WO2023125803A1 - 杂芳环氮氧化合物及其制备方法和应用 - Google Patents
杂芳环氮氧化合物及其制备方法和应用 Download PDFInfo
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- WO2023125803A1 WO2023125803A1 PCT/CN2022/143381 CN2022143381W WO2023125803A1 WO 2023125803 A1 WO2023125803 A1 WO 2023125803A1 CN 2022143381 W CN2022143381 W CN 2022143381W WO 2023125803 A1 WO2023125803 A1 WO 2023125803A1
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- membered
- alkyl
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- cycloalkyl
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- -1 Heteroaromatic nitrogen-oxide compound Chemical class 0.000 title claims abstract description 232
- 238000002360 preparation method Methods 0.000 title claims abstract description 42
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 title abstract description 14
- 229960003753 nitric oxide Drugs 0.000 title abstract 3
- 235000019391 nitrogen oxide Nutrition 0.000 title abstract 3
- 125000000217 alkyl group Chemical group 0.000 claims description 657
- 125000000623 heterocyclic group Chemical group 0.000 claims description 365
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 249
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- 125000003118 aryl group Chemical group 0.000 claims description 130
- 125000005843 halogen group Chemical group 0.000 claims description 126
- 125000003342 alkenyl group Chemical group 0.000 claims description 118
- 125000002950 monocyclic group Chemical group 0.000 claims description 116
- 125000005915 C6-C14 aryl group Chemical group 0.000 claims description 108
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- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 97
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 77
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 76
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- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 59
- 229910052757 nitrogen Inorganic materials 0.000 claims description 57
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 11
- 125000005842 heteroatom Chemical group 0.000 claims description 11
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- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 8
- 206010060862 Prostate cancer Diseases 0.000 claims description 8
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- 125000004429 atom Chemical group 0.000 claims description 8
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- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 7
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 7
- 125000005907 alkyl ester group Chemical group 0.000 claims description 7
- 125000002619 bicyclic group Chemical group 0.000 claims description 7
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 7
- 150000001924 cycloalkanes Chemical class 0.000 claims description 7
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 7
- 201000001320 Atherosclerosis Diseases 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 6
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical group [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims description 6
- 229940125782 compound 2 Drugs 0.000 claims description 6
- 229940126214 compound 3 Drugs 0.000 claims description 6
- 125000004122 cyclic group Chemical group 0.000 claims description 6
- 238000002347 injection Methods 0.000 claims description 6
- 239000007924 injection Substances 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 230000000699 topical effect Effects 0.000 claims description 6
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 5
- 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 claims description 5
- BJHCYTJNPVGSBZ-YXSASFKJSA-N 1-[4-[6-amino-5-[(Z)-methoxyiminomethyl]pyrimidin-4-yl]oxy-2-chlorophenyl]-3-ethylurea Chemical compound CCNC(=O)Nc1ccc(Oc2ncnc(N)c2\C=N/OC)cc1Cl BJHCYTJNPVGSBZ-YXSASFKJSA-N 0.000 claims description 5
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 5
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
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- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 4
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- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 3
- KZOWNALBTMILAP-JBMRGDGGSA-N ancitabine hydrochloride Chemical compound Cl.N=C1C=CN2[C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3OC2=N1 KZOWNALBTMILAP-JBMRGDGGSA-N 0.000 claims description 3
- 125000002393 azetidinyl group Chemical group 0.000 claims description 3
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- 229940125904 compound 1 Drugs 0.000 claims description 3
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- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- 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
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D498/04—Ortho-condensed systems
Definitions
- the present invention relates to heteroaromatic nitrogen oxide compounds and their preparation methods and applications, in particular to compounds that inhibit, regulate and/or regulate signal transduction of c-Met kinase, their preparation methods, pharmaceutical compositions containing them and their applications .
- Protein kinases are the enzymatic components of signaling pathways that catalyze the transfer of terminal phosphates from ATP to the hydroxyl groups of tyrosine, serine and/or threonine residues of proteins. Compounds that inhibit protein kinase function are therefore valuable tools for assessing the physiological consequences of protein kinase activity.
- Overexpression or inappropriate expression of normal or mutant protein kinases in mammals has been the subject of extensive research and has been demonstrated in many diseases, including diabetes, angiogenesis, psoriasis, restenosis, eye diseases, schizophrenia, It plays an important role in the development of rheumatoid arthritis, atherosclerosis, cardiovascular disease and cancer. Protein kinase inhibitors have particular utility in the treatment of human and animal diseases.
- Hepatocyte growth factor receptor is a transmembrane protein encoded by the MET gene, which belongs to the tyrosine kinase receptor superfamily and is mainly expressed in epithelial cells.
- Hepatocyte growth factor also known as scatter factor (SF)
- SF scatter factor
- HGF When HGF binds to c-Met in the extracellular domain, it triggers the dimerization of c-Met, and promotes the transphosphorylation of the two catalytic active sites Tyr1234 and Tyr1235 at the c-Met activation loop, which in turn leads to its terminal Tyr1349 and Tyr1349. Tyr1356 undergoes autophosphorylation, thereby recruiting a variety of downstream cellular effectors and effector molecules, and activating a series of downstream signaling pathways, such as PI3K-AKT, RAS-MAPK, STAT, and Wnt/ ⁇ -catenin.
- c-Met/HGF plays an important role in promoting cell proliferation, cell growth, cell migration, invasion of blood vessels and angiogenesis.
- c-Met gene abnormalities mainly include MET exon 14 skipping mutation, MET gene amplification and c-Met protein overexpression. Abnormal c-Met gene will lead to abnormal activation of c-Met pathway, which will cause excessive activation of downstream pathways and induce cancer.
- the c-Met small-molecule kinase inhibitor is the most promising and has the most therapeutic potential.
- Small-molecule kinase inhibitors can act on the catalytic domain in the membrane to prevent protein phosphorylation, thereby blocking signal transduction, and achieving targeted therapy for cancer.
- c-Met small molecule kinase inhibitors can be divided into three types, namely type I, type II and type III.
- Type I are c-Met kinase-specific inhibitors that compete with ATP for binding to the ATP binding site pocket, where the aspartate-phenylalanine-glycine (DFG) moiety points to the ATP binding site, representative inhibitors include Crizotinib, capmatinib, tepotinib, savotinib, PLB1001 and glutatinib, etc.
- DFG aspartate-phenylalanine-glycine
- Type I inhibitors can be further divided into type Ia and type Ib, type Ia such as crizotinib, in addition to targeting the kinase domain, is also able to interact with the solvent front residue G1163; type Ib such as capmatinib, tepotinib and Savolitinib et al., only target the kinase domain.
- Type II are ATP-competitive multi-target kinase inhibitors, which can extend and occupy the DFG pocket in addition to competing with ATP for binding to the ATP-binding pocket of the inactive conformational c-Met kinase, such as cabozantinib, Glesatinib, and Merestinib wait.
- Type III is a non-ATP competitive inhibitor, such as Tivantinib.
- c-Met kinase inhibitors include crizotinib, capmatinib, tepotinib and cabozantinib. It has been clinically found that c-Met kinase inhibitors are effective in the treatment of non-small cell patients with MET exon 14 skipping mutations, and the response rate (ORR) is between 25% and 68%, but the clinical side effects are relatively large, and After 9-16 months, patients will inevitably develop drug resistance. Drug resistance to type I kinase inhibitors is mainly caused by mutations at D1228 and Y1230, and mutation to type II inhibitors is mainly caused by mutations at sites F1200 and L1195. Weak, making kinase inhibitors ineffective. Preclinical studies have found that drug-resistant mutations caused by type I inhibitors are still sensitive to type II inhibitors. In contrast, resistance mutations caused by type II inhibitors are sensitive to type I inhibitors.
- the present invention provides a heteroaromatic nitrogen oxide compound capable of overcoming the abnormality of the c-Met gene, which has the structure shown in the following formula I:
- A is selected from 5-14 membered heteroaryl substituted by R 1 , 3-14 membered heterocyclic group substituted by R 1 , 6-14 membered aryl substituted by R 1 and 3-12 membered aryl substituted by R 1 Cycloalkyl, the 5-14 membered heteroaryl group substituted by R 1 , the 3-14 membered heterocyclic group substituted by R 1 , the 6-14 membered aryl group substituted by R 1 and the substituted by R 1
- the 3-12 membered cycloalkyl group is optionally substituted by one or more R 2
- the 5-14 membered heteroaryl group substituted by R 1 and the 6-14 membered aryl group substituted by R 1 include monocyclic or Condensed ring
- the 3-14 membered heterocyclic group substituted by R 1 and the 3-12 membered cycloalkyl group substituted by R 1 include a monocyclic ring, a spiro ring or a bridged ring;
- Z is selected from 6-14 membered aryl, 5-14 membered heteroaryl, 3-12 membered cycloalkyl and 3-14 membered heterocyclic group, the 6-14 membered aryl, 5-14 membered heteroaryl
- the base, the 3-12 membered cycloalkyl group and the 3-14 membered heterocyclyl group are optionally substituted by one or more R3 ;
- R 1 is selected from R 8 substituted by one or more hydroxyl groups
- R 1 and R 2 together with the connected atoms form a 5-14 membered ring group, and the group is substituted by one or more R 1 ;
- R 2 and R 8 can form a 5-14-membered ring group together with the connected atoms, and the group is substituted by one or more R 1 ;
- R 4 , R 5 , R 6 and R 7 are each independently selected from hydrogen atom, halogen atom, OR e , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-12-membered Cycloalkyl, 3-20 membered heterocyclic group, 6-20 membered aryl group and 5-20 membered heteroaryl group, wherein said 3-12 membered cycloalkyl group and 3-20 membered heterocyclic group include monocyclic, spiro ring or bridging ring, the 6-20 membered aryl and 5-20 membered heteroaryl include single ring or condensed ring, the C 1-6 alkyl, C 2-6 alkenyl, C 2- 6- alkynyl, 3-12-membered cycloalkyl, 3-20-membered heterocyclic group, 6-20-membered aryl and 5-20-membered heteroaryl are optionally substituted by one or more groups independently selected from the following
- R 4 and R 5 together with the carbon atom they are connected to form a 3-12 membered monocyclic ring, spiro ring or bridged ring optionally substituted by one or more R m ;
- R 6 and R 7 together with the nitrogen atom to which they are attached form a saturated, partially unsaturated or fully unsaturated 3-20 membered heterocyclic ring optionally substituted by one or more R m , which optionally contains One or more heteroatoms selected from N, O or S;
- R a and R b together with the carbon atom to which they are attached form a 3-12 membered monocyclic ring, spiro ring or bridged ring optionally substituted by one or more R m ;
- R a or R b together with the carbon atom or adjacent nitrogen atom to which it is attached forms a 5-14 membered heteroaryl, 6-14 membered aryl, 3-14 membered heteroaryl optionally substituted by one or more R m Cyclic group or 3-12 membered cycloalkyl group;
- R b and R c form a 3-12 membered monocyclic ring, spiro ring, bridged ring or condensed ring optionally substituted by one or more R m together with the nitrogen atom to which they are attached;
- R e and R f are each independently selected from a hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-12 membered cycloalkyl, 3-20 membered heterocyclic group, 6-20 membered aryl and 5-20 membered heteroaryl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-12 membered cycloalkyl, 3- 20-membered heterocyclic group, 6-20-membered aryl group and 5-20-membered heteroaryl group are optionally substituted by one or more C 1-6 alkyl or halogen atoms;
- R' is selected from a hydrogen atom, a C 1-6 alkyl group, a 3-12 membered cycloalkyl group, a 3-12 membered cycloalkenyl group, a 3-12 membered heterocyclyl group, a 6-14 membered aryl group and a 5-14 membered heterocyclic group Aryl, the C 1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclic group, 6-14 membered aryl and 5-14 membered heteroaryl
- the group is optionally substituted by one or more R m ;
- the 3-12 membered cycloalkyl group, 3-12 membered cycloalkenyl group and 3-12 membered heterocyclic group include monocyclic, spiro ring or bridged ring, so
- the 6-14 membered aryl and 5-14 membered heteroaryl include single ring or condensed
- Y 1 is O or S
- t, m1 and n1 are each independently 0, 1, 2, 3, 4, 5 or 6;
- R 1 is not hydroxyalkyl, however, R 1 is substituted for NH except, such as R can be hydroxy C 1-6 alkyl, wherein D is selected from N or CH, and G is selected from NH, O or S;
- R When A is replaced by R1
- A is selected from a 5-14 membered heteroaryl group substituted by R 1 , and the 5-14 membered heteroaryl group substituted by R 1 includes a single ring or a condensed ring, optionally replaced by one or a plurality of R 2 substitutions;
- A is selected from the group substituted by R 1 optionally substituted by one or more R 2 ;
- Z is selected from 6-14 membered aryl and 5-10 membered heteroaryl optionally substituted by one or more R;
- Z is selected from the following groups optionally substituted by one or more R3 :
- X is selected from NR 4 , O, S or is absent;
- X is selected from NR 4 , O and S.
- E 1 , E 2 , and E 3 are each independently selected from CR a R b and N.
- G is selected from (CR a R b ) n1 -6-20 membered aryl, (CR a R b ) n1 -5-20 membered heteroaryl, (CR a R b ) n1 -3 -12 membered cycloalkyl group and (CR a R b ) n1 -3-20 membered heterocyclic group, said (CR a R b ) n1 -6-20 membered aryl group, (CR a R b ) n1 -5 -20 membered heteroaryl, (CR a R b ) n1 -3-12 membered cycloalkyl and (CR a R b ) n1 -3-20 membered heterocyclic group are optionally selected from one or more The following group substitution: halogen atom, nitro, oxo, CN, OR e , SR e , NR e R f , C 1-12 alkyl,
- G is selected from 6-20 membered aryl and 5-20 membered heteroaryl, wherein said 6-20 membered aryl and 5-20 membered heteroaryl are optionally replaced by one or A plurality of groups independently selected from the following substituents: halogen atom, nitro, oxo, CN, OR e , SR e , NR e R f , C 1-12 alkyl, halogenated C 1-12 alkyl, C 1-6 alkoxy-C 1-12 alkyl, halogenated C 1-6 alkoxy-C 1-12 alkyl, R a R b NC 1-6 alkyl, C 2-8 alkenyl, Halogenated C 2-8 alkenyl, C 2-8 alkynyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl-C 1-6 alkyl or 3-20 membered heterocyclic group.
- R 1 is selected from R 8 substituted by one or two hydroxyl groups
- R 8 is selected from -NR b R c , -OR b , -SR b , R b R c NC 1-6 alkyl, R b R c NC 1-6 alkoxy, C 1-6 alkyl, C 2 -8 alkenyl, C 2-8 alkynyl, C 1-6 alkyl-R a , C 1-6 alkoxy-R b , 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3 -12-membered heterocyclyl, 6-14-membered aryl, 5-10-membered heteroaryl, 3-12-membered cycloalkyl-C 1-6 alkyl, 3-12-membered cycloalkenyl-C 1-6 alkane base, 3-12 membered heterocyclyl-C 1-6 alkyl, 6-14 membered aryl-C 1-6 alkyl and 5-10 membered heteroaryl-C 1-6 alkyl, the R
- R 8 is selected from -NR b R c , -OR b , C 1-6 alkyl, R b R c NC 1-6 alkyl, 3-12 membered heterocyclyl and 3-12 membered heterocyclyl -C 1-6 alkyl, said C 1-6 alkyl, R b R c NC 1-6 alkyl, 3-12 membered heterocyclyl and 3-12 membered heterocyclyl-C 1-6 alkane
- the group is optionally substituted by one or more R m , and the 3-12 membered heterocyclyl and 3-12 membered heterocyclyl-C 1-6 alkyl include monocyclic, spiro or bridged rings.
- R 2 and R 3 are independently selected from hydrogen atom, halogen atom, cyano group, nitro group, -NR b R c , -OR b , R b R c NC 1-6 alkyl, R b R c NC 1-6 alkoxy, C 1-6 alkyl, C 2-8 alkenyl , C 2-8 alkynyl, C 1-6 alkyl-R a , C 1-6 alkoxy-R b , 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, 3-12 membered cycloalkyl-C 1-6 alkyl and 3-12 membered heterocyclic group-C 1-6 alkyl, the R b R c NC 1-6 alkyl, R b R c NC 1-6 alkoxy, C 1-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkyl- R a , C 1-6 alkoxy-R b
- R 4 , R 5 , R 6 and R 7 are each independently selected from a hydrogen atom, a halogen atom, OR e , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 3-20 membered cycloalkyl, 3-20 membered heterocyclic group and 6-20 membered aryl group, wherein said 3-20 membered cycloalkyl group and 3-20 membered heterocyclic group include monocyclic, spiro Ring or bridging ring; said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-20 membered cycloalkyl, 3-20 membered heterocyclic group and 6-20 membered aromatic
- the group is optionally substituted by one or more groups independently selected from the following groups: halogen atom, CN, OR e , NR e R f , C 1-12 alkyl, C 2-8 alkenyl, C 2-8 Alky
- R 4 and R 5 together with the carbon atom they are connected to form a 3-12 membered monocyclic ring, spiro ring or bridged ring optionally substituted by one or more R m ;
- R 6 and R 7 together with the nitrogen atom to which they are attached form a saturated, partially unsaturated or fully unsaturated 3-20 membered heterocyclic ring optionally substituted by one or more R m , which optionally contains One or more heteroatoms selected from N, O or S;
- R 4 , R 5 , R 6 and R 7 are each independently selected from a hydrogen atom, OR e , C 1-6 alkyl, monocyclic or bicyclic 3-12-membered cycloalkyl, 3-20-membered Heterocyclic group and 6-20 membered aryl group, wherein said C 1-6 alkyl group, monocyclic or bicyclic 3-12 membered cycloalkyl group, 3-20 membered heterocyclic group and 6-20 membered aryl group Optionally substituted by one or more groups independently selected from the following groups: halogen atom, CN, OR e , NR e R f , C 1-12 alkyl, C 2-8 alkenyl, C 2-8 alkyne Base, 3-12 membered cycloalkyl or 3-20 membered heterocyclic group;
- R 4 and R 5 form a 3-12 membered monocyclic ring, a spiro ring or a bridged ring optionally substituted by one or more R m together with the carbon atoms to which they are attached, and the 3-12 membered monocyclic ring, spiro ring Or the bridging ring is optionally substituted by one or more groups independently selected from the following groups: halogen atom, C 1-6 alkyl or C 1-6 alkoxy;
- R 6 and R 7 form a saturated, partially unsaturated or fully unsaturated 3-20 membered heterocyclic ring optionally substituted by one or more R m together with the nitrogen atom to which they are attached, said 3 -
- the 20-membered heterocyclic ring is optionally substituted by one or more groups independently selected from the following groups: halogen atoms, C 1-6 alkyl or C 1-6 alkoxy.
- R b and R c together with the nitrogen atom to which they are attached form a 3-12 membered monocyclic ring, spiro ring, bridged ring or condensed ring optionally substituted by one or more R m ;
- R e and R f are each independently selected from a hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl, 3-12 membered cycloalkyl, 3-20 membered heterocyclic group, 6-20 membered aryl and 5-20 membered heteroaryl, wherein said C 1-6 alkyl, C 2-6 alkenyl, 3-12 membered cycloalkyl, 3-20 membered heterocyclic group, 6-20 membered aryl and 5 -20-membered heteroaryl is optionally substituted by one or more C 1-6 alkyl or halogen atoms;
- R g is C 1-6 alkyl or 6-20 membered aryl, wherein said C 1-6 alkyl and 6-20 membered aryl are optionally replaced by one or more groups independently selected from the following groups Substitution: halogen atom or OR e ;
- R' is selected from C1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-14 membered aryl and 5-10 membered heteroaryl,
- the C 1-6 alkyl group, 3-12 membered cycloalkyl group, 3-12 membered cycloalkenyl group, 3-12 membered heterocyclic group, 6-14 membered aryl group and 5-10 membered heteroaryl group are optionally is substituted by one or more R m ;
- said 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl and 3-12 membered heterocyclyl include monocyclic, spiro or bridged rings, said 6 - 14-membered aryl and 5-10-membered heteroaryl include single or condensed rings.
- R b and R c together with the nitrogen atom to which they are attached form a 3-12 membered monocyclic ring, spiro ring, bridged ring or condensed ring optionally substituted by one or more R m ;
- R e and R f are each independently selected from a hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl, 3-12 membered cycloalkyl and 3-20 membered heterocyclic group, wherein said C 1- 6 alkyl, C 2-6 alkenyl, 3-12 membered cycloalkyl and 3-20 membered heterocyclyl are optionally substituted by one or more C 1-6 alkyl or halogen atoms;
- R g is C 1-6 alkyl or 6-20 membered aryl, wherein said C 1-6 alkyl and 6-20 membered aryl are optionally replaced by one or more groups independently selected from the following groups Substitution: halogen atom or OR e ;
- R' is selected from C 1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl and 5-10 membered heteroaryl, the C 1-6 alkyl, 3-12 membered ring Alkyl, 3-12 membered heterocyclic group and 5-10 membered heteroaryl group are optionally substituted by one or more R m ; said 3-12 membered cycloalkyl group and 3-12 membered heterocyclic group include single ring, spiro ring or bridged ring, and the 5-10 membered heteroaryl includes a single ring or a condensed ring.
- R m is selected from deuterium atom, halogen atom, cyano, nitro, hydroxyl, mercapto, amino, carboxyl, C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl-C 1-6 alkoxy , C 1-6 alkoxy-C 1-6 alkoxy, C 1-6 alkylamino , ( C 1- 6 alkyl) 2 amino, C 1-6 alkyl ester group, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, C 1-6 alkylcarbonyl, C 1-6 alkane C 1-6 alkylcarbonyloxy, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 1-6 alkylsulfonyl Acyl, C 1-6 alkyl, C
- A is selected from 5-14 membered heteroaryls substituted by R 1 , and the 5-14 membered heteroaryls substituted by R 1 include single or condensed rings, optionally substituted by One or more R2 substitutions;
- Z is selected from 6-14 membered aryl and 5-10 membered heteroaryl optionally substituted by one or more R3 ;
- X is selected from NR 4 , O, S or absent;
- G is selected from (CR a R b ) n1 -6-20 membered aryl, (CR a R b ) n1 -5-20 membered heteroaryl, (CR a R b ) n1 -3-12 membered cycloalkyl and (CR a R b ) n1 -3-20 membered heterocyclic group, said (CR a R b ) n1 -6-20 membered aryl group, (CR a R b ) n1 -5-20 membered heteroaryl group, (CR a R b ) n1 -3-12 membered cycloalkyl and (CR a R b ) n1 -3-20 membered heterocyclyl are optionally substituted by one or more groups independently selected from the following groups: halogen atom, nitro, oxo, CN, OR e , SR e , NR e R f , C 1-12 alkyl, halogen
- R 1 is selected from R 8 substituted by one or two hydroxyl groups
- R 4 , R 5 , R 6 and R 7 are independently selected from hydrogen atom, halogen atom, OR e , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-20 member Cycloalkyl, 3-20 membered heterocyclic group and 6-20 membered aryl group, wherein said 3-20 membered cycloalkyl group and 3-20 membered heterocyclic group include monocyclic, spiro ring or bridged ring; said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-20 membered cycloalkyl, 3-20 membered heterocyclic group and 6-20 membered aryl are optionally replaced by one or Multiple substitutions independently selected from the following groups: halogen atom, CN, OR e , NR e R f , C 1-12 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, 3-12 member Cycloalkyl
- R 4 and R 5 together with the carbon atom they are connected to form a 3-12 membered monocyclic ring, spiro ring or bridged ring optionally substituted by one or more R m ;
- R 6 and R 7 together with the nitrogen atom to which they are attached form a saturated, partially unsaturated or fully unsaturated 3-20 membered heterocyclic ring optionally substituted by one or more R m , which optionally contains One or more heteroatoms selected from N, O or S;
- R 8 is selected from -NR b R c , -OR b , -SR b , R b R c NC 1-6 alkyl, R b R c NC 1-6 alkoxy, C 1-6 alkyl, C 2 -8 alkenyl, C 2-8 alkynyl, C 1-6 alkyl-R a , C 1-6 alkoxy-R b , 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3 -12 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl, 3-12 membered cycloalkyl-C 1-6 alkyl, 3-12 membered cycloalkenyl-C 1-6 alkane base, 3-12 membered heterocyclyl-C 1-6 alkyl, 6-14 membered aryl-C 1-6 alkyl and 5-10 membered heteroaryl-C 1-6 alkyl, the R b R c
- R b and R c together with the nitrogen atom to which they are attached form a 3-12 membered monocyclic ring, spiro ring, bridged ring or condensed ring optionally substituted by one or more R m ;
- R e and R f are each independently selected from a hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl, 3-12 membered cycloalkyl, 3-20 membered heterocyclic group, 6-20 membered aryl and 5-20 membered heteroaryl, wherein said C 1-6 alkyl, C 2-6 alkenyl, 3-12 membered cycloalkyl, 3-20 membered heterocyclic group, 6-20 membered aryl and 5 -20-membered heteroaryl is optionally substituted by one or more C 1-6 alkyl or halogen atoms;
- R g is a C 1-6 alkyl group and a 6-20 membered aryl group, wherein the C 1-6 alkyl group and a 6-20 membered aryl group are optionally replaced by one or more groups independently selected from the following groups Substitution: halogen atom or OR e ;
- R' is selected from C1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-14 membered aryl and 5-10 membered heteroaryl,
- the C 1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclic group, 6-14 membered aryl and 5-10 membered heteroaryl are optionally is substituted by one or more R m ;
- said 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl and 3-12 membered heterocyclyl include monocyclic, spiro or bridged rings, said 6 -14 membered aryl and 5-10 membered heteroaryl include single ring or condensed ring;
- Y 1 is O or S
- t, m1 and n1 are each independently 0, 1, 2, 3, 4, 5 or 6.
- A is selected from the group substituted by R 1 optionally substituted by one or more R 2 ;
- Z is selected from the following groups optionally substituted by one or more R3 :
- X is selected from NR4 , O and S;
- E 1 , E 2 , E 3 are each independently selected from CR a R b and N;
- G is selected from 6-20 membered aryl and 5-20 membered heteroaryl, wherein said 6-20 membered aryl and 5-20 membered heteroaryl are optionally selected from one or more of the following independently Group substitution: halogen atom, nitro, oxo, CN, OR e , SR e , NR e R f , C 1-12 alkyl, halogenated C 1-12 alkyl, C 1-6 alkoxy- C 1-12 alkyl, halogenated C 1-6 alkoxy-C 1-12 alkyl, R a R b NC 1-6 alkyl, C 2-8 alkenyl, halogenated C 2-8 alkenyl , C 2-8 alkynyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl-C 1-6 alkyl or 3-20 membered heterocyclic group;
- R 1 is selected from R 8 substituted by one or two hydroxyl groups
- R 2 and R 3 are each independently selected from a hydrogen atom, a halogen atom, a cyano group, a nitro group, -NR b R c , -OR b , R b R c NC 1-6 alkyl, R b R c NC 1- 6 alkoxy, C 1-6 alkyl, C 2-8 alkenyl , C 2-8 alkynyl, C 1-6 alkyl-R a , C 1-6 alkoxy-R b , 3-12 Membered cycloalkyl, 3-12 membered heterocyclic group, 3-12 membered cycloalkyl-C 1-6 alkyl and 3-12 membered heterocyclic group-C 1-6 alkyl, the R b R c NC 1-6 alkyl, R b R c NC 1-6 alkoxy, C 1-6 alkyl, C 2-8 alkenyl , C 2-8 alkynyl, C 1-6 alkyl-R a , C 1-6
- R 4 , R 5 , R 6 and R 7 are each independently selected from a hydrogen atom, OR e , C 1-6 alkyl, monocyclic or bicyclic 3-12 membered cycloalkyl, 3-20 membered heterocyclic group and 6-20 membered aryl, wherein said C 1-6 alkyl, monocyclic or bicyclic 3-12 membered cycloalkyl, 3-20 membered heterocyclic group and 6-20 membered aryl are optionally Substituted by one or more groups independently selected from the following groups: halogen atom, CN, OR e , NR e R f , C 1-12 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, 3 -12-membered cycloalkyl or 3-20-membered heterocyclyl;
- R 4 and R 5 form a 3-12 membered monocyclic ring, a spiro ring or a bridged ring optionally substituted by one or more R m together with the carbon atoms to which they are attached, and the 3-12 membered monocyclic ring, spiro ring Or the bridging ring is optionally substituted by one or more groups independently selected from the following groups: halogen atom, C 1-6 alkyl or C 1-6 alkoxy;
- R 6 and R 7 form a saturated, partially unsaturated or fully unsaturated 3-20 membered heterocyclic ring optionally substituted by one or more R m together with the nitrogen atom to which they are attached, said 3 -The 20-membered heterocyclic ring is optionally substituted by one or more groups independently selected from the following groups: halogen atom, C 1-6 alkyl or C 1-6 alkoxy;
- R 8 is selected from -NR b R c , -OR b , C 1-6 alkyl, R b R c NC 1-6 alkyl, 3-12 membered heterocyclyl and 3-12 membered heterocyclyl-C 1 -6 alkyl, the C 1-6 alkyl, R b R c NC 1-6 alkyl, 3-12 membered heterocyclic group and 3-12 membered heterocyclic group-C 1-6 alkyl are optional is substituted by one or more R m , and the 3-12 membered heterocyclyl and 3-12 membered heterocyclyl-C 1-6 alkyl include monocyclic, spiro or bridged rings;
- R b and R c together with the nitrogen atom to which they are attached form a 3-12 membered monocyclic ring, spiro ring, bridged ring or condensed ring optionally substituted by one or more R m ;
- R e and R f are each independently selected from a hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl, 3-12 membered cycloalkyl, 3-20 membered heterocyclic group, 6-20 membered aryl and 5-20 membered heteroaryl, wherein said C 1-6 alkyl, C 2-6 alkenyl, 3-12 membered cycloalkyl, 3-20 membered heterocyclic group, 6-20 membered aryl and 5 -20-membered heteroaryl is optionally substituted by one or more C 1-6 alkyl or halogen atoms;
- R g is C 1-6 alkyl or 6-20 membered aryl, wherein said C 1-6 alkyl and 6-20 membered aryl are optionally replaced by one or more groups independently selected from the following groups Substitution: halogen atom or OR e ;
- R' is selected from C 1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl and 5-10 membered heteroaryl, the C 1-6 alkyl, 3-12 membered ring Alkyl, 3-12 membered heterocyclic group and 5-10 membered heteroaryl group are optionally substituted by one or more R m ; said 3-12 membered cycloalkyl group and 3-12 membered heterocyclic group include single Ring, spiro ring or bridged ring, the 5-10 membered heteroaryl includes single ring or condensed ring;
- R m is selected from deuterium atom, halogen atom, cyano, nitro, hydroxyl, mercapto, amino, carboxyl, C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 Alkoxy, C 1-6 alkyl-C 1-6 alkoxy, C 1-6 alkoxy- C 1-6 alkoxy, C 1-6 alkylamino, (C 1-6 alkyl ) 2 amino, C 1-6 alkyl ester group, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonyloxy C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 2-8 alkenyl, C 2
- t 0, 1, 2, 3, 4, 5 or 6.
- A is selected from the group substituted by R 1 optionally substituted by one or more R 2 ;
- Z is selected from benzene, pyridine and naphthalene rings optionally substituted by one or more R3 :
- X is selected from NR4 ;
- E 1 , E 2 , E 3 are each independently selected from CR a R b and N;
- G is selected from 6-20 membered aryl, pyridine and pyrazole, wherein said 6-20 membered aryl, pyridine and pyrazole are optionally substituted by one or more groups independently selected from the following groups: halogen atom, Nitro, Oxo, CN, Methoxy, Ethoxy, Amino, Methylamino, Ethylamino, Dimethylamino, Methyl, Ethyl, Isopropyl, Vinyl, CF 3 , Methoxymethyl, Trifluoromethoxymethyl, cyclopropyl, cyclopropylmethyl;
- R is selected from the following groups:
- R 2 and R 3 are each independently selected from a hydrogen atom, a hydroxyl group, a mercapto group, a halogen atom, a cyano group, a nitro group, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a hydroxyl-C 1-6 alkyl, amino-C 1-6 alkyl, halogenated C 1-6 alkyl , C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 alkoxy- C 1-6 alkyl, C 1-6 alkyl -C 1-6 alkoxy, C 1-6 alkoxy -C 1-6 alkoxy, 3-12 membered cycloalkyl, 3-12 membered Heterocyclyl, 3-12 membered cycloalkyl-C 1-6 alkyl and 3-12 membered heterocyclyl-C 1-6 alkyl, the C 1-6 alkyl, C 2-6 alken
- R is independently selected from a hydrogen atom, methyl, ethyl, trifluoromethyl and cyclopropyl;
- R a does not exist or is each independently selected from a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, an amino group, a mercapto group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 1-6 alkylamino group, ( C 1-6 alkyl) 2 amino, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkyl sulfone, C 1-6 Alkyl sulfoxide, halogenated C 1-6 alkyl sulfone, C 1-6 alkoxy-C 1-6 alkyl, C 2-8 alkenyl, 3-12 membered cycloalkyl and 3-12 Member heterocyclic group, the C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkoxy,
- R b does not exist or is selected from hydrogen atom, C 1-6 alkyl, halogen atom, C 1-6 alkoxy, C 1-6 alkyl-3-12 membered cycloalkyl, C 1-6 alkyl- 3-12 membered heterocyclyl, 3-12 membered cycloalkyl-C 1-6 alkyl, 3-12 membered heterocyclyl-C 1-6 alkyl, 3-12 membered cycloalkyl and 3-12 membered Heterocyclyl, the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl-3-12 membered cycloalkyl, C 1-6 alkyl-3-12 membered heterocycle Group, 3-12 membered cycloalkyl-C 1-6 alkyl, 3-12 membered heterocyclyl-C 1-6 alkyl, 3-12 membered cycloalkyl and 3-12 membered heterocyclic group optionally replaced by one or more R m ;
- R a and R b form a 3-12 membered monocyclic ring, spiro ring, bridged ring or condensed ring optionally substituted by one or more R m together with the nitrogen atom to which they are attached;
- R m are each independently selected from deuterium atom, halogen atom, cyano, nitro, hydroxyl, mercapto, amino, carboxyl, C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkoxy, C 1-6 alkyl-C 1-4 alkoxy , C 1-4 alkoxy-C 1-4 alkoxy, C 1-4 alkylamino , ( C 1- 4 alkyl) 2 amino, C 1-4 alkyl ester group, C 1-4 alkylaminocarbonyl, (C 1-4 alkyl) 2 aminocarbonyl, C 1-4 alkylcarbonyl, C 1-4 alkane C 1-4 alkylcarbonyloxy, C 1-4 alkylcarbonylamino, C 1-4 alkylsulfonylamino, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, C 1-4 alkylsulfonyl Acyl, C 1-4 alkyl
- the compound shown in formula I is selected from the following compounds:
- the application provides a method for preparing a compound of formula I, the method comprising reacting compound 1 with compound M under basic conditions to form compound 2, and then oxidizing compound 2 under acidic conditions Forming compound 3, compound 3 reacts with compound 4 to form the step of the compound shown in formula I;
- X 1 is a halogen atom
- A, L, Z, X, Y, E 1 , E 2 , E 3 and G are as defined above,
- the base is selected from cesium fluoride, cesium carbonate;
- the acid is selected from trifluoroacetic acid.
- the application provides a pharmaceutical composition comprising the above compound and a pharmaceutically acceptable carrier or excipient; preferably, the pharmaceutical composition is a tablet, capsule, pill, granule, Powder, suppository, injection, solution, suspension, ointment, patch, lotion, drop, liniment, spray.
- the present application provides the application of the above-mentioned compound or pharmaceutical composition in the preparation of a medicament for treating diseases related to protein kinases.
- the protein kinase-associated disease is selected from c-Met, VEGFR-2, AXL, TAM, NTRK or RET-associated diseases.
- the protein kinase-associated disease is a tumor.
- the diseases associated with protein kinases include head and neck cancer, nasopharyngeal cancer, melanoma, bladder cancer, esophageal cancer, anaplastic large cell lymphoma, renal cancer, breast cancer, colorectal cancer , ovarian cancer, cervical cancer, pancreatic cancer, glioma, glioblastoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, gastric cancer, lung cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, Squamous cell carcinoma, cholangiocarcinoma, endometrial carcinoma, multiple myeloma, or mesothelioma; atherosclerosis and pulmonary fibrosis.
- the present application provides the application of the above compounds and/or pharmaceutical compositions in the preparation of antitumor drugs.
- the tumor comprises head and neck cancer, nasopharyngeal cancer, melanoma, bladder cancer, esophageal cancer, anaplastic large cell lymphoma, renal cancer, breast cancer, colorectal cancer, ovarian cancer, cervical cancer Carcinoma, pancreatic cancer, glioma, glioblastoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, gastric cancer, lung cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, squamous cell carcinoma, Cholangiocarcinoma, endometrial cancer, multiple myeloma, and mesothelioma.
- the present application provides a method for treating a protein kinase-associated disease in a subject, comprising administering to the subject an effective amount of the above compound or a pharmaceutically acceptable salt, stereoisomer, tautomer Isomers, deuterated substances, prodrug molecules, hydrates or solvates or the above pharmaceutical compositions, the subject is preferably a mammal, and the mammal is preferably a human.
- the mode of administration includes oral, mucosal, sublingual, ophthalmic, topical, parenteral, rectal, cisternal, vaginal, peritoneal, bladder, nasal administration.
- the protein kinase-associated disease is selected from c-Met, VEGFR-2, AXL, TAM, NTRK or RET-associated diseases.
- the protein kinase-associated disease is a tumor.
- the diseases associated with protein kinases include head and neck cancer, nasopharyngeal cancer, melanoma, bladder cancer, esophageal cancer, anaplastic large cell lymphoma, renal cancer, breast cancer, colorectal cancer , ovarian cancer, cervical cancer, pancreatic cancer, glioma, glioblastoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, gastric cancer, lung cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, Squamous cell carcinoma, cholangiocarcinoma, endometrial carcinoma, multiple myeloma, or mesothelioma; atherosclerosis and pulmonary fibrosis.
- the present application provides a method for treating a tumor in a subject, comprising administering to the subject an effective amount of the above compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterium Substitutes, prodrug molecules, hydrates or solvates or the above pharmaceutical compositions, the subject is preferably a mammal, and the mammal is preferably a human.
- the mode of administration includes oral, mucosal, sublingual, ophthalmic, topical, parenteral, rectal, cisternal, vaginal, peritoneal, bladder, nasal administration.
- the tumor comprises: head and neck cancer, nasopharyngeal cancer, melanoma, bladder cancer, esophageal cancer, anaplastic large cell lymphoma, renal cancer, breast cancer, colorectal cancer, ovarian cancer, Cervical cancer, pancreatic cancer, glioma, glioblastoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, gastric cancer, lung cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, squamous cell carcinoma , cholangiocarcinoma, endometrial cancer, multiple myeloma and mesothelioma.
- the present invention relates to the compound shown in formula I or its pharmaceutically acceptable salt, stereoisomer, tautomer, deuterium, prodrug molecule, hydrate or solvate
- A is selected from 5-14 membered heteroaryl substituted by R 1 , 3-14 membered heterocyclic group substituted by R 1 , 6-14 membered aryl substituted by R 1 and 3-12 membered aryl substituted by R 1 Cycloalkyl, the 5-14 membered heteroaryl group substituted by R 1 , the 3-14 membered heterocyclic group substituted by R 1 , the 6-14 membered aryl group substituted by R 1 and the substituted by R 1
- the 3-12 membered cycloalkyl group is optionally substituted by one or more R 2
- the 5-14 membered heteroaryl group substituted by R 1 and the 6-14 membered aryl group substituted by R 1 include monocyclic or Condensed ring
- the 3-14 membered heterocyclic group substituted by R 1 and the 3-12 membered cycloalkyl group substituted by R 1 include a monocyclic ring, a spiro ring or a bridged ring;
- Z is selected from 6-14 membered aryl, 5-14 membered heteroaryl, 3-12 membered cycloalkyl and 3-14 membered heterocyclic group, the 6-14 membered aryl, 5-14 membered heteroaryl
- the base, the 3-12 membered cycloalkyl group and the 3-14 membered heterocyclyl group are optionally substituted by one or more R3 ;
- R 1 is selected from R 8 substituted by one or more hydroxyl groups
- R 1 and R 2 together with the connected atoms form a 5-14 membered ring group, and the group is substituted by one or more R 1 ;
- R 2 and R 8 can form a 5-14-membered ring group together with the connected atoms, and the group is substituted by one or more R 1 ;
- R 4 , R 5 , R 6 and R 7 are each independently selected from hydrogen atom, halogen atom, OR e , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-12-membered Cycloalkyl, 3-20 membered heterocyclic group, 6-20 membered aryl group and 5-20 membered heteroaryl group, wherein said 3-12 membered cycloalkyl group and 3-20 membered heterocyclic group include monocyclic, spiro ring or bridging ring, the 6-20 membered aryl and 5-20 membered heteroaryl include single ring or condensed ring; the C 1-6 alkyl, C 2-6 alkenyl, C 2- 6- alkynyl, 3-12-membered cycloalkyl, 3-20-membered heterocyclic group, 6-20-membered aryl and 5-20-membered heteroaryl are optionally substituted by one or more groups independently selected from the following
- R 4 and R 5 together with the carbon atom they are connected to form a 3-12 membered monocyclic ring, spiro ring or bridged ring optionally substituted by one or more R m ;
- R 6 and R 7 together with the nitrogen atom to which they are attached form a saturated, partially unsaturated or fully unsaturated 3-20 membered heterocyclic ring optionally substituted by one or more R m , which optionally contains One or more heteroatoms selected from N, O or S;
- R a and R b together with the carbon atom to which they are attached form a 3-12 membered monocyclic ring, spiro ring or bridged ring optionally substituted by one or more R m ;
- R a or R b together with the carbon atom or adjacent nitrogen atom to which it is attached forms a 5-14 membered heteroaryl, 6-14 membered aryl, 3-14 membered heteroaryl optionally substituted by one or more R m Cyclic group or 3-12 membered cycloalkyl group;
- R b and R c together with the nitrogen atom to which they are attached form a 3-12 membered monocyclic ring, spiro ring, bridged ring or condensed ring optionally substituted by one or more R m ;
- R e and R f are each independently selected from a hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-12 membered cycloalkyl, 3-20 membered heterocyclic group, 6-20 membered aryl and 5-20 membered heteroaryl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-12 membered cycloalkyl, 3- 20-membered heterocyclic group, 6-20-membered aryl group and 5-20-membered heteroaryl group are optionally substituted by one or more C 1-6 alkyl or halogen atoms;
- R' is selected from a hydrogen atom, a C 1-6 alkyl group, a 3-12 membered cycloalkyl group, a 3-12 membered cycloalkenyl group, a 3-12 membered heterocyclyl group, a 6-14 membered aryl group and a 5-14 membered heterocyclic group Aryl, the C 1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclic group, 6-14 membered aryl and 5-14 membered heteroaryl
- the group is optionally substituted by one or more R m ;
- the 3-12 membered cycloalkyl group, 3-12 membered cycloalkenyl group and 3-12 membered heterocyclic group include monocyclic, spiro ring or bridged ring, so
- the 6-14 membered aryl and 5-14 membered heteroaryl include single ring or condensed
- Y 1 is O or S
- t, m1 and n1 are each independently 0, 1, 2, 3, 4, 5 or 6;
- R 1 is not hydroxyalkyl, however, R 1 is substituted for NH except, such as R can be hydroxy C 1-6 alkyl, wherein D is selected from N or CH, and G is selected from NH, O or S;
- R 1 is not hydroxy C 1-6 alkyl, wherein, D is selected from N or CH, and G is selected from NH, O or S;
- A is selected from a 5-14 membered heteroaryl group substituted by R 1 , and the 5-14 membered heteroaryl group substituted by R 1 includes a single ring or a condensed ring, optionally replaced by one or a plurality of R 2 substitutions;
- A is selected from the group substituted by R 1 optionally substituted by one or more R 2 ;
- Z is selected from 6-14 membered aryl and 5-10 membered heteroaryl optionally substituted by one or more R;
- Z is selected from the following groups optionally substituted by one or more R3 :
- X is selected from NR 4 , O, S or is absent;
- X is selected from NR 4 , O and S.
- E 1 , E 2 , and E 3 are each independently selected from CR a R b and N.
- G is selected from (CR a R b ) n1 -6-20 membered aryl, (CR a R b ) n1 -5-20 membered heteroaryl, (CR a R b ) n1 -3 -12 membered cycloalkyl group and (CR a R b ) n1 -3-20 membered heterocyclic group, said (CR a R b ) n1 -6-20 membered aryl group, (CR a R b ) n1 -5 -20 membered heteroaryl, (CR a R b ) n1 -3-12 membered cycloalkyl and (CR a R b ) n1 -3-20 membered heterocyclic group are optionally selected from one or more The following group substitution: halogen atom, nitro, oxo, CN, OR e , SR e , NR e R f , C 1-12 alkyl,
- G is selected from 6-20 membered aryl and 5-20 membered heteroaryl, wherein said 6-20 membered aryl and 5-20 membered heteroaryl are optionally replaced by one or A plurality of groups independently selected from the following substituents: halogen atom, nitro, oxo, CN, OR e , SR e , NR e R f , C 1-12 alkyl, halogenated C 1-12 alkyl, C 1-6 alkoxy-C 1-12 alkyl, halogenated C 1-6 alkoxy-C 1-12 alkyl, R a R b NC 1-6 alkyl, C 2-8 alkenyl, Halogenated C 2-8 alkenyl, C 2-8 alkynyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl-C 1-6 alkyl or 3-20 membered heterocyclic group.
- R 1 is selected from R 8 substituted by one or two hydroxyl groups
- R 8 is selected from -NR b R c , -OR b , -SR b , R b R c NC 1-6 alkyl, R b R c NC 1-6 alkoxy, C 1-6 alkyl, C 2 -8 alkenyl, C 2-8 alkynyl, C 1-6 alkyl-R a , C 1-6 alkoxy-R b , 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3 -12-membered heterocyclyl, 6-14-membered aryl, 5-10-membered heteroaryl, 3-12-membered cycloalkyl-C 1-6 alkyl, 3-12-membered cycloalkenyl-C 1-6 alkane base, 3-12 membered heterocyclyl-C 1-6 alkyl, 6-14 membered aryl-C 1-6 alkyl and 5-10 membered heteroaryl-C 1-6 alkyl, the R
- R 8 is selected from -NR b R c , -OR b , C 1-6 alkyl, R b R c NC 1-6 alkyl, 3-12 membered heterocyclyl and 3-12 membered heterocyclyl -C 1-6 alkyl, said C 1-6 alkyl, R b R c NC 1-6 alkyl, 3-12 membered heterocyclyl and 3-12 membered heterocyclyl-C 1-6 alkane
- the group is optionally substituted by one or more R m , and the 3-12 membered heterocyclyl and 3-12 membered heterocyclyl-C 1-6 alkyl include monocyclic, spiro or bridged rings.
- R 2 and R 3 are independently selected from hydrogen atom, halogen atom, cyano group, nitro group, -NR b R c , -OR b , R b R c NC 1-6 alkyl, R b R c NC 1-6 alkoxy, C 1-6 alkyl, C 2-8 alkenyl , C 2-8 alkynyl, C 1-6 alkyl-R a , C 1-6 alkoxy-R b , 3-12 membered cycloalkyl, 3-12 membered heterocyclic group, 3-12 membered cycloalkyl-C 1-6 alkyl and 3-12 membered heterocyclic group-C 1-6 alkyl, the R b R c NC 1-6 alkyl, R b R c NC 1-6 alkoxy, C 1-6 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkyl- R a , C 1-6 alkoxy-R b
- R 4 , R 5 , R 6 and R 7 are each independently selected from a hydrogen atom, a halogen atom, OR e , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 3-20 membered cycloalkyl, 3-20 membered heterocyclic group and 6-20 membered aryl group, wherein said 3-20 membered cycloalkyl group and 3-20 membered heterocyclic group include monocyclic, spiro Ring or bridging ring; said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-20 membered cycloalkyl, 3-20 membered heterocyclic group and 6-20 membered aromatic
- the group is optionally substituted by one or more groups independently selected from the following groups: halogen atom, CN, OR e , NR e R f , C 1-12 alkyl, C 2-8 alkenyl, C 2-8 Alky
- R 4 and R 5 together with the carbon atom they are connected to form a 3-12 membered monocyclic ring, spiro ring or bridged ring optionally substituted by one or more R m ;
- R 6 and R 7 together with the nitrogen atom to which they are attached form a saturated, partially unsaturated or fully unsaturated 3-20 membered heterocyclic ring optionally substituted by one or more R m , which optionally contains One or more heteroatoms selected from N, O or S;
- R 4 , R 5 , R 6 and R 7 are each independently selected from a hydrogen atom, OR e , C 1-6 alkyl, monocyclic or bicyclic 3-12-membered cycloalkyl, 3-20-membered Heterocyclic group and 6-20 membered aryl group, wherein said C 1-6 alkyl group, monocyclic or bicyclic 3-12 membered cycloalkyl group, 3-20 membered heterocyclic group and 6-20 membered aryl group Optionally substituted by one or more groups independently selected from the following groups: halogen atom, CN, OR e , NR e R f , C 1-12 alkyl, C 2-8 alkenyl, C 2-8 alkyne Base, 3-12 membered cycloalkyl or 3-20 membered heterocyclic group;
- R 4 and R 5 form a 3-12 membered monocyclic ring, a spiro ring or a bridged ring optionally substituted by one or more R m together with the carbon atoms to which they are attached, and the 3-12 membered monocyclic ring, spiro ring Or the bridging ring is optionally substituted by one or more groups independently selected from the following groups: halogen atom, C 1-6 alkyl or C 1-6 alkoxy;
- R 6 and R 7 form a saturated, partially unsaturated or fully unsaturated 3-20 membered heterocyclic ring optionally substituted by one or more R m together with the nitrogen atom to which they are attached, said 3 -
- the 20-membered heterocyclic ring is optionally substituted by one or more groups independently selected from the following groups: halogen atoms, C 1-6 alkyl or C 1-6 alkoxy.
- R b and R c together with the nitrogen atom to which they are attached form a 3-12 membered monocyclic ring, spiro ring, bridged ring or condensed ring optionally substituted by one or more R m ;
- R e and R f are each independently selected from a hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl, 3-12 membered cycloalkyl, 3-20 membered heterocyclic group, 6-20 membered aryl and 5-20 membered heteroaryl, wherein said C 1-6 alkyl, C 2-6 alkenyl, 3-12 membered cycloalkyl, 3-20 membered heterocyclic group, 6-20 membered aryl and 5 -20-membered heteroaryl is optionally substituted by one or more C 1-6 alkyl or halogen atoms;
- R g is C 1-6 alkyl or 6-20 membered aryl, wherein said C 1-6 alkyl and 6-20 membered aryl are optionally replaced by one or more groups independently selected from the following groups Substitution: halogen atom or OR e ;
- R' is selected from C1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocyclyl, 6-14 membered aryl and 5-10 membered heteroaryl,
- the C 1-6 alkyl group, 3-12 membered cycloalkyl group, 3-12 membered cycloalkenyl group, 3-12 membered heterocyclic group, 6-14 membered aryl group and 5-10 membered heteroaryl group are optionally is substituted by one or more R m ;
- said 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl and 3-12 membered heterocyclyl include monocyclic, spiro or bridged rings, said 6 -14 membered aryl and 5-10 membered heteroaryl include single ring or condensed ring;
- R b and R c together with the nitrogen atom to which they are attached form a 3-12 membered monocyclic ring, spiro ring, bridged ring or condensed ring optionally substituted by one or more R m ;
- R e and R f are each independently selected from a hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl, 3-12 membered cycloalkyl and 3-20 membered heterocyclic group, wherein said C 1- 6 alkyl, C 2-6 alkenyl, 3-12 membered cycloalkyl and 3-20 membered heterocyclyl are optionally substituted by one or more C 1-6 alkyl or halogen atoms;
- R g is C 1-6 alkyl or 6-20 membered aryl, wherein said C 1-6 alkyl and 6-20 membered aryl are optionally replaced by one or more groups independently selected from the following groups Substitution: halogen atom or OR e ;
- R' is selected from C 1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl and 5-10 membered heteroaryl, the C 1-6 alkyl, 3-12 membered ring Alkyl, 3-12 membered heterocyclic group and 5-10 membered heteroaryl group are optionally substituted by one or more R m ; said 3-12 membered cycloalkyl group and 3-12 membered heterocyclic group include single ring, spiro ring or bridged ring, and the 5-10 membered heteroaryl includes a single ring or a condensed ring.
- R m is selected from deuterium atom, halogen atom, cyano, nitro, hydroxyl, mercapto, amino, carboxyl, C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl-C 1-6 alkoxy , C 1-6 alkoxy-C 1-6 alkoxy, C 1-6 alkylamino , ( C 1- 6 alkyl) 2 amino, C 1-6 alkyl ester group, C 1-6 alkylaminocarbonyl, (C 1-6 alkyl) 2 aminocarbonyl, C 1-6 alkylcarbonyl, C 1-6 alkane C 1-6 alkylcarbonyloxy, C 1-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 1-6 alkylsulfonyl Acyl, C 1-6 alkyl, C
- the minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix (Ca-b)alkyl indicates any alkyl group containing "a" to "b” carbon atoms.
- (C 1-6 )alkyl refers to an alkyl group containing 1 to 6 carbon atoms. Said alkyl group is branched or straight chained.
- Atoms described in compounds of the present application include isotopes thereof, for example, hydrogen may be deuterium or tritium.
- Alkyl refers to a straight chain or branched, monovalent, saturated hydrocarbon group, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl radical, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and other similar groups.
- C 1-8 alkyl is preferred. More preferred is C 1-6 alkyl. More preferably C 1-4 alkyl.
- Cycloalkyl means a saturated monocyclic, bicyclic, spiro, fused or bridged cycloalkyl group, possibly in combination with other groups. Cycloalkyl groups include, but are not limited to, eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. A 3-8 membered cycloalkyl group is preferred. More preferred is a 3-6 membered cycloalkyl group. More preferred is a 3-4 membered cycloalkyl group.
- Alkenyl refers to a straight chain, branched or cyclic hydrocarbon group containing one or more double bonds, including but not limited to vinyl, propenyl, (E)-2-methylvinyl, (Z) -2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl base.
- C 2-6 alkenyl is preferred. More preferably C 2-4 alkenyl.
- Alkynyl refers to a straight chain, branched chain or cyclic hydrocarbon group containing one or more triple bonds, including but not limited to ethynyl, prop-1-ynyl, prop-2-ynyl, but-1 -alkynyl, but-2-ynyl, but-3-ynyl. C 2-6 alkynyl is preferred. More preferably C 2-4 alkynyl.
- Alkoxy refers to a linear or branched, monovalent, saturated alkyl group bonded to an oxygen atom, including but not limited to methoxy, ethoxy, propoxy, butoxy , isobutoxy, tert-butoxy and other similar groups.
- C 1-8 alkoxy is preferred. More preferred is C 1-6 alkoxy. More preferred is C 1-4 alkoxy.
- Halogen means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine and bromine.
- Haloalkyl means an alkyl group as defined herein in which one or more hydrogens has been replaced by the same or different halogen. Including but not limited to -CH 2 Cl, -CHF2, -CH 2 CF 3 , -CH 2 CCl 3 , perfluoroalkyl (eg -CF 3 ), etc.
- Aryl refers to a substituted or unsubstituted monocyclic or polycyclic aromatic group, including but not limited to phenyl, naphthyl. A 6-10 membered monocyclic or bicyclic aromatic group is preferred. More preferred is phenyl or naphthyl. Phenyl is most preferred.
- Heterocyclyl means a substituted or unsubstituted 3-10 membered non-aromatic monocyclic saturated ring system containing 1-3 heteroatoms independently selected from N, O, or S, and the remaining ring atoms are carbon atoms .
- heterocyclyl moieties include, but are not limited to: azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, oxopiperidinyl, oxo Piperazinyl, oxohomopiperazinyl, tetrahydrofuryl, imidazolinyl, morpholinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, quinuclidinyl, thiadiazole Alkyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, etc.
- a 4-7 membered heterocyclic group is preferred. More preferred is a
- Heteroaryl means a substituted or unsubstituted 5-membered or 6-membered monoheteroaromatic ring system, or a substituted or unsubstituted 9-membered or 10-membered fused or diheteroaryl ring system containing 1-4 independent is selected from N, O, or S heteroatoms, and the remaining ring atoms are carbon atoms.
- heteroaryl moieties include, but are not limited to: thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiadiazolyl, triazolyl, pyridyl, pyridazine yl, pyrimidinyl, indolyl, indazolyl, quinolinyl, isoquinolyl, benzimidazolyl or benzothiazolyl.
- “Bridged ring” means a polycyclic group in which any two rings share two atoms not directly connected, may contain one or more double bonds, but none of the rings has a fully conjugated ⁇ electron system, and the ring atoms may be Full carbon atoms can also be used where one or more ring atoms are selected from N, O, S, SO or SO2 . 7-10 rings are preferred.
- Spiro ring refers to a polycyclic group in which any two rings share carbon atoms, which may contain one or more double bonds, but none of the rings has a fully conjugated ⁇ electron system, and the ring atoms can be all carbon atoms or wherein one or more ring atoms are selected from N, O, S, SO or SO 2 . Preferably 5-10 rings.
- the number of constituent rings it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
- a cyclic group can be bonded to another group in a variety of ways. If the bonding mode is not specified, it means that all possible modes are included. For example, “pyridyl” includes 2-, 3-, or 4-pyridyl, and “thienyl” includes 2- or 3-thienyl.
- “Pharmaceutically acceptable salt” refers to conventional acid addition salts or base addition salts, which retain the biological effectiveness and properties of the compounds of formula I, which are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases.
- acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, phosphoric, and nitric acids, and from organic acids.
- the organic acids such as acetic acid, propionic acid, glycolic acid, oxalic acid, stearic acid, ascorbic acid, p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, oxalic acid, succinic acid, citric acid, maleic acid, Hydroxymaleic acid, lactic acid, fumaric acid, tartaric acid, malic acid, isethionic acid, benzenesulfonic acid, trifluoroacetic acid, mandelic acid, etc.
- base addition salts include those derived from inorganic bases such as ammonium, calcium, iron, aluminum, sodium, potassium, zinc, magnesium, and from organic acids.
- the organic bases include salts of primary, secondary and tertiary amines, such as trimethylamine, triethylamine, tripropylamine, diethanolamine, ethylenediamine, ethanolamine, and the like.
- Chemical modification of pharmaceutical compounds (ie drugs) into salts is a well known technique to pharmacists to obtain improved physical and chemical stability, hygroscopicity, flow and solubility of compounds.
- Prodrug refers to a prodrug that can be transformed into the structure of the compound involved in the present invention and the pharmaceutically acceptable salt thereof in vivo.
- the present application also relates to processes for the preparation of compounds of formula I.
- the compounds of the invention may be prepared by any conventional means. Suitable methods for synthesizing these compounds are provided in the Examples. In multi-step synthetic routes, the order of reactions can be adjusted in specific cases.
- the application provides a method for preparing a compound of formula I, the method comprising reacting compound 1 with compound M under basic conditions to form compound 2, and then oxidizing compound 2 under acidic conditions Forming compound 3, compound 3 reacts with compound 4 to form the step of the compound shown in formula I;
- X 1 is halogen
- A, L, Z, X, Y, E 1 , E 2 , E 3 and G are as defined above,
- the base is selected from cesium fluoride, cesium carbonate;
- the acid is selected from trifluoroacetic acid.
- compositions of heteroaromatic nitrogen oxides as c-Met kinase inhibitors are provided.
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising the heteroaromatic nitrogen oxide compound as a c-Met kinase inhibitor and a pharmaceutically acceptable carrier or excipient.
- pharmaceutical composition refers to the combination of one or more of the compounds of the present invention or their pharmaceutically acceptable salts, solvates, hydrates or prodrugs with other chemical components, such as pharmaceutical acceptable carrier, excipient or diluent.
- pharmaceutical acceptable carrier such as pharmaceutical acceptable carrier, excipient or diluent.
- the purpose of the pharmaceutical composition is to facilitate the process of administration to animals.
- “Pharmaceutically acceptable carrier” means a pharmaceutically acceptable substance, ingredient or medium, such as liquid or solid filler, diluent, excipient, solvent or potting material, which participates in the The loading or delivery of a compound from one location, body fluid, tissue, organ (internal or external), or body part to another location, body fluid, organ (internal or external), or body part.
- a pharmaceutically acceptable carrier can be a medium, diluent, excipient or other materials that are not unduly toxic or side effects and can be used in contact with animal tissues.
- Typical pharmaceutically acceptable carriers include sugars, starches, celluloses, maltose, tragacanth, gelatin, Ringer's solution, alginic acid, physiological saline, buffers and the like.
- Each pharmaceutically acceptable carrier should be compatible with other components, such as forming a preparation with the conjugate provided in the present invention, without excessive toxicity, irritation, allergic reaction, immunogenicity or other problems to biological living tissues or organs Or complications, and have a more reasonable benefit-risk ratio.
- Some pharmaceutically acceptable carrier materials include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as carboxymethyl Sodium cellulose, ethyl cellulose, cellulose acetate; (4) Tragacanth powder; (5) Maltose; (6) Gelatin; (7) Talc; (8) Excipients such as cocoa butter and suppositories Waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol Alcohol, mannitol and polyethylene glycol; (12) Lipids, such as ethyl oleate, ethyl laurate; (13) Agar gel; (14) Buffers, such as magnesium hydroxide and aluminum hydroxide; (15) (16) Sterile
- the pharmaceutical composition may include pharmaceutically acceptable excipients to simulate physiological conditions, such as pH adjustment and buffering agents, toxicity modifiers, etc., such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc.
- the pharmaceutical composition can be prepared in any suitable dosage form, such as solid dosage form (eg tablet, capsule, powder, granule, etc.) and liquid dosage form (eg aqueous solution, emulsion, elixir, syrup, etc.).
- suitable dosage form eg tablet, capsule, powder, granule, etc.
- liquid dosage form eg aqueous solution, emulsion, elixir, syrup, etc.
- the preparation method of the pharmaceutical composition is well known and can be prepared according to conventional techniques, such as provided in Remington, The Science and Practice of Pharmacy (Gennaro ed.20th edition, Williams & Wilkins PA, USA) (2000).
- the compounds or pharmaceutical compositions provided in the present invention can be formulated into dosage forms suitable for drug release, and administered by injection routes (such as subcutaneous, intravenous, intramuscular, arterial, thecal, intrathecal, intrathecal, intrathecal, etc.) intracardiac, intradermal, intraperitoneal, transtracheal, epidermal, intraarticular, subcapsular, subarachnoid, intraspinal, intrasternal, and/or infusion) and non-injection routes (e.g., oral, enteral, Oral, nasal, intranasal, mucosal, epidermal, patch, dermal, ophthalmic, pulmonary, sublingual, rectal, vaginal, or epidermal).
- injection routes such as subcutaneous, intravenous, intramuscular, arterial, thecal, intrathecal, intrathecal, intrathecal, etc.
- intracardiac intradermal, intraperitoneal, transtracheal, epidermal, intraarticular, subcapsular, subarachnoid, intra
- Suitable dosage forms include (but are not limited to) dosage forms for parenteral use such as emulsions, solutions and suspensions, dosage forms for oral use such as tablets, capsules, pills, dragees, powders and granules, topical or transdermal Dosage forms such as sprays, ointments, pastes, creams, lotions, gels, solutions, medicated patches and inhalants, vaginal or rectal dosage forms such as suppositories. These dosage forms can be prepared under suitable conditions according to the compound and suitable excipients. The preparation methods and processes are well known, such as provided by Remington: in The Science and Practice of Pharmacy (Gennaro ed.20th edition, Williams & Wilkins PA, USA) (2000) .
- the present application provides a pharmaceutical composition comprising the above compound and a pharmaceutically acceptable carrier or excipient.
- the pharmaceutical composition is a tablet, capsule, pill, granule, powder, suppository, injection, solution, suspension, ointment, patch, lotion, drop, liniment, spray agent
- Another aspect of the present invention provides the application of the above-mentioned compound or pharmaceutical composition in preparing medicine and treating diseases.
- the present application provides the application of the above-mentioned compound or pharmaceutical composition in the preparation of a disease or medicine for treating protein kinase-related diseases.
- the protein kinase-associated disease is selected from c-Met, VEGFR-2, AXL, TAM, NTRK or RET-associated diseases
- the protein kinase-associated disease is a tumor.
- the diseases associated with protein kinases include head and neck cancer, nasopharyngeal cancer, melanoma, bladder cancer, esophageal cancer, anaplastic large cell lymphoma, renal cancer, breast cancer, colorectal cancer Carcinoma, ovarian cancer, cervical cancer, pancreatic cancer, glioma, glioblastoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, gastric cancer, lung cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer , squamous cell carcinoma, cholangiocarcinoma, endometrial carcinoma, multiple myeloma, or mesothelioma; atherosclerosis and pulmonary fibrosis.
- the present application provides the application of the above compounds and/or pharmaceutical compositions in the preparation of antitumor drugs.
- the tumor comprises head and neck cancer, nasopharyngeal cancer, melanoma, bladder cancer, esophageal cancer, anaplastic large cell lymphoma, renal cancer, breast cancer, colorectal cancer, ovarian cancer, cervical cancer Carcinoma, pancreatic cancer, glioma, glioblastoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, gastric cancer, lung cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, squamous cell carcinoma, Cholangiocarcinoma, endometrial cancer, multiple myeloma, and mesothelioma.
- the present application provides a method for treating a tumor in a subject, comprising administering to the subject an effective amount of the above compound or pharmaceutical composition, the subject is preferably a mammal, and the mammal is preferably a human .
- the mode of administration includes oral, mucosal, sublingual, ocular, topical, parenteral, rectal, cisternal, vaginal, peritoneal, bladder, nasal administration.
- the compounds or pharmaceutical compositions involved in the present invention can enter the living body through any suitable route, such as oral administration, intravenous injection, intranasal application, external application, intramuscular injection, intradermal injection, transdermal administration or subcutaneous administration.
- the administration of the compounds or pharmaceutical compositions of the present invention includes oral, mucosal, sublingual, ocular, topical, parenteral, rectal, cisternal, vaginal, peritoneal, bladder, nasal administration medicine.
- the combination or pharmaceutical composition of the present invention can be administered simultaneously with the second active substance, so that additive or even synergistic effects can be achieved in vivo.
- the compound involved in the present invention can be combined with the second active substance into a pharmaceutical composition, or administered simultaneously as separate compositions, or administered sequentially as separate compositions.
- Second active substances that can be administered simultaneously with the compounds of the present invention for the treatment of cancer include, but are not limited to: fluorouracil, doxorubicin, daunorubicin, tamoxifen, leuprolide, goserelin, fluorouracil Tatamide, Nilutamide, Finasteride, Dexamethasone, Aminoglutethimide, Amsacridine, Anastrozole, Asparaginase, BCG, Bicalutamide, Bleomycin, Buxiao Ann, camptothecin, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, actinomycin d, daunomycin, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, doxorubicin, epirub
- the conjugates provided herein can be used concurrently with non-chemical methods for cancer treatment. In certain embodiments, the conjugates provided herein are administered concurrently with radiation therapy. In some embodiments, the conjugate provided by the present invention can be used in combination with surgery, tumor thermal therapy, focused ultrasound therapy, cryotherapy or several of the above therapies.
- the conjugates provided herein can be used concurrently with steroids.
- Suitable steroids include, but are not limited to: acetonide, beclomethasone, betamethasone, budesonide, cprednisone, clobetasol, corticosterone, cortisone, oxyprednisolone, Hydroxymethasone, Dexamethasone, Diflurasone, Diflumethasone, Diflupregna, Glycyrrhetinic Acid, Fluzacortisone, Flumethasone, Flunisolide, Flulonide, Fluocinolone Acetate, Fluocinolone Acetate, Fluocinol Butyl Ester, Fluocinolone, Fluoridolone Acetone, Fluperidone Acetate, Fluprednidine Acetate, Fluprednisolone, Fludrocetone, Fluoride Propionate, Aldehydesulfone, Clobetasol Propionate, Halcyonide,
- the compounds provided herein can be used concurrently with immunotherapeutic agents.
- immunotherapeutic agents include: tumor cell multidrug resistance reversal agents (such as verapamil), rapamycin, mycophenolate mofetil, thalidomide, cyclophosphamide, cyclosporine, and monoclonal Cloned antibodies.
- the first step 4-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine
- the second step 4-chloro-3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine
- the first step 5-((3-bromophenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione
- the third step 5-chloro-6-(4-fluorophenyl)picolinic acid
- the first step 2-cyano-5-(methyl-d 3 )-6-chloropyridine
- the third step 5-(methyl-d 3 )-6-(4-fluorophenyl)picolinic acid
- the second step 6-(4-fluorophenyl)-5-(methylthio)picolinic acid
- 6-(4-fluorophenyl)-5-(methylthio)picolinic acid (280 mg, 1.1 mmol) was added to acetonitrile (10 mL), and carbamide peroxide (996 mg, 10.6 mmol) and TFAA (2.2 g, 10.6mmol), heated to 65°C and stirred overnight, after the reaction was monitored by TLC, the reaction solution was poured into water (20mL), the mixture was extracted with ethyl acetate (20mL ⁇ 3), the organic phases were combined and washed with saturated brine (20mL), washed with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was added to dichloromethane (10mL) for slurry, filtered, and the filter residue was dried to obtain 6-carboxy-2-(4-fluorophenyl)- 3-(Methylsulfonyl)pyridine 1-oxide (pale yellow powder, 140 mg). Yield: 42.
- the first step methyl 5-cyclopropyl-6-(4-fluorophenyl)picolinate
- 3-Hydroxypicolinic acid (10 g, 72 mmol) was dissolved in ethanol (20 mL) at room temperature, concentrated sulfuric acid (10 mL) was slowly added dropwise under ice-cooling, and the temperature was raised to 80° C. and stirred for 16 h.
- 6-carboxy-3-fluoro-2-(4-fluorophenyl)pyridine 1-oxide 200 mg, 0.79 mmol
- DMF dimethyl Aqueous amine solution
- 30% dimethyl Aqueous amine solution 359mg, 2.39mmol
- the reaction was completed, it was lowered to room temperature, the mixture was poured into water (30mL), filtered, and the filter cake was washed and dried to obtain the crude product 6-carboxy-3-(dimethylamino)-2-(4-fluorophenyl)pyridine 1- Oxide (160 mg, white solid), yield: 73.1%.
- MS (ESI + ) m/z 277.1 [M+H] + .
- 2-(4-fluorophenyl)-6-methylpyrimidine 1-oxide 300mg, 1.47mmol
- 1,4-dioxane 5mL
- di Selenium oxide 326mg, 2.94mmol
- intermediates B36 and B37 were prepared.
- the first step 4-(2-chloro-4-nitrophenoxy)-3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine
- the third step 2-((3-chloro-4-((3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl) Oxy)phenyl)carbamoyl)-6-(4-fluorophenyl)pyridine 1-oxide
- intermediate C2 was synthesized according to the synthesis method of intermediate C1.
- the fifth step (R)-2-((3-fluoro-4-((3-((1-(2,2,2-trifluoroacetoxy)propan-2-yl)amino)-1H- Pyrazolo[3,4-b]pyridin-4-yl)oxy)phenyl)carbamoyl)-6-(4-fluorophenyl)pyridine 1-oxide
- Example 2-108 Final products 3, 5-6, 8-12, 15-18, 20, 23-25, 27, 29-36, 42-50, 52-54, 56-67, 69-70, Preparation of 79-83, 85-87, 89, 91-99, 103, 113-129, 133-135, 138-139, 141-142, 145-146, 149, 151-155, 157-160, 174
- the first step 2-((3-fluoro-4-((3-(4-hydroxypiperidin-1-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3, 4-b]pyridin-4-yl)oxy)phenyl)carbamoyl)-6-(4-fluorophenyl)pyridine 1-oxide
- the first step 4-chloro-5-((2-(trimethylsilyl)ethoxy)methyl)-5H pyrrolo[3,2-d]pyrimidine
- the fourth step 5-(3-((tert-butyldimethylsilyl)oxy)propyl)-4-(2-fluoro-4-nitrophenoxy)-5H pyrrolo[3,2 -d]pyrimidine
- the fifth step 4-((5-(3-((tert-butyldimethylsilyl)oxy)propyl)-5H pyrrolo[3,2-d]pyrimidin-4-yl)oxy) -3-fluoroaniline
- the sixth step 2-((4-((5-(3-((tert-butyldimethylsilyl)oxy)propyl)-5H pyrrolo[3,2-d]pyrimidin-4-yl )Oxygen)-3-fluorophenyl)carbamoyl)-6-(4-fluorophenyl)pyridine 1-oxide
- the seventh step 2-((3-fluoro-4-((5-(3-hydroxypropyl)-5H pyrrolo[3,2-d]pyrimidin-4-yl)oxy)phenyl)aminomethyl Acyl)-6-(4-fluorophenyl)pyridine 1-oxide
- Example 120 ((R)-2-((3-fluoro-4-((5-((1-hydroxypropan-2-yl)oxy)-6-methoxyquinazolin-4-yl )Oxy)phenyl)carbamoyl)-6-(4-fluorophenyl)pyridine 1-oxide preparation (final product 176)
- HTRF KinEASE-TK Using the HTRF KinEASE-TK kit, its activity was determined by detecting the remaining amount of ATP after the reaction of wild-type or mutant MET protein kinase. The intensity of the tested luminescence signal is positively correlated with the amount of remaining ATP in the reaction, and negatively correlated with the kinase activity.
- the compound was determined on the selected kinase, and a solvent control was set, and a total of 10 concentrations were detected, according to 3-fold dilution, with 2 replicate wells for each concentration.
- Enzyme inhibition percentage (%) 100-(Signal cmpd -Signal Ave_PC )/(Signal Ave_VC -Signal Ave_PC ) ⁇ 100
- Table 4 shows the inhibitory IC 50 of the compounds of the present invention on wild-type WT, mutant F1200I and D1228N MET kinase activities.
- the compound of the present invention has good inhibitory activity on wild-type WT, mutant F1200I and D1228N MET kinases, and the inhibitory IC 50 reaches nanomolar level.
- CellTiter-Glo TM Live Cell Detection Kit uses luciferase as the detection substance, and luciferase needs the participation of ATP in the process of luminescence.
- Add CellTiter-Glo TM reagent to the cell culture medium measure the luminescence value, the light signal is directly proportional to the amount of ATP in the system, and ATP is positively correlated with the number of viable cells. Therefore, by using the CellTiter-Glo kit to detect the ATP content, the cell proliferation can be detected.
- the celltiter-Glo (CTG) method was used to measure the inhibitory effects of the above-prepared compounds on the proliferation of tumor cell lines Hs746T, EBC-1 and H1993, and the 50% inhibitory concentration IC 50 was calculated.
- the compounds were tested on the selected cells, and a vehicle control was set, and a total of 10 concentrations were detected, with 2 replicate wells for each concentration.
- Cell viability (%) (Lum test drug -Lum culture medium control )/(Lum cell control -Lum culture medium control ) ⁇ 100%.
- Table 5 shows the IC 50 of the compounds of the present invention on Hs 746T cell line, H1993 cell line and EBC-1 cell line in inhibiting proliferation.
- the compound of the present invention has better anti-proliferation activity on Hs746T cell line, H1993 cell line and EBC-1 cell line.
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Abstract
Description
Claims (11)
- 式I所示的化合物或其药学上可接受的盐,立体异构体,互变异构体,氘代物,前药分子,水合物或溶剂化物其中,在式I中,A选自被R 1取代的5-14元杂芳基、被R 1取代的3-14元杂环基、被R 1取代的6-14元芳基和被R 1取代的3-12元环烷基,所述的被R 1取代的5-14元杂芳基、被R 1取代的3-14元杂环基、被R 1取代的6-14元芳基和被R 1取代的3-12元环烷基任选地被一个或者多个R 2取代,所述的被R 1取代的5-14元杂芳基和被R 1取代的6-14元芳基包括单环或稠环,所述的被R 1取代的3-14元杂环基和被R 1取代的3-12元环烷基包括单环、螺环或桥环;L选自O、S、CR aR b、NR b、C(=O)、SO 2和SO;Z选自6-14元芳基、5-14元杂芳基、3-12元环烷基和3-14元杂环基,所述的6-14元芳基、5-14元杂芳基、3-12元环烷基和3-14元杂环基任选地被一个或者多个R 3取代;X不存在或选自NR 4、O、S、CR 4R 5和C(=O);Y不存在或选自(CR aR b) n1-C(=O)、C(=S)、C(=NR 4)、SO 2、SO、NR 4、O、S和CR 4R 5;E 1、E 2和E 3各自不存在或各自独立地选自CR aR b、N、C(=O)、C(=S)和C(=NR 4);G选自(CR aR b) n1-6-20元芳基、(CR aR b) n1-5-20元杂芳基、(CR aR b) n1-3-12元环烷基、(CR aR b) n1-3-20元杂环基、(CR aR b) n1-O-(CR aR b) m1-芳基、(CR aR b) n1-OR 6、(CR aR b) n1-NR 6R 7、(CR aR b) n1-NR 6C(=O)R 7、C 1-6烷基、C 2-6烯基和C 2-6炔基,其中所述的(CR aR b) n1-6-20元芳基、(CR aR b) n1-5-20元杂芳基、(CR aR b) n1-3-12元环烷基、(CR aR b) n1-3-20元杂环基、(CR aR b) n1-O-(CR aR b) m1-芳基、C 1-6烷基、C 2-6烯基和C 2-6炔基任选地被一个或多个独立地选自如下的基团取代:卤素原子、硝基、 氧代(=O)、SO 2R f、CN、OR e、SR e、NR eR f、-NR eC(=O)R f、(CR aR b) n1-C(=O)R e、-C(=O)NR eR f、-C(=O)OR e、C 1-12烷基、卤代C 1-12烷基、C 1-6烷氧基-C 1-12烷基、卤代C 1-6烷氧基-C 1-12烷基、R aR bN-C 1-6烷基、C 2-8烯基、卤代C 2-8烯基、C 2-8炔基、3-12元环烷基、3-20元杂环基、6-20元芳基或5-20元杂芳基;R 1选自被一个或多个羟基取代的R 8;R 2、R 3和R 8各自独立地选自氢原子、卤素原子、氰基、硝基、-SO-R a、-NR bR c、-OR b、-SR b、R aSO-C 1-6烷基、R bR cN-C 1-6烷基、R bR cNC(=Y 1)-C 1-6烷基、R aSO-C 1-6烷氧基、R bR cN-C 1-6烷氧基、R bR cNC(=Y 1)-C 1-6烷氧基、-C(=Y 1)R a、-C(=Y 1)OR b、-C(=Y 1)NR bR c、-C(=Y 1)NR c(CR aR b) n1NR bR c、-OC(=Y 1)R a、-OC(=Y 1)NR bR c、-OC(=Y 1)OR b、-NR bC(=Y 1)NR bR c、-NR bC(=Y 1)OR c、-NR bC(=Y 1)R a、-OR bC(=Y 1)OR c、-SO 2-NR bR c、-SO 2R a、-NR bSO 2R a、C 1-6烷基、C 2-8烯基、C 2-8炔基、C 1-6烷基-R a、C 1-6烷氧基-R b、3-12元环烷基、3-12元环烯基、3-12元杂环基、6-14元芳基、5-10元杂芳基、C 1-6烷氧基-C 1-6烷基、3-12元环烷基-C 1-6烷基、3-12元环烯基-C 1-6烷基、3-12元杂环基-C 1-6烷基、6-14元芳基-C 1-6烷基和5-10元杂芳基-C 1-6烷基,所述的R aSO-C 1-6烷基、R bR cN-C 1-6烷基、R bR cNC(=Y 1)-C 1-6烷基、R aSO-C 1-6烷氧基、R bR cN-C 1-6烷氧基、R bR cNC(=Y 1)-C 1-6烷氧基、C 1-6烷基、C 2-8烯基、C 2-8炔基、C 1-6烷基-R a、C 1-6烷氧基-R b、3-12元环烷基、3-12元环烯基、3-12元杂环基、6-14元芳基、5-10元杂芳基、C 1-6烷氧基-C 1-6烷基、3-12元环烷基-C 1-6烷基、3-12元环烯基-C 1-6烷基、3-12元杂环基-C 1-6烷基、6-14元芳基-C 1-6烷基和5-10元杂芳基-C 1-6烷基任选地被一个或者多个R m取代,所述的3-12元环烷基、3-12元环烯基、3-12元杂环基、3-12元环烷基-C 1-6烷基、3-12元环烯基-C 1-6烷基和3-12元杂环基-C 1-6烷基包括单环、螺环或桥环,所述的6-14元芳基、5-10元杂芳基、6-14元芳基-C 1-6烷基和5-10元杂芳基-C 1-6烷基包括单环或稠环;或者R 1和R 2与所连接的原子一起形成5-14元环状基团,且该基团被一个或多个R 1取代;或者R 2和R 8与所连接的原子一起形成5-14元环状基团,且该基团被一个或多个R 1取代;R 4、R 5、R 6和R 7各自独立地选自氢原子、卤素原子、OR e、C 1-6烷基、C 2-6烯基、C 2-6炔基、3-12元环烷基、3-20元杂环基、6-20元芳基和5-20元杂芳基, 其中所述的3-12元环烷基和3-20元杂环基包括单环、螺环或桥环,所述的6-20元芳基和5-20元杂芳基包括单环或稠环,所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、3-12元环烷基、3-20元杂环基、6-20元芳基和5-20元杂芳基任选地被一个或者多个独立地选自如下的基团取代:卤素原子、SO 2R g、CN、OR e、NR eR f、C(=O)NR eR f、CR eC(=O)R f、C 1-12烷基、C 2-8烯基、C 2-8炔基、3-12元环烷基、3-20元杂环基、6-20元芳基或5-20元杂芳基;或者R 4和R 5与其连接的碳原子一起形成任选地被一个或多个R m取代的3-12元单环、螺环或桥环;或者R 6和R 7与它们所连接的氮原子一起形成任选地被一个或多个R m取代的饱和的、部分不饱和的或者完全不饱和的3-20元杂环,其任选含有一个或者多个选自N,O或者S杂原子;R a不存在或选自氢原子、卤素原子、氰基、羟基、巯基、羧基、硝基、-NR bR c、-C(=O)R d、-C(=O)OR b、-C(=O)NR bR c、-OC(=O)NR bR c、-NR bC(=O)R d、-NR bC(=O)OR d、-SO-NR bR c、-SO 2-NR bR c、-SO-R d、-SO 2R d、-NR bSO 2R d、C 1-6烷基、C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基-R’、C 1-6烷氧基-R’、-OR’、-SR’、-C(=O)-R’、-SO 2R’、-NR bC(=O)-R’、3-12元环烷基、3-12元环烯基、3-12元杂环基、6-14元芳基和5-10元杂芳基,所述的C 1-6烷基、C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基-R’、C 1-6烷氧基-R’、3-12元环烷基、3-12元环烯基、3-12元杂环基、6-14元芳基和5-10元杂芳基任选地被一个或者多个R m取代,所述的3-12元环烷基、3-12元环烯基和3-12元杂环基包括单环、螺环或桥环,所述的6-14元芳基和5-10元杂芳基包括单环或稠环;R b、R c和R d各自不存在或者各自独立地选自氢原子、羟基、巯基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6烷基-R’、R’-C 1-6烷基、C 1-6烷氧基-R’、-OR’、-C(=O)-R’、-SO 2-R’、3-12元环烷基、3-12元环烯基、3-12元杂环基、6-14元芳基和5-10元杂芳基,所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6烷基-R’、R’-C 1-6烷基、C 1-6烷氧基-R’、3-12元环烷基、3-12元环烯基、3-12元杂环基、6-14元芳基和5-10元杂芳基任选地被一个或者多个R m取代,所述的3-12元环烷基、3-12元环烯基和3-12元杂环基包括单环、螺环或桥环,所述的6-14元芳基和5-10元杂芳基包括单环或稠环;或者R a和R b与其连接的碳原子一起形成任选地被一个或多个R m取代的 3-12元单环、螺环或桥环;或者R a或R b与其连接的碳原子或邻位氮原子一起形成任选地被一个或多个R m取代的5-14元杂芳基、6-14元芳基、3-14元杂环基或3-12元环烷基;或者R b和R c与其连接的氮原子一起形成任选地被一个或者多个R m取代的3-12元单环、螺环、桥环或稠环;R e和R f各自独立地选自氢原子、C 1-6烷基、C 2-6烯基、C 2-6炔基、3-12元环烷基、3-20元杂环基、6-20元芳基和5-20元杂芳基,其中所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、3-12元环烷基、3-20元杂环基、6-20元芳基和5-20元杂芳基任选地被一个或者多个C 1-6烷基或者卤素原子取代;R g选自C 1-6烷基、3-12元环烷基、3-20元杂环基、氨基、C 1-6烷基氨基、二(C 1-6烷基)氨基和6-20元芳基,其中所述的C 1-6烷基、3-12元环烷基、3-20元杂环基、C 1-6烷基氨基、二(C 1-6烷基)氨基和6-20元芳基任选地被一个或者多个独立地选自如下的基团取代:卤素原子、OR e或-C(=O)NR eR f;R’选自氢原子、C 1-6烷基、3-12元环烷基、3-12元环烯基、3-12元杂环基、6-14元芳基和5-14元杂芳基,所述的C 1-6烷基、3-12元环烷基、3-12元环烯基、3-12元杂环基、6-14元芳基和5-14元杂芳基任选地被一个或者多个R m取代;所述的3-12元环烷基、3-12元环烯基和3-12元杂环基包括单环、螺环或桥环,所述的6-14元芳基和5-14元杂芳基包括单环或稠环;R m选自氘原子、卤素原子、氰基、硝基、-OR a、-SR a、-C(=Y 1)R a、-C(=Y 1)OR a、-C(=Y 1)NR bR c、-(CR aR b) n1-NR bR c、-NR bC(=Y 1)R c、-NR bC(=Y 1)OR c、-NR dC(=Y 1)NR bR c、-NR bSO 2R a、-OC(=Y 1)R a、-OC(=Y 1)OR b、-OC(=Y 1)NR aR b、-OSO 2(OR b)、-OP(=Y 1)(OR b)(OR c)、-OP(OR b)(OR c)、-SOR a、-SO 2R a、-SO 2NR bR c、-SO(OR b)、-SO 2(OR b)、-SC(=Y 1)R a、-SC(=Y 1)OR b、-SC(=Y 1)NR bR c、C 1-12烷基、卤代C 1-12烷基、C 1-12烷氧基-C 1-12烷基、C 1-12烷基-C 1-12烷氧基、C 1-12烷氧基-C 1-12烷氧基、C 2-8烯基、C 2-8炔基、3-12元环烷基、5-14元杂环基、6-20元芳基、5-20元杂芳基、(CR aR d) tNR bR c、叠氮基和氧代,所述的3-12元环烷基和5-14元杂环基包括单环、螺环或桥环,所述的6-20元芳基和5-20元杂芳基包括单环或稠环;Y 1为O或S;t、m1和n1各自独立地为0、1、2、3、4、5或6;条件是:E 3不为C=O、C=S或者C=NR a;当E 3为CH时,E 1不为C=O且E 2不为NR b;当E 3不存在时,E 2不为C=O、C=S或者C=NR a。
- 根据权利要求1所述的化合物或者其药学上可接受的盐、立体异构体、互变异构体、氘代物、前药分子、水合物或者溶剂化物,其中,在式I中,A选自被R 1取代的5-14元杂芳基,所述的被R 1取代的5-14元杂芳基包括单环或稠环,任选地被一个或者多个R 2取代;优选地,在式I中,A选自被R 1取代的以下基团,所述以下基团任选地被一个或者多个R 2取代;在式I中,L选自O、S、CR aR b、NR b和C(=O);优选地,在式I中,L选自O、S、C(=O)和NH;在式I中,Z选自任选地被一个或者多个R 3取代的6-14元芳基和5-10元杂芳基;优选地,在式I中,Z选自任选地被一个或者多个R 3取代的以下基团:在式I中,X选自NR 4、O、S或者不存在;优选地,在式I中,X选自NR 4、O和S;在式I中,Y选自C(=O)、C(=S)、C(=NR 4)或者不存在;优选地,在式I中,Y选自C(=O)和C(=S);在式I中,E1、E2、E3各自独立地选自CR aR b、N、C(=O)和C(=S);优选地,在式I中,E 1、E 2、E 3各自独立地选自CR aR b和N。
- 根据权利要求1或2所述的化合物或者其药学上可接受的盐、立体异构体、互变异构体、氘代物、前药分子、水合物或者溶剂化物,其中,在式I中,G选自(CR aR b) n1-6-20元芳基、(CR aR b) n1-5-20元杂芳基、(CR aR b) n1-3-12元环烷基和(CR aR b) n1-3-20元杂环基,所述的(CR aR b) n1-6-20元芳基、(CR aR b) n1-5-20元杂芳基、(CR aR b) n1-3-12元环烷基和(CR aR b) n1-3-20元杂环基任选地被一个或者多个独立地选自如下的基团取代:卤素原子、硝基、氧代、CN、OR e、SR e、NR eR f、C 1-12烷基、卤代C 1-12烷基、C 1-6烷氧基-C 1-12烷基、卤代C 1-6烷氧基-C 1-12烷基、R aR bN-C 1-6烷基、C 2-8烯基、卤代C 2-8烯基、C 2-8炔基、3-12元环烷基或3-20元杂环基;优选地,在式I中,G选自6-20元芳基和5-20元杂芳基,其中所述的6-20元芳基和5-20元杂芳基任选地被一个或者多个独立地选自如下的基团取代:卤素原子、硝基、氧代、CN、OR e、SR e、NR eR f、C 1-12烷基、卤代C 1-12烷基、C 1-6烷氧基-C 1-12烷基、卤代C 1-6烷氧基-C 1-12烷基、R aR bN-C 1-6烷基、C 2-8烯基、卤代C 2-8烯基、C 2-8炔基、3-12元环烷基、3-12元环烷基-C 1-6烷基或3-20元杂环基;R 1选自被一个或者两个羟基取代的R 8;R 8选自-NR bR c、-OR b、-SR b、R bR cN-C 1-6烷基、R bR cN-C 1-6烷氧基、C 1-6烷基、C 2-8烯基、C 2-8炔基、C 1-6烷基-R a、C 1-6烷氧基-R b、3-12元环烷基、3-12元环烯基、3-12元杂环基、6-14元芳基、5-10元杂芳基、3-12元环烷基-C 1-6烷基、3-12元环烯基-C 1-6烷基、3-12元杂环基-C 1-6烷基、6-14元芳基-C 1-6烷基和5-10元杂芳基-C 1-6烷基,所述的R bR cN-C 1-6烷基、R bR cN-C 1-6烷氧基、C 1-6烷基、C 2-8烯基、C 2-8炔基、C 1-6烷基-R a、C 1-6烷氧基-R b、3-12元环烷基、3-12元环烯基、3-12元杂环基、6-14元芳基、5-10元杂芳基、3-12元环烷基-C 1-6烷基、3-12元环烯基-C 1-6烷基、3-12元杂环基-C 1-6烷基、6-14元芳基-C 1-6烷基和5-10元杂芳基-C 1-6烷基任选地被一个或者多个R m取代,所述的3-12元环烷基、3-12元环烯基和3-12元杂环基包括单环、螺环或桥环,所述的6-14元芳基和5-10元杂芳基包括单环或稠环;优选地,R 8选自-NR bR c、-OR b、C 1-6烷基、R bR cN-C 1-6烷基、3-12元杂环基和3-12元杂环基-C 1-6烷基,所述的C 1-6烷基、R bR cN-C 1-6烷基、3-12元杂环基和3-12元杂环基-C 1-6烷基任选地被一个或者多个R m取代,所述的3-12元杂环基和3-12元杂环基-C 1-6烷基包括单环、螺环或桥环;R 2和R 3各自独立地选自氢原子、卤素原子、氰基、硝基、-NR bR c、-OR b、R bR cN-C 1-6烷基、R bR cN-C 1-6烷氧基、-C(=Y 1)R a、-C(=Y 1)NR bR c、C 1-6烷基、C 2-8烯基、C 2-8炔基、C 1-6烷基-R a、C 1-6烷氧基-R b、3-12元环烷基、3-12元杂环基、3-12元环烷基-C 1-6烷基、3-12元杂环基-C 1-6烷基和5-10元杂芳基-C 1-6烷基,所述的R bR cN-C 1-6烷基、R bR cN-C 1-6烷氧基、C 1-6烷基、C 2-8烯基、C 2-8炔基、C 1-6烷基-R a、C 1-6烷氧基-R b、3-12元环烷基、3-12元杂环基、3-12元环烷基-C 1-6烷基、3-12元杂环基-C 1-6烷基和5-10元杂芳基-C 1-6烷基任选地被一个或者多个R m取代,所述的3-12元环烷基、3-12元杂环基、3-12元环烷基-C 1-6烷基和3-12元杂环基-C 1-6烷基包括单环、螺环或桥环,所述5-10元杂芳基-C 1-6烷基包括单环或稠环;优选地,R 2和R 3各自独立地选自氢原子、卤素原子、氰基、硝基、-NR bR c、-OR b、R bR cN-C 1-6烷基、R bR cN-C 1-6烷氧基、C 1-6烷基、C 2-8烯基、C 2-8炔基、C 1-6烷基-R a、C 1-6烷氧基-R b、3-12元环烷基、3-12元杂环基、3-12元环烷基-C 1-6烷基和3-12元杂环基-C 1-6烷基,所述的R bR cN-C 1-6烷基、R bR cN-C 1-6烷氧基、C 1-6烷基、C 2-8烯基、C 2-8炔基、C 1-6烷基-R a、C 1-6烷氧基-R b、3-12元环烷基、3-12 元杂环基、3-12元环烷基-C 1-6烷基和3-12元杂环基-C 1-6烷基任选地被一个或者多个R m取代,所述的3-12元环烷基、3-12元杂环基、3-12元环烷基-C 1-6烷基和3-12元杂环基-C 1-6烷基包括单环、螺环或桥环。
- 根据权利要求1至3中任一项所述的化合物或者其药学上可接受的盐、立体异构体、互变异构体、氘代物、前药分子、水合物或者溶剂化物,其中,R 4、R 5、R 6和R 7各自独立地选自氢原子、卤素原子、OR e、C 1-6烷基、C 2-6烯基、C 2-6炔基、3-20元环烷基、3-20元杂环基和6-20元芳基,其中所述的3-20元环烷基和3-20元杂环基包括单环、螺环或桥环;所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、3-20元环烷基、3-20元杂环基和6-20元芳基任选地被一个或者多个独立地选自如下的基团取代:卤素原子、CN、OR e、NR eR f、C 1-12烷基、C 2-8烯基、C 2-8炔基、3-12元环烷基或3-20元杂环基;或者R 4和R 5与其连接的碳原子一起形成任选地被一个或多个R m取代的3-12元单环、螺环或桥环;或者R 6和R 7与它们所连接的氮原子一起形成任选地被一个或者多个R m取代的饱和的、部分不饱和的或者完全不饱和的3-20元杂环,其任选含有一个或者多个选自N,O或者S杂原子;优选地,R 4、R 5、R 6和R 7各自独立地选自氢原子、OR e、C 1-6烷基、单环或者二环的3-12元环烷基、3-20元杂环基和6-20元芳基,其中所述的C 1-6烷基、单环或者二环的3-12元环烷基、3-20元杂环基和6-20元芳基任选地被一个或者多个独立地选自如下的基团取代:卤素原子、CN、OR e、NR eR f、C 1-12烷基、C 2-8烯基、C 2-8炔基、3-12元环烷基或3-20元杂环基;或者R 4和R 5与其连接的碳原子一起形成任选地被一个或多个R m取代的3-12元单环、螺环或桥环,所述的3-12元单环、螺环或桥环任选地被一个或者多个独立地选自如下的基团取代:卤素原子、C 1-6烷基或C 1-6烷氧基;或者R 6和R 7与它们所连接的氮原子一起形成任选地被一个或多个R m取代的饱和的、部分不饱和的或者完全不饱和的3-20元杂环,所述的3-20元杂环任选地被一个或者多个独立地选自如下的基团取代:卤素原子、C 1-6烷基或C 1-6烷氧基。
- 根据权利要求1至4中任一项所述的化合物或者其药学上可接受的盐、立体异构体、互变异构体、氘代物、前药分子、水合物或者溶剂化物,其中,R a不存在或者选自氢原子、卤素原子、氰基、羟基、巯基、羧基、硝基、-NR bR c、-C(=O)R d、C 1-6烷基、C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基-R’、C 1-6烷氧基-R’、-OR’、-SR’、-SOR d、-SO 2R d、3-12元环烷基、3-12元环烯基、3-12元杂环基、6-14元芳基和5-10元杂芳基,所述C 1-6烷基、C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基-R’、C 1-6烷氧基-R’、3-12元环烷基、3-12元环烯基、3-12元杂环基、6-14元芳基和5-10元杂芳基任选地被一个或者多个R m取代;R b、R c和R d各自不存在或者各自独立地选自氢原子、羟基、巯基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6烷基-R’、R’-C 1-6烷基、C 1-6烷氧基-R’、-OR’、-C(=O)-R’、3-12元环烷基、3-12元环烯基、3-12元杂环基、6-14元芳基和5-10元杂芳基,所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6烷基-R’、R’-C 1-6烷基、C 1-6烷氧基-R’、3-12元环烷基、3-12元环烯基、3-12元杂环基、6-14元芳基和5-10元杂芳基任选地被一个或者多个R m取代;或者R b和R c与其连接的氮原子一起形成任选地被一个或多个R m取代的3-12元单环、螺环、桥环或稠环;R e和R f各自独立地选自氢原子、C 1-6烷基、C 2-6烯基、3-12元环烷基、3-20元杂环基、6-20元芳基和5-20元杂芳基,其中所述的C 1-6烷基、C 2-6烯基、3-12元环烷基、3-20元杂环基、6-20元芳基和5-20元杂芳基任选地被一个或者多个C 1-6烷基或者卤素原子取代;R g为C 1-6烷基或6-20元芳基,其中所述的C 1-6烷基和6-20元芳基任选地被一个或者多个独立地选自如下的基团取代:卤素原子或OR e;R’选自C 1-6烷基、3-12元环烷基、3-12元环烯基、3-12元杂环基、6-14元芳基和5-10元杂芳基,所述的C 1-6烷基、3-12元环烷基、3-12元环烯基、3-12元杂环基、6-14元芳基和5-10元杂芳基任选地被一个或者多个R m取代;所述的3-12元环烷基、3-12元环烯基和3-12元杂环基包括单环、螺环或桥环,所述的6-14元芳基和5-10元杂芳基包括单环或稠环;优选地,R a不存在或者选自氢原子、卤素原子、氰基、羟基、-NR bR c、-C(=O)R d、C 1-6烷基、C 1-6烷氧基、C 2-8烯基、C 1-6烷基-R’、C 1-6烷氧基-R’、-OR’、-SR’、-SOR d、-SO 2R d、3-12元环烷基、3-12元环烯基和3-12元杂环基,所述C 1-6烷基、C 1-6烷氧基、C 2-8烯基、C 1-6烷基-R’、C 1-6烷氧基-R’、3-12元环烷基、3-12元环烯基和3-12元杂环基任选地被一个或者多个R m取代;R b、R c和R d各自不存在或者各自独立地选自氢原子、羟基、巯基、C 1-6烷基、卤素原子、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6烷基-R’、R’-C 1-6烷基、C 1-6烷氧基-R’、-OR’、-C(=O)-R’、3-12元环烷基和3-12元杂环基,所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6烷基-R’、R’-C 1-6烷基、C 1-6烷氧基-R’、-OR’、-C(=O)-R’、3-12元环烷基和3-12元杂环基任选地被一个或者多个R m取代;或者R b和R c与其连接的氮原子一起形成任选地被一个或多个R m取代的3-12元单环、螺环、桥环或稠环;R e和R f各自独立地选自氢原子、C 1-6烷基、C 2-6烯基、3-12元环烷基和3-20元杂环基,其中所述的C 1-6烷基、C 2-6烯基、3-12元环烷基和3-20元杂环基任选地被一个或者多个C 1-6烷基或者卤素原子取代;R g为C 1-6烷基或6-20元芳基,其中所述的C 1-6烷基和6-20元芳基任选地被一个或者多个独立地选自如下的基团取代:卤素原子或OR e;R’选自C 1-6烷基、3-12元环烷基、3-12元杂环基和5-10元杂芳基,所述的C 1-6烷基、3-12元环烷基、3-12元杂环基和5-10元杂芳基任选地被一个或者多个R m取代;所述的3-12元环烷基和3-12元杂环基包括单环、螺环或桥环,所述的5-10元杂芳基包括单环或稠环。
- 根据权利要求1至5中任一项所述的化合物或者其药学上可接受的盐、立体异构体、互变异构体、氘代物、前药分子、水合物或者溶剂化物,其中,R m独立地选自氘原子、卤素原子、氰基、硝基、-OR a、-SR a、-C(=Y 1)R a、-C(=Y 1)OR a、-C(=Y 1)NR bR c、-NR bR c、-NR bC(=Y 1)R c、-NR bSO 2R a、-OC(=Y 1)R a、-SO 2R a、C 1-12烷基、卤代C 1-12烷基、C 1-12烷氧基-C 1-12烷基、C 1-12烷基-C 1-12烷氧基、C 1-12烷氧基-C 1-12烷氧基、C 2-8烯基、C 2-8炔基、3-12元环烷基、3-20元杂环基、6-20元芳基、5-20元杂芳基、(CR aR d) tNR bR c和氧代,所述的3-12元环烷基和3-20元杂环基包括单环、螺环或桥环,所述的6-20元芳基和5-20元杂芳基包括单环或稠环;优选地,R m选自氘原子、卤素原子、氰基、硝基、羟基、巯基、氨基、羧基、C 1-6烷基、C 1-6烷氧基-C 1-6烷基、C 1-6烷氧基、C 1-6烷基-C 1-6烷氧基、C 1-6烷氧基-C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷基酯基、C 1-6烷基氨基羰基、(C 1-6烷基) 2氨基羰基、C 1-6烷基羰基、C 1-6烷基羰基氧基、C 1-6烷基羰基 氨基、C 1-6烷基磺酰氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 1-6烷基磺酰基、C 1-6烷基硫基、C 2-8烯基、C 2-8炔基、3-8元环烷基、3-8元杂环基、6-10元芳基、3-8元杂芳基、-(CR aR d) tNR bR c和氧代。
- 根据权利要求1至6中任一项所述的化合物或者其药学上可接受的盐、立体异构体、互变异构体、氘代物、前药分子、水合物或者溶剂化物,其中,A选自被R 1取代的5-14元杂芳基,所述的被R 1取代的5-14元杂芳基包括单环或稠环,任选地被一个或者多个R 2取代;L选自O、S、CR aR b、NR b和C(=O);Z选自任选地被一个或者多个R 3取代的6-14元芳基和5-10元杂芳基;X选自NR 4、O、S或者不存在;Y选自C(=O)、C(=S)、C(=NR 4)或者不存在;E 1、E 2、E 3各自独立地选自CR aR b、N、C(=O)和C(=S);G选自(CR aR b) n1-6-20元芳基、(CR aR b) n1-5-20元杂芳基、(CR aR b) n1-3-12元环烷基和(CR aR b) n1-3-20元杂环基,所述的(CR aR b) n1-6-20元芳基、(CR aR b) n1-5-20元杂芳基、(CR aR b) n1-3-12元环烷基和(CR aR b) n1-3-20元杂环基任选地被一个或者多个独立地选自如下的基团取代:卤素原子、硝基、氧代、CN、OR e、SR e、NR eR f、C 1-12烷基、卤代C 1-12烷基、C 1-6烷氧基-C 1-12烷基、卤代C 1-6烷氧基-C 1-12烷基、R aR bN-C 1-6烷基、C 2-8烯基、卤代C 2-8烯基、C 2-8炔基、3-12元环烷基或3-20元杂环基;R 1选自被一个或者两个羟基取代的R 8;R 2和R 3各自独立地选自氢原子、卤素原子、氰基、硝基、-NR bR c、-OR b、R bR cN-C 1-6烷基、R bR cN-C 1-6烷氧基、-C(=Y 1)R a、-C(=Y 1)NR bR c、C 1-6烷基、C 2-8烯基、C 2-8炔基、C 1-6烷基-R a、C 1-6烷氧基-R b、3-12元环烷基、3-12元杂环基、3-12元环烷基-C 1-6烷基、3-12元杂环基-C 1-6烷基和5-10元杂芳基-C 1-6烷基,所述的R bR cN-C 1-6烷基、R bR cN-C 1-6烷氧基、C 1-6烷基、C 2-8烯基、C 2-8炔基、C 1-6烷基-R a、C 1-6烷氧基-R b、3-12元环烷基、3-12元杂环基、3-12元环烷基-C 1-6烷基、3-12元杂环基-C 1-6烷基和5-10元杂芳基-C 1-6烷基任选地被一个或者多个R m取代,所述的3-12元环烷基、3-12元杂环基、3-12元环烷基-C 1-6烷基和3-12元杂环基-C 1-6烷基包括单环、螺环或桥环,所述5-10元杂芳基-C 1-6烷基包括单环或稠环;R 4、R 5、R 6和R 7各自独立地选自氢原子、卤素原子、OR e、C 1-6烷基、C 2-6烯基、C 2-6炔基、3-20元环烷基、3-20元杂环基和6-20元芳基,其中所述的3-20元环烷基和3-20元杂环基包括单环、螺环或桥环;所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、3-20元环烷基、3-20元杂环基和6-20元芳基任选地被一个或者多个独立地选自如下的基团取代:卤素原子、CN、OR e、NR eR f、C 1-12烷基、C 2-8烯基、C 2-8炔基、3-12元环烷基或3-20元杂环基;或者R 4和R 5与其连接的碳原子一起形成任选地被一个或多个R m取代的3-12元单环、螺环或桥环;或者R 6和R 7与它们所连接的氮原子一起形成任选地被一个或者多个R m取代的饱和的、部分不饱和的或者完全不饱和的3-20元杂环,其任选含有一个或者多个选自N,O或者S杂原子;R 8选自-NR bR c、-OR b、-SR b、R bR cN-C 1-6烷基、R bR cN-C 1-6烷氧基、C 1-6烷基、C 2-8烯基、C 2-8炔基、C 1-6烷基-R a、C 1-6烷氧基-R b、3-12元环烷基、3-12元环烯基、3-12元杂环基、6-14元芳基、5-10元杂芳基、3-12元环烷基-C 1-6烷基、3-12元环烯基-C 1-6烷基、3-12元杂环基-C 1-6烷基、6-14元芳基-C 1-6烷基和5-10元杂芳基-C 1-6烷基,所述的R bR cN-C 1-6烷基、R bR cN-C 1-6烷氧基、C 1-6烷基、C 2-8烯基、C 2-8炔基、C 1-6烷基-R a、C 1-6烷氧基-R b、3-12元环烷基、3-12元环烯基、3-12元杂环基、6-14元芳基、5-10元杂芳基、3-12元环烷基-C 1-6烷基、3-12元环烯基-C 1-6烷基、3-12元杂环基-C 1-6烷基、6-14元芳基-C 1-6烷基和5-10元杂芳基-C 1-6烷基任选地被一个或者多个R m取代,所述的3-12元环烷基、3-12元环烯基和3-12元杂环基包括单环、螺环或桥环,所述的6-14元芳基和5-10元杂芳基包括单环或稠环;R a不存在或者选自氢原子、卤素原子、氰基、羟基、巯基、羧基、硝基、-NR bR c、-C(=O)R d、C 1-6烷基、C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基-R’、C 1-6烷氧基-R’、-OR’、-SR’、-SOR d、-SO 2R d、3-12元环烷基、3-12元环烯基、3-12元杂环基、6-14元芳基和5-10元杂芳基,所述C 1-6烷基、C 1-6烷氧基、C 2-8烯基、C 2-8炔基、C 1-6烷基-R’、C 1-6烷氧基-R’、3-12元环烷基、3-12元环烯基、3-12元杂环基、6-14元芳基和5-10元杂芳基任选地被一个或者多个R m取代;R b、R c和R d各自不存在或者各自独立地选自氢原子、羟基、巯基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6烷基-R’、R’-C 1-6烷基、C 1-6烷氧基-R’、 -OR’、-C(=O)-R’、3-12元环烷基、3-12元环烯基、3-12元杂环基、6-14元芳基和5-10元杂芳基,所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6烷基-R’、R’-C 1-6烷基、C 1-6烷氧基-R’、3-12元环烷基、3-12元环烯基、3-12元杂环基、6-14元芳基和5-10元杂芳基任选地被一个或者多个R m取代;或者R b和R c与其连接的氮原子一起形成任选地被一个或多个R m取代的3-12元单环、螺环、桥环或稠环;R e和R f各自独立地选自氢原子、C 1-6烷基、C 2-6烯基、3-12元环烷基、3-20元杂环基、6-20元芳基和5-20元杂芳基,其中所述的C 1-6烷基、C 2-6烯基、3-12元环烷基、3-20元杂环基、6-20元芳基和5-20元杂芳基任选地被一个或者多个C 1-6烷基或者卤素原子取代;R g为C 1-6烷基或6-20元芳基,其中所述的C 1-6烷基和6-20元芳基任选地被一个或者多个独立地选自如下的基团取代:卤素原子或OR e;R’选自C 1-6烷基、3-12元环烷基、3-12元环烯基、3-12元杂环基、6-14元芳基和5-10元杂芳基,所述的C 1-6烷基、3-12元环烷基、3-12元环烯基、3-12元杂环基、6-14元芳基和5-10元杂芳基任选地被一个或者多个R m取代;所述的3-12元环烷基、3-12元环烯基和3-12元杂环基包括单环、螺环或桥环,所述的6-14元芳基和5-10元杂芳基包括单环或稠环;R m独立地选自氘原子、卤素原子、氰基、硝基、-OR a、-SR a、-C(=Y 1)R a、-C(=Y 1)OR a、-C(=Y 1)NR bR c、-NR bR c、-NR bC(=Y 1)R c、-NR bSO 2R a、-OC(=Y 1)R a、-SO 2R a、C 1-12烷基、卤代C 1-12烷基、C 1-12烷氧基-C 1-12烷基、C 1-12烷基-C 1-12烷氧基、C 1-12烷氧基-C 1-12烷氧基、C 2-8烯基、C 2-8炔基、3-12元环烷基、3-20元杂环基、6-20元芳基、5-20元杂芳基、(CR aR d) tNR bR c和氧代,所述的3-12元环烷基和3-20元杂环基包括单环、螺环或桥环,所述的6-20元芳基和5-20元杂芳基包括单环或稠环;Y 1为O或S;t、m1和n1各自独立地为0、1、2、3、4、5或6;优选地,在式I中,A选自被R 1取代的以下基团,所述以下基团任选地被一个或者多个R 2取代;L选自O、S、C(=O)和NH;Z选自任选地被一个或者多个R 3取代的以下基团:X选自NR 4、O和S;Y选自C(=O)和C(=S);E 1、E 2、E 3各自独立地选自CR aR b和N;G选自6-20元芳基和5-20元杂芳基,其中所述的6-20元芳基和5-20元杂芳基任选地被一个或者多个独立地选自如下的基团取代:卤素原子、硝基、氧代、CN、OR e、SR e、NR eR f、C 1-12烷基、卤代C 1-12烷基、C 1-6烷氧基-C 1-12烷基、卤代C 1-6烷氧基-C 1-12烷基、R aR bN-C 1-6烷基、C 2-8烯基、卤代C 2-8烯基、C 2-8炔基、3-12元环烷基、3-12元环烷基-C 1-6烷基或3-20元杂环基;R 1选自被一个或者两个羟基取代的R 8;R 2和R 3各自独立地选自氢原子、卤素原子、氰基、硝基、-NR bR c、-OR b、R bR cN-C 1-6烷基、R bR cN-C 1-6烷氧基、C 1-6烷基、C 2-8烯基、C 2-8炔基、C 1-6烷基-R a、C 1-6烷氧基-R b、3-12元环烷基、3-12元杂环基、3-12元环烷基-C 1-6烷基和3-12元杂环基-C 1-6烷基,所述的R bR cN-C 1-6烷基、R bR cN-C 1-6烷氧基、C 1-6烷基、C 2-8烯基、C 2-8炔基、C 1-6烷基-R a、C 1-6烷氧基-R b、3-12元环烷基、3-12元杂环基、3-12元环烷基-C 1-6烷基和3-12元杂环基-C 1-6烷基任选地被一个或者多个R m取代,所述的3-12元环烷基、3-12元杂环基、3-12元环烷基-C 1-6烷基和3-12元杂环基-C 1-6烷基包括单环、螺环或桥环;R 4、R 5、R 6和R 7各自独立地选自氢原子、OR e、C 1-6烷基、单环或者二环的 3-12元环烷基、3-20元杂环基和6-20元芳基,其中所述的C 1-6烷基、单环或者二环的3-12元环烷基、3-20元杂环基和6-20元芳基任选地被一个或者多个独立地选自如下的基团取代:卤素原子、CN、OR e、NR eR f、C 1-12烷基、C 2-8烯基、C 2-8炔基、3-12元环烷基或3-20元杂环基;或者R 4和R 5与其连接的碳原子一起形成任选地被一个或多个R m取代的3-12元单环、螺环或桥环,所述的3-12元单环、螺环或桥环任选地被一个或者多个独立地选自如下的基团取代:卤素原子、C 1-6烷基或C 1-6烷氧基;或者R 6和R 7与它们所连接的氮原子一起形成任选地被一个或多个R m取代的饱和的、部分不饱和的或者完全不饱和的3-20元杂环,所述的3-20元杂环任选地被一个或者多个独立地选自如下的基团取代:卤素原子、C 1-6烷基或C 1-6烷氧基;R 8选自-NR bR c、-OR b、C 1-6烷基、R bR cN-C 1-6烷基、3-12元杂环基和3-12元杂环基-C 1-6烷基,所述的C 1-6烷基、R bR cN-C 1-6烷基、3-12元杂环基和3-12元杂环基-C 1-6烷基任选地被一个或者多个R m取代,所述的3-12元杂环基和3-12元杂环基-C 1-6烷基包括单环、螺环或桥环;R a不存在或者选自氢原子、卤素原子、氰基、羟基、-NR bR c、-C(=O)R d、C 1-6烷基、C 1-6烷氧基、C 2-8烯基、C 1-6烷基-R’、C 1-6烷氧基-R’、-OR’、-SR’、-SOR d、-SO 2R d、3-12元环烷基、3-12元环烯基和3-12元杂环基,所述C 1-6烷基、C 1-6烷氧基、C 2-8烯基、C 1-6烷基-R’、C 1-6烷氧基-R’、3-12元环烷基、3-12元环烯基和3-12元杂环基任选地被一个或者多个R m取代;R b、R c和R d各自不存在或者各自独立地选自氢原子、羟基、巯基、C 1-6烷基、卤素原子、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6烷基-R’、R’-C 1-6烷基、C 1-6烷氧基-R’、-OR’、-C(=O)-R’、3-12元环烷基和3-12元杂环基,所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6烷基-R’、R’-C 1-6烷基、C 1-6烷氧基-R’、-OR’、-C(=O)-R’、3-12元环烷基和3-12元杂环基任选地被一个或者多个R m取代;或者R b和R c与其连接的氮原子一起形成任选地被一个或多个R m取代的3-12元单环、螺环、桥环或稠环;R e和Rf各自独立地选自氢原子、C 1-6烷基、C 2-6烯基、3-12元环烷基和3-20元杂环基,其中所述的C 1-6烷基、C 2-6烯基、3-12元环烷基和3-20元杂环基任 选地被一个或者多个C 1-6烷基或者卤素原子取代;R g为C 1-6烷基或6-20元芳基,其中所述的C 1-6烷基和6-20元芳基任选地被一个或者多个独立地选自如下的基团取代:卤素原子或OR e;R’选自C 1-6烷基、3-12元环烷基、3-12元杂环基和5-10元杂芳基,所述的C 1-6烷基、3-12元环烷基、3-12元杂环基和5-10元杂芳基任选地被一个或者多个R m取代;所述的3-12元环烷基和3-12元杂环基包括单环、螺环或桥环,所述的5-10元杂芳基包括单环或稠环;R m选自氘原子、卤素原子、氰基、硝基、羟基、巯基、氨基、羧基、C 1-6烷基、C 1-6烷氧基-C 1-6烷基、C 1-6烷氧基、C 1-6烷基-C 1-6烷氧基、C 1-6烷氧基-C 1-6烷氧基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷基酯基、C 1-6烷基氨基羰基、(C 1-6烷基) 2氨基羰基、C 1-6烷基羰基、C 1-6烷基羰基氧基、C 1-6烷基羰基氨基、C 1-6烷基磺酰氨基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 1-6烷基磺酰基、C 1-6烷基硫基、C 2-8烯基、C 2-8炔基、3-8元环烷基、3-8元杂环基、6-10元芳基、3-8元杂芳基、-(CR aR d) tNR bR c和氧代;t为0、1、2、3、4、5或6;更优选地,在式I中,A选自被R 1取代的以下基团,所述以下基团任选地被一个或者多个R 2取代;L选自O、C=O和NH;Z选自任选地被一个或者多个R 3取代的苯环、吡啶和萘环:X选自NR 4;Y选自C(=O);E 1、E 2、E 3各自独立地选自CR aR b和N;G选自6-20元芳基、吡啶和吡唑,其中所述的6-20元芳基、吡啶和吡唑任选地被一个或者多个独立地选自如下的基团取代:卤素原子、硝基、氧代、CN、 甲氧基、乙氧基、氨基、甲氨基、乙氨基、二甲氨基、甲基、乙基、异丙基、乙烯基、CF 3、甲氧基甲基、三氟甲氧基甲基、环丙基、环丙基甲基;R 1选自以下基团:R 2和R 3各自独立地选自氢原子、羟基、巯基、卤素原子、氰基、硝基、C 1-6烷基、C 2-6烯基、C 2-6炔基、羟基-C 1-6烷基、氨基-C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6烷氧基-C 1-6烷基、C 1-6烷基-C 1-6烷氧基、C 1-6烷氧基-C 1-6烷氧基、3-12元环烷基、3-12元杂环基、3-12元环烷基-C 1-6烷基和3-12元杂环基-C 1-6烷基,所述C 1-6烷基、C 2-6烯基、C 2-6炔基、羟基-C 1-6烷基、氨基 -C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6烷氧基-C 1-6烷基、C 1-6烷基-C 1-6烷氧基、C 1-6烷氧基-C 1-6烷氧基、3-12元环烷基、3-12元杂环基、3-12元环烷基-C 1-6烷基和3-12元杂环基-C 1-6烷基任选地被一个或者多个R m取代;R 4独立地选自氢原子、甲基、乙基、三氟甲基和环丙基;R a不存在或者各自选自氢原子、卤素原子、氰基、羟基、氨基、巯基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6烷基硫基、C 1-6烷基砜基、C 1-6烷基亚砜基、卤代C 1-6烷基砜基、C 1-6烷氧基-C 1-6烷基、C 2-8烯基、3-12元环烷基和3-12元杂环基,所述C 1-6烷基、卤代C 1-6烷基、C 1-6烷基氨基、(C 1-6烷基) 2氨基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6烷基硫基、C 1-6烷基砜基、C 1-6烷基亚砜基、卤代C 1-6烷基砜基、C 1-6烷氧基-C 1-6烷基、C 2-8烯基、3-12元环烷基和3-12元杂环基任选地被一个或多个R m取代;R b不存在或者独立地选自氢原子、C 1-6烷基、卤素原子、C 1-6烷氧基、C 1-6烷基-3-12元环烷基、C 1-6烷基-3-12元杂环基、3-12元环烷基-C 1-6烷基、3-12元杂环基-C 1-6烷基、3-12元环烷基和3-12元杂环基,所述的C 1-6烷基、C 1-6烷氧基、C 1-6烷基-3-12元环烷基、C 1-6烷基-3-12元杂环基、3-12元环烷基-C 1-6烷基、3-12元杂环基-C 1-6烷基、3-12元环烷基和3-12元杂环基任选地被一个或者多个R m取代;或者R a和R b与其连接的碳原子一起形成任选地被一个或多个R m取代的3-12元单环、螺环、桥环或稠环;R m各自独立地选自氘原子、卤素原子、氰基、硝基、羟基、巯基、氨基、羧基、C 1-4烷基、C 1-4烷氧基-C 1-4烷基、C 1-4烷氧基、C 1-6烷基-C 1-4烷氧基、C 1-4烷氧基-C 1-4烷氧基、C 1-4烷基氨基、(C 1-4烷基) 2氨基、C 1-4烷基酯基、C 1-4烷基氨基羰基、(C 1-4烷基) 2氨基羰基、C 1-4烷基羰基、C 1-4烷基羰基氧基、C 1-4烷基羰基氨基、C 1-4烷基磺酰氨基、卤代C 1-4烷基、卤代C 1-4烷氧基、C 1-4烷基磺酰基、C 1-4烷基硫基、乙烯基、乙炔基、环丙基、环丁基、环戊基、环己基、环庚基、苯基、环氧乙烷基、环氧环丁基、四氢呋喃基、四氢吡喃基、氧杂环辛基、氮杂丙啶基、氮杂环丁基、四氢吡咯基、哌啶基、哌嗪基、环氧乙烷基甲基、环氧环丁基甲基、四氢呋喃基甲基、四氢吡喃基甲基、氧杂环辛基甲基、氮丙啶基甲基、 氮杂环丁基甲基、四氢吡咯基甲基、哌啶基甲基、哌嗪基甲基、吡咯基、呋喃基、噻吩基、噁唑基、异噁唑基、吡唑基、噻唑基、吡啶基、嘧啶基、哒嗪基和氧代;最优选地,式I所示的化合物选自下列的化合物:
- 包含如权利要求1-7中任一项所述的化合物或者其药学上可接受的盐、立体异构体、互变异构体、氘代物、前药分子、水合物或者溶剂化物以及药学上可接受的载体或者赋形剂的药物组合物;优选地,所述药物组合物为片剂、胶囊剂、丸剂、颗粒剂、散剂、栓剂、注射剂、溶液剂、混悬剂、膏剂、贴剂、洗剂、滴剂、擦剂、喷雾剂。
- 根据权利要求1-7中任一项所述的化合物或者其药学上可接受的盐、立体异构体、互变异构体、氘代物、前药分子、水合物或者溶剂化物或者权利要求9所述的组合物在制备用于治疗与蛋白激酶相关的疾病的药物中的应用;优选地,所述与蛋白激酶相关的疾病选自与c-Met、VEGFR-2、AXL、TAM、 NTRK或者RET相关的疾病;优选地,所述与蛋白激酶相关的疾病为肿瘤;优选地,所述与蛋白激酶相关的疾病包括头颈部癌、鼻咽癌、黑色素瘤、膀胱癌、食道癌、间变性大细胞淋巴瘤、肾癌、乳腺癌、结肠直肠癌、卵巢癌、宫颈癌、胰腺癌、胶质瘤、胶质母细胞瘤、前列腺癌、白血病、淋巴瘤、非霍奇金淋巴瘤、胃癌、肺癌、肝癌、胃肠道基质瘤、甲状腺癌、鳞状细胞癌、胆管癌、子宫内膜癌、多发性骨髓瘤或者间皮瘤;动脉粥样硬化和肺纤维化。
- 一种治疗主体中与蛋白激酶相关的疾病的方法,该方法包括向所述主体给予治疗有效量的权利要求1至7中任一项所述的化合物或者其药学上可接受的盐、立体异构体、互变异构体、氘代物、前药分子、水合物或者溶剂化物或权利要求9所述的药物组合物;优选地,所述的主体为哺乳动物,所述哺乳动物优选为人;优选地,所述与蛋白激酶相关的疾病选自与c-Met、VEGFR-2、AXL、TAM、NTRK或者RET相关的疾病;优选地,所述与蛋白激酶相关的疾病为肿瘤;优选地,所述与蛋白激酶相关的疾病包括头颈部癌、鼻咽癌、黑色素瘤、膀胱癌、食道癌、间变性大细胞淋巴瘤、肾癌、乳腺癌、结肠直肠癌、卵巢癌、宫颈癌、胰腺癌、胶质瘤、胶质母细胞瘤、前列腺癌、白血病、淋巴瘤、非霍奇金淋巴瘤、胃癌、肺癌、肝癌、胃肠道基质瘤、甲状腺癌、鳞状细胞癌、胆管癌、子宫内膜癌、多发性骨髓瘤或者间皮瘤;动脉粥样硬化和肺纤维化;优选地,在治疗过程中,给药方式包括口腔、粘膜、舌下、眼部、局部、肠道外、直肠、脑池、阴道、腹膜、膀胱、鼻部给药。
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