesion protein type III repeat units. It is a common feature of cell adhesion molecules.
  • Axl kinase belongs to the TAM family of receptor tyrosine kinases. It can activate Axl’s tyrosine kinase activity when combined with the ligand Gas6, thereby activating its downstream signal transduction pathways, participating in cell growth, migration, aggregation and apoptosis, etc. Process (Rothlin, CV; Ghosh, S.; Zuniga, EI; Oldstone, MBA; Lemke, G.
  • TAM receptors are pleiotropic inhibitors of the innate immune response.
  • Axl and Tyro-3 have the most similar gene structures, while Axl and Mer have the most similar tyrosine kinase domain amino acid sequences.
  • RTKs receptor tyrosine kinases
  • the structure of the TAM family includes an extracellular domain, a transmembrane domain, and a conserved intracellular kinase domain.
  • the extracellular domain contains two immunoglobulin-like (Ig) domains and two fibronectin domain III (FNIII) repetitive sequences, which are the binding sites for endogenous ligands; the conserved amino acid sequence KW in the kinase domain (I/L)A(I/L)ES is a unique structural feature of the TAM family.
  • Members of the TAM family have a common ligand—Growth Inhibition Specific Protein 6 (Gas 6), which can bind to all TAM receptor tyrosine kinases.
  • Gas 6 Greenth Inhibition Specific Protein 6
  • Axl and Gas 6 have the strongest binding force, which is better than
  • the weakest Mer is 3 to 10 times stronger (Zago'rska A, et al.
  • Axl kinase is overexpressed or activated in a variety of cancers, including ovarian cancer, melanoma, renal cell carcinoma, uterine leiomyoma, endometrial cancer, thyroid cancer, gastric cancer, breast cancer, NSCLC, CML, AML, colon Cancer, prostate cancer, various lymphomas, and esophageal cancer.
  • Trk or tropomyosin receptor kinase
  • Trk receptors are divided into TrkA, TrkB and TrkC, and their corresponding ligands are NGF, BDNF and NT-3, respectively.
  • the other ligand of TrkB is NT4/5. NT-3 can also act on TrkA and TrkB.
  • Trk receptors mainly carry out signal transduction and effect through the autophosphorylation of Trk receptors (Huang, E.J.; Reichardt, L.F. TRK receptors: roles in neuronal signal transduction. Annu. Rev. Biochem. 2003, 72, 609-642).
  • NTRK gene fusions involving NTRK1, NTRK2, or NTRK3 are oncogenic drivers of various adult and pediatric tumor types.
  • TRK fusion protein has ligand-independent kinase activity, can activate downstream signaling pathways related to it, stimulate cell growth and survival, and trigger cancers that are mutually exclusive with other carcinogenic drivers in humans.
  • TRK fusion proteins such as larotrectinib or entrectinib
  • TRK fusion-positive cancer patients E.Cocco,E.;Scaltriti,M.;Drilon,A.,NTRK fusion-positive cancers and TRK inhibitor therapy.Nat Rev Clin Oncol.2018, 15(12):731–747.
  • Immunotherapy refers to a treatment method that artificially enhances or suppresses the immune function of the body to achieve the purpose of curing diseases.
  • immunotherapy methods which are suitable for the treatment of many diseases.
  • Tumor immunotherapy aims to activate the human immune system, relying on autoimmune function to kill cancer cells and tumor tissues.
  • the target of immunotherapy is not tumor cells and tissues, but the body's own immune system.
  • Protein kinase inhibitors have attracted a lot of attention as new immunomodulatory, anti-inflammatory and anti-cancer drugs. Therefore, new or improved reagents that inhibit protein kinases such as Axl kinase and Trk kinase can be used as immunomodulators, antineoplastic agents, analgesics, and anti-organ fibrosis drugs for organ transplantation, and can also be used to prevent and treat autoimmune diseases ( For example, multiple sclerosis, psoriasis, rheumatoid arthritis, asthma, type I diabetes, inflammatory bowel disease, Crohn’s disease, polycythemia vera, essential thrombocythemia, bone marrow fibrosis, self Immune thyroid disease, Alzheimer's disease), diseases involving excessive activation of inflammatory response (e.g., eczema), allergies, chronic obstructive pulmonary disease, bronchitis, fibrosis, cancer (e.g., stomach cancer, liver cancer, lung
  • the present invention provides a class of compounds that inhibit, regulate and/or regulate the activity of one or more protein kinases, such as TAM kinases (Axl, Mer and Tyro3) and Trk kinases, for the treatment of proliferative diseases, autologous Immune diseases, allergic diseases, inflammatory diseases, pain, fibrosis, transplant rejection and their complications.
  • protein kinases such as TAM kinases (Axl, Mer and Tyro3) and Trk kinases
  • the compound of the present invention has better pharmacological activity.
  • the compound of the present invention shows excellent inhibitory activity and optimized kinase selectivity for the target kinase.
  • the compound of the present invention also has excellent membrane permeability and exhibits excellent pharmacokinetic properties in animals. Therefore, the compound of the present invention has very good development prospects.
  • the articles “a”, “an” and “said” used in the present invention are intended to include “at least one” or “one or more”. Therefore, these articles used in the present invention refer to articles of one or more than one (ie, at least one) object.
  • a component refers to one or more components, that is, there may be more than one component considered to be adopted or used in the embodiment of the described embodiment.
  • Stereoisomers refer to compounds that have the same chemical structure but differ in the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. .
  • tautomer or "tautomeric form” refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of tautomers can be reached.
  • proton tautomers also called prototropic tautomers
  • keto-enol tautomerism include interconversion through the recombination of some bond-forming electrons.
  • keto-enol tautomerism are the tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerism is phenol-ketone tautomerism.
  • a specific example of phenol-ketone tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.
  • the compounds of the present invention can be optionally substituted with one or more substituents, such as the compounds of the general formula of the present invention, or special examples, subclasses, and the present invention includes A class of compounds.
  • substituents can be substituted at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from specific groups, then the substituents can be substituted at each position with the same or different positions.
  • C 1 -C 6 alkyl refers particularly to the disclosure independently methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • alkyl or “alkyl group” used in the present invention refers to a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may optionally Ground is substituted by one or more substituents described in this invention.
  • alkyl groups contain 1-20 carbon atoms. In one embodiment, the alkyl group contains 1-12 carbon atoms; in another embodiment, the alkyl group contains 1-6 carbon atoms; in another embodiment, the alkyl group contains 1 -4 carbon atoms; in yet another embodiment, the alkyl group contains 1-3 carbon atoms.
  • the alkyl group may be optionally substituted with one or more substituents described herein.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH (CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl -2-Butyl (-C(CH 3 ) 2
  • haloalkyl or “haloalkoxy” means that an alkyl or alkoxy group is substituted by one or more halogen atoms. Examples of this include, but are not limited to, trifluoromethyl (-CF 3 ), Trifluoromethoxy (-OCF 3 ), difluoroethyl (-CH 2 CHF 2 , -CF 2 CH 3 , -CHFCH 2 F), trifluoroethyl (-CH 2 CF 3 , -CF 2 CH 2 F, -CFHCHF 2 ) and so on.
  • -CF 3 trifluoromethyl
  • -OCF 3 Trifluoromethoxy
  • difluoroethyl -CH 2 CHF 2 , -CF 2 CH 3 , -CHFCH 2 F
  • trifluoroethyl -CH 2 CF 3 , -CF 2 CH 2 F, -CFHCHF 2
  • hydroxyalkyl and “hydroxyalkoxy” refer to alkyl or alkoxy groups, as the case may be, substituted by one or more hydroxy groups, where "hydroxyalkyl” and “hydroxyalkyl”””Group” can be used interchangeably, such examples include, but are not limited to, hydroxymethyl (-CH 2 OH), 2-hydroxyethyl (-CH 2 CH 2 OH), 1-hydroxyethyl (-CH(OH) )CH 3 ), 2-hydroxyprop-2-yl (-COH(CH 3 ) 2 ), 2-hydroxy-2-methylpropyl (-CH 2 COH(CH 3 ) 2 ), 3-hydroxypropyl (-CH 2 CH 2 CH 2 OH), 2-hydroxypropyl (-CH 2 CH(OH)CH 3 ), hydroxymethoxy (-OCH 2 OH), etc.
  • cycloalkyl refers to a monovalent or multivalent saturated monocyclic, bicyclic or tricyclic ring system containing 3-12 carbon atoms.
  • Bicyclic cycloalkyls include spirobicycloalkyls, fused bicycloalkyls, and bridged bicycloalkyls.
  • the cycloalkyl group contains 3-12 carbon atoms; in other embodiments, the cycloalkyl group contains 3-10 carbon atoms; in other embodiments, the cycloalkyl group contains 3-8 carbon atoms.
  • the cycloalkyl group contains 3-7 carbon atoms; in other embodiments, the cycloalkyl group contains 3-6 carbon atoms; still in some embodiments, the cycloalkyl group is C 7 -C 12 cycloalkyl, which includes C 7 -C 12 monocycloalkyl, C 7 -C 12 bicycloalkyl (such as C 7 -C 12 spiro bicycloalkyl, C 7 -C 12 fused bicycloalkyl and C 7 -C 12 bridged bicycloalkyl) or C 7 -C 12 tricycloalkyl.
  • the cycloalkyl group may be independently unsubstituted or substituted with one or more substituents described in the present invention.
  • the term "monocyclic cycloalkyl” or “monocyclic alkyl” refers to a cycloalkyl of a monocyclic system, wherein the cycloalkyl has the definition as described above, and the monocyclic cycloalkyl group may independently Unsubstituted or substituted by one or more substituents described in the present invention.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclo Pentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl , Cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc.
  • cycloalkylalkyl includes cycloalkyl substituted alkyl groups.
  • a cycloalkylalkyl group refers to a "lower cycloalkylalkyl” group, that is, the cycloalkyl group is attached to a C1-6 alkyl group.
  • the cycloalkylalkyl group refers to a "phenylalkylene" containing a C1-3 alkyl group.
  • cyclopropylmethyl cyclobutylmethyl
  • cyclopentylmethyl cyclohexylmethyl
  • cyclopentylethyl cyclohexylethyl
  • the cycloalkyl group on the cycloalkylalkyl group may be further substituted with one or more substituents described in the present invention.
  • heterocyclic group and “heterocyclic ring” are used interchangeably herein, and both refer to a monovalent or multivalent, saturated or partially unsaturated, non-aromatic monocyclic ring containing 3-12 ring atoms.
  • the heterocyclyl or heterocyclic ring contains 4-12 ring atoms.
  • the heterocyclyl or heterocyclic ring contains 5-12 ring atoms.
  • the heterocyclyl or heterocyclic ring contains 5-8 ring atoms.
  • the heterocyclyl or heterocyclic ring contains 5-7 ring atoms.
  • the heterocyclic group includes a saturated heterocyclic group (heterocycloalkyl) and a partially unsaturated heterocyclic group. The heterocyclic group has one or more points of attachment to the rest of the molecule.
  • heterocyclic groups include, but are not limited to: oxirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, pyrazoline, pyrazole Alkyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxanyl, dithiocyclopentyl, tetrahydropyranyl , Dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithia Alkyl, Thioxanyl, Homopiperazinyl, Homopiperidinyl, Oxepanyl, Thi
  • 1,4-thiazepine Base 1,2-thiazepine Group
  • indolinyl 1,2,3,4-tetrahydroisoquinolinyl, 1,3-benzodioxanyl, 2-oxa-5-azabicyclo[2.2.1]heptan- 5-yl, 2-azaspiro[4.4]nonyl, 1,6-dioxaspiro[4.4]nonyl, 2-azaspiro[4.5]decyl, 8-azaspiro[4.5 ]Decyl, 7-azaspiro[4.5]decyl, 3-azaspiro[5.5]undecyl, 2-azaspiro[5.5]undecyl, octahydro-1H-isoindyl Dolyl, octahydrocyclopenta[c]pyrrolyl, indolinyl, 1,2,3,4-tetrahydroisoquinolinyl, hexahydrofuro[3,2-b]
  • Examples in which the sulfur atom in the heterocyclic group is oxidized include, but are not limited to, a sulfolane group and a 1,1-dioxothiomorpholinyl group.
  • the heterocyclic group may be optionally substituted by one or more substituents described in the present invention.
  • the heterocyclic group is a heterocyclic group composed of 4-7 atoms, which refers to a monovalent or multivalent, saturated or partially unsaturated non-aromatic monocyclic ring containing 4-7 ring atoms Or a bicyclic ring, where at least one ring atom is selected from nitrogen, sulfur and oxygen atoms.
  • the sulfur atom of the ring can optionally be oxidized to S-oxide.
  • the nitrogen atom of the ring can optionally be oxidized to an N-oxygen compound.
  • the heterocyclic group composed of 4-7 atoms has one or more connection points to connect with the rest of the molecule.
  • examples of monocyclic heterocyclic groups composed of 4-7 atoms include, but are not limited to: azetidinyl, oxetanyl, thietane, pyrrolidinyl, pyrrolinyl , Pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, tetrahydropyranyl, dihydropyranyl, 2H -Pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiazinyl, 1,2-o
  • heterocyclylalkyl includes heterocyclyl-substituted alkyl groups, wherein both heterocyclyl and alkyl have the meanings described in the present invention. Examples of this include, but are not limited to, tetrahydrofurylmethyl, pyrrole- 2-ylmethyl, morpholin-4-ylethyl, piperazin-4-ylethyl, piperidin-4-ylethyl, etc.
  • aryl means a monocyclic, bicyclic and tricyclic carbocyclic ring system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic Family, where each ring system contains a ring composed of 3-7 atoms, and there are one or more points of attachment to the rest of the molecule.
  • aryl can be used interchangeably with the term “aromatic ring”. Examples of aryl groups may include phenyl, naphthyl, and anthracenyl. The aryl group may be independently optionally substituted with one or more substituents described in the present invention.
  • arylalkyl or “aralkyl” includes aryl substituted alkyl groups.
  • an arylalkyl group refers to a "lower arylalkyl” group, that is, the aryl group is attached to a C1-6 alkyl group.
  • the arylalkyl group refers to a "phenylalkylene” containing a C 1-3 alkyl group. Specific examples thereof include, but are not limited to, benzyl, diphenylmethyl, phenethyl and the like.
  • the aryl group on the arylalkyl group may be further substituted with one or more substituents described in the present invention.
  • heteroaryl refers to monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, in which at least one ring is aromatic, and At least one aromatic ring contains one or more heteroatoms, and each ring system contains a ring composed of 5-7 atoms, and there are one or more connection points connected to the rest of the molecule.
  • heteroaryl can be used interchangeably with the terms “heteroaromatic ring” or “heteroaromatic compound”.
  • the heteroaryl group is a heteroaryl group consisting of 5-12 atoms including 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In another embodiment, the heteroaryl group is a heteroaryl group consisting of 5-10 atoms including 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In another embodiment, the heteroaryl group is a heteroaryl group consisting of 5-6 atoms including 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N.
  • the heteroaryl group is optionally substituted with one or more substituents described in the present invention.
  • heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl , 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-thi
  • heteroarylalkyl means that an alkyl group is substituted by one or more heteroaryl groups, wherein both the heteroaryl group and the alkyl group have the meanings described in the present invention.
  • heteroarylalkyl include, but not Limited to pyridine-2-methyl, imidazole-2-methyl, furan-2-ethyl, indole-3-methyl, etc.
  • halogen refers to F, Cl, Br or I.
  • the "pharmaceutically acceptable salt” used in the present invention refers to the organic and inorganic salts of the compound of the present invention.
  • Pharmaceutically acceptable salts are well-known in the field, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19.
  • Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups include hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or other methods described in books and literature such as ion exchange These salts.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphor sulfonate, cyclopentyl propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3 -Phenylpropylprop
  • Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the present invention also contemplates the quaternary ammonium salt formed by any compound containing the N group.
  • Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
  • Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts, and amine cations that resist counterion formation, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, and C 1 -8 Sulfonates and aromatic sulfonates.
  • solvate of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention.
  • Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • hydrate refers to the association formed by the solvent molecule being water.
  • the present invention discloses a class of novel compounds that can be used as inhibitors of protein kinase activity, especially TAM family kinases (including TYRO3, AXL and MER) and NTRK family kinases (including NTRKA, NTRKB, and NTRKC).
  • Compounds that are protein kinase inhibitors can be used to treat diseases related to inappropriate protein kinase activity, especially inappropriate TAM kinase and NTRK kinase activity.
  • the compound of the present invention has better pharmacological activity.
  • the compound of the present invention shows excellent inhibitory activity and optimized kinase selectivity for the target kinase.
  • the compound of the present invention also has excellent membrane permeability and exhibits excellent pharmacokinetic properties in animals. Therefore, the compound of the present invention has very good development prospects.
  • the compound disclosed in the present invention can show strong inhibitory activity on one or more protein kinases.
  • the present invention relates to a compound having a structure represented by formula (I):
  • U 1 and U 2 are each independently N or -C(R a )-;
  • R 1 , R 2 and R 4 are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, cyano substituted C 1 -6 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl, C 1-6 alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl, C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl C 1-6 alkyl, C 1-9 heteroaryl, C 1-9 heteroaryl C 1-6 alkyl; wherein each C 1-6 alkane Group, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, cyano substituted C 1-6 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkane C 1-6 alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl C 1-6 alkyl, C 6-12 ary
  • R a , R 3 , R 5 , R 6 , R 7 and R 8 is independently H, D, F, Cl, Br, -OH, -CN, -NO 2 , -NR c R d , C 1 -6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, cyano substituted C 1-6 alkyl, C 3-8 cycloalkyl, C 3- 8 Cycloalkyl C 1-6 alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl C 1-6 Alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-6 alkyl; wherein each C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 ring Alkyl C 1-6 alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl C 1-6 alkyl, C 6-12
  • R 2 and R 3 together with the carbon atom and nitrogen atom to which they are connected, optionally form a heterocyclic ring consisting of 4-12 atoms, wherein the heterocyclic ring consisting of 4-12 atoms is optionally substituted by 0, 1 , 2, 3, 4 or 5 R 13 substitutions;
  • n 0, 1, or 2.
  • R 2 is H, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, cyano substituted C 1-4 alkyl, C 3-8 Cycloalkyl, C 3-8 cycloalkyl C 1-4 alkyl, C 2-7 heterocyclyl, or C 2-7 heterocyclyl C 1-4 alkyl; wherein each C 1-4 alkane Group, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, cyano substituted C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkane C 1-4 alkyl, C 2-7 heterocyclyl and C 2-7 heterocyclyl C 1-4 alkyl are independently optionally substituted with 0, 1, 2, 3 or 4 R 12 ;
  • R 3 is H, D, -CN, C 1-4 alkyl, wherein each C 1-4 alkyl is optionally substituted with 0, 1, 2, 3 or 4 R 11 ;
  • R 2 and R 3 together with the carbon atom and nitrogen atom to which they are connected, optionally form a heterocyclic ring consisting of 5-12 atoms, wherein the heterocyclic ring consisting of 5-12 atoms is optionally substituted by 0, 1 , 2, 3, 4 or 5 R 13 substitutions.
  • the compound of the present invention has a structure represented by formula (II):
  • Each t1 and t2 are independently 0, 1, 2, or 3;
  • n 0, 1, 2, 4, or 5.
  • each t1 and t2 are independently 0, 1, 2, or 3; and m is 0, 1, 2, or 4, respectively.
  • R 1 is C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, cyano substituted C 1-4 alkyl , C 3-8 cycloalkyl, phenyl, or C 1-9 heteroaryl; wherein each of the C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1- 4 aminoalkyl, cyano substituted C 1-4 alkyl, C 3-8 cycloalkyl, phenyl and C 1-9 heteroaryl are independently optionally substituted by 0, 1, 2, 3 or 4 R 11 replaced.
  • U 1 and U 2 are each independently N or -C(R a )-;
  • Each R a and R 8 are each independently H, D, F, Cl, Br, -OH, -CN, -NO 2, -NH 2, or C 1-4 alkyl; wherein each of said C 1-4 Alkyl groups are independently optionally substituted with 0, 1, 2, 3 or 4 R 12 ; and
  • n 0, 1, or 2.
  • R 4 is H, D, methyl, ethyl, propyl, isopropyl, butyl, C 1-4 haloalkyl, C 1-4 aminoalkyl, cyano substituted C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl, C 1-4 alkyl, C 2-7 heterocyclyl, or C 2-7 heterocyclyl C 1-4 alkyl .
  • R 5 is H, D, -NR c R d , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, Or C 1-4 alkyl substituted with cyano.
  • R 6 and R 7 are each independently H, D, F, Cl, Br, -OH, -NR c R d , -CN, -NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, or C 1-4 alkyl substituted with cyano.
  • the compound of the present invention is a compound having one of the following structures:
  • the compounds disclosed in the present invention may contain asymmetric or chiral centers, and therefore may exist in different stereoisomer forms.
  • the present invention aims to make all stereoisomeric forms of the compounds represented by formula (I) or (II), including but not limited to diastereomers, enantiomers, atropisomers and geometric (or Conformation) isomers, and their mixtures, such as racemic mixtures, form part of the present invention.
  • stereochemistry of any specific chiral atom when the stereochemistry of any specific chiral atom is not specified, all stereoisomers of the structure are considered in the present invention and are included in the present invention as the compound disclosed in the present invention .
  • stereochemistry is indicated by a solid wedge or dashed line representing a specific configuration, then the stereoisomer of the structure is clear and defined.
  • the compound represented by formula (I) or (II) may exist in the form of a salt.
  • the salt refers to a pharmaceutically acceptable salt.
  • pharmaceutically acceptable means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients of the formulation and/or the mammal to be treated with it.
  • the salt is not necessarily a pharmaceutically acceptable salt, and can be used to prepare and/or purify the compound of formula (I) or (II) and/or to isolate the compound of formula (I) Or an intermediate of the enantiomer of the compound shown in (II).
  • the present invention relates to intermediates for the preparation of compounds represented by formula (I) and (II).
  • the present invention relates to methods for the preparation, separation and purification of compounds represented by formula (I) and (II).
  • the present invention provides a pharmaceutical composition comprising a compound of the present invention.
  • the pharmaceutical composition of the present invention further includes pharmaceutically acceptable excipients, diluents or carriers, or combinations thereof.
  • the pharmaceutical composition can be in liquid, solid, semi-solid, gel or spray form.
  • the pharmaceutical composition of the present invention further comprises an additional therapeutic agent.
  • the present invention relates to a method of using the compound of the present invention or the pharmaceutical composition of the present invention to prevent or treat one or more Axl and/or Trk protein kinase-mediated diseases and/ Or the use of disease in medicine.
  • the disease and/or condition is selected from proliferative diseases, autoimmune diseases, allergic diseases, inflammatory diseases, or transplant rejection.
  • the disease and/or disorder is selected from the group consisting of treating and preventing TAM kinases involved in signaling pathways, and NTRK kinase-mediated diseases.
  • diseases include proliferative diseases, autoimmune diseases, allergic diseases, inflammatory diseases, transplant rejection, and their complications.
  • the compounds of the present invention can be used to treat the following diseases, such as cancer, polycythemia vera, essential thrombocythemia, myelofibrosis, myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia (CML ), chronic obstructive pulmonary disease (COPD), asthma, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren's syndrome, psoriasis, type I diabetes, respiratory allergic diseases, sinusitis , Eczema, measles, food allergy, insect venom allergy, inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, organ transplant rejection, tissue transplant rejection, cell transplantation Repulsion, etc.
  • diseases such as cancer, polycythemia vera, essential thrombocyth
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound disclosed in the present invention, or a compound listed in the examples; and pharmaceutically acceptable excipients, diluents, carriers, vehicles, or combinations thereof.
  • the amount of the compound in the pharmaceutical composition disclosed in the present invention refers to the amount that can effectively detect the inhibition of protein kinase in biological samples or patients.
  • compositions of the present invention may exist in free form for treatment, or may exist in the form of their pharmaceutically acceptable derivatives if appropriate.
  • pharmaceutically acceptable derivatives include pharmaceutically acceptable salts, esters, and salts of these esters, or can directly or indirectly provide the compound of the present invention or the compound of the present invention when administered to a patient in need Any additional adducts or derivatives of metabolites or residues.
  • the pharmaceutical composition provided by the present invention can be formulated with other active ingredients that do not impair the expected therapeutic effect, or with substances that supplement the expected effect.
  • the present invention provides the use of the compounds and pharmaceutical compositions disclosed in the present invention to treat, prevent, or ameliorate one or more protein kinases, such as TAM family kinases (including Tyro3, AXL and MER kinases), or NTRK family kinases (NTRKA, NTRKB and NTRKC) behavior-mediated or otherwise affected diseases or disorders, or by one or more protein kinases, such as TAM family kinases (including Tyro3, AXL and MER kinases), or NTRK family kinases (NTRKA, NTRKB and NTRKC) A method for one or more symptoms of a disease or disorder that is behavior-mediated or otherwise affected.
  • protein kinases such as TAM family kinases (including Tyro3, AXL and MER kinases), or NTRK family kinases (NTRKA, NTRKB and NTRKC)
  • TAM family kinases including Tyro3, AXL and MER kinases
  • the TAM family kinases (including Tyro3, AXL and MER kinases), or NTRK family kinases (NTRKA, NTRKB and NTRKC) may be wild-type and/or mutations of the included kinases.
  • the present invention provides a class of compounds disclosed in the present invention or pharmaceutical compositions containing the compounds disclosed in the present invention for the treatment, prevention, or amelioration of diseases mediated or otherwise affected by inappropriate AXL kinase behavior
  • a disease or disorder or one or more symptoms of a disease or disorder mediated or otherwise affected by inappropriate AXL kinase behavior is related to inappropriate MER kinase behavior.
  • the disease, disorder, or one or more symptoms of the disease or disorder is associated with inappropriate TYRO3 kinase behavior.
  • the present invention provides a class of compounds disclosed in the present invention or pharmaceutical compositions containing the compounds disclosed in the present invention for the treatment, prevention or amelioration of inappropriate NTRK-A kinase behavior mediated or otherwise
  • the affected disease or disorder or one or more symptoms of the disease or disorder mediated or otherwise affected by inappropriate NTRK-A kinase behavior is associated with inappropriate NTRK-B kinase behavior.
  • the disease, disorder, or one or more symptoms of the disease or disorder is associated with inappropriate NTRK-C kinase behavior.
  • Inappropriate AXL kinase behavior refers to AXL kinase behavior that deviates from normal AXL kinase behavior in a specific patient. Inappropriate AXL kinase behavior can take the form of, for example, an abnormal increase in activity, or a deviation in the time point and control of AXL kinase behavior. This inappropriate kinase behavior stems from, for example, inappropriate or uncontrolled behavior caused by overexpression or mutation of protein kinase. Therefore, the present invention provides methods for treating these diseases and disorders.
  • myeloproliferative diseases such as polycythemia vera (PCV), idiopathic thrombocythemia, idiopathic myelofibrosis (IMF); leukemia,
  • myeloid leukemia includes chronic myeloid leukemia (CML), imatinib-resistant CML forms, acute myeloid leukemia (AML) and subtypes of AML, acute megakaryoblastic leukemia (AMKL); lymphoproliferative diseases, such as Acute lymphocytic leukemia (ALL) and myeloma
  • cancers include head and neck cancer, prostate cancer, breast cancer, ovarian cancer, melanoma, lung cancer, brain tumor, pancreatic cancer, urothelial cancer, liver cancer, stomach cancer and kidney cancer Etc.
  • inflammatory diseases or disorders related to immune dysfunction, immunodeficiency, immune regulation, autoimmune diseases, tissue transplant rejection include inflammatory diseases or disorders related to immune dysfunction, immunodeficiency, immune regulation,
  • the present invention provides a class of compounds disclosed in the present invention or pharmaceutical compositions containing the compounds disclosed in the present invention, which are used to prevent and/or treat proliferative diseases, autoimmune diseases, and allergic diseases in mammals (including humans). Disease, inflammatory disease, or transplant rejection.
  • the present invention provides a method of treating a mammal suffering from or at risk of suffering from a disease disclosed in the present invention, the method comprising administering an amount effective to treat a disorder or an amount effective to prevent a disorder.
  • Pharmaceutical composition or compound comprising
  • the proliferative disease is selected from cancer (such as colon cancer, malignant glioma, endometrial cancer, liver cancer, lung cancer, melanoma, kidney cancer, thyroid cancer, lymphoma, lymphoproliferative disorder, small cell lung cancer) , Squamous cell lung cancer, glioma, breast cancer, prostate cancer, ovarian cancer, cervical cancer, etc.; hematological malignancies, such as acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), myelodysplastic disease (MPD) ), chronic myelogenous leukemia (CML), T-cell acute lymphoblastic leukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL), non-Hodgkin’s lymphoma (NHL), B-cell lymphoma; true Polycythemia, essential thrombocythemia, bone marrow fibrosis, multiple myeloma, etc.
  • cancer such
  • the present invention provides a method for treating and/or preventing a mammal susceptible to or suffering from an autoimmune disease, the method comprising administering an effective therapeutic amount or an effective preventive amount of one or more of the drugs disclosed in the present invention Composition or compound.
  • the autoimmune disease is selected from COPD, asthma, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren’s syndrome, psoriasis, type I diabetes and inflammatory bowel disease .
  • the present invention provides a method for treating and/or preventing a mammal susceptible to or suffering from an allergic disease, the method comprising administering an effective therapeutic amount or an effective preventive amount of one or more drugs disclosed in the present invention Composition or compound.
  • the allergic disease is selected from respiratory allergic diseases, sinusitis, eczema and measles, food allergy and insect venom allergy.
  • the allergic disease is selected from respiratory allergic diseases, sinusitis, eczema and measles, food allergy and insect venom allergy.
  • the present invention provides a method of treating and/or preventing a mammal susceptible to or suffering from an inflammatory disease, the method comprising administering an effective therapeutic amount or an effective preventive amount of one or more drugs disclosed in the present invention Composition or compound.
  • the present invention provides a class of compounds disclosed in the present invention for use as a medicine, especially as a medicine for treating and/or preventing the diseases of the present invention. Also provided is the use of the compounds disclosed in the present invention to prepare medicines for treating and/or preventing the diseases described in the present invention.
  • the compounds of the present invention may be administered as a single active agent, or may be administered in combination with other therapeutic agents, including other compounds that have the same or similar therapeutic activity and are determined to be safe and effective for such combined administration.
  • the present invention provides a method for treating, preventing or ameliorating a disease or condition, which comprises administering a safe and effective amount of a combination drug comprising a compound disclosed in the present invention and one or more therapeutically active agents.
  • the combination drug contains one or two other therapeutic agents.
  • therapeutic agents include, but are not limited to: anti-cancer agents, including chemotherapeutic agents and anti-proliferative agents; anti-inflammatory agents; and immune modulators or immunosuppressive agents.
  • the present invention provides a product comprising the compound of the present invention and at least one other therapeutic agent, which can be prepared as a combination for simultaneous, separate or sequential administration during treatment.
  • the treatment is for the treatment of diseases or symptoms mediated by the activity of one or more protein kinases, such as AXL kinase, or NTRK kinase.
  • the products provided by the joint preparation include a composition containing the disclosed compound of the present invention and other therapeutic agents in the same pharmaceutical composition, or the disclosed compound of the present invention and other therapeutic agents in different forms, for example, a kit.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound disclosed in the present invention and another one or more therapeutic agents.
  • the pharmaceutical composition may include pharmaceutically acceptable excipients as described above.
  • the present invention provides a kit containing two or more separate pharmaceutical compositions, wherein at least one pharmaceutical composition contains the compound disclosed in the present invention.
  • the kit includes means for separately holding the composition, such as a container, a separate bottle or a separate foil box.
  • An example of such a kit is a blister pack, which is commonly used for packaging tablets, capsules and the like.
  • the compounds disclosed in the present invention can be administered as a single active ingredient or as, for example, adjuvants, co-administered with other therapeutic agents.
  • the other therapeutic agents include chemotherapeutic agents and/or anti-proliferative agents.
  • chemotherapeutic drugs include, but are not limited to, other therapies or anticancer drugs that can be used in combination with the compounds of the present invention, surgery, and radiotherapy (a few examples are gamma radiation, neutron beam radiotherapy, electron beam radiotherapy, proton Therapies, brachytherapy and systemic radioisotope therapy), endocrine therapy, taxanes (taxol, docetaxel, etc.), platinum derivatives (cisplatin, carboplatin) ), biological response modifiers (interferon, interleukin), tumor necrosis factor (TNF, TRAIL receptor target), hyperthermia and cryotherapy, agents to reduce any adverse reactions (such as antiemetics), and other drugs Approved chemotherapy drugs, including but not limited to alkylating drugs (mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide)
  • Anti-angiogenic agents (avastin, etc.). Monoclonal antibodies (belimumab, brentuximab, cetuximab, gemtuzumab, ipilimumab, ofatumumab, panitumumab, panitumumab) Monoclonal antibody (ranibizumab), rituximab (rituximab), tositumomab (tositumomab), trastuzumab (trastuzumab)).
  • kinase inhibitors imatinib, sunitinib, sorafenib, erlotinib, gefitinib, dasatinib
  • nilotinib lapatinib
  • crizotinib ruxolitinib
  • vemurafenib vandetanib
  • par Zopanib pazopanib, etc.
  • Drugs inhibit or activate cancer pathways such as mTOR, HIF (hypoxia inducible factor) pathway and others.
  • the compound disclosed in the present invention can also be combined with other treatment processes to improve curative effect. For example, give hormone therapy or special radiation therapy.
  • the compounds disclosed in the present invention are especially useful as radiosensitizers, especially for the treatment of tumors that are less sensitive to radiotherapy.
  • “Combination” means a fixed combination in a single dosage unit form or a kit of parts for combined administration, wherein the compound disclosed in the present invention and the combination partner can be administered independently at the same time or can be administered separately within a certain time interval , Especially for joint partners to show cooperation, such as synergy.
  • the terms "co-administration” or “co-administration” and the like as used in the present invention are intended to encompass the administration of a selected joint partner to a single individual (for example, a patient) in need thereof, and are intended to include substances in which the substance does not have to be administered through the same route of administration or Simultaneous administration of the treatment plan.
  • the treatment method disclosed in the present invention includes administering a safe and effective amount of the compound of the present invention or a pharmaceutical composition containing the compound of the present invention to a patient in need.
  • the various embodiments disclosed in the present invention include methods for treating the diseases mentioned in the present invention by administering a safe and effective amount of the compound disclosed in the present invention or a pharmaceutical composition containing the compound disclosed in the present invention to a patient in need.
  • the compound disclosed in the present invention or the pharmaceutical composition containing the compound disclosed in the present invention may be administered at one time, or according to the dosing schedule, administered several times at different time intervals within a specified time period. For example, it is administered once, twice, three times or four times a day. In one embodiment, it is administered once a day. In yet another embodiment, it is administered twice a day. It can be administered until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely.
  • the appropriate dosage regimen of the compound disclosed in the present invention or the pharmaceutical composition containing the compound disclosed in the present invention depends on the pharmacokinetic properties of the compound, such as dilution, distribution, and half-life, which can be determined by the skilled person.
  • the appropriate dosage regimen of the compound disclosed in the present invention or the pharmaceutical composition containing the compound disclosed in the present invention depends on the disease being treated, the severity of the disease being treated, the age of the patient being treated, and The physical condition, the medical history of the patient being treated, the nature of the simultaneous therapy, the desired therapeutic effect, and other factors are within the scope of the technician's knowledge and experience. Such technicians should also understand that the individual patient's response to the dosing regimen, or when individual patients need to change over time, may require adjustments to the dosing regimen.
  • the compounds disclosed in the present invention can be administered simultaneously with, or before or after, one or more other therapeutic agents.
  • the compound of the present invention and other therapeutic agents can be administered separately through the same or different administration routes, or they can be administered in the same pharmaceutical composition.
  • the compounds of the present invention can be prepared by the methods described in the present invention, unless there are further instructions, wherein the definition of the substituents is as shown in formula (I) or (II).
  • the following reaction schemes and examples are used to further illustrate the content of the present invention.
  • Anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained by refluxing and drying with sodium metal.
  • Anhydrous dichloromethane and chloroform are obtained by refluxing and drying with calcium hydride.
  • Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide are dried in advance with anhydrous sodium sulfate.
  • reaction flask is plugged with a suitable rubber stopper, and the substrate is injected through a syringe.
  • the glassware is all dried.
  • the chromatographic column is a silica gel column.
  • Silica gel 300-400 mesh was purchased from Qingdao Ocean Chemical Plant.
  • 1 H NMR spectra were recorded using a Bruker 300MHz, 400MHz, or 600MHz nuclear magnetic resonance spectrometer.
  • 1 H NMR spectrum uses CDC1 3 , DMSO-d 6 , CD 3 OD or acetone-d 6 as the solvent (in ppm), and uses TMS (0 ppm) or chloroform (7.26 ppm) as the reference standard.
  • the measurement conditions for low-resolution mass spectrometry (MS) data are: Agilent 6120 quadrupole HPLC-M (column model: Zorbax SB-C18, 2.1 ⁇ 30mm, 3.5 microns, 6min, flow rate 0.6mL/min.
  • Mobile phase 5 %-95% (CH 3 CN containing 0.1% formic acid) in (H 2 O containing 0.1% formic acid) using electrospray ionization (ESI), and UV detection at 210nm/254nm.
  • each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , U 1 , U 2 and n has the definition as described in the present invention;
  • PG 1 and PG 2 is a protecting group.
  • the compound of the present invention having the structure represented by formula (6) can be prepared by the general synthesis method described in Synthesis Scheme 1, and the specific steps can refer to the examples.
  • the boron ester derivative (1) in a suitable base such as cesium carbonate, potassium carbonate, sodium carbonate, etc.
  • a suitable Pd catalyst such as Pd(OAc) 2 , Pd( Under the action of dppf) 2 Cl 2 or Pd 2 (dba) 3, etc.
  • the compound (3) can be obtained by coupling reaction with the substituted heteroaryl compound (2 ) .
  • the aromatic amine derivative (4) is obtained after removing the protective group PG 1 .
  • the carboxylic acid derivative (5) is condensed with the compound (4) in the presence of a condensing agent (such as EDCI or HATU ) to obtain the target kinase inhibitor (6) .
  • a condensing agent such as EDCI or HATU
  • Carboxylic acid derivatives (5) can be found in the literature (see, for example, "Practical synthesis of bicyclic pyrazol-5-one derivatives.” Xuejin Feng, Michael A. Xi, Yanjun Wu, Xiaogang Wang, Ning Xi Tetrahedron Lett. 2017, 58, 46-49; Facile synthesis of bicyclic1-arylpyrazol-5-ones.”Wu,Y.;Wang,K.;Li,Z.;Bai,X.; Xi,N.Tetrahedron Lett.2014,55,142-147) The synthesis method described is obtained.
  • the compound of the present invention having the structure represented by formula (6) can also be prepared by the general synthesis method described in Synthesis Scheme 2, and the specific steps can refer to the examples.
  • the aryl or heteroaryl compound (7) is condensed with the compound (5) in the presence of a condensing agent (such as EDCI or HATU ) to obtain the compound (8) .
  • a condensing agent such as EDCI or HATU
  • the boronic ester derivative (10 ) is used in a suitable base (such as cesium carbonate, potassium carbonate, sodium carbonate, etc.), and a suitable Pd catalyst (such as Pd(OAc) 2 , Pd(dppf) 2 Cl 2 Or under the action of Pd 2 (dba) 3, etc.), the compound (9) can be obtained by coupling reaction with the substituted heteroaryl compound (8 ) .
  • a suitable base such as cesium carbonate, potassium carbonate, sodium carbonate, etc.
  • a suitable Pd catalyst such as Pd(OAc) 2 , Pd(dppf) 2 Cl 2 Or under the action of Pd 2 (dba) 3, etc.
  • the boronic ester derivative (9) can be used in a suitable base (such as cesium carbonate, potassium carbonate, sodium carbonate, etc.), and a suitable Pd catalyst (such as Pd(OAc) 2 , Pd(dppf) 2 Cl 2 Or under the action of Pd 2 (dba) 3, etc.), a coupling reaction occurs with the substituted heteroaryl derivative (2) to obtain the target kinase inhibitor (6) .
  • a suitable base such as cesium carbonate, potassium carbonate, sodium carbonate, etc.
  • a suitable Pd catalyst such as Pd(OAc) 2 , Pd(dppf) 2 Cl 2 Or under the action of Pd 2 (dba) 3, etc.
  • Step 2) N-(5-Bromopyridin-2-yl)-2-oxo-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1 ,4]oxazine-3-carboxamide
  • the reaction solution was heated to reflux and stirred for 7 hours under the protection of nitrogen, and concentrated under reduced pressure.
  • Step 1) (4-(4-Amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl) tert-butyl carbamate
  • the aqueous phase was separated and extracted with dichloromethane (200 mL), the organic phases were combined and washed with water (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (2.58 g, 81%) as a yellow solid.
  • Step 2) (4-(4-chloro-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl) tert-butyl carbamate
  • Step 2) N-(3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2- Oxy-1-phenyl-2,4,5,6-tetrahydro-1H-pyrrolo[1,2-b]pyrazole-3-carboxamide
  • Step 2) N-(4-Bromo-2-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
  • Step 2) 1,5-Dimethyl-3-oxo-2-phenyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborole (Pentan-2-yl)phenyl)-2,3-dihydro-1H-pyrazole-4-carboxamide
  • Step 2) (4-(4-Chloro-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl) tert-butyl carbamate
  • Examples 14 to 17 and Example 20 were prepared by a method similar to Example 2, and Examples 18 to 19 were prepared by a method similar to Example 10. See Table E for details:
  • the analytical LC/MS/MS system includes Agilent 1200 series vacuum degassing furnace, binary syringe pump, orifice automatic sampler, column incubator, Agilent G6430 three-stage quadrupole mass spectrometer with electrospray ionization (ESI) source .
  • the quantitative analysis is carried out in MRM mode, and the parameters of MRM conversion are shown in Table A:
  • the Agilent XDB-C18, 2.1 ⁇ 30mm, 3.5 ⁇ M column was used for analysis, and 5 ⁇ L of sample was injected. Analysis conditions: the mobile phase is 0.1% formic acid aqueous solution (A) and 0.1% formic acid methanol solution (B). The flow rate is 0.4 mL/min.
  • the mobile phase gradient is shown in Table B:
  • Agilent 6330 series LC/MS/MS spectrometers are used for analysis, equipped with G1312A binary syringe pump, G1367A automatic sampler and G1314C UV detector; LC/MS/MS spectrometers use ESI radiation source.
  • a Capcell MP-C18 column was used, the specification was: 100 ⁇ 4.6mm I.D., 5 ⁇ M (Phenomenex, Torrance, California, USA).
  • the mobile phase is 5mM ammonium acetate, 0.1% methanol aqueous solution (A): 5mM ammonium acetate, 0.1% methanol acetonitrile solution (B) (70:30, v/v); the flow rate is 0.6mL/min; the column temperature is kept at room temperature; Inject 20 ⁇ L of sample.
  • a typical incubation mixture includes human or rat liver microsomes (0.5 mg protein/mL), target compound (5 ⁇ M) and a total volume of 200 ⁇ L NADPH (1.0 mM) potassium phosphate buffer (PBS, 100 mM, pH 7.4) ), the test compound is dissolved in DMSO and diluted with PBS to make the final DMSO solution concentration of 0.05%.
  • the concentration of the compound in the incubation mixture of human or rat liver microsomes is determined by the method of LC/MS/MS.
  • the linear range of the concentration range is determined for each test compound.
  • the parallel incubation test used denatured microsomes as a negative control, incubated at 37°C, and the reaction was terminated at different time points (0, 15 and 60 minutes).
  • Verapamil (1 ⁇ M) was used as a positive control, incubated at 37°C, and the reaction was terminated at different time points (0, 5, 10, 15, 30, and 60 minutes).
  • Each assay method includes positive and negative control samples to ensure the integrity of the microsome incubation system.
  • the stability data of the compound of the present invention in human or rat liver microsomes can also be obtained from the following experiments. Place human or rat liver microsomes in a polypropylene test tube and incubate in double holes.
  • a typical incubation mixture includes human or rat liver microsomes (final concentration: 0.5 mg protein/mL), test compound (final concentration: 1.5 ⁇ M) and a total volume of 30 ⁇ L potassium phosphate buffer solution (containing 1.0 mM EDTA, 100 mM) , PH 7.4).
  • the test compound was dissolved in DMSO and diluted with potassium phosphate buffer solution to make the final concentration of DMSO 0.2%.
  • NADPH final concentration: 2mM
  • acetonitrile including IS
  • Centrifuge 4000 rpm for 10 minutes to remove proteins, collect the supernatant, and analyze by LC-MS/MS.
  • ketanserin (1 ⁇ M) was selected as the positive control, incubated at 37°C, and the reaction was terminated at different time points (0, 15, 30, and 60 minutes).
  • Each assay method includes positive and negative control samples to ensure the integrity of the microsome incubation system.
  • the concentration of the compound in the human or rat liver microsomes incubation (expressed as a percentage) is plotted as a percentage relative to the zero time point to infer the in vivo liver intrinsic clearance CL int (see for example, Naritomi Y, Terashita S, Kimura S, Suzuki A, Kagayama A, Sugiyama Y. Prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans.Drug Metabolism and Disposition 2001,29: 1316- 1324.).
  • the compound of the present invention When the compound of the present invention is incubated in human and rat liver microsomes, the compound of the present invention shows suitable stability.
  • Example B Pharmacokinetic evaluation of the compound of the present invention after oral or intravenous injection in mice, rats, dogs and monkeys
  • the pharmacokinetic studies of the compounds of the invention in mice, rats, dogs or monkeys were evaluated.
  • the compound of the present invention is administered in the form of aqueous solution or 2% HPMC+1% Tween-80 aqueous solution, 5% DMSO+5% saline solution, 4% MC or capsule form.
  • animals are given a dose of 1 or 2 mg/kg.
  • oral dose p.o.
  • it is 5 or 10 mg/kg for rats and mice, and 10 mg/kg for dogs and monkeys.
  • Blood (0.3 mL) was taken at time points of 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12 and 24 hours, and centrifuged at 3,000 or 4,000 rpm for 10 minutes.
  • the plasma solution was collected and stored at -20°C or -70°C until the aforementioned LC/MS/MS analysis.
  • the compound provided by the present invention When the compound provided by the present invention is administered by intravenous injection or oral administration, the compound of the present invention exhibits good pharmacokinetic properties, is well absorbed and has an ideal half-life (T 1/2 ) and high oral biological Utilization (F).
  • the kinase test is done by detecting myelin base protein (MBP) incorporated into ⁇ - 33 P-ATP.
  • MBP myelin base protein
  • TBS Tris Buffered Salt Solution
  • Greiner high binding white 384-well plate
  • kinase reaction in a total volume of 34 ⁇ L kinase buffer (prepared as needed, for example, 5mM Hepes pH 7.6, 15mM NaCl, 0.01% bovine serum albumin (Sigma#I-5506), 10mM MgCl 2 , 1mM DTT, 0.02% TritonX -100).
  • the compound was dissolved in DMSO and added to each well.
  • the final concentration of the compound in the DMSO solution was 1%. At least two tests are performed for each compound. For example, the final concentration of the enzyme is 10 nM or 20 nM.
  • Test method described above can be obtained IC 50 and / or suppression of the inhibitory constant K i.
  • the IC 50 is defined as the concentration of the compound that inhibits 50% of the enzyme activity under the test conditions.
  • Use 1/2log dilution factor to make a curve containing 10 concentration points, and estimate IC 50 value (for example, make a typical curve with the following compound concentration: 3 ⁇ M, 1 ⁇ M, 0.3 ⁇ M, 0.1 ⁇ M, 0.03 ⁇ M, 0.01 ⁇ M , 0.003 ⁇ M, 0.001 ⁇ M, 0.0003 ⁇ M, 0 ⁇ M), or 10 ⁇ M, 3 ⁇ M, 1 ⁇ M, 0.3 ⁇ M, 0.1 ⁇ M, 0.03 ⁇ M, 0.01 ⁇ M, 0.003 ⁇ M, 0.001 ⁇ M, 0 ⁇ M).
  • the reaction started after adding the MgATP mixture. After incubating at room temperature for 40 minutes, a phosphoric acid solution was added to it to a concentration of 0.5% to terminate the reaction. 10 ⁇ L of the reaction solution was distributed on the P30 filter in a spot shape, and washed with 0.425% phosphoric acid solution 4 times in 4 minutes, and washed with methanol once. After drying, measure with a scintillation counter.
  • the reaction started after adding the MgATP mixture. After incubating at room temperature for 40 minutes, a phosphoric acid solution was added to it to a concentration of 0.5% to terminate the reaction. 10 ⁇ L of the reaction solution was distributed on the P30 filter in a spot shape, and washed with 0.425% phosphoric acid solution 4 times in 4 minutes, and washed with methanol once. After drying, measure with a scintillation counter.
  • the reaction started after adding the MgATP mixture. After incubating at room temperature for 40 minutes, a phosphoric acid solution was added to it to a concentration of 0.5% to terminate the reaction. 10 ⁇ L of the reaction solution was distributed on the filter A in a spot shape, and washed 4 times with a 0.425% phosphoric acid solution in 4 minutes, and washed once with methanol. After drying, measure with a scintillation counter.
  • the cells in the 96-well plate were cultured overnight at 37°C, 5% CO 2 and 95% humidity.
  • cell survival rate (%) (Lum test drug- Lum culture medium control )/(Lum cell control- Lum medium control ) ⁇ 100%.
  • the cytochrome P450 induction assay can identify the potential of the test compound to induce CYP1A2, CYP2B6 or CYP3A4 in human hepatocytes.
  • CYP enzyme positive control drug indicaciones
  • negative control drug usually flumazenil
  • probe substrate only used for enzyme activity determination, if you only do mRNA analysis, you do not need to use probe substrate.
  • Common CYP enzyme tool drugs are shown in Table 8 below. Other types of tool drugs can be selected according to the purpose of reference.
  • the methods can be CCK-8, LDH, MTT and neutral red.
  • the required culture model such as monolayer cell, sandwich culture and 3D culture, etc.
  • Inducer incubation Add a freshly prepared and pre-warmed dosing solution containing positive/negative control drug or test drug in the corresponding well with the incubation solution. Incubate for 2-3 days and change the medium every day. Multiple wells for each compound Parallel operation. If necessary, samples can be taken at multiple time points on the last day of incubation of the test drug and its actual concentration can be analyzed.
  • the enzyme induction experiment calculates the induction multiple of mRNA level, the induction multiple of enzyme activity, and the induction activity of each relative to the positive control drug; the cytotoxicity experiment calculates the ratio of cell viability to the blank group after administration of each compound.
  • ⁇ Ct ⁇ Ct-control/sample- ⁇ Ct-vehicle control
  • the confirmed analysis method was used to detect the specific metabolites of each CYP subenzyme probe substrate, and the enzyme activity induction was calculated by comparing the difference between the metabolites of the test group and the vehicle control group.
  • the relative positive control activity is calculated according to the following formula:
  • Relative positive control activity (test group sample activity-vehicle group sample activity) / (positive control group sample activity-vehicle group sample activity) ⁇ 100.
  • the enzyme activity induction factor of the positive control drug is ⁇ 2 times, and the mRNA level induction factor ⁇ 4 times is considered to be a normal experimental system.
  • the standard can be appropriately lowered.
  • Cell viability ⁇ 70% in the test drug group is considered to be hepatotoxic.
  • the test drug is considered to have a risk of induction when the mRNA level is induced ⁇ 2 times and the mRNA induction level is ⁇ 20% relative to the positive control drug.
  • the risk of induction is also considered.

Abstract

La présente invention se rapporte au domaine des produits pharmaceutiques et concerne en particulier un composé hétéroaryle substitué tel que représenté par la formule (I), ou un stéréoisomère, un tautomère, un oxyde d'azote, un solvate, un métabolite ou un sel pharmaceutiquement acceptable de celui-ci, une composition pharmaceutique comprenant le composé, et des utilisations du composé et de la composition pharmaceutique correspondante dans la préparation d'un médicament pour le traitement de maladies prolifératives, de maladies auto-immunes, de maladies allergiques, de maladies inflammatoires, du rejet de greffe, du cancer ou d'autres maladies chez des mammifères. Le composé selon l'invention présente une activité inhibitrice élevée et une sélectivité de kinase optimisée par rapport à une kinase cible. De plus, le composé selon l'invention présente également d'excellentes propriétés transmembranaires, présente d'excellentes propriétés pharmacocinétiques chez un animal ; par conséquent, le composé selon l'invention présente de grandes perspectives de développement.
PCT/CN2020/078990 2019-03-13 2020-03-12 Composé hétéroaryle substitué, composition correspondante et utilisations associées WO2020182188A1 (fr)

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WO2022166610A1 (fr) * 2021-02-05 2022-08-11 四川科伦博泰生物医药股份有限公司 Composé hétérocyclique de pyridazinone, son procédé de préparation et son utilisation
CN115850301A (zh) * 2021-09-24 2023-03-28 中山医诺维申新药研发有限公司 吡唑酮类化合物及其组合物和用途

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Publication number Priority date Publication date Assignee Title
WO2021233236A1 (fr) * 2020-05-18 2021-11-25 北京范恩柯尔生物科技有限公司 Composé hétéroaryle substitué, composition et utilisation associées
WO2022166610A1 (fr) * 2021-02-05 2022-08-11 四川科伦博泰生物医药股份有限公司 Composé hétérocyclique de pyridazinone, son procédé de préparation et son utilisation
CN115850301A (zh) * 2021-09-24 2023-03-28 中山医诺维申新药研发有限公司 吡唑酮类化合物及其组合物和用途

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