WO2021254464A1 - 取代喹唑啉类化合物、其制备方法、药物组合及应用 - Google Patents
取代喹唑啉类化合物、其制备方法、药物组合及应用 Download PDFInfo
- Publication number
- WO2021254464A1 WO2021254464A1 PCT/CN2021/100775 CN2021100775W WO2021254464A1 WO 2021254464 A1 WO2021254464 A1 WO 2021254464A1 CN 2021100775 W CN2021100775 W CN 2021100775W WO 2021254464 A1 WO2021254464 A1 WO 2021254464A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- piperidinyl
- methyl
- piperazine
- methylene
- piperazinyl
- Prior art date
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- -1 quinazoline compound Chemical class 0.000 title claims abstract description 2110
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 62
- 150000003839 salts Chemical class 0.000 claims abstract description 35
- 239000012453 solvate Substances 0.000 claims abstract description 23
- 201000010099 disease Diseases 0.000 claims abstract description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 16
- 102100029823 Tyrosine-protein kinase BTK Human genes 0.000 claims abstract description 14
- 229940079593 drug Drugs 0.000 claims abstract description 9
- 239000003814 drug Substances 0.000 claims abstract description 9
- 125000003386 piperidinyl group Chemical group 0.000 claims description 455
- 239000001257 hydrogen Substances 0.000 claims description 418
- 229910052739 hydrogen Inorganic materials 0.000 claims description 418
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 365
- 239000011737 fluorine Substances 0.000 claims description 365
- 229910052731 fluorine Inorganic materials 0.000 claims description 365
- 150000002431 hydrogen Chemical class 0.000 claims description 255
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 209
- 125000000217 alkyl group Chemical group 0.000 claims description 200
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 162
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 162
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 162
- 229910052794 bromium Inorganic materials 0.000 claims description 162
- 239000000460 chlorine Substances 0.000 claims description 162
- 229910052801 chlorine Inorganic materials 0.000 claims description 162
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 162
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 155
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 claims description 152
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 142
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 120
- 229910052760 oxygen Inorganic materials 0.000 claims description 111
- 239000001301 oxygen Substances 0.000 claims description 109
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 108
- 125000003545 alkoxy group Chemical group 0.000 claims description 105
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 103
- 125000004193 piperazinyl group Chemical group 0.000 claims description 91
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 73
- 125000001424 substituent group Chemical group 0.000 claims description 72
- 229910052757 nitrogen Inorganic materials 0.000 claims description 60
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 44
- 241000009298 Trigla lyra Species 0.000 claims description 39
- 125000002883 imidazolyl group Chemical group 0.000 claims description 37
- 125000005842 heteroatom Chemical group 0.000 claims description 32
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 28
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 25
- 239000000651 prodrug Substances 0.000 claims description 24
- 229940002612 prodrug Drugs 0.000 claims description 24
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 22
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 22
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 22
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 19
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 19
- OYHQAXYDSYSGEI-UHFFFAOYSA-N 4-ethoxypiperidine Chemical compound CCOC1CCNCC1 OYHQAXYDSYSGEI-UHFFFAOYSA-N 0.000 claims description 18
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical group 0.000 claims description 18
- DVOVBGJJSFSOPZ-UHFFFAOYSA-N 2-acetamidopropanamide Chemical group NC(=O)C(C)NC(C)=O DVOVBGJJSFSOPZ-UHFFFAOYSA-N 0.000 claims description 17
- GGFAQOYXKBFQIA-UHFFFAOYSA-N CCCS(NN(NS(CC)(=O)=O)S(C(C)(C(NC(CN(C)C)=O)(NC(CO)=O)NC(COC)=O)NS(C)(=O)=O)(=O)=O)(=O)=O Chemical compound CCCS(NN(NS(CC)(=O)=O)S(C(C)(C(NC(CN(C)C)=O)(NC(CO)=O)NC(COC)=O)NS(C)(=O)=O)(=O)=O)(=O)=O GGFAQOYXKBFQIA-UHFFFAOYSA-N 0.000 claims description 17
- WMSPXQIQBQAWLL-UHFFFAOYSA-N cyclopropanesulfonamide Chemical compound NS(=O)(=O)C1CC1 WMSPXQIQBQAWLL-UHFFFAOYSA-N 0.000 claims description 17
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 17
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 16
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 claims description 15
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 14
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 14
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 13
- 125000002733 (C1-C6) fluoroalkyl group Chemical group 0.000 claims description 12
- JNRLEMMIVRBKJE-UHFFFAOYSA-N 4,4'-Methylenebis(N,N-dimethylaniline) Chemical compound C1=CC(N(C)C)=CC=C1CC1=CC=C(N(C)C)C=C1 JNRLEMMIVRBKJE-UHFFFAOYSA-N 0.000 claims description 12
- 125000003047 N-acetyl group Chemical group 0.000 claims description 12
- 125000006262 isopropyl amino sulfonyl group Chemical group 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 125000006261 methyl amino sulfonyl group Chemical group [H]N(C([H])([H])[H])S(*)(=O)=O 0.000 claims description 12
- 206010028980 Neoplasm Diseases 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 125000002252 acyl group Chemical group 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 10
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 6
- 150000004885 piperazines Chemical group 0.000 claims description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- 210000003719 b-lymphocyte Anatomy 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- 230000001404 mediated effect Effects 0.000 claims description 4
- 125000006823 (C1-C6) acyl group Chemical group 0.000 claims description 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 3
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 3
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 3
- 230000036210 malignancy Effects 0.000 claims description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 3
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 6
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 3
- 230000002378 acidificating effect Effects 0.000 claims 3
- 229910052751 metal Inorganic materials 0.000 claims 3
- 239000002184 metal Substances 0.000 claims 3
- 229910052763 palladium Inorganic materials 0.000 claims 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims 2
- 238000005859 coupling reaction Methods 0.000 claims 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 2
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims 1
- 229910000024 caesium carbonate Inorganic materials 0.000 claims 1
- 239000003054 catalyst Substances 0.000 claims 1
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 claims 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 claims 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims 1
- 229940098779 methanesulfonic acid Drugs 0.000 claims 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical group [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims 1
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims 1
- 229910000105 potassium hydride Inorganic materials 0.000 claims 1
- 230000003449 preventive effect Effects 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 1
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- 239000012312 sodium hydride Substances 0.000 claims 1
- 229910000104 sodium hydride Inorganic materials 0.000 claims 1
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- 102100039810 Protein-tyrosine kinase 6 Human genes 0.000 abstract description 15
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
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- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 4
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- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 3
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- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
- 229950007153 zanubrutinib Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
- C07D239/84—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—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
- C07D401/02—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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—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
- C07D401/14—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 three or more hetero rings
Definitions
- the present invention relates to the field of medicinal chemistry, in particular, to a class of substituted quinazoline compounds with BRK and/or BTK kinase inhibitory activity, and pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof, and a preparation method thereof ,
- BRK kinase Bactet al, Bacillus subtilis, Bacillus subtilis, Bacillus subtilis, Bacillus subtilis, Bacillus subtilis, Bacillus subtilis, Bacillus subtilis, Bacillus subtilis, Bacillus subtilis, Bacillus subtilis, Bacillus subtilis, Bacillus subtilis, Bacillus subtilis, Bacillus subtilis, Bacillus subtilis, Bacillus subtilis, Bacillus, BRK, BRK also has a higher level of expression in colon cancer cells (Derry et al, Molecular and Cellular Biology, 2000, 20, 6114-6126); in human oral squamous cell carcinoma, head BRK expression has been detected in cervical and cervical squamous cell carcinoma and skin T-cell lymphoma (Petro et al, Oral Oncology, 2004, 40, 1040-1047; Lin et al, Archives of Otolaryngology-Head&Neck Surgery, 2004 ,130,311-316; Kasprzy
- small molecule inhibitors targeting BRK can effectively inhibit the growth of tumor cells with high BRK expression at cell and animal levels (Jiang et al, Cancer research, 2017, 77, 175-186). Therefore, the development of highly active and highly specific BRK inhibitors is conducive to the development of targeted drugs for tumor treatment, especially breast cancer treatment.
- BTK kinase (Bruton's tyrosine kinase) plays a very important role in the development, differentiation and signal transduction of B cells, and participates in and maintains the malignant phenotypes of B-cell lymphoma and B-cell leukemia (Hendriks et al, Nature Reviews Cancer, 2014 ,14,219-232). Inhibiting the activity of BTK to treat B-cell malignancies has also achieved good results. For example, Ibrutinib has been marketed in many countries and regions for the treatment of mantle cell lymphoma, chronic lymphocytic leukemia and small lymphocytic lymphoma.
- BTK inhibitors on the market are acalabrutinib and zanubrutinib.
- these inhibitors are all covalent inhibitors, which depend to a large extent on the formation of a covalent bond with the sulfhydryl group of cysteine 481 of BTK.
- Development of drug resistance (Woyach et al, New England Journal of Medicine, 2014, 370, 2286-2294), therefore, the development of new non-covalent inhibitors is conducive to overcoming drug resistance and meeting clinical needs.
- the present invention provides compounds of the following general formula:
- An object of the present invention is to provide a class of compounds with the activity of inhibiting BRK and/or BTK kinase and their stereoisomers, their prodrugs, their pharmaceutically acceptable salts or their pharmaceutically acceptable solvates.
- Another object of the present invention is to provide a method for preparing the above-mentioned compound.
- Another object of the present invention is to provide a pharmaceutical composition containing the above-mentioned compound.
- Another object of the present invention is to provide the use of the above-mentioned compound and a pharmaceutical composition containing the above-mentioned compound in the preparation of drugs for the prevention and/or treatment of cancer or other diseases mediated by BRK, BTK kinase or both.
- Another object of the present invention is to provide a method of treating cancer, the method comprising administering to a subject an effective amount of the compound or composition of the present invention.
- the present invention is achieved through the following technical solutions.
- the present invention provides a compound of the following general formula:
- R 1 is selected from:
- Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- Carbamoyl methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, cyclopropylcarbamoyl, cyclobutylcarbamoyl, cyclopentylcarbamoyl, Cyclohexylcarbamoyl,
- Tetrahydropyrrole-1-formyl 3-(N,N-dimethylamino)tetrahydropyrrolyl-1-formyl, 3-(N,N-diethylamino)tetrahydropyrrolyl-1- Formyl,
- Piperidinyl-1-formyl 4-hydroxypiperidinyl-1-formyl, 4-(N,N-dimethylamino)piperidinyl-1-formyl, 4-(N,N-di Ethylamino)piperidinyl-1-formyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl-1-piperazinyl) Piperidinyl-1-formyl,
- Tetrahydropyrrole-1-sulfonyl 3-(N,N-dimethylamino)tetrahydropyrrolyl-1-sulfonyl, 3-(N,N-diethylamino)tetrahydropyrrolyl-1- Sulfonyl,
- Piperidinyl-1-sulfonyl 4-hydroxypiperidine-1-sulfonyl, 4-(N,N-dimethylamino)piperidinyl-1-sulfonyl, 4-(N,N-diethyl Amino)piperidinyl-1-sulfonyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-sulfonyl, 4-(N-ethyl-1-piperazinyl)piper Pyridyl-1-sulfonyl,
- Carbamoylamino methylcarbamoylamino, ethylcarbamoylamino, propylcarbamoylamino, isopropylcarbamoylamino, cyclopropylcarbamoylamino, cyclobutylcarbamoylamino, cyclic Pentylcarbamoylamino, piperidinyl-1-carboxamido, 4-hydroxypiperidinyl-1-carboxamido, 4-N,N-dimethylpiperidinyl-1-carboxamido, 4 -N,N-Diethylpiperidinyl-1-carboxamido, tetrahydropyrrolyl-1-carboxamido, 3-N,N-dimethyltetrahydropyrrolyl-1-carboxamido, 3 -N,N-Diethyltetrahydropyrrolyl-1-carboxamido, N-methyl
- Z3 and Z4 can form an oxygen-containing substituted or unsubstituted five-seven-membered ring; the substituent can be selected from the same substituents as described above for Z1,
- Z3 and Z4 can form a nitrogen-containing substituted or unsubstituted five-seven-membered ring; the substituents can be selected from the same substituents as described above for Z1;
- R 2 is selected from:
- Hydrogen methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, cyclopropylamino, N,N-dimethylamino, methyl N,N-diethylamino, N,N-diisopropylamino;
- R 3 is selected from:
- W 1 , W 2 , W 3 , W 4 , and W 5 are each independently selected from the following, and are not hydrogen at the same time:
- R a and R b are each independently selected from:
- R a , R b and N form a substituted or unsubstituted 3-7 membered ring containing 1 to 2 heteroatoms, and the substituent is halogen, C1-C6 alkyl or C3-C6 cycloalkyl;
- R a and R b are the same as defined in (4);
- L is selected from direct bonds
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from:
- L, Y 2 , Y 3 , Y 4 , Y 5 are the same as defined in (7),
- L, Y 1 , Y 2 , Y 4 , Y 5 are the same as defined in (7);
- W 2 , W 3 , W 4 , W 5 are the same as defined in 1), and can be hydrogen at the same time;
- W 1 , W 3 , W 4 , W 5 are the same as defined in 1), and can be hydrogen at the same time;
- W 1 , W 2 , W 4 , and W 5 are the same as defined in 1), and they can be hydrogen at the same time.
- R 1 is selected from:
- Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- Tetrahydropyrrole-1-formyl 3-(N,N-dimethylamino)tetrahydropyrrolyl-1-formyl, 3-(N,N-diethylamino)tetrahydropyrrolyl-1- Formyl,
- Piperidinyl-1-formyl 4-hydroxypiperidinyl-1-formyl, 4-(N,N-dimethylamino)piperidinyl-1-formyl, 4-(N,N-di Ethylamino)piperidinyl-1-formyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl-1-piperazinyl) Piperidinyl-1-formyl,
- Z 1 , Z 3 , Z 4 , and Z 5 are the same as defined in 1);
- Z 1 , Z 2 , Z 5 are the same as defined in 1), and can be hydrogen at the same time;
- R x1 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1 -C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, C3-C6 cycloalkyl;
- Z 1 , Z 2 , Z 5 are the same as defined in 1), and can be hydrogen at the same time;
- R x2 and R y are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1 -C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, C3-C6 cycloalkyl;
- Z 2 , Z 5 are the same as defined in 1), and can be hydrogen at the same time;
- R x3 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1-C6 alkane Oxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, C3-C6 cycloalkyl;
- Z 1 , Z 2 , Z 5 are the same as defined in 1), and can be hydrogen at the same time;
- R x4 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1 -C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, C3-C6 cycloalkyl;
- R 1 is selected from:
- Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- Z 1 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- Z 1 , Z 2 , and Z 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkoxy;
- R x1 is selected from hydrogen, fluorine, chlorine, bromine, Iodine, nitro, cyano, C1-C6 alkyl;
- Z 1 , Z 2 , Z 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl;
- R x2 , R y are each independently selected from hydrogen, fluorine , Chloro, bromo, iodo, nitro, cyano, C1-C6 alkyl;
- Z 2 and Z 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl;
- R x3 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro , Cyano, C1-C6 alkyl;
- Z 1 , Z 2 , and Z 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl;
- R x4 is selected from hydrogen, fluorine, chlorine, bromine, and iodine , Nitro, cyano, C1-C6 alkyl;
- R 1 is selected from:
- Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- Z 1 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- Z 1 , Z 2 , and Z 5 are each independently selected from hydrogen, fluorine, and methoxy; R x1 is methyl;
- Z 1 , Z 2 , and Z 5 are hydrogen; R x2 and R y are methyl;
- Z 2 and Z 5 are hydrogen; R x3 is isopropyl;
- Z 1 , Z 2 , and Z 5 are hydrogen; R x4 is hydrogen;
- R 3 is selected from:
- W 1 and W 4 are each independently selected from the following, and are not hydrogen at the same time:
- R a and R b are each independently selected from:
- R a , R b and N form a substituted or unsubstituted 3-7 membered ring containing 1 to 2 heteroatoms, and the substituent is halogen, C1-C6 alkyl or C3-C6 cycloalkyl,
- R a , R b are the same as defined in (4),
- L is selected from direct bond
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from:
- L, Y 2 , Y 3 , Y 4 , Y 5 are the same as defined in (7),
- L, Y 1 , Y 2 , Y 4 , Y 5 are the same as defined in (7);
- W 1 and W 4 are the same as defined in 1), and can be hydrogen at the same time;
- W 1 and W 4 are the same as defined in 1), and can be hydrogen at the same time;
- W 1 and W 5 have the same definition as W 1 in 1), and they can be hydrogen at the same time.
- R 3 is selected from:
- W 1 and W 4 are each independently selected from the following, and are not hydrogen at the same time:
- R a and R b are each independently selected from:
- R a , R b and N form a substituted or unsubstituted 3-7 membered ring containing 1 to 2 heteroatoms, and the substituent is halogen, C1-C6 alkyl or C3-C6 cycloalkyl;
- R a and R b are the same as defined in (4);
- L is selected from direct bonds
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from:
- L, Y 2 , Y 3 , Y 4 , Y 5 are the same as defined in (7),
- L, Y 1 , Y 2 , Y 4 , Y 5 are the same as defined in (7);
- W 1 and W 5 have the same definition as W 1 in 1), and they can be hydrogen at the same time.
- R 3 is selected from:
- W 1 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl , C1-C6 fluorine-containing alkoxy group,
- W 4 is selected from:
- R a and R b are each independently selected from:
- R a , R b and N form a substituted or unsubstituted 3-7 membered ring containing 1 to 2 heteroatoms, and the substituent is halogen, C1-C6 alkyl or C3-C6 cycloalkyl;
- R a and R b are the same as defined in (3);
- L is selected from direct bonds
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from:
- L, Y 2 , Y 3 , Y 4 , Y 5 are the same as defined in (6),
- L, Y 1 , Y 3 , Y 4 , Y 5 are the same as defined in (6),
- W 1 and W 5 have the same definition as W 1 in 1), and they can be hydrogen at the same time.
- the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt, wherein the inorganic acid salt is hydrochloride, hydrobromide, hydroiodide, nitrate, bicarbonate Salt and carbonate, sulfate or phosphate, the organic acid salt is formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartaric acid Salt, citrate, ascorbate, ⁇ -ketoglutarate, ⁇ -glycerol phosphate, alkyl sulfonate or aryl sulfonate; preferably, the alkyl sulfonate is methanesulfonic acid Salt or ethyl sulfonate; the aryl sulfonate is benzene sulfonate or p-toluene sulfonate.
- the inorganic acid salt is hydrochloride, hydrobromide, hydroiodide, nitrate, bi
- the present invention provides the following compounds:
- R 1 is selected from:
- Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- Carbamoyl methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, cyclopropylcarbamoyl, cyclobutylcarbamoyl, cyclopentylcarbamoyl, Cyclohexylcarbamoyl,
- Tetrahydropyrrole-1-formyl 3-(N,N-dimethylamino)tetrahydropyrrolyl-1-formyl, 3-(N,N-diethylamino)tetrahydropyrrolyl-1- Formyl,
- Piperidinyl-1-formyl 4-hydroxypiperidinyl-1-formyl, 4-(N,N-dimethylamino)piperidinyl-1-formyl, 4-(N,N-di Ethylamino)piperidinyl-1-formyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl-1-piperazinyl) Piperidinyl-1-formyl,
- Tetrahydropyrrole-1-sulfonyl 3-(N,N-dimethylamino)tetrahydropyrrolyl-1-sulfonyl, 3-(N,N-diethylamino)tetrahydropyrrolyl-1- Sulfonyl,
- Piperidinyl-1-sulfonyl 4-hydroxypiperidine-1-sulfonyl, 4-(N,N-dimethylamino)piperidinyl-1-sulfonyl, 4-(N,N-diethyl Amino)piperidinyl-1-sulfonyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-sulfonyl, 4-(N-ethyl-1-piperazinyl)piper Pyridyl-1-sulfonyl,
- Carbamoylamino methylcarbamoylamino, ethylcarbamoylamino, propylcarbamoylamino, isopropylcarbamoylamino, cyclopropylcarbamoylamino, cyclobutylcarbamoylamino, cyclic Pentylcarbamoylamino, piperidinyl-1-carboxamido, 4-hydroxypiperidinyl-1-carboxamido, 4-N,N-dimethylpiperidinyl-1-carboxamido, 4 -N,N-Diethylpiperidinyl-1-carboxamido, tetrahydropyrrolyl-1-carboxamido, 3-N,N-dimethyltetrahydropyrrolyl-1-carboxamido, 3 -N,N-Diethyltetrahydropyrrolyl-1-carboxamido, N-methyl
- Z3 and Z4 can form an oxygen-containing substituted or unsubstituted five-seven-membered ring; the substituent can be selected from the same substituents as described above for Z1,
- Z3 and Z4 can form a nitrogen-containing substituted or unsubstituted five-seven-membered ring; the substituents can be selected from the same substituents as described above for Z1;
- Z 2 , Z 3 , Z 4 , Z 5 are the same as defined in 1);
- Z 1 , Z 3 , Z 4 , and Z 5 are the same as defined in 1);
- Z 1 , Z 2 , Z 4 , and Z 5 are the same as defined in 1);
- Z 1 , Z 3 , and Z 5 are the same as defined in 1);
- R 2 is selected from:
- Hydrogen methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, cyclopropylamino, N,N-dimethylamino, methyl N,N-diethylamino, N,N-diisopropylamino;
- W 1 , W 2 , W 3 , and W 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing Alkyl group, C1-C6 fluorine-containing alkyl group, C1-C6 fluorine-containing alkoxy group, C3-C6 cycloalkyl group;
- R is selected from:
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from:
- Y 2 , Y 3 , Y 4 , Y 5 are the same as defined in 2),
- Y 1 , Y 3 , Y 4 , Y 5 are the same as defined in 2),
- Y 1 , Y 2 , Y 4 , Y 5 are the same as defined in 2)
- Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are the same as defined in 2).
- R 1 is selected from:
- Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- Tetrahydropyrrole-1-formyl 3-(N,N-dimethylamino)tetrahydropyrrolyl-1-formyl, 3-(N,N-diethylamino)tetrahydropyrrolyl-1- Formyl,
- Piperidinyl-1-formyl 4-hydroxypiperidinyl-1-formyl, 4-(N,N-dimethylamino)piperidinyl-1-formyl, 4-(N,N-di Ethylamino)piperidinyl-1-formyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl-1-piperazinyl) Piperidinyl-1-formyl,
- Z 1 , Z 3 , Z 4 , and Z 5 are the same as defined in 1);
- Z 1 , Z 2 , Z 5 are the same as defined in 1), and can be hydrogen at the same time;
- R x1 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1 -C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, C3-C6 cycloalkyl;
- Z 1 , Z 2 , Z 5 are the same as defined in 1), and can be hydrogen at the same time;
- R x2 and R y are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1 -C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, C3-C6 cycloalkyl;
- Z 2 , Z 5 are the same as defined in 1), and can be hydrogen at the same time;
- R x3 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1-C6 alkane Oxy group, C1-C6 oxygen-containing alkyl group, C1-C6 fluorine-containing alkyl group, C1-C6 fluorine-containing alkoxy group, C3-C6 cycloalkyl group;
- Z 1 , Z 2 , Z 5 are the same as defined in 1), and can be hydrogen at the same time;
- R x4 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1 -C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, C3-C6 cycloalkyl;
- R 1 is selected from:
- Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- Z 1 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- Z 1 , Z 2 , and Z 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkoxy;
- R x1 is selected from hydrogen, fluorine, chlorine, bromine, Iodine, nitro, cyano, C1-C6 alkyl;
- Z 1 , Z 2 , Z 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl;
- R x2 , R y are each independently selected from hydrogen, fluorine , Chloro, bromo, iodo, nitro, cyano, C1-C6 alkyl;
- Z 2 and Z 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl;
- R x3 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro , Cyano, C1-C6 alkyl;
- Z 1 , Z 2 , and Z 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl;
- R x4 is selected from hydrogen, fluorine, chlorine, bromine, and iodine , Nitro, cyano, C1-C6 alkyl;
- R 1 is selected from:
- Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- Z 1 , Z 2 , and Z 5 are each independently selected from hydrogen, fluorine, methoxy, ethoxy, and isopropoxy, and one of Z 3 and Z 4 is selected from the following, and the other is selected from hydrogen , Methyl, Fluorine:
- N-methylpiperazine-1-formyl 4-hydroxypiperidinyl, N-methyl-4-piperidinyl, N-methylpiperazinyl, 4-(N-methylpiperazine-1- )Piperidinyl, 4-(N-(2-hydroxyethyl)piperazine-1-)piperidinyl, 4-(N-(2-N,N-dimethylaminoethyl)piperazine-1 -)Piperidinyl, 4-(tetrahydropyrrol-1-)piperidinyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl, 2-(N,N- Dimethylamino)acetamido;
- Z 1 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- Z 1 and Z 5 are each independently selected from hydrogen and methoxy, and one of Z 3 and Z 4 is selected from the following, and the other is hydrogen:
- Z 1 , Z 2 , and Z 5 are each independently selected from hydrogen, fluorine, and methoxy; R x1 is methyl;
- Z 1 , Z 2 , and Z 5 are hydrogen; R x2 and R y are methyl;
- Z 2 and Z 5 are hydrogen; R x3 is isopropyl;
- Z 1 , Z 2 , and Z 5 are hydrogen; R x4 is hydrogen;
- R 2 is selected from hydrogen, methyl, ethyl, isopropyl.
- W 1 , W 2 , W 3 , and W 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, and C1-C6 alkyl.
- W 1 , W 2 , W 3 , and W 5 are each independently selected from hydrogen and methyl.
- W 2 , W 3 , and W 5 are hydrogen, and W 1 is methyl.
- R is selected from:
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from:
- Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are the same as defined in 2).
- R is selected from:
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from:
- Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from:
- Y 1 , Y 3 , Y 4 , Y 5 are each independently selected from:
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from:
- R is selected from:
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from:
- Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from:
- Y 1 , Y 3 , Y 4 , Y 5 are each independently selected from:
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from:
- the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt, wherein the inorganic acid salt is hydrochloride, hydrobromide, hydroiodide, nitrate, bicarbonate Salt and carbonate, sulfate or phosphate, the organic acid salt is formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartaric acid Salt, citrate, ascorbate, ⁇ -ketoglutarate, ⁇ -glycerol phosphate, alkyl sulfonate or aryl sulfonate; preferably, the alkyl sulfonate is methanesulfonic acid Salt or ethyl sulfonate; the aryl sulfonate is benzene sulfonate or p-toluene sulfonate.
- the inorganic acid salt is hydrochloride, hydrobromide, hydroiodide, nitrate, bi
- the present invention provides the following compounds:
- R 1 is selected from:
- Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- Carbamoyl methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, cyclopropylcarbamoyl, cyclobutylcarbamoyl, cyclopentylcarbamoyl, Cyclohexylcarbamoyl,
- Tetrahydropyrrole-1-formyl 3-(N,N-dimethylamino)tetrahydropyrrolyl-1-formyl, 3-(N,N-diethylamino)tetrahydropyrrolyl-1- Formyl,
- Piperidinyl-1-formyl 4-hydroxypiperidinyl-1-formyl, 4-(N,N-dimethylamino)piperidinyl-1-formyl, 4-(N,N-di Ethylamino)piperidinyl-1-formyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl-1-piperazinyl) Piperidinyl-1-formyl,
- Tetrahydropyrrole-1-sulfonyl 3-(N,N-dimethylamino)tetrahydropyrrolyl-1-sulfonyl, 3-(N,N-diethylamino)tetrahydropyrrolyl-1- Sulfonyl,
- Piperidinyl-1-sulfonyl 4-hydroxypiperidine-1-sulfonyl, 4-(N,N-dimethylamino)piperidinyl-1-sulfonyl, 4-(N,N-diethyl Amino)piperidinyl-1-sulfonyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-sulfonyl, 4-(N-ethyl-1-piperazinyl)piper Pyridyl-1-sulfonyl,
- Carbamoylamino methylcarbamoylamino, ethylcarbamoylamino, propylcarbamoylamino, isopropylcarbamoylamino, cyclopropylcarbamoylamino, cyclobutylcarbamoylamino, cyclic Pentylcarbamoylamino, piperidinyl-1-carboxamido, 4-hydroxypiperidinyl-1-carboxamido, 4-N,N-dimethylpiperidinyl-1-carboxamido, 4 -N,N-Diethylpiperidinyl-1-carboxamido, tetrahydropyrrolyl-1-carboxamido, 3-N,N-dimethyltetrahydropyrrolyl-1-carboxamido, 3 -N,N-Diethyltetrahydropyrrolyl-1-carboxamido, N-methyl
- Z3 and Z4 can form an oxygen-containing substituted or unsubstituted five-seven-membered ring; the substituent can be selected from the same substituents as described above for Z1,
- Z3 and Z4 can form a nitrogen-containing substituted or unsubstituted five-seven-membered ring; the substituents can be selected from the same substituents as described above for Z1;
- Z 2 , Z 3 , Z 4 , Z 5 are the same as defined in 1);
- Z 1 , Z 3 , Z 4 , and Z 5 are the same as defined in 1);
- Z 1 , Z 2 , Z 4 , and Z 5 are the same as defined in 1);
- Z 1 , Z 3 , and Z 5 are the same as defined in 1);
- R 2 is selected from:
- Hydrogen methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, cyclopropylamino, N,N-dimethylamino, methyl N,N-diethylamino, N,N-diisopropylamino;
- W 1 , W 2 , W 3 , and W 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing Alkyl group, C1-C6 fluorine-containing alkyl group, C1-C6 fluorine-containing alkoxy group, C3-C6 cycloalkyl group;
- R’ is selected from:
- R a and R b are each independently selected from:
- R a , R b and N form a substituted or unsubstituted 3-7 membered ring containing 1 to 2 heteroatoms, and the substituent is halogen, C1-C6 alkyl or C3-C6 cycloalkyl;
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from:
- R 1 is Z 1 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- R 1 is Z 1 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- R 1 is Z 1 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- R 2 is methyl
- W 1 , W 2 , W 3 , and W 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, and C1-C6 alkyl.
- W 1 , W 2 , W 3 , and W 5 are each independently selected from hydrogen and methyl.
- W 2 , W 3 , and W 5 are hydrogen, and W 1 is hydrogen or methyl.
- R' is selected from:
- R a and R b are each independently selected from:
- R a , R b and N form a substituted or unsubstituted piperazine ring, and the substituent is halogen, C1-C6 alkyl or C3-C6 cycloalkyl;
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from:
- R' is selected from:
- R a and R b are each independently selected from:
- R a , R b and N form a substituted or unsubstituted piperazine ring, and the substituent is a C1-C6 alkyl group;
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from:
- R' is selected from:
- R a and R b are each independently selected from hydrogen, methyl, ethyl, cyclopropyl,
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from:
- the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt, wherein the inorganic acid salt is hydrochloride, hydrobromide, hydroiodide, nitrate, bicarbonate Salt and carbonate, sulfate or phosphate, the organic acid salt is formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartaric acid Salt, citrate, ascorbate, ⁇ -ketoglutarate, ⁇ -glycerol phosphate, alkyl sulfonate or aryl sulfonate; preferably, the alkyl sulfonate is methanesulfonic acid Salt or ethyl sulfonate; the aryl sulfonate is benzene sulfonate or p-toluene sulfonate.
- the inorganic acid salt is hydrochloride, hydrobromide, hydroiodide, nitrate, bi
- the present invention provides the following compounds:
- R 1 is selected from:
- Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- Carbamoyl methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, cyclopropylcarbamoyl, cyclobutylcarbamoyl, cyclopentylcarbamoyl, Cyclohexylcarbamoyl,
- Tetrahydropyrrole-1-formyl 3-(N,N-dimethylamino)tetrahydropyrrolyl-1-formyl, 3-(N,N-diethylamino)tetrahydropyrrolyl-1- Formyl,
- Piperidinyl-1-formyl 4-hydroxypiperidinyl-1-formyl, 4-(N,N-dimethylamino)piperidinyl-1-formyl, 4-(N,N-di Ethylamino)piperidinyl-1-formyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl-1-piperazinyl) Piperidinyl-1-formyl,
- Tetrahydropyrrole-1-sulfonyl 3-(N,N-dimethylamino)tetrahydropyrrolyl-1-sulfonyl, 3-(N,N-diethylamino)tetrahydropyrrolyl-1- Sulfonyl,
- Piperidinyl-1-sulfonyl 4-hydroxypiperidine-1-sulfonyl, 4-(N,N-dimethylamino)piperidinyl-1-sulfonyl, 4-(N,N-diethyl Amino)piperidinyl-1-sulfonyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-sulfonyl, 4-(N-ethyl-1-piperazinyl)piper Pyridyl-1-sulfonyl,
- Carbamoylamino methylcarbamoylamino, ethylcarbamoylamino, propylcarbamoylamino, isopropylcarbamoylamino, cyclopropylcarbamoylamino, cyclobutylcarbamoylamino, cyclic Pentylcarbamoylamino, piperidinyl-1-carboxamido, 4-hydroxypiperidinyl-1-carboxamido, 4-N,N-dimethylpiperidinyl-1-carboxamido, 4 -N,N-Diethylpiperidinyl-1-carboxamido, tetrahydropyrrolyl-1-carboxamido, 3-N,N-dimethyltetrahydropyrrolyl-1-carboxamido, 3 -N,N-Diethyltetrahydropyrrolyl-1-carboxamido, N-methyl
- Z3 and Z4 can form an oxygen-containing substituted or unsubstituted five-seven-membered ring; the substituent can be selected from the same substituents as described above for Z1,
- Z3 and Z4 can form a nitrogen-containing substituted or unsubstituted five-seven-membered ring; the substituents can be selected from the same substituents as described above for Z1;
- Z 2 , Z 3 , Z 4 , Z 5 are the same as defined in 1);
- Z 1 , Z 3 , Z 4 , and Z 5 are the same as defined in 1);
- Z 1 , Z 2 , Z 4 , and Z 5 are the same as defined in 1);
- Z 1 , Z 3 , and Z 5 are the same as defined in 1);
- R 2 is selected from:
- Hydrogen methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, cyclopropylamino, N,N-dimethylamino, methyl N,N-diethylamino, N,N-diisopropylamino;
- W 1 , W 3 , W 4 , and W 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing Alkyl group, C1-C6 fluorine-containing alkyl group, C1-C6 fluorine-containing alkoxy group, C3-C6 cycloalkyl group.
- R 1 is Z 1 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- R 1 is Z 1 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- R 1 is Z 1 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time: hydrogen, 4-N,N-dimethylaminopiperidinyl .
- R 2 is isopropyl
- W 1 , W 3 , W 4 , and W 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, and C1-C6 alkyl.
- W 1 , W 3 , W 4 , and W 5 are each independently selected from hydrogen and methyl.
- W 1 , W 3 , and W 4 are hydrogen, and W 5 is hydrogen or methyl.
- the present invention provides a compound of the following general formula:
- R 1 is selected from:
- Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- Carbamoyl methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, cyclopropylcarbamoyl, cyclobutylcarbamoyl, cyclopentylcarbamoyl, Cyclohexylcarbamoyl,
- Tetrahydropyrrole-1-formyl 3-(N,N-dimethylamino)tetrahydropyrrolyl-1-formyl, 3-(N,N-diethylamino)tetrahydropyrrolyl-1- Formyl,
- Piperidinyl-1-formyl 4-hydroxypiperidinyl-1-formyl, 4-(N,N-dimethylamino)piperidinyl-1-formyl, 4-(N,N-di Ethylamino)piperidinyl-1-formyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl-1-piperazinyl) Piperidinyl-1-formyl,
- Tetrahydropyrrole-1-sulfonyl 3-(N,N-dimethylamino)tetrahydropyrrolyl-1-sulfonyl, 3-(N,N-diethylamino)tetrahydropyrrolyl-1- Sulfonyl,
- Piperidinyl-1-sulfonyl 4-hydroxypiperidine-1-sulfonyl, 4-(N,N-dimethylamino)piperidinyl-1-sulfonyl, 4-(N,N-diethyl Amino)piperidinyl-1-sulfonyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-sulfonyl, 4-(N-ethyl-1-piperazinyl)piper Pyridyl-1-sulfonyl,
- Carbamoylamino methylcarbamoylamino, ethylcarbamoylamino, propylcarbamoylamino, isopropylcarbamoylamino, cyclopropylcarbamoylamino, cyclobutylcarbamoylamino, cyclic Pentylcarbamoylamino, piperidinyl-1-carboxamido, 4-hydroxypiperidinyl-1-carboxamido, 4-N,N-dimethylpiperidinyl-1-carboxamido, 4 -N,N-Diethylpiperidinyl-1-carboxamido, tetrahydropyrrolyl-1-carboxamido, 3-N,N-dimethyltetrahydropyrrolyl-1-carboxamido, 3 -N,N-Diethyltetrahydropyrrolyl-1-carboxamido, N-methyl
- Z3 and Z4 can form an oxygen-containing substituted or unsubstituted five-seven-membered ring; the substituent can be selected from the same substituents as described above for Z1,
- Z3 and Z4 can form a nitrogen-containing substituted or unsubstituted five-seven-membered ring; the substituents can be selected from the same substituents as described above for Z1;
- R 2 is selected from:
- Hydrogen methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, cyclopropylamino, N,N-dimethylamino, methyl N,N-diethylamino, N,N-diisopropylamino;
- R 3 is selected from:
- W 1 , W 2 , W 3 , W 4 , and W 5 are each independently selected from the following, and are not hydrogen at the same time:
- R a and R b are each independently selected from:
- R a , R b and N form a substituted or unsubstituted 3-7 membered ring containing 1 to 2 heteroatoms, and the substituent is halogen, C1-C6 alkyl or C3-C6 cycloalkyl;
- R a and R b are the same as defined in (4);
- L is selected from direct bonds
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from:
- L, Y 2 , Y 3 , Y 4 , Y 5 are the same as defined in (7),
- L, Y 1 , Y 2 , Y 4 , Y 5 are the same as defined in (7);
- W 2 , W 3 , W 4 , W 5 are the same as defined in 1), and can be hydrogen at the same time;
- W 1 , W 3 , W 4 , W 5 are the same as defined in 1), and can be hydrogen at the same time;
- W 1 , W 2 , W 4 , and W 5 are the same as defined in 1), and they can be hydrogen at the same time.
- R 1 is selected from:
- Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- Tetrahydropyrrole-1-formyl 3-(N,N-dimethylamino)tetrahydropyrrolyl-1-formyl, 3-(N,N-diethylamino)tetrahydropyrrolyl-1- Formyl,
- Piperidinyl-1-formyl 4-hydroxypiperidinyl-1-formyl, 4-(N,N-dimethylamino)piperidinyl-1-formyl, 4-(N,N-di Ethylamino)piperidinyl-1-formyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl-1-piperazinyl) Piperidinyl-1-formyl,
- Z 1 , Z 3 , Z 4 , and Z 5 are the same as defined in 1);
- Z 1 , Z 2 , Z 5 are the same as defined in 1), and can be hydrogen at the same time;
- R x1 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1 -C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, C3-C6 cycloalkyl;
- Z 1 , Z 2 , Z 5 are the same as defined in 1), and can be hydrogen at the same time;
- R x2 and R y are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1 -C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, C3-C6 cycloalkyl;
- Z 2 , Z 5 are the same as defined in 1), and can be hydrogen at the same time;
- R x3 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1-C6 alkane Oxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, C3-C6 cycloalkyl;
- Z 1 , Z 2 , Z 5 are the same as defined in 1), and can be hydrogen at the same time;
- R x4 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1 -C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, C3-C6 cycloalkyl;
- R 1 is selected from:
- Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- Z 1 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- Z 1 , Z 2 , and Z 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkoxy;
- R x1 is selected from hydrogen, fluorine, chlorine, bromine, Iodine, nitro, cyano, C1-C6 alkyl;
- Z 1 , Z 2 , Z 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl;
- R x2 , R y are each independently selected from hydrogen, fluorine , Chloro, bromo, iodo, nitro, cyano, C1-C6 alkyl;
- Z 2 and Z 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl;
- R x3 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro , Cyano, C1-C6 alkyl;
- Z 1 , Z 2 , and Z 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl;
- R x4 is selected from hydrogen, fluorine, chlorine, bromine, and iodine , Nitro, cyano, C1-C6 alkyl;
- R 1 is selected from:
- Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- Z 1 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- Z 1 , Z 2 , and Z 5 are each independently selected from hydrogen, fluorine, and methoxy; R x1 is methyl;
- Z 1 , Z 2 , and Z 5 are hydrogen; R x2 and R y are methyl;
- Z 2 and Z 5 are hydrogen; R x3 is isopropyl;
- Z 1 , Z 2 , and Z 5 are hydrogen; R x4 is hydrogen;
- R 3 is selected from:
- W 1 and W 4 are each independently selected from the following, and are not hydrogen at the same time:
- R a and R b are each independently selected from:
- R a , R b and N form a substituted or unsubstituted 3-7 membered ring containing 1 to 2 heteroatoms, and the substituent is halogen, C1-C6 alkyl or C3-C6 cycloalkyl,
- R a , R b are the same as defined in (4),
- L is selected from direct bond
- Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently selected from:
- L, Y 2 , Y 3 , Y 4 , Y 5 are the same as defined in (7),
- L, Y 1 , Y 2 , Y 4 , Y 5 are the same as defined in (7);
- W 1 and W 4 are the same as defined in 1), and can be hydrogen at the same time;
- W 1 and W 4 are the same as defined in 1), and can be hydrogen at the same time;
- W 1 and W 5 have the same definition as W 1 in 1), and they can be hydrogen at the same time.
- R 3 is selected from:
- W 1 and W 4 are each independently selected from the following, and are not hydrogen at the same time:
- R a and R b are each independently selected from:
- R a , R b and N form a substituted or unsubstituted 3-7 membered ring containing 1 to 2 heteroatoms, and the substituent is halogen, C1-C6 alkyl or C3-C6 cycloalkyl;
- R a and R b are the same as defined in (4);
- L is selected from direct bonds
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from:
- L, Y 2 , Y 3 , Y 4 , Y 5 are the same as defined in (7),
- L, Y 1 , Y 2 , Y 4 , Y 5 are the same as defined in (7);
- W 1 and W 5 have the same definition as W 1 in 1), and they can be hydrogen at the same time.
- R 3 is selected from:
- W 1 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl , C1-C6 fluorine-containing alkoxy group,
- W 4 is selected from:
- R a and R b are each independently selected from:
- R a , R b and N form a substituted or unsubstituted 3-7 membered ring containing 1 to 2 heteroatoms, and the substituent is halogen, C1-C6 alkyl or C3-C6 cycloalkyl;
- R a and R b are the same as defined in (3);
- L is selected from direct bonds
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from:
- L, Y 2 , Y 3 , Y 4 , Y 5 are the same as defined in (6),
- L, Y 1 , Y 3 , Y 4 , Y 5 are the same as defined in (6),
- W 1 and W 5 have the same definition as W 1 in 1), and they can be hydrogen at the same time.
- the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt, wherein the inorganic acid salt is hydrochloride, hydrobromide, hydroiodide, nitrate, bicarbonate Salt and carbonate, sulfate or phosphate, the organic acid salt is formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartaric acid Salt, citrate, ascorbate, ⁇ -ketoglutarate, ⁇ -glycerol phosphate, alkyl sulfonate or aryl sulfonate; preferably, the alkyl sulfonate is methanesulfonic acid Salt or ethyl sulfonate; the aryl sulfonate is benzene sulfonate or p-toluene sulfonate.
- the inorganic acid salt is hydrochloride, hydrobromide, hydroiodide, nitrate, bi
- the present invention provides the following compounds:
- R 1 is selected from:
- Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- Carbamoyl methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, cyclopropylcarbamoyl, cyclobutylcarbamoyl, cyclopentylcarbamoyl, Cyclohexylcarbamoyl,
- Tetrahydropyrrole-1-formyl 3-(N,N-dimethylamino)tetrahydropyrrolyl-1-formyl, 3-(N,N-diethylamino)tetrahydropyrrolyl-1- Formyl,
- Piperidinyl-1-formyl 4-hydroxypiperidinyl-1-formyl, 4-(N,N-dimethylamino)piperidinyl-1-formyl, 4-(N,N-di Ethylamino)piperidinyl-1-formyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl-1-piperazinyl) Piperidinyl-1-formyl,
- Tetrahydropyrrole-1-sulfonyl 3-(N,N-dimethylamino)tetrahydropyrrolyl-1-sulfonyl, 3-(N,N-diethylamino)tetrahydropyrrolyl-1- Sulfonyl,
- Piperidinyl-1-sulfonyl 4-hydroxypiperidine-1-sulfonyl, 4-(N,N-dimethylamino)piperidinyl-1-sulfonyl, 4-(N,N-diethyl Amino)piperidinyl-1-sulfonyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-sulfonyl, 4-(N-ethyl-1-piperazinyl)piper Pyridyl-1-sulfonyl,
- Carbamoylamino methylcarbamoylamino, ethylcarbamoylamino, propylcarbamoylamino, isopropylcarbamoylamino, cyclopropylcarbamoylamino, cyclobutylcarbamoylamino, cyclic Pentylcarbamoylamino, piperidinyl-1-carboxamido, 4-hydroxypiperidinyl-1-carboxamido, 4-N,N-dimethylpiperidinyl-1-carboxamido, 4 -N,N-Diethylpiperidinyl-1-carboxamido, tetrahydropyrrolyl-1-carboxamido, 3-N,N-dimethyltetrahydropyrrolyl-1-carboxamido, 3 -N,N-Diethyltetrahydropyrrolyl-1-carboxamido, N-methyl
- Z3 and Z4 can form an oxygen-containing substituted or unsubstituted five-seven-membered ring; the substituent can be selected from the same substituents as described above for Z1,
- Z3 and Z4 can form a nitrogen-containing substituted or unsubstituted five-seven-membered ring; the substituents can be selected from the same substituents as described above for Z1;
- Z 2 , Z 3 , Z 4 , Z 5 are the same as defined in 1);
- Z 1 , Z 3 , Z 4 , and Z 5 are the same as defined in 1);
- Z 1 , Z 2 , Z 4 , and Z 5 are the same as defined in 1);
- Z 1 , Z 3 , and Z 5 are the same as defined in 1);
- R 2 is selected from:
- Hydrogen methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, cyclopropylamino, N,N-dimethylamino, methyl N,N-diethylamino, N,N-diisopropylamino;
- W 1 , W 2 , W 3 , and W 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing Alkyl group, C1-C6 fluorine-containing alkyl group, C1-C6 fluorine-containing alkoxy group, C3-C6 cycloalkyl group;
- R is selected from:
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from:
- Y 2 , Y 3 , Y 4 , Y 5 are the same as defined in 2),
- Y 1 , Y 3 , Y 4 , Y 5 are the same as defined in 2),
- R 1 is selected from:
- Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- Tetrahydropyrrole-1-formyl 3-(N,N-dimethylamino)tetrahydropyrrolyl-1-formyl, 3-(N,N-diethylamino)tetrahydropyrrolyl-1- Formyl,
- Piperidinyl-1-formyl 4-hydroxypiperidinyl-1-formyl, 4-(N,N-dimethylamino)piperidinyl-1-formyl, 4-(N,N-di Ethylamino)piperidinyl-1-formyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl-1-piperazinyl) Piperidinyl-1-formyl,
- Z 1 , Z 3 , Z 4 , and Z 5 are the same as defined in 1);
- Z 1 , Z 2 , Z 5 are the same as defined in 1), and can be hydrogen at the same time;
- R x1 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1 -C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, C3-C6 cycloalkyl;
- Z 1 , Z 2 , Z 5 are the same as defined in 1), and can be hydrogen at the same time;
- R x2 and R y are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1 -C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, C3-C6 cycloalkyl;
- Z 2 , Z 5 are the same as defined in 1), and can be hydrogen at the same time;
- R x3 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1-C6 alkane Oxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, C3-C6 cycloalkyl;
- Z 1 , Z 2 , Z 5 are the same as defined in 1), and can be hydrogen at the same time;
- R x4 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1 -C6 alkoxy, C1-C6 oxygen-containing alkyl, C1-C6 fluorine-containing alkyl, C1-C6 fluorine-containing alkoxy, C3-C6 cycloalkyl;
- R 1 is selected from:
- Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- Z 1 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- Z 1 , Z 2 , and Z 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkoxy;
- R x1 is selected from hydrogen, fluorine, chlorine, bromine, Iodine, nitro, cyano, C1-C6 alkyl;
- Z 1 , Z 2 , Z 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl;
- R x2 , R y are each independently selected from hydrogen, fluorine , Chloro, bromo, iodo, nitro, cyano, C1-C6 alkyl;
- Z 2 and Z 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl;
- R x3 is selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro , Cyano, C1-C6 alkyl;
- Z 1 , Z 2 , and Z 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl;
- R x4 is selected from hydrogen, fluorine, chlorine, bromine, and iodine , Nitro, cyano, C1-C6 alkyl;
- R 1 is selected from:
- Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- Z 1 , Z 2 , and Z 5 are each independently selected from hydrogen, methoxy, ethoxy, and isopropoxy, and one of Z 3 and Z 4 is selected from the following, and the other is selected from hydrogen, methyl base:
- N-methylpiperazine-1-formyl 4-hydroxypiperidinyl, N-methyl-4-piperidinyl, N-methylpiperazinyl, (N-methylpiperazine-1-)piper Ridinyl, 4-(tetrahydropyrrole-1-)piperidinyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl, 2-(N,N-dimethyl Amino)acetamido;
- Z 1 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- Z 1 and Z 5 are each independently selected from hydrogen and methoxy, and one of Z 3 and Z 4 is selected from the following, and the other is hydrogen:
- Z 1 , Z 2 , and Z 5 are each independently selected from hydrogen, fluorine, and methoxy; R x1 is methyl;
- Z 1 , Z 2 , and Z 5 are hydrogen; R x2 and R y are methyl;
- Z 2 and Z 5 are hydrogen; R x3 is isopropyl;
- Z 1 , Z 2 , and Z 5 are hydrogen; R x4 is hydrogen;
- R 2 is selected from hydrogen, methyl, isopropyl.
- W 1 , W 2 , W 3 , and W 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, and C1-C6 alkyl.
- W 1 , W 2 , W 3 , and W 5 are each independently selected from hydrogen and methyl.
- W 2 , W 3 , and W 5 are hydrogen, and W 1 is methyl.
- R is selected from:
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from:
- Y 2 , Y 3 , Y 4 , Y 5 are the same as defined in 2).
- R is selected from:
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from:
- Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from:
- R is selected from:
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from:
- Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from:
- the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt, wherein the inorganic acid salt is hydrochloride, hydrobromide, hydroiodide, nitrate, bicarbonate Salt and carbonate, sulfate or phosphate, the organic acid salt is formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartaric acid Salt, citrate, ascorbate, ⁇ -ketoglutarate, ⁇ -glycerol phosphate, alkyl sulfonate or aryl sulfonate; preferably, the alkyl sulfonate is methanesulfonic acid Salt or ethyl sulfonate; the aryl sulfonate is benzene sulfonate or p-toluene sulfonate.
- the inorganic acid salt is hydrochloride, hydrobromide, hydroiodide, nitrate, bi
- the present invention provides the following compounds:
- R 1 is selected from:
- Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- Carbamoyl methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, cyclopropylcarbamoyl, cyclobutylcarbamoyl, cyclopentylcarbamoyl, Cyclohexylcarbamoyl,
- Tetrahydropyrrole-1-formyl 3-(N,N-dimethylamino)tetrahydropyrrolyl-1-formyl, 3-(N,N-diethylamino)tetrahydropyrrolyl-1- Formyl,
- Piperidinyl-1-formyl 4-hydroxypiperidinyl-1-formyl, 4-(N,N-dimethylamino)piperidinyl-1-formyl, 4-(N,N-di Ethylamino)piperidinyl-1-formyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl-1-piperazinyl) Piperidinyl-1-formyl,
- Tetrahydropyrrole-1-sulfonyl 3-(N,N-dimethylamino)tetrahydropyrrolyl-1-sulfonyl, 3-(N,N-diethylamino)tetrahydropyrrolyl-1- Sulfonyl,
- Piperidinyl-1-sulfonyl 4-hydroxypiperidine-1-sulfonyl, 4-(N,N-dimethylamino)piperidinyl-1-sulfonyl, 4-(N,N-diethyl Amino)piperidinyl-1-sulfonyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-sulfonyl, 4-(N-ethyl-1-piperazinyl)piper Pyridyl-1-sulfonyl,
- Carbamoylamino methylcarbamoylamino, ethylcarbamoylamino, propylcarbamoylamino, isopropylcarbamoylamino, cyclopropylcarbamoylamino, cyclobutylcarbamoylamino, cyclic Pentylcarbamoylamino, piperidinyl-1-carboxamido, 4-hydroxypiperidinyl-1-carboxamido, 4-N,N-dimethylpiperidinyl-1-carboxamido, 4 -N,N-Diethylpiperidinyl-1-carboxamido, tetrahydropyrrolyl-1-carboxamido, 3-N,N-dimethyltetrahydropyrrolyl-1-carboxamido, 3 -N,N-Diethyltetrahydropyrrolyl-1-carboxamido, N-methyl
- Z3 and Z4 can form an oxygen-containing substituted or unsubstituted five-seven-membered ring; the substituent can be selected from the same substituents as described above for Z1,
- Z3 and Z4 can form a nitrogen-containing substituted or unsubstituted five-seven-membered ring; the substituents can be selected from the same substituents as described above for Z1;
- Z 2 , Z 3 , Z 4 , Z 5 are the same as defined in 1);
- Z 1 , Z 3 , Z 4 , and Z 5 are the same as defined in 1);
- Z 1 , Z 2 , Z 4 , and Z 5 are the same as defined in 1);
- Z 1 , Z 3 , and Z 5 are the same as defined in 1);
- R 2 is selected from:
- Hydrogen methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, cyclopropylamino, N,N-dimethylamino, methyl N,N-diethylamino, N,N-diisopropylamino;
- W 1 , W 2 , W 3 , and W 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing Alkyl group, C1-C6 fluorine-containing alkyl group, C1-C6 fluorine-containing alkoxy group, C3-C6 cycloalkyl group;
- R’ is selected from:
- R a and R b are each independently selected from:
- R a , R b and N form a substituted or unsubstituted 3-7 membered ring containing 1 to 2 heteroatoms, and the substituent is halogen, C1-C6 alkyl or C3-C6 cycloalkyl;
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from:
- R 1 is Z 1 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- R 1 is Z 1 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- R 1 is Z 1 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- R 2 is methyl
- W 1 , W 2 , W 3 , and W 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, and C1-C6 alkyl.
- W 1 , W 2 , W 3 , and W 5 are each independently selected from hydrogen and methyl.
- W 2 , W 3 , and W 5 are hydrogen, and W 1 is hydrogen or methyl.
- R' is selected from:
- R a and R b are each independently selected from:
- R a , R b and N form a substituted or unsubstituted piperazine ring, and the substituent is halogen, C1-C6 alkyl or C3-C6 cycloalkyl;
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from:
- R' is selected from:
- R a and R b are each independently selected from:
- R a , R b and N form a substituted or unsubstituted piperazine ring, and the substituent is a C1-C6 alkyl group;
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from:
- R' is selected from:
- R a and R b are each independently selected from hydrogen, methyl, ethyl, cyclopropyl,
- Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from:
- the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt, wherein the inorganic acid salt is hydrochloride, hydrobromide, hydroiodide, nitrate, bicarbonate Salt and carbonate, sulfate or phosphate, the organic acid salt is formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartaric acid Salt, citrate, ascorbate, ⁇ -ketoglutarate, ⁇ -glycerol phosphate, alkyl sulfonate or aryl sulfonate; preferably, the alkyl sulfonate is methanesulfonic acid Salt or ethyl sulfonate; the aryl sulfonate is benzene sulfonate or p-toluene sulfonate.
- the inorganic acid salt is hydrochloride, hydrobromide, hydroiodide, nitrate, bi
- the present invention provides the following compounds:
- R 1 is selected from:
- Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 2 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- Carbamoyl methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, cyclopropylcarbamoyl, cyclobutylcarbamoyl, cyclopentylcarbamoyl, Cyclohexylcarbamoyl,
- Tetrahydropyrrole-1-formyl 3-(N,N-dimethylamino)tetrahydropyrrolyl-1-formyl, 3-(N,N-diethylamino)tetrahydropyrrolyl-1- Formyl,
- Piperidinyl-1-formyl 4-hydroxypiperidinyl-1-formyl, 4-(N,N-dimethylamino)piperidinyl-1-formyl, 4-(N,N-di Ethylamino)piperidinyl-1-formyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-formyl, 4-(N-ethyl-1-piperazinyl) Piperidinyl-1-formyl,
- Tetrahydropyrrole-1-sulfonyl 3-(N,N-dimethylamino)tetrahydropyrrolyl-1-sulfonyl, 3-(N,N-diethylamino)tetrahydropyrrolyl-1- Sulfonyl,
- Piperidinyl-1-sulfonyl 4-hydroxypiperidine-1-sulfonyl, 4-(N,N-dimethylamino)piperidinyl-1-sulfonyl, 4-(N, N-diethyl Amino)piperidinyl-1-sulfonyl, 4-(N-methyl-1-piperazinyl)piperidinyl-1-sulfonyl, 4-(N-ethyl-1-piperazinyl)piper Pyridyl-1-sulfonyl,
- Carbamoylamino methylcarbamoylamino, ethylcarbamoylamino, propylcarbamoylamino, isopropylcarbamoylamino, cyclopropylcarbamoylamino, cyclobutylcarbamoylamino, cyclic Pentylcarbamoylamino, piperidinyl-1-carboxamido, 4-hydroxypiperidinyl-1-carboxamido, 4-N,N-dimethylpiperidinyl-1-carboxamido, 4 -N,N-Diethylpiperidinyl-1-carboxamido, tetrahydropyrrolyl-1-carboxamido, 3-N,N-dimethyltetrahydropyrrolyl-1-carboxamido, 3 -N,N-Diethyltetrahydropyrrolyl-1-carboxamido, N-methyl
- Z3 and Z4 can form an oxygen-containing substituted or unsubstituted five-seven-membered ring; the substituent can be selected from the same substituents as described above for Z1,
- Z3 and Z4 can form a nitrogen-containing substituted or unsubstituted five-seven-membered ring; the substituents can be selected from the same substituents as described above for Z1;
- Z 2 , Z 3 , Z 4 , Z 5 are the same as defined in 1);
- Z 1 , Z 3 , Z 4 , and Z 5 are the same as defined in 1);
- Z 1 , Z 2 , Z 4 , and Z 5 are the same as defined in 1);
- Z 1 , Z 3 , and Z 5 are the same as defined in 1);
- R 2 is selected from:
- Hydrogen methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy, methylamino, ethylamino, cyclopropylamino, N,N-dimethylamino, methyl N,N-diethylamino, N,N-diisopropylamino;
- W 1 , W 3 , W 4 , and W 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 oxygen-containing Alkyl group, C1-C6 fluorine-containing alkyl group, C1-C6 fluorine-containing alkoxy group, C3-C6 cycloalkyl group.
- R 1 is Z 1 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- R 1 is Z 1 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time:
- R 1 is Z 1 , Z 3 , Z 4 , and Z 5 are each independently selected from the following, and Z 1 , Z 3 , Z 4 , and Z 5 are not hydrogen at the same time: hydrogen, 4-N,N-dimethylaminopiperidinyl .
- R 2 is isopropyl
- W 1 , W 3 , W 4 , and W 5 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyano, and C1-C6 alkyl.
- W 1 , W 3 , W 4 , and W 5 are each independently selected from hydrogen and methyl.
- W 1 , W 3 , and W 4 are hydrogen, and W 5 is hydrogen or methyl.
- the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt, wherein the inorganic acid salt is hydrochloride, hydrobromide, hydroiodide, nitrate, bicarbonate Salt and carbonate, sulfate or phosphate, the organic acid salt is formate, acetate, propionate, benzoate, maleate, fumarate, succinate, tartaric acid Salt, citrate, ascorbate, ⁇ -ketoglutarate, ⁇ -glycerol phosphate, alkyl sulfonate or aryl sulfonate; preferably, the alkyl sulfonate is methanesulfonic acid Salt or ethyl sulfonate; the aryl sulfonate is benzene sulfonate or p-toluene sulfonate.
- the inorganic acid salt is hydrochloride, hydrobromide, hydroiodide, nitrate, bi
- C 1 -C 6 alkyl refers to any straight or branched chain group containing 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, Isobutyl, tert-butyl, sec-butyl, n-pentyl, tert-pentyl, n-hexyl, etc.
- C 1 -C 3 alkyl refers to any straight or branched chain group containing 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl and the like.
- oxyalkyl group refers to a group formed by the substitution of one or more alkoxy groups on the alkyl backbone, for example, methoxyethyl, methoxyethoxymethyl, etc. .
- a C1-C6 oxygen-containing alkyl group refers to a group formed by replacing the C1-C6 alkyl skeleton with one or more C1-C6 alkoxy groups, for example, methoxyethyl, methoxyethoxy Base methyl and so on.
- a C1-C3 oxygen-containing alkyl group refers to a group formed by replacing the C1-C3 alkyl skeleton with one or more C1-C6 alkoxy groups.
- C 3 -C 8 cycloalkyl refers to a hydrocarbon of a 3-8 membered monocyclic ring system with a saturated ring.
- C 3 -C 8 cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclo Hexyl etc.
- C 3 -C 6 cycloalkyl refers to a hydrocarbon of a 3-6 membered monocyclic ring system with a saturated ring.
- the C 3 -C 6 cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclo Hexyl etc.
- cyano refers to a -CN residue.
- nitro refers to the -NO 2 group.
- alkoxy refers to any of the above-mentioned alkyl groups (e.g., C 1 -C 6 alkyl, C 1 -C 3 alkyl, etc.), cycloalkyl (e.g. C 3- C 6 cycloalkyl), which is connected to the rest of the molecule through an oxygen atom (-O-).
- alkyl groups e.g., C 1 -C 6 alkyl, C 1 -C 3 alkyl, etc.
- cycloalkyl e.g. C 3- C 6 cycloalkyl
- heteroaryl refers to an aromatic heterocyclic ring, usually a 5-, 6-, 7-, 8-membered heterocyclic ring with 1 to 3 heteroatoms selected from N, O or S; heteroaromatic
- the base ring may optionally be further fused or connected to aromatic and non-aromatic carbocyclic and heterocyclic rings.
- heteroaryl group are, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl, thiazolyl, isothiazolyl, thiaoxazolyl, pyrrolyl, benzene Pyrrolyl, furanyl, phenyl-furyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, benzofuranyl, benzothienyl, benzol,3-dioxolane (Benzodioxocene), isoindolinyl, benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl, 1,2,3-triazolyl, 1-phenyl-1, 2,3-triazolyl, 2,3-indolinyl, 2,3-dihydrobenzofuranyl, 2,3-
- heterocyclyl also known as “heterocycloalkyl” refers to 3-, 4-, 5-, 6-, and 7-membered saturated or partially unsaturated carbocyclic rings with one or more carbon atoms Replaced by heteroatoms such as nitrogen, oxygen and sulfur.
- heterocyclic groups are, for example, pyran, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, thiazoline, thiazolidine, dihydrofuran, tetrahydrofuran, 1,3- Dioxolane, piperidine, piperazine, morpholine, morpholinyl, tetrahydropyrrolyl, thiomorpholinyl, etc.
- 6-membered heterocyclyl refers to a 6-membered saturated or partially unsaturated carbocyclic ring in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen, and sulfur.
- heteroatoms such as nitrogen, oxygen, and sulfur.
- 6-membered heterocyclic groups are, for example, pyran, piperidine, piperazine, morpholine, morpholinyl, thiomorpholinyl and the like.
- 5-membered heterocyclyl refers to a 5-membered saturated or partially unsaturated carbocyclic ring in which one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen, and sulfur.
- Non-limiting examples of 5-membered heterocyclic groups are, for example, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, thiazoline, thiazolidine, 1,3-dioxolane and the like.
- heterocyclic group means that the above-mentioned “heterocyclic group” is substituted by one or more of "C1-C6 alkyl", “C1-C3 alkyl”, “C3-C6 cycloalkyl", etc. replace.
- Fluorine-containing alkyl group refers to a group formed by replacing the alkyl skeleton with one or more fluorine groups, for example, monofluoromethyl, difluoroethyl, trifluoromethyl, and the like.
- C1-C6 fluorine-containing alkyl group refers to a group formed by replacing the C1-C6 alkyl skeleton with one or more fluorine groups, for example, monofluoromethyl, difluoroethyl, trifluoromethyl and the like.
- C1-C3 fluorinated alkyl group refers to a group in which the C1-C3 alkyl skeleton is substituted by one or more fluorine groups, for example, monofluoromethyl, difluoroethyl, trifluoromethyl Base etc.
- C1-C6 heteroatom-containing alkyl group refers to a group formed by replacing one or more carbon atoms in the C1-C6 alkyl skeleton with one or more heteroatoms, for example, Wait.
- C3-C8 heteroatom-containing cycloalkyl refers to a group formed by replacing one or more carbon atoms in the C3-C8 cycloalkyl skeleton with one or more heteroatoms, such as pyrrolidine, imidazolidine, Pyrazolidine, thiazolidine, piperidine, piperazine, morpholine, morpholinyl, thiomorpholinyl, etc.
- alkoxy refers to any of the above-mentioned alkyl groups (e.g., C 1 -C 6 alkyl, C 1 -C 3 alkyl, etc.), cycloalkyl (e.g. C 3- C 6 cycloalkyl), which is connected to the rest of the molecule through an oxygen atom (-O-).
- alkyl groups e.g., C 1 -C 6 alkyl, C 1 -C 3 alkyl, etc.
- cycloalkyl e.g. C 3- C 6 cycloalkyl
- the name is any group whose name is a compound name, such as "fluorine-containing oxygen-containing alkyl", which should refer to the part conventionally derived therefrom, such as from a fluoro group.
- a substituted oxygen-containing alkyl group is constructed, where the alkyl group is as defined above.
- fluorine-containing alkoxy groups shall refer to a moiety conventionally derived therefrom, such as constructed from an amino group substituted with an aryl group, where the aryl group is as defined above.
- heteroarylamino can be understood.
- the meaning of "hydroxysulfonyl", “aminosulfonyl” and the like can be understood.
- any terms such as alkylamino, dialkylamino, alkoxycarbonyl, alkoxycarbonylamino, heterocyclylcarbonyl, heterocyclylcarbonylamino, cycloalkyloxycarbonyl, alkoxyformyl, etc. include group, wherein the alkyl, alkoxy, aryl, C 3 -C 7 cycloalkyl and heterocyclyl portions are as defined above.
- each of the aforementioned substituents may be further substituted with one or more of the aforementioned groups.
- oxygen-containing substituted or unsubstituted five-seven-membered ring or "nitrogen-containing substituted or unsubstituted five-seven-membered ring” refers to a 5-, 6-, or 7-membered saturated or partially unsaturated carbon Rings in which one or more carbon atoms are replaced by oxygen or nitrogen.
- Non-limiting examples are, for example, pyran, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, dihydrofuran, tetrahydrofuran, 1,3-dioxolane, piperidine, piperazine , Morpholine, tetrahydropyrrolyl, hexamethyleneimine, etc.
- substituted or unsubstituted 3-7 membered ring containing 1 to 2 heteroatoms refers to a 3-, 4-, 5-, 6- or 7-membered saturated or partially unsaturated carbocyclic ring, one of which is Multiple carbon atoms are replaced by heteroatoms.
- Non-limiting examples are, for example, pyran, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, dihydrofuran, tetrahydrofuran, 1,3-dioxolane, piperidine, piperazine , Morpholine, tetrahydropyrrolyl, hexamethyleneimine, etc.
- the heteroatom is N, O or S.
- prodrug refers to a derivative that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide a compound of the present invention. Prodrugs only undergo this reaction under biological conditions to become active compounds, or they are active in their non-reactive form. Prodrugs can generally be prepared using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff, 5th edition).
- salts are organic acid addition salts formed by organic acids that form pharmaceutically acceptable anions, including but not limited to formates, acetates, propionates, benzoates, and maleates.
- Suitable inorganic salts can also be formed, including but not limited to hydrochloride, hydrobromide, hydroiodide, nitrate, bicarbonate and carbonate, sulfate or phosphate, and the like.
- compositions can be obtained using standard procedures well known in the art, for example, by reacting a sufficient amount of a basic compound with a suitable acid that provides a pharmaceutically acceptable anion.
- treatment generally refers to obtaining a desired pharmacological and/or physiological effect.
- the effect may be prophylactic in terms of completely or partially preventing the disease or its symptoms; and/or may be therapeutic in terms of partially or completely stabilizing or curing the disease and/or side effects due to the disease.
- Treatment covers any treatment of a patient's disease, including: (a) preventing diseases or symptoms in patients who are susceptible to diseases or symptoms but have not yet been diagnosed with the disease; (b) suppressing disease symptoms, That is to prevent its development; or (c) alleviate the symptoms of the disease, that is, cause the disease or symptoms to degenerate.
- the compound, its stereoisomer, its prodrug, or its pharmaceutically acceptable salt or pharmaceutically acceptable solvate, wherein the compound is the following example One of the compounds described in.
- the present invention provides a pharmaceutical composition, which comprises the compound described in any of the above technical solutions, its stereoisomer, its prodrug, or its pharmaceutically acceptable salt or pharmaceutically acceptable solvate.
- a pharmaceutical composition which comprises the compound described in any of the above technical solutions, its stereoisomer, its prodrug, or its pharmaceutically acceptable salt or pharmaceutically acceptable solvate.
- the pharmaceutical preparations of the present invention are manufactured by known methods, including conventional mixing, dissolving or freeze-drying methods.
- the compounds of the present invention can be formulated into pharmaceutical compositions and administered to patients in various routes suitable for the selected mode of administration, for example, oral or parenteral (by intravenous, intramuscular, topical or subcutaneous routes).
- the compound of the present invention combined with a pharmaceutically acceptable carrier can be administered systemically, for example, orally. They can be enclosed in hard or soft shell gelatin capsules and can be compressed into tablets.
- a pharmaceutically acceptable carrier such as an inert diluent or an assimilable edible carrier
- the active compound can be combined with one or more excipients and in the form of swallowable tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, discs, etc. use.
- Such compositions and preparations should contain at least 0.1% of active compound.
- the ratio of such compositions to preparations can of course vary and can comprise from about 1% to about 99% of the weight of a given unit dosage form.
- the amount of active compound is such that an effective dosage level can be obtained.
- Tablets, lozenges, pills, capsules, etc. may also contain: binders, such as tragacanth, acacia, corn starch or gelatin; excipients, such as dicalcium phosphate; disintegrating agents, such as corn starch, Potato starch, alginic acid, etc.; lubricants, such as magnesium stearate; and sweeteners, such as sucrose, fructose, lactose, or aspartame; or flavoring agents, such as peppermint, wintergreen oil or cherry flavor.
- binders such as tragacanth, acacia, corn starch or gelatin
- excipients such as dicalcium phosphate
- disintegrating agents such as corn starch, Potato starch, alginic acid, etc.
- lubricants such as magnesium stearate
- sweeteners such as sucrose, fructose, lactose, or aspartame
- flavoring agents such as peppermint, wintergreen oil or cherry flavor.
- any material used to prepare any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amount used.
- the active compound can be incorporated into sustained-release preparations and sustained-release devices.
- the active compound can also be administered intravenously or intraperitoneally by infusion or injection.
- An aqueous solution of the active compound or its salt can be prepared, optionally mixed with a non-toxic surfactant.
- Dispersants in glycerin, liquid polyethylene glycol, triacetin and mixtures thereof, and oils can also be prepared. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
- the pharmaceutical dosage form suitable for injection or infusion may include a sterile aqueous solution or dispersion containing the active ingredient (optionally encapsulated in liposomes) suitable for an immediate preparation of a sterile injectable or infusion solution or dispersion Agent or sterile powder.
- the final dosage form must be sterile, liquid and stable under the conditions of production and storage.
- the liquid carrier can be a solvent or liquid dispersion medium, including, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oil, non-toxic glyceride, and suitable mixtures thereof.
- the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersants, or by the use of surfactants.
- Various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.
- isotonic agents such as sugars, buffers, or sodium chloride.
- Prolonged absorption of the injectable composition can be produced by using compositions that delay absorption (e.g., aluminum monostearate and gelatin).
- Sterile injectable solutions are prepared by combining the required amount of the active compound in a suitable solvent with the various other ingredients enumerated above as required, and then performing filter sterilization.
- the preferred preparation methods are vacuum drying and freeze-drying techniques, which will produce a powder of the active ingredient plus any other required ingredients previously present in the sterile filtered solution .
- Useful solid carriers include pulverized solids (such as talc, clay, microcrystalline cellulose, silica, alumina, etc.).
- Useful liquid carriers include water, ethanol or ethylene glycol or water-ethanol/ethylene glycol mixtures, and the compound of the present invention can be dissolved or dispersed in an effective content optionally with the help of a non-toxic surfactant.
- Adjuvants such as fragrance
- additional antimicrobial agents can be added to optimize the properties for a given application.
- Thickeners (such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified cellulose or modified inorganic materials) can also be used with liquid carriers to form coatable pastes, gels, and ointments , Soap, etc., directly applied to the user's skin.
- the therapeutic requirement of the compound or its active salt or derivative depends not only on the specific salt selected, but also on the method of administration, the nature of the disease to be treated and the age and state of the patient, and ultimately depends on the physician or clinician present decision.
- the above formulations may be presented in a unit dosage form, which is a physically dispersed unit containing a unit dose, suitable for administration to humans and other mammals.
- the unit dosage form can be a capsule or tablet, or a number of capsules or tablets.
- the unit dose of the active ingredient can be varied or adjusted from about 0.1 to about 1000 mg or more.
- emulsion liposomes such as emulsion liposomes, microspheres and nanospheres
- particle dispersion systems including polymeric micelles, nanoemulsions, and submicroemuls.
- Drugs prepared from microcapsules, microspheres, liposomes and niosomes also called nonionic surfactant vesicles.
- the present invention also provides a method for preparing the compound described in any of the above technical solutions, which includes the following steps:
- R 1 , R 2 , and R 3 are detailed in the previous description.
- the metal palladium catalyst is selected from palladium acetate, tetrakis(triphenylphosphine)palladium, bistriphenylphosphorus palladium dichloride, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride , Three (dibenzylideneacetone) two palladium;
- the alkaline conditions refer to the conditions under which any of the following substances exist: triethylamine, diisopropylethylamine, pyridine, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, hydroxide Potassium, sodium hydride, potassium hydride;
- the acidic conditions refer to the conditions under which any of the following substances exist: acetic acid, trifluoroacetic acid, hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid, and camphorsulfonic acid.
- the present invention also provides a method for preparing the compound described in any of the above technical solutions, which includes the following steps:
- Reaction conditions (a) Metal palladium-catalyzed heteroaryl chloride or bromide and carbon-carbon bond of boric acid or boric acid ester to form a coupling reaction; (b) Metal palladium-catalyzed heteroaryl chloride and amine compound The coupling reaction of carbon-nitrogen bond formation, or the nucleophilic substitution reaction of amine compounds to heteroaryl chlorides under acidic conditions, or the nucleophilic substitution reaction of amine compounds to heteroaryl chlorides under alkaline conditions; (c ) The nucleophilic substitution reaction of amine compounds to heteroaryl chlorides under acidic conditions, or the nucleophilic substitution reaction of amine compounds to heteroaryl chlorides under alkaline conditions;
- heteroaryl chloride or bromide includes the following types:
- the boric acid or boric acid ester is selected from substituted or unsubstituted phenylboronic acid or boric acid esters and their derivatives;
- the amine compound is selected from substituted or unsubstituted five-membered or six-membered heterocyclic amines, anilines and Its derivatives, C1-C6 alkyl amines, C3-C7 cycloalkyl amines, C1-C6 oxygen-containing alkyl amines, C3-C7 oxygen-containing cycloalkyl amines, please refer to the previous description for details;
- the metal palladium catalyst is selected from palladium acetate, tetrakis(triphenylphosphine)palladium, bistriphenylphosphorus palladium dichloride, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride , Tris(dibenzylideneacetone)dipalladium;
- the basic conditions refer to the presence of any of the following substances: triethylamine, diisopropylethylamine, pyridine, sodium bicarbonate, sodium carbonate, potassium carbonate, Cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride;
- the acidic conditions refer to the presence of any of the following substances: acetic acid, trifluoroacetic acid, hydrochloric acid, methanesulfonic acid, p-toluenesulfonic acid , Camphor sulfonic acid.
- the present invention provides a pharmaceutical composition, which comprises the compound described in any of the above technical solutions, its stereoisomer, its prodrug, or its pharmaceutically acceptable salt or pharmaceutically acceptable solvate.
- a pharmaceutical composition which comprises the compound described in any of the above technical solutions, its stereoisomer, its prodrug, or its pharmaceutically acceptable salt or pharmaceutically acceptable solvate.
- the present invention also provides the compound, its stereoisomer, its prodrug, or its pharmaceutically acceptable salt or pharmaceutically acceptable solvate as described in any of the above technical solutions, and a compound containing the compound
- the pharmaceutical composition is used in the preparation of drugs for the prevention and/or treatment of BRK, BTK kinase or both of the cancer and other diseases, especially in the preparation of drugs for the prevention and/or treatment of breast cancer and B cell malignancies Use in medicines.
- the present invention provides a method for preventing and/or treating BRK, BTK kinase or both of cancer and other diseases, which includes administering a preventive and/or therapeutically effective amount of any of the above techniques to a subject in need
- a preventive and/or therapeutically effective amount of any of the above techniques to a subject in need
- the compound described in the scheme or its stereoisomer, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate, or the above-mentioned pharmaceutical composition is administered to a subject in need.
- the method is used to prevent and/or treat breast cancer and B cell malignancies.
- the present invention provides the compound or its stereoisomer, its prodrug, its pharmaceutically acceptable salt or its pharmaceutically acceptable solvate according to any of the above technical solutions, or the above pharmaceutical composition It is used to prevent and/or treat diseases mediated by BRK, BTK kinase or both in organisms, especially for the prevention and/or treatment of breast cancer and B-cell malignancies.
- vertebrates refer to mammals. Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice, and rats. In certain embodiments, the mammal refers to a human.
- an amount refers to an amount effective to achieve the desired therapeutic or preventive effect at the necessary dose and time.
- the "therapeutically effective amount” of the substance/molecule of the present invention may vary according to factors such as the individual's disease state, age, sex, and weight, and the ability of the substance/molecule to elicit a desired response in the individual.
- a therapeutically effective amount also encompasses an amount in which the therapeutically beneficial effects of the substance/molecule outweigh any toxic or harmful consequences.
- “Prophylactically effective amount” refers to an amount effective to achieve the desired preventive effect at the necessary dose and time.
- the preventive effective dose will be lower than the therapeutically effective dose.
- the therapeutically effective dose of the drug can reduce the number of cancer cells; reduce the tumor volume; inhibit (ie slow down, preferably stop) the infiltration of cancer cells into the surrounding organs; inhibit (ie slow down, preferably stop) ) Tumor metastasis; inhibit tumor growth to a certain extent; and/or reduce one or more symptoms related to cancer to a certain extent.
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Abstract
Description
Claims (10)
- 以下通式化合物:或所述化合物的立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物,其中:R 1选自:1)氢,C1-C6烷基,C1-C6含氟烷基,C3-C8环烷基,C1-C6含杂原子烷基,C3-C8含杂原子环烷基;2)2-N,N-二甲基氨基乙基,2-(N-甲基哌嗪基)乙基,2-(N-乙酰基哌嗪基)乙基,2-吗啡啉基乙基,2-硫啡啉基乙基,2-哌啶基乙基,2-羟基乙基,2-甲氧基乙基,3-N,N-二甲基氨基丙基,N-甲基-4-哌啶基,N-乙基-4-哌啶基,N-丙基-4-哌啶基,N-异丙基-4-哌啶基,N-羟乙基-4-哌啶基,N-氰甲基-4-哌啶基,N-(2-氰基乙基)-4-哌啶基,N-乙酰基-4-哌啶基,N-丙酰基-4-哌啶基,N-异丙酰基-4-哌啶基,N-环丙基甲酰基-4-哌啶基,N-甲基磺酰基-4-哌啶基,N-乙基磺酰基-4-哌啶基,N-丙基磺酰基-4-哌啶基,N-异丙基磺酰基-4-哌啶基,N-环丙基磺酰基-4-哌啶基,3-N,N-二甲基氨基环戊基,3-N,N-二乙基基氨基环戊基,3-N,N-二丙基氨基环戊基,3-N,N-异丙基氨基环戊基,4-氨基环己基,4-N,N-二甲基氨基环己基,4-N,N-二乙基氨基环己基,4-N,N-二丙基氨基环己基,4-N,N-二异丙基氨基环己基,4-乙酰氨基环己基,4-丙酰氨基环己基,4-异丙基甲酰氨基环己基,4-甲基磺酰氨基环己基,4-乙基磺酰氨基环己基,4-丙基磺酰氨基环己基,4-异丙基磺酰氨基环己基,4-环丙基磺酰氨基环己基,4-羟基环己基,4-甲氧基环己基,4-乙氧基环己基,4-异丙氧基环己基;3)1-甲基-3-吡咯基,1-乙基-3-吡咯基,1-异丙基-3-吡咯基,1-环丙基-3-吡咯基,1-甲基-3-吡唑基,1-乙基-3-吡唑基,1-异丙基-3-吡唑基,1-环丙基-3-吡唑基,1-羟乙基-3-吡唑基,1-甲基-4-吡唑基,1-乙基-4-吡唑基,1-异丙基-4-吡唑基,1-环丙基-4-吡唑基,1-羟乙基-4-吡唑基,1-(N-甲基-4-哌啶基)-4-吡唑基,1-(N-叔丁氧羰基-4-哌啶基)-4-吡唑基,1,3-二甲基-5-吡唑基,1-甲基-4-咪唑基,3-甲基-5-异噁唑基;(1)氢,氟,氯,溴,碘,硝基,氰基,(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6环烷基,(3)2-N,N-二甲基氨基乙氧基,3-N,N-二甲基氨基丙氧基,2-(N-甲基哌嗪基)乙氧基,2-(N-乙酰基哌嗪基)乙氧基,2-吗啡啉基乙氧基,2-硫啡啉基乙氧基,2-哌啶基乙氧基,3-N,N-二甲基氨基丙氧基,3-N,N-二乙基氨基丙氧基,3-N,N-二异丙基氨基丙氧基,3-(N-甲基哌嗪基)丙氧基,3-(N-乙酰基哌嗪基)丙氧基,3-吗啉基丙氧基,3-硫啡啉基丙氧基,3-哌啶基丙氧基,2-吡啶基甲氧基,3-吡啶基甲氧基,4-吡啶基甲氧基,苯基甲氧基,单卤素取代苯基甲氧基,偕二卤素取代苯基甲氧基,杂二卤素取代苯基甲氧基,(4)哌嗪基,N-甲基哌嗪基,N-乙基哌嗪基,N-正丙基哌嗪基,N-异丙基哌嗪基, N-环丙基哌嗪基,N-(2-羟基乙基)哌嗪基,N-(2-N,N-二甲基氨基乙基)哌嗪基,N-(2-N,N-二乙基氨基乙基)哌嗪基,N-(2-氰基乙基)哌嗪基,N-氰甲基哌嗪基,N-(3-羟基丙基)哌嗪基,N-(3-N,N-二甲基氨基丙基)哌嗪基,N-(3-N,N-二乙基氨基丙基)哌嗪基,N-(N-甲基-4-哌啶基)哌嗪基,N-(N-乙基-4-哌啶基)哌嗪基,N-叔丁氧羰基哌嗪基,N-乙酰基哌嗪基,N-丙酰基哌嗪基,N-异丁酰基哌嗪基,N-环丙基甲酰基哌嗪基,N-甲磺酰基哌嗪基,N-乙基磺酰基哌嗪基,N-正丙基磺酰基哌嗪基,N-异丙基磺酰基哌嗪基,N-环丙基磺酰基哌嗪基,2-氧代-哌嗪-4-基,(5)吗啡啉基,2,6-二甲基吗啡啉基,硫啡啉基,(6)四氢吡咯基,3-(N,N-二甲基氨基)四氢吡咯基,3-(N,N-二乙基氨基)四氢吡咯基,(7)咪唑基,4-甲基-1-咪唑基,(8)哌啶基,4-N,N-二甲基氨基哌啶基,4-N,N-二乙基氨基哌啶基,4-N,N-二异丙基氨基哌啶基,4-羟基哌啶基,4-甲氧基哌啶基,4-乙氧基哌啶基,4-(N-甲基哌嗪-1-)哌啶基,4-(N-乙基哌嗪-1-)哌啶基,4-(N-异丙基哌嗪-1-)哌啶基,4-(N-乙酰基哌嗪-1-)哌啶基,4-(N-叔丁氧羰基哌嗪-1-)哌啶基,4-(N-甲磺酰基哌嗪-1-)哌啶基,4-(N-(2-羟基乙基)哌嗪-1-)哌啶基,4-(N-(2-氰基乙基)哌嗪-1-)哌啶基,4-(N-(3-羟基丙基)哌嗪-1-)哌啶基,4-(N-(2-N,N-二甲基氨基乙基)哌嗪-1-)哌啶基,4-(N-(2-N,N-二乙基乙基)哌嗪-1-)哌啶基,4-(N-(3-N,N-二甲基丙基)哌嗪-1-)哌啶基,4-(N-(3-N,N-二乙基丙基)哌嗪-1-)哌啶基,4-(四氢吡咯-1-)哌啶基,4-(3-N,N-二甲基氨基四氢吡咯-1-)哌啶基,4-(3-N,N-二乙基氨基四氢吡咯-1-)哌啶基,(9)哌啶-4-基,N-甲基-4-哌啶基,N-乙基-4-哌啶基,N-异丙基-4-哌啶基,N-乙酰基-4-哌啶基,N-叔丁氧羰基-4-哌啶基,N-甲磺酰基-4-哌啶基,N-(2-羟基乙基)-4-哌啶基,N-(2-N,N-二甲基氨基乙基)-4-哌啶基,N-(2-N,N-二乙基氨基乙基)-4-哌啶基,N-(2-氰基乙基)-4-哌啶基,N-(3-羟基丙基)-4-哌啶基,N-(3-N,N-二甲基氨基丙基)-4-哌啶基,N-(3-N,N-二乙基氨基丙基)-4-哌啶基,N-(3-氰基丙基)-4-哌啶基,N-氰基亚甲基-4-哌啶基,(10)氨基,N,N-二甲基氨基,N,N-二乙基氨基,N,N-二正丙基氨基,N,N-二异丙基氨基,2-N,N-二甲基氨基乙基氨基,2-吗啡啉基乙基氨基,2-(N-甲基哌嗪基)乙基氨基,3-N,N-二甲基氨基丙基氨基,3-N,N-二乙基氨基丙基氨基,3-N,N-二异丙基氨基丙基氨基,3-吗啉基丙基氨基,3-(N-甲基哌嗪基)丙基氨基,N-甲基哌啶-4-氨基,N-乙基哌啶-4-氨基,N-正丙基哌啶-4-氨基,N-异丙基哌啶-4-氨基,乙酰胺基,丙酰胺基,2-(N,N-二甲基氨基)乙酰胺基,2-羟基乙酰胺基,2-甲氧基乙酰胺基,甲磺酰胺基,乙磺酰胺基,正丙基磺酰胺基,异丙基磺酰胺基,环丙基磺酰胺基,N-甲基-N-(N-甲基-3-四氢吡咯基)氨基,N-(N-甲基-3-四氢吡咯基)氨基,N-甲基-N-(2-N,N-二甲基氨基)乙基氨基,(11)氨基亚甲基,N,N-二甲基氨基亚甲基,N,N-二乙基氨基亚甲基,4-甲基-1-哌嗪亚甲基,4-乙基-1-哌嗪亚甲基,4-丙基-1-哌嗪亚甲基,4-异丙基-1-哌嗪亚甲基,4-(2-羟基乙基)-1-哌嗪亚甲基,4-(2-N,N-二甲基氨基乙基)-1-哌嗪亚甲基,哌啶-1-亚甲基,4-(N,N-二甲基氨基)-1-哌啶亚甲基,4-羟基哌啶-1-亚甲基,四氢吡咯-1-亚甲基,3-(N,N-二甲基氨基)-1-四氢吡咯亚甲基,(12)氨基甲酰基,甲胺基甲酰基,二甲胺基甲酰基,乙胺基甲酰基,环丙基胺基甲酰基,环丁基胺基甲酰基,环戊基胺基甲酰基,环己基胺基甲酰基,四氢吡咯-1-甲酰基,3-(N,N-二甲基氨基)四氢吡咯基-1-甲酰基,3-(N,N-二乙基氨基)四氢吡咯基-1-甲酰基,吗啡啉基-4-甲酰基,硫啡啉基-4-甲酰基,2,6-二甲基吗啡啉基-4-甲酰基,哌啶基-1-甲酰基,4-羟基哌啶基-1-甲酰基,4-(N,N-二甲基氨基)哌啶基-1-甲酰基,4-(N,N-二乙基氨基)哌啶基-1-甲酰基,4-(N-甲基-1-哌嗪基)哌啶基-1-甲酰基,4-(N-乙基-1-哌嗪基)哌啶基-1-甲酰基,N-甲基哌嗪-1-甲酰基,N-乙基哌嗪-1-甲酰基,N-异丙基哌嗪-1-甲酰基,N-(2-羟基乙基)哌嗪-1-甲酰基,N-(2-N,N-二甲基氨基乙基)哌嗪-1-甲酰基,N-(2-N,N-二乙基氨基乙基) 哌嗪-1-甲酰基,4-(N-甲基-4-哌啶基)哌嗪-1-甲酰基,4-(N-乙基-4-哌啶基)哌嗪-1-甲酰基,(13)羟基甲酰基,甲氧基甲酰基,乙氧基甲酰基,丙氧基甲酰基,异丙氧基甲酰基,正丁氧基甲酰基,异丁氧基甲酰基,叔丁氧基甲酰基,(14)羟基磺酰基,氨基磺酰基,甲胺基磺酰基,乙胺基磺酰基,丙胺基磺酰基,异丙胺基磺酰基,环丙胺基磺酰基,环丁基基磺酰基,环戊胺基磺酰基,环己胺基磺酰基,四氢吡咯-1-磺酰基,3-(N,N-二甲基氨基)四氢吡咯基-1-磺酰基,3-(N,N-二乙基氨基)四氢吡咯基-1-磺酰基,吗啡啉基-4-磺酰基,硫啡啉基-4-磺酰基,2 6-二甲基吗啡啉基-4-磺酰基,哌啶基-1-磺酰基,4-羟基哌啶-1-磺酰基,4-(N,N-二甲基氨基)哌啶基-1-磺酰基,4-(N,N-二乙基氨基)哌啶基-1-磺酰基,4-(N-甲基-1-哌嗪基)哌啶基-1-磺酰基,4-(N-乙基-1-哌嗪基)哌啶基-1-磺酰基,N-甲基哌嗪-1-磺酰基,N-乙基哌嗪-1-磺酰基,N-异丙基哌嗪-1-磺酰基,N-(2-羟基乙基)哌嗪-1-磺酰基,N-(2-N,N-二甲基氨基乙基)哌嗪-1-磺酰基,N-(2-N,N-二乙基氨基乙基)哌嗪-1-磺酰基,4-(N-甲基-4-哌啶基)哌嗪-1-磺酰基,4-(N-乙基-4-哌啶基)哌嗪-1-磺酰基,(15)氨基甲酰氨基,甲氨基甲酰氨基,乙氨基甲酰氨基,丙氨基甲酰氨基,异丙氨基甲酰氨基,环丙基氨基甲酰氨基,环丁基氨基甲酰氨基,环戊基氨基甲酰氨基,哌啶基-1-甲酰氨基,4-羟基哌啶基-1-甲酰氨基,4-N,N-二甲基哌啶基-1-甲酰氨基,4-N,N-二乙基哌啶基-1-甲酰氨基,四氢吡咯基-1-甲酰氨基,3-N,N-二甲基四氢吡咯基-1-甲酰氨基,3-N,N-二乙基四氢吡咯基-1-甲酰氨基,N-甲基哌嗪基-1-甲酰氨基,N-乙基哌嗪基-1-甲酰氨基,N-乙酰基哌嗪基-1-甲酰氨基,N-叔丁氧羰基哌嗪基-1-甲酰氨基,N-(2-羟基乙基)哌嗪基-1-甲酰氨基,N-(2-氰基乙基)哌嗪基-1-甲酰氨基,N-(2-N,N-二甲基氨基乙基)哌嗪基-1-甲酰氨基,N-(2-N,N-二乙基氨基乙基)哌嗪基-1-甲酰氨基,N-(3-羟基丙基)哌嗪基-1-甲酰氨基,N-(3-N,N-二甲基丙基)哌嗪基-1-甲酰氨基,N-(3-N,N-二乙基丙基)哌嗪基-1-甲酰氨基,吗啉基-1-甲酰氨基,3,5-二甲基吗啉基-1-甲酰氨基,4-(四氢吡咯基)哌啶基-1-甲酰氨基,4-(N-甲基-1-哌嗪基)哌啶基-1-甲酰氨基,4-(N-乙基-1-哌嗪基)哌啶基-1-甲酰氨基,4-(N-乙酰基-1-哌嗪基)哌啶基-1-甲酰氨基,N-(N-甲基-4-哌啶基)哌嗪基-1-甲酰氨基,(16)Z3与Z4可以形成含氧的取代或未取代的五-七元环;取代基可以选自与Z1相同的上述取代基,(17)Z3与Z4可以形成含氮的取代或未取代的五-七元环;取代基可以选自与Z1相同的上述取代基;R 2选自:氢,甲基,乙基,异丙基,环丙基,甲氧基,乙氧基,异丙氧基,甲氨基,乙氨基,环丙基氨基,N,N-二甲基氨基,甲基乙基氨基,N,N-二乙基氨基,N,N-二异丙基氨基;R 3选自:其中,W 1,W 2,W 3,W 4,W 5各自独立地选自以下,且不同时为氢:(1)氢,(2)氟,氯,溴,碘,硝基,氰基,(3)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6环烷基,氢,C1-C6烷基,C3-C6环烷基,或者R a,R b及N形成取代或未取代的含1~2个杂原子的3-7元环,所述取代基为卤素,C1-C6烷基或C3-C6环烷基;(6)羟基甲酰基,C1-C6烷氧基甲酰基;Y 1,Y 2,Y 3,Y 4,Y 5各自独立地选自:(a)氢,氟,氯,溴,碘,硝基,氰基,(b)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6环烷基,C1-C6酰基,(c)氨基亚甲基,N,N-二甲基氨基亚甲基,N,N-二乙基氨基亚甲基,N-甲基-1-哌嗪亚甲基,N-乙基-1-哌嗪亚甲基,N-丙基-1-哌嗪亚甲基,N-异丙基-1-哌嗪亚甲基,N-环丙基-1-哌嗪亚甲基,N-(2-羟基乙基)-1-哌嗪亚甲基,N-(2-N,N-二甲基氨基乙基)-1-哌嗪亚甲基,N-(2-氰基乙基)-1-哌嗪亚甲基,哌啶-1-亚甲基,4-氨基哌啶-1-亚甲基,4-(N,N-二甲基 氨基)-1-哌啶亚甲基,4-(N,N-二乙基氨基)-1-哌啶亚甲基,4-(N,N-二丙基氨基)-1-哌啶亚甲基,4-(N,N-二异丙基氨基)-1-哌啶亚甲基,4-羟基哌啶-1-亚甲基,4-甲氧基哌啶-1-亚甲基,4-乙氧基哌啶-1-亚甲基,4-丙氧基哌啶-1-亚甲基,4-异丙氧基哌啶-1-亚甲基,吗啡啉-4-亚甲基,硫啡啉基-4-亚甲基,2,6-二甲基吗啡啉基-4-亚甲基,四氢吡咯-1-亚甲基,3-氨基-1-四氢吡咯亚甲基,3-(N,N-二甲基氨基)-1-四氢吡咯亚甲基,3-(N,N-二乙基氨基)-1-四氢吡咯亚甲基,3-(N,N-二丙基氨基)-1-四氢吡咯亚甲基,3-(N,N-二异丙基氨基)-1-四氢吡咯亚甲基,氮杂环丁烷-1-亚甲基,(d)咪唑基,4-甲基咪唑基,吡咯基,吡唑基,3-甲基吡唑基,4-甲基吡唑基,3-甲基-5-异噁唑基,优选地,R 3选自:其中,W 1,W 4各自独立地选自以下,且不同时为氢:(1)氢,(2)氟,氯,溴,碘,硝基,氰基,(3)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6环烷基,氢,C1-C6烷基,或者R a,R b及N形成取代或未取代的含1~2个杂原子的3-7元环,所述取代基为卤素,C1-C6烷基或C3-C6环烷基,(6)羟基甲酰基,C1-C6烷氧基甲酰基,Y 1,Y 2,Y 3,Y 4,Y 5各自独立地选自:(a)氢,氟,氯,溴,碘,硝基,氰基,(b)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6环烷基,C1-C6酰基,(c)氨基亚甲基,N,N-二甲基氨基亚甲基,N,N-二乙基氨基亚甲基,N-甲基-1-哌嗪亚甲基,N-乙基-1-哌嗪亚甲基,N-丙基-1-哌嗪亚甲基,N-异丙基-1-哌嗪亚甲基,N-环丙基-1-哌嗪亚甲基,N-(2-羟基乙基)-1-哌嗪亚甲基,N-(2-N,N-二甲基氨基乙基)-1-哌嗪亚甲基,N-(2-氰基乙基)-1-哌嗪亚甲基,哌啶-1-亚甲基,4-氨基哌啶-1-亚甲基,4-(N,N-二甲基氨基)-1-哌啶亚甲基,4-(N,N-二乙基氨基)-1-哌啶亚甲基,4-(N,N-二丙基氨基)-1-哌啶亚甲基,4-(N,N-二异丙基氨基)-1-哌啶亚甲基,4-羟基哌啶-1-亚甲基,4-甲氧基哌啶-1-亚甲基,4-乙氧基哌啶-1-亚甲基,4-丙氧基哌啶-1-亚甲基,4-异丙氧基哌啶-1-亚甲基,吗啡啉-4-亚甲基,硫啡啉基-4-亚甲基,2,6-二甲基吗啡啉基-4-亚甲基,四氢吡咯-1-亚甲基,3-氨基-1-四氢吡咯亚甲基,3-(N,N-二甲基氨基)-1-四氢吡咯亚甲基,3-(N,N-二乙基氨基)-1-四氢吡咯亚甲基,3-(N,N-二丙基氨基)-1-四氢吡咯亚甲基,3-(N,N-二异丙基氨基)-1-四氢吡咯亚甲基,氮杂环丁烷-1-亚甲基,(d)咪唑基,4-甲基咪唑基,吡咯基,吡唑基,3-甲基吡唑基,4-甲基吡唑基,3-甲基-5-异噁唑基,更优选地,R 3选自:其中,W 1,W 4各自独立地选自以下,且不同时为氢:(1)氢,(2)氟,氯,溴,碘,硝基,氰基,(3)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6环烷基,氢,C1-C6烷基,或者R a,R b及N形成取代或未取代的含1~2个杂原子的3-7元环,所述取代基为卤素,C1-C6烷基或C3-C6环烷基;(6)羟基甲酰基,C1-C6烷氧基甲酰基;Y 1,Y 2,Y 3,Y 4,Y 5各自独立地选自:(a)氢,氟,氯,溴,碘,硝基,氰基,(b)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6环烷基,C1-C6酰基,(c)氨基亚甲基,N,N-二甲基氨基亚甲基,N,N-二乙基氨基亚甲基,N-甲基-1-哌嗪亚甲基,N-乙基-1-哌嗪亚甲基,N-丙基-1-哌嗪亚甲基,N-异丙基-1-哌嗪亚甲基,N-环丙基-1-哌嗪亚甲基,N-(2-羟基乙基)-1-哌嗪亚甲基,N-(2-N,N-二甲基氨基乙基)-1-哌嗪亚甲基,N-(2-氰基乙基)-1-哌嗪亚甲基,哌啶-1-亚甲基,4-氨基哌啶-1-亚甲基,4-(N,N-二甲基氨基)-1-哌啶亚甲基,4-(N,N-二乙基氨基)-1-哌啶亚甲基,4-(N,N-二丙基氨基)-1-哌啶亚甲基,4-(N,N-二异丙基氨基)-1-哌啶亚甲基,4-羟基哌啶-1-亚甲基,4-甲氧基哌啶-1-亚甲基,4-乙氧基哌啶-1-亚甲基,4-丙氧基哌啶-1-亚甲基,4-异丙氧基哌啶-1-亚甲基,吗啡啉-4-亚甲基,硫啡啉基-4-亚甲基,2,6-二甲基吗啡啉基-4-亚甲基,四氢吡咯-1-亚甲基,3-氨基-1-四氢吡咯亚甲基,3-(N,N-二甲基氨基)-1-四氢吡咯亚甲基,3-(N,N-二乙基氨基)-1-四氢吡咯亚甲基,3-(N,N-二丙基氨基)-1-四氢吡咯亚甲基,3-(N,N-二异丙基氨基)-1-四氢吡咯亚甲基,氮杂环丁烷-1-亚甲基,(d)咪唑基,4-甲基咪唑基,吡咯基,吡唑基,3-甲基吡唑基,4-甲基吡唑基,3-甲基-5-异噁唑基,最优选地,R 3选自:其中,W 1选自氢,氟,氯,溴,碘,硝基,氰基,C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,W 4选自:(1)氟,氯,溴,碘,硝基,氰基,(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,氢,C1-C6烷基,或者R a,R b及N形成取代或未取代的含1~2个杂原子的3-7元环,所述取代基为卤素,C1-C6烷基或C3-C6环烷基;(5)羟基甲酰基,C1-C6烷氧基甲酰基;Y 1,Y 2,Y 3,Y 4,Y 5各自独立地选自:(a)氢,氟,氯,溴,碘,硝基,氰基,(b)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6环烷基,C1-C6酰基,(c)氨基亚甲基,N,N-二甲基氨基亚甲基,N,N-二乙基氨基亚甲基,N-甲基-1-哌嗪亚甲基,N-乙基-1-哌嗪亚甲基,N-丙基-1-哌嗪亚甲基,N-异丙基-1-哌嗪亚甲基,N-环丙基-1-哌嗪亚甲基,N-(2-羟基乙基)-1-哌嗪亚甲基,N-(2-N,N-二甲基氨基乙基)-1-哌嗪亚甲基,N-(2-氰基乙基)-1-哌嗪亚甲基,哌啶-1-亚甲基,4-氨基哌啶-1-亚甲基,4-(N,N-二甲基氨基)-1-哌啶亚甲基,4-(N,N-二乙基氨基)-1-哌啶亚甲基,4-(N,N-二丙基氨基)-1-哌啶亚甲基,4-(N,N-二异丙基氨基)-1-哌啶亚甲基,4-羟基哌啶-1-亚甲基,4-甲氧基哌啶-1-亚甲基,4-乙氧基哌啶-1-亚甲基,4-丙氧基哌啶-1-亚甲基,4-异丙氧基哌啶-1-亚甲基,吗啡啉-4-亚甲基,硫啡啉基-4-亚甲基,2,6-二甲基吗啡啉基-4-亚甲基,四氢吡咯-1-亚甲基,3-氨基-1-四氢吡咯亚甲基,3-(N,N-二甲基氨基)-1-四氢吡咯亚甲基,3-(N,N-二乙基氨基)-1-四氢吡咯亚甲基,3-(N,N-二丙基氨基)-1-四氢吡咯亚甲基,3-(N,N-二异丙基氨基)-1-四氢吡咯亚甲基,氮杂环丁烷-1-亚甲基,(d)咪唑基,4-甲基咪唑基,吡咯基,吡唑基,3-甲基吡唑基,4-甲基吡唑基,3-甲基-5-异噁唑基,
- 根据权利要求1的化合物,其为以下:或所述化合物的立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物,其中:R 1选自:(1)氢,氟,氯,溴,碘,硝基,氰基,(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6环烷基,(3)2-N,N-二甲基氨基乙氧基,3-N,N-二甲基氨基丙氧基,2-(N-甲基哌嗪基)乙氧基,2-(N-乙酰基哌嗪基)乙氧基,2-吗啡啉基乙氧基,2-硫啡啉基乙氧基,2-哌啶基乙氧基,3-N,N-二甲基氨基丙氧基,3-N,N-二乙基氨基丙氧基,3-N,N-二异丙基氨基丙氧基,3-(N-甲基哌嗪基)丙氧基,3-(N-乙酰基哌嗪基)丙氧基,3-吗啉基丙氧基,3-硫啡啉基丙氧基,3-哌啶基丙氧基,2-吡啶基甲氧基,3-吡啶基甲氧基,4-吡啶基甲氧基,苯基甲氧基,单卤素取代苯基甲氧基,偕二卤素取代苯基甲氧基,杂二卤素取代苯基甲氧基,(4)哌嗪基,N-甲基哌嗪基,N-乙基哌嗪基,N-正丙基哌嗪基,N-异丙基哌嗪基,N-环丙基哌嗪基,N-(2-羟基乙基)哌嗪基,N-(2-N,N-二甲基氨基乙基)哌嗪基,N-(2-N,N-二乙基氨基乙基)哌嗪基,N-(2-氰基乙基)哌嗪基,N-氰甲基哌嗪基,N-(3-羟基丙基)哌嗪基,N-(3-N,N-二甲基氨基丙基)哌嗪基,N-(3-N,N-二乙基氨基丙基)哌嗪基,N-(N-甲基-4-哌啶基)哌嗪基,N-(N-乙基-4-哌啶基)哌嗪基,N-叔丁氧羰基哌嗪基,N-乙酰基哌嗪基,N-丙酰基哌嗪基,N-异丁酰基哌嗪基,N-环丙基甲酰基哌嗪基,N-甲磺酰基哌嗪基,N-乙基磺酰基哌嗪基,N-正丙基磺酰基哌嗪基,N-异丙基磺酰基哌嗪基,N-环丙基磺酰基哌嗪基,2-氧代-哌嗪-4-基,(5)吗啡啉基,2,6-二甲基吗啡啉基,硫啡啉基,(6)四氢吡咯基,3-(N,N-二甲基氨基)四氢吡咯基,3-(N,N-二乙基氨基)四氢吡咯基,(7)咪唑基,4-甲基-1-咪唑基,(8)哌啶基,4-N,N-二甲基氨基哌啶基,4-N,N-二乙基氨基哌啶基,4-N,N-二异丙基氨基哌啶基,4-羟基哌啶基,4-甲氧基哌啶基,4-乙氧基哌啶基,4-(N-甲基哌嗪-1-)哌啶基,4-(N-乙基哌嗪-1-)哌啶基,4-(N-异丙基哌嗪-1-)哌啶基,4-(N-乙酰基哌嗪-1-)哌啶基,4-(N-叔丁氧羰基哌嗪-1-)哌啶基,4-(N-甲磺酰基哌嗪-1-)哌啶基,4-(N-(2-羟基乙基)哌嗪-1-)哌啶基,4-(N-(2-氰基乙基)哌嗪-1-)哌啶基,4-(N-(3-羟基丙基)哌嗪-1-)哌啶基,4-(N-(2-N,N-二甲基氨基乙基)哌嗪-1-)哌啶基,4-(N-(2-N,N-二乙基乙基)哌嗪-1-)哌啶基,4-(N-(3-N,N-二甲基丙基)哌嗪-1-)哌啶基,4-(N-(3-N,N-二乙基丙基)哌嗪-1-)哌啶基,4-(四氢吡咯-1-)哌啶基,4-(3-N,N-二甲基氨基四氢吡咯-1-)哌啶基,4-(3-N,N-二乙基氨基四氢吡咯-1-)哌啶基,(9)哌啶-4-基,N-甲基-4-哌啶基,N-乙基-4-哌啶基,N-异丙基-4-哌啶基,N-乙酰基-4-哌啶基,N-叔丁氧羰基-4-哌啶基,N-甲磺酰基-4-哌啶基,N-(2-羟基乙基)-4-哌啶基,N-(2-N,N-二甲基氨基乙基)-4-哌啶基,N-(2-N,N-二乙基氨基乙基)-4-哌啶基,N-(2-氰基乙基)-4-哌啶基,N-(3-羟基丙基)-4-哌啶基,N-(3-N,N-二甲基氨基丙基)-4-哌啶基,N-(3-N,N-二乙基氨基丙基)-4-哌啶基,N-(3-氰基丙基)-4-哌啶基,N-氰基亚甲基-4-哌啶基,(10)氨基,N,N-二甲基氨基,N,N-二乙基氨基,N,N-二正丙基氨基,N,N-二异丙基氨基,2-N,N-二甲基氨基乙基氨基,2-吗啡啉基乙基氨基,2-(N-甲基哌嗪基)乙基氨基,3-N,N-二甲基氨基丙基氨基,3-N,N-二乙基氨基丙基氨基,3-N,N-二异丙基氨基丙基氨基,3-吗啉基丙基氨基,3-(N-甲基哌嗪基)丙基氨基,N-甲基哌啶-4-氨基,N-乙基哌啶-4-氨基,N-正丙基哌啶-4-氨基,N-异丙基哌啶-4-氨基,乙酰胺基,丙酰胺基,2-(N,N-二甲基氨基)乙酰胺基,2-羟基乙酰胺基,2-甲氧基乙酰胺基,甲磺酰胺基,乙磺酰胺基,正丙基磺酰胺基,异丙基磺酰胺基,环丙基磺酰胺基,N-甲基-N-(N-甲基-3-四氢吡咯基)氨基,N-(N-甲基-3-四氢吡咯基)氨基,N-甲基-N-(2-N,N-二甲基氨基)乙基氨基,(11)氨基亚甲基,N,N-二甲基氨基亚甲基,N,N-二乙基氨基亚甲基,4-甲基-1-哌嗪亚甲基,4-乙基-1-哌嗪亚甲基,4-丙基-1-哌嗪亚甲基,4-异丙基-1-哌嗪亚甲基,4-(2-羟基乙基)-1-哌嗪亚甲基,4-(2-N,N-二甲基氨基乙基)-1-哌嗪亚甲基,哌啶-1-亚甲基,4-(N,N-二甲基氨基)-1-哌啶亚甲基,4-羟基哌啶-1-亚甲基,四氢吡咯-1-亚甲基,3-(N,N-二甲基氨基)-1-四氢吡咯亚甲基,(12)氨基甲酰基,甲胺基甲酰基,二甲胺基甲酰基,乙胺基甲酰基,环丙基胺基甲酰基,环丁基胺基甲酰基,环戊基胺基甲酰基,环己基胺基甲酰基,四氢吡咯-1-甲酰基,3-(N,N-二甲基氨基)四氢吡咯基-1-甲酰基,3-(N,N-二乙基氨基)四氢吡咯基-1-甲酰基,吗啡啉基-4-甲酰基,硫啡啉基-4-甲酰基,2,6-二甲基吗啡啉基-4-甲酰基,哌啶基-1-甲酰基,4-羟基哌啶基-1-甲酰基,4-(N,N-二甲基氨基)哌啶基-1-甲酰基,4-(N,N-二乙基氨基)哌啶基-1-甲酰基,4-(N-甲基-1-哌嗪基)哌啶基-1-甲酰基,4-(N-乙基-1-哌嗪基)哌啶基-1-甲酰基,N-甲基哌嗪-1-甲酰基,N-乙基哌嗪-1-甲酰基,N-异丙基哌嗪-1-甲酰基,N-(2-羟基乙基)哌嗪-1-甲酰基,N-(2-N,N-二甲基氨基乙基)哌嗪-1-甲酰基,N-(2-N,N-二乙基氨基乙基)哌嗪-1-甲酰基,4-(N-甲基-4-哌啶基)哌嗪-1-甲酰基,4-(N-乙基-4-哌啶基)哌嗪-1-甲酰基,(13)羟基甲酰基,甲氧基甲酰基,乙氧基甲酰基,丙氧基甲酰基,异丙氧基甲酰基,正丁氧基甲酰基,异丁氧基甲酰基,叔丁氧基甲酰基,(14)羟基磺酰基,氨基磺酰基,甲胺基磺酰基,乙胺基磺酰基,丙胺基磺酰基,异丙胺基磺酰基,环丙胺基磺酰基,环丁基基磺酰基,环戊胺基磺酰基,环己胺基磺酰基,四氢吡咯-1-磺酰基,3-(N,N-二甲基氨基)四氢吡咯基-1-磺酰基,3-(N,N-二乙基氨基)四氢吡咯基-1-磺酰基,吗啡啉基-4-磺酰基,硫啡啉基-4-磺酰基,2 6-二甲基吗啡啉基-4-磺酰基,哌啶基-1-磺酰基,4-羟基哌啶-1-磺酰基,4-(N,N-二甲基氨基)哌啶基-1-磺酰基,4-(N,N-二乙基氨基)哌啶基-1-磺酰基,4-(N-甲基-1-哌嗪基)哌啶基-1-磺酰基,4-(N-乙基-1-哌嗪 基)哌啶基-1-磺酰基,N-甲基哌嗪-1-磺酰基,N-乙基哌嗪-1-磺酰基,N-异丙基哌嗪-1-磺酰基,N-(2-羟基乙基)哌嗪-1-磺酰基,N-(2-N,N-二甲基氨基乙基)哌嗪-1-磺酰基,N-(2-N,N-二乙基氨基乙基)哌嗪-1-磺酰基,4-(N-甲基-4-哌啶基)哌嗪-1-磺酰基,4-(N-乙基-4-哌啶基)哌嗪-1-磺酰基,(15)氨基甲酰氨基,甲氨基甲酰氨基,乙氨基甲酰氨基,丙氨基甲酰氨基,异丙氨基甲酰氨基,环丙基氨基甲酰氨基,环丁基氨基甲酰氨基,环戊基氨基甲酰氨基,哌啶基-1-甲酰氨基,4-羟基哌啶基-1-甲酰氨基,4-N,N-二甲基哌啶基-1-甲酰氨基,4-N,N-二乙基哌啶基-1-甲酰氨基,四氢吡咯基-1-甲酰氨基,3-N,N-二甲基四氢吡咯基-1-甲酰氨基,3-N,N-二乙基四氢吡咯基-1-甲酰氨基,N-甲基哌嗪基-1-甲酰氨基,N-乙基哌嗪基-1-甲酰氨基,N-乙酰基哌嗪基-1-甲酰氨基,N-叔丁氧羰基哌嗪基-1-甲酰氨基,N-(2-羟基乙基)哌嗪基-1-甲酰氨基,N-(2-氰基乙基)哌嗪基-1-甲酰氨基,N-(2-N,N-二甲基氨基乙基)哌嗪基-1-甲酰氨基,N-(2-N,N-二乙基氨基乙基)哌嗪基-1-甲酰氨基,N-(3-羟基丙基)哌嗪基-1-甲酰氨基,N-(3-N,N-二甲基丙基)哌嗪基-1-甲酰氨基,N-(3-N,N-二乙基丙基)哌嗪基-1-甲酰氨基,吗啉基-1-甲酰氨基,3,5-二甲基吗啉基-1-甲酰氨基,4-(四氢吡咯基)哌啶基-1-甲酰氨基,4-(N-甲基-1-哌嗪基)哌啶基-1-甲酰氨基,4-(N-乙基-1-哌嗪基)哌啶基-1-甲酰氨基,4-(N-乙酰基-1-哌嗪基)哌啶基-1-甲酰氨基,N-(N-甲基-4-哌啶基)哌嗪基-1-甲酰氨基,(16)Z3与Z4可以形成含氧的取代或未取代的五-七元环;取代基可以选自与Z1相同的上述取代基,(17)Z3与Z4可以形成含氮的取代或未取代的五-七元环;取代基可以选自与Z1相同的上述取代基;6)1-甲基-3-吡咯基,1-乙基-3-吡咯基,1-异丙基-3-吡咯基,1-环丙基-3-吡咯基,1-甲基-3-吡唑基,1-乙基-3-吡唑基,1-异丙基-3-吡唑基,1-环丙基-3-吡唑基,1-羟乙基-3-吡唑基,1-甲基-4-吡唑基,1-乙基-4-吡唑基,1-异丙基-4-吡唑基,1-环丙基-4-吡唑基,1-羟乙基-4-吡唑基,1-(N-甲基-4-哌啶基)-4-吡唑基,1-(N-叔丁氧羰基-4-哌啶基)-4-吡唑基,1,3-二甲基-5-吡唑基,1-甲基-4-咪唑基,3-甲基-5-异噁唑基;优选地,R 1选自:(1)氢,氟,氯,溴,碘,硝基,氰基,(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6环烷基,(3)哌嗪基,N-甲基哌嗪基,N-乙基哌嗪基,N-正丙基哌嗪基,N-异丙基哌嗪基,N-环丙基哌嗪基,N-(2-羟基乙基)哌嗪基,N-(2-N,N-二甲基氨基乙基)哌嗪基,N-(2-N,N-二乙基氨基乙基)哌嗪基,N-(2-氰基乙基)哌嗪基,N-氰甲基哌嗪基,N-(3-羟基丙基)哌嗪基,N-(3-N,N-二甲基氨基丙基)哌嗪基,N-(3-N,N-二乙基氨基丙基)哌嗪基,N-(N-甲基-4-哌啶基)哌嗪基,N-(N-乙基-4-哌啶基)哌嗪基,N-叔丁氧羰基哌嗪基,N-乙酰基哌嗪基,N-丙酰基哌嗪基,N-异丁酰基哌嗪基,N-环丙基甲酰基哌嗪基,N-甲磺酰基哌嗪基,N-乙基磺酰基哌嗪基,N-正丙基磺酰基哌嗪基,N-异丙基磺酰基哌嗪基,N-环丙基磺酰基哌嗪基,2-氧代-哌嗪-4-基,(4)哌啶基,4-N,N-二甲基氨基哌啶基,4-N,N-二乙基氨基哌啶基,4-N,N-二异丙基氨基哌啶基,4-羟基哌啶基,4-甲氧基哌啶基,4-乙氧基哌啶基,4-(N-甲基哌嗪-1-)哌啶基,4-(N-乙基哌嗪-1-)哌啶基,4-(N-异丙基哌嗪-1-)哌啶基,4-(N-乙酰基哌嗪-1-)哌啶基,4-(N-叔丁氧羰基哌嗪-1-)哌啶基,4-(N-甲磺酰基哌嗪-1-)哌啶基,4-(N-(2-羟基乙基)哌嗪-1-)哌啶基,4-(N-(2-氰基乙基)哌嗪-1-)哌啶基,4-(N-(3-羟基丙基)哌嗪-1-)哌啶基,4-(N-(2-N,N-二甲基氨基乙基)哌嗪-1-)哌啶基,4-(N-(2-N,N-二乙基乙基)哌嗪-1-)哌啶基,4-(N-(3-N,N-二甲基丙基)哌嗪-1-)哌啶基,4-(N-(3-N,N-二乙基丙基)哌嗪-1-)哌啶基,4-(四氢吡咯-1-)哌啶基,4-(3-N,N-二甲基氨基四氢吡咯-1-)哌啶基,4-(3-N,N-二乙基氨基四氢吡咯-1-)哌啶基,(5)哌啶-4-基,N-甲基-4-哌啶基,N-乙基-4-哌啶基,N-异丙基-4-哌啶基,N-乙酰基-4-哌啶基,N-叔丁氧羰基-4-哌啶基,N-甲磺酰基-4-哌啶基,N-(2-羟基乙基)-4-哌啶基,N-(2-N,N-二甲基氨基乙基)-4-哌啶基,N-(2-N,N-二乙基氨基乙基)-4-哌啶基,N-(2-氰基乙基)-4-哌啶基,N-(3-羟基丙基)-4-哌啶基,N-(3-N,N-二甲基氨基丙基)-4-哌啶基,N-(3-N,N-二乙基氨基丙基)-4-哌啶基,N-(3-氰基丙基)-4-哌啶基,N-氰基亚甲基-4-哌啶基,(6)氨基,N,N-二甲基氨基,N,N-二乙基氨基,N,N-二正丙基氨基,N,N-二异丙基氨基,2-N,N-二甲基氨基乙基氨基,2-吗啡啉基乙基氨基,2-(N-甲基哌嗪基)乙基氨基,3-N,N-二甲基氨基丙基氨基,3-N,N-二乙基氨基丙基氨基,3-N,N-二异丙基氨基丙基氨基,3-吗啉基丙基氨基,3-(N-甲基哌嗪基)丙基氨基,N-甲基哌啶-4-氨基,N-乙基哌啶-4-氨基,N-正丙基哌啶-4-氨基,N-异丙基哌啶-4-氨基,乙酰胺基,丙酰胺基,2-(N,N-二甲基氨基)乙酰胺基,2-羟基乙酰胺基,2-甲氧基乙酰胺基,甲磺酰胺基,乙磺酰胺基,正丙基磺酰胺基,异丙基磺酰胺基,环丙基磺酰胺基,N-甲基-N-(N-甲基-3-四氢吡咯基)氨基,N-(N-甲基-3-四氢吡咯基)氨基,N-甲基-N-(2-N,N-二甲基氨基)乙基氨基,(7)氨基甲酰基,甲胺基甲酰基,二甲胺基甲酰基,乙胺基甲酰基,环丙基胺基甲酰基,环丁基胺基甲酰基,环戊基胺基甲酰基,环己基胺基甲酰基,四氢吡咯-1-甲酰基,3-(N,N-二甲基氨基)四氢吡咯基-1-甲酰基,3-(N,N-二乙基氨基)四氢吡咯基-1-甲酰基,吗啡啉基-4-甲酰基,硫啡啉基-4-甲酰基,2,6-二甲基吗啡啉基-4-甲酰基,哌啶基-1-甲酰基,4-羟基哌啶基-1-甲酰基,4-(N,N-二甲基氨基)哌啶基-1-甲酰基,4-(N,N-二乙基氨基)哌啶基-1-甲酰基,4-(N-甲基-1-哌嗪基)哌啶基-1-甲酰基,4-(N-乙基-1-哌嗪基)哌啶基-1-甲酰基,N-甲基哌嗪-1-甲酰基,N-乙基哌嗪-1-甲酰基,N-异丙基哌嗪-1-甲酰基,N-(2-羟基乙基)哌嗪-1-甲酰基,N-(2-N,N-二甲基氨基乙基)哌嗪-1-甲酰基,N-(2-N,N-二乙基氨基乙基)哌嗪-1-甲酰基,4-(N-甲基-4-哌啶基)哌嗪-1-甲酰基,4-(N-乙基-4-哌啶基)哌嗪-1-甲酰基;3) 其中:Z 1,Z 2,Z 5与1)中定义相同,且可以同时为氢;R x1选自氢,氟,氯,溴,碘,硝基,氰基,C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6环烷基;4) 其中:Z 1,Z 2,Z 5与1)中定义相同,且可以同时为氢;R x2、R y各自独立地选自氢,氟,氯,溴,碘,硝基,氰基,C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6环烷基;5) 其中:Z 2,Z 5与1)中定义相同,且可以同时为氢;R x3选自氢,氟,氯,溴,碘,硝基,氰基,C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6环烷基;6) 其中:Z 1,Z 2,Z 5与1)中定义相同,且可以同时为氢;R x4选自氢,氟,氯,溴,碘,硝基,氰基,C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6环烷基;7)1-甲基-3-吡咯基,1-乙基-3-吡咯基,1-异丙基-3-吡咯基,1-甲基-3-吡唑基,1-乙基-3-吡唑基,1-异丙基-3-吡唑基,1-甲基-4-吡唑基,1-乙基-4-吡唑基,1-异丙基-4-吡唑基,1-甲基-4-咪唑基,3-甲基-5-异噁唑基;更优选地,R 1选自:(1)氢,氟,氯,溴,碘,硝基,氰基,(2)C1-C6烷基,C1-C6烷氧基,(3)哌嗪基,N-甲基哌嗪基,N-乙基哌嗪基,N-正丙基哌嗪基,N-异丙基哌嗪基, N-环丙基哌嗪基,N-(2-羟基乙基)哌嗪基,N-(2-N,N-二甲基氨基乙基)哌嗪基,N-(2-N,N-二乙基氨基乙基)哌嗪基,N-(2-氰基乙基)哌嗪基,N-氰甲基哌嗪基,N-(3-羟基丙基)哌嗪基,N-(3-N,N-二甲基氨基丙基)哌嗪基,N-(3-N,N-二乙基氨基丙基)哌嗪基,(4)哌啶基,4-N,N-二甲基氨基哌啶基,4-N,N-二乙基氨基哌啶基,4-N,N-二异丙基氨基哌啶基,4-羟基哌啶基,4-甲氧基哌啶基,4-乙氧基哌啶基,4-(N-甲基哌嗪-1-)哌啶基,4-(N-乙基哌嗪-1-)哌啶基,4-(N-异丙基哌嗪-1-)哌啶基,4-(N-(2-羟基乙基)哌嗪-1-)哌啶基,4-(N-(2-氰基乙基)哌嗪-1-)哌啶基,4-(N-(3-羟基丙基)哌嗪-1-)哌啶基,4-(N-(2-N,N-二甲基氨基乙基)哌嗪-1-)哌啶基,4-(N-(2-N,N-二乙基乙基)哌嗪-1-)哌啶基,4-(N-(3-N,N-二甲基丙基)哌嗪-1-)哌啶基,4-(N-(3-N,N-二乙基丙基)哌嗪-1-)哌啶基,4-(四氢吡咯-1-)哌啶基,4-(3-N,N-二甲基氨基四氢吡咯-1-)哌啶基,4-(3-N,N-二乙基氨基四氢吡咯-1-)哌啶基,(5)哌啶-4-基,N-甲基-4-哌啶基,N-乙基-4-哌啶基,N-异丙基-4-哌啶基,N-(2-羟基乙基)-4-哌啶基,N-(2-N,N-二甲基氨基乙基)-4-哌啶基,N-(2-N,N-二乙基氨基乙基)-4-哌啶基,N-(2-氰基乙基)-4-哌啶基,N-(3-羟基丙基)-4-哌啶基,N-(3-N,N-二甲基氨基丙基)-4-哌啶基,N-(3-N,N-二乙基氨基丙基)-4-哌啶基,N-(3-氰基丙基)-4-哌啶基,N-氰基亚甲基-4-哌啶基,(6)乙酰胺基,丙酰胺基,2-(N,N-二甲基氨基)乙酰胺基,2-羟基乙酰胺基,2-甲氧基乙酰胺基,(7)4-(N-甲基-1-哌嗪基)哌啶基-1-甲酰基,4-(N-乙基-1-哌嗪基)哌啶基-1-甲酰基,N-甲基哌嗪-1-甲酰基,N-乙基哌嗪-1-甲酰基,N-异丙基哌嗪-1-甲酰基,N-(2-羟基乙基)哌嗪-1-甲酰基,N-(2-N,N-二甲基氨基乙基)哌嗪-1-甲酰基,N-(2-N,N-二乙基氨基乙基)哌嗪-1-甲酰基;(1)氢,氟,氯,溴,碘,硝基,氰基,(2)C1-C6烷基,C1-C6烷氧基,(3)哌嗪基,N-甲基哌嗪基,N-乙基哌嗪基,N-正丙基哌嗪基,N-异丙基哌嗪基,N-环丙基哌嗪基,N-(2-羟基乙基)哌嗪基,N-(2-N,N-二甲基氨基乙基)哌嗪基,N-(2-N,N-二乙基氨基乙基)哌嗪基,N-(2-氰基乙基)哌嗪基,N-氰甲基哌嗪基,N-(3-羟基丙基)哌嗪基,N-(3-N,N-二甲基氨基丙基)哌嗪基,N-(3-N,N-二乙基氨基丙基)哌嗪基,(4)哌啶基,4-N,N-二甲基氨基哌啶基,4-N,N-二乙基氨基哌啶基,4-N,N-二异丙基氨基哌啶基,4-羟基哌啶基,4-甲氧基哌啶基,4-乙氧基哌啶基,4-(N-甲基哌嗪-1-)哌啶基,4-(N-乙基哌嗪-1-)哌啶基,4-(N-异丙基哌嗪-1-)哌啶基,(5)N-甲基-N-(N-甲基-3-四氢吡咯基)氨基,N-(N-甲基-3-四氢吡咯基)氨基,N-甲基-N-(2-N,N-二甲基氨基)乙基氨基;7)1-甲基-3-吡唑基,1-乙基-3-吡唑基,1-异丙基-3-吡唑基,1-甲基-4-吡唑基,1-乙基-4-吡唑基,1-异丙基-4-吡唑基;最优选地,R 1选自:氢、甲基、氟、甲氧基、乙氧基、异丙氧基、N-甲基哌嗪-1-甲酰基、4-羟基哌啶基、N-甲基-4-哌啶基、N-甲基哌嗪基、4-(N-甲基哌嗪-1-)哌啶基、4-(N-(2-羟基乙基)哌嗪-1-)哌啶基、4-(N-(2-N,N-二甲基氨基乙基)哌嗪-1-)哌啶基、4-(四氢吡咯-1-)哌啶基、4-(N-甲基-1-哌嗪基)哌啶基-1-甲酰基、2-(N,N-二甲基氨基)乙酰胺基,优选地,Z 1,Z 2,Z 5各自独立地选自氢、氟、甲氧基、乙氧基、异丙氧基,且Z 3,Z 4之一选自以下,另一选自氢、甲基、氟:N-甲基哌嗪-1-甲酰基、4-羟基哌啶基、N-甲基-4-哌啶基、N-甲基哌嗪基、4-(N-甲基哌嗪-1-)哌啶基、4-(N-(2-羟基乙基)哌嗪-1-)哌啶基、4-(N-(2-N,N-二甲基氨基乙基)哌嗪-1-)哌啶基、4-(四氢吡咯-1-)哌啶基、4-(N-甲基-1-哌嗪基)哌啶基-1-甲酰基、2-(N,N-二甲基氨基)乙酰胺基;氢、甲基、甲氧基、4-羟基哌啶基、4-甲氧基哌啶基、4-N,N-二甲基氨基哌啶基、N-甲基-N-(N-甲基-3-四氢吡咯基)氨基、N-甲基哌嗪基、4-(N-甲基哌嗪-1-)哌啶基,优选地,Z 1,Z 5各自独立地选自氢、甲氧基,且Z 3,Z 4之一选自以下,另一为氢:甲基、4-羟基哌啶基、4-甲氧基哌啶基、4-N,N-二甲基氨基哌啶基、N-甲基-N-(N-甲基-3-四氢吡咯基)氨基、N-甲基哌嗪基、4-(N-甲基哌嗪-1-)哌啶基;7)1-甲基-3-吡唑基;R 2选自:氢,甲基,乙基,异丙基,环丙基,甲氧基,乙氧基,异丙氧基,甲氨基,乙氨基,环丙基氨基,N,N-二甲基氨基,甲基乙基氨基,N,N-二乙基氨基,N,N-二异丙基氨基;优选地,R 2选自氢,甲基,乙基,异丙基;W 1,W 2,W 3,W 5各自独立地选自氢,氟,氯,溴,碘,硝基,氰基,C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6环烷基;优选地,W 1,W 2,W 3,W 5各自独立地选自氢,氟,氯,溴,碘,硝基,氰基,C1-C6烷基;更优选地,W 1,W 2,W 3,W 5各自独立地选自氢,甲基;最优选地,W 2,W 3,W 5为氢,W 1为甲基;R选自:1)氢,C1-C6烷基,C3-C6环烷基,(a)氢,氟,氯,溴,碘,硝基,氰基,(b)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6环烷基,C1-C6酰基,(c)氨基亚甲基,N,N-二甲基氨基亚甲基,N,N-二乙基氨基亚甲基,N-甲基-1-哌嗪亚甲基,N-乙基-1-哌嗪亚甲基,N-丙基-1-哌嗪亚甲基,N-异丙基-1-哌嗪亚甲基,N-环丙基-1-哌嗪亚甲基,N-(2-羟基乙基)-1-哌嗪亚甲基,N-(2-N,N-二甲基氨基乙基)-1-哌嗪亚甲基,N-(2-氰基乙基)-1-哌嗪亚甲基,哌啶-1-亚甲基,4-氨基哌啶-1-亚甲基,4-(N,N-二甲基氨基)-1-哌啶亚甲基,4-(N,N-二乙基氨基)-1-哌啶亚甲基,4-(N,N-二丙基氨基)-1-哌啶亚甲基,4-(N,N-二异丙基氨基)-1-哌啶亚甲基,4-羟基哌啶-1-亚甲基,4-甲氧基哌啶-1-亚甲基,4-乙氧基哌啶-1-亚甲基,4-丙氧基哌啶-1-亚甲基,4-异丙氧基哌啶-1-亚甲基,吗啡啉-4-亚甲基,硫啡啉基-4-亚甲基,2,6-二甲基吗啡啉基-4-亚甲基,四氢吡咯-1-亚甲基,3-氨基-1- 四氢吡咯亚甲基,3-(N,N-二甲基氨基)-1-四氢吡咯亚甲基,3-(N,N-二乙基氨基)-1-四氢吡咯亚甲基,3-(N,N-二丙基氨基)-1-四氢吡咯亚甲基,3-(N,N-二异丙基氨基)-1-四氢吡咯亚甲基,氮杂环丁烷-1-亚甲基,(d)咪唑基,4-甲基咪唑基,吡咯基,吡唑基,3-甲基吡唑基,4-甲基吡唑基,3-甲基-5-异噁唑基,优选地,R选自:1)氢,C1-C6烷基,(a)氢,氟,氯,溴,碘,硝基,氰基,(b)C1-C6烷基,C1-C6烷氧基,C1-C6含氟烷基,C1-C6酰基,(c)N-甲基-1-哌嗪亚甲基,N-乙基-1-哌嗪亚甲基,N-丙基-1-哌嗪亚甲基,N-异丙基-1-哌嗪亚甲基,N-环丙基-1-哌嗪亚甲基,N-(2-羟基乙基)-1-哌嗪亚甲基,N-(2-N,N-二甲基氨基乙基)-1-哌嗪亚甲基,N-(2-氰基乙基)-1-哌嗪亚甲基,吗啡啉-4-亚甲基,硫啡啉基-4-亚甲基,2,6-二甲基吗啡啉基-4-亚甲基,四氢吡咯-1-亚甲基,3-氨基-1-四氢吡咯亚甲基,3-(N,N-二甲基氨基)-1-四氢吡咯亚甲基,3-(N,N-二乙基氨基)-1-四氢吡咯亚甲基,3-(N,N-二丙基氨基)-1-四氢吡咯亚甲基,3-(N,N-二异丙基氨基)-1-四氢吡咯亚甲基,氮杂环丁烷-1-亚甲基,更优选地,R选自:1)氢,(a)氢,氟,氯,溴,硝基,(b)C1-C6烷基,C1-C6烷氧基,C1-C6含氟烷基,(c)N-甲基-1-哌嗪亚甲基,吗啡啉-4-亚甲基,四氢吡咯-1-亚甲基,氮杂环丁烷-1-亚甲基,(d)甲酰基、乙酰基、丙酰基、丁酰基、2-甲基丙酰基,(a)氢,氟,溴,(b)C1-C6烷基,C1-C6含氟烷基;氢,氯,氢,C1-C6含氟烷基,最优选地,R选自:1)氢,氢,氟,氯,溴,硝基,甲基,甲氧基,乙酰基,三氟甲基,N-甲基-1-哌嗪亚甲基,吗啡啉-4-亚甲基,四氢吡咯-1-亚甲基,氮杂环丁烷-1-亚甲基,氢,氟,溴,三氟甲基,氢,氯,氢,三氟甲基。
- 根据权利要求1的化合物,其为以下:或所述化合物的立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物,其中:R 1选自:(1)氢,氟,氯,溴,碘,硝基,氰基,(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6环烷基,(3)2-N,N-二甲基氨基乙氧基,3-N,N-二甲基氨基丙氧基,2-(N-甲基哌嗪基)乙氧基,2-(N-乙酰基哌嗪基)乙氧基,2-吗啡啉基乙氧基,2-硫啡啉基乙氧基,2-哌啶基乙氧基,3-N,N-二甲基氨基丙氧基,3-N,N-二乙基氨基丙氧基,3-N,N-二异丙基氨基丙氧基,3-(N-甲基哌嗪基)丙氧基,3-(N-乙酰基哌嗪基)丙氧基,3-吗啉基丙氧基,3-硫啡啉基丙氧基,3-哌啶基丙氧基,2-吡啶基甲氧基,3-吡啶基甲氧基,4-吡啶基甲氧基,苯基甲氧基,单卤素取代苯基甲氧基,偕二卤素取代苯基甲氧基,杂二卤素取代苯基甲氧基,(4)哌嗪基,N-甲基哌嗪基,N-乙基哌嗪基,N-正丙基哌嗪基,N-异丙基哌嗪基,N-环丙基哌嗪基,N-(2-羟基乙基)哌嗪基,N-(2-N,N-二甲基氨基乙基)哌嗪基,N-(2-N,N-二乙基氨基乙基)哌嗪基,N-(2-氰基乙基)哌嗪基,N-氰甲基哌嗪基,N-(3-羟基丙基)哌嗪基,N-(3-N,N-二甲基氨基丙基)哌嗪基,N-(3-N,N-二乙基氨基丙基)哌嗪基,N-(N-甲基-4-哌啶基)哌嗪基,N-(N-乙基-4-哌啶基)哌嗪基,N-叔丁氧羰基哌嗪基,N-乙酰基哌嗪基,N-丙酰基哌嗪基,N-异丁酰基哌嗪基,N-环丙基甲酰基哌嗪基,N-甲磺酰基哌嗪基,N-乙基磺酰基哌嗪基,N-正丙基磺酰基哌嗪基,N-异丙基磺酰基哌嗪基,N-环丙基磺酰基哌嗪基,2-氧代-哌嗪-4-基,(5)吗啡啉基,2,6-二甲基吗啡啉基,硫啡啉基,(6)四氢吡咯基,3-(N,N-二甲基氨基)四氢吡咯基,3-(N,N-二乙基氨基)四氢吡咯基,(7)咪唑基,4-甲基-1-咪唑基,(8)哌啶基,4-N,N-二甲基氨基哌啶基,4-N,N-二乙基氨基哌啶基,4-N,N-二异丙基氨基哌啶基,4-羟基哌啶基,4-甲氧基哌啶基,4-乙氧基哌啶基,4-(N-甲基哌嗪-1-)哌啶基,4-(N-乙基哌嗪-1-)哌啶基,4-(N-异丙基哌嗪-1-)哌啶基,4-(N-乙酰基哌嗪-1-)哌啶基,4-(N-叔丁氧羰基哌嗪-1-)哌啶基,4-(N-甲磺酰基哌嗪-1-)哌啶基,4-(N-(2-羟基乙基)哌嗪-1-)哌啶基,4-(N-(2-氰基乙基)哌嗪-1-)哌啶基,4-(N-(3-羟基丙基)哌嗪-1-)哌啶基,4-(N-(2-N,N-二甲基氨基乙基)哌嗪-1-)哌啶基,4-(N-(2-N,N-二乙基乙基)哌嗪-1-)哌啶基,4-(N-(3-N,N-二甲基丙基)哌嗪-1-)哌啶基,4-(N-(3-N,N-二乙基丙基)哌嗪-1-)哌啶基,4-(四氢吡咯-1-)哌啶基,4-(3-N,N-二甲基氨基四氢吡咯-1-)哌啶基,4-(3-N,N-二乙基氨基四氢吡咯-1-)哌啶基,(9)哌啶-4-基,N-甲基-4-哌啶基,N-乙基-4-哌啶基,N-异丙基-4-哌啶基,N-乙酰基-4-哌啶基,N-叔丁氧羰基-4-哌啶基,N-甲磺酰基-4-哌啶基,N-(2-羟基乙基)-4-哌啶基,N-(2-N,N-二甲基氨基乙基)-4-哌啶基,N-(2-N,N-二乙基氨基乙基)-4-哌啶基,N-(2-氰基乙基)-4-哌啶基,N-(3-羟基丙基)-4-哌啶基,N-(3-N,N-二甲基氨基丙基)-4-哌啶基,N-(3-N,N-二乙基氨基丙基)-4-哌啶基,N-(3-氰基丙基)-4-哌啶基,N-氰基亚甲基-4-哌啶基,(10)氨基,N,N-二甲基氨基,N,N-二乙基氨基,N,N-二正丙基氨基,N,N-二异丙基氨基,2-N,N-二甲基氨基乙基氨基,2-吗啡啉基乙基氨基,2-(N-甲基哌嗪基)乙基氨基,3-N,N-二甲基氨基丙基氨基,3-N,N-二乙基氨基丙基氨基,3-N,N-二异丙基氨基丙基氨基,3-吗啉基丙基氨基,3-(N-甲基哌嗪基)丙基氨基,N-甲基哌啶-4-氨基,N-乙基哌啶-4-氨基,N-正丙基哌啶-4-氨基,N-异丙基哌啶-4-氨基,乙酰胺基,丙酰胺基,2-(N,N-二甲基氨基)乙酰胺基,2-羟基乙酰胺基,2-甲氧基乙酰胺基,甲磺酰胺基,乙磺酰胺基,正丙基磺酰胺基,异丙基磺酰胺基,环丙基磺酰胺基,N-甲基-N-(N-甲基-3-四氢吡咯基)氨基,N-(N-甲基-3-四氢吡咯基)氨基,N-甲基-N-(2-N,N-二甲基氨基)乙基氨基,(11)氨基亚甲基,N,N-二甲基氨基亚甲基,N,N-二乙基氨基亚甲基,4-甲基-1-哌嗪亚甲基,4-乙基-1-哌嗪亚甲基,4-丙基-1-哌嗪亚甲基,4-异丙基-1-哌嗪亚甲基,4-(2-羟基乙基)-1-哌嗪亚甲基,4-(2-N,N-二甲基氨基乙基)-1-哌嗪亚甲基,哌啶-1-亚甲基,4-(N,N-二甲基氨基)-1-哌啶亚甲基,4-羟基哌啶-1-亚甲基,四氢吡咯-1-亚甲基,3-(N,N-二甲基氨基)-1-四氢吡咯亚甲基,(12)氨基甲酰基,甲胺基甲酰基,二甲胺基甲酰基,乙胺基甲酰基,环丙基胺基甲酰基,环丁基胺基甲酰基,环戊基胺基甲酰基,环己基胺基甲酰基,四氢吡咯-1-甲酰基,3-(N,N-二甲基氨基)四氢吡咯基-1-甲酰基,3-(N,N-二乙基氨基)四氢吡咯基-1-甲酰基,吗啡啉基-4-甲酰基,硫啡啉基-4-甲酰基,2,6-二甲基吗啡啉基-4-甲酰基,哌啶基-1-甲酰基,4-羟基哌啶基-1-甲酰基,4-(N,N-二甲基氨基)哌啶基-1-甲酰基,4-(N,N-二乙基氨基)哌啶基-1-甲酰基,4-(N-甲基-1-哌嗪基)哌啶基-1-甲酰基,4-(N-乙基-1-哌嗪基)哌啶基-1-甲酰基,N-甲基哌嗪-1-甲酰基,N-乙基哌嗪-1-甲酰基,N-异丙基哌嗪-1-甲酰基,N-(2-羟基乙基)哌嗪-1-甲酰基,N-(2-N,N-二甲基氨基乙基)哌嗪-1-甲酰基,N-(2-N,N-二乙基氨基乙基)哌嗪-1-甲酰基,4-(N-甲基-4-哌啶基)哌嗪-1-甲酰基,4-(N-乙基-4-哌啶基)哌嗪-1-甲酰基,(13)羟基甲酰基,甲氧基甲酰基,乙氧基甲酰基,丙氧基甲酰基,异丙氧基甲酰基,正丁氧基甲酰基,异丁氧基甲酰基,叔丁氧基甲酰基,(14)羟基磺酰基,氨基磺酰基,甲胺基磺酰基,乙胺基磺酰基,丙胺基磺酰基,异丙胺基磺酰基,环丙胺基磺酰基,环丁基基磺酰基,环戊胺基磺酰基,环己胺基磺酰基,四氢吡咯-1-磺酰基,3-(N,N-二甲基氨基)四氢吡咯基-1-磺酰基,3-(N,N-二乙基氨基)四氢吡咯基-1-磺酰基,吗啡啉基-4-磺酰基,硫啡啉基-4-磺酰基,2 6-二甲基吗啡啉基-4-磺酰基,哌啶基-1-磺酰基,4-羟基哌啶-1-磺酰基,4-(N,N-二甲基氨基)哌啶基-1-磺酰基,4-(N,N-二乙基氨基)哌啶基-1-磺酰基,4-(N-甲基-1-哌嗪基)哌啶基-1-磺酰基,4-(N-乙基-1-哌嗪基)哌啶基-1-磺酰基,N-甲基哌嗪-1-磺酰基,N-乙基哌嗪-1-磺酰基,N-异丙基哌嗪-1-磺酰基,N-(2-羟基乙基)哌嗪-1-磺酰基,N-(2-N,N-二甲基氨基乙基)哌嗪-1-磺酰基,N-(2-N,N-二乙基氨基乙基)哌嗪-1-磺酰基,4-(N-甲基-4-哌啶基)哌嗪-1-磺酰基,4-(N-乙基-4-哌啶基)哌嗪-1-磺酰基,(15)氨基甲酰氨基,甲氨基甲酰氨基,乙氨基甲酰氨基,丙氨基甲酰氨基,异丙氨基甲酰氨基,环丙基氨基甲酰氨基,环丁基氨基甲酰氨基,环戊基氨基甲酰氨基,哌啶基-1-甲酰氨基,4-羟基哌啶基-1-甲酰氨基,4-N,N-二甲基哌啶基-1-甲酰氨基,4-N,N-二乙基哌啶基-1-甲酰氨基,四氢吡咯基-1-甲酰氨基,3-N,N-二甲基四氢吡咯基-1-甲酰氨基,3-N,N-二乙基四氢吡咯基-1-甲酰氨基,N-甲基哌嗪基-1-甲酰氨基,N-乙基哌嗪基-1-甲酰氨基,N-乙酰基哌嗪基-1-甲酰氨基,N-叔丁氧羰基哌嗪基-1-甲酰氨基,N-(2-羟基乙基)哌嗪基-1-甲酰氨基,N-(2-氰基乙基)哌嗪基-1-甲酰氨基,N-(2-N,N-二甲基氨基乙基)哌嗪基-1-甲酰氨基,N-(2-N,N-二乙基氨基乙基)哌嗪基-1-甲酰氨基,N-(3-羟基丙基)哌嗪基-1-甲酰氨基,N-(3-N,N-二甲基丙基)哌嗪基-1-甲酰氨基,N-(3-N,N-二乙基丙基)哌嗪基-1-甲酰氨基,吗啉基-1-甲酰氨基,3,5-二甲基吗啉基-1-甲酰氨基,4-(四氢吡咯基)哌啶基-1-甲酰氨基,4-(N-甲基-1-哌嗪基)哌啶基-1-甲酰氨基,4-(N-乙基-1-哌嗪基)哌啶基-1-甲酰氨基,4-(N-乙酰基-1-哌嗪基)哌啶基-1-甲酰氨基,N-(N-甲基-4-哌啶基)哌嗪基-1-甲酰氨基,(16)Z3与Z4可以形成含氧的取代或未取代的五-七元环;取代基可以选自与Z1相同的上述取代基,(17)Z3与Z4可以形成含氮的取代或未取代的五-七元环;取代基可以选自与Z1相同的上述取代基;(1)氢,氟,氯,溴,碘,硝基,氰基,(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟 烷氧基,C3-C6环烷基,(3)哌啶基,4-N,N-二甲基氨基哌啶基,4-N,N-二乙基氨基哌啶基,4-N,N-二异丙基氨基哌啶基,4-羟基哌啶基,4-甲氧基哌啶基,4-乙氧基哌啶基,4-(N-甲基哌嗪-1-)哌啶基,4-(N-乙基哌嗪-1-)哌啶基,4-(N-异丙基哌嗪-1-)哌啶基,4-(N-乙酰基哌嗪-1-)哌啶基,4-(N-叔丁氧羰基哌嗪-1-)哌啶基,4-(N-甲磺酰基哌嗪-1-)哌啶基,4-(N-(2-羟基乙基)哌嗪-1-)哌啶基,4-(N-(2-氰基乙基)哌嗪-1-)哌啶基,4-(N-(3-羟基丙基)哌嗪-1-)哌啶基,4-(N-(2-N,N-二甲基氨基乙基)哌嗪-1-)哌啶基,4-(N-(2-N,N-二乙基乙基)哌嗪-1-)哌啶基,4-(N-(3-N,N-二甲基丙基)哌嗪-1-)哌啶基,4-(N-(3-N,N-二乙基丙基)哌嗪-1-)哌啶基,4-(四氢吡咯-1-)哌啶基,4-(3-N,N-二甲基氨基四氢吡咯-1-)哌啶基,4-(3-N,N-二乙基氨基四氢吡咯-1-)哌啶基,(4)哌啶-4-基,N-甲基-4-哌啶基,N-乙基-4-哌啶基,N-异丙基-4-哌啶基,N-乙酰基-4-哌啶基,N-叔丁氧羰基-4-哌啶基,N-甲磺酰基-4-哌啶基,N-(2-羟基乙基)-4-哌啶基,N-(2-N,N-二甲基氨基乙基)-4-哌啶基,N-(2-N,N-二乙基氨基乙基)-4-哌啶基,N-(2-氰基乙基)-4-哌啶基,N-(3-羟基丙基)-4-哌啶基,N-(3-N,N-二甲基氨基丙基)-4-哌啶基,N-(3-N,N-二乙基氨基丙基)-4-哌啶基,N-(3-氰基丙基)-4-哌啶基,N-氰基亚甲基-4-哌啶基;(1)氢,氟,氯,溴,碘,硝基,氰基,(2)C1-C6烷基,(3)哌啶基,4-N,N-二甲基氨基哌啶基,4-N,N-二乙基氨基哌啶基,4-N,N-二异丙基氨基哌啶基,4-羟基哌啶基,4-甲氧基哌啶基,4-乙氧基哌啶基;氢、甲基、4-N,N-二甲基氨基哌啶基;R 2选自:氢,甲基,乙基,异丙基,环丙基,甲氧基,乙氧基,异丙氧基,甲氨基,乙氨基,环丙基氨基,N,N-二甲基氨基,甲基乙基氨基,N,N-二乙基氨基,N,N-二异丙基氨基;优选地,R 2为甲基;W 1,W 2,W 3,W 5各自独立地选自氢,氟,氯,溴,碘,硝基,氰基,C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6环烷基;优选地,W 1,W 2,W 3,W 5各自独立地选自氢,氟,氯,溴,碘,硝基,氰基,C1-C6烷基;更优选地,W 1,W 2,W 3,W 5各自独立地选自氢,甲基;最优选地,W 2,W 3,W 5为氢,W 1为氢或甲基;R’选自:氢,C1-C6烷基,C3-C6环烷基,或者R a,R b及N形成取代或未取代的含1~2个杂原子的3-7元环,所述取代基为卤 素,C1-C6烷基或C3-C6环烷基;2)羟基,C1-C6烷氧基;(a)氢,氟,氯,溴,碘,硝基,氰基,(b)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6环烷基,(c)氨基亚甲基,N,N-二甲基氨基亚甲基,N,N-二乙基氨基亚甲基,N-甲基-1-哌嗪亚甲基,N-乙基-1-哌嗪亚甲基,N-丙基-1-哌嗪亚甲基,N-异丙基-1-哌嗪亚甲基,N-环丙基-1-哌嗪亚甲基,N-(2-羟基乙基)-1-哌嗪亚甲基,N-(2-N,N-二甲基氨基乙基)-1-哌嗪亚甲基,N-(2-氰基乙基)-1-哌嗪亚甲基,哌啶-1-亚甲基,4-氨基哌啶-1-亚甲基,4-(N,N-二甲基氨基)-1-哌啶亚甲基,4-(N,N-二乙基氨基)-1-哌啶亚甲基,4-(N,N-二丙基氨基)-1-哌啶亚甲基,4-(N,N-二异丙基氨基)-1-哌啶亚甲基,4-羟基哌啶-1-亚甲基,4-甲氧基哌啶-1-亚甲基,4-乙氧基哌啶-1-亚甲基,4-丙氧基哌啶-1-亚甲基,4-异丙氧基哌啶-1-亚甲基,吗啡啉-4-亚甲基,硫啡啉基-4-亚甲基,2,6-二甲基吗啡啉基-4-亚甲基,四氢吡咯-1-亚甲基,3-氨基-1-四氢吡咯亚甲基,3-(N,N-二甲基氨基)-1-四氢吡咯亚甲基,3-(N,N-二乙基氨基)-1-四氢吡咯亚甲基,3-(N,N-二丙基氨基)-1-四氢吡咯亚甲基,3-(N,N-二异丙基氨基)-1-四氢吡咯亚甲基,氮杂环丁烷-1-亚甲基,(d)咪唑基,4-甲基咪唑基,吡咯基,吡唑基,3-甲基吡唑基,4-甲基吡唑基,3-甲基-5-异噁唑基;优选地,R’选自:氢,C1-C6烷基,C3-C6环烷基,或者R a,R b及N形成取代或未取代的哌嗪环,所述取代基为卤素,C1-C6烷基或C3-C6环烷基;2)羟基,C1-C6烷氧基;(a)氢,氟,氯,溴,碘,硝基,氰基,(b)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6环烷基,(c)N-甲基-1-哌嗪亚甲基,N-乙基-1-哌嗪亚甲基,N-丙基-1-哌嗪亚甲基,N-异丙基-1-哌嗪亚甲基,N-环丙基-1-哌嗪亚甲基,N-(2-羟基乙基)-1-哌嗪亚甲基,N-(2-N,N-二甲基氨基乙基)-1-哌嗪亚甲基,N-(2-氰基乙基)-1-哌嗪亚甲基,(d)咪唑基,4-甲基咪唑基,吡咯基,吡唑基,3-甲基吡唑基,4-甲基吡唑基,3-甲基-5-异噁唑基;更优选地,R’选自:氢,C1-C6烷基,C3-C6环烷基,或者R a,R b及N形成取代或未取代的哌嗪环,所述取代基为C1-C6烷基;2)羟基,C1-C6烷氧基;(a)氢,氟,氯,溴,碘,硝基,氰基,(b)C1-C6含氟烷基,(c)N-甲基-1-哌嗪亚甲基,N-乙基-1-哌嗪亚甲基,N-丙基-1-哌嗪亚甲基,N-异丙基-1-哌嗪亚甲基,(d)咪唑基,4-甲基咪唑基;最优选地,R’选自:2)羟基,甲氧基,乙氧基;氢,三氟甲基,N-甲基-1-哌嗪亚甲基,4-甲基咪唑基。
- 根据权利要求1的化合物,其为以下:或所述化合物的立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物,其中:R 1选自:(1)氢,氟,氯,溴,碘,硝基,氰基,(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6环烷基,(3)2-N,N-二甲基氨基乙氧基,3-N,N-二甲基氨基丙氧基,2-(N-甲基哌嗪基)乙氧基,2-(N-乙酰基哌嗪基)乙氧基,2-吗啡啉基乙氧基,2-硫啡啉基乙氧基,2-哌啶基乙氧基,3-N,N-二甲基氨基丙氧基,3-N,N-二乙基氨基丙氧基,3-N,N-二异丙基氨基丙氧基,3-(N-甲基 哌嗪基)丙氧基,3-(N-乙酰基哌嗪基)丙氧基,3-吗啉基丙氧基,3-硫啡啉基丙氧基,3-哌啶基丙氧基,2-吡啶基甲氧基,3-吡啶基甲氧基,4-吡啶基甲氧基,苯基甲氧基,单卤素取代苯基甲氧基,偕二卤素取代苯基甲氧基,杂二卤素取代苯基甲氧基,(4)哌嗪基,N-甲基哌嗪基,N-乙基哌嗪基,N-正丙基哌嗪基,N-异丙基哌嗪基,N-环丙基哌嗪基,N-(2-羟基乙基)哌嗪基,N-(2-N,N-二甲基氨基乙基)哌嗪基,N-(2-N,N-二乙基氨基乙基)哌嗪基,N-(2-氰基乙基)哌嗪基,N-氰甲基哌嗪基,N-(3-羟基丙基)哌嗪基,N-(3-N,N-二甲基氨基丙基)哌嗪基,N-(3-N,N-二乙基氨基丙基)哌嗪基,N-(N-甲基-4-哌啶基)哌嗪基,N-(N-乙基-4-哌啶基)哌嗪基,N-叔丁氧羰基哌嗪基,N-乙酰基哌嗪基,N-丙酰基哌嗪基,N-异丁酰基哌嗪基,N-环丙基甲酰基哌嗪基,N-甲磺酰基哌嗪基,N-乙基磺酰基哌嗪基,N-正丙基磺酰基哌嗪基,N-异丙基磺酰基哌嗪基,N-环丙基磺酰基哌嗪基,2-氧代-哌嗪-4-基,(5)吗啡啉基,2,6-二甲基吗啡啉基,硫啡啉基,(6)四氢吡咯基,3-(N,N-二甲基氨基)四氢吡咯基,3-(N,N-二乙基氨基)四氢吡咯基,(7)咪唑基,4-甲基-1-咪唑基,(8)哌啶基,4-N,N-二甲基氨基哌啶基,4-N,N-二乙基氨基哌啶基,4-N,N-二异丙基氨基哌啶基,4-羟基哌啶基,4-甲氧基哌啶基,4-乙氧基哌啶基,4-(N-甲基哌嗪-1-)哌啶基,4-(N-乙基哌嗪-1-)哌啶基,4-(N-异丙基哌嗪-1-)哌啶基,4-(N-乙酰基哌嗪-1-)哌啶基,4-(N-叔丁氧羰基哌嗪-1-)哌啶基,4-(N-甲磺酰基哌嗪-1-)哌啶基,4-(N-(2-羟基乙基)哌嗪-1-)哌啶基,4-(N-(2-氰基乙基)哌嗪-1-)哌啶基,4-(N-(3-羟基丙基)哌嗪-1-)哌啶基,4-(N-(2-N,N-二甲基氨基乙基)哌嗪-1-)哌啶基,4-(N-(2-N,N-二乙基乙基)哌嗪-1-)哌啶基,4-(N-(3-N,N-二甲基丙基)哌嗪-1-)哌啶基,4-(N-(3-N,N-二乙基丙基)哌嗪-1-)哌啶基,4-(四氢吡咯-1-)哌啶基,4-(3-N,N-二甲基氨基四氢吡咯-1-)哌啶基,4-(3-N,N-二乙基氨基四氢吡咯-1-)哌啶基,(9)哌啶-4-基,N-甲基-4-哌啶基,N-乙基-4-哌啶基,N-异丙基-4-哌啶基,N-乙酰基-4-哌啶基,N-叔丁氧羰基-4-哌啶基,N-甲磺酰基-4-哌啶基,N-(2-羟基乙基)-4-哌啶基,N-(2-N,N-二甲基氨基乙基)-4-哌啶基,N-(2-N,N-二乙基氨基乙基)-4-哌啶基,N-(2-氰基乙基)-4-哌啶基,N-(3-羟基丙基)-4-哌啶基,N-(3-N,N-二甲基氨基丙基)-4-哌啶基,N-(3-N,N-二乙基氨基丙基)-4-哌啶基,N-(3-氰基丙基)-4-哌啶基,N-氰基亚甲基-4-哌啶基,(10)氨基,N,N-二甲基氨基,N,N-二乙基氨基,N,N-二正丙基氨基,N,N-二异丙基氨基,2-N,N-二甲基氨基乙基氨基,2-吗啡啉基乙基氨基,2-(N-甲基哌嗪基)乙基氨基,3-N,N-二甲基氨基丙基氨基,3-N,N-二乙基氨基丙基氨基,3-N,N-二异丙基氨基丙基氨基,3-吗啉基丙基氨基,3-(N-甲基哌嗪基)丙基氨基,N-甲基哌啶-4-氨基,N-乙基哌啶-4-氨基,N-正丙基哌啶-4-氨基,N-异丙基哌啶-4-氨基,乙酰胺基,丙酰胺基,2-(N,N-二甲基氨基)乙酰胺基,2-羟基乙酰胺基,2-甲氧基乙酰胺基,甲磺酰胺基,乙磺酰胺基,正丙基磺酰胺基,异丙基磺酰胺基,环丙基磺酰胺基,N-甲基-N-(N-甲基-3-四氢吡咯基)氨基,N-(N-甲基-3-四氢吡咯基)氨基,N-甲基-N-(2-N,N-二甲基氨基)乙基氨基,(11)氨基亚甲基,N,N-二甲基氨基亚甲基,N,N-二乙基氨基亚甲基,4-甲基-1-哌嗪亚甲基,4-乙基-1-哌嗪亚甲基,4-丙基-1-哌嗪亚甲基,4-异丙基-1-哌嗪亚甲基,4-(2-羟基乙基)-1-哌嗪亚甲基,4-(2-N,N-二甲基氨基乙基)-1-哌嗪亚甲基,哌啶-1-亚甲基,4-(N,N-二甲基氨基)-1-哌啶亚甲基,4-羟基哌啶-1-亚甲基,四氢吡咯-1-亚甲基,3-(N,N-二甲基氨基)-1-四氢吡咯亚甲基,(12)氨基甲酰基,甲胺基甲酰基,二甲胺基甲酰基,乙胺基甲酰基,环丙基胺基甲酰基,环丁基胺基甲酰基,环戊基胺基甲酰基,环己基胺基甲酰基,四氢吡咯-1-甲酰基,3-(N,N-二甲基氨基)四氢吡咯基-1-甲酰基,3-(N,N-二乙基氨基)四氢吡咯基-1-甲酰基,吗啡啉基-4-甲酰基,硫啡啉基-4-甲酰基,2,6-二甲基吗啡啉基-4-甲酰基,哌啶基-1-甲酰基,4-羟基哌啶基-1-甲酰基,4-(N,N-二甲基氨基)哌啶基-1-甲酰基,4-(N, N-二乙基氨基)哌啶基-1-甲酰基,4-(N-甲基-1-哌嗪基)哌啶基-1-甲酰基,4-(N-乙基-1-哌嗪基)哌啶基-1-甲酰基,N-甲基哌嗪-1-甲酰基,N-乙基哌嗪-1-甲酰基,N-异丙基哌嗪-1-甲酰基,N-(2-羟基乙基)哌嗪-1-甲酰基,N-(2-N,N-二甲基氨基乙基)哌嗪-1-甲酰基,N-(2-N,N-二乙基氨基乙基)哌嗪-1-甲酰基,4-(N-甲基-4-哌啶基)哌嗪-1-甲酰基,4-(N-乙基-4-哌啶基)哌嗪-1-甲酰基,(13)羟基甲酰基,甲氧基甲酰基,乙氧基甲酰基,丙氧基甲酰基,异丙氧基甲酰基,正丁氧基甲酰基,异丁氧基甲酰基,叔丁氧基甲酰基,(14)羟基磺酰基,氨基磺酰基,甲胺基磺酰基,乙胺基磺酰基,丙胺基磺酰基,异丙胺基磺酰基,环丙胺基磺酰基,环丁基基磺酰基,环戊胺基磺酰基,环己胺基磺酰基,四氢吡咯-1-磺酰基,3-(N,N-二甲基氨基)四氢吡咯基-1-磺酰基,3-(N,N-二乙基氨基)四氢吡咯基-1-磺酰基,吗啡啉基-4-磺酰基,硫啡啉基-4-磺酰基,2 6-二甲基吗啡啉基-4-磺酰基,哌啶基-1-磺酰基,4-羟基哌啶-1-磺酰基,4-(N,N-二甲基氨基)哌啶基-1-磺酰基,4-(N,N-二乙基氨基)哌啶基-1-磺酰基,4-(N-甲基-1-哌嗪基)哌啶基-1-磺酰基,4-(N-乙基-1-哌嗪基)哌啶基-1-磺酰基,N-甲基哌嗪-1-磺酰基,N-乙基哌嗪-1-磺酰基,N-异丙基哌嗪-1-磺酰基,N-(2-羟基乙基)哌嗪-1-磺酰基,N-(2-N,N-二甲基氨基乙基)哌嗪-1-磺酰基,N-(2-N,N-二乙基氨基乙基)哌嗪-1-磺酰基,4-(N-甲基-4-哌啶基)哌嗪-1-磺酰基,4-(N-乙基-4-哌啶基)哌嗪-1-磺酰基,(15)氨基甲酰氨基,甲氨基甲酰氨基,乙氨基甲酰氨基,丙氨基甲酰氨基,异丙氨基甲酰氨基,环丙基氨基甲酰氨基,环丁基氨基甲酰氨基,环戊基氨基甲酰氨基,哌啶基-1-甲酰氨基,4-羟基哌啶基-1-甲酰氨基,4-N,N-二甲基哌啶基-1-甲酰氨基,4-N,N-二乙基哌啶基-1-甲酰氨基,四氢吡咯基-1-甲酰氨基,3-N,N-二甲基四氢吡咯基-1-甲酰氨基,3-N,N-二乙基四氢吡咯基-1-甲酰氨基,N-甲基哌嗪基-1-甲酰氨基,N-乙基哌嗪基-1-甲酰氨基,N-乙酰基哌嗪基-1-甲酰氨基,N-叔丁氧羰基哌嗪基-1-甲酰氨基,N-(2-羟基乙基)哌嗪基-1-甲酰氨基,N-(2-氰基乙基)哌嗪基-1-甲酰氨基,N-(2-N,N-二甲基氨基乙基)哌嗪基-1-甲酰氨基,N-(2-N,N-二乙基氨基乙基)哌嗪基-1-甲酰氨基,N-(3-羟基丙基)哌嗪基-1-甲酰氨基,N-(3-N,N-二甲基丙基)哌嗪基-1-甲酰氨基,N-(3-N,N-二乙基丙基)哌嗪基-1-甲酰氨基,吗啉基-1-甲酰氨基,3,5-二甲基吗啉基-1-甲酰氨基,4-(四氢吡咯基)哌啶基-1-甲酰氨基,4-(N-甲基-1-哌嗪基)哌啶基-1-甲酰氨基,4-(N-乙基-1-哌嗪基)哌啶基-1-甲酰氨基,4-(N-乙酰基-1-哌嗪基)哌啶基-1-甲酰氨基,N-(N-甲基-4-哌啶基)哌嗪基-1-甲酰氨基,(16)Z3与Z4可以形成含氧的取代或未取代的五-七元环;取代基可以选自与Z1相同的上述取代基,(17)Z3与Z4可以形成含氮的取代或未取代的五-七元环;取代基可以选自与Z1相同的上述取代基;(1)氢,氟,氯,溴,碘,硝基,氰基,(2)C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6环烷基,(3)哌啶基,4-N,N-二甲基氨基哌啶基,4-N,N-二乙基氨基哌啶基,4-N,N-二异丙基氨基哌啶基,4-羟基哌啶基,4-甲氧基哌啶基,4-乙氧基哌啶基,4-(N-甲基哌嗪-1-)哌啶基,4-(N-乙基哌嗪-1-)哌啶基,4-(N-异丙基哌嗪-1-)哌啶基,4-(N-乙酰基哌嗪-1-)哌啶基,4-(N-叔丁氧羰基哌嗪-1-)哌啶基,4-(N-甲磺酰基哌嗪-1-)哌啶基,4-(N-(2-羟基乙基)哌嗪-1-)哌啶基,4-(N-(2-氰基乙基)哌嗪-1-)哌啶基,4-(N-(3-羟基丙基)哌嗪-1-)哌啶基,4-(N-(2-N,N-二甲基氨基乙基)哌嗪-1-)哌啶基,4-(N-(2-N,N-二乙基乙基)哌嗪-1-)哌啶基,4-(N-(3-N,N-二甲基丙基)哌嗪-1-)哌啶基,4-(N-(3-N,N-二乙基丙基)哌嗪-1-)哌啶基,4-(四氢吡咯-1-)哌啶基,4-(3-N,N-二甲基氨基四氢吡咯-1-)哌啶基,4-(3-N,N-二乙基氨基四氢吡咯-1-)哌啶基,(4)哌啶-4-基,N-甲基-4-哌啶基,N-乙基-4-哌啶基,N-异丙基-4-哌啶基,N-乙酰基-4-哌啶基,N-叔丁氧羰基-4-哌啶基,N-甲磺酰基-4-哌啶基,N-(2-羟基乙基)-4-哌啶基,N-(2-N,N-二甲基氨基乙基)-4-哌啶基,N-(2-N,N-二乙基氨基乙基)-4-哌啶基,N-(2-氰基乙基)-4-哌啶基,N-(3-羟基丙基)-4-哌啶基,N-(3-N,N-二甲基氨基丙基)-4-哌啶基,N-(3-N,N-二乙基氨基丙基)-4-哌啶基,N-(3-氰基丙基)-4-哌啶基,N-氰基亚甲基-4-哌啶基;(1)氢,氟,氯,溴,碘,硝基,氰基,(2)C1-C6烷基,(3)哌啶基,4-N,N-二甲基氨基哌啶基,4-N,N-二乙基氨基哌啶基,4-N,N-二异丙基氨基哌啶基,4-羟基哌啶基,4-甲氧基哌啶基,4-乙氧基哌啶基;氢、4-N,N-二甲基氨基哌啶基;R 2选自:氢,甲基,乙基,异丙基,环丙基,甲氧基,乙氧基,异丙氧基,甲氨基,乙氨基,环丙基氨基,N,N-二甲基氨基,甲基乙基氨基,N,N-二乙基氨基,N,N-二异丙基氨基;优选地,R 2为异丙基;W 1,W 3,W 4,W 5各自独立地选自氢,氟,氯,溴,碘,硝基,氰基,C1-C6烷基,C1-C6烷氧基,C1-C6含氧烷基,C1-C6含氟烷基,C1-C6含氟烷氧基,C3-C6环烷基;优选地,W 1,W 3,W 4,W 5各自独立地选自氢,氟,氯,溴,碘,硝基,氰基,C1-C6烷基;更优选地,W 1,W 3,W 4,W 5各自独立地选自氢,甲基;最优选地,W 1,W 3,W 4为氢,W 5为氢或甲基。
- 制备权利要求中1-5任一项所述的化合物的方法,包括下面步骤:其中,R 1、R 2、R 3的定义如权利要求1-5中任一项所述,反应条件:(a)金属钯催化的偶联反应;(b)金属钯催化的偶联反应,或酸性条件下的亲核取代反应,或碱性条件下的亲核取代反应;(c)酸性条件下的亲核取代反应,或碱性条件下的亲核取代反应;所述金属钯催化剂选自醋酸钯、四(三苯基膦)钯、双三苯基磷二氯化钯、[1,1'-双(二苯基膦)二茂铁]二氯化钯、三(二亚苄基丙酮)二钯;所述碱性条件指以下任意物质存在的条件:三乙胺、二异丙基乙基胺、吡啶、碳酸氢钠、碳酸钠、碳酸钾、碳酸铯、氢氧化锂、氢氧化钠、氢氧化钾、氢化钠、氢化钾;所述酸性条件指以下任意物质存在的条件:乙酸、三氟乙酸、盐酸、甲磺酸、对甲苯磺酸、樟脑磺酸。
- 药物组合物,其包含权利要求1-5中任一项的化合物或其立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物以及任选的药学上可以接受的赋形剂。
- 权利要求1-5中任一项的化合物或其立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物或者权利要求7所述的药物组合物在制备用于预防和/或治疗生物体内BRK、BTK激酶或二者介导的疾病的药物中的用途,尤其是在制备用于预防和/或治疗乳腺癌、B细胞恶性肿瘤的药物中的用途。
- 预防和/治疗BRK、BTK激酶或二者介导的癌症及其他疾病的方法,其包括给予有需要的受试者预防和/或治疗有效量的权利要求1-5中任一项的化合物或其立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物或者权利要求7所述的药物组 合物;优选地,所述方法用于预防和/或治疗乳腺癌、B细胞恶性肿瘤。
- 权利要求1-5中任一项的化合物或其立体异构体、其前药、其药学上可接受的盐或其药学上可接受的溶剂合物或者权利要求7所述的药物组合物,其用于预防和/或治疗生物体内BRK、BTK激酶或二者介导的疾病,优选用于预防和/或治疗乳腺癌、B细胞恶性肿瘤。
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WO2006039718A2 (en) * | 2004-10-01 | 2006-04-13 | Amgen Inc | Aryl nitrogen-containing bicyclic compounds and their use as kinase inhibitors |
WO2009046448A1 (en) * | 2007-10-04 | 2009-04-09 | Intellikine, Inc. | Chemical entities and therapeutic uses thereof |
CN103140480A (zh) * | 2010-06-22 | 2013-06-05 | 弗维亚医药品公司 | 杂环化合物、它们的制备和它们的治疗应用 |
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WO2019204768A1 (en) * | 2018-04-20 | 2019-10-24 | The Regents Of The University Of California | Beta-adrenergic receptor allosteric modulators |
WO2021013084A1 (zh) * | 2019-07-19 | 2021-01-28 | 中国科学院上海药物研究所 | 稠环嘧啶氨基化合物、其制备方法、药物组合物及应用 |
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WO2006039718A2 (en) * | 2004-10-01 | 2006-04-13 | Amgen Inc | Aryl nitrogen-containing bicyclic compounds and their use as kinase inhibitors |
WO2009046448A1 (en) * | 2007-10-04 | 2009-04-09 | Intellikine, Inc. | Chemical entities and therapeutic uses thereof |
CN103140480A (zh) * | 2010-06-22 | 2013-06-05 | 弗维亚医药品公司 | 杂环化合物、它们的制备和它们的治疗应用 |
CN109305944A (zh) * | 2017-07-28 | 2019-02-05 | 深圳睿熙生物科技有限公司 | 布鲁顿酪氨酸激酶的抑制剂 |
WO2019204768A1 (en) * | 2018-04-20 | 2019-10-24 | The Regents Of The University Of California | Beta-adrenergic receptor allosteric modulators |
WO2021013084A1 (zh) * | 2019-07-19 | 2021-01-28 | 中国科学院上海药物研究所 | 稠环嘧啶氨基化合物、其制备方法、药物组合物及应用 |
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