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WO2020182188A1 - 取代的杂芳基化合物及其组合物和用途 - Google Patents

取代的杂芳基化合物及其组合物和用途 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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Prior art keywords
alkyl
cycloalkyl
heteroaryl
aryl
heterocyclyl
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PCT/CN2020/078990
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English (en)
French (fr)
Inventor
习宁
Original Assignee
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/zh

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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.

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Abstract

属于药物领域，具体涉及如式(I)所示的取代的杂芳基化合物、或其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物或药学上可接受的盐，和包含所述化合物的药物组合物以及使用所述化合物及其药物组合物在制备治疗哺乳动物的增殖性疾病、自身免疫性疾病、过敏性疾病、炎性疾病、移植排斥、癌症或其他疾病的药物中的用途。提供的化合物对目标激酶显示出优异的抑制活性和优化的激酶选择性。此外，提供的化合物还具有优良的透膜性质，在动物体内显示出优良的药代动力学性质，因此，提供的化合物具有非常好的开发前景。

Description

取代的杂芳基化合物及其组合物和用途 发明领域
本发明属于药物领域，具体涉及一类新的取代的杂芳基化合物、其药学上可接受的盐和包含所述化合物的药物组合物以及使用所述化合物及其药物组合物在制备治疗哺乳动物的增殖性疾病、自身免疫性疾病、过敏性疾病、炎性疾病、移植排斥、癌症或其他疾病的药物中的用途。更具体地说，本发明所述的化合物可以调节TAM激酶家族(包括Axl、Mer和Tyro-3)、和Trk激酶家族(原肌球蛋白受体激酶，包括TrkA、TrkB和TrkC)等的活性，进而调节细胞内外的信号转导。
发明背景
蛋白激酶家族包含一大类结构相关的酶，它们控制细胞内的各种信号转导过程，催化靶标蛋白质底物的磷酸化。许多疾病与蛋白激酶介导的事件引发的异常细胞应答有关。这些疾病包括良性的和恶性的增殖性疾病、免疫系统不适当激活导致的疾病、同种异体移植排斥、移植物抗宿主疾病、自身免疫性疾病、炎性疾病、骨疾病、代谢病、神经疾病和神经变性疾病、癌症、心血管疾病、变态反应和哮喘、阿尔茨海默病和激素相关疾病。相应地，医药领域已研发出治疗疾病有效的蛋白激酶抑制剂。
激酶可以通过磷酸化的底物分为多个家族(例如，蛋白质-酪氨酸，蛋白质-丝氨酸/苏氨酸，脂质，等)。酪氨酸磷酸化是调节各种生物学过程比如细胞增殖、迁移、分化和生存的中心事件之一。多个家族的受体和非受体酪氨酸激酶控制催化磷酸从ATP转移至特定细胞蛋白质靶标的酪氨酸基团。目前，已确认上述各个激酶家族一般相应的基序(Hanks et al.,FASEB J.,1995,9,576-596；Knighton et.al.,Science,1991,253,407-414；Garcia-Bustos en al.EMBO J.,1994,13:2352-2361)。蛋白激酶家族中的激酶的实例包括，但不限于，Aurora、Axl、abl、Akt、bcr-abl、Blk、Brk、Btk、c-Met、c-src、c-fms、CDKl、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和Zap70等(Robinson,D.R.；Wu,Y.M.；Lin,S.F.The protein tyrosine kinase family of the human genome.Oncogene 2000,19,5548-5557)。
癌症(和其它过度增殖性疾病)的特征在于不受控制的细胞增殖。与正常组织相比，在人体肿瘤中许多蛋白质激酶的活性升高，并且这种升高的活性可能是由于许多因素，包括激酶水平升高，共活化剂或抑制性蛋白质的表达发生突变。
Axl是一种受体酪氨酸激酶(配体：生长抑制特异性蛋白质6，Gas6)，其独特之处在于具有两个串联的免疫球蛋白样重复单位和两个粘连蛋白III型重复单位，是细胞粘着分子的常见特征。Axl激酶属于受体酪氨酸激酶TAM家族，与配体Gas 6结合可激活Axl的酪氨酸激酶活性，从而活化其下游的信号转导通路，参与细胞的生长、迁移、聚集和凋亡等进程(Rothlin,C.V.；Ghosh,S.；Zuniga,E.I.；Oldstone,M.B.A.；Lemke,G.TAM receptors are pleiotropic inhibitors of the innate immune response.Cell 2007,131,1124-1136)。Axl和Tyro-3具有最为相似的基因结构，而Axl和Mer具有最为相似的酪氨酸激酶域氨基酸序列。与其他受体酪氨酸激酶(RTKs)一样，TAM家族的结构包含胞外域、跨膜域和保守的胞内激酶域。胞外域含有两个类免疫球蛋白(Ig)结构域和两个纤连蛋白结构域Ⅲ(FNⅢ)重复序列，是内源性配体的结合位点；位于激酶结构域中的保守氨基酸序列KW(I/L)A(I/L)ES，是TAM家族所独有的结构特征。TAM家族成员有一个共同配体—生长抑制特异性蛋白6(Gas 6)，该配体能够与所有TAM受体酪氨酸激酶结合，其中Axl与Gas 6的结合力是最强的，要比最弱的Mer强3～10倍(Zago′rska A,et al.Diversification of TAM receptor tyrosine kinase function.Nature Immunology 2014，15:920–928；Nagata K,Ohashi K,Nakano T,et al.Identification of the Product of Growth Arrest-specific Gene 6 as a Common Ligand for Axl,Sky,and Mer Receptor Tyrosine Kinases.Journal of Biological Chemistry,1996,271(47):30022-30027.)。
Axl激酶在多种癌症中都存在超表达或激活，包括卵巢癌、黑色素瘤、肾细胞癌、子宫平滑肌瘤、子宫内膜癌、甲状腺癌、胃癌、乳腺癌、NSCLC、CML、AML、结肠癌、前列腺癌、各种淋巴瘤、和食道癌。近期研究表明，在经过化疗和受体酪氨酸激酶抑制剂(TKI)治疗后产生抗药性的癌细胞中，Axl的 超表达现象尤为严重，是产生耐药性的重要原因之一(Zhang,Z.；Lee,J.C.；Lin,L.；et al Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer.Nat.Genet.2012,44,852-860)。目前，癌症病人出现耐药性仍然是癌症治疗过程中的难点，而抑制Axl活性可以增强化疗敏感度及延缓耐药性的发生，因此，Axl原癌基因是用于发现和开发新治疗剂的有吸引力的和有价值的靶标(Feneyrolles C,Spenlinhauer A,Guiet L,et al.Axl Kinase as a Key Target for Oncology:Focus on Small Molecule Inhibitors.Mol Cancer Ther,2014,13(9):2141-2148)。基于在多种人恶性肿瘤中的牵连，需要设计特异性的和选择性的抑制剂来治疗癌症和Axl激酶介导的和/或与之相关的其它病况。本发明满足这些需要并且提供其它相关利益。
Trk即原肌球蛋白受体激酶，是原癌基因trk的产物，由原肌球蛋白和酪氨酸激酶融合产生，是受体酪氨酸激酶(RTK)家族中的成员。Trk受体分为TrkA、TrkB和TrkC，其相应的配基分别为NGF、BDNF和NT-3，TrkB的另一个配基为NT4/5，NT-3也可作用于TrkA和TrkB。NTs家族成员主要通过Trk受体的自身磷酸化进行信号转导，产生效应(Huang,E.J.；Reichardt,L.F.TRK receptors:roles in neuronal signal transduction.Annu.Rev.Biochem.2003,72,609-642)。
涉及NTRK1，NTRK2或NTRK3(分别编码神经营养蛋白受体TrkA，TrkB和TrkC)的NTRK基因融合体是各种成年和小儿肿瘤类型的致癌驱动因素。TRK融合蛋白具有配体非依赖性的激酶活性，能够激活与之有关的下游信号通路，刺激细胞的生长和存活，引发在人类体内与其他致癌驱动因素互斥的癌症。数据表明，抑制TRK融合蛋白(例如larotrectinib或entrectinib)可治疗NTRK融合阳性的癌症患者。(E.Cocco,E.；Scaltriti,M.；Drilon,A.,NTRK fusion-positive cancers and TRK inhibitor therapy.Nat Rev Clin Oncol.2018，15(12):731–747.)
免疫疗法是指针对机体低下或亢进的免疫状态，人为地增强或抑制机体的免疫功能以达到治疗疾病目的的治疗方法。免疫治疗的方法有很多，适用于多种疾病的治疗。肿瘤的免疫治疗旨在激活人体免疫系统，依靠自身免疫机能杀灭癌细胞和肿瘤组织。与以往的手术、化疗、放疗和靶向治疗不同的是，免疫治疗针对的靶标不是肿瘤细胞和组织，而是人体自身的免疫系统。
蛋白激酶抑制剂作为新的免疫调节、抗炎作用药和抗癌症药聚集了众多关注。因此，抑制蛋白激酶如Axl激酶、和Trk激酶的新试剂或改进试剂可作为器官移植的免疫调节剂、抗肿瘤剂，止痛剂，抗器官纤维化药物，也可用于预防和治疗自体免疫疾病(例如，多发性硬化症、银屑病、类风湿性关节炎、哮喘、I型糖尿病、炎症性肠病、克罗恩病、真性红细胞增多症、原发性血小板增多症、骨髓纤维化、自身免疫性甲状腺病、阿尔兹海默病)，涉及过度活化炎症反应的疾病(例如，湿疹)，过敏，慢性阻塞性肺病，支气管炎，纤维化，癌症(例如，胃癌，肝癌，肺癌，结肠直肠癌，前列腺癌、急性髓细胞性白血病、慢性髓细胞性白血病、急性淋巴细胞白血病、白血病、多发性骨髓瘤)和其他治疗引起的免疫反应(例如，皮疹、接触性皮炎或腹泻)，慢性疼痛和急性疼痛，或者其中所述疼痛与癌症、外科手术、骨折、由肿瘤转移引起的骨痛、骨关节炎、银肩病关节炎、类风湿性关节炎、间质性膀胱炎、慢性胰腺炎、内脏痛、偏头痛、慢性腰背痛、膀胱疼痛综合征或神经性疼痛相关，等等。
本发明描述的化合物、组合物和方法直接对应这些需要和其他目的。具体地，本发明提供了一类抑制、调节和/或调控一种或多种蛋白激酶，如TAM激酶(Axl、Mer和Tyro3)、和Trk激酶活性的化合物，用于治疗增殖性疾病、自体免疫疾病、过敏性疾病、炎性疾病、疼痛、纤维化、移植排斥以及它们的并发症。与已有的同类化合物相比，本发明的化合物具有更好的药理活性，具体而言，本发明化合物对目标激酶显示出优异的抑制活性和优化的激酶选择性。此外，本发明化合物还具有优良的透膜性质，在动物体内显示出优良的药代动力学性质，因此，本发明化合物具有非常好的开发前景。
发明内容
术语定义
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在所附权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本发明所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本发明所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术，等等)，以本申请为准。
除非另有说明或者上下文中有明显的冲突，本发明所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此，本发明所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如，“一组分”指一个或多个组分，即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。
“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体，等等。
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。
像本发明所描述的，本发明的化合物可以任选地被一个或多个取代基所取代，如本发明的通式化合物，或者像实施例里面特殊的例子、子类，以及本发明所包含的一类化合物。
应了解“任选取代的”这个术语与“取代或非取代的”这个术语可以交换使用。一般而言，术语“取代的”表示所给结构中的一个或多个氢原子被具体取代基所取代。“任选地”除非其他方面表明，一个任选的取代基团可以在基团各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。
术语“任选地被……所取代”，可以与术语“未取代或被……所取代”交换使用，即所述结构是未取代的或者被一个或多个本发明所述的取代基所取代，本发明所述的取代基包括，但不限于H、D、氧代(＝O)、F、Cl、Br、-OH、-CN、-NO 2、-NR cR d、-C(＝O)R 9、-OC(＝O)R 9、-C(＝O)OR 9a、-S(＝O) 0-2R 9、-OS(＝O) 1-2R 9、-S(＝O) 1-2OR 9a、-N(R 10a)C(＝O)R 10、-C(＝O)NR 10aR 10、-OC(＝O)NR 10aR 10、-N(R 10a)S(＝O) 1-2R 10、-S(＝O) 1-2NR 10aR 10、-N(R 10a)C(＝O)NR 10aR 10、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基、氰基取代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-6烷基；其中所述各C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、C 1-9杂芳基C 1-6烷基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-OH、-NH 2、-CN、-NO 2、C 1-6烷基和C 1-6烷氧基的基团取代等等。其中，R c、R d、R 9、R 9a、R 10和R 10a具有如本发明所述的含义。
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C 1-C 6烷基”特别指独立公开的甲基、乙基、C 3烷基、C 4烷基、C 5烷基和C 6烷基。
本发明使用的术语“烷基”或“烷基基团”，表示含有1至20个碳原子，饱和的直链或支链一价烃基基团，其中，所述烷基基团可以任选地被一个或多个本发明描述的取代基所取代。除非另外详细说明，烷基基团含有1-20个碳原子。在一实施方案中，烷基基团含有1-12个碳原子；在另一实施方案中，烷基基团含有1-6个碳原子；在又一实施方案中，烷基基团含有1-4个碳原子；还在一实施方案中，烷基基团含有1-3个碳原子。所述烷基基团可任选地被一个或多个本发明描述的取代基所取代。
烷基基团的实例包含，但并不限于，甲基(Me、-CH 3)，乙基(Et、-CH 2CH 3)，正丙基(n-Pr、-CH 2CH 2CH 3)，异丙基(i-Pr、-CH(CH 3) 2)，正丁基(n-Bu、-CH 2CH 2CH 2CH 3)，异丁基(i-Bu、-CH 2CH(CH 3) 2)，仲丁基(s-Bu、-CH(CH 3)CH 2CH 3)，叔丁基(t-Bu、-C(CH 3) 3)，正戊基(-CH 2CH 2CH 2CH 2CH 3)，2-戊基(-CH(CH 3)CH 2CH 2CH 3)，3-戊基(-CH(CH 2CH 3) 2)，2-甲基-2-丁基(-C(CH 3) 2CH 2CH 3)，3-甲基-2-丁基(-CH(CH 3)CH(CH 3) 2)，3-甲基-1-丁基(-CH 2CH 2CH(CH 3) 2)，2-甲基-1-丁基(-CH 2CH(CH 3)CH 2CH 3)，正己基(-CH 2CH 2CH 2CH 2CH 2CH 3)，2-己基(-CH(CH 3)CH 2CH 2CH 2CH 3)，3-己基(-CH(CH 2CH 3)(CH 2CH 2CH 3))，2-甲基-2-戊基(-C(CH 3) 2CH 2CH 2CH 3)，3-甲基-2-戊基(-CH(CH 3)CH(CH 3)CH 2CH 3)，4-甲基-2-戊基 (-CH(CH 3)CH 2CH(CH 3) 2)，3-甲基-3-戊基(-C(CH 3)(CH 2CH 3) 2)，2-甲基-3-戊基(-CH(CH 2CH 3)CH(CH 3) 2)，2,3-二甲基-2-丁基(-C(CH 3) 2CH(CH 3) 2)，3,3-二甲基-2-丁基(-CH(CH 3)C(CH 3) 3)，正庚基，正辛基，等等。
术语“卤代烷基”或“卤代烷氧基”表示烷基或烷氧基基团被一个或多个卤素原子所取代，这样的实例包含，但并不限于，三氟甲基(-CF 3)、三氟甲氧基(-OCF 3)、二氟乙基(-CH 2CHF 2,-CF 2CH 3,-CHFCH 2F)、三氟乙基(-CH 2CF 3,-CF 2CH 2F,-CFHCHF 2)等。
术语“羟基烷基”和“羟基烷氧基”表示烷基或烷氧基基团，视情况而定，被一个或多个羟基基团所取代，其中，“羟基烷基”与“羟烷基”可以交换使用，这样的实例包含，但并不限于，羟甲基(-CH 2OH)、2-羟乙基(-CH 2CH 2OH)、1-羟乙基(-CH(OH)CH 3)、2-羟基丙-2-基(-COH(CH 3) 2)、2-羟基-2-甲基丙基(-CH 2COH(CH 3) 2)、3-羟基丙基(-CH 2CH 2CH 2OH)、2-羟基丙基(-CH 2CH(OH)CH 3)、羟基甲氧基(-OCH 2OH)等。
术语“环烷基”表示含有3-12个碳原子的，单价或多价的饱和单环，双环或三环体系。双环环烷基包含螺双环烷基、稠合双环烷基和桥双环烷基。在一些实施方案，环烷基包含3-12个碳原子；在另一些实施方案中，环烷基包含3-10个碳原子；在另一些实施方案中，环烷基包含3-8个碳原子；在另一些实施方案中，环烷基包含3-7个碳原子；在另一些实施方案中，环烷基包含3-6个碳原子；还在一些实施方案，环烷基为C 7-C 12环烷基，其包含C 7-C 12单环烷基、C 7-C 12双环烷基(如C 7-C 12螺双环烷基、C 7-C 12稠合双环烷基和C 7-C 12桥双环烷基)或C 7-C 12三环烷基。所述环烷基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。术语“单环环烷基”或“单环烷基”表示单环体系的环烷基，其中所述环烷基具有如前所述的定义，所述单环环烷基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。环烷基基团的实例包括，但不限于，环丙基、环丁基、环戊基、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-1-烯基、1-环己基-2-烯基、1-环己基-3-烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基、环十二烷基，等等。
术语“环烷基烷基”包括环烷基取代的烷基基团。在一些实施方案，环烷基烷基基团是指“较低级的环烷基烷基”基团，即环烷基基团连接到C 1-6的烷基基团上。在另一些实施方案，环烷基烷基基团是指含C 1-3的烷基的“苯烷撑”。其中具体实例包括，但不限于，环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基、环戊基乙基、环己基乙基等。环烷基烷基上的环烷基可进一步被一个或多个本发明所描述的取代基所取代。
术语“杂环基”和“杂环”在此处可交换使用，都是指包含3-12个环原子的，单价或多价的，饱和或部分不饱和的，非芳香性的单环、双环或三环体系，其中至少一个环原子选自氮、硫和氧原子。在一些实施方案，杂环基或杂环包含4-12个环原子。在一些实施方案，杂环基或杂环包含5-12个环原子。在一些实施方案，杂环基或杂环包含5-8个环原子。在一些实施方案，杂环基或杂环包含5-7个环原子。除非另外说明，杂环基可以是碳基或氮基，且-CH 2-基团可以任选地被-C(＝O)-替代，环的硫原子可以任选地被氧化成S-氧化物，环的氮原子可以任选地被氧化成N-氧化合物。杂环基包含饱和的杂环基(杂环烷基)和部分不饱和的杂环基。所述的杂环基具有一个或多个连接点与分子的其余部分相连。杂环基的实例包括，但不限于：环氧乙烷基、氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡咯啉基、吡唑啉基、吡唑烷基、咪唑啉基、咪唑烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、1,3-二氧环戊基、二硫环戊基、四氢吡喃基、二氢吡喃基、2H-吡喃基、4H-吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、二噁烷基、二噻烷基、噻噁烷基、高哌嗪基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氮单杂环庚烷、氧氮杂
Figure PCTCN2020078990-appb-000001
基(如，1,4-氧氮杂
Figure PCTCN2020078990-appb-000002
基、1,2-氧氮杂
Figure PCTCN2020078990-appb-000003
基)、二氮杂
Figure PCTCN2020078990-appb-000004
基(如，1,4-二氮杂
Figure PCTCN2020078990-appb-000005
基、1,2-二氮杂
Figure PCTCN2020078990-appb-000006
基)、二氧杂
Figure PCTCN2020078990-appb-000007
基(如，1,4-二氧杂
Figure PCTCN2020078990-appb-000008
基、1,2-二氧杂
Figure PCTCN2020078990-appb-000009
基)、硫氮杂
Figure PCTCN2020078990-appb-000010
基(如1,4-硫氮杂
Figure PCTCN2020078990-appb-000011
基、1,2-硫氮杂
Figure PCTCN2020078990-appb-000012
基)、吲哚啉基、1,2,3,4-四氢异喹啉基、1,3-苯并二噁茂基、2-氧杂-5-氮杂双环[2.2.1]庚-5-基、2-氮杂螺[4.4]壬烷基、1,6-二氧杂螺[4.4]壬烷基、2-氮杂螺[4.5]癸烷基、8-氮杂螺[4.5]癸烷基、7-氮杂螺[4.5]癸烷基、3-氮杂螺[5.5]十一烷基、2-氮杂螺[5.5]十一烷基、八氢-1H-异吲哚基、八氢环戊烷并[c]吡咯基、二氢吲哚基、1,2,3,4-四氢异喹啉基、六氢呋喃并[3,2-b]呋喃基和十二氢异喹啉基，等。杂环基中-CH2-基团被-C(＝O)-替代的实例包括，但不限于，2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-哌啶酮基和3,5-二氧代哌啶基。杂环基中硫原子被氧化的实例包括，但不限于，环丁砜基、1,1-二氧代硫代吗啉基。所述的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。
还在一实施方案中，杂环基为4-7个原子组成的杂环基，是指包含4-7个环原子的单价或多价的，饱和或部分不饱和的非芳香性的单环或双环，其中至少一个环原子选自氮、硫和氧原子。除非另外说明，4-7个原子组成的杂环基可以是碳基或氮基，且-CH 2-基团可以任选地被-C(＝O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。所述4-7个原子组成的杂环基具有一个或多个连接点与分子的其余部分相连。其中，4-7个原子组成的单环杂环基的实例包括，但不限于：氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、吡咯烷基、吡咯啉基、吡唑啉基、吡唑烷基、咪唑啉基、咪唑烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、四氢吡喃基、二氢吡喃基、2H-吡喃基、4H-吡喃基、四氢噻喃基、哌啶基、吗啉基、硫代吗啉基、哌嗪基、二噁烷基、二噻烷基、噻噁烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂
Figure PCTCN2020078990-appb-000013
基(1,4-氧氮杂
Figure PCTCN2020078990-appb-000014
基、1,2-氧氮杂
Figure PCTCN2020078990-appb-000015
基)、二氮杂
Figure PCTCN2020078990-appb-000016
基(1,4-二氮杂
Figure PCTCN2020078990-appb-000017
基、1,2-二氮杂
Figure PCTCN2020078990-appb-000018
基)和硫氮杂
Figure PCTCN2020078990-appb-000019
基(1,4-硫氮杂
Figure PCTCN2020078990-appb-000020
基、1,2-硫氮杂
Figure PCTCN2020078990-appb-000021
基)等；4-7个原子组成的双环杂环基的实例包括，但不限于：3-氮杂双环[3,2,0]庚烷、3-氧代双环[3,2,0]庚烷等；4-7个原子组成的杂环基中-CH2-基团被-C(＝O)-替代的实例包括，但不限于，2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-哌啶酮基和3,5-二氧代哌啶基；4-7个原子组成的杂环基中硫原子被氧化的实例包括，但不限于，环丁砜基、1,1-二氧代四氢噻吩、1,1-二氧代四氢噻喃、1,1-二氧代硫代吗啉基。所述的4-7个原子组成的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。
术语“杂环基烷基”包括杂环基取代的烷基，其中杂环基和烷基均具有如本发明所述的含义，这样的实例包括，但并不限于四氢呋喃基甲基、吡咯-2-基甲基、吗啉-4-基乙基、哌嗪-4-基乙基、哌啶-4-基乙基等。
术语“芳基”表示含有6-14个环原子，或6-12个环原子，或6-10个环原子的单环、双环和三环的碳环体系，其中，至少一个环体系是芳香族的，其中每一个环体系包含3-7个原子组成的环，且有一个或多个连接点与分子的其余部分相连。术语“芳基”可以和术语“芳香环”交换使用。芳基基团的实例可以包括苯基、萘基和蒽基。所述芳基基团可以独立任选地被一个或多个本发明所描述的取代基所取代。
术语“芳基烷基”或“芳烷基”包括芳基取代的烷基基团。在一些实施方案，芳基烷基基团是指“较低级的芳基烷基”基团，即芳基基团连接到C 1-6的烷基基团上。在另一些实施方案，芳基烷基基团是指含C 1-3的烷基的“苯烷撑”。其中具体实例包括，但不限于，苄基、二苯基甲基、苯乙基等。芳基烷基上的芳基可进一步被一个或多个本发明所描述的取代基所取代。
术语“杂芳基”表示含有5-12个环原子，或5-10个环原子，或5-6个环原子的单环、双环和三环体系，其中至少一个环是芳香族的，且至少一个芳香环包含一个或多个杂原子，其中每一个环体系包含5-7个原子组成的环，且有一个或多个连接点与分子其余部分相连。术语“杂芳基”可以与术语“杂芳环”或“杂芳族化合物”交换使用。在一实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-12个原子组成的杂芳基。在另一实施案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-10个原子组成的杂芳基。在另一实施方案中，杂芳基为包含1，2，3或4个独立选自O，S和N的杂原子的5-6个原子组成的杂芳基。所述杂芳基基团任选地被一个或多个本发明所描述的取代基所取代。
杂芳基基团的实例包括，但并不限于，2-呋喃基、3-呋喃基、N-咪唑基、2-咪唑基、4-咪唑基、5-咪唑基、3-异噁唑基、4-异噁唑基、5-异噁唑基、2-噁唑基、4-噁唑基、5-噁唑基、N-吡咯基、2-吡咯基、3-吡咯基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-嘧啶基、哒嗪基(如3-哒嗪基)、2-噻唑基、4-噻唑基、5-噻唑基、四唑基(如5-四唑基)、三唑基(如2-三唑基和5-三唑基)、2-噻吩基、3-噻吩基、吡唑基(如2-吡唑基)、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、吡嗪基、1,3,5-三嗪基；也包括以下的双环，但绝不限于这些双环：苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基(如2-吲哚基)、嘌呤基、喹啉基(如2-喹啉基，3-喹啉基，4-喹啉基)、异喹啉基(如1-异喹啉基、3-异喹啉基或4-异喹啉基)、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基、[1,2,4]三唑并[1,5-a]吡啶基，等等。
术语“杂芳基烷基”表示烷基基团被一个或多个杂芳基所取代，其中杂芳基和烷基基团均具有本发明所述的含义，这样的实例包括，但并不限于，吡啶-2-甲基、咪唑-2-甲基、呋喃-2-乙基、吲哚-3-甲基等。
术语“卤素”是指F，Cl，Br或I。
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐有盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，和有机酸盐如乙酸盐，草酸盐，马来酸盐，酒石酸盐，柠檬酸盐，琥珀酸盐，丙二酸盐，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐，藻酸盐，抗坏血酸盐，天冬氨酸盐，苯磺酸盐，苯甲酸盐，重硫酸盐，硼酸盐，丁酸盐，樟脑酸盐，樟脑磺酸盐，环戊基丙酸盐，二葡萄糖酸盐，十二烷基硫酸盐，乙磺酸盐，甲酸盐，反丁烯二酸盐，葡庚糖酸盐，甘油磷酸盐，葡萄糖酸盐，半硫酸盐，庚酸盐，己酸盐，氢碘酸盐，2-羟基-乙磺酸盐，乳糖醛酸盐，乳酸盐，月桂酸盐，月桂基硫酸盐，苹果酸盐，丙二酸盐，甲磺酸盐，2-萘磺酸盐，烟酸盐，硝酸盐，油酸盐，棕榈酸盐，扑酸盐，果胶酸盐，过硫酸盐，3-苯基丙酸盐，苦味酸盐，特戊酸盐，丙酸盐，硬脂酸盐，硫氰酸盐，对甲苯磺酸盐，十一酸盐，戊酸盐，等等。通过适当的碱得到的盐包括碱金属，碱土金属，铵和N +(C 1-4烷基) 4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠，锂，钾，钙，镁，等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C 1-8磺酸化物和芳香磺酸化物。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸和氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。
本发明化合物的描述
本发明公开了一类新颖的化合物，可作为蛋白激酶活性，特别是TAM家族激酶(包括TYRO3、AXL和MER)、和NTRK家族激酶(包括NTRKA、NTRKB、和NTRKC)活性的抑制剂。作为蛋白激酶抑制剂的化合物可用于治疗与不适当的蛋白激酶活性，特别是不适当的TAM激酶、和NTRK激酶活性相关的疾病。与已有的同类化合物相比，本发明的化合物具有更好的药理活性，具体而言，本发明化合物对目标激酶显示出优异的抑制活性和优化的激酶选择性。此外，本发明化合物还具有优良的透膜性质，在动物体内显示出优良的药代动力学性质，因此，本发明化合物具有非常好的开发前景。
本发明公开化合物可显示对一种或多种蛋白激酶显示较强的抑制活性。一方面，本发明涉及一种化合物，其具有式(I)所示结构：
Figure PCTCN2020078990-appb-000022
或其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物或药学上可接受的盐；
其中，
U 1和U 2分别独立地为N或-C(R a)-；
R 1、R 2和R 4分别独立地为H、C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基、氰基取代的C 1-6烷基、C 3-10环烷基、C 3-10环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、C 1-9杂芳基C 1-6烷基；其中所述各C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基、氰基取代的C 1-6烷基、C 3-10环烷基、C 3-10环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基和C 1-9杂芳基C 1-6烷基独立任选地被0、1，2，3或4个R 11取代；
各R a、R 3、R 5、R 6、R 7和R 8分别独立地为H、D、F、Cl、Br、-OH、-CN、-NO 2、-NR cR d、C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基、氰基取代的C 1-6烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-6烷基；其中所述各C 1-6烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基和C 1-9杂芳基C 1-6烷基独立任选地被0、1，2，3或4个R 12取代；
或者R 2和R 3同与之相连的碳原子和氮原子一起任选地形成4-12个原子组成的杂环，其中所述4-12个原子组成的杂环任选地被0、1、2、3、4或5个R 13取代；
各R 11、R 12和R 13分别独立地为H、D、氧代(＝O)、F、Cl、Br、-OH、-CN、-NO 2、-NR cR d、-C(＝O)R 9、-OC(＝O)R 9、-C(＝O)OR 9a、-S(＝O) 0-2R 9、-OS(＝O) 1-2R 9、-S(＝O) 1-2OR 9a、-N(R 10a)C(＝O)R 10、-C(＝O)NR 10aR 10、-OC(＝O)NR 10aR 10、-N(R 10a)S(＝O) 1-2R 10、-S(＝O) 1-2NR 10aR 10、-N(R 10a)C(＝O)NR 10aR 10、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基、氰基取代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-6烷基；其中所述各C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、C 1-9杂芳基C 1-6烷基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-OH、-NH 2、-CN、-NO 2、C 1-6烷基和C 1-6烷氧基的基团取代；
各R c、R d、R 9、R 9a、R 10和R 10a分别独立地为H、D、C 1-6烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-6烷基；其中所述各C 1-6烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基和C 1-9杂芳基C 1-6烷基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-OH、-NH 2、-CN、-NO 2、C 1-6烷基和C 1-6烷氧基的基团取代；和
n是0、1、或2。
在一些实施方案，其中，
R 2是H、C 1-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基、氰基取代的C 1-4烷基、C 3-8环烷基、C 3-8环烷基C 1-4烷基、C 2-7杂环基、或C 2-7杂环基C 1-4烷基；其中所述各C 1-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基、氰基取代的C 1-4烷基、C 3-8环烷基、C 3-8环烷基C 1-4烷基、C 2-7杂环基和C 2-7杂环基C 1-4烷基独立任选地被0、1，2，3或4个R 12取代；
R 3是H、D、-CN、C 1-4烷基，其中所述各C 1-4烷基任选地被0、1，2，3或4个R 11取代；
或者R 2和R 3同与之相连的碳原子和氮原子一起任选地形成5-12个原子组成的杂环，其中所述5-12个原子组成的杂环任选地被0、1、2、3、4或5个R 13取代。
在另一些实施方案，本发明所述化合物具有式(II)所示结构：
Figure PCTCN2020078990-appb-000023
其中，
X 1是O、S、-N(R 13a)-、-C(＝O)-、-(CH 2) t1-、-X 2-(CH 2) t1-、或-(CH 2) t1-X 2-(CH 2) t2-；
X 2是O、S、-N(R 13a)-、或-C(＝O)-；
各R 13a分别独立地为H、D、氧代(＝O)、F、Cl、Br、-OH、-CN、-NO 2、氨基、C 1-6烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、C 1-9杂芳基C 1-6烷基、-C(＝O)R 9、-C(＝O)OR 9a、-S(＝O) 0-2R 9、-S(＝O) 1-2OR 9a、-S(＝O) 1-2NR 10aR 10、或 -C(＝O)NR 10aR 10，其中所述各C 1-6烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基和C 1-9杂芳基C 1-6烷基独立任选地被0、1，2，3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-OH、-NH 2、-CN、-NO 2、C 1-6烷基和C 1-6烷氧基的基团取代；
各t1和t2分别独立地为0、1、2、或3；和
m是0、1、2、4、或5。
在一些实施方案，其中，X 1是O、S、-N(R 13a)-、-C(＝O)-、-(CH 2) t1-、-X 2-(CH 2) t1-、或-(CH 2) t1-X 2-(CH 2) t2-；和X 2是O、S、或-N(R 13a)-。
在一些实施方案，R 13分别独立地为H、D、氧代(＝O)、F、Cl、Br、-OH、-NH 2、-CN、-NO 2、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、C 3-8环烷基、C 3-8环烷基C 1-4烷基、C 2-7杂环基、C 2-7杂环基C 1-4烷基、C 6-12芳基、C 6-12芳基C 1-4烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-4烷基；其中所述各C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、C 1-4烷基氨基、C 3-8环烷基、C 3-8环烷基C 1-4烷基、C 2-7杂环基、C 2-7杂环基C 1-4烷基、C 6-12芳基、C 6-12芳基C 1-4烷基、C 1-9杂芳基和C 1-9杂芳基C 1-4烷基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-OH、-NH 2、-CN、-NO 2、C 1-4烷基和C 1-4烷氧基的基团取代。
在一些实施方案，各R 13a分别独立地为H、D、氧代(＝O)、F、Cl、Br、-OH、-CN、-NO 2、氨基、C 1-4烷基、C 3-8环烷基、C 3-8环烷基C 1-4烷基、C 2-7杂环基、C 2-7杂环基C 1-4烷基、C 6-12芳基、C 6-12芳基C 1-4烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-4烷基；其中所述各C 1-4烷基C 3-8环烷基、C 3-8环烷基C 1-4烷基、C 2-7杂环基、C 2-7杂环基C 1-4烷基、C 6-12芳基、C 6-12芳基C 1-4烷基、C 1-9杂芳基和C 1-9杂芳基C 1-4烷基独立任选地被0、1，2，3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-OH、-NH 2、-CN、-NO 2、C 1-6烷基和C 1-6烷氧基的基团取代。
在一些实施方案，各t1和t2分别独立地为0、1、2、或3；和m是0、1、2、或4。
在一些实施方案，其中，R 1是C 1-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基、氰基取代的C 1-4烷基、C 3-8环烷基、苯基、或C 1-9杂芳基；其中所述各C 1-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基、氰基取代的C 1-4烷基、C 3-8环烷基、苯基和C 1-9杂芳基独立任选地被0、1，2，3或4个R 11取代。
在一些实施方案，其中，
U 1和U 2分别独立地为N或-C(R a)-；
各R a和R 8分别独立地为H、D、F、Cl、Br、-OH、-CN、-NO 2、-NH 2、或C 1-4烷基；其中所述各C 1-4烷基独立任选地被0、1，2，3或4个R 12取代；和
n是0、1、或2。
在一些实施方案，其中，R 4是H、D、甲基、乙基、丙基、异丙基、丁基、C 1-4卤代烷基、C 1-4氨基烷基、氰基取代的C 1-4烷基、C 3-6环烷基、C 3-6环烷基C 1-4烷基、C 2-7杂环基、或C 2-7杂环基C 1-4烷基。
在一些实施方案，其中，R 5是H、D、-NR cR d、C 1-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基、或氰基取代的C 1-4烷基。
在一些实施方案，其中，R 6和R 7分别独立地为H、D、F、Cl、Br、-OH、-NR cR d、-CN、-NO 2、C 1-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基、或氰基取代的C 1-4烷基。
在一些实施方案，其中，各R 11、R 12和R 13分别独立地为H、D、氧代(＝O)、F、Cl、Br、-OH、-CN、-NO 2、-NR cR d、C 1-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基、氰基取代的C 1-4烷基、C 1-4烷氧基、或C 1-4烷基氨基；其中所述各C 1-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基、氰基取代的C 1-4烷基、C 1-4烷氧基和C 1-4烷基氨基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-OH、-NH 2、-CN、-NO 2和C 1-4烷氧基的基团取代。
在一些实施方案，其中，各R c、R d、R 9、R 9a、R 10和R 10a分别独立地为H、D、C 1-4烷基、C 3-6环烷基、或C 2-7杂环基；其中所述各C 1-4烷基C 3-6环烷基和C 2-7杂环基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-OH、-NH 2、-CN、-NO 2、C 1-6烷基和C 1-6烷氧基的基团取代。
在一些实施方案，本发明所述化合物为具有以下结构之一的化合物：
Figure PCTCN2020078990-appb-000024
或其立体异构体、互变异构体、氮氧化物、溶剂化物、代谢产物或药学上可接受的盐。
除非另有说明，式(I)和(II)所示化合物的立体异构体、互变异构体、溶剂化物、代谢产物或药学上可接受的盐均包含在本发明范围内。
本发明公开化合物可含有不对称或手性中心，因此可以不同的立体异构体形式存在。本发明旨在使式(I)或(II)所示化合物的所有立体异构体形式，包括但不限于非对映异构体、对映异构体、阻转异构体和几何(或构象)异构体，以及它们的混合物如外消旋混合物，成为本发明的组成部分。
在本发明公开的结构中，当任意特定的手性原子的立体化学未指明时，则该结构的所有立体异构体均考虑在本发明之内，并且作为本发明公开化合物包括在本发明中。当立体化学被表示特定构型的实楔形线(solid wedge)或虚线指明时，则该结构的立体异构体就此明确和定义。
式(I)或(II)所示化合物可以盐的形式存在。在一实施方案，所述盐是指药学上可接受的盐。术语“药学上可接受的”是指物质或组合物必须与包含制剂的其它成分和/或用其治疗的哺乳动物化学上和/或毒理学上相容。在另一实施方案，所述盐不一定是药学上可接受的盐，可以是用于制备和/或提纯式(I)或(II)所示化合物和/或用于分离本式(I)或(II)所示化合物的对映体的中间体。
另一方面，本发明涉及制备式(I)和(II)所示化合物的中间体。
另一方面，本发明涉及式(I)和(II)所示化合物的制备、分离和纯化的方法。
另一方面，本发明提供一种药物组合物，所述药物组合物包含本发明化合物。在一实施方案中，本发明所述药物组合物，更进一步包括药学上可接受的辅料、稀释剂或载体、或其组合。在另一实施方案，所述药物组合物可以是液体、固体、半固体、凝胶或喷雾剂型。
在一些实施方案，本发明所述药物组合物进一步包含附加治疗剂。
另一方面，本发明涉及一种使用本发明所述的化合物或本发明所述的药物组合物在制备用于预防或治疗一种或多种Axl和/或Trk蛋白激酶介导的疾病和/或病症的药物中的用途。
在一些实施方案，所述疾病和/或病症选自增殖性疾病、自体免疫疾病、过敏性疾病、炎性疾病、或移植排斥。
在一些实施方案，所述疾病和/或病症选自治疗和预防涉及信号通路的TAM激酶、和NTRK激酶介导的疾病。此类疾病包括增殖性疾病、自体免疫疾病、过敏性疾病、炎性疾病、移植排斥、以及它们的并发症。特别地，本发明化合物可以用来治疗下列疾病，例如癌症、真性红细胞增多症、原发性血小板增多症、骨髓纤维化、性髓细胞性白血病、急性淋巴细胞白血病、慢性髓细胞性白血病(CML)、慢性阻塞性肺疾病(COPD)、哮喘、系统性红斑狼疮、皮肤型红斑狼疮、狼疮性肾炎、皮肌炎、干燥综合征、银屑病、I型糖尿病、呼吸道过敏性疾病、鼻窦炎、湿疹、麻疹、食物过敏、昆虫毒液过敏、炎性肠病、克罗恩病、类风湿性关节炎、幼年型关节炎、银屑病性关节炎、器官移植排斥、组织移植排斥、细胞移植排斥，等等。
本发明化合物的药物组合物、制剂和给药
本发明提供一种药物组合物，其包含本发明公开化合物，或实施例中所列化合物；和药学上可接受的辅料、稀释剂、载体、溶媒或其组合。本发明公开的药物组合物中化合物的量是指能有效检测到抑制生物样本或患者体内蛋白激酶的量。
也应认识到，本发明的某些化合物可以以游离形式存在用于治疗，或者如果适当可以以其药学上可接受的衍生物的形式存在。药学上可接受衍生物的一些非限制性的实施方案包括药学上可接受的盐，酯，这些酯的盐，或者对有需要的患者给药时能直接或间接提供本发明所述化合物或其代谢产物或残留物的任何另外的加合物或衍生物。
在文献例如Remington:The Science and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York中披露了用于配置药学上可接受的组合物的各种载体，和用于其制备的公知技术，这些文献各自的内容通过引用并入本发明。除任何诸如因产生任何不期望的生物作用，或以有害方式与药学上可接受组合物中的任何其它成分发生相互作用而与本发明公开化合物不相容的任何常用载体外，关注其应用属于本发明的范围。
本发明提供的药物组合物可以与不会损害预期的治疗作用的其它活性成分共同配制，或者与补充预期的作用的物质共同配制。
本发明化合物和组合物的用途
本发明提供使用本发明所公开的化合物和药物组合物治疗、预防，或改善由一种或多种蛋白激酶，如TAM家族激酶(包括Tyro3，AXL和MER激酶)，或NTRK家族激酶(NTRKA，NTRKB和NTRKC)行为介导或以其他方式影响的疾病或紊乱，或者由一种或多种蛋白激酶，如TAM家族激酶(包括Tyro3，AXL和MER激酶)，或NTRK家族激酶(NTRKA，NTRKB和NTRKC)行为介导或以其他方式影响的疾病或紊乱的一种或多种症状的方法。
TAM家族激酶(包括Tyro3，AXL和MER激酶)，或NTRK家族激酶(NTRKA，NTRKB和NTRKC)可以是所包括激酶的野生型和/或突变。
在一些实施方案，本发明提供一类本发明所公开的化合物或包含本发明所公开化合物的药物组合物，用于治疗、预防或改善由不适当的AXL激酶行为介导或以其他方式影响的疾病或紊乱或者由不适当的AXL激酶行为介导或以其他方式影响的疾病或紊乱的一种或多种症状。在另一实施方案中，所述疾病、紊乱或者疾病或紊乱的一种或多种症状与不适当的MER激酶行为相关。还在一实施方案中，所述疾病、紊乱或者疾病或紊乱的一种或多种症状与不适当的TYRO3激酶行为相关。
在一些实施方案，本发明提供一类本发明所公开的化合物或包含本发明所公开化合物的药物组合物，用于治疗、预防或改善由不适当的NTRK-A激酶行为介导或以其他方式影响的疾病或紊乱或者由不适当的NTRK-A激酶行为介导或以其他方式影响的疾病或紊乱的一种或多种症状。在另一些实施方案中，所述疾病、紊乱或者疾病或紊乱的一种或多种症状与不适当的NTRK-B激酶行为相关。还在一些实施方案，所述疾病、紊乱或者疾病或紊乱的一种或多种症状与不适当的NTRK-C激酶行为相关。
“不适当的AXL激酶行为”是指发生在特定患者身上偏离正常AXL激酶行为的AXL激酶行为。不适当的AXL激酶行为可以表现为例如活性的不正常增长、或AXL激酶行为时间点和控制上的偏差的形式。这种不适当的激酶行为源于，例如，蛋白激酶的过度表达或突变而导致的不适当或不受控的行为。因此，本发明提供治疗这些疾病和紊乱的方法。
同上面的描述相一致，这样的疾病或紊乱包括但不限于：骨髓增殖性疾病，例如真性红细胞增多症(PCV)、特发性血小板增多症、特发性骨髓纤维化(IMF)；白血病，例如髓系白血病包括慢性髓系白血病(CML)、耐伊马替尼的CML形式、急性髓系白血病(AML)和AML的亚型、急性成巨核细胞白血病(AMKL)；淋巴增殖性疾病，例如急性淋巴细胞白血病(ALL)和骨髓瘤等；癌症包括头颈部癌、前列腺癌、乳癌、卵巢癌、黑素瘤、肺癌、脑肿瘤、胰腺癌、尿路上皮癌、肝癌、胃癌和肾癌等；和与免疫功能紊乱、免疫缺陷、免疫调节有关的炎症性疾病或紊乱、自身免疫性疾病、组织移植排斥、移植物抗宿主病、伤口愈合、肾病、多发性硬化、甲状腺炎、I型糖尿病、结节病、银屑病、变应性鼻炎、炎症性肠病包括克罗恩病和溃疡性结肠炎(UC)、系统性红斑狼疮(SLE)、关节炎、骨关节炎、类风湿性关节炎、骨质疏松症、哮喘和慢性阻塞性肺病(COPD)和干眼综合征(或干燥性角膜结膜炎(KCS))。
一方面，本发明提供一类本发明所公开的化合物或包含本发明所公开化合物的药物组合物，用于预防和/或治疗哺乳动物(包括人类)的增殖性疾病、自体免疫疾病、过敏性疾病、炎性疾病、或移植排斥。
在另一方面，本发明提供一种治疗罹患或有风险罹患本发明所公开疾病的哺乳动物的方法，所述方法包括给予有效治疗病症量或有效预防病症量的一种或多种本发明公开的药物组合物或化合物。
在特定实例中，增殖性疾病选自癌症(如结肠癌，恶性胶质瘤，子宫内膜癌，肝癌，肺癌，黑色素瘤，肾癌，甲状腺癌，淋巴瘤，淋巴增生性障碍，小细胞肺癌，鳞状细胞肺癌，胶质瘤，乳腺癌，前列腺癌，卵巢癌，宫颈癌等；恶性血液病，如急性骨髓性白血病(AML)，脊髓发育异常综合征(MDS)，骨髓增生病(MPD)，慢性骨髓性白血病(CML)，T细胞急性淋巴细胞白血病(T-ALL)，B细胞急性淋巴细胞白血病(B-ALL)，非霍奇金淋巴瘤(NHL)，B细胞淋巴瘤；真性红细胞增多症、原发性血小板增多症、骨髓纤维化、多发性骨髓瘤等。
在另一方面，本发明提供治疗和/或预防易患或患有自体免疫疾病的哺乳动物的方法，所述方法包括给予有效治疗量或有效预防量的一种或多种本发明公开的药物组合物或化合物。
在特定的实施方案中，自体免疫疾病选自COPD，哮喘，系统性红斑狼疮，皮肤型红斑狼疮，狼疮性肾炎，皮肌炎，干燥综合征，银屑病，I型糖尿病和炎性肠病。
在另一方面，本发明提供治疗和/或预防易患或患有过敏性疾病的哺乳动物的方法，所述方法包括给予有效治疗量或有效预防量的一种或多种本发明公开的药物组合物或化合物。在特定的实施方案中，过敏性疾病选自呼吸道过敏性疾病，鼻窦炎，湿疹和麻疹，食物过敏和昆虫毒液过敏。
在特定的实施方案中，过敏性疾病选自呼吸道过敏性疾病，鼻窦炎，湿疹和麻疹，食物过敏和昆虫毒液过敏。
在另一方面，本发明提供治疗和/或预防易患或患有炎性疾病的哺乳动物的方法，所述方法包括给予有效治疗量或有效预防量的一种或多种本发明公开的药物组合物或化合物。
在另一方面，本发明提供一类用作药物尤其用作治疗和/或预防本发明所述疾病药物的本发明公开的化合物。也提供使用本发明公开化合物制备治疗和/或预防本发明所述疾病的药物。
联合治疗
本发明化合物可以作为单独的活性试剂给药，或者可以与其它治疗剂联合给药，包括具有相同或相似治疗活性并且对于此类联合给药确定为安全且有效的其它化合物。
一方面，本发明提供治疗、预防或改善疾病或病症的方法，包括给予安全有效量的包含本发明公开化合物与一种或多种治疗活性剂的联合药物。在一实施方案中，联合药物包含一种或两种其他治疗剂。
其它治疗剂的实例包括包括但不限于：抗癌剂，包括化疗剂和抗增殖剂；抗炎剂；和免疫调剂剂或免疫抑制剂。
另一方面，本发明提供包括本发明化合物和至少一种其它治疗剂的产品，可制备成在治疗中同时、分别或顺序施用的组合。在一些实施方案，治疗是针对由一种或多种蛋白激酶，如AXL激酶、或NTRK激酶活性介导的疾病或病征的治疗。联合制备提供的产品包括存在于同一药物组合物中包含本发明公开化合物和其他治疗剂的组合物，或者以不同形式存在的本发明公开化合物和其他治疗剂，例如，药盒。
另一方面，本发明提供一种包含本发明公开化合物和另外一种或多种治疗剂的药物组合物。在一实施方案中，药物组合物可以包含如上所述的药学上可接受的辅料。
另一方面，本发明提供包含两种或以上的单独药物组合物的药盒，其中至少一种药物组合物包含本发明公开化合物。在一实施方案中，药盒包括单独保持所述组合物的工具，例如容器、分开的瓶或分开的箔盒。这类药盒的实例是泡罩包装，其通常用于包装片剂、胶囊剂等。
本发明公开化合物可以作为单一活性组分施用或作为例如佐剂，与其它治疗剂共同施用。
在一些实施方案，所述其它治疗剂包括，化疗剂和/或抗增殖剂。已知的化疗药物包括，但并不限于，可与本发明化合物联合使用的其他疗法或抗癌药物、手术、放射疗法(少许例子如γ辐射，中子束放射疗法，电子束放射疗法，质子疗法，近距离放射疗法和系统放射性同位素疗法)，内分泌疗法、紫杉烷类(紫杉醇(taxol)，多西紫杉醇(taxotere)等)、铂衍生物(顺铂(cisplatin)、卡铂(carboplatin))、生物反应调节剂(干扰素，白细胞间素)、肿瘤坏死因子(TNF，TRAIL受体靶向物)、过热和冷冻疗法、减轻任何不良反应的试剂(如止吐药)、和其他被认可的化疗药物、包括但并不限于，烷化药物(氮芥(mechlorethamine)，苯丁酸氮芥(chlorambucil)、环磷酰胺(cyclophosphamide)、马法兰(melphalan)、异环磷酰胺(ifosfamide))、抗代谢物(甲氨蝶呤(methotrexate)、培美曲塞(pemetrexed)等等)、嘌呤拮抗剂和嘧啶拮抗剂(6-巯嘌呤(6-mercaptopurine)、5-氟尿嘧啶(5-fluorouracil)、阿糖胞苷(cytarabile)、吉西他滨(gemcitabine))、纺锤体抑制剂(长春碱(vinblastine)、长春新碱(vincristine)、长春瑞滨(vinorelbine))、鬼臼毒素(依托泊苷(etoposide)、伊立替康(irinotecan)、托泊替康(topotecan))、抗生素(多柔比星(doxorubicin)、博莱霉素(bleomycin)、丝裂霉素(mitomycin))、亚硝基脲(卡莫司汀(carmustine)、洛莫司汀(lomustine))、细胞分裂周期抑制剂(KSP通过有丝分裂驱动蛋白抑制剂，CENP-E和CDK抑制剂)、酶(天门冬酰胺酶(asparaginase))、激素(它莫昔芬(tamoxifen)、亮丙瑞林(leuprolide)、氟他胺(flutamide)、甲地孕酮(megestrol)、地塞米松(dexamethasone)等等)。抗血管生成试剂(阿瓦斯丁(avastin)等)。单抗(贝利单抗(belimumab)，brentuximab、西妥昔单抗(cetuximab)、吉妥单抗(gemtuzumab)、伊匹单抗(ipilimumab)、ofatumumab、帕尼单抗(panitumumab)、雷珠单抗(ranibizumab)、利妥昔单抗(rituximab)、托西莫单抗(tositumomab)、曲妥珠单抗(trastuzumab))。激酶抑制剂(伊马替尼(imatinib)、舒尼替尼(sunitinib)、索拉非尼(sorafenib)、厄洛替尼(erlotinib)、吉非替尼(gefitinib)、达沙替尼(dasatinib)、尼洛替尼(nilotinib)、拉帕替尼(lapatinib)、克卓替尼(crizotinib)、鲁索替尼(ruxolitinib)、维罗非尼(vemurafenib)、凡德他尼(vandetanib)、帕唑帕尼(pazopanib)等等)。药物抑制或激活癌症的途径如mTOR，HIF(缺氧诱导因子)途径及其他。
本发明公开的化合物还可以与其它治疗过程联合，提高疗效。例如，给予激素治疗或者特殊的放射治疗。本发明公开的化合物尤其被用作放射增敏剂，特别用于对那些放射治疗敏感性弱地肿瘤治疗。
“联合”表示在单个剂量单位形式中的固定联合或用于联合给药的部分的药盒，其中本发明公开的化合物和联合伴侣可以在同一时间独立施用或者可以在一定的时间间隔内分别施用，特别是使联合伴侣表现出合作、例如协同作用。如本发明所用的术语“共同给药”或“联合给药”等意欲囊括将所选的联合伴侣施用于需要其的单个个体(例如患者)，并且意欲包括其中物质不必通过相同给药途径或同时给药的治疗方案。
治疗方法
在一实施方案中，本发明公开的治疗方法包括对有需要的患者给予安全有效量的本发明化合物或包含本发明化合物的药物组合物。本发明公开的各实施方案包括通过对有需要的患者给予安全有效量的本发明公开化合物或包含本发明公开化合物的药物组合物，来治疗本发明所提及疾病的方法。
在其中实施方案，本发明公开化合物或包含本发明公开化合物的药物组合物可以一次性给药，或者根据给药方案，在指定时间段内，在不同的时间间隔给药若干次。例如，每天给药一次、两次、三次或四次。在其中一个实施方案，每天给药一次。在又一实施方案中，每天给药两次。可以给药直至达到想要的治疗效果或无限期地维持想要的治疗效果。本发明公开化合物或包含本发明公开化合物的药物组合物的合适给药方案取决于该化合物的药代动力学性质，例如稀释、分布和半衰期，这些可以由技术人员测定。此外，本发明公开化合物或包含本发明公开化合物的药物组合物的合适给药方案，包括实施该方案的持续时间，取决于被治疗的疾病，被治疗疾病的严重程度、被治疗患者的年龄和身体状况、被治疗患者的医疗史、同时疗法的性质、想要的治疗效果等在技术人员知识和经验范围内的因素。这样的技术人员还应该理解，对于个体患者对给药方案的反应，或随着时间推移个体患者需要变化时，可要求调整事宜的给药方案。
本发明公开化合物可以与一种或多种其它治疗剂同时，或在其之前或之后给药。本发明化合物可以与其他治疗剂通过相同或不同给药途径分别给药，或与之以同以药物组合物形式给药。
一般合成方案
为描述本发明，以下列出了实施例。但需要理解，本发明不限于这些实施例，只是提供实践本发明的方法。
一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义如式(I)或(II)所示。下面的反应方案和实施例用于进一步举例说明本发明的内容。
下面所描述的实施例，除非其他方面表明所有的温度定为摄氏度。试剂购买于商品供应商如Aldrich Chemical Company,Arco Chemical Company and Alfa Chemical Company，使用时都没有经过进一步纯化，除非其他方面表明。一般的试剂从汕头西陇化工厂，广州化学试剂厂，天津市福晨化学试剂厂，武汉鑫华远科技发展有限公司，和青岛海洋化工厂购买得到。
无水四氢呋喃，二氧六环，甲苯，乙醚是经过金属钠回流干燥得到。无水二氯甲烷和氯仿是经过氢化钙回流干燥得到。乙酸乙酯，石油醚，正己烷，N,N-二甲基乙酰胺和N,N-二甲基甲酰胺是经无水硫酸钠事先干燥使用。
以下反应一般是在氮气或氩气正压下或在无水溶剂上套一干燥管(除非其他方面表明)，反应瓶都塞上合适的橡皮塞，底物通过注射器打入。玻璃器皿都是干燥过的。
色谱柱是使用硅胶柱。硅胶(300-400目)购于青岛海洋化工厂。
1H NMR谱使用Bruker 300MHz、400MHz或600MHz核磁共振谱仪记录。 1H NMR谱以CDC1 3、DMSO-d 6、CD 3OD或丙酮-d 6为溶剂(以ppm为单位)，用TMS(0ppm)或氯仿(7.26ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet，单峰)、d(doublet，双峰)、t(triplet，三重峰)、m(multiplet，多重峰)、br(broadened，宽峰)、brs(broadened singlet，宽单峰)、dd(doublet of doublets，双二重峰)、dt(doublet of triplets，双三重峰)。偶合常数，用赫兹(Hz)表示。
低分辨率质谱(MS)数据的测定条件是：Agilent 6120四级杆HPLC-M(柱子型号：Zorbax SB-C18,2.1×30mm,3.5微米,6min,流速为0.6mL/min。流动相：5％-95％(含0.1％甲酸的CH 3CN)在(含0.1％甲酸的H 2O)中的比例)，采用电喷雾电离(ESI)，在210nm/254nm下，用UV检测。
纯的化合物的使用Agilent 1260 pre-HPLC或Calesep pump 250 pre-HPLC(柱子型号：NOVASEP 50/80 mm DAC)，在210nm/254nm用UV检测。
制备本发明公开化合物的典型合成步骤如下面的合成方案1～2所示。除非另外说明，各R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、U 1、U 2和n均具有如本发明所述的定义；PG 1和PG 2是保护基团。
合成方案1：
Figure PCTCN2020078990-appb-000025
具有如式 (6)所示结构的本发明化合物可以通过合成方案1描述的一般合成方法制备得到，具体步骤可参考实施例。合成方案1中，在碱性条件下，硼酯衍生物 (1)在合适的碱(如碳酸铯，碳酸钾，碳酸钠等)，以及合适的Pd催化剂(如Pd(OAc) 2、Pd(dppf) 2Cl 2或Pd 2(dba) 3等)的作用下，与取代的杂芳基化合物 (2)发生偶联反应得到化合物 (3)。脱除保护基团PG 1后得到芳香胺衍生物 (4)。羧酸衍生物 (5)在缩合剂(如EDCI或HATU)存在下与化合物 (4)缩合得到目标激酶抑制剂 (6)。
羧酸衍生物 (5)可通过文献(例如参见，“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)中描述的合成方法得到。
合成方案2：
Figure PCTCN2020078990-appb-000026
具有如式 (6)所示结构的本发明化合物还可以通过合成方案2描述的一般合成方法制备得到，具体步骤可参考实施例。合成方案2中，芳基或杂芳基化合物 (7)在缩合剂(如EDCI或HATU)存在下与化合物 (5)缩合得到化合物 (8)。在碱性条件下，硼酯衍生物 (10)在合适的碱(如碳酸铯，碳酸钾，碳酸钠等)，以及合适的Pd催化剂(如Pd(OAc) 2、Pd(dppf) 2Cl 2或Pd 2(dba) 3等)的作用下，与取代的杂芳基化合物 (8)发生偶联反应得到化合物 (9)。在碱性条件下，硼酯衍生物 (9)在合适的碱(如碳酸铯，碳酸钾，碳酸钠等)，以及合适的Pd催化剂(如Pd(OAc) 2、Pd(dppf) 2Cl 2或Pd 2(dba) 3等)的作用下，与取代的杂芳基衍生物 (2)发生偶联反应得到目标激酶抑制剂 (6)。
实施例
实施例1 N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺
Figure PCTCN2020078990-appb-000027
步骤1)N-(4-溴苯基)-2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺
将含有2-氧代-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酸(650mg，65％，1.636mmol)，三乙醇胺(0.7mL，5mmol)，4-溴苯胺(282mg，1.639mmol)和HATU(622mg，1.636mmol)的二氯甲烷(20mL)混合液室温搅拌23小时。向反应液中加入水(20mL)稀释，用二氯甲烷(30mL x 2)萃取，合并有机相并 减压浓缩，所得残余物经硅胶柱层析纯化(EtOAc/MeOH(v/v)＝100/1)，得到黄色固体状的标题化合物(386.8mg，57.35％)。MS(ESI,pos.ion)m/z:414.2[M+H] +。 1H NMR(400MHz,CDCl 3)δ(ppm):10.61(s,1H),7.54(dd,J＝16.0,8.3Hz,4H),7.45(t,J＝7.4Hz,1H),7.42-7.31(m,4H),3.55(t,J＝5.9Hz,2H),3.38(t,J＝6.4Hz,2H),2.12-2.02(m,2H),1.96-1.86(m,2H)。
步骤2)2-氧-1-苯基-N-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺
向含有N-(4-溴苯基)-2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(386mg，0.936mmol)、双联频哪醇基二硼(268mg，1.056mmol)和1,1’-双(二苯基膦)二茂铁二氯化钯(II)(104mg，0.142mmol)的1,4-二氧六环(8mL)溶液中加入乙酸钾(235mg，2.395mmol)。将反应液在氮气的保护下加热至回流搅拌7.5小时，减压浓缩。所得残余物经硅胶柱层析纯化(PE/EtOAc(v/v)＝2/1)，得到白色固体状的标题化合物(368.5mg，85.70％)。MS(ESI,pos.ion)m/z:460.2[M+H] +。 1H NMR(400MHz,CDCl 3)δ(ppm):10.67(s,1H),7.75(d,J＝8.4Hz,2H),7.68(d,J＝8.5Hz,2H),7.53(t,J＝7.6Hz,2H),7.44(t,J＝7.4Hz,2H),7.35(d,J＝7.3Hz,2H),3.55(t,J＝5.9Hz,2H),3.40(t,J＝6.4Hz,2H),2.07(dt,J＝11.6,5.8Hz,3H),1.91(m,3H),1.33(s,13H)。
步骤3)N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺
向含有2-氧-1-苯基-N-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基]-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺(368mg，0.801mmol)和5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(182mg，0.801mmol)的1,4-二氧六环(8mL)溶液中加入1,1’-双(二苯基膦)二茂铁二氯化钯(II)二氯甲烷络合物(134mg，0.161mmol)和碳酸铯(522mg，1.602mmol)。将反应液在氮气的保护下加热至110℃搅拌15小时，减压浓缩。所得残余物经硅胶柱层析纯化(DCM/MeOH(v/v)＝10/1)得到黄色固体，再经阴离子分离柱纯化后得到白色固体状的标题化合物(14.7mg，3.46％)。MS(ESI,pos.ion)m/z:480.4[M+H] +。HRMS(ESI +)计算值C 27H 26N 7O 2[M+H] +:480.21，实测值480.2155。 1H NMR(400MHz,CDCl 3)δ(ppm):10.66(s,1H),8.33(s,1H),7.75(d,J＝8.5Hz,2H),7.55(t,J＝7.6Hz,2H),7.45(t,J＝7.5Hz,1H),7.39(dd,J＝14.3,7.9Hz,4H),5.11(s,2H),3.83(s,3H),3.57(t,J＝5.9Hz,2H),3.42(t,J＝6.4Hz,3H),2.13-2.05(m,3H),1.97-1.89(m,3H)。
实施例2 N-(5-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)吡啶-2-基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺
Figure PCTCN2020078990-appb-000028
步骤1)2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰氯
向含有2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酸(480mg，1.845mmol)的四氢呋喃(10mL)溶液中加入草酰氯(0.6mL，7mmol)。将反应液加热至60℃搅拌4h，减压浓缩，得到黄色固体状的标题化合物(515mg，100.2％)。
步骤2)N-(5-溴吡啶-2-基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺
将含有5-溴吡啶-2-胺(320mg，1.849mmol)和三乙胺(0.8mL，6mmol)的二氯甲烷(20mL)溶液室温搅拌10分钟之后，向该混合液中加入2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰氯(515mg，1.848mmol)。将反应液室温搅拌24小时，逐滴加水(20mL)稀释，并用二氯甲烷萃取(50mL)。分离有机相并减压浓缩，所得残余物经硅胶柱层析纯化(DCM/MeOH(v/v)＝100/1)，收集到的黄色固体在二氯甲烷/甲醇/石油醚(6mL/0.5mL/12mL)混合溶液中重结晶，得到白色固体状的标题化合物(380mg，49.53％)。MS(ESI,pos.ion)m/z:415.0[M+H] +。 1H NMR(400MHz,CDCl 3)δ(ppm):10.58(s,1H),8.13(s,1H),7.99(d,J＝8.8Hz,1H),7.57(dd,J＝8.8,2.0Hz,1H),7.37(t,J＝7.5Hz,2H),7.30(d,J＝6.8Hz,1H),7.21(d,J＝7.6Hz,2H),5.04(s,2H),3.97(t,J＝4.8Hz,2H),3.50(t,J＝4.7Hz,2H)。
步骤3)2-氧-1-苯基-N-(5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶-2-基)-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺
向含有N-(5-溴吡啶-2-基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺(380mg，0.915mmol)、双联频哪醇基二硼(260mg，1.024mmol)和四(三苯基膦)钯(0)(151mg，0.130mmol)的1,4-二氧六环(10mL)溶液中加入乙酸钾(278mg，2.833mmol)。将反应液在氮气的保护下加热至回流搅拌5小时，减压浓缩，得到白色固体状的标题化合物(425mg，100.4％)。
步骤4)N-(5-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)吡啶-2-基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺
向含有2-氧-1-苯基-N-(5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶-2-基)-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺(425mg，0.919mmol)和5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(235mg，1.035mmol)的1,4-二氧六环(10mL)和水(5mL)的混合液中加入四(三苯基膦)钯(0)(215mg，0.186mmol)和碳酸钾(390mg，2.794mmol)。将反应液在氮气的保护下加热至105℃搅拌20小时，减压浓缩。所得残余物经硅胶柱层析纯化(DCM/MeOH(v/v)＝50/1)得到黄色固体，再经阴离子分离柱纯化后得到白色固体状的标题化合物(73mg，16.46％)。MS(ESI,pos.ion)m/z:483.1[M+H] +。HRMS(ESI +)计算值C 25H 22N 8O 3([M+H] +):483.18,实测值483.1886。 1H NMR(400MHz,DMSO-d 6)δ(ppm):10.77(s,1H),8.37(d,J＝1.7Hz,1H),8.27(d,J＝8.5Hz,1H),8.16(s,1H),7.84(dd,J＝8.5,2.1Hz,1H),7.64-7.58(m,2H),7.56-7.50(m,3H),7.37(s,1H),6.18(s,2H),5.13(s,2H),4.12-4.08(m,2H),3.74(s,3H),3.70(t,J＝4.5Hz,2H)。 13C NMR(151MHz,CDCl 3)δ(ppm):163.48,161.98,156.86,155.43,152.09,151.22,151.04,147.73,137.79,132.95,129.63,128.80,126.57,125.68,124.08,113.97,112.34,101.16,98.26,47.39,31.24,23.76,22.58,19.69。
实施例3 N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺
Figure PCTCN2020078990-appb-000029
步骤1)N-(4-溴苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺
将含有2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酸(700mg，2.87mmol，100％)、4-溴苯胺(490mg，2.87mmol)和HATU(1.15g，2.87mmol)的二氯甲烷(20mL)溶液在室温下搅拌4小时。将反应液用水(30mL)淬灭后，用二氯甲烷(50mL x 3)萃取，合并有机相并用盐水(10mL)洗，无水硫酸钠干燥，过滤并减压浓缩，得到白色固体状的标题化合物(1020mg，89.4％)。MS(ESI,pos.ion)m/z:398.1[M+H] +。
步骤2)2-氧-1-苯基-N-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺
向含有N-(4-溴苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺(1020mg，2.56mmol)、双联频哪醇基二硼(733mg，2.88mmol)和Pd(dppf)Cl 2(II)(285mg，0.39mmol)的1,4-二氧六环(20mL)溶液中加入乙酸钾(630mg，6.42mmol)。将反应液在氮气的保护下加热至回流搅拌7小时，减压浓缩。所得残余物经硅胶柱层析纯化(DCM/MeOH(v/v)＝20/1)，得到白色固体状的标题化合物(900mg，78.9％)。MS(ESI,pos.ion)m/z:446.3[M+H] +。
步骤3)N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺
向含有2-氧-1-苯基-N-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺(600mg，1.34mmol)和5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(343mg，1.51mmol)的1,4-二氧六环(20mL)和水(2mL)混合液中加入Pd(dppf)Cl 2(II)(200mg，0.269mmol)和碳酸铯(876mg，2.69mmol)。将反应液在氮气的保护下加热至回流搅拌7小时，减压浓缩。所得残余物经硅胶柱层析纯化(MeOH/DCM(v/v)＝1/20)，得到白色固体状的标题化合物(120mg，19.13％)。
MS(ESI,pos.ion)m/z:466.1[M+H] +。HRMS(ESI +)计算值C 26H 23N 7O 2[M+H] +:466.1913，实测值466.1983。 1H NMR(400MHz,CDCl 3)δ(ppm):10.27(s,1H),8.36(s,1H),7.79(d,J＝8.4Hz,2H),7.54(d,J＝7.6Hz,2H),7.45(d,J＝8.4Hz,4H),6.94(s,1H),5.14(s,2H),3.86(s,3H),3.75(s,2H),3.36(s,2H),2.56(s,2H),1.28(s,2H)。 13C NMR(101MHz,DMSO-d 6)(ppm):165.82,161.80,160.73,157.62,151.98,151.61,150.89,137.81,134.86,129.99,129.79,129.39,127.77,125.57,124.59,123.87,119.91,115.22,100.35,98.84,97.02,49.94,31.18,26.01,22.26。
实施例4 N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺
Figure PCTCN2020078990-appb-000030
步骤1)(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)氨基甲酸叔丁基酯
向含有(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-苯基)氨基甲酸叔丁基酯(16.88g，52.88mmol)，5-溴-7-甲基-吡咯并[2,3-d]嘧啶-4-胺(10g，44.04mmol)的1,4-二氧六环(200mL)和水(50mL)的混合液中加入四(三苯基膦)钯(0)(5.2g，4.50mmol)和碳酸铯(36g，110mmol)。将反应液在氮气的保护下加热至105℃搅拌24.5小时，加入水(200mL)和乙酸乙酯(100mL)搅拌10min后分液，水相用乙酸乙酯(250mL x 3)萃取，合并有机相，减压浓缩。残余物经硅胶柱层析纯化(PE/EtOAc(v/v)＝1/1)，得到黄色固体状的标题化合物(11.63g,77.8％)。
步骤2)5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺
将含有(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)氨基甲酸叔丁基酯(4.5g，13mmol)和浓盐酸(13mL，12M)的甲醇(75mL)溶液加热至60℃搅拌5小时。将反应液减压浓缩，加入二氯甲烷(100mL)，用饱和碳酸氢钠溶液(100mL)碱化。分离水相用二氯甲烷萃取(200mL)，合并有机相并用水洗(50mL)，无水硫酸钠干燥，过滤，减压浓缩，得到黄色固体状的标题化合物(2.58g，81％)。
步骤3)N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酰胺
向含有2-氧-1-苯基-2,4,6,7-四氢-1H-吡唑并[5,1-c][1,4]噁嗪-3-甲酸(100mg，0.384mmol)和5-(4-氨基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(90mg，0.376mmol)的N,N-二甲基甲酰胺(4mL)溶液中加入EDCI(101mg，0.516mmol)和HOAT(112mg，0.806mmol)。将反应液加热至55℃搅拌6小时，减压浓缩。将残余物用水(10mL)洗，得到棕色固体状的标题化合物(65.6mg，32.0％)。MS(ESI,pos.ion)m/z:482.1[M+H] +。HRMS(ESI +)计算值C 26H 24N 7O 3[M+H] +:482.19，实测值482.1928。 1H NMR(400MHz,DMSO-d 6)δ(ppm):10.48(s,1H),8.12(s,1H),7.74(d,J＝8.6Hz,2H),7.64-7.57(m,2H),7.56-7.48(m,6H),7.15(s,2H),6.64(s,1H),5.13(s,2H),4.10(t,J＝4.8Hz,2H),3.73-3.68(m,5H)。 13C NMR(151MHz,DMSO-d 6)δ(ppm):162.07,161.09,151.56,149.67,138.83,137.15,132.36,129.98,129.74,129.63,129.32,127.63,126.95,121.18,119.54,102.86,98.57,96.04,63.56,63.23,45.70,30.18。
实施例5 N-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺
Figure PCTCN2020078990-appb-000031
步骤1)4-氯-7-环丙基-5-碘-7H-吡咯并[2,3-d]嘧啶
向含有4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶(5.00g，17.89mmol)的DCE(300ml)溶液中加入环丙基硼酸(3.07g，35.78mmol)、醋酸铜(3.57g，17.89mmol)、碳酸钠(3.79g，35.78mmol)和2,2’-二吡啶(2.79g， 17.89mmol)。将反应液加热至回流搅拌1小时，减压浓缩,所得残余物经硅胶柱层析纯化(EtOAc/PE(v/v)＝1/10)，得到白色固体状的标题化合物(2.30g，40.2％)。MS(ESI,pos.ion)m/z:320.0[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ(ppm):8.64(s,1H),7.93(s,1H),3.65-3.55(m,1H),1.07(dd,J＝10.2,3.2Hz,4H)。
步骤2)(4-(4-氯-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)氨基甲酸叔丁基酯
向含有4-氯-7-环丙基-5-碘-7H-吡咯并[2,3-d]嘧啶(2.30g，7.20mmol)的1,4-二氧六环(75mL)和水(15ml)的混合液中加入(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)氨基甲酸叔丁基酯(2.30g，7.20mmol)、1,1’-双(二苯基膦)二茂铁二氯化钯(II)(0.53g，0.72mmol)和碳酸钠(2.29g，21.60mmol)。将反应液加热至回流搅拌8小时，减压浓缩，所得残余物经硅胶柱层析纯化(EtOAc/PE(v/v)＝1/3)，得到白色固体状的标题化合物(2.40g，86.6％)。MS(ESI,pos.ion)m/z:385.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ(ppm):9.42(s,1H),8.66(s,1H),7.70(s,1H),7.51(d,J＝8.4Hz,2H),7.39(d,J＝8.5Hz,2H),3.70-3.60(m,1H),1.14(s,2H),1.10(d,J＝2.4Hz,2H),1.07(s,9H)。
步骤3)5-(4-氨基苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺
在高压釜中，向含有(4-(4-氯-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)氨基甲酸叔丁基酯(1.50g，3.90mmol)的1,4-二氧六环(10ml)溶液中加入氨水(50ml，25％的水溶液)。将反应液加热至130℃搅拌24小时，减压浓缩，所得残余物经硅胶柱层析纯化(MeOH/DCM(v/v)＝1/30)，得到黄色固体状的标题化合物(0.70g，68.0％)。MS(ESI,pos.ion)m/z:266.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ(ppm):8.12(s,1H),7.10(d,J＝8.2Hz,2H),7.03(s,1H),6.65(d,J＝8.2Hz,2H),5.98(s,2H),5.19(s,2H),3.58-3.49(m,1H),1.04-0.97(m,4H)。
步骤4)N-(4-(4-氨基-7-环丙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺
向含有5-(4-氨基苯基)-7-环丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(0.25g，0.94mmol)的二氯甲烷(30ml)溶液中加入2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酸(0.23g，0.94mmol)、EDCI(0.36g，1.89mmol)和HOAT(0.26g，1.89mmol)。将反应液加热至回流搅拌过夜，用水(50ml)淬灭后，用二氯甲烷(200mL x 3)萃取。合并有机相，用饱和碳酸氢钠溶液(50mL)和盐水(100mL x 2)洗，无水硫酸钠干燥，过滤并减压浓缩。所得残余物经硅胶柱层析纯化(MeOH/DCM(v/v)＝1/30)，得到黄色固体状的标题化合物(0.30g，65.0％)。MS(ESI,pos.ion)m/z:492.2[M+H] +。HRMS(ESI +)计算值C 28H 26N 7O 2[M+H] +:492.2148，实测值492.2140。 1H NMR(400MHz,DMSO-d 6)δ(ppm):10.26(s,1H),8.18(s,1H),7.72(d,J＝8.4Hz,2H),7.54(dd,J＝14.5,7.2Hz,4H),7.42(d,J＝8.3Hz,3H),7.25(s,1H),6.17(s,2H),3.81(t,J＝6.9Hz,2H),3.59-3.48(m,1H),3.18(t,J＝7.3Hz,2H),2.47-2.38(m,2H),1.04(dd,J＝7.9,6.1Hz,4H)。 13C NMR(151MHz,DMSO-d 6)δ(ppm):165.79,161.79,160.73,157.30,151.85,151.60,151.57,151.55,137.87,134.83,129.81,129.74,129.47,129.34,127.78,123.84,123.02,121.21,119.81,115.27,100.76,96.98,60.23,49.95,27.12,26.02,22.26,6.50。
实施例6 N-(5-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)吡啶-2-基)-2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺
Figure PCTCN2020078990-appb-000032
步骤1)N-(5-溴吡啶-2-基)-2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺
向2-氧-1-苯基-4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-羧酸(1.6g，6.2mmol)的DCM(50mL)混合物中加入1-羟基7-氮杂苯并三唑(170mg，1.22mmol)，1-(3-二甲基氨基丙基)-3-乙基碳二亚胺氢溴酸盐(1.6g，8.2mmol)和5-溴吡啶-2-胺(1.2g，6.7mmol)。将此混合物加热至45℃，并搅拌21h。TLC显示不存在起始物料，然后将水(20mL)滴加至混合物中，所得混合物用DCM(50mL)萃取两次，真空浓缩，得到黄色固体。残余物经快速柱色谱法纯化(PE:EtOAc＝1:1-0:1)，得到N-(5-溴-2-吡啶基)-2-氧-1-苯基-4,5,6,7- 四氢吡唑并[1,5-a]吡啶-3-甲酰胺为黄色固体(1.35g，3.27mmol，收率53％)。MS(ESI,pos.ion)m/z:412.9[M+H] +。
步骤2)2-氧-1-苯基-N-(5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡啶-2-基)-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺
向N-(5-溴-2-吡啶基)-2-氧-1-苯基-4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-甲酰胺(1.35g，3.27mmol)，4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1,3,2-二氧杂硼杂环戊烷(0.95g，3.7mmol)和Pd(dppf) 2Cl 2(0.4g，0.5mmol)的悬浮液中加入KOAc(0.8g，8mmol)的1,4-二氧六环(30mL)溶液。将反应混合物在N 2气氛下回流搅拌5h。TLC显示不存在起始物料，真空浓缩，得到标题化合物(1.5g，3.27mmol，收率100.0％)。
步骤3)N-(5-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)吡啶-2-基)-2-氧-1-苯基-1,2,4,5,6,7-六氢吡咯并[1,5-a]吡啶-3-甲酰胺
向2-氧-1-苯基-N-[5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-2-吡啶]-4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-甲酰胺(1.5g，3.3mmol)和5-溴-7-甲基-吡咯并[2,3-d]嘧啶-4-胺(1.0g，4.4mmol)，H 2O(5mL)的1,4-二氧六环(10mL)的溶液中加入1,1'-双(二苯基膦基)二茂铁-钯(II)二氯化物二氯甲烷复合物(0.66g，0.79mmol)和Cs 2CO 3(2.6g，8.0mmol)。将混合物在N 2气氛下、在105℃下搅拌过夜，真空浓缩。残余物经快速柱色谱法纯化(DCM:MeOH＝50:1-10:1)，得到黄色固体(240mg)。用阴离子分离柱纯化固体，得到N-(5-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)吡啶-2-基)-2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺为白色固体(6.9mg，0.014mmol，收率0.44％)。MS(ESI,pos.ion)m/z:481.4[M+H]+。 1H NMR(600MHz,DMSO)δ11.84(s,1H),8.62(d,J＝8.3Hz,1H),8.48(s,1H),8.15(dd,J＝7.9,1.4Hz,1H),7.51–7.48(m,1H),7.26(d,J＝8.7Hz,2H),7.25–7.21(m,1H),6.92(d,J＝8.7Hz,2H),5.41(s,2H),3.72(s,4H),2.55(s,3H)。 13C NMR(151MHz,CDCl 3)δ163.48,161.98,156.86,155.43,152.09,151.22,151.04,147.73,137.79,132.95,129.63,128.80,126.57,125.68,124.08,113.97,112.34,101.16,98.26,47.39,31.24,23.76,22.58,19.69。
实施例7 N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺
Figure PCTCN2020078990-appb-000033
步骤1)N-(4-溴-3-氟苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺
向4-溴-3-氟苯胺(200mg，1.0mmol)的CH 2Cl 2(6mL)溶液中加入2-氧-1-苯基-5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-羧酸(274mg，1.1mmol)，EDCI(240mg，12mmol)和HOAT(28mg，0.2mmol)。回流搅拌过夜后，将反应混合物真空浓缩。残余物经硅胶柱色谱法纯化(石油醚/乙酸乙酯＝1/1)，得到标题化合物为黄色固体(260mg，61％)。MS(ESI,pos.ion)m/z:416.0(M+1)。 1H NMR(400MHz,CDCl 3)δ10.31(s,1H),7.84-7.81(dd,J＝10.9,2.3Hz,1H),7.56-7.52(t,J＝7.8Hz,2H),7.47-7.39(m,4H),7.19-7.17(dd,J＝8.6,1.9Hz,1H),3.76-3.73(t,J＝6.9Hz,2H),3.34-3.31(t,J＝7.4Hz,2H),2.59-2.52(m,2H)。
步骤2)N-(3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺
向N-(4-溴-3-氟苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺(260mg，0.62mmol)的二氧六环(6mL)溶液中加入4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1,3,2-二氧杂硼杂环戊烷(178mg，0.69mmol)，Pd(dppf)Cl 2.CH 2Cl 2(52mg，0.063mmol)和醋酸钾(161mg，1.6mmol)。反应用氮气脱气，混合物回流搅拌过夜后，将反应混合物真空浓缩。残余物经硅胶柱色谱法纯化(石油醚/乙酸乙酯＝2/1)，得到标题化合物为黄色固体(210mg，73％)。MS(ESI,pos.ion)m/z:464.2(M+1)。
步骤3)N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-3-氟苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺
向N-(3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺(210mg，0.45mmol)的二氧六环(6mL)/H 2O(1mL)的溶液中加入5-溴-7-甲基-吡咯并[2,3-d]嘧啶-4-胺(108mg，0.45mmol)，Pd(dppf)Cl 2.CH 2Cl 2(37mg，0.045mmol)和碳酸铯(301mg，0.91mmol)。反应用氮气脱气，混合物回流搅拌过夜后，将反应混合物真空浓缩。残余物经硅胶柱色谱法纯化(二氯甲烷/甲醇＝500/1)，得到标题化合物为黄色固体(46mg，21％)。MS(ESI,pos.ion)m/z:484.2(M+1)。 1H NMR(400MHz,DMSO)δ10.38(s,1H),8.15(s,1H),7.88-7.85(d,J＝12.8Hz,1H),7.60-7.52(m,4H),7.45-7.41(t,J＝7.3Hz,1H),7.36-7.35(m,2H),7.30(s,1H),6.03(s,2H),3.85-2.81(t,J＝6.9Hz,2H),3.75(s,3H),3.20-3.17(t,J＝6.8Hz,2H),2.46-2.43(m,2H)。
实施例8 N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺
Figure PCTCN2020078990-appb-000034
步骤1)2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-碳酰氯
向2-氧-1-苯基-5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-羧酸(200mg，0.82mmol)的CH 2Cl 2(5mL)溶液中加入DMF(1mg，0.014mmol)和草酰氯(0.1mL，1mmol)。在室温下搅拌4小时后，将反应混合物真空浓缩，其无需进一步纯化即可用于下一步骤。
步骤2)N-(4-溴-2-氟苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺
向4-溴-2-氟苯胺(175mg，0.9mmol)的CH 2Cl 2(3mL)溶液中加入三乙胺(0.25mL，1.8mmol)，将反应混合物在0℃搅拌。向反应混合物中加入2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-碳酰氯(215mg，0.82mmol)的CH 2Cl 2(2mL)溶液。在室温下搅拌过夜后，将反应混合物真空浓缩。残余物经硅胶柱色谱法纯化(石油醚/乙酸乙酯＝1/1)，得到标题化合物为黄色固体(0.15g，44％，两步)。MS(ESI,pos.ion)m/z:416.0(M+1)。 1H NMR(400MHz,CDCl 3)δ10.47(s,1H),8.46-8.42(t,J＝8.6Hz,1H),7.55-7.51(t,J＝7.8Hz,2H),7.45-7.43(d,J＝7.6Hz,2H),7.41-7.37(t,J＝7.4Hz,1H),7.30-7.25(m,2H),3.76-3.73(t,J＝6.9Hz,2H),3.35-3.31(t,J＝7.4Hz,2H),2.59-2.51(m,2H)。
步骤3)N-(2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺
向N-(4-溴-2-氟苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺(150mg，0.36mmol)的二氧六环(6mL)溶液中加入4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1,3,2-二氧杂硼杂环戊烷(187mg，0.72mmol)，Pd(dppf)Cl 2.CH 2Cl 2(30mg，0.036mmol)和醋酸钾(93mg，0.9mmol)。反应用氮气脱气。混合物回流搅拌过夜后，将反应混合物真空浓缩。残余物经硅胶柱色谱法纯化(石油醚/乙酸乙酯＝2/1)，得到标题化合物为黄色固体(135mg，81％)。MS(ESI,pos.ion)m/z:464.3(M+1)。 1H NMR(400MHz,CDCl 3)δ10.59-10.58(d,J＝2.3Hz,1H),8.57-8.53(t,J＝7.8Hz,1H),7.59-7.54(dd,J＝11.6,6.5Hz,2H),7.52-7.50(d,J＝8.0Hz,2H),7.45-7.44(d,J＝7.6Hz,2H),7.40-7.36(t,J＝7.3Hz,1H),3.76-3.72(t,J＝6.9Hz,2H),3.36-3.32(t,J＝7.4Hz,2H),2.58-2.51(m,2H),1.35(s,12H)。
步骤4)N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺
向N-(2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺(135mg，0.29mmol)的二氧六环(6mL)/H 2O(1mL)溶液中加入5-溴-7-甲基-吡咯并[2,3-d]嘧啶-4-胺(70mg，0.29mmol)，Pd(dppf)Cl 2.CH 2Cl 2(24mg，0.029mmol)和碳酸铯(194mg，0.58mmol)。反应用氮气脱气。混合物回流搅拌过夜后，将反应混合物真空浓缩。残余物经硅胶柱色谱法纯化(二氯甲烷/甲醇＝500/1)，得到标题化合物为黄色固体(46mg，33％)。MS(ESI,pos.ion)m/z:484.2(M+1)。 1H NMR(400MHz,DMSO)δ10.51-10.50(d,J＝1.8Hz,1H),8.53-8.49(t,J＝8.4Hz,1H),8.16(s,1H),7.59-7.52(m,4H),7.45-7.41(t,J＝7.0Hz,1H),7.35-7.32(m,2H),7.27-7.25(d,J＝8.5Hz,1H),6.18 (s,2H),3.84-3.81(t,J＝6.8Hz,2H),3.74(s,3H),3.20-3.17(t,J＝7.2Hz,2H),2.48-2.41(m,2H)。
实施例9 N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-1,5-二甲基-3–氧-2-苯基-2,3-二氢-1H-吡唑-4-甲酰胺
Figure PCTCN2020078990-appb-000035
步骤1)1,5-二甲基-3-氧-2-苯基-2,3-二氢-1H-吡唑-4-碳酰氯
向1,5-二甲基-3-氧-2-苯基-吡唑-4-羧酸(300mg，1.3mmol)的CH 2Cl 2(6mL)溶液中加入DMF(1mg，0.014mmol)和草酰氯(0.2mL,2mmol)。在室温下搅拌4小时后，将反应混合物真空浓缩，其无需进一步纯化即可用于下一步骤。
步骤2)N-(4-溴-2-氟苯基)-1,5-二甲基-3-氧-2-苯基-2,3-二氢-1H-吡唑-4-甲酰胺
向4-溴-2-氟苯胺(274mg，1.4mmol)的CH 2Cl 2(4mL)溶液中加入三乙胺(0.36mL，2.6mmol)，将反应混合物在0℃下搅拌。向反应混合物中加入1,5-二甲基-3-氧-2-苯基-2,3-二氢-1H-吡唑-4-碳酰氯(322mg，1.3mmol)的CH 2Cl 2(2mL)溶液。在室温下搅拌过夜后，将反应混合物真空浓缩。残余物经硅胶柱色谱法纯化(石油醚/乙酸乙酯＝1/1)，得到标题化合物为黄色固体(0.44g，85％，两步)。MS(ESI,pos.ion)m/z:404.0(M+1)。 1H NMR(400MHz,CDCl3)δ10.98(s,1H),8.46-8.42(t,J＝8.7Hz,1H),7.58-7.54(t,J＝7.6Hz,2H),7.49-7.46(t,J＝7.4Hz,1H),7.39-3.37(d,J＝7.4Hz,2H),7.28-7.25(m,2H),3.37(s,3H),2.80(s,3H)。
步骤3)N-(2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)-1,5-二甲基-3-氧-2-苯基-2,3-二氢-1H-吡唑-4-甲酰胺
向N-(4-溴-2-氟苯基)-1,5-二甲基-3-氧-2-苯基-2,3-二氢-1H-吡唑-4-甲酰胺(440mg，1.1mmol)的二氧六环(6mL)溶液中加入4,4,5,5-四甲基-2-(4,4,5,5–四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1,3,2-二氧杂硼杂环戊烷(564mg,2.2mmol)，Pd(dppf)Cl 2.CH 2Cl 2(90mg,0.11mmol)和醋酸钾(281mg，2.7mmol)。反应用氮气脱气。混合物回流搅拌过夜后，将反应混合物真空浓缩。残余物经硅胶柱色谱法纯化(石油醚/乙酸乙酯＝2/1)，得到标题化合物为黄色固体(410mg，83％)。MS(ESI,pos.ion)m/z:452.3(M+1)。 1H NMR(600MHz,CDCl 3)δ11.10(s,1H),8.57-8.54(t,J＝7.8Hz,1H),7.58-7.53(m,4H),7.48-7.45(t,J＝7.5Hz,1H),7.39-7.37(d,J＝7.4Hz,2H),3.37(s,3H),2.81(s,3H),1.35(s,12H)。
步骤4)N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯基)-1,5-二甲基-3–氧-2-苯基-2,3-二氢-1H-吡唑-4-甲酰胺
向N-(2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)-1,5-二甲基-3-氧-2-苯基-2,3-二氢-1H-吡唑-4-甲酰胺(410mg，0.91mmol)的二氧六环(8mL)/H 2O(1.5mL)溶液中加入5-溴-7-甲基-吡咯并[2,3-d]嘧啶-4-胺(217mg，0.91mmol)，Pd(dppf)Cl 2.CH 2Cl 2(75mg，0.091mmol)和碳酸铯(604mg，1.8mmol)。反应用氮气脱气。混合物回流搅拌过夜后，将反应混合物真空浓缩。残余物经硅胶柱色谱法纯化(二氯甲烷/甲醇＝500/1)，得到标题化合物为黄色固体(78mg，18％)。MS(ESI,pos.ion)m/z:472.1(M+1)。 1H NMR(400MHz,DMSO)δ11.05(s,1H),8.54-8.50(t,J＝8.4Hz,1H),8.16(s,1H),7.62-7.59(t,J＝7.5Hz,2H),7.55-7.51(m,1H),7.46-7.44(d,J＝7.6Hz,2H),7.35-7.30(m,2H),7.26-7.24(d,J＝8.3Hz,1H),6.17(s,2H),3.74(s,3H),3.38(s,3H),2.73(s,3H)。
实施例10 N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-1,5-二甲基-3-氧-2-苯基-2,3-二氢-1H-吡唑-4-甲酰胺
Figure PCTCN2020078990-appb-000036
步骤1)N-(4-溴苯基)-1,5-二甲基-3-氧-2-苯基-2,3-二氢-1H-吡唑-4-甲酰胺
向4-溴苯胺(500mg，2.9mmol)的CH 2Cl 2(15mL)溶液中加入1,5-二甲基-3-氧-2-苯基-吡唑-4-羧酸(739mg，3.2mmol)，EDCI(675mg，3.5mmol)和HOAT(80mg，0.58mmol)。回流搅拌过夜后，将反应混合物真空浓缩。残余物经硅胶柱色谱法纯化(石油醚/乙酸乙酯＝1/1)，得到标题化合物为黄色固体(340mg，31％)。MS(ESI,pos.ion)m/z:386.0(M+1)。 1H NMR(400MHz,CDCl 3)δ10.74(s,1H),7.59-7.55(m,4H),7.50-7.47(t,J＝7.4Hz,1H),7.43-7.41(d,J＝8.8Hz,2H),7.38-7.36(d,J＝7.7Hz,2H),3.37(s,3H),2.80(s,3H)。
步骤2)1,5-二甲基-3-氧-2-苯基-N-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)-2,3-二氢-1H-吡唑-4-甲酰胺
向N-(4-溴苯基)-1,5-二甲基-3-氧-2-苯基-2,3-二氢-1H-吡唑-4-甲酰胺(340mg，0.88mmol)的二氧六环(6mL)溶液中加入4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1,3,2-二氧杂硼杂环戊烷(250mg，0.97mmol)，Pd(dppf)Cl 2.CH 2Cl 2(73mg，0.088mmol)和醋酸钾(227mg，2.2mmol)。反应用氮气脱气。混合物回流搅拌过夜后，将反应混合物真空浓缩。残余物经硅胶柱色谱法纯化(石油醚/乙酸乙酯＝1/1)，得到标题化合物为黄色固体(280mg，73％)。MS(ESI,pos.ion)m/z:434.3(M+1)。 1H NMR(400MHz,CDCl3)δ10.81(s,1H),7.79-7.77(d,J＝8.3Hz,2H),7.71-7.69(d,J＝8.3Hz,2H),7.58-7.54(t,J＝7.7Hz,2H),7.49-7.46(t,J＝7.4Hz,1H),7.38-7.37(d,J＝7.5Hz,2H),3.36(s,3H),2.81(s,3H),1.35(s,12H)。
步骤3)N-(4-(4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-1,5-二甲基-3-氧-2-苯基-2,3-二氢-1H-吡唑-4-甲酰胺
向1,5-二甲基-3-氧-2-苯基-N-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基)-2,3-二氢-1H-吡唑-4-甲酰胺(280mg，0.65mmol)的二氧六环(6mL)/H 2O(1mL)溶液中加入5-溴-7-甲基-吡咯并[2,3-d]嘧啶-4-胺(154mg，0.64mmol)，Pd(dppf)Cl 2.CH 2Cl 2(53mg，0.064mmol)和碳酸铯(430mg，1.3mmol)。反应用氮气脱气。混合物回流搅拌过夜后，将反应混合物真空浓缩。残余物经硅胶柱色谱法纯化(二氯甲烷/甲醇＝500/1)，得到标题化合物为黄色固体(68mg，23％)。MS(ESI,pos.ion)m/z:454.3(M+1)。 1H NMR(400MHz,DMSO)δ10.82(s,1H),8.15(s,1H),7.71-7.69(d,J＝8.5Hz,2H),7.62-7.58(t,J＝7.6Hz,2H),7.54-7.50(t,J＝7.4Hz,1H),7.46-7.44(d,J＝7.4Hz,2H),7.41-7.39(d,J＝8.4Hz,2H),7.28(s,1H),6.06(s,2H),3.74(s,3H),3.37(s,3H),2.72(s,3H)。
实施例11 N-(4-(4-氨基-7-异丙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-1,2,4,5,6,7-六氢吡唑并[1,5-a]吡啶-3-甲酰胺
Figure PCTCN2020078990-appb-000037
向5-(4-氨基苯基)-7-异丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(100mg，0.37mmol)的CH 2Cl 2(2mL)溶液中加入2-氧-1-苯基-4,5,6,7-四氢吡唑并[1,5-a]吡啶-3-羧酸(116mg，0.45mmol)，EDCI(110mg，0.56mmol)和HOAT(10mg,0.072mmol)。回流搅拌8h后，将反应混合物真空浓缩。残余物经硅胶柱色谱法纯化(二氯甲烷/甲醇＝100/0)，得到标题化合物为黄色固体(97mg，51％)。MS(ESI,pos.ion)m/z:508.4(M+1)。 1H NMR(400MHz,DMSO)δ10.68(s,1H),8.13(s,1H),7.71-7.69(d,J＝8.4Hz,2H),7.61-7.57(t,J＝7.5Hz,2H),7.53-7.51(d,J＝7.2Hz,1H),7.48-7.46(d,J＝7.4Hz,2H),7.43-7.41(m,3H),6.05(s,2H),5.02-4.92(m,1H),3.59-3.56(t,J＝5.7Hz,2H),3.24-3.21(t,J＝6.2Hz,2H),1.99-1.98(m,2H),1.84-1.81(m,2H),1.47-1.45(d,J＝6.7Hz,6H)。
实施例12 N-(4-(4-氨基-7-异丙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺
Figure PCTCN2020078990-appb-000038
步骤1)4-氯-5-碘-7-异丙基-7H-吡咯并[2,3-d]嘧啶
向4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶(2.0g，7.0mmol)的THF(35mL)溶液中加入叔丁醇钾(1.23g，10.7mmol)，将反应混合物搅拌0.5h。向反应混合物中加入2-碘丙烷(0.9mL，9.0mmol)。在70℃下搅拌过夜后，将反应混合物真空浓缩。残余物经硅胶柱色谱法纯化(石油醚/乙酸乙酯＝3/1)，得到标题化合物为黄色固体(1.42g，63％)。MS(ESI,pos.ion)m/z:322.1(M+1)。 1H NMR(400MHz,CDCl3)δ8.61(s,1H),7.47(s,1H),5.18-5.08(m,1H),1.54-1.52(d,J＝6.8Hz,6H)。
步骤2)4-(4-氯-7-异丙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺
向4-氯-5-碘-7-异丙基-7H-吡咯并[2,3-d]嘧啶(1.31g，4.07mmol)的二氧六环(20mL)/H 2O(5mL)的溶液中加入4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯胺(0.91g，4.1mmol)，Pd(dppf)Cl 2.CH 2Cl 2(0.34g，0.41mmol)和碳酸钠(0.87g,8.2mmol)。反应用氮气脱气。混合物在90℃下搅拌过夜后，将反应混合物真空浓缩。残余物经硅胶柱色谱法纯化(石油醚/乙酸乙酯＝5/1)，得到标题化合物为黄色固体(0.68g，58％)。MS(ESI,pos.ion)m/z:287.2(M+1)。 1H NMR(400MHz,DMSO)δ8.60(s,1H),7.80(s,1H),7.19-7.17(d,J＝8.3Hz,2H),6.63-6.61(d,J＝8.3Hz,2H),5.14(s,2H),5.11-5.06(m,1H),1.52-1.50(d,J＝6.7Hz,6H)。
步骤3)5-(4-氨基苯基)-7-异丙基-7H-吡咯并[2,3-d]嘧啶-4-胺
向4-(4-氯-7-异丙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯胺(0.68g，2.4mmol)的二氧六环(20mL)溶液中加入氢氧化铵(20mL)。混合物在密闭管中于130℃下搅拌24小时后，将反应混合物真空浓缩。残余物经硅胶柱色谱法纯化(二氯甲烷/甲醇＝100/1)，得到标题化合物为黄色固体(0.30g，47％)。MS(ESI,pos.ion)m/z:268.2(M+1)。 1H NMR(400MHz,DMSO)δ8.09(s,1H),7.23(s,1H),7.13-7.11(d,J＝8.2Hz,2H),6.67-6.65(d,J＝8.2Hz,2H),5.97(s,2H),5.16(s,2H),4.99-4.89(m,1H),1.45-1.43(d,J＝6.7Hz,6H)。
步骤4)N-(4-(4-氨基-7-异丙基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺
向5-(4-氨基苯基)-7-异丙基-7H-吡咯并[2,3-d]嘧啶-4-胺(100mg，0.37mmol)的CH 2Cl 2(2mL)溶液中加入2-氧-1-苯基-5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-羧酸(110mg，0.45mmol)，EDCI(110mg，0.56mmol)和HOAT(10mg，0.072mmol)。混合物回流搅拌9h后，将反应混合物真空浓缩。残余物经硅胶柱色谱法纯化(二氯甲烷/甲醇＝100/0)，得到标题化合物为黄色固体(94mg，51％)。MS(ESI,pos.ion)m/z:494.2(M+1)。 1H NMR(400MHz,DMSO)δ10.26(s,1H),8.13(s,1H),7.74-7.72(d,J＝8.3Hz,2H),7.59-7.51(m,4H),7.44-7.41(m,4H),6.06(s,2H),5.00-4.92(td,J＝13.3,6.6Hz,1H),3.82-3.79(t,J＝6.8Hz,2H),3.20-3.17(t,J＝5.8Hz,3H),2.46-2.40(m,2H),1.47-1.46(d,J＝6.7Hz,6H)。
实施例13 N-(4-(4-氨基-7-(环丙基甲基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺
Figure PCTCN2020078990-appb-000039
步骤1)4-氯-7-(环丙基甲基)-5-碘-7H-吡咯并[2,3-d]嘧啶
将4-氯-5-碘-7H-吡咯并[2,3-d]嘧啶(12.00g，42.94mmol)，KOH(4.82g，85.9mmol)的DMSO(60mL)混合物在53℃下搅拌反应。然后向混合物中逐滴加入2-溴乙醇(12mL)，将反应混合物保持24小时。将混合物倒入水(150mL)中，真空过滤，得到标题化合物为黄色油状物(11.53g，83.00％)。MS(ESI,pos.ion)m/z:323.90[M+H] +。 1H NMR(400MHz,DMSO)δ8.63(s,1H),7.98(s,1H),4.93(t,J＝5.4Hz,1H), 4.31(t,J＝5.4Hz,2H),3.75(q,J＝5.4Hz,2H)。
步骤2)(4-(4-氯-7-(环丙基甲基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)氨基甲酸叔丁酯
将(4-(4-氯-7-(环丙基甲基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)氨基甲酸叔丁酯(2.66g，7.97mmol)，N-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基]氨基甲酸叔丁酯(3.03g,9.49mmol)，H 2O(7.5mL)，Pd(dppf)Cl 2(0.85g，0.79mmol)和Na 2CO 3(2.12g，20.0mmol)的1,4-二氧六环(35mL)混合物在93℃下搅拌12h，然后真空浓缩。残余物经快速柱色谱法纯化(PE:EA＝5:1)，得到标题化合物为黄色固体(1.37mg，43.1％)。MS(ESI,pos.ion)m/z:399.10[M+H] +。
步骤3)(4-(4-氨基-7-(环丙基甲基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)氨基甲酸叔丁酯
将(4-(4-氨基-7-(环丙基甲基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)氨基甲酸叔丁酯(1.37g，3.43mmol)和NH 4OH(28％，40mL)的1,4-二氧六环(10mL)混合物在120℃下搅拌37h，然后真空浓缩。残余物经快速柱色谱法纯化(DCM:MeOH＝30:1)，得到标题化合物为黄色固体(675.6mg，51.8％)。MS(ESI,pos.ion)m/z:280.20[M+H] +。
步骤4)5-(4-氨基苯基)-7-(环丙基甲基)-7H-吡咯并[2,3-d]嘧啶-4-胺
将5-(4-氨基苯基)-7-(环丙基甲基)-7H-吡咯并[2,3-d]嘧啶-4-胺(675.6mg，1.78mmol)和HCl(37％，5mL)的甲醇(10mL)混合物在60℃下搅拌5h，然后真空浓缩。真空过滤，得到标题化合物为黄色固体(312.5mg，62.85％)。MS(ESI,pos.ion)m/z:280.20[M+H] +。
步骤5)N-(4-(4-氨基-7-(环丙基甲基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-2-氧-1-苯基-2,4,5,6-四氢-1H-吡咯并[1,2-b]吡唑-3-甲酰胺
将2-氧-1-苯基-5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-羧酸(139.6mg，0.57mmol)，5-(4-氨基苯基)-7-(环丙基甲基)吡咯并[2,3-d]嘧啶-4-胺(159.9mg，0.5725mmol)，HOAT(24.3mg，0.18mmol)和EDCI(198.5mg，1.03mmol)的DCM(10mL)混合物在45℃下搅拌12h。将混合物真空浓缩，得到标题化合物为黄色固体(103.5g，35.76％)。 1H NMR(400MHz,DMSO)δ10.26(s,1H),8.14(s,1H),7.73(d,J＝8.4Hz,2H),7.63–7.49(m,4H),7.46–7.33(m,4H),6.09(s,2H),4.02(d,J＝7.1Hz,2H),3.80(t,J＝6.8Hz,2H),3.18(dd,J＝9.5,4.9Hz,2H),2.47–2.38(m,2H),0.92–0.77(m,1H),0.57–0.46(m,2H),0.43(d,J＝4.0Hz,2H)。 13C NMR(151MHz,DMSO)δ165.80,161.80,160.73,157.70,151.98,150.57,137.78,134.84,130.06,129.80,129.41,127.77,123.84,123.57,119.87,115.24,100.33,97.01,49.95,48.51,26.02,22.26,12.08,4.13。MS(ESI,pos.ion)m/z:503.20[M+H] +。
通过与实施例2类似的方法制备得到了实施例14至17以及实施例20，并通过与实施例10类似的方法制备得到了实施例18至19，具体参见表E：
表E
Figure PCTCN2020078990-appb-000040
Figure PCTCN2020078990-appb-000041
生物试验
分析用的LC/MS/MS系统包括Agilent 1200系列真空脱气炉，二元注射泵，孔板自动采样器，柱恒温箱，带电喷雾电离(ESI)源的Agilent G6430三级四级杆质谱仪。定量分析在MRM模式下进行，MRM转换的参数如表A所示：
表A
多反应检测扫描 490.2→383.1
碎裂电压 230V
毛细管电压 55V
干燥气温度 350℃
雾化器 0.276MPa
干燥气流速 10L/min
分析使用Agilent XDB-C18，2.1×30mm，3.5μM柱，注入5μL样品。分析条件：流动相为0.1％的甲酸水溶液(A)和0.1％的甲酸甲醇溶液(B)。流速为0.4mL/min。流动相梯度如表B所示：
表B
时间 流动相B的梯度
0.5min 5％
1.0min 95％
2.2min 95％
2.3min 5％
5.0min 终止
此外，用于分析的还有Agilent 6330系列LC/MS/MS光谱仪，配备有G1312A二元注射泵，G1367A自动采样器和G1314C UV检测器；LC/MS/MS光谱仪采用ESI放射源。使用标准液对每一个分析物进行合适的阳离子模型处理和MRM转换进行最佳的分析。在分析期间使用Capcell MP-C18柱，规格为：100×4.6mm I.D.，5μM(Phenomenex,Torrance,California,USA)。流动相是5mM醋酸铵，0.1％甲醇水溶液(A)：5mM醋酸铵，0.1％甲醇乙腈溶液(B)(70:30，v/v)；流速为0.6mL/min；柱温保持在室温；注入20μL样品。
实施例A人和大鼠肝微粒体中的稳定性
将人或大鼠肝微粒体置于聚丙烯试管中双复孔孵育。典型的孵育混合液包括人或大鼠肝微粒体(0.5mg蛋白质/mL)，目标化合物(5μM)和总体积为200μL的NADPH(1.0mM)磷酸钾缓冲液(PBS，100mM，pH值为7.4)，将待测化合物溶解在DMSO中，并使用PBS将其稀释，使其最终的DMSO溶液的浓度为0.05％。并在37℃下与空气相通的水浴中进行孵育，预孵育3分钟后向混合液中加入蛋白并开始反应。在不同的时间点(0、5、10、15、30和60分钟)，加入同体积冰冷乙腈终止反应。样品于–80℃下保存直到进行LC/MS/MS分析。
化合物在人或大鼠肝微粒体孵育混合物中的浓度是通过LC/MS/MS的方法来测定的。浓度范围的线性范围是通过每一个受试化合物来确定的。
平行孵育试验使用变性的微粒体作为阴性对照，在37℃下孵化，反应在不同的时间点(0、15和60分钟)终止。
维拉帕米(1μΜ)作为阳性对照，在37℃下孵化，反应在不同的时间点(0、5、10、15、30和60分钟)终止。每一种测定方法中都包括阳性和阴性对照样品，以保证微粒体孵化体系的完整性。
此外，本发明所述化合物在人或大鼠肝微粒体中的稳定性数据也可由以下试验得到。将人或大鼠肝微粒体置于聚丙烯试管中双复孔孵育。典型的孵育混合物包括人或大鼠肝微粒体(最终浓度：0.5mg蛋白/mL)，待测化合物(最终浓度：1.5μM)和总体积为30μL的磷酸钾缓冲溶液(含1.0mM EDTA，100mM，pH 7.4)。将待测化合物溶解在DMSO中，并用磷酸钾缓冲溶液稀释，使DMSO的最终浓度为0.2％。预孵育10分钟后，加入15μL NADPH(最终浓度：2mM)进行酶促反应，整个试验在37℃的孵育管中进行。在不同的时间点(0、15、30和60分钟)，加入135μL乙腈(含IS)终止反应。以4000rpm离心10分钟，除去蛋白，收集上层清液，用LC-MS/MS分析。在上述试验中，酮色林(1μM)被选作阳性对照，在37℃下孵化，反应在不同的时间点(0、15、30和60分钟)终止。每一种测定方法中都包括阳性和阴性对照样品，以保证微粒体孵化体系的完整性。
数据分析
对于每一个反应，将化合物在人或大鼠肝微粒体孵育中的浓度(以百分比表示)按相对零时间点的百分比作图，以此来推断体内肝固有清除率CL int(参见例如，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.)。
将本发明化合物孵育在人和大鼠肝微粒体中时，本发明所述化合物表现出合适的稳定性。
表1人和大鼠的肝微粒稳定性
Figure PCTCN2020078990-appb-000042
实施例B小鼠、大鼠、犬和猴子口服或静脉注射定量本发明化合物后的药代动力学评价
对本发明化合物在小鼠、大鼠、犬或猴子体内的药代动力学研究进行了评估。本发明化合物以水溶液或2％HPMC+1％土温-80的水溶液，5％DMSO+5％的盐水溶液，4％MC或胶囊形式进行给药。对于静脉注射给药，动物给予1或2mg/kg的剂量。对于口服剂量(p.o.)，大鼠和小鼠是5或10mg/kg，犬和猴子是10mg/kg。在时间点为0.25，0.5，1.0，2.0，3.0，4.0，6.0，8.0，12和24小时取血(0.3mL)，并在3,000或4,000rpm下离心10分钟。收集血浆溶液，并于-20℃或-70℃下保存直到进行上述的LC/MS/MS分析。
将本发明提供的化合物静脉注射给药或口服给药时，本发明所述化合物表现出良好的药代动力学性质，吸收良好且具有理想的半衰期(T 1/2)和较高的口服生物利用度(F)。
表2大鼠PK数据
Figure PCTCN2020078990-appb-000043
Figure PCTCN2020078990-appb-000044
表3小鼠PK数据
Figure PCTCN2020078990-appb-000045
表4犬PK数据
Figure PCTCN2020078990-appb-000046
表5猴PK数据
Figure PCTCN2020078990-appb-000047
实施例C激酶活性试验
本发明公开化合物作为蛋白激酶抑制剂的效用可以通过下面的实验来评价。
激酶试验通过检测掺入γ- 33P-ATP的髓磷脂碱基蛋白(MBP)来完成的。制备20μg/ml的MBP(Sigma#M-1891)三羟甲基氨基甲烷缓冲盐溶液(TBS；50mM Tris pH＝8.0，138mM NaCl，2.7mM KCl)，包被高结合性的白384孔板(Greiner)，每孔60μL。4℃下，孵育24小时。之后用100μL TBS洗板3次。激酶反应在总体积为34μL的激酶缓冲液(根据需要配制，例如，5mM Hepes pH 7.6，15mM NaCl，0.01％牛血清白蛋白(Sigma#I-5506)，10mM MgCl 2，1mM DTT，0.02％TritonX-100)中进行。将化合物溶解在DMSO中，加入各孔中，DMSO溶液中化合物的最终浓度为1％。每个化合物的测定至少进行两次试验。比如，酶的最终浓度为10nM或20nM。加入没有标记的ATP(10μM)和γ- 33P标记的ATP(每孔2×10 6cpm，3000 Ci/mmol)开始反应。反应在室温下震荡进行1个小时。384孔板用7×的PBS清洗，然后加入每孔50μL的闪烁液。用Wallac Trilux计数器检测结果。对于所属领域的技术人员来说，这仅是众多检测方法中的一种，其他的方法亦可。
上述试验方法可以得到抑制的IC 50和/或抑制常数K i。IC 50定义为在试验条件下，抑制50％酶活性时的化合物浓度。利用1/2log的稀释倍数做出包含10个浓度点的曲线，估算IC 50值(例如，通过以下化合物浓度做出一条典型的曲线：3μM、1μM、0.3μM、0.1μM、0.03μM、0.01μM、0.003μM、0.001μM、0.0003μM、0μM)，或者10μM、3μM、1μM、0.3μM、0.1μM、0.03μM、0.01μM、0.003μM、0.001μM、0μM)。
AXL(h)
AXL(h)在8mM MOPS pH＝7.0，0.2mM EDTA，250μM KKSRGDYMTMQIG，10mM醋酸镁和[γ- 33P-ATP](比活性和浓度根据需求确定)存在的条件下进行孵育。加入MgATP混合物后开始反应。室温下孵育40分钟之后，向其中加入磷酸溶液至0.5％浓度来终止反应。将10μL的反应液呈斑点状分布于P30过滤器上，用4分钟以0.425％磷酸溶液清洗4次，甲醇清洗1次。干燥后用闪烁计数器测定。
TrkA(h)
TrkA(h)在8mM MOPS pH＝7.0，0.2mM EDTA，250μM KKKSPGEYVNIEFG，10mM醋酸镁和[γ- 33P-ATP](比活性和浓度根据需求确定)存在的条件下进行孵育。加入MgATP混合物后开始反应。室温下孵育40分钟之后，向其中加入磷酸溶液至0.5％浓度来终止反应。将10μL的反应液呈斑点状分布于P30过滤器上，用4分钟以0.425％磷酸溶液清洗4次，甲醇清洗1次。干燥后用闪烁计数器测定。
TrkB(h)
TrkB(h)在8mM MOPS pH＝7.0，0.2mM EDTA，0.1mg/mL聚(Glu,Tyr)4:1,10mM醋酸镁和[γ- 33P-ATP](比活性和浓度根据需求确定)存在的条件下进行孵育。加入MgATP混合物后开始反应。室温下孵育40分钟之后，向其中加入磷酸溶液至0.5％浓度来终止反应。将10μL的反应液呈斑点状分布于A过滤器上，用4分钟以0.425％磷酸溶液清洗4次，甲醇清洗1次。干燥后用闪烁计数器测定。
TrkC(h)
TrkB(h)在8mM MOPS pH＝7.0，0.2mM EDTA，500μM GEEPLYWSFPAKKK,10mM醋酸镁和[γ- 33P-ATP](比活性和浓度根据需求确定)存在的条件下进行孵育。加入MgATP混合物后开始反应。室温下孵育40分钟之后，向其中加入磷酸溶液至0.5％浓度来终止反应。将10μL的反应液呈斑点状分布于A过滤器上，用4分钟以0.425％磷酸溶液清洗4次，甲醇清洗1次。干燥后用闪烁计数器测定。
表6本发明提供的化合物的Axl(h)、TrkA(h)、TrkB和TrkC激酶实验结果
Figure PCTCN2020078990-appb-000048
Figure PCTCN2020078990-appb-000049
Figure PCTCN2020078990-appb-000050
由表6可知，本发明所述化合物在激酶试验中显示出较好的AXL(h)、TrkA(h)、TrkB和TrkC激酶抑制活性。
实施例D细胞活性试验
通过检测两个化合物对Ba/F3 AXL cell line和Ba/F3 parental cell line两株细胞生长的抑制作用来完成的。收获处于对数生长期的细胞并采用血小板计数器进行细胞计数，用台盼蓝排斥法检测细胞活力，确保细胞活力在90％以上；调整细胞浓度；分别添加90μL细胞悬液至96孔板中；将96孔板中的细胞置于37℃、5％CO 2、95％湿度条件下培养过夜。配制10倍药物溶液，最高浓度为100μM，9个浓度，3.16倍稀释，在接种有细胞的96孔板中每孔加入10μL药物溶液，每个药物浓度设置三个复孔；将已加药的96孔板中的细胞置于37℃、5％CO 2、95％湿度条件下继续培养72小时，之后进行CTG分析。融化CTG试剂并平衡细胞板至室温30分钟，每孔加入等体积的CTG溶液，在定轨摇床上振动5分钟使细胞裂解，将细胞板放置于室温20分钟以稳定冷光信号，读取冷光值。使用GraphPad Prism 5.0软件分析数据，利用非线性S曲线回归来拟合数据得出剂量-效应曲线，并由此计算IC 50值，细胞存活率(％)＝(Lum 待测药-Lum 培养液对照)/(Lum 细胞对照-Lum 培养液对照)×100％。
表7本发明提供的化合物对Ba/F3两株细胞生长的抑制作用
Figure PCTCN2020078990-appb-000051
实施例E细胞色素P450酶诱导实验
细胞色素P450诱导测定可鉴定受试化合物诱导人肝细胞中CYP1A2，CYP2B6或CYP3A4的潜力。
实验体系
诱导剂和底物：
选择合适的CYP酶阳性对照药(诱导剂)、阴性对照药(常用氟马西尼)和探针底物(仅用于酶活测定，若只做mRNA分析则无需用到探针底物)。常见CYP酶工具药见下表8，根据目的可参考文献选取其他种类的工具药。
表8常见CYP酶工具药
Figure PCTCN2020078990-appb-000052
肝细胞供体：
使用三名供体的肝细胞进行诱导能力的评价。
细胞毒性测试：
诱导实验中应平行检测受试药对肝细胞活性的影响，方法可以采用CCK-8、LDH、MTT及中性红等。
实验步骤
肝细胞复苏/传代、种板：
将冻存肝细胞复苏或达到要求的肝细胞传代，按一定密度接种于合适的细胞培养板上。按照所需培养模型(如单层细胞、三明治培养及3D培养等)的培养要求操作以达到细胞生长要求。
诱导剂孵育在相应孔中加入用孵育液新鲜配制并预热好的含阳性/阴性对照药或受试药的给药溶液，连续孵育2-3天并每天换液，每个化合物多复孔平行操作。如有需要可在受试药孵育的最后一天的多个时间点采样并分析其实际浓度。
底物孵育和CCK-8孵育：
末次给药后在培养板中加入配制并预热好的底物工作溶液孵育一定时间。细胞毒测试板则加入CCK-8溶液孵育一定时间。
细胞毒性和酶活性测试：
采用酶标仪或分光光度计进行吸光度的测定以计算细胞毒性。底物工作溶液孵育后经样品处理后分析以计算酶活性。
mRNA的提取、反转录和荧光定量PCR：
根据相关试剂盒说明书进行上述实验步骤的操作。
数据处理
酶诱导实验分别对mRNA水平的诱导倍数、酶活性的诱导倍数、以及各自相对阳性对照药的诱导活性进行计算；细胞毒实验则计算各化合物给药后细胞活力相对空白组的比率。
mRNA水平的诱导倍数计算：
将检测得目的基因Ct值减去内参(如18s)的Ct值，得到目的基因的ΔCt值，再参与mRNA相对表达差异(诱导倍数)计算，即如下公式，用以判定对mRNA表达水平的诱导情况。
ΔCt＝Ct-目的基因-Ct18s
ΔΔCt＝ΔCt-对照/样本-ΔCt-溶媒对照
相对表达差异＝2-ΔΔCt。
相对酶活性计算：
采用已确认的分析方法检测各CYP亚酶探针底物的特异性代谢产物，通过比较测试组及溶媒对照组的代谢产物的差异来计算酶活性诱导。相对阳性对照活性依照下列公式来计算：
相对阳性对照活性(％)＝(测试组样本活性－溶媒组样本活性)/(阳性对照组样本活性－溶媒组样本活性)×100。
评价标准：
通常以阳性对照药的酶活性诱导倍数≧2倍，mRNA水平诱导倍数≧4倍认为实验体系正常，有些细胞个别亚酶被诱导的能力偏弱时其标准可适当降低。受试药组出现细胞活力<70％则认为有肝细胞毒性。受试药以mRNA水平诱导倍数≧2倍且mRNA诱导水平相对阳性对照药≧20％认为有诱导风险。同时，为了减少假阴性，若满足mRNA水平诱导倍数≧4倍、酶活性诱导倍数≧2倍且酶活性诱导相对阳性对照药≧20％二者任一时，也认为存在诱导风险。
在10μM浓度下，本发明中一些化合物的酶诱导实验结果如表9所示：
表9本发明化合物酶诱导实验结果
Figure PCTCN2020078990-appb-000053
最后，需要注意的是，还有其他方式用来实施本发明。相应地，本发明的实施例是将作为例证进行说明，但并不限于本发明所描述的内容，还可能是在本发明范围内所作的修改或在权利要求中所添加的等同内容。本发明所引用的所有出版物或专利都将作为本发明的参考文献。

Claims (10)

  1. 化合物，其具有式(I)所示结构：
    Figure PCTCN2020078990-appb-100001
    或其立体异构体、互变异构体、氮氧化物、溶剂化物、或药学上可接受的盐；
    其中，
    U 1和U 2分别独立地为N或-C(R a)-；
    R 1、R 2和R 4分别独立地为H、C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基、氰基取代的C 1-6烷基、C 3-10环烷基、C 3-10环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、C 1-9杂芳基C 1-6烷基；其中所述各C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基、氰基取代的C 1-6烷基、C 3-10环烷基、C 3-10环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基和C 1-9杂芳基C 1-6烷基独立任选地被0、1、2、3或4个R 11取代；
    各R a、R 3、R 5、R 6、R 7和R 8分别独立地为H、D、F、Cl、Br、-OH、-CN、-NO 2、-NR cR d、C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基、氰基取代的C 1-6烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-6烷基；其中所述各C 1-6烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基和C 1-9杂芳基C 1-6烷基独立任选地被0、1、2、3或4个R 12取代；
    或者R 2和R 3同与之相连的碳原子和氮原子一起任选地形成4-12个原子组成的杂环，其中所述4-12个原子组成的杂环任选地被0、1、2、3、4或5个R 13取代；
    各R 11、R 12和R 13分别独立地为H、D、氧代(＝O)、F、Cl、Br、-OH、-CN、-NO 2、-NR cR d、-C(＝O)R 9、-OC(＝O)R 9、-C(＝O)OR 9a、-S(＝O) 0-2R 9、-OS(＝O) 1-2R 9、-S(＝O) 1-2OR 9a、-N(R 10a)C(＝O)R 10、-C(＝O)NR 10aR 10、-OC(＝O)NR 10aR 10、-N(R 10a)S(＝O) 1-2R 10、-S(＝O) 1-2NR 10aR 10、-N(R 10a)C(＝O)NR 10aR 10、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基、氰基取代的C 1-6烷基、C 1-6烷氧基、C 1-6烷基氨基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-6烷基；其中所述各C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、C 1-9杂芳基C 1-6烷基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-OH、-NH 2、-CN、-NO 2、C 1-6烷基和C 1-6烷氧基的基团取代；
    各R c、R d、R 9、R 9a、R 10和R 10a分别独立地为H、D、C 1-6烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-6烷基；其中所述各C 1-6烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基和C 1-9杂芳基C 1-6烷基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-OH、-NH 2、-CN、-NO 2、C 1-6烷基和C 1-6烷氧基的基团取代；和
    n是0、1、或2。
  2. 根据权利要求1所述的化合物，其具有式(II)所示结构：
    Figure PCTCN2020078990-appb-100002
    其中，
    X 1是O、S、-N(R 13a)-、-C(＝O)-、-(CH 2) t1-、-X 2-(CH 2) t1-、或-(CH 2) t1-X 2-(CH 2) t2-；
    X 2是O、S、-N(R 13a)-、或-C(＝O)-；
    各R 13a分别独立地为H、D、氧代(＝O)、F、Cl、Br、-OH、-CN、-NO 2、氨基、C 1-6烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、C 1-9杂芳基C 1-6烷基、-C(＝O)R 9、-C(＝O)OR 9a、-S(＝O) 0-2R 9、-S(＝O) 1-2OR 9a、-S(＝O) 1-2NR 10aR 10、或-C(＝O)NR 10aR 10，其中所述各C 1-6烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基和C 1-9杂芳基C 1-6烷基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-OH、-NH 2、-CN、-NO 2、C 1-6烷基和C 1-6烷氧基的基团取代；
    各t1和t2分别独立地为0、1、2、或3；和
    m是0、1、2、4、或5。
  3. 根据权利要求1或2所述的化合物，其中，
    R 1是C 1-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基、氰基取代的C 1-4烷基、C 3-8环烷基、苯基、或C 1-9杂芳基；其中所述各C 1-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基、氰基取代的C 1-4烷基、C 3-8环烷基、苯基和C 1-9杂芳基独立任选地被0、1、2、3或4个R 11取代。
  4. 根据权利要求1或2所述的化合物，其中，
    R 4是H、D、甲基、乙基、丙基、异丙基、丁基、C 1-4卤代烷基、C 1-4氨基烷基、氰基取代的C 1-4烷基、C 3-6环烷基、C 3-6环烷基C 1-4烷基、C 2-7杂环基、或C 2-7杂环基C 1-4烷基。
  5. 根据权利要求1所述的化合物，其为具有以下结构之一的化合物：
    Figure PCTCN2020078990-appb-100003
    Figure PCTCN2020078990-appb-100004
    或其立体异构体、互变异构体、氮氧化物、溶剂化物、或药学上可接受的盐。
  6. 药物组合物，所述药物组合物包含权利要求1-5中任一项所述的化合物或其立体异构体、互变异构体、氮氧化物、溶剂化物、或药学上可接受的盐，以及药学上可接受的辅料、稀释剂或载体、或其组合。
  7. 根据权利要求6所述的药物组合物，其进一步包含附加治疗剂。
  8. 使用根据权利要求1-5任一项所述的化合物或权利要求6-7任一项所述的药物组合物在制备用于预防或治疗一种或多种Axl和/或Trk蛋白激酶介导的疾病和/或病症的药物中的用途。
  9. 根据权利要求8所述的用途，所述疾病和/或病症选自增殖性疾病、自体免疫疾病、过敏性疾病、炎性疾病、或移植排斥。
  10. 根据权利要求9所述的用途，所述疾病和/或病症选自癌症、真性红细胞增多症、原发性血小板增多症、、急性髓细胞性白血病、急性淋巴细胞白血病、骨髓纤维化、急性髓细胞性白血病、慢性髓细胞性白血病、急性淋巴细胞白血病、慢性阻塞性肺疾病、哮喘、系统性红斑狼疮、皮肤型红斑狼疮、狼疮性肾炎、皮肌炎、干燥综合征、银屑病、I型糖尿病、呼吸道过敏性疾病、鼻窦炎、湿疹、麻疹、食物过敏、昆虫毒液过敏、炎性肠病、克罗恩病、类风湿性关节炎、幼年型关节炎、银屑病性关节炎、器官移植排斥、组织移植排斥或细胞移植排斥。
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