JP5503655B2 - Ｔｒｋキナーゼ阻害剤としての置換イミダゾ［１，２ｂ］ピリダジン化合物 - Google Patents

Ｔｒｋキナーゼ阻害剤としての置換イミダゾ［１，２ｂ］ピリダジン化合物 Download PDF

Info

Publication number: JP5503655B2
Authority: JP; Japan
Prior art keywords: alkyl; difluorophenyl; imidazo; pyridazin; pyrrolidin
Prior art date: 2008-09-22
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.): Expired - Fee Related

Application number

JP2011528046A

Other languages

English (en)

Japanese (ja)

Other versions

JP2012503018A5 (2

JP2012503018A (ja

Inventor

スティーブンダブリュー．アンドリューズ，

ジュリアハーズ，

ユートンチャン，

ガンチャン，

Original Assignee

アレイバイオファーマ、インコーポレイテッド

Priority date (The priority date 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 date listed.)

2008-09-22

Filing date

2009-09-21

Publication date

2014-05-28

2009-09-21 Application filed by アレイバイオファーマ、インコーポレイテッド filed Critical アレイバイオファーマ、インコーポレイテッド

2012-02-02 Publication of JP2012503018A publication Critical patent/JP2012503018A/ja

2012-11-01 Publication of JP2012503018A5 publication Critical patent/JP2012503018A5/ja

2014-05-28 Application granted granted Critical

2014-05-28 Publication of JP5503655B2 publication Critical patent/JP5503655B2/ja

Status Expired - Fee Related legal-status Critical Current

2029-09-21 Anticipated expiration legal-status Critical

Links

150000004942 imidazo[1,2-b]pyridazines Chemical class 0.000 title description 5
229940043355 kinase inhibitor Drugs 0.000 title 1
239000003757 phosphotransferase inhibitor Substances 0.000 title 1
125000000217 alkyl group Chemical group 0.000 claims description 260
150000001875 compounds Chemical class 0.000 claims description 163
125000001424 substituent group Chemical group 0.000 claims description 86
-1 hetAr 3 Chemical group 0.000 claims description 83
229910052736 halogen Inorganic materials 0.000 claims description 68
150000002367 halogens Chemical class 0.000 claims description 68
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 63
WIEBBBIZJOGRCE-HXUWFJFHSA-N tert-butyl 4-[[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]carbamoyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 WIEBBBIZJOGRCE-HXUWFJFHSA-N 0.000 claims description 48
125000000623 heterocyclic group Chemical group 0.000 claims description 47
125000003545 alkoxy group Chemical group 0.000 claims description 46
125000005842 heteroatom Chemical group 0.000 claims description 42
238000000034 method Methods 0.000 claims description 42
229910052757 nitrogen Inorganic materials 0.000 claims description 40
229910052739 hydrogen Inorganic materials 0.000 claims description 37
150000003839 salts Chemical class 0.000 claims description 37
206010028980 Neoplasm Diseases 0.000 claims description 32
208000002193 Pain Diseases 0.000 claims description 32
125000002768 hydroxyalkyl group Chemical group 0.000 claims description 30
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 27
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 26
238000002360 preparation method Methods 0.000 claims description 26
125000004433 nitrogen atom Chemical group N* 0.000 claims description 25
201000011510 cancer Diseases 0.000 claims description 23
201000010099 disease Diseases 0.000 claims description 21
239000000203 mixture Substances 0.000 claims description 19
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 19
241000124008 Mammalia Species 0.000 claims description 17
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 17
125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 16
IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
125000001963 4 membered heterocyclic group Chemical group 0.000 claims description 15
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 15
239000003153 chemical reaction reagent Substances 0.000 claims description 15
239000001257 hydrogen Substances 0.000 claims description 15
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 12
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 12
125000001153 fluoro group Chemical group F* 0.000 claims description 11
125000003709 fluoroalkyl group Chemical group 0.000 claims description 11
230000008878 coupling Effects 0.000 claims description 10
238000010168 coupling process Methods 0.000 claims description 10
238000005859 coupling reaction Methods 0.000 claims description 10
229910052717 sulfur Inorganic materials 0.000 claims description 10
125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 9
206010061218 Inflammation Diseases 0.000 claims description 9
229910002091 carbon monoxide Inorganic materials 0.000 claims description 9
125000000753 cycloalkyl group Chemical group 0.000 claims description 9
230000004054 inflammatory process Effects 0.000 claims description 9
229910052731 fluorine Inorganic materials 0.000 claims description 8
125000005843 halogen group Chemical group 0.000 claims description 7
230000004770 neurodegeneration Effects 0.000 claims description 7
208000015122 neurodegenerative disease Diseases 0.000 claims description 7
239000008194 pharmaceutical composition Substances 0.000 claims description 6
241000223104 Trypanosoma Species 0.000 claims description 5
HULVFUOUBDMOIO-HXUWFJFHSA-N ethyl 1-[[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]carbamoyl]piperidine-4-carboxylate Chemical compound C1CC(C(=O)OCC)CCN1C(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 HULVFUOUBDMOIO-HXUWFJFHSA-N 0.000 claims description 5
208000015181 infectious disease Diseases 0.000 claims description 5
230000000010 osteolytic effect Effects 0.000 claims description 5
230000008569 process Effects 0.000 claims description 5
AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical group OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 claims description 4
125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 4
125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 4
DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 4
125000003118 aryl group Chemical group 0.000 claims description 4
125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 4
229910052799 carbon Inorganic materials 0.000 claims description 4
150000003857 carboxamides Chemical class 0.000 claims description 4
239000003085 diluting agent Substances 0.000 claims description 4
FICIXBQKZAGGEY-MRXNPFEDSA-N n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-3-hydroxyazetidine-1-carboxamide Chemical compound C1C(O)CN1C(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 FICIXBQKZAGGEY-MRXNPFEDSA-N 0.000 claims description 4
DRODGWWMTPIVDP-OAHLLOKOSA-N n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]acetamide Chemical compound C1([C@H]2CCCN2C=2C=CC3=NC=C(N3N=2)NC(=O)C)=CC(F)=CC=C1F DRODGWWMTPIVDP-OAHLLOKOSA-N 0.000 claims description 4
ZTUMJOIBOSSLKA-GOSISDBHSA-N n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]piperidine-1-carboxamide Chemical compound FC1=CC=C(F)C([C@@H]2N(CCC2)C2=NN3C(NC(=O)N4CCCCC4)=CN=C3C=C2)=C1 ZTUMJOIBOSSLKA-GOSISDBHSA-N 0.000 claims description 4
HPTIFCCXNOOCCB-UHFFFAOYSA-N n-[6-[2-(3-fluorophenyl)piperidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-3-hydroxyazetidine-1-carboxamide Chemical compound C1C(O)CN1C(=O)NC1=CN=C2N1N=C(N1C(CCCC1)C=1C=C(F)C=CC=1)C=C2 HPTIFCCXNOOCCB-UHFFFAOYSA-N 0.000 claims description 4
UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical group OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims description 4
DRBCXNCIJRRAQF-DYESRHJHSA-N tert-butyl (2r)-4-[[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]carbamoyl]-2-methylpiperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)[C@H](C)CN1C(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 DRBCXNCIJRRAQF-DYESRHJHSA-N 0.000 claims description 4
DRBCXNCIJRRAQF-LAUBAEHRSA-N tert-butyl (2s)-4-[[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]carbamoyl]-2-methylpiperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1C(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 DRBCXNCIJRRAQF-LAUBAEHRSA-N 0.000 claims description 4
JSJOUFCSIYXYAC-RHSMWYFYSA-N (3r)-n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-3-hydroxypyrrolidine-1-carboxamide Chemical compound C1[C@H](O)CCN1C(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 JSJOUFCSIYXYAC-RHSMWYFYSA-N 0.000 claims description 3
DWYRMDHKMLLZPU-BRWVUGGUSA-N (3r,4r)-n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-3,4-dihydroxypyrrolidine-1-carboxamide Chemical compound C1[C@@H](O)[C@H](O)CN1C(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 DWYRMDHKMLLZPU-BRWVUGGUSA-N 0.000 claims description 3
JSJOUFCSIYXYAC-WMLDXEAASA-N (3s)-n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-3-hydroxypyrrolidine-1-carboxamide Chemical compound C1[C@@H](O)CCN1C(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 JSJOUFCSIYXYAC-WMLDXEAASA-N 0.000 claims description 3
VWCONLJBMSCZJJ-KBXCAEBGSA-N (3s)-n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-3-methylpiperazine-1-carboxamide Chemical compound C1CN[C@@H](C)CN1C(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 VWCONLJBMSCZJJ-KBXCAEBGSA-N 0.000 claims description 3
LVJPLDQUBMPWQX-WOJBJXKFSA-N (3s)-n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-3-propan-2-ylpiperazine-1-carboxamide Chemical compound C1CN[C@@H](C(C)C)CN1C(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 LVJPLDQUBMPWQX-WOJBJXKFSA-N 0.000 claims description 3
SAUORZAOVJFPPP-HXUWFJFHSA-N 1-(4-cyanophenyl)-3-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]urea Chemical compound FC1=CC=C(F)C([C@@H]2N(CCC2)C2=NN3C(NC(=O)NC=4C=CC(=CC=4)C#N)=CN=C3C=C2)=C1 SAUORZAOVJFPPP-HXUWFJFHSA-N 0.000 claims description 3
UMBVWIJDKYVLNX-LJQANCHMSA-N 1-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-3-(3,4,5-trimethoxyphenyl)urea Chemical compound COC1=C(OC)C(OC)=CC(NC(=O)NC=2N3N=C(C=CC3=NC=2)N2[C@H](CCC2)C=2C(=CC=C(F)C=2)F)=C1 UMBVWIJDKYVLNX-LJQANCHMSA-N 0.000 claims description 3
BIMXQSQMCRDMNQ-QGZVFWFLSA-N 1-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-3-(3,5-dimethyl-1,2-oxazol-4-yl)urea Chemical compound CC1=NOC(C)=C1NC(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 BIMXQSQMCRDMNQ-QGZVFWFLSA-N 0.000 claims description 3
HMHYOWXNEDWDPI-LJQANCHMSA-N 1-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-3-(4-fluorophenyl)urea Chemical compound C1=CC(F)=CC=C1NC(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 HMHYOWXNEDWDPI-LJQANCHMSA-N 0.000 claims description 3
RZADJPXSDZIQQE-HXUWFJFHSA-N 1-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-3-(4-methoxyphenyl)urea Chemical compound C1=CC(OC)=CC=C1NC(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 RZADJPXSDZIQQE-HXUWFJFHSA-N 0.000 claims description 3
MGRUDMITAKQXEM-LJQANCHMSA-N 1-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-3-[3-(trifluoromethyl)phenyl]urea Chemical compound FC1=CC=C(F)C([C@@H]2N(CCC2)C2=NN3C(NC(=O)NC=4C=C(C=CC=4)C(F)(F)F)=CN=C3C=C2)=C1 MGRUDMITAKQXEM-LJQANCHMSA-N 0.000 claims description 3
DQANMQMIIOKILD-CQSZACIVSA-N 1-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-3-methylurea Chemical compound C1([C@H]2CCCN2C=2C=CC3=NC=C(N3N=2)NC(=O)NC)=CC(F)=CC=C1F DQANMQMIIOKILD-CQSZACIVSA-N 0.000 claims description 3
RFMPFKSMPLNSHR-LJQANCHMSA-N 1-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-3-phenylurea Chemical compound FC1=CC=C(F)C([C@@H]2N(CCC2)C2=NN3C(NC(=O)NC=4C=CC=CC=4)=CN=C3C=C2)=C1 RFMPFKSMPLNSHR-LJQANCHMSA-N 0.000 claims description 3
YDRGHAGUQRODRF-GOSISDBHSA-N 1-[[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]carbamoyl]piperidine-4-carboxylic acid Chemical compound C1CC(C(=O)O)CCN1C(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 YDRGHAGUQRODRF-GOSISDBHSA-N 0.000 claims description 3
125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 3
OQLRDZUVESCUGH-OAHLLOKOSA-N 3-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-1,1-dimethylurea Chemical compound C1([C@H]2CCCN2C=2C=CC3=NC=C(N3N=2)NC(=O)N(C)C)=CC(F)=CC=C1F OQLRDZUVESCUGH-OAHLLOKOSA-N 0.000 claims description 3
WQGWEUYLAOTLQL-MRXNPFEDSA-N 3-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-1-(2-hydroxyethyl)-1-methylurea Chemical compound C1([C@H]2CCCN2C=2C=CC3=NC=C(N3N=2)NC(=O)N(CCO)C)=CC(F)=CC=C1F WQGWEUYLAOTLQL-MRXNPFEDSA-N 0.000 claims description 3
RQRUPABQPZQPJR-GOSISDBHSA-N N1CC(C1)C(C(=O)OC(NC1=CN=C2N1N=C(C=C2)N2[C@H](CCC2)C2=C(C=CC(=C2)F)F)=O)(C)C Chemical compound N1CC(C1)C(C(=O)OC(NC1=CN=C2N1N=C(C=C2)N2[C@H](CCC2)C2=C(C=CC(=C2)F)F)=O)(C)C RQRUPABQPZQPJR-GOSISDBHSA-N 0.000 claims description 3
AZAHXWKHBNORBH-CYBMUJFWSA-N [6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]urea Chemical compound C1([C@H]2CCCN2C=2C=CC3=NC=C(N3N=2)NC(=O)N)=CC(F)=CC=C1F AZAHXWKHBNORBH-CYBMUJFWSA-N 0.000 claims description 3
125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 3
ZRBJDFXMLCWRQJ-GOSISDBHSA-N n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-1-methyl-6-oxopyridine-3-carboxamide Chemical compound C1=CC(=O)N(C)C=C1C(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 ZRBJDFXMLCWRQJ-GOSISDBHSA-N 0.000 claims description 3
AUYIFEWYWPVPCL-JFIBYHEFSA-N n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-3,5-dimethylpiperazine-1-carboxamide Chemical compound C1C(C)NC(C)CN1C(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 AUYIFEWYWPVPCL-JFIBYHEFSA-N 0.000 claims description 3
OFPUYTXFSMNQPA-QGZVFWFLSA-N n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-3-methoxyazetidine-1-carboxamide Chemical compound C1C(OC)CN1C(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 OFPUYTXFSMNQPA-QGZVFWFLSA-N 0.000 claims description 3
PCLWKGDIYYLZBK-MRXNPFEDSA-N n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-3-oxopiperazine-1-carboxamide Chemical compound FC1=CC=C(F)C([C@@H]2N(CCC2)C2=NN3C(NC(=O)N4CC(=O)NCC4)=CN=C3C=C2)=C1 PCLWKGDIYYLZBK-MRXNPFEDSA-N 0.000 claims description 3
CDMQMPKUGUVGIR-HXUWFJFHSA-N n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-4-(methanesulfonamido)benzamide Chemical compound C1=CC(NS(=O)(=O)C)=CC=C1C(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 CDMQMPKUGUVGIR-HXUWFJFHSA-N 0.000 claims description 3
ZSQPJEXCTAOQSR-GOSISDBHSA-N n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-4-hydroxypiperidine-1-carboxamide Chemical compound C1CC(O)CCN1C(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 ZSQPJEXCTAOQSR-GOSISDBHSA-N 0.000 claims description 3
RWIABVRWALKQEZ-GOSISDBHSA-N n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-4-methylpiperazine-1-carboxamide Chemical compound C1CN(C)CCN1C(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 RWIABVRWALKQEZ-GOSISDBHSA-N 0.000 claims description 3
VLMNOKZIQOOGCW-MRXNPFEDSA-N n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]azetidine-1-carboxamide Chemical compound FC1=CC=C(F)C([C@@H]2N(CCC2)C2=NN3C(NC(=O)N4CCC4)=CN=C3C=C2)=C1 VLMNOKZIQOOGCW-MRXNPFEDSA-N 0.000 claims description 3
WDNBFCZIRHNJQB-QGZVFWFLSA-N n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]morpholine-4-carboxamide Chemical compound FC1=CC=C(F)C([C@@H]2N(CCC2)C2=NN3C(NC(=O)N4CCOCC4)=CN=C3C=C2)=C1 WDNBFCZIRHNJQB-QGZVFWFLSA-N 0.000 claims description 3
125000006239 protecting group Chemical group 0.000 claims description 3
125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 claims description 3
SWJIQPPGWGNTMW-LJQANCHMSA-N tert-butyl n-[1-[[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]carbamoyl]azetidin-3-yl]carbamate Chemical compound C1C(NC(=O)OC(C)(C)C)CN1C(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 SWJIQPPGWGNTMW-LJQANCHMSA-N 0.000 claims description 3
VWCONLJBMSCZJJ-RDTXWAMCSA-N (3r)-n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-3-methylpiperazine-1-carboxamide Chemical compound C1CN[C@H](C)CN1C(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 VWCONLJBMSCZJJ-RDTXWAMCSA-N 0.000 claims description 2
JMSUQDYOPPYZHK-LJQANCHMSA-N 1-(2,4-dichlorophenyl)-3-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]urea Chemical compound FC1=CC=C(F)C([C@@H]2N(CCC2)C2=NN3C(NC(=O)NC=4C(=CC(Cl)=CC=4)Cl)=CN=C3C=C2)=C1 JMSUQDYOPPYZHK-LJQANCHMSA-N 0.000 claims description 2
QXZHIVNVOWGEHU-LJQANCHMSA-N 1-(3,5-dichlorophenyl)-3-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]urea Chemical compound FC1=CC=C(F)C([C@@H]2N(CCC2)C2=NN3C(NC(=O)NC=4C=C(Cl)C=C(Cl)C=4)=CN=C3C=C2)=C1 QXZHIVNVOWGEHU-LJQANCHMSA-N 0.000 claims description 2
MOZJCFCPMONZAG-HXUWFJFHSA-N 1-(3-cyanophenyl)-3-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]urea Chemical compound FC1=CC=C(F)C([C@@H]2N(CCC2)C2=NN3C(NC(=O)NC=4C=C(C=CC=4)C#N)=CN=C3C=C2)=C1 MOZJCFCPMONZAG-HXUWFJFHSA-N 0.000 claims description 2
IIUHIEHPXSVTPQ-MRXNPFEDSA-N 1-tert-butyl-3-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]urea Chemical compound C1([C@H]2CCCN2C=2C=CC3=NC=C(N3N=2)NC(=O)NC(C)(C)C)=CC(F)=CC=C1F IIUHIEHPXSVTPQ-MRXNPFEDSA-N 0.000 claims description 2
238000010586 diagram Methods 0.000 claims description 2
VEPAWPDJRAOXCL-QGZVFWFLSA-N n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-1-methyl-6-oxopyridazine-3-carboxamide Chemical compound C1=CC(=O)N(C)N=C1C(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 VEPAWPDJRAOXCL-QGZVFWFLSA-N 0.000 claims description 2
RFUWUZBTSXDASW-CYBMUJFWSA-N n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-2,2,2-trifluoroacetamide Chemical compound FC1=CC=C(F)C([C@@H]2N(CCC2)C2=NN3C(NC(=O)C(F)(F)F)=CN=C3C=C2)=C1 RFUWUZBTSXDASW-CYBMUJFWSA-N 0.000 claims description 2
JBOCEQMXBSZMDR-MRXNPFEDSA-N n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-3,3-difluoropyrrolidine-1-carboxamide Chemical compound FC1=CC=C(F)C([C@@H]2N(CCC2)C2=NN3C(NC(=O)N4CC(F)(F)CC4)=CN=C3C=C2)=C1 JBOCEQMXBSZMDR-MRXNPFEDSA-N 0.000 claims description 2
NJKOCMCDZLEINR-GOSISDBHSA-N n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-3,3-dimethylpiperazine-1-carboxamide Chemical compound C1CNC(C)(C)CN1C(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 NJKOCMCDZLEINR-GOSISDBHSA-N 0.000 claims description 2
BTHIMTVFWHCJFD-LADRWXRNSA-N n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxamide Chemical compound FC1=CC=C(F)C([C@@H]2N(CCC2)C2=NN3C(NC(=O)N4CC5CCC(N5)C4)=CN=C3C=C2)=C1 BTHIMTVFWHCJFD-LADRWXRNSA-N 0.000 claims description 2
MVXJDZPCXDUCME-QGZVFWFLSA-N n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]piperazine-1-carboxamide Chemical compound FC1=CC=C(F)C([C@@H]2N(CCC2)C2=NN3C(NC(=O)N4CCNCC4)=CN=C3C=C2)=C1 MVXJDZPCXDUCME-QGZVFWFLSA-N 0.000 claims description 2
125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
239000007787 solid Substances 0.000 description 63
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 61
239000012467 final product Substances 0.000 description 52
YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 46
238000006243 chemical reaction Methods 0.000 description 40
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
238000011282 treatment Methods 0.000 description 30
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 28
239000000243 solution Substances 0.000 description 28
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 23
239000003112 inhibitor Substances 0.000 description 21
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
239000000047 product Substances 0.000 description 19
238000003756 stirring Methods 0.000 description 19
101150111783 NTRK1 gene Proteins 0.000 description 17
108010025020 Nerve Growth Factor Proteins 0.000 description 16
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
235000019439 ethyl acetate Nutrition 0.000 description 14
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 13
101150056950 Ntrk2 gene Proteins 0.000 description 13
239000002585 base Substances 0.000 description 13
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
239000000843 powder Substances 0.000 description 12
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
238000004440 column chromatography Methods 0.000 description 11
239000012071 phase Substances 0.000 description 11
239000002904 solvent Substances 0.000 description 11
NZHPVPMRNASEQK-UHFFFAOYSA-N 3-isocyanatobenzonitrile Chemical compound O=C=NC1=CC=CC(C#N)=C1 NZHPVPMRNASEQK-UHFFFAOYSA-N 0.000 description 10
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
208000005615 Interstitial Cystitis Diseases 0.000 description 10
102000007072 Nerve Growth Factors Human genes 0.000 description 10
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
UQUPQEUNHVVNKW-UHFFFAOYSA-N azetidin-1-ium-3-ol;chloride Chemical compound Cl.OC1CNC1 UQUPQEUNHVVNKW-UHFFFAOYSA-N 0.000 description 10
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
210000000988 bone and bone Anatomy 0.000 description 9
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
238000003556 assay Methods 0.000 description 8
239000012044 organic layer Substances 0.000 description 8
239000011541 reaction mixture Substances 0.000 description 8
230000002441 reversible effect Effects 0.000 description 8
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
102100035108 High affinity nerve growth factor receptor Human genes 0.000 description 7
101710091869 High affinity nerve growth factor receptor Proteins 0.000 description 7
230000037361 pathway Effects 0.000 description 7
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 6
OBDKGAQWHPVRJR-CYBMUJFWSA-N 6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-amine Chemical compound C1([C@H]2CCCN2C=2C=CC3=NC=C(N3N=2)N)=CC(F)=CC=C1F OBDKGAQWHPVRJR-CYBMUJFWSA-N 0.000 description 6
LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
102000015336 Nerve Growth Factor Human genes 0.000 description 6
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 6
239000013058 crude material Substances 0.000 description 6
BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 6
229940053128 nerve growth factor Drugs 0.000 description 6
239000011734 sodium Substances 0.000 description 6
239000000725 suspension Substances 0.000 description 6
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
150000001412 amines Chemical class 0.000 description 5
239000012267 brine Substances 0.000 description 5
239000012043 crude product Substances 0.000 description 5
208000035475 disorder Diseases 0.000 description 5
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
125000004076 pyridyl group Chemical group 0.000 description 5
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
229910052727 yttrium Inorganic materials 0.000 description 5
102100035080 BDNF/NT-3 growth factors receptor Human genes 0.000 description 4
101710101214 BDNF/NT-3 growth factors receptor Proteins 0.000 description 4
206010027476 Metastases Diseases 0.000 description 4
208000003076 Osteolysis Diseases 0.000 description 4
210000004556 brain Anatomy 0.000 description 4
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
229910052801 chlorine Inorganic materials 0.000 description 4
230000005764 inhibitory process Effects 0.000 description 4
208000029791 lytic metastatic bone lesion Diseases 0.000 description 4
230000009401 metastasis Effects 0.000 description 4
239000000377 silicon dioxide Substances 0.000 description 4
SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 3
SROHFTOYGFCJAF-UHFFFAOYSA-N 4-[(methylsulfonyl)amino]benzoic acid Chemical compound CS(=O)(=O)NC1=CC=C(C(O)=O)C=C1 SROHFTOYGFCJAF-UHFFFAOYSA-N 0.000 description 3
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
206010001935 American trypanosomiasis Diseases 0.000 description 3
206010006187 Breast cancer Diseases 0.000 description 3
208000024699 Chagas disease Diseases 0.000 description 3
208000000094 Chronic Pain Diseases 0.000 description 3
206010009944 Colon cancer Diseases 0.000 description 3
208000035473 Communicable disease Diseases 0.000 description 3
102000004190 Enzymes Human genes 0.000 description 3
108090000790 Enzymes Proteins 0.000 description 3
206010065390 Inflammatory pain Diseases 0.000 description 3
206010027452 Metastases to bone Diseases 0.000 description 3
BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
208000001132 Osteoporosis Diseases 0.000 description 3
206010060862 Prostate cancer Diseases 0.000 description 3
208000000236 Prostatic Neoplasms Diseases 0.000 description 3
RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
125000004432 carbon atom Chemical group C* 0.000 description 3
125000001309 chloro group Chemical group Cl* 0.000 description 3
230000001684 chronic effect Effects 0.000 description 3
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
238000001816 cooling Methods 0.000 description 3
239000000706 filtrate Substances 0.000 description 3
239000006260 foam Substances 0.000 description 3
238000005187 foaming Methods 0.000 description 3
229910052740 iodine Inorganic materials 0.000 description 3
239000010410 layer Substances 0.000 description 3
229960005181 morphine Drugs 0.000 description 3
208000004296 neuralgia Diseases 0.000 description 3
208000021722 neuropathic pain Diseases 0.000 description 3
239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 3
125000003386 piperidinyl group Chemical group 0.000 description 3
108090000765 processed proteins & peptides Proteins 0.000 description 3
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
229920006395 saturated elastomer Polymers 0.000 description 3
125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 3
230000011664 signaling Effects 0.000 description 3
150000003384 small molecules Chemical class 0.000 description 3
239000000758 substrate Substances 0.000 description 3
ILYHXMXVVSLMDV-OBFZPWGMSA-N tert-butyl 3-[[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]carbamoyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Chemical compound C1([C@H]2CCCN2C=2C=CC3=NC=C(N3N=2)NC(=O)N2CC3CCC(C2)N3C(=O)OC(C)(C)C)=CC(F)=CC=C1F ILYHXMXVVSLMDV-OBFZPWGMSA-N 0.000 description 3
XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
NEPLBHLFDJOJGP-BYPYZUCNSA-N (2s)-2-(5-fluoro-2,4-dinitroanilino)propanamide Chemical compound NC(=O)[C@H](C)NC1=CC(F)=C([N+]([O-])=O)C=C1[N+]([O-])=O NEPLBHLFDJOJGP-BYPYZUCNSA-N 0.000 description 2
RGZCKPXTNJAWMR-UHFFFAOYSA-N 1-methyl-6-oxopyridine-3-carboxylic acid Chemical compound CN1C=C(C(O)=O)C=CC1=O RGZCKPXTNJAWMR-UHFFFAOYSA-N 0.000 description 2
CEQSSECBLRKFSY-UHFFFAOYSA-N 6-[2-(3-fluorophenyl)piperidin-1-yl]imidazo[1,2-b]pyridazin-3-amine Chemical compound N=1N2C(N)=CN=C2C=CC=1N1CCCCC1C1=CC=CC(F)=C1 CEQSSECBLRKFSY-UHFFFAOYSA-N 0.000 description 2
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 2
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
239000005695 Ammonium acetate Substances 0.000 description 2
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
206010065687 Bone loss Diseases 0.000 description 2
208000026310 Breast neoplasm Diseases 0.000 description 2
206010058019 Cancer Pain Diseases 0.000 description 2
239000004215 Carbon black (E152) Substances 0.000 description 2
208000001333 Colorectal Neoplasms Diseases 0.000 description 2
206010012438 Dermatitis atopic Diseases 0.000 description 2
ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
206010058467 Lung neoplasm malignant Diseases 0.000 description 2
239000007993 MOPS buffer Substances 0.000 description 2
241000699670 Mus sp. Species 0.000 description 2
101150117329 NTRK3 gene Proteins 0.000 description 2
206010029260 Neuroblastoma Diseases 0.000 description 2
GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
206010033128 Ovarian cancer Diseases 0.000 description 2
206010061535 Ovarian neoplasm Diseases 0.000 description 2
206010061902 Pancreatic neoplasm Diseases 0.000 description 2
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
206010035226 Plasma cell myeloma Diseases 0.000 description 2
102000003923 Protein Kinase C Human genes 0.000 description 2
108090000315 Protein Kinase C Proteins 0.000 description 2
201000004681 Psoriasis Diseases 0.000 description 2
241000700159 Rattus Species 0.000 description 2
206010038389 Renal cancer Diseases 0.000 description 2
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
208000024770 Thyroid neoplasm Diseases 0.000 description 2
239000013504 Triton X-100 Substances 0.000 description 2
229920004890 Triton X-100 Polymers 0.000 description 2
241000223109 Trypanosoma cruzi Species 0.000 description 2
208000005298 acute pain Diseases 0.000 description 2
229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
150000008041 alkali metal carbonates Chemical class 0.000 description 2
229940043376 ammonium acetate Drugs 0.000 description 2
235000019257 ammonium acetate Nutrition 0.000 description 2
238000010171 animal model Methods 0.000 description 2
239000007864 aqueous solution Substances 0.000 description 2
239000012131 assay buffer Substances 0.000 description 2
208000006673 asthma Diseases 0.000 description 2
125000004429 atom Chemical group 0.000 description 2
201000008937 atopic dermatitis Diseases 0.000 description 2
HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 2
125000002393 azetidinyl group Chemical group 0.000 description 2
239000004202 carbamide Substances 0.000 description 2
210000004027 cell Anatomy 0.000 description 2
239000003795 chemical substances by application Substances 0.000 description 2
150000004683 dihydrates Chemical class 0.000 description 2
239000003814 drug Substances 0.000 description 2
239000003480 eluent Substances 0.000 description 2
125000001207 fluorophenyl group Chemical group 0.000 description 2
210000001035 gastrointestinal tract Anatomy 0.000 description 2
239000003102 growth factor Substances 0.000 description 2
229930195733 hydrocarbon Natural products 0.000 description 2
CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
230000002757 inflammatory effect Effects 0.000 description 2
230000002401 inhibitory effect Effects 0.000 description 2
239000000543 intermediate Substances 0.000 description 2
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
210000004072 lung Anatomy 0.000 description 2
208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
230000035772 mutation Effects 0.000 description 2
IYNXOXOHULFFSV-OAHLLOKOSA-N n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-3,3-difluoroazetidine-1-carboxamide Chemical compound FC1=CC=C(F)C([C@@H]2N(CCC2)C2=NN3C(NC(=O)N4CC(F)(F)C4)=CN=C3C=C2)=C1 IYNXOXOHULFFSV-OAHLLOKOSA-N 0.000 description 2
GXGABCOHBHOWDE-QGZVFWFLSA-N n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-3-(hydroxymethyl)azetidine-1-carboxamide Chemical compound C1C(CO)CN1C(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 GXGABCOHBHOWDE-QGZVFWFLSA-N 0.000 description 2
FWPFVUFHOGAMTA-MRXNPFEDSA-N n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-3-hydroxy-3-methylazetidine-1-carboxamide Chemical compound C1C(C)(O)CN1C(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 FWPFVUFHOGAMTA-MRXNPFEDSA-N 0.000 description 2
229910017604 nitric acid Inorganic materials 0.000 description 2
229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
239000003921 oil Substances 0.000 description 2
229940005483 opioid analgesics Drugs 0.000 description 2
210000000963 osteoblast Anatomy 0.000 description 2
201000002528 pancreatic cancer Diseases 0.000 description 2
208000008443 pancreatic carcinoma Diseases 0.000 description 2
230000007170 pathology Effects 0.000 description 2
125000004193 piperazinyl group Chemical group 0.000 description 2
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
238000000746 purification Methods 0.000 description 2
PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 2
125000000719 pyrrolidinyl group Chemical group 0.000 description 2
102000005962 receptors Human genes 0.000 description 2
108020003175 receptors Proteins 0.000 description 2
238000011160 research Methods 0.000 description 2
206010039073 rheumatoid arthritis Diseases 0.000 description 2
238000010898 silica gel chromatography Methods 0.000 description 2
239000002002 slurry Substances 0.000 description 2
239000012453 solvate Substances 0.000 description 2
QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
238000001356 surgical procedure Methods 0.000 description 2
208000024891 symptom Diseases 0.000 description 2
NHTBSGSOPWDMCE-CYBMUJFWSA-N tert-butyl (2r)-2-(2,5-difluorophenyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@@H]1C1=CC(F)=CC=C1F NHTBSGSOPWDMCE-CYBMUJFWSA-N 0.000 description 2
OLQZHZDJCBKIGA-BDPMCISCSA-N tert-butyl n-[1-[[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]carbamoyl]piperidin-3-yl]carbamate Chemical compound C1C(NC(=O)OC(C)(C)C)CCCN1C(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 OLQZHZDJCBKIGA-BDPMCISCSA-N 0.000 description 2
238000012360 testing method Methods 0.000 description 2
NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
238000002560 therapeutic procedure Methods 0.000 description 2
125000001544 thienyl group Chemical group 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
102000015533 trkA Receptor Human genes 0.000 description 2
108010064884 trkA Receptor Proteins 0.000 description 2
PFEASGLQPCZPNN-SATBOSKTSA-N (3r)-n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-3-hydroxypyrrolidine-1-carboxamide;hydrochloride Chemical compound Cl.C1[C@H](O)CCN1C(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 PFEASGLQPCZPNN-SATBOSKTSA-N 0.000 description 1
WBRYIQBTQYPMAK-KEZWHQCISA-N (3r)-n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-3-methylpiperazine-1-carboxamide;hydrochloride Chemical compound Cl.C1CN[C@H](C)CN1C(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 WBRYIQBTQYPMAK-KEZWHQCISA-N 0.000 description 1
JHHZLHWJQPUNKB-SCSAIBSYSA-N (3r)-pyrrolidin-3-ol Chemical compound O[C@@H]1CCNC1 JHHZLHWJQPUNKB-SCSAIBSYSA-N 0.000 description 1
QJRIUWQPJVPYSO-GHMZBOCLSA-N (3r,4r)-1-benzylpyrrolidine-3,4-diol Chemical compound C1[C@@H](O)[C@H](O)CN1CC1=CC=CC=C1 QJRIUWQPJVPYSO-GHMZBOCLSA-N 0.000 description 1
JCZPOYAMKJFOLA-QWWZWVQMSA-N (3r,4r)-pyrrolidine-3,4-diol Chemical compound O[C@@H]1CNC[C@H]1O JCZPOYAMKJFOLA-QWWZWVQMSA-N 0.000 description 1
PFEASGLQPCZPNN-SQQLFYIASA-N (3s)-n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-3-hydroxypyrrolidine-1-carboxamide;hydrochloride Chemical compound Cl.C1[C@@H](O)CCN1C(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 PFEASGLQPCZPNN-SQQLFYIASA-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
125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
XEFUJGURFLOFAN-UHFFFAOYSA-N 1,3-dichloro-5-isocyanatobenzene Chemical compound ClC1=CC(Cl)=CC(N=C=O)=C1 XEFUJGURFLOFAN-UHFFFAOYSA-N 0.000 description 1
LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
NFDXQGNDWIPXQL-UHFFFAOYSA-N 1-cyclooctyldiazocane Chemical group C1CCCCCCC1N1NCCCCCC1 NFDXQGNDWIPXQL-UHFFFAOYSA-N 0.000 description 1
DSVGFKBFFICWLZ-UHFFFAOYSA-N 1-fluoro-4-isocyanatobenzene Chemical compound FC1=CC=C(N=C=O)C=C1 DSVGFKBFFICWLZ-UHFFFAOYSA-N 0.000 description 1
SXJYSIBLFGQAND-UHFFFAOYSA-N 1-isocyanato-3-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC(N=C=O)=C1 SXJYSIBLFGQAND-UHFFFAOYSA-N 0.000 description 1
FMDGXCSMDZMDHZ-UHFFFAOYSA-N 1-isocyanato-4-methoxybenzene Chemical compound COC1=CC=C(N=C=O)C=C1 FMDGXCSMDZMDHZ-UHFFFAOYSA-N 0.000 description 1
VSWNRKPYWTWWBV-UHFFFAOYSA-N 1-methyl-6-oxopyridazine-3-carboxylic acid Chemical compound CN1N=C(C(O)=O)C=CC1=O VSWNRKPYWTWWBV-UHFFFAOYSA-N 0.000 description 1
MLUHUAVKQZFTCA-UHFFFAOYSA-N 1-phenyl-3-[6-(1-phenylethylamino)imidazo[1,2-b]pyridazin-3-yl]urea Chemical compound C=1C=CC=CC=1C(C)NC(=NN12)C=CC1=NC=C2NC(=O)NC1=CC=CC=C1 MLUHUAVKQZFTCA-UHFFFAOYSA-N 0.000 description 1
WNMQSIGDRWCJMO-UHFFFAOYSA-N 1-tert-butylpyrrolidine Chemical compound CC(C)(C)N1CCCC1 WNMQSIGDRWCJMO-UHFFFAOYSA-N 0.000 description 1
FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
OLBJNSPBWLCTOT-UHFFFAOYSA-N 2,4-dichloro-1-isocyanatobenzene Chemical compound ClC1=CC=C(N=C=O)C(Cl)=C1 OLBJNSPBWLCTOT-UHFFFAOYSA-N 0.000 description 1
125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 description 1
IFNWESYYDINUHV-UHFFFAOYSA-N 2,6-dimethylpiperazine Chemical compound CC1CNCC(C)N1 IFNWESYYDINUHV-UHFFFAOYSA-N 0.000 description 1
YTYUBQPJRNWHGE-UHFFFAOYSA-N 2-(3-fluorophenyl)piperidine Chemical compound FC1=CC=CC(C2NCCCC2)=C1 YTYUBQPJRNWHGE-UHFFFAOYSA-N 0.000 description 1
XCRCSPKQEDMVBO-UHFFFAOYSA-N 2-bromo-1,4-difluorobenzene Chemical compound FC1=CC=C(F)C(Br)=C1 XCRCSPKQEDMVBO-UHFFFAOYSA-N 0.000 description 1
MGOLNIXAPIAKFM-UHFFFAOYSA-N 2-isocyanato-2-methylpropane Chemical compound CC(C)(C)N=C=O MGOLNIXAPIAKFM-UHFFFAOYSA-N 0.000 description 1
125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
CDBAEFXTCRKJPZ-UHFFFAOYSA-N 3,3-difluoroazetidine;hydron;chloride Chemical compound Cl.FC1(F)CNC1 CDBAEFXTCRKJPZ-UHFFFAOYSA-N 0.000 description 1
YYVPZQADFREIFR-UHFFFAOYSA-N 3,3-difluoropyrrolidine;hydrochloride Chemical compound [Cl-].FC1(F)CC[NH2+]C1 YYVPZQADFREIFR-UHFFFAOYSA-N 0.000 description 1
125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
LKDJYZBKCVSODK-UHFFFAOYSA-N 3,8-diazabicyclo[3.2.1]octane Chemical compound C1NCC2CCC1N2 LKDJYZBKCVSODK-UHFFFAOYSA-N 0.000 description 1
FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
YUOKKSCYCKTWAA-PKLMIRHRSA-N 3-amino-n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]azetidine-1-carboxamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1C(N)CN1C(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 YUOKKSCYCKTWAA-PKLMIRHRSA-N 0.000 description 1
125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
YWFPGZXICYWLAP-UHFFFAOYSA-N 3-hydroxypyrrolidine-1-carboxamide Chemical compound NC(=O)N1CCC(O)C1 YWFPGZXICYWLAP-UHFFFAOYSA-N 0.000 description 1
KSXGQRBTBLQJEF-UHFFFAOYSA-N 3-methoxyazetidine;hydrochloride Chemical compound Cl.COC1CNC1 KSXGQRBTBLQJEF-UHFFFAOYSA-N 0.000 description 1
WEAZZOCWAJWPRL-UHFFFAOYSA-N 3-methylazetidin-3-ol;hydrochloride Chemical compound Cl.CC1(O)CNC1 WEAZZOCWAJWPRL-UHFFFAOYSA-N 0.000 description 1
125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
AXPLSJSIKGZOMF-UHFFFAOYSA-N 4-(trifluoromethyl)piperidin-4-ol Chemical compound FC(F)(F)C1(O)CCNCC1 AXPLSJSIKGZOMF-UHFFFAOYSA-N 0.000 description 1
NNDVLAPMFXYAAS-HXUWFJFHSA-N 4-[6-[(2r)-2-(3-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]benzonitrile Chemical compound FC1=CC=CC([C@@H]2N(CCC2)C2=NN3C(C=4C=CC(=CC=4)C#N)=CN=C3C=C2)=C1 NNDVLAPMFXYAAS-HXUWFJFHSA-N 0.000 description 1
QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 description 1
125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
JJQYAGYVYNMYGE-UHFFFAOYSA-N 4-isocyanato-3,5-dimethyl-1,2-oxazole Chemical compound CC1=NOC(C)=C1N=C=O JJQYAGYVYNMYGE-UHFFFAOYSA-N 0.000 description 1
TVSXDZNUTPLDKY-UHFFFAOYSA-N 4-isocyanatobenzonitrile Chemical compound O=C=NC1=CC=C(C#N)C=C1 TVSXDZNUTPLDKY-UHFFFAOYSA-N 0.000 description 1
125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
MJJXWPHZDBIHIM-UHFFFAOYSA-N 5-isocyanato-1,2,3-trimethoxybenzene Chemical compound COC1=CC(N=C=O)=CC(OC)=C1OC MJJXWPHZDBIHIM-UHFFFAOYSA-N 0.000 description 1
AVAPWRVUZBKTEN-CYBMUJFWSA-N 6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]-3-nitroimidazo[1,2-b]pyridazine Chemical compound C1([C@H]2CCCN2C=2C=CC3=NC=C(N3N=2)[N+](=O)[O-])=CC(F)=CC=C1F AVAPWRVUZBKTEN-CYBMUJFWSA-N 0.000 description 1
IJEZMDPWGDWYKJ-UHFFFAOYSA-N 6-chloro-3-nitroimidazo[1,2-b]pyridazine Chemical compound C1=CC(Cl)=NN2C([N+](=O)[O-])=CN=C21 IJEZMDPWGDWYKJ-UHFFFAOYSA-N 0.000 description 1
MPZDNIJHHXRTIQ-UHFFFAOYSA-N 6-chloroimidazo[1,2-b]pyridazine Chemical compound N1=C(Cl)C=CC2=NC=CN21 MPZDNIJHHXRTIQ-UHFFFAOYSA-N 0.000 description 1
208000010507 Adenocarcinoma of Lung Diseases 0.000 description 1
208000024827 Alzheimer disease Diseases 0.000 description 1
206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
206010003571 Astrocytoma Diseases 0.000 description 1
206010005003 Bladder cancer Diseases 0.000 description 1
208000010392 Bone Fractures Diseases 0.000 description 1
208000006386 Bone Resorption Diseases 0.000 description 1
206010005949 Bone cancer Diseases 0.000 description 1
208000018084 Bone neoplasm Diseases 0.000 description 1
0 C*(C=C(C=C1)N(C)C)C1=O Chemical compound C*(C=C(C=C1)N(C)C)C1=O 0.000 description 1
LQARKZHQCRYSNG-UHFFFAOYSA-N CN(C(C=C1)=O)C(C2=CN=C(C=C3)N2N=C3N(CCC2)C2C(C=C(C=C2)F)=C2F)=C1C(N)=O Chemical compound CN(C(C=C1)=O)C(C2=CN=C(C=C3)N2N=C3N(CCC2)C2C(C=C(C=C2)F)=C2F)=C1C(N)=O LQARKZHQCRYSNG-UHFFFAOYSA-N 0.000 description 1
HMOMGFBEIZDQDA-YPBPMMDISA-O C[C@H](CN(CC1)C(Nc2cnc(/C=C\C(N(CCC3)[C@H]3c(cc(cc3)F)c3F)=[NH2+])[nH]2)=O)N1C(OC(C)(C)C)=O Chemical compound C[C@H](CN(CC1)C(Nc2cnc(/C=C\C(N(CCC3)[C@H]3c(cc(cc3)F)c3F)=[NH2+])[nH]2)=O)N1C(OC(C)(C)C)=O HMOMGFBEIZDQDA-YPBPMMDISA-O 0.000 description 1
241000282472 Canis lupus familiaris Species 0.000 description 1
KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
241000700198 Cavia Species 0.000 description 1
206010009900 Colitis ulcerative Diseases 0.000 description 1
MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
241000699800 Cricetinae Species 0.000 description 1
208000011231 Crohn disease Diseases 0.000 description 1
XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
206010011796 Cystitis interstitial Diseases 0.000 description 1
208000016192 Demyelinating disease Diseases 0.000 description 1
206010012305 Demyelination Diseases 0.000 description 1
206010012335 Dependence Diseases 0.000 description 1
201000004624 Dermatitis Diseases 0.000 description 1
206010067601 Dysmyelination Diseases 0.000 description 1
238000012286 ELISA Assay Methods 0.000 description 1
208000030814 Eating disease Diseases 0.000 description 1
FIYJZADCEWRRIV-FCRIDUQTSA-N FC1=C(C=C(C=C1)F)[C@@H]1N(CCC1)C=1C=CC=2N(N1)C(=CN2)N.C(#N)C=2C=C(C=CC2)NC(=O)NC2=CN=C1N2N=C(C=C1)N1[C@H](CCC1)C1=C(C=CC(=C1)F)F Chemical compound FC1=C(C=C(C=C1)F)[C@@H]1N(CCC1)C=1C=CC=2N(N1)C(=CN2)N.C(#N)C=2C=C(C=CC2)NC(=O)NC2=CN=C1N2N=C(C=C1)N1[C@H](CCC1)C1=C(C=CC(=C1)F)F FIYJZADCEWRRIV-FCRIDUQTSA-N 0.000 description 1
GBGPWCMTRKDJKI-DKAPBGRZSA-N FC1=C(C=C(C=C1)F)[C@@H]1N(CCC1)C=1C=CC=2N(N1)C(=CN2)N.FC2=C(C=C(C=C2)F)[C@@H]2N(CCC2)C=2C=CC=1N(N2)C(=CN1)NC(C(F)(F)F)=O Chemical compound FC1=C(C=C(C=C1)F)[C@@H]1N(CCC1)C=1C=CC=2N(N1)C(=CN2)N.FC2=C(C=C(C=C2)F)[C@@H]2N(CCC2)C=2C=CC=1N(N2)C(=CN1)NC(C(F)(F)F)=O GBGPWCMTRKDJKI-DKAPBGRZSA-N 0.000 description 1
CPDWFDVMTRVUND-GFJIOCRJSA-N FC1=C(C=C(C=C1)F)[C@@H]1N(CCC1)C=1C=CC=2N(N1)C(=CN2)N.N2(CCOCC2)C(=O)NC2=CN=C1N2N=C(C=C1)N1[C@H](CCC1)C1=C(C=CC(=C1)F)F Chemical compound FC1=C(C=C(C=C1)F)[C@@H]1N(CCC1)C=1C=CC=2N(N1)C(=CN2)N.N2(CCOCC2)C(=O)NC2=CN=C1N2N=C(C=C1)N1[C@H](CCC1)C1=C(C=CC(=C1)F)F CPDWFDVMTRVUND-GFJIOCRJSA-N 0.000 description 1
208000019454 Feeding and Eating disease Diseases 0.000 description 1
241000282326 Felis catus Species 0.000 description 1
208000032612 Glial tumor Diseases 0.000 description 1
206010018338 Glioma Diseases 0.000 description 1
208000002250 Hematologic Neoplasms Diseases 0.000 description 1
241000282412 Homo Species 0.000 description 1
108010001336 Horseradish Peroxidase Proteins 0.000 description 1
208000037147 Hypercalcaemia 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
208000022559 Inflammatory bowel disease Diseases 0.000 description 1
208000008839 Kidney Neoplasms Diseases 0.000 description 1
OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
208000019693 Lung disease Diseases 0.000 description 1
206010025323 Lymphomas Diseases 0.000 description 1
208000000172 Medulloblastoma Diseases 0.000 description 1
208000037848 Metastatic bone disease Diseases 0.000 description 1
241001465754 Metazoa Species 0.000 description 1
208000034578 Multiple myelomas Diseases 0.000 description 1
OPKOKAMJFNKNAS-UHFFFAOYSA-N N-methylethanolamine Chemical compound CNCCO OPKOKAMJFNKNAS-UHFFFAOYSA-N 0.000 description 1
206010052399 Neuroendocrine tumour Diseases 0.000 description 1
CDASDLXRLNZVHS-UHFFFAOYSA-O O=C(NC1=CN=C(C=C2)[N+]1=C2N(CCC1)C1c(cc(cc1)F)c1F)N1CCCCC1 Chemical compound O=C(NC1=CN=C(C=C2)[N+]1=C2N(CCC1)C1c(cc(cc1)F)c1F)N1CCCCC1 CDASDLXRLNZVHS-UHFFFAOYSA-O 0.000 description 1
208000010191 Osteitis Deformans Diseases 0.000 description 1
102000038030 PI3Ks Human genes 0.000 description 1
108091007960 PI3Ks Proteins 0.000 description 1
208000027868 Paget disease Diseases 0.000 description 1
208000030852 Parasitic disease Diseases 0.000 description 1
208000018737 Parkinson disease Diseases 0.000 description 1
239000004743 Polypropylene Substances 0.000 description 1
229920001213 Polysorbate 20 Polymers 0.000 description 1
241000288906 Primates Species 0.000 description 1
102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 description 1
108050003243 Prostaglandin G/H synthase 1 Proteins 0.000 description 1
102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 1
108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 1
102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
206010037075 Protozoal infections Diseases 0.000 description 1
206010070834 Sensitisation Diseases 0.000 description 1
206010041549 Spinal cord compression Diseases 0.000 description 1
208000005250 Spontaneous Fractures Diseases 0.000 description 1
102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 description 1
101710112791 Tyrosine-protein kinase JAK2 Proteins 0.000 description 1
208000025865 Ulcer Diseases 0.000 description 1
201000006704 Ulcerative Colitis Diseases 0.000 description 1
206010046543 Urinary incontinence Diseases 0.000 description 1
HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
AZAHXWKHBNORBH-UHFFFAOYSA-N [6-[2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]urea Chemical compound N=1N2C(NC(=O)N)=CN=C2C=CC=1N1CCCC1C1=CC(F)=CC=C1F AZAHXWKHBNORBH-UHFFFAOYSA-N 0.000 description 1
238000002835 absorbance Methods 0.000 description 1
229960001138 acetylsalicylic acid Drugs 0.000 description 1
239000002253 acid Substances 0.000 description 1
230000002378 acidificating effect Effects 0.000 description 1
230000009471 action Effects 0.000 description 1
230000004913 activation Effects 0.000 description 1
239000012190 activator Substances 0.000 description 1
239000013543 active substance Substances 0.000 description 1
230000001154 acute effect Effects 0.000 description 1
230000032683 aging Effects 0.000 description 1
229910000147 aluminium phosphate Inorganic materials 0.000 description 1
150000001408 amides Chemical class 0.000 description 1
125000003277 amino group Chemical group 0.000 description 1
229910021529 ammonia Inorganic materials 0.000 description 1
230000003321 amplification Effects 0.000 description 1
229940035676 analgesics Drugs 0.000 description 1
208000022531 anorexia Diseases 0.000 description 1
230000003042 antagnostic effect Effects 0.000 description 1
239000000730 antalgic agent Substances 0.000 description 1
230000003110 anti-inflammatory effect Effects 0.000 description 1
230000001139 anti-pruritic effect Effects 0.000 description 1
239000002246 antineoplastic agent Substances 0.000 description 1
239000003908 antipruritic agent Substances 0.000 description 1
230000006907 apoptotic process Effects 0.000 description 1
239000008346 aqueous phase Substances 0.000 description 1
229910052786 argon Inorganic materials 0.000 description 1
208000010668 atopic eczema Diseases 0.000 description 1
AQUVQGSNKVDBBF-UHFFFAOYSA-N azetidin-3-ylmethanol;hydrochloride Chemical compound Cl.OCC1CNC1 AQUVQGSNKVDBBF-UHFFFAOYSA-N 0.000 description 1
PVXOUGHWLCBJOW-UHFFFAOYSA-N azetidine-1-carboxamide Chemical compound NC(=O)N1CCC1 PVXOUGHWLCBJOW-UHFFFAOYSA-N 0.000 description 1
KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 1
JFDZBHWFFUWGJE-KWCOIAHCSA-N benzonitrile Chemical group N#[11C]C1=CC=CC=C1 JFDZBHWFFUWGJE-KWCOIAHCSA-N 0.000 description 1
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
230000033228 biological regulation Effects 0.000 description 1
201000001531 bladder carcinoma Diseases 0.000 description 1
230000000903 blocking effect Effects 0.000 description 1
230000037396 body weight Effects 0.000 description 1
230000008468 bone growth Effects 0.000 description 1
210000002805 bone matrix Anatomy 0.000 description 1
208000024883 bone remodeling disease Diseases 0.000 description 1
230000024279 bone resorption Effects 0.000 description 1
125000001246 bromo group Chemical group Br* 0.000 description 1
239000002775 capsule Substances 0.000 description 1
239000000969 carrier Substances 0.000 description 1
230000001413 cellular effect Effects 0.000 description 1
125000000068 chlorophenyl group Chemical group 0.000 description 1
238000004587 chromatography analysis Methods 0.000 description 1
239000003593 chromogenic compound Substances 0.000 description 1
210000001072 colon Anatomy 0.000 description 1
239000012141 concentrate Substances 0.000 description 1
235000008504 concentrate Nutrition 0.000 description 1
229960004544 cortisone Drugs 0.000 description 1
239000007822 coupling agent Substances 0.000 description 1
239000010779 crude oil Substances 0.000 description 1
125000004802 cyanophenyl group Chemical group 0.000 description 1
239000003260 cyclooxygenase 1 inhibitor Substances 0.000 description 1
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
201000003146 cystitis Diseases 0.000 description 1
230000002559 cytogenic effect Effects 0.000 description 1
230000001086 cytosolic effect Effects 0.000 description 1
229940127089 cytotoxic agent Drugs 0.000 description 1
206010061428 decreased appetite Diseases 0.000 description 1
238000010511 deprotection reaction Methods 0.000 description 1
229960003957 dexamethasone Drugs 0.000 description 1
UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
125000004188 dichlorophenyl group Chemical group 0.000 description 1
230000004069 differentiation Effects 0.000 description 1
125000004212 difluorophenyl group Chemical group 0.000 description 1
235000014632 disordered eating Nutrition 0.000 description 1
239000002552 dosage form Substances 0.000 description 1
229940079593 drug Drugs 0.000 description 1
230000000694 effects Effects 0.000 description 1
229920001971 elastomer Polymers 0.000 description 1
239000002895 emetic Substances 0.000 description 1
239000000839 emulsion Substances 0.000 description 1
ZCRZCMUDOWDGOB-UHFFFAOYSA-N ethanesulfonimidic acid Chemical group CCS(N)(=O)=O ZCRZCMUDOWDGOB-UHFFFAOYSA-N 0.000 description 1
PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 1
RUJPPJYDHHAEEK-UHFFFAOYSA-N ethyl piperidine-4-carboxylate Chemical compound CCOC(=O)C1CCNCC1 RUJPPJYDHHAEEK-UHFFFAOYSA-N 0.000 description 1
230000005284 excitation Effects 0.000 description 1
239000000284 extract Substances 0.000 description 1
239000000835 fiber Substances 0.000 description 1
239000000945 filler Substances 0.000 description 1
229960002714 fluticasone Drugs 0.000 description 1
MGNNYOODZCAHBA-GQKYHHCASA-N fluticasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(O)[C@@]2(C)C[C@@H]1O MGNNYOODZCAHBA-GQKYHHCASA-N 0.000 description 1
235000003599 food sweetener Nutrition 0.000 description 1
239000012458 free base Substances 0.000 description 1
230000006870 function Effects 0.000 description 1
206010017758 gastric cancer Diseases 0.000 description 1
208000010749 gastric carcinoma Diseases 0.000 description 1
239000000499 gel Substances 0.000 description 1
230000014509 gene expression Effects 0.000 description 1
239000011521 glass Substances 0.000 description 1
125000001072 heteroaryl group Chemical group 0.000 description 1
238000004128 high performance liquid chromatography Methods 0.000 description 1
150000003840 hydrochlorides Chemical class 0.000 description 1
UVYKKFKLOUEFAR-UHFFFAOYSA-N hydron;piperazine-1-carboxamide;chloride Chemical compound Cl.NC(=O)N1CCNCC1 UVYKKFKLOUEFAR-UHFFFAOYSA-N 0.000 description 1
125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
230000000148 hypercalcaemia Effects 0.000 description 1
208000030915 hypercalcemia disease Diseases 0.000 description 1
229960001680 ibuprofen Drugs 0.000 description 1
LFKYBJLFJOOKAE-UHFFFAOYSA-N imidazol-2-ylidenemethanone Chemical compound O=C=C1N=CC=N1 LFKYBJLFJOOKAE-UHFFFAOYSA-N 0.000 description 1
125000002883 imidazolyl group Chemical group 0.000 description 1
238000003018 immunoassay Methods 0.000 description 1
229960000905 indomethacin Drugs 0.000 description 1
208000027866 inflammatory disease Diseases 0.000 description 1
238000001802 infusion Methods 0.000 description 1
239000004615 ingredient Substances 0.000 description 1
238000002347 injection Methods 0.000 description 1
239000007924 injection Substances 0.000 description 1
230000003993 interaction Effects 0.000 description 1
125000002346 iodo group Chemical group I* 0.000 description 1
LSACYLWPPQLVSM-UHFFFAOYSA-N isobutyric acid anhydride Chemical compound CC(C)C(=O)OC(=O)C(C)C LSACYLWPPQLVSM-UHFFFAOYSA-N 0.000 description 1
125000000842 isoxazolyl group Chemical group 0.000 description 1
DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
229960000991 ketoprofen Drugs 0.000 description 1
201000010982 kidney cancer Diseases 0.000 description 1
238000000021 kinase assay Methods 0.000 description 1
208000032839 leukemia Diseases 0.000 description 1
239000007788 liquid Substances 0.000 description 1
GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
230000004807 localization Effects 0.000 description 1
201000005249 lung adenocarcinoma Diseases 0.000 description 1
201000005202 lung cancer Diseases 0.000 description 1
201000005296 lung carcinoma Diseases 0.000 description 1
208000020816 lung neoplasm Diseases 0.000 description 1
230000002101 lytic effect Effects 0.000 description 1
210000002540 macrophage Anatomy 0.000 description 1
238000012423 maintenance Methods 0.000 description 1
208000027202 mammary Paget disease Diseases 0.000 description 1
238000004519 manufacturing process Methods 0.000 description 1
239000000463 material Substances 0.000 description 1
230000007246 mechanism Effects 0.000 description 1
230000001404 mediated effect Effects 0.000 description 1
238000002483 medication Methods 0.000 description 1
201000001441 melanoma Diseases 0.000 description 1
239000012528 membrane Substances 0.000 description 1
230000009245 menopause Effects 0.000 description 1
206010061289 metastatic neoplasm Diseases 0.000 description 1
HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 1
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
239000012046 mixed solvent Substances 0.000 description 1
BAVYZALUXZFZLV-UHFFFAOYSA-N mono-methylamine Natural products NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
125000002757 morpholinyl group Chemical group 0.000 description 1
238000010172 mouse model Methods 0.000 description 1
201000006417 multiple sclerosis Diseases 0.000 description 1
210000003205 muscle Anatomy 0.000 description 1
230000023105 myelination Effects 0.000 description 1
201000000050 myeloid neoplasm Diseases 0.000 description 1
SMBBZHGTZJNSRQ-UHFFFAOYSA-N n'-(6,6-dichlorohexyl)methanediimine Chemical compound ClC(Cl)CCCCCN=C=N SMBBZHGTZJNSRQ-UHFFFAOYSA-N 0.000 description 1
SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
VMECXRQIDTWJAO-GMUIIQOCSA-N n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-3,3-dimethylpiperazine-1-carboxamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1CNC(C)(C)CN1C(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 VMECXRQIDTWJAO-GMUIIQOCSA-N 0.000 description 1
DNNPBTYZRRUEIG-HDEXBNFLSA-N n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-3,8-diazabicyclo[3.2.1]octane-3-carboxamide;hydrochloride Chemical compound Cl.FC1=CC=C(F)C([C@@H]2N(CCC2)C2=NN3C(NC(=O)N4CC5CCC(N5)C4)=CN=C3C=C2)=C1 DNNPBTYZRRUEIG-HDEXBNFLSA-N 0.000 description 1
MGNQVIFAUIYZSN-UNTBIKODSA-N n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-3-(hydroxymethyl)azetidine-1-carboxamide;hydrochloride Chemical compound Cl.C1C(CO)CN1C(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 MGNQVIFAUIYZSN-UNTBIKODSA-N 0.000 description 1
HHBOJEIYZAERKH-PKLMIRHRSA-N n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]-3-hydroxy-3-methylazetidine-1-carboxamide;hydrochloride Chemical compound Cl.C1C(C)(O)CN1C(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 HHBOJEIYZAERKH-PKLMIRHRSA-N 0.000 description 1
NYUJZDXOERISBR-GMUIIQOCSA-N n-[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]piperidine-1-carboxamide;hydrochloride Chemical compound Cl.FC1=CC=C(F)C([C@@H]2N(CCC2)C2=NN3C(NC(=O)N4CCCCC4)=CN=C3C=C2)=C1 NYUJZDXOERISBR-GMUIIQOCSA-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
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
210000005036 nerve Anatomy 0.000 description 1
208000019382 nerve compression syndrome Diseases 0.000 description 1
230000001537 neural effect Effects 0.000 description 1
208000016065 neuroendocrine neoplasm Diseases 0.000 description 1
201000011519 neuroendocrine tumor Diseases 0.000 description 1
210000002569 neuron Anatomy 0.000 description 1
230000006576 neuronal survival Effects 0.000 description 1
239000003900 neurotrophic factor Substances 0.000 description 1
230000003472 neutralizing effect Effects 0.000 description 1
238000006396 nitration reaction Methods 0.000 description 1
238000003199 nucleic acid amplification method Methods 0.000 description 1
210000004248 oligodendroglia Anatomy 0.000 description 1
210000005009 osteogenic cell Anatomy 0.000 description 1
230000002188 osteogenic effect Effects 0.000 description 1
230000002611 ovarian Effects 0.000 description 1
230000002018 overexpression Effects 0.000 description 1
125000004430 oxygen atom Chemical group O* 0.000 description 1
125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
238000007911 parenteral administration Methods 0.000 description 1
239000002245 particle Substances 0.000 description 1
230000001717 pathogenic effect Effects 0.000 description 1
238000005897 peptide coupling reaction Methods 0.000 description 1
208000028169 periodontal disease Diseases 0.000 description 1
230000002093 peripheral effect Effects 0.000 description 1
102000013415 peroxidase activity proteins Human genes 0.000 description 1
108040007629 peroxidase activity proteins Proteins 0.000 description 1
238000005191 phase separation Methods 0.000 description 1
DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 1
230000026731 phosphorylation Effects 0.000 description 1
238000006366 phosphorylation reaction Methods 0.000 description 1
DCWXELXMIBXGTH-UHFFFAOYSA-N phosphotyrosine Chemical compound OC(=O)C(N)CC1=CC=C(OP(O)(O)=O)C=C1 DCWXELXMIBXGTH-UHFFFAOYSA-N 0.000 description 1
IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical compound O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 description 1
HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 1
SEHDKKMNXXAYLS-UHFFFAOYSA-N piperidine-1-carboxamide;hydrochloride Chemical compound Cl.NC(=O)N1CCCCC1 SEHDKKMNXXAYLS-UHFFFAOYSA-N 0.000 description 1
239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
229920001155 polypropylene Polymers 0.000 description 1
229910000027 potassium carbonate Inorganic materials 0.000 description 1
230000002265 prevention Effects 0.000 description 1
102000004196 processed proteins & peptides Human genes 0.000 description 1
230000002062 proliferating effect Effects 0.000 description 1
230000001737 promoting effect Effects 0.000 description 1
125000003373 pyrazinyl group Chemical group 0.000 description 1
125000003226 pyrazolyl group Chemical group 0.000 description 1
125000000714 pyrimidinyl group Chemical group 0.000 description 1
NYCVCXMSZNOGDH-UHFFFAOYSA-N pyrrolidine-1-carboxylic acid Chemical compound OC(=O)N1CCCC1 NYCVCXMSZNOGDH-UHFFFAOYSA-N 0.000 description 1
150000003254 radicals Chemical class 0.000 description 1
102000027426 receptor tyrosine kinases Human genes 0.000 description 1
108091008598 receptor tyrosine kinases Proteins 0.000 description 1
208000020615 rectal carcinoma Diseases 0.000 description 1
210000000664 rectum Anatomy 0.000 description 1
230000002829 reductive effect Effects 0.000 description 1
238000010992 reflux Methods 0.000 description 1
230000026749 regulation of bone remodeling Effects 0.000 description 1
201000010174 renal carcinoma Diseases 0.000 description 1
230000000241 respiratory effect Effects 0.000 description 1
238000004366 reverse phase liquid chromatography 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
230000008313 sensitization Effects 0.000 description 1
238000000926 separation method Methods 0.000 description 1
230000019491 signal transduction Effects 0.000 description 1
239000000741 silica gel Substances 0.000 description 1
229910002027 silica gel Inorganic materials 0.000 description 1
229910000029 sodium carbonate Inorganic materials 0.000 description 1
229960001945 sparteine Drugs 0.000 description 1
SLRCCWJSBJZJBV-AJNGGQMLSA-N sparteine Chemical compound C1N2CCCC[C@H]2[C@@H]2CN3CCCC[C@H]3[C@H]1C2 SLRCCWJSBJZJBV-AJNGGQMLSA-N 0.000 description 1
210000003594 spinal ganglia Anatomy 0.000 description 1
239000007921 spray Substances 0.000 description 1
238000010561 standard procedure Methods 0.000 description 1
150000003431 steroids Chemical class 0.000 description 1
210000002784 stomach Anatomy 0.000 description 1
201000000498 stomach carcinoma Diseases 0.000 description 1
239000000126 substance Substances 0.000 description 1
239000000829 suppository Substances 0.000 description 1
230000004083 survival effect Effects 0.000 description 1
239000003765 sweetening agent Substances 0.000 description 1
239000006188 syrup Substances 0.000 description 1
235000020357 syrup Nutrition 0.000 description 1
239000003826 tablet Substances 0.000 description 1
DATRVIMZZZVHMP-MRVPVSSYSA-N tert-butyl (2r)-2-methylpiperazine-1-carboxylate Chemical compound C[C@@H]1CNCCN1C(=O)OC(C)(C)C DATRVIMZZZVHMP-MRVPVSSYSA-N 0.000 description 1
DATRVIMZZZVHMP-QMMMGPOBSA-N tert-butyl (2s)-2-methylpiperazine-1-carboxylate Chemical compound C[C@H]1CNCCN1C(=O)OC(C)(C)C DATRVIMZZZVHMP-QMMMGPOBSA-N 0.000 description 1
NZTWGWFHWJARJX-SNVBAGLBSA-N tert-butyl (2s)-2-propan-2-ylpiperazine-1-carboxylate Chemical compound CC(C)[C@H]1CNCCN1C(=O)OC(C)(C)C NZTWGWFHWJARJX-SNVBAGLBSA-N 0.000 description 1
KIGPOOKMIMVRLZ-DHIUTWEWSA-N tert-butyl (2s)-4-[[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]carbamoyl]-2-propan-2-ylpiperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)[C@@H](C(C)C)CN1C(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 KIGPOOKMIMVRLZ-DHIUTWEWSA-N 0.000 description 1
DVMUNQAGXAMHOR-UHFFFAOYSA-N tert-butyl 2,2-dimethylpiperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1(C)C DVMUNQAGXAMHOR-UHFFFAOYSA-N 0.000 description 1
HNINFCBLGHCFOJ-UHFFFAOYSA-N tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate Chemical compound C1NCC2CCC1N2C(=O)OC(C)(C)C HNINFCBLGHCFOJ-UHFFFAOYSA-N 0.000 description 1
YQRQELKDHNQKAF-OAQYLSRUSA-N tert-butyl 4-[[6-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]carbamoyl]-2,2-dimethylpiperazine-1-carboxylate Chemical compound C1C(C)(C)N(C(=O)OC(C)(C)C)CCN1C(=O)NC1=CN=C2N1N=C(N1[C@H](CCC1)C=1C(=CC=C(F)C=1)F)C=C2 YQRQELKDHNQKAF-OAQYLSRUSA-N 0.000 description 1
NEMXVXVJGXZDRR-UHFFFAOYSA-N tert-butyl n-(azetidin-3-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC1CNC1 NEMXVXVJGXZDRR-UHFFFAOYSA-N 0.000 description 1
WUOQXNWMYLFAHT-UHFFFAOYSA-N tert-butyl n-piperidin-3-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CCCNC1 WUOQXNWMYLFAHT-UHFFFAOYSA-N 0.000 description 1
CKXZPVPIDOJLLM-UHFFFAOYSA-N tert-butyl n-piperidin-4-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CCNCC1 CKXZPVPIDOJLLM-UHFFFAOYSA-N 0.000 description 1
CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
230000001225 therapeutic effect Effects 0.000 description 1
125000000335 thiazolyl group Chemical group 0.000 description 1
201000002510 thyroid cancer Diseases 0.000 description 1
210000001685 thyroid gland Anatomy 0.000 description 1
210000001519 tissue Anatomy 0.000 description 1
238000011269 treatment regimen Methods 0.000 description 1
125000001425 triazolyl group Chemical group 0.000 description 1
125000001680 trimethoxyphenyl group Chemical group 0.000 description 1
102000047459 trkC Receptor Human genes 0.000 description 1
108010064892 trkC Receptor Proteins 0.000 description 1
210000004881 tumor cell Anatomy 0.000 description 1
230000004614 tumor growth Effects 0.000 description 1
150000003668 tyrosines Chemical class 0.000 description 1
231100000397 ulcer Toxicity 0.000 description 1
210000003932 urinary bladder Anatomy 0.000 description 1
208000010570 urinary bladder carcinoma Diseases 0.000 description 1
208000012991 uterine carcinoma Diseases 0.000 description 1
210000004291 uterus Anatomy 0.000 description 1
230000002792 vascular Effects 0.000 description 1
238000005406 washing Methods 0.000 description 1
239000003643 water by type Substances 0.000 description 1

Classifications

- 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
- 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
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—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
- 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
- A61K31/54—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 sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines containing further heterocyclic rings
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
- C07C53/15—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen containing halogen
- C07C53/16—Halogenated acetic acids
- C07C53/18—Halogenated acetic acids containing fluorine
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Landscapes

Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Veterinary Medicine (AREA)
Public Health (AREA)
Medicinal Chemistry (AREA)
Pharmacology & Pharmacy (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
General Chemical & Material Sciences (AREA)
Chemical Kinetics & Catalysis (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Physical Education & Sports Medicine (AREA)
Epidemiology (AREA)
Rheumatology (AREA)
Orthopedic Medicine & Surgery (AREA)
Biomedical Technology (AREA)
Neurology (AREA)
Neurosurgery (AREA)
Tropical Medicine & Parasitology (AREA)
Pain & Pain Management (AREA)
Pulmonology (AREA)
Dermatology (AREA)
Oil, Petroleum & Natural Gas (AREA)
Hospice & Palliative Care (AREA)
Immunology (AREA)
Reproductive Health (AREA)
Endocrinology (AREA)
Oncology (AREA)
Psychiatry (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

JP2011528046A 2008-09-22 2009-09-21 Ｔｒｋキナーゼ阻害剤としての置換イミダゾ［１，２ｂ］ピリダジン化合物 Expired - Fee Related JP5503655B2 (ja)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
US9903008P	2008-09-22	2008-09-22
US61/099,030		2008-09-22
PCT/US2009/057729 WO2010033941A1 (en)	2008-09-22	2009-09-21	Substituted imidazo[1,2b]pyridazine compounds as trk kinase inhibitors

Related Child Applications (1)

Application Number	Title	Priority Date	Filing Date
JP2014051319A Division JP5941938B2 (ja)	2008-09-22	2014-03-14	Ｔｒｋキナーゼ阻害剤としての置換イミダゾ［１，２ｂ］ピリダジン化合物

Publications (3)

Publication Number	Publication Date
JP2012503018A JP2012503018A (ja)	2012-02-02
JP2012503018A5 JP2012503018A5 (2)	2012-11-01
JP5503655B2 true JP5503655B2 (ja)	2014-05-28

Family

ID=41328652

Family Applications (5)

Application Number	Title	Priority Date	Filing Date
JP2011528046A Expired - Fee Related JP5503655B2 (ja)	2008-09-22	2009-09-21	Ｔｒｋキナーゼ阻害剤としての置換イミダゾ［１，２ｂ］ピリダジン化合物
JP2014051319A Expired - Fee Related JP5941938B2 (ja)	2008-09-22	2014-03-14	Ｔｒｋキナーゼ阻害剤としての置換イミダゾ［１，２ｂ］ピリダジン化合物
JP2016102373A Expired - Fee Related JP6267741B2 (ja)	2008-09-22	2016-05-23	Ｔｒｋキナーゼ阻害剤としての置換イミダゾ［１，２ｂ］ピリダジン化合物
JP2017245786A Pending JP2018044010A (ja)	2008-09-22	2017-12-22	Ｔｒｋキナーゼ阻害剤としての置換イミダゾ［１，２ｂ］ピリダジン化合物
JP2019224980A Expired - Fee Related JP6858240B2 (ja)	2008-09-22	2019-12-13	Ｔｒｋキナーゼ阻害剤としての置換イミダゾ［１，２ｂ］ピリダジン化合物

Family Applications After (4)

Application Number	Title	Priority Date	Filing Date
JP2014051319A Expired - Fee Related JP5941938B2 (ja)	2008-09-22	2014-03-14	Ｔｒｋキナーゼ阻害剤としての置換イミダゾ［１，２ｂ］ピリダジン化合物
JP2016102373A Expired - Fee Related JP6267741B2 (ja)	2008-09-22	2016-05-23	Ｔｒｋキナーゼ阻害剤としての置換イミダゾ［１，２ｂ］ピリダジン化合物
JP2017245786A Pending JP2018044010A (ja)	2008-09-22	2017-12-22	Ｔｒｋキナーゼ阻害剤としての置換イミダゾ［１，２ｂ］ピリダジン化合物
JP2019224980A Expired - Fee Related JP6858240B2 (ja)	2008-09-22	2019-12-13	Ｔｒｋキナーゼ阻害剤としての置換イミダゾ［１，２ｂ］ピリダジン化合物

Country Status (16)

Country	Link
US (6)	US8450322B2 (2)
EP (1)	EP2350075B1 (2)
JP (5)	JP5503655B2 (2)
CN (2)	CN103965200B (2)
CA (2)	CA2738026C (2)
CY (1)	CY1115107T1 (2)
DK (1)	DK2350075T3 (2)
ES (1)	ES2464461T3 (2)
HR (1)	HRP20140481T1 (2)
PL (1)	PL2350075T3 (2)
PT (1)	PT2350075E (2)
RS (1)	RS53350B (2)
SI (1)	SI2350075T1 (2)
SM (1)	SMT201400123B (2)
TW (1)	TWI433849B (2)
WO (1)	WO2010033941A1 (2)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
JP2016147911A (ja) *	2008-09-22	2016-08-18	アレイバイオファーマ、インコーポレイテッド	Ｔｒｋキナーゼ阻害剤としての置換イミダゾ［１，２ｂ］ピリダジン化合物

Families Citing this family (91)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
WO2008058126A2 (en) *	2006-11-06	2008-05-15	Supergen, Inc.	Imidazo[1,2-b]pyridazine and pyrazolo[1,5-a]pyrimidine derivatives and their use as protein kinase inhibitors
KR101324804B1 (ko)	2008-05-13	2013-11-01	아이알엠 엘엘씨	키나제 억제제로서의 질소 함유 융합 헤테로사이클 및 그의 조성물
MY169791A (en)	2008-10-22	2019-05-15	Array Biopharma Inc	Substituted pyrazolo [1,5-a] pyrimidine compounds as trk kinase inhibitors
AR077468A1 (es) *	2009-07-09	2011-08-31	Array Biopharma Inc	Compuestos de pirazolo (1,5 -a) pirimidina sustituidos como inhibidores de trk- quinasa
ME03376B (me)	2010-05-20	2020-01-20	Array Biopharma Inc	Makrociklička jedinjenja kао inhibiтori trk kinaze
UY33597A (es)	2010-09-09	2012-04-30	Irm Llc	Compuestos y composiciones como inhibidores de la trk
CA2835835C (en)	2011-05-13	2019-04-02	Array Biopharma Inc.	Pyrrolidinyl urea and pyrrolidinyl thiourea compounds as trka kinase inhibitors
EP2731439A4 (en)	2011-07-12	2014-12-03	Merck Sharp & Dohme	TRKA KINASE INHIBITORS, COMPOSITIONS AND METHOD THEREFOR
EP3812387A1 (en)	2011-07-21	2021-04-28	Sumitomo Dainippon Pharma Oncology, Inc.	Heterocyclic protein kinase inhibitors
WO2013134219A1 (en) *	2012-03-09	2013-09-12	Lexicon Pharmaceuticals, Inc.	Imidazo [1, 2 - b] pyridazine - based compounds, compositions comprising them, and uses thereof
WO2013176970A1 (en)	2012-05-22	2013-11-28	Merck Sharp & Dohme Corp.	TrkA KINASE INHIBITORS, COMPOSITIONS AND METHODS THEREOF
TWI585088B (zh) *	2012-06-04	2017-06-01	第一三共股份有限公司	作爲激酶抑制劑之咪唑并［１，２－ｂ］嗒衍生物
WO2014078325A1 (en) *	2012-11-13	2014-05-22	Array Biopharma Inc.	N-(monocyclic aryl),n'-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
WO2014078331A1 (en) *	2012-11-13	2014-05-22	Array Biopharma Inc.	N-(arylalkyl)-n'-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
US9981959B2 (en)	2012-11-13	2018-05-29	Array Biopharma Inc.	Thiazolyl and oxazolyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
WO2014078378A1 (en) *	2012-11-13	2014-05-22	Array Biopharma Inc.	Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
WO2014078372A1 (en)	2012-11-13	2014-05-22	Array Biopharma Inc.	Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
WO2014078328A1 (en) *	2012-11-13	2014-05-22	Array Biopharma Inc.	N-bicyclic aryl,n'-pyrazolyl urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
MX374242B (es)	2012-11-13	2025-03-05	Array Biopharma Inc	Compuestos de n-pirrolidinil, n' -pirazolil-urea, tiourea, guanidina y cianoguanidina como inhibidores de trka cinasa.
WO2014078417A1 (en)	2012-11-13	2014-05-22	Array Biopharma Inc.	Pyrazolyl urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
RS55593B1 (sr)	2012-11-13	2017-06-30	Array Biopharma Inc	Jedinjenja biciklične uree, tiouree, guanidina i cijanoguanidina korisna za lečenje bola
US9822118B2 (en)	2012-11-13	2017-11-21	Array Biopharma Inc.	Bicyclic heteroaryl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
WO2015039333A1 (en)	2013-09-22	2015-03-26	Merck Sharp & Dohme Corp.	TrkA KINASE INHIBITORS, COMPOSITIONS AND METHODS THEREOF
WO2015039334A1 (en)	2013-09-22	2015-03-26	Merck Sharp & Dohme Corp.	TrkA KINASE INHIBITORS, COMPOSITIONS AND METHODS THEREOF
ES2933350T3 (es)	2014-01-24	2023-02-06	Turning Point Therapeutics Inc	Macrociclos de diarilo como moduladores de proteína quinasas
WO2015143652A1 (en) *	2014-03-26	2015-10-01	Merck Sharp & Dohme Corp.	TrkA KINASE INHIBITORS,COMPOSITIONS AND METHODS THEREOF
WO2015143653A1 (en)	2014-03-26	2015-10-01	Merck Sharp & Dohme Corp.	TrkA KINASE INHIBITORS,COMPOSITIONS AND METHODS THEREOF
WO2015143654A1 (en)	2014-03-26	2015-10-01	Merck Sharp & Dohme Corp.	TrkA KINASE INHIBITORS,COMPOSITIONS AND METHODS THEREOF
MA40434B1 (fr)	2014-05-15	2019-09-30	Array Biopharma Inc	1-((3s,4r)-4-(3-fluorophényl)-1-(2-méthoxyéthyl)pyrrolidin-3-yl)-3-(4-méthyl-3-(2-méthylpyrimidin-5-yl)-1-phényl-1h-pyrazol-5-yl)urée comme inhibiteur de la kinase trka
CN113354649B (zh)	2014-11-16	2024-12-10	阵列生物制药公司	一种新的晶型
CN104672121B (zh) *	2015-02-16	2017-10-24	上海华默西医药科技有限公司	2r‑(2,5‑二氟苯基)吡咯烷盐酸盐的制备方法
WO2016161572A1 (en)	2015-04-08	2016-10-13	Merck Sharp & Dohme Corp.	TrkA KINASE INHIBITORS, COMPOSITIONS AND METHODS THEREOF
HK1253093A1 (zh)	2015-06-01	2019-06-06	Loxo Oncology Inc.	诊断和治疗癌症的方法
AU2016287568B2 (en)	2015-07-02	2020-08-20	Turning Point Therapeutics, Inc.	Chiral diaryl macrocycles as modulators of protein kinases
RU2765181C2 (ru)	2015-07-06	2022-01-26	Тёрнинг Поинт Терапьютикс, Инк.	Полиморфная форма диарильного макроцикла
BR112018000808A2 (pt)	2015-07-16	2018-09-04	Array Biopharma Inc	compostos de pirazolo[1,5-a]piridina substituída como inibidores de ret cinase
PT3733187T (pt)	2015-07-21	2024-11-08	Turning Point Therapeutics Inc	Macrociclo de diarilo quiral e utilização do mesmo no tratamento do cancro
EP3368039A1 (en)	2015-10-26	2018-09-05	The Regents of The University of Colorado, A Body Corporate	Point mutations in trk inhibitor-resistant cancer and methods relating to the same
AU2017246547B2 (en)	2016-04-04	2023-02-23	Loxo Oncology, Inc.	Methods of treating pediatric cancers
US10045991B2 (en)	2016-04-04	2018-08-14	Loxo Oncology, Inc.	Methods of treating pediatric cancers
FI3439662T3 (fi)	2016-04-04	2024-09-04	Loxo Oncology Inc	(s)-n-(5-((r)-2-(2,5-difluorifenyyli)pyrrolidin-1-yyli)pyratsolo[1,5-a]pyrimidin-3-yyli)-3-hydroksipyrrolidiini-1-karboksamidin nesteformulaatioita
EP3458456B1 (en)	2016-05-18	2020-11-25	Loxo Oncology Inc.	Preparation of (s)-n-(5-((r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
US10689400B2 (en)	2016-07-28	2020-06-23	Turning Point Therapeutics, Inc.	Macrocycle kinase inhibitors
TWI752098B (zh)	2016-10-10	2022-01-11	美商亞雷生物製藥股份有限公司	作為ret激酶抑制劑之經取代吡唑并[1,5-a]吡啶化合物
TWI704148B (zh)	2016-10-10	2020-09-11	美商亞雷生物製藥股份有限公司	作為ｒｅｔ激酶抑制劑之經取代吡唑并[1,5-a]吡啶化合物
JOP20190092A1 (ar)	2016-10-26	2019-04-25	Array Biopharma Inc	عملية لتحضير مركبات بيرازولو[1، 5-a]بيريميدين وأملاح منها
CN108003161B (zh) *	2016-10-28	2020-10-09	正大天晴药业集团股份有限公司	神经营养因子酪氨酸激酶受体抑制剂
ES2896943T3 (es)	2016-10-28	2022-02-28	Chia Tai Tianqing Pharmaceutical Group Co Ltd	Compuesto de amino pirazolopirimidina usado como inhibidor de receptores con actividad tirosina quinasa de factores neurotróficos
CN106632353A (zh) *	2016-11-18	2017-05-10	山东友帮生化科技有限公司	3‑硝基‑6‑氯咪唑并[1,2‑b]哒嗪的合成方法
WO2018136663A1 (en)	2017-01-18	2018-07-26	Array Biopharma, Inc.	Ret inhibitors
WO2018136661A1 (en)	2017-01-18	2018-07-26	Andrews Steven W	SUBSTITUTED PYRAZOLO[1,5-a]PYRAZINE COMPOUNDS AS RET KINASE INHIBITORS
TWI808958B (zh)	2017-01-25	2023-07-21	美商特普醫葯公司	涉及二芳基巨環化合物之組合療法
JOP20190213A1 (ar)	2017-03-16	2019-09-16	Array Biopharma Inc	مركبات حلقية ضخمة كمثبطات لكيناز ros1
CN107286070B (zh) *	2017-07-19	2019-07-16	浙江师范大学	(r)-2-(2,5-二氟苯基)吡咯烷的合成方法及中间体
CN111182903A (zh)	2017-07-28	2020-05-19	特普医药公司	巨环化合物及其用途
FI3661935T3 (fi) *	2017-08-11	2023-01-13		Kinaasin estäjinä käyttökelpoiset pyratsolipyrimidiinit
CA3071032A1 (en)	2017-08-23	2019-02-28	Chia Tai Tianqing Pharmaceutical Group Co., Ltd.	Macrocycle containing aminopyrazole and pyrimidine and pharmaceutical composition and use thereof
TWI791053B (zh)	2017-10-10	2023-02-01	美商亞雷生物製藥股份有限公司	6-(2-羥基-2-甲基丙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮雜雙環[3.1.1]庚-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈之結晶形式及其醫藥組合物
TWI876442B (zh)	2017-10-10	2025-03-11	美商絡速藥業公司	6-(2-羥基-2-甲基丙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮雜雙環[3.1.1]庚-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈之調配物
WO2019084285A1 (en)	2017-10-26	2019-05-02	Qian Zhao	FORMULATIONS OF A MACROCYCLIC TRK KINASE INHIBITOR
LT3728271T (lt)	2017-12-19	2022-12-12	Turning Point Therapeutics, Inc.	Makrocikliniai junginiai, skirti ligų gydymui
US11472802B2 (en)	2018-01-18	2022-10-18	Array Biopharma Inc.	Substituted pyrazolyl[4,3-c]pyridine compounds as RET kinase inhibitors
EP3740490A1 (en)	2018-01-18	2020-11-25	Array Biopharma, Inc.	Substituted pyrazolo[3,4-d]pyrimidine compounds as ret kinase inhibitors
JP7060694B2 (ja)	2018-01-18	2022-04-26	アレイバイオファーマインコーポレイテッド	Ｒｅｔキナーゼ阻害剤としての置換ピロロ［２，３－ｄ］ピリミジン化合物
CN108218754B (zh) *	2018-01-23	2021-05-07	广东赛烽医药科技有限公司	一种2-(2,5-二氟苯基)吡咯烷的制备方法
CN111936500B (zh) *	2018-03-14	2023-09-01	重庆复尚源创医药技术有限公司	作为TRK激酶抑制剂的取代的(2-氮杂双环[3.1.0]己-2-基)吡唑[1,5-a]嘧啶和咪唑[1,2-b]哒嗪化合物
WO2019191659A1 (en)	2018-03-29	2019-10-03	Loxo Oncology, Inc.	Treatment of trk-associated cancers
CN111902417B (zh)	2018-04-25	2023-07-28	北京普祺医药科技股份有限公司	一种二芳基巨环化合物、药物组合物以及其用途
GB201811825D0 (en) *	2018-07-19	2018-09-05	Benevolentai Bio Ltd	Organic compounds
CN117285467A (zh)	2018-07-31	2023-12-26	罗索肿瘤学公司	喷雾干燥的分散体和制剂
CN110857304B (zh) *	2018-08-24	2021-05-18	北京富龙康泰生物技术有限公司	Trk抑制剂、其制备方法和用途
JP7443373B2 (ja)	2018-09-03	2024-03-05	タイリガンドバイオサイエンス（シャンハイ）リミテッド	抗がん性薬物としてのｔｒｋ阻害剤
CN112996794A (zh)	2018-09-10	2021-06-18	阿雷生物药品公司	作为ret激酶抑制剂的稠合杂环化合物
CN111039947A (zh) *	2018-10-15	2020-04-21	上海轶诺药业有限公司	一类蛋白受体激酶抑制剂的制备和应用
CN111171019A (zh) *	2018-11-13	2020-05-19	上海轶诺药业有限公司	一类五元并六元杂环化合物及其作为蛋白受体激酶抑制剂的用途
CN111269233A (zh) *	2018-12-05	2020-06-12	上海轶诺药业有限公司	一类咪唑并芳环类化合物的制备和应用
CN109354578A (zh) *	2018-12-06	2019-02-19	浙江师范大学	一种替尼中间体以及替尼的合成方法
US12351571B2 (en)	2018-12-19	2025-07-08	Array Biopharma Inc.	Substituted quinoxaline compounds as inhibitors of FGFR tyrosine kinases
EP3898626A1 (en)	2018-12-19	2021-10-27	Array Biopharma, Inc.	Substituted pyrazolo[1,5-a]pyridine compounds as inhibitors of fgfr tyrosine kinases
KR20260008165A (ko)	2019-02-12	2026-01-15	스미토모 파마 아메리카, 인크.	헤테로시클릭 단백질 키나제 억제제를 포함하는 제제
US20220177477A1 (en)	2019-03-19	2022-06-09	Central China Normal University	Pyrazolopyrimidine compound, pharmaceutical composition, and application therefor
EA202192575A1 (ru)	2019-03-21	2022-01-14	Онксео	Соединения dbait в сочетании с ингибиторами киназ для лечения рака
CN112867717B (zh)	2019-05-08	2023-01-10	浙江同源康医药股份有限公司	用作激酶抑制剂的化合物及其应用
WO2021047584A1 (en) *	2019-09-11	2021-03-18	Fochon Pharmaceuticals, Ltd.	SUBSTITUTED (2-AZABICYCLO [3.1.0] HEXAN-2-YL) PYRAZOLO [1, 5-a] PYRIMIDINE AND IMIDAZO [1, 2-b] PYRIDAZINE COMPOUNDS AS TRK KINASES INHIBITORS
CN114761006A (zh)	2019-11-08	2022-07-15	Inserm(法国国家健康医学研究院)	对激酶抑制剂产生耐药性的癌症的治疗方法
CN112812118A (zh) *	2019-11-18	2021-05-18	上海轶诺药业有限公司	一类蛋白受体激酶抑制剂的制备和应用
AU2021209418A1 (en) *	2020-01-22	2022-07-21	Benevolentai Bio Limited	Topical pharmaceutical compositions comprising imidazo[1,2-b]pyridazine compounds
WO2021148581A1 (en)	2020-01-22	2021-07-29	Onxeo	Novel dbait molecule and its use
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
CN113831344B (zh) *	2021-04-13	2022-09-16	深圳市新樾生物科技有限公司	炔苯基苯酰胺类化合物及其应用
AU2021453749A1 (en) *	2021-07-01	2023-12-21	Nuvation Bio Inc.	Crystalline forms of 3-{4-[(2r)-2-aminopropoxy]phenyl}-n-[(1r)- 1-(3-fluorophenyl) ethyl]imidazo[1,2-b]pyridazin-6-amine and salts thereof

Family Cites Families (188)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
DE69422306T4 (de)	1993-11-30	2000-09-07	G.D. Searle & Co., Chicago	Substituierte pyrazolyl-benzolsulfonamide zur behandlung von entzündungen
US5430021A (en)	1994-03-18	1995-07-04	Pharmavene, Inc.	Hydrophobic drug delivery systems
US5844092A (en)	1994-03-18	1998-12-01	Genentech, Inc.	Human TRK receptors and neurotrophic factor inhibitors
US5877016A (en)	1994-03-18	1999-03-02	Genentech, Inc.	Human trk receptors and neurotrophic factor inhibitors
CA2206201A1 (en)	1996-05-29	1997-11-29	Yoshiaki Isobe	Pyrazole derivatives and their pharmaceutical use
CA2285264A1 (en)	1997-04-25	1998-11-05	Michiyo Gyoten	Condensed pyridazine derivatives, their production and use
US6534085B1 (en)	1999-09-23	2003-03-18	Bioresponse L.L.C.	Phytochemicals for promoting weight loss
CA2412494C (en)	2000-06-22	2012-10-23	Genentech, Inc.	Agonist anti-trk-c monoclonal antibodies
TWI312347B (en)	2001-02-08	2009-07-21	Eisai R&D Man Co Ltd	Bicyclic nitrogen-containing condensed ring compounds
CA2975521A1 (en)	2001-05-30	2002-12-05	Genentech, Inc.	Anti-ngf antibodies for the treatment of various disorders
US20030199525A1 (en)	2002-03-21	2003-10-23	Hirst Gavin C.	Kinase inhibitors
US7449488B2 (en)	2002-06-04	2008-11-11	Schering Corporation	Pyrazolopyrimidines as protein kinase inhibitors
ITMI20021620A1 (it)	2002-07-23	2004-01-23	Novuspharma Spa	Composto ad ativita' antitumorale
JP4024624B2 (ja)	2002-08-26	2007-12-19	富士通株式会社	半導体装置の製造方法及び製造装置
US8580782B2 (en)	2002-09-04	2013-11-12	Merck Sharp & Dohme Corp.	Substituted pyrazolo[1,5-a]pyrimidines as cyclin dependent kinase inhibitors
US7196078B2 (en)	2002-09-04	2007-03-27	Schering Corpoartion	Trisubstituted and tetrasubstituted pyrazolopyrimidines as cyclin dependent kinase inhibitors
MXPA05002571A (es)	2002-09-04	2005-09-08	Schering Corp	Pirazolopirimidinas como inhibidores de cinasa dependientes de ciclina.
AU2003298942A1 (en)	2002-12-11	2004-06-30	Merck And Co., Inc.	Tyrosine kinase inhibitors
US7550470B2 (en)	2002-12-11	2009-06-23	Merck & Co. Inc.	Substituted pyrazolo[1,5-A]pyrimidines as tyrosine kinase inhibitors
GB0303910D0 (en)	2003-02-20	2003-03-26	Merck Sharp & Dohme	Therapeutic agents
ES2325440T3 (es)	2003-02-20	2009-09-04	Smithkline Beecham Corporation	Compuestos de pirimidina.
WO2004082458A2 (en)	2003-02-21	2004-09-30	The Johns Hopkins University	Tyrosine kinome
JP2004277337A (ja)	2003-03-14	2004-10-07	Sumitomo Pharmaceut Co Ltd	ピラゾロ［１，５−ａ］ピリミジン誘導体
US20070179161A1 (en)	2003-03-31	2007-08-02	Vernalis (Cambridge) Limited.	Pyrazolopyrimidine compounds and their use in medicine
JP2006522744A (ja)	2003-04-11	2006-10-05	ノボ　ノルディスク　アクティーゼルスカブ	グルココルチコイド受容体アゴニスト療法に伴う副作用を最小化するための、１１β−ヒドロキシステロイドデヒドロゲナーゼ１型阻害剤およびグルココルチコイド受容体アゴニストを使用する併用療法
US20060094699A1 (en)	2003-04-11	2006-05-04	Kampen Gita Camilla T	Combination therapy using an 11beta-hydroxysteroid dehydrogenase type 1 inhibitor and a glucocorticoid receptor agonist to minimize the side effects associated with glucocorticoid receptor agonist therapy
WO2004089471A2 (en)	2003-04-11	2004-10-21	Novo Nordisk A/S	NEW PYRAZOLO[1,5-a] PYRIMIDINES DERIVATIVES AND PHARMACEUTICAL USE THEREOF
US20070042941A1 (en)	2003-04-28	2007-02-22	Mitsuomi Hirashima	Galectin 9-inducing factors
JO2785B1 (en)	2003-05-27	2014-03-15	شركة جانسين فارماسوتيكا ان. في	Quinazoline derivatives
JP2005008581A (ja)	2003-06-20	2005-01-13	Kissei Pharmaceut Co Ltd	新規なピラゾロ［１，５−ａ］ピリミジン誘導体、それを含有する医薬組成物およびそれらの用途
EA009517B1 (ru)	2003-06-27	2008-02-28	Байер Кропсайенс Аг	Пиразолопиримидины
AR045056A1 (es)	2003-07-15	2005-10-12	Amgen Inc	Anticuerpos anti-ngf humanos neutralizantes como inhibidores selectivos de la via de ngf
US7491794B2 (en)	2003-10-14	2009-02-17	Intermune, Inc.	Macrocyclic compounds as inhibitors of viral replication
MY141220A (en)	2003-11-17	2010-03-31	Astrazeneca Ab	Pyrazole derivatives as inhibitors of receptor tyrosine kinases
MXPA06007017A (es)	2003-12-18	2006-08-31	Janssen Pharmaceutica Nv	Derivados de pirido y pirimidopirimidina como agentes antiproliferativos.
CN1925855B (zh)	2003-12-19	2010-06-16	普莱希科公司	开发Ret调节剂的化合物和方法
WO2005068424A1 (en)	2004-01-20	2005-07-28	Cell Therapeutics Europe S.R.L.	Indolinone derivatives as receptor tyrosine kinase ihibitors
US20050222171A1 (en)	2004-01-22	2005-10-06	Guido Bold	Organic compounds
WO2005099363A2 (en)	2004-03-26	2005-10-27	Whitehead Institute For Biomedical Research	Methods of diagnosing, preventing and treating cancer metastasis
CN1938311A (zh)	2004-03-30	2007-03-28	因特蒙公司	作为病毒复制抑制剂的大环化合物
GB0512324D0 (en)	2005-06-16	2005-07-27	Novartis Ag	Organic compounds
PE20060664A1 (es)	2004-09-15	2006-08-04	Novartis Ag	Amidas biciclicas como inhibidores de cinasa
PT1812440E (pt)	2004-11-04	2011-01-25	Vertex Pharma	Pirazolo[1,5-a]pirimidinas úteis enquanto inibidores de proteínas cinases
JO3088B1 (ar)	2004-12-08	2017-03-15	Janssen Pharmaceutica Nv	مشتقات كوينازولين كبيرة الحلقات و استعمالها بصفتها موانع كينيز متعددة الاهداف
DE102005003687A1 (de)	2005-01-26	2006-07-27	Sphingo Tec Gmbh	Immunoassay zur Bestimmung der Freisetzung von Neurotensin in die Zirkulation
CN101119996A (zh)	2005-02-16	2008-02-06	阿斯利康(瑞典)有限公司	化学化合物
ES2347172T3 (es)	2005-02-16	2010-10-26	Astrazeneca Ab	Compuestos quimicos.
EP1869049B1 (en)	2005-03-21	2009-03-04	Eli Lilly And Company	Imidazopyridazine compounds
CN101208093A (zh)	2005-04-27	2008-06-25	阿斯利康(瑞典)有限公司	吡唑-嘧啶衍生物在治疗疼痛中的用途
US20080287437A1 (en)	2005-05-16	2008-11-20	Astrazeneca Ab	Pyrazolylaminopyrimidine Derivatives Useful as Tyrosine Kinase Inhibitors
CN100406650C (zh)	2005-06-05	2008-07-30	徐斌	一种抗特大变位的模块式梳型桥梁伸缩缝装置
ITRM20050290A1 (it)	2005-06-07	2006-12-08	Lay Line Genomics Spa	Uso di molecole in grado di inibire il legame tra ngf e il suo recettore trka come analgesici ad effetto prolungato.
US20070025540A1 (en)	2005-07-07	2007-02-01	Roger Travis	Call center routing based on talkativeness
MX2008001166A (es)	2005-07-25	2008-03-18	Intermune Inc	Nuevos inhibidores macrociclicos de la replicacion del virus de hepatitis c.
EP1910369A1 (en) *	2005-07-29	2008-04-16	Astellas Pharma Inc.	Fused heterocycles as lck inhibitors
CN101232871A (zh)	2005-08-03	2008-07-30	伊士曼化工公司	生育酚聚乙二醇琥珀酸酯粉末及其制备方法
EP1926734A1 (en)	2005-08-22	2008-06-04	Amgen Inc.	Pyrazolopyridine and pyrazolopyrimidine compounds useful as kinase enzymes modulators
US20070049591A1 (en)	2005-08-25	2007-03-01	Kalypsys, Inc.	Inhibitors of MAPK/Erk Kinase
WO2007022999A1 (en)	2005-08-25	2007-03-01	Creabilis Therapeutics S.P.A.	Polymer conjugates of k-252a and derivatives thereof
DE102005042742A1 (de)	2005-09-02	2007-03-08	Schering Ag	Substituierte Imidazo[1,2b]pyridazine als Kinase-Inhibitoren, deren Herstellung und Verwendung als Arzneimittel
US20070078136A1 (en)	2005-09-22	2007-04-05	Bristol-Myers Squibb Company	Fused heterocyclic compounds useful as kinase modulators
BRPI0616985B1 (pt)	2005-10-06	2021-10-26	Merck Sharp & Dohme Corp.	Composto de pirazolo[1,5-a]pirimidina, e, uso de um composto
AR057979A1 (es)	2005-10-06	2008-01-09	Schering Corp	PIRAZOLPIRIMIDINAS COMO INHIBIDORAS DE PROTEíNA QUINASA. COMPOSICIONES FARMACEUTICAS.
ATE519757T1 (de)	2005-10-11	2011-08-15	Centre Nat Rech Scient	3 hydroxyflavon-derivate zur erkennung und quantifizierung von zell-apoptosen
AU2006301966A1 (en)	2005-10-11	2007-04-19	Array Biopharma, Inc.	Compounds and methods for inhibiting hepatitis C viral replication
US8372851B2 (en)	2005-10-21	2013-02-12	Exelixis, Inc.	Pyrazolo pyrimidines as casein kinase II (CK2) modulators
GB0524436D0 (en)	2005-11-30	2006-01-11	Novartis Ag	Organic compounds
US8399442B2 (en)	2005-12-30	2013-03-19	Astex Therapeutics Limited	Pharmaceutical compounds
US20080108611A1 (en)	2006-01-19	2008-05-08	Battista Kathleen A	Substituted thienopyrimidine kinase inhibitors
KR100846988B1 (ko)	2006-03-06	2008-07-16	제일약품주식회사	신규한 티에노피리미딘 유도체 또는 이의 약학적으로허용가능한 염, 이의 제조방법 및 이를 함유하는 약학조성물
WO2007103308A2 (en)	2006-03-07	2007-09-13	Array Biopharma Inc.	Heterobicyclic pyrazole compounds and methods of use
GB0606805D0 (en)	2006-04-04	2006-05-17	Novartis Ag	Organic compounds
WO2007129161A2 (en)	2006-04-26	2007-11-15	F. Hoffmann-La Roche Ag	Thieno [3, 2-d] pyrimidine derivative useful as pi3k inhibitor
CN104706637A (zh)	2006-05-18	2015-06-17	卫材R&D管理有限公司	针对甲状腺癌的抗肿瘤剂
US7389632B2 (en)	2006-06-10	2008-06-24	Uhlmann Pac-Systeme Gmbh & Co. Kg	Apparatus for distributing small objects in a fill station
EP1873157A1 (en)	2006-06-21	2008-01-02	Bayer Schering Pharma Aktiengesellschaft	Pyrazolopyrimidines and salts thereof, pharmaceutical compositions comprising same, methods of preparing same and uses of same
TWI419889B (zh)	2006-07-05	2013-12-21	Mitsubishi Tanabe Pharma Corp	吡唑并〔１，５-ａ〕嘧啶化合物
EP2058309A4 (en) *	2006-08-04	2010-12-22	Takeda Pharmaceutical	CONDENSED HETEROCYCLIC COMPOUND
US7531539B2 (en)	2006-08-09	2009-05-12	Bristol-Myers Squibb Company	Pyrrolotriazine kinase inhibitors
CN101594909A (zh)	2006-09-07	2009-12-02	比奥根艾迪克Ma公司	用于治疗炎性病症、细胞增殖性失调、免疫失调的irak调节剂
WO2008037477A1 (en)	2006-09-29	2008-04-03	Novartis Ag	Pyrazolopyrimidines as p13k lipid kinase inhibitors
JP2010508315A (ja) *	2006-10-30	2010-03-18	ノバルティスアーゲー	抗炎症剤としてのヘテロ環式化合物
WO2008058126A2 (en)	2006-11-06	2008-05-15	Supergen, Inc.	Imidazo[1,2-b]pyridazine and pyrazolo[1,5-a]pyrimidine derivatives and their use as protein kinase inhibitors
PE20121126A1 (es)	2006-12-21	2012-08-24	Plexxikon Inc	Compuestos pirrolo [2,3-b] piridinas como moduladores de quinasa
US20080234267A1 (en)	2007-03-20	2008-09-25	Karen Elizabeth Lackey	Compounds and Methods of Treatment
US20080234262A1 (en)	2007-03-21	2008-09-25	Wyeth	Pyrazolopyrimidine analogs and their use as mtor kinase and pi3 kinase inhibitors
CA2682016A1 (en)	2007-03-28	2008-10-02	Inovacia Ab	Pyrazolo [1,5-a]pyrimidines as inhibitors of stearoyl-coa desaturase
NZ580327A (en)	2007-04-03	2012-02-24	Array Biopharma Inc	IMIDAZO[1,2-a]PYRIDINE COMPOUNDS AS RECEPTOR TYROSINE KINASE INHIBITORS
EA019524B1 (ru)	2007-05-04	2014-04-30	Айрм Ллк	СОЕДИНЕНИЯ И КОМПОЗИЦИИ КАК ИНГИБИТОРЫ КИНАЗЫ с-kit И PDGFR
CA2687909C (en)	2007-06-21	2015-09-15	Janssen Pharmaceutica Nv	Indolin-2-ones and aza-indolin-2-ones
PT2176231T (pt)	2007-07-20	2016-12-09	Nerviano Medical Sciences Srl	Derivados de indazol substituídos activos como inibidores de quinases
MX2010001395A (es)	2007-08-10	2010-03-10	Regeneron Pharma	Anticuerpos humanos de alta afinidad de factor de crecimiento de nervio humano.
EA201000484A1 (ru)	2007-10-16	2010-12-30	ВАЙЕТ ЭлЭлСи	Тиенопиримидиновые и пиразолопиримидиновые соединения и их применение в качестве ингибиторов киназы mtor и киназы pi3
EP2214706A1 (en)	2007-10-23	2010-08-11	Novartis AG	Use of trkb antibodies for the treatment of respiratory disorders
EP2217601A1 (en) *	2007-11-08	2010-08-18	Centro Nacional de Investigaciones Oncológicas (CNIO)	Imidazopyridazines for use as protein kinase inhibitors
PE20091326A1 (es)	2008-01-17	2009-09-18	Irm Llc	Anticuerpos anti-trkb mejorados
JP2009203226A (ja)	2008-01-31	2009-09-10	Eisai R & D Management Co Ltd	ピリジン誘導体およびピリミジン誘導体を含有するレセプターチロシンキナーゼ阻害剤
KR101324804B1 (ko) *	2008-05-13	2013-11-01	아이알엠 엘엘씨	키나제 억제제로서의 질소 함유 융합 헤테로사이클 및 그의 조성물
WO2009143018A2 (en)	2008-05-19	2009-11-26	Plexxikon, Inc.	Compounds and methods for kinase modulation, and indications therefor
ES2554513T3 (es)	2008-05-23	2015-12-21	Novartis Ag	Derivados de quinolinas y quinoxalinas como inhibidores de la proteína tirosina quinasa
EP2323664B1 (en)	2008-07-29	2015-01-07	Nerviano Medical Sciences S.r.l.	Use of a cdk inhibitor for the treatment of glioma
WO2010033941A1 (en) *	2008-09-22	2010-03-25	Array Biopharma Inc.	Substituted imidazo[1,2b]pyridazine compounds as trk kinase inhibitors
MY169791A (en)	2008-10-22	2019-05-15	Array Biopharma Inc	Substituted pyrazolo [1,5-a] pyrimidine compounds as trk kinase inhibitors
EP2348860B1 (en)	2008-10-31	2015-05-27	Genentech, Inc.	Pyrazolopyrimidine jak inhibitor compounds and methods
WO2010058006A1 (en)	2008-11-24	2010-05-27	Nerviano Medical Sciences S.R.L.	Cdk inhibitor for the treatment of mesothelioma
JO3265B1 (ar)	2008-12-09	2018-09-16	Novartis Ag	مثبطات بيريديلوكسى اندولات vegf-r2 واستخدامها لعلاج المرض
EP3266795A1 (en)	2009-02-12	2018-01-10	Cell Signaling Technology, Inc.	Method for detecting a fig-ros fusion polynucleotide
AR077468A1 (es)	2009-07-09	2011-08-31	Array Biopharma Inc	Compuestos de pirazolo (1,5 -a) pirimidina sustituidos como inhibidores de trk- quinasa
ES2594927T3 (es)	2010-02-18	2016-12-23	INSERM (Institut National de la Santé et de la Recherche Médicale)	Métodos para prevenir las metástasis cancerosas
JP2013526852A (ja)	2010-04-06	2013-06-27	カリスライフサイエンシズルクセンブルクホールディングス	疾患に対する循環バイオマーカー
US8383793B2 (en)	2010-04-15	2013-02-26	St. Jude Children's Research Hospital	Methods and compositions for the diagnosis and treatment of cancer resistant to anaplastic lymphoma kinase (ALK) kinase inhibitors
TWI510487B (zh)	2010-04-21	2015-12-01	Plexxikon Inc	用於激酶調節的化合物和方法及其適應症
US8543395B2 (en)	2010-05-18	2013-09-24	Shazam Entertainment Ltd.	Methods and systems for performing synchronization of audio with corresponding textual transcriptions and determining confidence values of the synchronization
ME03376B (me)	2010-05-20	2020-01-20	Array Biopharma Inc	Makrociklička jedinjenja kао inhibiтori trk kinaze
WO2012024650A2 (en)	2010-08-19	2012-02-23	Abbott Laboratories	Anti-ngf antibodies and their use
UY33597A (es) *	2010-09-09	2012-04-30	Irm Llc	Compuestos y composiciones como inhibidores de la trk
WO2012034095A1 (en)	2010-09-09	2012-03-15	Irm Llc	Compounds and compositions as trk inhibitors
EP2646468B1 (en)	2010-12-01	2018-07-25	AlderBio Holdings LLC	Anti-ngf compositions and use thereof
MA34969B1 (fr)	2011-02-25	2014-03-01	Irm Llc	Composes et compositions en tant qu inibiteurs de trk
CA2835835C (en)	2011-05-13	2019-04-02	Array Biopharma Inc.	Pyrrolidinyl urea and pyrrolidinyl thiourea compounds as trka kinase inhibitors
WO2013059740A1 (en)	2011-10-21	2013-04-25	Foundation Medicine, Inc.	Novel alk and ntrk1 fusion molecules and uses thereof
EP2779833A4 (en)	2011-11-14	2015-03-18	Tesaro Inc	MODULATION OF SPECIFIC TYROSINE KINASES
AU2012351748B2 (en)	2011-12-12	2016-04-14	Dr. Reddy's Laboratories Ltd.	Substituted pyrazolo[1,5-a] pyridine as tropomyosin receptor kinase (Trk) inhibitors
US8377946B1 (en)	2011-12-30	2013-02-19	Pharmacyclics, Inc.	Pyrazolo[3,4-d]pyrimidine and pyrrolo[2,3-d]pyrimidine compounds as kinase inhibitors
TW201350479A (zh)	2012-04-26	2013-12-16	Ono Pharmaceutical Co	Ｔｒｋ阻害化合物
ES2751944T3 (es)	2012-05-23	2020-04-02	Nerviano Medical Sciences Srl	Proceso para la preparación de N-[5-(3,5-difluoro-bencil)-1H-indazol-3-il]-4-(4-metil-piperazin-1-il)-2-(tetrahidro-piran-4-ilamino)-benzamida
TWI585088B (zh)	2012-06-04	2017-06-01	第一三共股份有限公司	作爲激酶抑制劑之咪唑并［１，２－ｂ］嗒衍生物
EP2890815B1 (en)	2012-08-31	2019-03-20	The Regents of the University of Colorado	Methods for diagnosis and treatment of cancer
JP6513567B2 (ja)	2012-09-07	2019-05-15	エクセリクシス，インク．	肺腺癌の治療で使用するためのｍｅｔ、ｖｅｇｆｒ、およびｒｅｔの阻害剤
US20140084039A1 (en)	2012-09-24	2014-03-27	Electro Scientific Industries, Inc.	Method and apparatus for separating workpieces
JP2014082984A (ja)	2012-10-23	2014-05-12	Astellas Pharma Inc	新規ｎｔｒｋ２活性化変異の検出法
US11230589B2 (en)	2012-11-05	2022-01-25	Foundation Medicine, Inc.	Fusion molecules and uses thereof
EP2914621B1 (en)	2012-11-05	2023-06-07	Foundation Medicine, Inc.	Novel ntrk1 fusion molecules and uses thereof
US9981959B2 (en)	2012-11-13	2018-05-29	Array Biopharma Inc.	Thiazolyl and oxazolyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
WO2014078331A1 (en)	2012-11-13	2014-05-22	Array Biopharma Inc.	N-(arylalkyl)-n'-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
RS55593B1 (sr)	2012-11-13	2017-06-30	Array Biopharma Inc	Jedinjenja biciklične uree, tiouree, guanidina i cijanoguanidina korisna za lečenje bola
WO2014078325A1 (en)	2012-11-13	2014-05-22	Array Biopharma Inc.	N-(monocyclic aryl),n'-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
MX374242B (es)	2012-11-13	2025-03-05	Array Biopharma Inc	Compuestos de n-pirrolidinil, n' -pirazolil-urea, tiourea, guanidina y cianoguanidina como inhibidores de trka cinasa.
US9822118B2 (en)	2012-11-13	2017-11-21	Array Biopharma Inc.	Bicyclic heteroaryl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors
WO2014078417A1 (en)	2012-11-13	2014-05-22	Array Biopharma Inc.	Pyrazolyl urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
WO2014078372A1 (en)	2012-11-13	2014-05-22	Array Biopharma Inc.	Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
WO2014078328A1 (en)	2012-11-13	2014-05-22	Array Biopharma Inc.	N-bicyclic aryl,n'-pyrazolyl urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
CA2877847A1 (en)	2012-11-29	2014-06-05	Yeda Research And Development Co. Ltd.	Methods of preventing tumor metastasis, treating and prognosing cancer and identifying agents which are putative metastasis inhibitors
US9447135B2 (en)	2012-12-14	2016-09-20	University Of Kentucky Research Foundation	Semi-synthetic mithramycin derivatives with anti-cancer activity
US9127055B2 (en)	2013-02-08	2015-09-08	Astellas Pharma Inc.	Method of treating pain with anti-human NGF antibody
AU2014219855B2 (en)	2013-02-19	2017-09-28	Ono Pharmaceutical Co., Ltd.	Trk-inhibiting compound
WO2014130975A1 (en)	2013-02-22	2014-08-28	Bastian Boris C	Fusion polynucleotides and fusion polypeptides associated with cancer and particularly melanoma and their uses as therapeutic and diagnostic targets
WO2014134096A1 (en)	2013-02-27	2014-09-04	Oregon Health & Science University	Methods of treating cancers characterized by aberrent ros1 activity
WO2014151117A1 (en)	2013-03-15	2014-09-25	The Board Of Trustees Of The Leland Stanford Junior University	Identification and use of circulating nucleic acid tumor markers
EP2968551B1 (en)	2013-03-15	2021-05-05	The Trustees of Columbia University in the City of New York	Fusion proteins and methods thereof
WO2014152777A2 (en)	2013-03-15	2014-09-25	Insight Genetics, Inc.	Methods and compositions for the diagnosis and treatment of cancers resistant to ros1 inhibitors
AR095308A1 (es)	2013-03-15	2015-10-07	Glaxosmithkline Ip Dev Ltd	Compuesto de 2-piridona, composición farmacéutica que lo comprende y su uso para preparar un medicamento
US10072298B2 (en)	2013-04-17	2018-09-11	Life Technologies Corporation	Gene fusions and gene variants associated with cancer
AU2014254394B2 (en)	2013-04-17	2020-06-18	Life Technologies Corporation	Gene fusions and gene variants associated with cancer
EP3019489A4 (en)	2013-07-11	2016-12-28	Betta Pharmaceuticals Co Ltd	MODULATORS OF TYROSINE KINASE PROTEIN AND METHODS OF USE
US10705087B2 (en)	2013-07-26	2020-07-07	Japanese Foundation For Cancer Research	Detection method for NTRK3 fusion
EP3628749A1 (en)	2013-07-30	2020-04-01	Blueprint Medicines Corporation	Ntrk2 fusions
CN105848654B (zh)	2013-10-24	2018-10-02	乔治城大学	用于治疗癌症的方法和组合物
JPWO2015064621A1 (ja)	2013-10-29	2017-03-09	公益財団法人がん研究会	新規融合体及びその検出法
ES2933350T3 (es)	2014-01-24	2023-02-06	Turning Point Therapeutics Inc	Macrociclos de diarilo como moduladores de proteína quinasas
KR101723997B1 (ko)	2014-02-05	2017-04-06	브이엠 온콜로지 엘엘씨	화합물의 조성물 및 이의 용도
TWI672141B (zh)	2014-02-20	2019-09-21	美商醫科泰生技	投予ｒｏｓ１突變癌細胞之分子
MA40434B1 (fr)	2014-05-15	2019-09-30	Array Biopharma Inc	1-((3s,4r)-4-(3-fluorophényl)-1-(2-méthoxyéthyl)pyrrolidin-3-yl)-3-(4-méthyl-3-(2-méthylpyrimidin-5-yl)-1-phényl-1h-pyrazol-5-yl)urée comme inhibiteur de la kinase trka
WO2015183837A1 (en)	2014-05-27	2015-12-03	Brian Haynes	Compositions, methods, and uses related to ntrk2-tert fusions
WO2015184443A1 (en)	2014-05-30	2015-12-03	The Regents Of The University Of Colorado	Activating ntrk1 gene fusions predictive of kinase inhibitor therapy
US20160032404A1 (en)	2014-08-01	2016-02-04	Pharmacyclics Llc	Biomarkers for predicting response of dlbcl to treatment with a btk inhibitor
US10399959B2 (en)	2014-08-18	2019-09-03	Ono Pharmaceutical Co., Ltd.	Acid-addition salt of Trk-inhibiting compound
EP4245376A3 (en)	2014-10-14	2023-12-13	Novartis AG	Antibody molecules to pd-l1 and uses thereof
CN113354649B (zh)	2014-11-16	2024-12-10	阵列生物制药公司	一种新的晶型
CA2971024C (en)	2014-12-15	2023-09-26	Handok Inc.	Fused ring heteroaryl compounds and their use as trk inhibitors
IL294183B2 (en)	2015-05-20	2023-10-01	Dana Farber Cancer Inst Inc	shared neoantigens
MA43943A (fr)	2015-05-29	2018-12-12	Ignyta Inc	Compositions et procédés pour traiter des patients avec des cellules mutantes rtk
HK1253093A1 (zh)	2015-06-01	2019-06-06	Loxo Oncology Inc.	诊断和治疗癌症的方法
AU2015101722A4 (en)	2015-06-19	2016-05-19	Macau University Of Science And Technology	Oncogenic ros1 and alk kinase inhibitor
US9782400B2 (en)	2015-06-19	2017-10-10	Macau University Of Science And Technology	Oncogenic ROS1 and ALK kinase inhibitor
GB201511546D0 (en)	2015-07-01	2015-08-12	Immatics Biotechnologies Gmbh	Novel peptides and combination of peptides for use in immunotherapy against ovarian cancer and other cancers
AU2016287568B2 (en)	2015-07-02	2020-08-20	Turning Point Therapeutics, Inc.	Chiral diaryl macrocycles as modulators of protein kinases
EP3368039A1 (en)	2015-10-26	2018-09-05	The Regents of The University of Colorado, A Body Corporate	Point mutations in trk inhibitor-resistant cancer and methods relating to the same
US20170224662A1 (en)	2016-01-22	2017-08-10	The Medicines Company	Aqueous Formulations and Methods of Preparation and Use Thereof
JPWO2017155018A1 (ja)	2016-03-11	2019-01-17	小野薬品工業株式会社	Ｔｒｋ阻害剤抵抗性の癌治療剤
FI3439662T3 (fi)	2016-04-04	2024-09-04	Loxo Oncology Inc	(s)-n-(5-((r)-2-(2,5-difluorifenyyli)pyrrolidin-1-yyli)pyratsolo[1,5-a]pyrimidin-3-yyli)-3-hydroksipyrrolidiini-1-karboksamidin nesteformulaatioita
US10045991B2 (en)	2016-04-04	2018-08-14	Loxo Oncology, Inc.	Methods of treating pediatric cancers
CN109475545A (zh)	2016-04-19	2019-03-15	埃克塞里艾克西斯公司	三阴性乳腺癌治疗方法
WO2017201156A1 (en)	2016-05-18	2017-11-23	Duke University	Method of treating kras wild-type metastatic colorectal cell carcinoma using cabozantinib plus panitumumab
EP3458456B1 (en)	2016-05-18	2020-11-25	Loxo Oncology Inc.	Preparation of (s)-n-(5-((r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
JOP20190092A1 (ar)	2016-10-26	2019-04-25	Array Biopharma Inc	عملية لتحضير مركبات بيرازولو[1، 5-a]بيريميدين وأملاح منها
JOP20190213A1 (ar)	2017-03-16	2019-09-16	Array Biopharma Inc	مركبات حلقية ضخمة كمثبطات لكيناز ros1
WO2019084285A1 (en)	2017-10-26	2019-05-02	Qian Zhao	FORMULATIONS OF A MACROCYCLIC TRK KINASE INHIBITOR

2009
- 2009-09-21 WO PCT/US2009/057729 patent/WO2010033941A1/en not_active Ceased
- 2009-09-21 PT PT09792796T patent/PT2350075E/pt unknown
- 2009-09-21 JP JP2011528046A patent/JP5503655B2/ja not_active Expired - Fee Related
- 2009-09-21 US US13/063,894 patent/US8450322B2/en active Active
- 2009-09-21 SI SI200930929T patent/SI2350075T1/sl unknown
- 2009-09-21 CA CA2738026A patent/CA2738026C/en not_active Expired - Fee Related
- 2009-09-21 ES ES09792796.6T patent/ES2464461T3/es active Active
- 2009-09-21 HR HRP20140481AT patent/HRP20140481T1/hr unknown
- 2009-09-21 CA CA2952692A patent/CA2952692C/en not_active Expired - Fee Related
- 2009-09-21 DK DK09792796.6T patent/DK2350075T3/da active
- 2009-09-21 CN CN201410121093.3A patent/CN103965200B/zh not_active Expired - Fee Related
- 2009-09-21 CN CN200980146463.6A patent/CN102224153B/zh not_active Expired - Fee Related
- 2009-09-21 PL PL09792796T patent/PL2350075T3/pl unknown
- 2009-09-21 EP EP09792796.6A patent/EP2350075B1/en active Active
- 2009-09-21 RS RS20140259A patent/RS53350B/sr unknown
- 2009-09-22 TW TW98132033A patent/TWI433849B/zh not_active IP Right Cessation
2012
- 2012-09-13 US US13/614,968 patent/US9227975B2/en active Active
2014
- 2014-03-14 JP JP2014051319A patent/JP5941938B2/ja not_active Expired - Fee Related
- 2014-05-26 CY CY20141100370T patent/CY1115107T1/el unknown
- 2014-09-04 SM SM201400123T patent/SMT201400123B/xx unknown
2015
- 2015-12-30 US US14/984,353 patent/US10011604B2/en active Active
2016
- 2016-05-23 JP JP2016102373A patent/JP6267741B2/ja not_active Expired - Fee Related
2017
- 2017-01-09 US US15/401,792 patent/US9796723B2/en active Active
- 2017-01-09 US US15/401,969 patent/US9795611B2/en active Active
- 2017-12-22 JP JP2017245786A patent/JP2018044010A/ja active Pending
2018
- 2018-07-02 US US16/025,281 patent/US10590139B2/en active Active
2019
- 2019-12-13 JP JP2019224980A patent/JP6858240B2/ja not_active Expired - Fee Related

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
JP2016147911A (ja) *	2008-09-22	2016-08-18	アレイバイオファーマ、インコーポレイテッド	Ｔｒｋキナーゼ阻害剤としての置換イミダゾ［１，２ｂ］ピリダジン化合物

Also Published As

Publication number	Publication date
US8450322B2 (en)	2013-05-28
TWI433849B (zh)	2014-04-11
JP6858240B2 (ja)	2021-04-14
JP5941938B2 (ja)	2016-06-29
CN102224153A (zh)	2011-10-19
CA2738026A1 (en)	2010-03-25
PT2350075E (pt)	2014-06-09
CN103965200A (zh)	2014-08-06
US9795611B2 (en)	2017-10-24
SMT201400123B (it)	2014-11-10
US20130217662A1 (en)	2013-08-22
JP2014111663A (ja)	2014-06-19
JP6267741B2 (ja)	2018-01-24
CA2738026C (en)	2017-01-24
US9227975B2 (en)	2016-01-05
PL2350075T3 (pl)	2014-07-31
TW201016701A (en)	2010-05-01
HRP20140481T1 (hr)	2014-07-04
US10590139B2 (en)	2020-03-17
US20170112849A1 (en)	2017-04-27
US20110166122A1 (en)	2011-07-07
JP2020050665A (ja)	2020-04-02
CY1115107T1 (el)	2016-12-14
CN102224153B (zh)	2014-04-30
US10011604B2 (en)	2018-07-03
CN103965200B (zh)	2016-06-08
JP2012503018A (ja)	2012-02-02
RS53350B (sr)	2014-10-31
ES2464461T3 (es)	2014-06-02
JP2016147911A (ja)	2016-08-18
US20170114068A1 (en)	2017-04-27
JP2018044010A (ja)	2018-03-22
EP2350075A1 (en)	2011-08-03
US9796723B2 (en)	2017-10-24
DK2350075T3 (da)	2014-05-26
SI2350075T1 (sl)	2014-06-30
WO2010033941A1 (en)	2010-03-25
CA2952692C (en)	2020-04-28
CA2952692A1 (en)	2010-03-25
EP2350075B1 (en)	2014-03-05
US20190169193A1 (en)	2019-06-06
US20160251357A1 (en)	2016-09-01

Legal Events

Date	Code	Title	Description
2012-09-12	A521	Request for written amendment filed	Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20120911
2012-09-12	A621	Written request for application examination	Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20120911
2014-02-07	TRDD	Decision of grant or rejection written
2014-02-13	A01	Written decision to grant a patent or to grant a registration (utility model)	Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20140212
2014-03-20	A61	First payment of annual fees (during grant procedure)	Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20140314
2014-03-20	R150	Certificate of patent or registration of utility model	Ref document number: 5503655 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150
2017-03-14	R250	Receipt of annual fees	Free format text: JAPANESE INTERMEDIATE CODE: R250
2018-03-13	R250	Receipt of annual fees	Free format text: JAPANESE INTERMEDIATE CODE: R250
2019-05-14	R250	Receipt of annual fees	Free format text: JAPANESE INTERMEDIATE CODE: R250
2019-11-11	RD02	Notification of acceptance of power of attorney	Free format text: JAPANESE INTERMEDIATE CODE: R3D02
2019-11-19	RD04	Notification of resignation of power of attorney	Free format text: JAPANESE INTERMEDIATE CODE: R3D04
2020-02-28	R250	Receipt of annual fees	Free format text: JAPANESE INTERMEDIATE CODE: R250
2021-02-26	R250	Receipt of annual fees	Free format text: JAPANESE INTERMEDIATE CODE: R250
2022-02-28	R250	Receipt of annual fees	Free format text: JAPANESE INTERMEDIATE CODE: R250
2023-03-20	LAPS	Cancellation because of no payment of annual fees

Publication	Publication Date	Title
JP6267741B2 (ja)	2018-01-24	Ｔｒｋキナーゼ阻害剤としての置換イミダゾ［１，２ｂ］ピリダジン化合物
JP6788649B2 (ja)	2020-11-25	ＴＲＫキナーゼ阻害剤としての置換ピラゾロ［１，５−ａ］ピリミジン化合物
AU2010271270B2 (en)	2015-01-22	Substituted pyrazolo[1,5-a]pyrimidine compounds as Trk kinase inhibitors
HK1195554B (en)	2017-09-01	Substituted imidazo[1,2-b]pyridazine compounds as trk kinase inhibitors
HK1195554A (en)	2014-11-14	Substituted imidazo[1,2-b]pyridazine compounds as trk kinase inhibitors

JP5503655B2 - Ｔｒｋキナーゼ阻害剤としての置換イミダゾ［１，２ｂ］ピリダジン化合物 - Google Patents

Info

Links

Classifications

Landscapes

Applications Claiming Priority (3)

Related Child Applications (1)

Publications (3)

Family

ID=41328652

Family Applications (5)

Family Applications After (4)

Country Status (16)

Cited By (1)

Families Citing this family (91)

Family Cites Families (188)

Cited By (1)

Also Published As

Similar Documents

Legal Events