ES2896943T3 - Compuesto de amino pirazolopirimidina usado como inhibidor de receptores con actividad tirosina quinasa de factores neurotróficos - Google Patents
Compuesto de amino pirazolopirimidina usado como inhibidor de receptores con actividad tirosina quinasa de factores neurotróficos Download PDFInfo
- Publication number
- ES2896943T3 ES2896943T3 ES17863410T ES17863410T ES2896943T3 ES 2896943 T3 ES2896943 T3 ES 2896943T3 ES 17863410 T ES17863410 T ES 17863410T ES 17863410 T ES17863410 T ES 17863410T ES 2896943 T3 ES2896943 T3 ES 2896943T3
- Authority
- ES
- Spain
- Prior art keywords
- group
- hydroxy
- independently selected
- optionally substituted
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- -1 Amino pyrazolopyrimidine compound Chemical class 0.000 title claims abstract description 201
- 230000000694 effects Effects 0.000 title claims description 20
- 108091008598 receptor tyrosine kinases Proteins 0.000 title claims description 7
- 102000027426 receptor tyrosine kinases Human genes 0.000 title claims description 7
- 108010025020 Nerve Growth Factor Proteins 0.000 title description 7
- 102000007072 Nerve Growth Factors Human genes 0.000 title description 5
- 239000003900 neurotrophic factor Substances 0.000 title description 5
- 239000003112 inhibitor Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 179
- 125000001424 substituent group Chemical group 0.000 claims abstract description 85
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 83
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 77
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 77
- 239000001257 hydrogen Substances 0.000 claims abstract description 77
- 125000003118 aryl group Chemical group 0.000 claims abstract description 53
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 53
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 31
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 25
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 25
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 15
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims abstract description 13
- 125000002757 morpholinyl group Chemical group 0.000 claims abstract description 11
- 101100079984 Caenorhabditis elegans nhr-9 gene Proteins 0.000 claims abstract description 9
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 8
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims abstract description 7
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 5
- YPJKMVATUPSWOH-UHFFFAOYSA-N nitrooxidanyl Chemical group [O][N+]([O-])=O YPJKMVATUPSWOH-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract 22
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 96
- 125000005843 halogen group Chemical group 0.000 claims description 59
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 43
- 125000001153 fluoro group Chemical group F* 0.000 claims description 41
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 33
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 29
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 23
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 23
- 125000002971 oxazolyl group Chemical group 0.000 claims description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims description 21
- 125000000335 thiazolyl group Chemical group 0.000 claims description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 19
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 17
- 201000010099 disease Diseases 0.000 claims description 16
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 16
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 15
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 14
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 14
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 14
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 13
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 12
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 11
- 125000002541 furyl group Chemical group 0.000 claims description 11
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 11
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 9
- 125000004076 pyridyl group Chemical group 0.000 claims description 9
- 230000001404 mediated effect Effects 0.000 claims description 8
- 125000005494 pyridonyl group Chemical group 0.000 claims description 8
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 claims description 7
- 125000004193 piperazinyl group Chemical group 0.000 claims description 7
- 125000003386 piperidinyl group Chemical group 0.000 claims description 7
- 125000003072 pyrazolidinyl group Chemical group 0.000 claims description 7
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 7
- 238000011282 treatment Methods 0.000 claims description 7
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 6
- 238000011321 prophylaxis Methods 0.000 claims description 6
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 6
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 4
- 125000004571 thiomorpholin-4-yl group Chemical group N1(CCSCC1)* 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 2
- SBUKLPSBNFWJCU-UHFFFAOYSA-N ClIBr Chemical group ClIBr SBUKLPSBNFWJCU-UHFFFAOYSA-N 0.000 claims description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 27
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract description 47
- 125000001475 halogen functional group Chemical group 0.000 abstract 8
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 114
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 99
- 239000000243 solution Substances 0.000 description 94
- 238000005160 1H NMR spectroscopy Methods 0.000 description 78
- 239000000203 mixture Substances 0.000 description 62
- 238000006243 chemical reaction Methods 0.000 description 56
- 0 C*(C(*)(CC1c(cc(cc2)F)c2F)CN1c1nc2c(C(*)=O)c(N(*)*)n[n]2cc1)=C Chemical compound C*(C(*)(CC1c(cc(cc2)F)c2F)CN1c1nc2c(C(*)=O)c(N(*)*)n[n]2cc1)=C 0.000 description 39
- 230000002829 reductive effect Effects 0.000 description 37
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- 238000010898 silica gel chromatography Methods 0.000 description 35
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- 239000000706 filtrate Substances 0.000 description 29
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 25
- 239000012074 organic phase Substances 0.000 description 25
- 239000011541 reaction mixture Substances 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- 238000000034 method Methods 0.000 description 20
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 17
- 238000003756 stirring Methods 0.000 description 17
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 16
- 239000012043 crude product Substances 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 14
- 229920006395 saturated elastomer Polymers 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 13
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 12
- 238000000746 purification Methods 0.000 description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- 101150111783 NTRK1 gene Proteins 0.000 description 10
- 108091000080 Phosphotransferase Proteins 0.000 description 10
- 238000003556 assay Methods 0.000 description 10
- 239000000546 pharmaceutical excipient Substances 0.000 description 10
- 102000020233 phosphotransferase Human genes 0.000 description 10
- HNYVPKNVKSTVJO-UHFFFAOYSA-N pyrazolo[1,5-a]pyrimidine-3-carboxylic acid Chemical compound C1=CC=NC2=C(C(=O)O)C=NN21 HNYVPKNVKSTVJO-UHFFFAOYSA-N 0.000 description 10
- 239000000523 sample Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 238000004809 thin layer chromatography Methods 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- 239000011550 stock solution Substances 0.000 description 8
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 7
- 241000124008 Mammalia Species 0.000 description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
- 101150117329 NTRK3 gene Proteins 0.000 description 7
- 101150056950 Ntrk2 gene Proteins 0.000 description 7
- YCAVTOUTYRMOGQ-UHFFFAOYSA-N ethyl 7-[3-[[3-(trifluoromethyl)benzoyl]amino]phenyl]pyrazolo[1,5-a]pyrimidine-3-carboxylate Chemical compound C=1C=NC2=C(C(=O)OCC)C=NN2C=1C(C=1)=CC=CC=1NC(=O)C1=CC=CC(C(F)(F)F)=C1 YCAVTOUTYRMOGQ-UHFFFAOYSA-N 0.000 description 7
- PUPFATUGTIQBQA-UZQPLGKSSA-N fluorophen Chemical compound C([C@@]1(C)C2=CC(O)=CC=C2C[C@H]2[C@@H]1C)CN2CCC1=CC=C(F)C=C1 PUPFATUGTIQBQA-UZQPLGKSSA-N 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- XMRIUEGHBZTNND-UHFFFAOYSA-N pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound C1=CC=NC2=C(C(=O)N)C=NN21 XMRIUEGHBZTNND-UHFFFAOYSA-N 0.000 description 7
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 235000019270 ammonium chloride Nutrition 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 229920001213 Polysorbate 20 Polymers 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 230000000875 corresponding effect Effects 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- 102000037865 fusion proteins Human genes 0.000 description 5
- 108020001507 fusion proteins Proteins 0.000 description 5
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 5
- 230000035772 mutation Effects 0.000 description 5
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 5
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 239000011535 reaction buffer Substances 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- LPCQBTAOTIZGAE-UHFFFAOYSA-N 2h-pyrimidine-1-carboxamide Chemical compound NC(=O)N1CN=CC=C1 LPCQBTAOTIZGAE-UHFFFAOYSA-N 0.000 description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- RRSNDVCODIMOFX-MPKOGUQCSA-N Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O Chemical compound Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O RRSNDVCODIMOFX-MPKOGUQCSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- VQFAIAKCILWQPZ-UHFFFAOYSA-N bromoacetone Chemical compound CC(=O)CBr VQFAIAKCILWQPZ-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 229910001873 dinitrogen Inorganic materials 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium ethoxide Chemical compound [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- LOHSQDXMJAKLOV-GFCCVEGCSA-N 2-amino-5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound NC(=O)c1c(N)nn2ccc(nc12)N1CCC[C@@H]1c1cc(F)ccc1F LOHSQDXMJAKLOV-GFCCVEGCSA-N 0.000 description 3
- XCRCSPKQEDMVBO-UHFFFAOYSA-N 2-bromo-1,4-difluorobenzene Chemical compound FC1=CC=C(F)C(Br)=C1 XCRCSPKQEDMVBO-UHFFFAOYSA-N 0.000 description 3
- OTLNPYWUJOZPPA-UHFFFAOYSA-M 4-nitrobenzoate Chemical compound [O-]C(=O)C1=CC=C([N+]([O-])=O)C=C1 OTLNPYWUJOZPPA-UHFFFAOYSA-M 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- 239000007995 HEPES buffer Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 229940126543 compound 14 Drugs 0.000 description 3
- 238000004590 computer program Methods 0.000 description 3
- 239000012470 diluted sample Substances 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 239000008298 dragée Substances 0.000 description 3
- 230000005284 excitation Effects 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 125000001207 fluorophenyl group Chemical group 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 125000002346 iodo group Chemical group I* 0.000 description 3
- 229910052742 iron Inorganic materials 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 125000003367 polycyclic group Chemical group 0.000 description 3
- 125000006413 ring segment Chemical group 0.000 description 3
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 2
- NCXSNNVYILYEBC-SNVBAGLBSA-N (2r)-2-(2,5-difluorophenyl)pyrrolidine Chemical compound FC1=CC=C(F)C([C@@H]2NCCC2)=C1 NCXSNNVYILYEBC-SNVBAGLBSA-N 0.000 description 2
- JSDBKAHWADVXFU-UHFFFAOYSA-N 1,3-dimethyluracil Chemical compound CN1C=CC(=O)N(C)C1=O JSDBKAHWADVXFU-UHFFFAOYSA-N 0.000 description 2
- HMVYYTRDXNKRBQ-UHFFFAOYSA-N 1,3-thiazole-4-carboxylic acid Chemical compound OC(=O)C1=CSC=N1 HMVYYTRDXNKRBQ-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- OTLNPYWUJOZPPA-UHFFFAOYSA-N 4-nitrobenzoic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1 OTLNPYWUJOZPPA-UHFFFAOYSA-N 0.000 description 2
- HVNKNWVPVZWGDW-UHFFFAOYSA-N 4-nitrobenzoic acid;hydrochloride Chemical compound Cl.OC(=O)C1=CC=C([N+]([O-])=O)C=C1 HVNKNWVPVZWGDW-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
- 102100035108 High affinity nerve growth factor receptor Human genes 0.000 description 2
- 101000596894 Homo sapiens High affinity nerve growth factor receptor Proteins 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 102100029166 NT-3 growth factor receptor Human genes 0.000 description 2
- 102000015336 Nerve Growth Factor Human genes 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 125000000392 cycloalkenyl group Chemical group 0.000 description 2
- 229910052805 deuterium Inorganic materials 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- KYTOUGMOZGVXTJ-PLNGDYQASA-N ethyl (z)-3-amino-4,4,4-trichloro-2-cyanobut-2-enoate Chemical compound CCOC(=O)C(\C#N)=C(/N)C(Cl)(Cl)Cl KYTOUGMOZGVXTJ-PLNGDYQASA-N 0.000 description 2
- VYBMXGPXEXCVID-UHFFFAOYSA-N ethyl 2-acetamido-5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate Chemical compound CCOC(=O)c1c(NC(C)=O)nn2ccc(Cl)nc12 VYBMXGPXEXCVID-UHFFFAOYSA-N 0.000 description 2
- XHUWDDXMORFULQ-UHFFFAOYSA-N ethyl 2h-pyrimidine-1-carboxylate Chemical compound CCOC(=O)N1CN=CC=C1 XHUWDDXMORFULQ-UHFFFAOYSA-N 0.000 description 2
- HRAWNPOJGRIJSB-UHFFFAOYSA-N ethyl 3,5-diamino-1h-pyrazole-4-carboxylate Chemical compound CCOC(=O)C=1C(N)=NNC=1N HRAWNPOJGRIJSB-UHFFFAOYSA-N 0.000 description 2
- VICYTAYPKBLQFB-UHFFFAOYSA-N ethyl 3-bromo-2-oxopropanoate Chemical compound CCOC(=O)C(=O)CBr VICYTAYPKBLQFB-UHFFFAOYSA-N 0.000 description 2
- KTTKLCJREVTRLS-UHFFFAOYSA-N ethyl 5-[2-(2,5-difluorophenyl)pyrrolidin-1-yl]-2-(methylcarbamoylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylate Chemical compound CCOC(=O)c1c(NC(=O)NC)nn2ccc(nc12)N1CCCC1c1cc(F)ccc1F KTTKLCJREVTRLS-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 2
- 229940053128 nerve growth factor Drugs 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- KBFZCYFAUHHOHW-UHFFFAOYSA-N pyrazolo[1,5-a]pyrimidin-2-amine Chemical compound N1=CC=CN2N=C(N)C=C21 KBFZCYFAUHHOHW-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 description 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 2
- JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- AXBIXVFQBHBANX-VUUHIHSGSA-N tert-butyl (4R)-2-(2,5-difluorophenyl)-4-hydroxypyrrolidine-1-carboxylate Chemical compound FC1=C(C=C(C=C1)F)C1N(C[C@@H](C1)O)C(=O)OC(C)(C)C AXBIXVFQBHBANX-VUUHIHSGSA-N 0.000 description 2
- ZVSAABUFHTUVQC-UHFFFAOYSA-N tert-butyl 2-(2,5-difluorophenyl)-4,4-difluoropyrrolidine-1-carboxylate Chemical compound FC1=C(C=C(C=C1)F)C1N(CC(C1)(F)F)C(=O)OC(C)(C)C ZVSAABUFHTUVQC-UHFFFAOYSA-N 0.000 description 2
- VQRKHCWOCAULBP-UHFFFAOYSA-N tert-butyl 2-(2,5-difluorophenyl)-4-oxopyrrolidine-1-carboxylate Chemical compound FC1=C(C=C(C=C1)F)C1N(CC(C1)=O)C(=O)OC(C)(C)C VQRKHCWOCAULBP-UHFFFAOYSA-N 0.000 description 2
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- 108010064892 trkC Receptor Proteins 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- NMLNIXYQBXUCPH-PVSHWOEXSA-N (3R)-5-(2,5-difluorophenyl)pyrrolidin-3-ol Chemical compound O[C@H]1CNC(C1)c1cc(F)ccc1F NMLNIXYQBXUCPH-PVSHWOEXSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- JHHZLHWJQPUNKB-BYPYZUCNSA-N (3s)-pyrrolidin-3-ol Chemical compound O[C@H]1CCNC1 JHHZLHWJQPUNKB-BYPYZUCNSA-N 0.000 description 1
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 1
- UCNGGGYMLHAMJG-UHFFFAOYSA-N 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole Chemical compound C1=NN(C)C=C1B1OC(C)(C)C(C)(C)O1 UCNGGGYMLHAMJG-UHFFFAOYSA-N 0.000 description 1
- WKHQADGJXFRQJD-UHFFFAOYSA-N 2,4,5-triphenyl-1,3-oxazole Chemical compound C1=CC=CC=C1C1=NC(C=2C=CC=CC=2)=C(C=2C=CC=CC=2)O1 WKHQADGJXFRQJD-UHFFFAOYSA-N 0.000 description 1
- MXAJVLBRTFIWOF-UHFFFAOYSA-N 2-(2,5-difluorophenyl)-1H-pyrrole Chemical compound FC1=CC(C2=CC=CN2)=C(F)C=C1 MXAJVLBRTFIWOF-UHFFFAOYSA-N 0.000 description 1
- HJYYBUFRTAGSFM-GFCCVEGCSA-N 2-amino-5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid Chemical compound Nc1nn2ccc(nc2c1C(O)=O)N1CCC[C@@H]1c1cc(F)ccc1F HJYYBUFRTAGSFM-GFCCVEGCSA-N 0.000 description 1
- GERGZDJWLXJWRG-JOYOIKCWSA-N 2-amino-5-[(2R,4S)-2-(2,5-difluorophenyl)-4-hydroxypyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound NC(=O)c1c(N)nn2ccc(nc12)N1C[C@@H](O)C[C@@H]1c1cc(F)ccc1F GERGZDJWLXJWRG-JOYOIKCWSA-N 0.000 description 1
- OYWAUYQPEXLVTP-HZMBPMFUSA-N 2-amino-5-[(2S,4S)-2-(2,5-difluorophenyl)-4-hydroxypyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile Chemical compound Nc1nn2ccc(nc2c1C#N)N1C[C@@H](O)C[C@H]1c1cc(F)ccc1F OYWAUYQPEXLVTP-HZMBPMFUSA-N 0.000 description 1
- INMDOYDAPWNQEW-UHFFFAOYSA-N 2-aminooxy-2-methylpropan-1-ol;hydrochloride Chemical compound Cl.OCC(C)(C)ON INMDOYDAPWNQEW-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- CESUXLKAADQNTB-ZETCQYMHSA-N 2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](N)=O CESUXLKAADQNTB-ZETCQYMHSA-N 0.000 description 1
- LSLNTJSQFVSWIW-UHFFFAOYSA-N 4-(2,2-dimethoxyethyl)morpholine Chemical compound COC(OC)CN1CCOCC1 LSLNTJSQFVSWIW-UHFFFAOYSA-N 0.000 description 1
- MCKOYDSNCWNCHG-UHFFFAOYSA-N 4-chloro-1-(2,5-difluorophenyl)butan-1-one Chemical compound FC1=CC=C(F)C(C(=O)CCCCl)=C1 MCKOYDSNCWNCHG-UHFFFAOYSA-N 0.000 description 1
- CDIIZULDSLKBKV-UHFFFAOYSA-N 4-chlorobutanoyl chloride Chemical compound ClCCCC(Cl)=O CDIIZULDSLKBKV-UHFFFAOYSA-N 0.000 description 1
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001826 4H-pyranyl group Chemical group O1C(=CCC=C1)* 0.000 description 1
- QIZHVCUPPAMGIW-UHFFFAOYSA-N 5-(2,5-difluorophenyl)-3,4-dihydro-2h-pyrrole Chemical compound FC1=CC=C(F)C(C=2CCCN=2)=C1 QIZHVCUPPAMGIW-UHFFFAOYSA-N 0.000 description 1
- AYRIJTTVHUWAEF-MRXNPFEDSA-N 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]-3-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-2-amine Chemical compound Cn1cc(cn1)-c1c(N)nn2ccc(nc12)N1CCC[C@@H]1c1cc(F)ccc1F AYRIJTTVHUWAEF-MRXNPFEDSA-N 0.000 description 1
- QNKFTFLPWYTPPR-UHFFFAOYSA-N 5-[2-(2,5-difluorophenyl)pyrrolidin-1-yl]-2-[(4-methoxyphenyl)methylamino]pyrazolo[1,5-a]pyrimidine-3-carbothioamide Chemical compound COc1ccc(CNc2nn3ccc(nc3c2C(N)=S)N2CCCC2c2cc(F)ccc2F)cc1 QNKFTFLPWYTPPR-UHFFFAOYSA-N 0.000 description 1
- LRYFLXCAOAMPRO-UHFFFAOYSA-N 5-[2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-2-amine Chemical compound Nc1cc2nc(ccn2n1)N1CCCC1c1cc(F)ccc1F LRYFLXCAOAMPRO-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 102100035080 BDNF/NT-3 growth factors receptor Human genes 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- HHWIJDSWVNBBCX-MAFKGAIPSA-N C/C=C/C(/C(C(CCC1)N1c(cc[n]1nc2N)nc1c2-c1nc(C)c[s]1)=C)=C/C=C(\C)/F Chemical compound C/C=C/C(/C(C(CCC1)N1c(cc[n]1nc2N)nc1c2-c1nc(C)c[s]1)=C)=C/C=C(\C)/F HHWIJDSWVNBBCX-MAFKGAIPSA-N 0.000 description 1
- WMGDQXDJYGTDSW-FNORWQNLSA-N C/N=C(\CCC1)/C1=O Chemical compound C/N=C(\CCC1)/C1=O WMGDQXDJYGTDSW-FNORWQNLSA-N 0.000 description 1
- ALEFTLDGTHBKDB-UHFFFAOYSA-N C1CC(N(C1)C2=NC3=C(C(=NN3C=C2)NC(=O)OC4=CC=C(C=C4)[N+](=O)[O-])C(=O)O)C5=C(C=CC(=C5)F)F Chemical compound C1CC(N(C1)C2=NC3=C(C(=NN3C=C2)NC(=O)OC4=CC=C(C=C4)[N+](=O)[O-])C(=O)O)C5=C(C=CC(=C5)F)F ALEFTLDGTHBKDB-UHFFFAOYSA-N 0.000 description 1
- QYYLABQOCUNFQK-UHFFFAOYSA-N CC(C)(C)OC(N(CCC1)C1(c1c(C)ccc(F)c1)O)=O Chemical compound CC(C)(C)OC(N(CCC1)C1(c1c(C)ccc(F)c1)O)=O QYYLABQOCUNFQK-UHFFFAOYSA-N 0.000 description 1
- KVZRLNKCJUCCCI-UHFFFAOYSA-N CC(C)(C)OC(Nc1n[n](ccc(N(CCC2)C2c(cc(cc2)F)c2F)n2)c2c1Br)=O Chemical compound CC(C)(C)OC(Nc1n[n](ccc(N(CCC2)C2c(cc(cc2)F)c2F)n2)c2c1Br)=O KVZRLNKCJUCCCI-UHFFFAOYSA-N 0.000 description 1
- PHOGGDQONSCZJK-UHFFFAOYSA-N CC(C)(C)[S-2](NC(CCCCl)c1cc(F)ccc1F)=O Chemical compound CC(C)(C)[S-2](NC(CCCCl)c1cc(F)ccc1F)=O PHOGGDQONSCZJK-UHFFFAOYSA-N 0.000 description 1
- NDWSQFNZFJNQGR-UHFFFAOYSA-N CC(C)(C)[SH-](N=C(CCCCl)c1cc(F)ccc1F)=O Chemical compound CC(C)(C)[SH-](N=C(CCCCl)c1cc(F)ccc1F)=O NDWSQFNZFJNQGR-UHFFFAOYSA-N 0.000 description 1
- LNNVTDNRPOYNRU-UHFFFAOYSA-N CC(C)c1cc(F)cc(C(C2)NCC2[O]=C)c1C(C)=C Chemical compound CC(C)c1cc(F)cc(C(C2)NCC2[O]=C)c1C(C)=C LNNVTDNRPOYNRU-UHFFFAOYSA-N 0.000 description 1
- APODMFKFJMXBCQ-UHFFFAOYSA-N CCCc(cc1)c(C(CC(CCO)=C2)N2c2nc3c(C(OCC)=O)c(N)n[n]3cc2)cc1F Chemical compound CCCc(cc1)c(C(CC(CCO)=C2)N2c2nc3c(C(OCC)=O)c(N)n[n]3cc2)cc1F APODMFKFJMXBCQ-UHFFFAOYSA-N 0.000 description 1
- GTWVIKDRWFUGIT-UHFFFAOYSA-N CCCc(cc1)c(C(CCC2)N2c2nc3c(C(OCC)=O)c(N)n[n]3cc2)cc1F Chemical compound CCCc(cc1)c(C(CCC2)N2c2nc3c(C(OCC)=O)c(N)n[n]3cc2)cc1F GTWVIKDRWFUGIT-UHFFFAOYSA-N 0.000 description 1
- RQFDSRSJBBSSJR-UHFFFAOYSA-N CCCc(cc1)c(C(CCC2)N2c2nc3cc(N)n[n]3cc2)cc1F Chemical compound CCCc(cc1)c(C(CCC2)N2c2nc3cc(N)n[n]3cc2)cc1F RQFDSRSJBBSSJR-UHFFFAOYSA-N 0.000 description 1
- CAZVMBHLALRBHK-QWAKEFERSA-N CCCc(cc1)c([C@@H]2CCC(Cc3nc4c(C(NCCN(C)C)=O)c(N)n[n]4cc3)CCC2)cc1F Chemical compound CCCc(cc1)c([C@@H]2CCC(Cc3nc4c(C(NCCN(C)C)=O)c(N)n[n]4cc3)CCC2)cc1F CAZVMBHLALRBHK-QWAKEFERSA-N 0.000 description 1
- NQQRUNYVAJATDA-UHFFFAOYSA-O CCOC(C(C(N)=N)=C([NH2+]C=C1)N=C1N(CC(C1)=O)C1c1c(C=CC)ccc(F)c1)=[O]=C Chemical compound CCOC(C(C(N)=N)=C([NH2+]C=C1)N=C1N(CC(C1)=O)C1c1c(C=CC)ccc(F)c1)=[O]=C NQQRUNYVAJATDA-UHFFFAOYSA-O 0.000 description 1
- SERUBTWFVJCHSV-UHFFFAOYSA-N CCOC(C/C(/N)=N\N1C=CC(N(CCC2)C2C2=CC(F)=CC(C)C2F)=NC1C)=O Chemical compound CCOC(C/C(/N)=N\N1C=CC(N(CCC2)C2C2=CC(F)=CC(C)C2F)=NC1C)=O SERUBTWFVJCHSV-UHFFFAOYSA-N 0.000 description 1
- VVGUCMMZWDVECE-UHFFFAOYSA-N CCOC(c(c(N)n[n]1cc2)c1nc2N(CC(O)=C1)C1c1c(C2CC2)ccc(F)c1)=O Chemical compound CCOC(c(c(N)n[n]1cc2)c1nc2N(CC(O)=C1)C1c1c(C2CC2)ccc(F)c1)=O VVGUCMMZWDVECE-UHFFFAOYSA-N 0.000 description 1
- CMDGQQACQLVQAN-CQSZACIVSA-N CCOC(c(c(N)n[n]1cc2)c1nc2N(CCC1)[C@H]1c(cc(cc1)F)c1F)=O Chemical compound CCOC(c(c(N)n[n]1cc2)c1nc2N(CCC1)[C@H]1c(cc(cc1)F)c1F)=O CMDGQQACQLVQAN-CQSZACIVSA-N 0.000 description 1
- VCHSBIMXYJSASK-UHFFFAOYSA-N CCc(c(C(CCC1)N1C(OC(C)(C)C)=O)c1)ccc1F Chemical compound CCc(c(C(CCC1)N1C(OC(C)(C)C)=O)c1)ccc1F VCHSBIMXYJSASK-UHFFFAOYSA-N 0.000 description 1
- MNTSXXXTFBZTOD-UHFFFAOYSA-N CCc(cc1)c(C(CC(C2)=O)N2C(OC(C)(C)C)=O)cc1F Chemical compound CCc(cc1)c(C(CC(C2)=O)N2C(OC(C)(C)C)=O)cc1F MNTSXXXTFBZTOD-UHFFFAOYSA-N 0.000 description 1
- HOQKXXKZPSGKBF-UHFFFAOYSA-N CCc(cc1)c(C(CCCNC(OC(C)(C)C)=O)O)cc1F Chemical compound CCc(cc1)c(C(CCCNC(OC(C)(C)C)=O)O)cc1F HOQKXXKZPSGKBF-UHFFFAOYSA-N 0.000 description 1
- PPEAAOCRUNMLHO-IWPPFLRJSA-N CCc(cc1[C@@H](CCC2)N2S(C(C)(C)C)=O)ccc1F Chemical compound CCc(cc1[C@@H](CCC2)N2S(C(C)(C)C)=O)ccc1F PPEAAOCRUNMLHO-IWPPFLRJSA-N 0.000 description 1
- NLYLYDRAUYUIOW-DYIOSXRMSA-N C[C@@H](C[C@@H]1c(cc(cc2)F)c2F)CN1C(C=C[n]1nc2N)Nc1c2C#N Chemical compound C[C@@H](C[C@@H]1c(cc(cc2)F)c2F)CN1C(C=C[n]1nc2N)Nc1c2C#N NLYLYDRAUYUIOW-DYIOSXRMSA-N 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- QWJTVDZSNQZZKT-UHFFFAOYSA-N Cc(cc1)c(C2NCCC2)cc1F Chemical compound Cc(cc1)c(C2NCCC2)cc1F QWJTVDZSNQZZKT-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 101000596896 Homo sapiens BDNF/NT-3 growth factors receptor Proteins 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- OXMXXXUBBHALNH-UHFFFAOYSA-N NC(c(c(N)n[n]1cc2)c1nc2N(CCC1)C1c(cc(cc1)F)c1F)=S Chemical compound NC(c(c(N)n[n]1cc2)c1nc2N(CCC1)C1c(cc(cc1)F)c1F)=S OXMXXXUBBHALNH-UHFFFAOYSA-N 0.000 description 1
- 229910019501 NaVO3 Inorganic materials 0.000 description 1
- UPOMOCVDUOVFEU-SWLSCSKDSA-N Nc1n[n](ccc(N(C[C@H](C2)F)[C@H]2c(cc(cc2)F)c2F)n2)c2c1C(NC1(CO)CC1)=O Chemical compound Nc1n[n](ccc(N(C[C@H](C2)F)[C@H]2c(cc(cc2)F)c2F)n2)c2c1C(NC1(CO)CC1)=O UPOMOCVDUOVFEU-SWLSCSKDSA-N 0.000 description 1
- BYLVLCCXPZEVOK-XHDPSFHLSA-N Nc1n[n](ccc(N(C[C@H](C2)F)[C@H]2c2cc(F)ccc2F)n2)c2c1C(NC1CC1)=O Chemical compound Nc1n[n](ccc(N(C[C@H](C2)F)[C@H]2c2cc(F)ccc2F)n2)c2c1C(NC1CC1)=O BYLVLCCXPZEVOK-XHDPSFHLSA-N 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 108091005682 Receptor kinases Proteins 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- DRUIESSIVFYOMK-UHFFFAOYSA-N Trichloroacetonitrile Chemical compound ClC(Cl)(Cl)C#N DRUIESSIVFYOMK-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 229940096912 Trk tyrosine kinase inhibitor Drugs 0.000 description 1
- 102000005937 Tropomyosin Human genes 0.000 description 1
- 108010030743 Tropomyosin Proteins 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- ULEMJGCUGKDKTD-UHFFFAOYSA-N [1-(hydroxymethyl)cyclopropyl]azanium;chloride Chemical compound Cl.OCC1(N)CC1 ULEMJGCUGKDKTD-UHFFFAOYSA-N 0.000 description 1
- PLIJFDZDSCTNQL-PIVQAISJSA-N [2-[2-amino-5-[2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-1,3-thiazol-4-yl]-[(3S)-3-hydroxypyrrolidin-1-yl]methanone Chemical compound Nc1nn2ccc(nc2c1-c1nc(cs1)C(=O)N1CC[C@H](O)C1)N1CCCC1c1cc(F)ccc1F PLIJFDZDSCTNQL-PIVQAISJSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000033 alkoxyamino group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 230000035578 autophosphorylation Effects 0.000 description 1
- 210000003050 axon Anatomy 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 238000010170 biological method Methods 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- PCDHSSHKDZYLLI-UHFFFAOYSA-N butan-1-one Chemical compound CCC[C]=O PCDHSSHKDZYLLI-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 239000000460 chlorine Chemical group 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 125000004465 cycloalkenyloxy group Chemical group 0.000 description 1
- 125000000000 cycloalkoxy group Chemical group 0.000 description 1
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 125000005054 dihydropyrrolyl group Chemical group [H]C1=C([H])C([H])([H])C([H])([H])N1* 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- 230000007783 downstream signaling Effects 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- KPIZQQISZJNLGX-UHFFFAOYSA-N ethyl 2-[2-amino-5-[2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-1,3-thiazole-4-carboxylate Chemical compound CCOC(=O)c1csc(n1)-c1c(N)nn2ccc(nc12)N1CCCC1c1cc(F)ccc1F KPIZQQISZJNLGX-UHFFFAOYSA-N 0.000 description 1
- SOXVSVKYFGDFIB-ZSOXZCCMSA-N ethyl 2-amino-5-[(4S)-2-(2,5-difluorophenyl)-4-hydroxypyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxylate Chemical compound [C@H]1(O)CC(C2=C(F)C=CC(F)=C2)N(C1)C1=NC2=C(C(=NN2C=C1)N)C(=O)OCC SOXVSVKYFGDFIB-ZSOXZCCMSA-N 0.000 description 1
- CMDGQQACQLVQAN-UHFFFAOYSA-N ethyl 2-amino-5-[2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxylate Chemical compound CCOC(=O)c1c(N)nn2ccc(nc12)N1CCCC1c1cc(F)ccc1F CMDGQQACQLVQAN-UHFFFAOYSA-N 0.000 description 1
- UKRYTIBFBUCJGB-UHFFFAOYSA-N ethyl 2-amino-5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate Chemical compound CCOC(=O)C1=C2N=C(Cl)C=CN2N=C1N UKRYTIBFBUCJGB-UHFFFAOYSA-N 0.000 description 1
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 description 1
- MYQGVTWETGWICD-UHFFFAOYSA-N ethyl 5-[2-(2,5-difluorophenyl)pyrrolidin-1-yl]-2-[(4-nitrophenoxy)carbonylamino]pyrazolo[1,5-a]pyrimidine-3-carboxylate Chemical compound CCOC(=O)c1c(NC(=O)Oc2ccc(cc2)[N+]([O-])=O)nn2ccc(nc12)N1CCCC1c1cc(F)ccc1F MYQGVTWETGWICD-UHFFFAOYSA-N 0.000 description 1
- JEMAMNBFHPIPCR-UHFFFAOYSA-N ethyl pyrazolo[1,5-a]pyrimidine-3-carboxylate Chemical compound C1=CC=NC2=C(C(=O)OCC)C=NN21 JEMAMNBFHPIPCR-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 125000000262 haloalkenyl group Chemical group 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Chemical group 0.000 description 1
- 239000011630 iodine Chemical group 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- VMOWKUTXPNPTEN-UHFFFAOYSA-N n,n-dimethylpropan-2-amine Chemical compound CC(C)N(C)C VMOWKUTXPNPTEN-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 description 1
- XWESXZZECGOXDQ-UHFFFAOYSA-N n-tert-butylhydroxylamine Chemical compound CC(C)(C)NO XWESXZZECGOXDQ-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000030363 nerve development Effects 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- XZTSFVPMMQNIAJ-UHFFFAOYSA-N o-(2-ethenoxyethyl)hydroxylamine Chemical group NOCCOC=C XZTSFVPMMQNIAJ-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000008203 oral pharmaceutical composition Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 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 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000013610 patient sample Substances 0.000 description 1
- 238000002732 pharmacokinetic assay Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000006920 protein precipitation Effects 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 102000034285 signal transducing proteins Human genes 0.000 description 1
- 108091006024 signal transducing proteins Proteins 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- CMZUMMUJMWNLFH-UHFFFAOYSA-N sodium metavanadate Chemical compound [Na+].[O-][V](=O)=O CMZUMMUJMWNLFH-UHFFFAOYSA-N 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- OWRVZENYEUUFKU-QFBILLFUSA-N tert-butyl (2R,4S)-2-(2,5-difluorophenyl)-4-(4-nitrobenzoyl)oxypyrrolidine-1-carboxylate Chemical compound FC1=C(C=C(C=C1)F)[C@@H]1N(C[C@H](C1)OC(C1=CC=C(C=C1)[N+](=O)[O-])=O)C(=O)OC(C)(C)C OWRVZENYEUUFKU-QFBILLFUSA-N 0.000 description 1
- SYENXVCLSYZWBK-GXFFZTMASA-N tert-butyl (2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidine-1-carboxylate Chemical compound FC1=C(C=C(C=C1)F)[C@@H]1N(C[C@H](C1)F)C(=O)OC(C)(C)C SYENXVCLSYZWBK-GXFFZTMASA-N 0.000 description 1
- SYENXVCLSYZWBK-GWCFXTLKSA-N tert-butyl (2S,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidine-1-carboxylate Chemical compound FC1=C(C=C(C=C1)F)[C@H]1N(C[C@H](C1)F)C(=O)OC(C)(C)C SYENXVCLSYZWBK-GWCFXTLKSA-N 0.000 description 1
- GJJYYMXBCYYXPQ-UHFFFAOYSA-N tert-butyl 2-oxopyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC1=O GJJYYMXBCYYXPQ-UHFFFAOYSA-N 0.000 description 1
- UDCCOLDRWMCMFI-NNJIEVJOSA-N tert-butyl N-[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-4-(2,5-difluorophenyl)-4-hydroxybutyl]carbamate Chemical compound [Si](C)(C)(C(C)(C)C)O[C@@H](CNC(OC(C)(C)C)=O)CC(O)C1=C(C=CC(=C1)F)F UDCCOLDRWMCMFI-NNJIEVJOSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610970314 | 2016-10-28 | ||
| CN201710044000 | 2017-01-21 | ||
| PCT/CN2017/108100 WO2018077246A1 (zh) | 2016-10-28 | 2017-10-27 | 用作神经营养因子酪氨酸激酶受体抑制剂的氨基吡唑并嘧啶化合物 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2896943T3 true ES2896943T3 (es) | 2022-02-28 |
Family
ID=62024344
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES17863410T Active ES2896943T3 (es) | 2016-10-28 | 2017-10-27 | Compuesto de amino pirazolopirimidina usado como inhibidor de receptores con actividad tirosina quinasa de factores neurotróficos |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US10829492B2 (https=) |
| EP (1) | EP3533796B1 (https=) |
| JP (1) | JP7046940B2 (https=) |
| KR (1) | KR102616249B1 (https=) |
| CN (1) | CN109890820B (https=) |
| AU (1) | AU2017348826B2 (https=) |
| CA (1) | CA3041942C (https=) |
| DK (1) | DK3533796T3 (https=) |
| ES (1) | ES2896943T3 (https=) |
| HU (1) | HUE057733T2 (https=) |
| MX (1) | MX380283B (https=) |
| PL (1) | PL3533796T3 (https=) |
| PT (1) | PT3533796T (https=) |
| RU (1) | RU2764523C2 (https=) |
| WO (1) | WO2018077246A1 (https=) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11286264B2 (en) * | 2017-07-28 | 2022-03-29 | Turning Point Therapeutics, Inc. | Macrocyclic compounds and uses thereof |
| DK3674307T3 (da) | 2017-08-23 | 2023-09-11 | Chia Tai Tianqing Pharmaceutical Group Co Ltd | Makrocyklus indeholdende aminopyrazol og pyrimidin og farmaceutisk sammensætning og anvendelse deraf |
| CN108794370A (zh) * | 2018-07-31 | 2018-11-13 | 上海弈柯莱生物医药科技有限公司 | 一种拉罗替尼中间体的制备方法 |
| CA3122136A1 (en) * | 2018-12-07 | 2021-06-11 | Betta Pharmaceuticals Co., Ltd | Tyrosine kinase inhibitors, compositions and methods there of |
| JP7209415B2 (ja) | 2019-03-19 | 2023-01-20 | セントラル チャイナ ノーマル ユニバーシティ | ピラゾロピリミジン化合物、医薬組成物、及びその使用 |
| CN112979654B (zh) * | 2019-12-16 | 2024-03-19 | 赛诺哈勃药业（成都）有限公司 | 杂芳基稠环化合物、其制备方法及应用 |
| TW202214635A (zh) * | 2020-06-11 | 2022-04-16 | 大陸商貝達藥業股份有限公司 | 酪氨酸激酶抑制劑的鹽型、晶型、藥物組合物及其用途 |
| CN111620881B (zh) * | 2020-07-08 | 2023-03-31 | 浙江合聚生物医药有限公司 | 拉罗替尼衍生物及其制备方法和应用 |
| CN113563343B (zh) * | 2020-07-27 | 2022-05-24 | 杭州邦顺制药有限公司 | 取代的吡唑并[1,5-a]嘧啶化合物及其用途 |
| CN112010860B (zh) * | 2020-08-05 | 2023-03-10 | 南京纳丁菲医药科技有限公司 | 苄氧基吡唑并嘧啶化合物和药物组合物及其应用 |
| CN114437075B (zh) * | 2020-11-03 | 2026-01-30 | 上海瑶琪生物科技有限公司 | 用作ntrk激酶抑制剂的化合物及其应用 |
| CN113200963A (zh) * | 2021-03-31 | 2021-08-03 | 广东石油化工学院 | N-(吡咯基)-3-吡唑基胺及其制备方法 |
| JP7840066B2 (ja) * | 2021-05-03 | 2026-04-03 | ジェービーケーラボ カンパニー リミテッド | ２，６－ジクロロ－４－（４－（４－ヒドロキシシクロヘキシルアミノ）－７ｈ－ピロロ［２，３－ｄ］ピリミジン－５－イル）フェノールを活性成分として含有する、がんを予防、緩和、または処置するための医薬組成物 |
| CN117751121A (zh) * | 2021-07-30 | 2024-03-22 | 正大天晴药业集团股份有限公司 | 氨基吡唑并嘧啶化合物的晶体 |
| WO2023011616A1 (zh) * | 2021-08-06 | 2023-02-09 | 正大天晴药业集团股份有限公司 | 氨基吡唑并嘧啶化合物在治疗trk激酶介导的肿瘤中的用途 |
| CN117088800B (zh) * | 2023-08-18 | 2024-05-28 | 龙曦宁（上海）医药科技有限公司 | 一种5-甲基吡咯烷-3-醇盐酸盐的制备方法 |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10356579A1 (de) | 2003-12-04 | 2005-07-07 | Merck Patent Gmbh | Aminderivate |
| WO2009140128A2 (en) | 2008-05-13 | 2009-11-19 | Irm Llc | Compounds and compositions as kinase inhibitors |
| RU2509078C2 (ru) | 2008-07-01 | 2014-03-10 | Дженентек, Инк. | Бициклические гетероциклы в качестве ингибиторов киназы мек |
| PT2350075E (pt) | 2008-09-22 | 2014-06-09 | Array Biopharma Inc | Compostos imidazo[1,2b]piridazina substituídos como inibidores da trk cinase |
| AR074052A1 (es) * | 2008-10-22 | 2010-12-22 | Array Biopharma Inc | Compuestos pirazolo{1,5-a}pirimidina sustituida como inhibidores de trk cinasa |
| AR077468A1 (es) | 2009-07-09 | 2011-08-31 | Array Biopharma Inc | Compuestos de pirazolo (1,5 -a) pirimidina sustituidos como inhibidores de trk- quinasa |
| WO2012034095A1 (en) * | 2010-09-09 | 2012-03-15 | Irm Llc | Compounds and compositions as trk inhibitors |
| WO2012116217A1 (en) | 2011-02-25 | 2012-08-30 | Irm Llc | Compounds and compositions as trk inhibitors |
| WO2013028263A1 (en) | 2011-08-24 | 2013-02-28 | Glaxosmithkline Llc | Pyrazolopyrimidine derivatives as pi3 kinase inhibitors |
| KR20140105508A (ko) * | 2011-12-12 | 2014-09-01 | 닥터 레디스 레보러터리즈 리미티드 | 트로포미오신 수용체 키나제(Trk) 억제제인 치환된 피라졸로[1,5-a]피리딘 |
| MX362181B (es) | 2013-02-19 | 2019-01-08 | Ono Pharmaceutical Co | Compuesto inhibidor de cinasa del receptor de tropomiosina (trk). |
| WO2014143242A1 (en) | 2013-03-15 | 2014-09-18 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of atr kinase |
| CN104650092B (zh) * | 2013-11-16 | 2017-11-10 | 广东东阳光药业有限公司 | 取代的杂芳基化合物及其组合物和用途 |
| DK3077397T3 (da) * | 2013-12-06 | 2019-12-16 | Vertex Pharma | 2-amino-6-fluor-n-[5-fluor-pyridin-3-yl]pyrazolo[1,5-a]pyrimidin-3-carboxamidforbindelse anvendelig som atr-kinase-inhibitor, dens fremstilling, forskellige faste former og radiomarkerede derivater deraf |
| CA2971024C (en) | 2014-12-15 | 2023-09-26 | Handok Inc. | Fused ring heteroaryl compounds and their use as trk inhibitors |
-
2017
- 2017-10-27 AU AU2017348826A patent/AU2017348826B2/en active Active
- 2017-10-27 KR KR1020197015241A patent/KR102616249B1/ko active Active
- 2017-10-27 WO PCT/CN2017/108100 patent/WO2018077246A1/zh not_active Ceased
- 2017-10-27 PT PT178634101T patent/PT3533796T/pt unknown
- 2017-10-27 HU HUE17863410A patent/HUE057733T2/hu unknown
- 2017-10-27 JP JP2019522962A patent/JP7046940B2/ja active Active
- 2017-10-27 MX MX2019004847A patent/MX380283B/es unknown
- 2017-10-27 PL PL17863410T patent/PL3533796T3/pl unknown
- 2017-10-27 ES ES17863410T patent/ES2896943T3/es active Active
- 2017-10-27 US US16/345,679 patent/US10829492B2/en active Active
- 2017-10-27 DK DK17863410.1T patent/DK3533796T3/da active
- 2017-10-27 RU RU2019114600A patent/RU2764523C2/ru active
- 2017-10-27 CA CA3041942A patent/CA3041942C/en active Active
- 2017-10-27 CN CN201780064022.6A patent/CN109890820B/zh active Active
- 2017-10-27 EP EP17863410.1A patent/EP3533796B1/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| PL3533796T3 (pl) | 2022-01-17 |
| CN109890820B (zh) | 2020-11-03 |
| US10829492B2 (en) | 2020-11-10 |
| MX380283B (es) | 2025-03-12 |
| KR102616249B1 (ko) | 2023-12-21 |
| EP3533796B1 (en) | 2021-09-29 |
| RU2019114600A3 (https=) | 2021-02-20 |
| US20190352306A1 (en) | 2019-11-21 |
| CA3041942C (en) | 2023-03-14 |
| MX2019004847A (es) | 2019-08-29 |
| KR20190067913A (ko) | 2019-06-17 |
| BR112019008656A8 (pt) | 2022-06-07 |
| WO2018077246A1 (zh) | 2018-05-03 |
| AU2017348826B2 (en) | 2021-12-02 |
| DK3533796T3 (da) | 2021-11-08 |
| EP3533796A4 (en) | 2020-06-03 |
| BR112019008656A2 (pt) | 2019-07-09 |
| PT3533796T (pt) | 2021-11-18 |
| EP3533796A1 (en) | 2019-09-04 |
| RU2019114600A (ru) | 2020-11-30 |
| JP7046940B2 (ja) | 2022-04-04 |
| JP2019537588A (ja) | 2019-12-26 |
| CA3041942A1 (en) | 2018-05-03 |
| CN109890820A (zh) | 2019-06-14 |
| AU2017348826A1 (en) | 2019-05-23 |
| HUE057733T2 (hu) | 2022-06-28 |
| RU2764523C2 (ru) | 2022-01-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2896943T3 (es) | Compuesto de amino pirazolopirimidina usado como inhibidor de receptores con actividad tirosina quinasa de factores neurotróficos | |
| ES2951427T3 (es) | Macrociclo que contiene aminopirazol y pirimidina y composición farmacéutica y uso del mismo | |
| ES2601004T3 (es) | Compuestos pirazol-4-il-heterociclil-carboxamida y métodos de uso | |
| CN119585287A (zh) | Kras g12d蛋白水解靶向嵌合体 | |
| US20260015363A1 (en) | Substituted pyrimidine-fused ring inhibitor, method for preparing same, and use thereof | |
| JP2024539269A (ja) | Ｃｒｂｎ ｅ３リガーゼリガンド化合物、当該リガンド化合物に基づいて開発したタンパク質分解剤及びそれらの応用 | |
| JP2025528126A (ja) | 複素環式化合物、その組成物、及びそれらによる処置方法 | |
| US20230167118A1 (en) | Degradation of bruton's tyrosine kinase (btk) by conjugation of btk inidbitors with e3 ligase ligand and methods of use | |
| ES3037595T3 (en) | Akt inhibitor | |
| EP2632898A1 (en) | Heterocyclic tyrosine kinase inhibitors | |
| CN116783183B (zh) | 用于治疗贫血和癌症的vhl抑制剂 | |
| CA3197470A1 (en) | Bicyclic compounds | |
| WO2023151635A1 (zh) | 基于喹唑啉取代戊二酰亚胺骨架的化合物及其应用 | |
| BR112019008656B1 (pt) | Composto de aminopirazolopirimidina, composição farmacêutica que compreende o mesmo e uso do dito composto para a profilaxia ou o tratamento de uma doença mediada por receptor de tirosina quinase de fator neurotrófico | |
| EA050708B1 (ru) | Деградация тирозинкиназы брутона (btk) посредством конъюгации ингибиторов btk с лигандом лигазы е3 и способы применения | |
| HK40002935B (en) | Amino pyrazolopyrimidine compound used as neurotrophic factor tyrosine kinase receptor inhibitor | |
| HK40002935A (en) | Amino pyrazolopyrimidine compound used as neurotrophic factor tyrosine kinase receptor inhibitor | |
| HK40019194A (en) | Macrocycle containing aminopyrazole and pyrimidine and pharmaceutical composition and use thereof | |
| HK40019194B (en) | Macrocycle containing aminopyrazole and pyrimidine and pharmaceutical composition and use thereof |