JP5832527B2 - Trkキナーゼ阻害剤としてのマクロ環化合物 - Google Patents
Trkキナーゼ阻害剤としてのマクロ環化合物 Download PDFInfo
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- JP5832527B2 JP5832527B2 JP2013511239A JP2013511239A JP5832527B2 JP 5832527 B2 JP5832527 B2 JP 5832527B2 JP 2013511239 A JP2013511239 A JP 2013511239A JP 2013511239 A JP2013511239 A JP 2013511239A JP 5832527 B2 JP5832527 B2 JP 5832527B2
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- alkyl
- fluoro
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- heptaene
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- 150000002678 macrocyclic compounds Chemical class 0.000 title description 2
- 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 324
- 150000001875 compounds Chemical class 0.000 claims description 298
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 63
- 229910052739 hydrogen Inorganic materials 0.000 claims description 62
- 150000003839 salts Chemical class 0.000 claims description 51
- 229910052736 halogen Inorganic materials 0.000 claims description 49
- 150000002367 halogens Chemical class 0.000 claims description 49
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 47
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- 241000124008 Mammalia Species 0.000 claims description 44
- 201000011510 cancer Diseases 0.000 claims description 44
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 41
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 40
- 125000001153 fluoro group Chemical group F* 0.000 claims description 38
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 38
- 229910052799 carbon Inorganic materials 0.000 claims description 35
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 34
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- 125000004429 atom Chemical group 0.000 claims description 29
- PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 claims description 27
- 239000003153 chemical reaction reagent Substances 0.000 claims description 26
- 201000010099 disease Diseases 0.000 claims description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
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- 125000001424 substituent group Chemical group 0.000 claims description 18
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
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- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 11
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
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- LDIJKUBTLZTFRG-UHFFFAOYSA-N pyrazolo[1,5-a]pyrimidine Chemical group N1=CC=CN2N=CC=C21 LDIJKUBTLZTFRG-UHFFFAOYSA-N 0.000 claims description 7
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- NXFFJDQHYLNEJK-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)methyl]-7-fluoro-5-methylsulfonyl-2,3-dihydro-1h-cyclopenta[b]indol-3-yl]acetic acid Chemical compound C1=2C(S(=O)(=O)C)=CC(F)=CC=2C=2CCC(CC(O)=O)C=2N1CC1=CC=C(Cl)C=C1 NXFFJDQHYLNEJK-UHFFFAOYSA-N 0.000 claims description 3
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- OSVMTWJCGUFAOD-KZQROQTASA-N formestane Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1O OSVMTWJCGUFAOD-KZQROQTASA-N 0.000 claims description 3
- 102000020233 phosphotransferase Human genes 0.000 claims description 3
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- 230000002441 reversible effect Effects 0.000 description 40
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- 229920006395 saturated elastomer Polymers 0.000 description 37
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 37
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
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- YCAVTOUTYRMOGQ-UHFFFAOYSA-N ethyl 7-[3-[[3-(trifluoromethyl)benzoyl]amino]phenyl]pyrazolo[1,5-a]pyrimidine-3-carboxylate Chemical compound C=1C=NC2=C(C(=O)OCC)C=NN2C=1C(C=1)=CC=CC=1NC(=O)C1=CC=CC(C(F)(F)F)=C1 YCAVTOUTYRMOGQ-UHFFFAOYSA-N 0.000 description 23
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
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Classifications
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- 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
- C07D487/22—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 four or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
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Description
しかしながら、疼痛、特に慢性疼痛の治療のため、並びに癌、炎症、神経変性疾患及び特定の感染性疾患の治療のための化合物及び方法がなお必要とされている。
一実施形態において、例えば、以下の項目が提供される。
(項目1)
下記一般式I:
[式中:
環Aは下記構造:
[式中、1と標記された波線は環Aの環Bへの結合点を示し、そして2と標記された波線は環AのWへの結合点を示す
]を有する環A−1、A−2及びA−3から選択され;
XはN又はCHであり;
YはH又はFであり;
R 1 はH、(1−3C)アルコキシ又はハロゲンであり;
環Bは下記構造:
[式中、3と標記された波線は環Aへの結合点を示し、そして4と標記された波線は式Iのピラゾロ[1,5−a]ピリミジン環への結合点を示す]を有する環B−1及びB−2から選択され;
WはO、NH又はCH 2 であり、ここで環AがA−2である場合は、WはCH 2 であり;mは0、1又は2であり;
Dは炭素であり、R 2 及びR 2a は独立してH、F、(1−3C)アルキル又はOH(ただしR 2 及びR 2a は共にOHではない)であり、そしてR 3 及びR 3a は独立してH、(1−3C)アルキル又はヒドロキシ(1−3C)アルキルであるか、又は
Dは炭素又は窒素であり、R 2 及びR 3 は存在せず、そしてR 2a 及びR 3a はそれらが結合している原子と一緒になって1〜2個の環ヘテロ原子を有する5〜6員のヘテロアリール環を形成し;
Zは * −NR 4a C(=O)−、 * −ONHC(=O)−、 * −NR 4b CH 2 −又は * −OC(=O)−であり、ここでアスタリスクはR 3 を担持している炭素へのZの結合点を示し;
R 4a はH、(1−6C)アルキル、フルオロ(1−6C)アルキル、ジフルオロ(1−6C)アルキル、トリフルオロ(1−6C)アルキル、ヒドロキシ(1−6Cアルキル)又はジヒドロキシ(2−6Cアルキル)であり;
R 4b はH、(1−6C)アルキル、フルオロ(1−6C)アルキル、ジフルオロ(1−6C)アルキル、トリフルオロ(1−6C)アルキル、ヒドロキシ(1−6Cアルキル)、ジヒドロキシ(2−6Cアルキル)、(1−6Cアルキル)C(O)−、(3−6Cシクロアルキル)C(O)−、Ar 1 C(O)−、HOCH 2 C(O)−、(1−6Cアルキル)スルホニル、(3−6Cシクロアルキル)スルホニル、Ar 2 (SO 2 )−、HO 2 CCH 2 −又は(1−6Cアルキル)NH(CO)−であり;
Ar 1 はハロゲン、(1−6C)アルキル及び(1−6C)アルコキシから独立して選択される置換基1つ以上で場合により置換されたフェニルであり;
Ar 2 はハロゲン、(1−6C)アルキル及び(1−6C)アルコキシから独立して選択される置換基1つ以上で場合により置換されたフェニルであり;そして、
R 5 及びR 6 は独立してH、ハロゲン、OH、(1−6C)アルキル又はヒドロキシ(1−6C)アルキルである]の化合物又は製薬上許容しうるその塩。
(項目2)
下記一般式:
[式中、環Aは下記構造:
[式中1と標記された波線は環Aの式Iのピロリジン環への結合点を示し、そして2と標記された波線は環AのWへの結合点を示す]を有する環A−1、A−2及びA−3から選択され;
XはN又はCHであり;
YはH又はFであり;
R 1 はH、(1−3C)アルコキシ又はハロゲンであり;
WはO、NH又はCH 2 であり、ここで環AがA−2である場合は、WはCH 2 であり;mは0、1又は2であり;
R 2 及びR 2a は独立してH、F又はOHであるが、ただしR 2 及びR 2a は共にOHではなく;
R 3 はH、(1−3C)アルキル又はヒドロキシ(1−3C)アルキル;
Zは * −NR 4a C(=O)−、 * −ONHC(=O)−、 * −NR 4b CH 2 −又は*−OC(=O)−であり、ここでアスタリスクはR 3 を担持している炭素へのZの結合点を示し;
R 4a はH、(1−6C)アルキル、フルオロ(1−6C)アルキル、ジフルオロ(1−6C)アルキル、トリフルオロ(1−6C)アルキル、ヒドロキシ(1−6Cアルキル)又はジヒドロキシ(2−6Cアルキル)であり;
R 4b はH、(1−6C)アルキル、フルオロ(1−6C)アルキル、ジフルオロ(1−6C)アルキル、トリフルオロ(1−6C)アルキル、ヒドロキシ(1−6Cアルキル)、ジヒドロキシ(2−6Cアルキル)、(1−6Cアルキル)C(O)−、(3−6Cシクロアルキル)C(O)−、Ar 1 C(O)−、HOCH 2 C(O)−、(1−6Cアルキル)スルホニル、(3−6Cシクロアルキル)スルホニル、Ar 2 (SO 2 )−、HO 2 CCH 2 −又は(1−6Cアルキル)NH(CO)−であり;
Ar 1 はハロゲン、(1−6C)アルキル及び(1−6C)アルコキシから独立して選択される置換基1つ以上で場合により置換されたフェニルであり;
Ar 2 はハロゲン、(1−6C)アルキル及び(1−6C)アルコキシから独立して選択される置換基1つ以上で場合により置換されたフェニルであり;そして、
R 5 及びR 6 は独立してH、ハロゲン、OH、(1−6C)アルキル又はヒドロキシ(1−6C)アルキルである]を有する項目1記載の化合物又は製薬上許容しうるその塩。
(項目3)
環Aが下記構造:
を有する環A−1である項目1又は2記載の化合物。
(項目4)
XがCHである項目3記載の化合物。
(項目5)
XがNである項目3記載の化合物。
(項目6)
環Aが下記構造:
を有する環A−3である項目1又は2記載の化合物。
(項目7)
WがOである項目1〜6の何れかに記載の化合物。
(項目8)
WがNHである項目1〜6の何れかに記載の化合物。
(項目9)
WがCHである項目1〜6の何れかに記載の化合物。
(項目10)
環Aが下記構造:
を有する環A−2である項目1又は2記載の化合物。
(項目11)
YがFである項目1〜10の何れかに記載の化合物。
(項目12)
YがHである項目1〜10の何れかに記載の化合物。
(項目13)
R 1 がHである項目1〜12の何れかに記載の化合物。
(項目14)
R 1 が(1−3C)アルキル又は(1−3C)アルコキシである項目1〜12の何れかに記載の化合物。
(項目15)
R 1 がメチル又はメトキシである項目14記載の化合物。
(項目16)
R 1 がハロゲンである項目1〜12の何れかに記載の化合物。
(項目17)
R 1 がフルオロである項目16記載の化合物。
(項目18)
Zが * −NR 4a C(=O)−である項目1〜17の何れかに記載の化合物。
(項目19)
R 4a が水素である項目18記載の化合物。
(項目20)
R 4a が(1−6C)アルキル、フルオロ(1−6C)アルキル、ジフルオロ(1−6C)アルキル、トリフルオロ(1−6C)アルキル、ヒドロキシ(1−6Cアルキル)又はジヒドロキシ(2−6Cアルキル)である項目18記載の化合物。
(項目21)
R 4a が(1−6C)アルキルである項目20記載の化合物。
(項目22)
Zが * −ONHC(=O)−である項目1〜17の何れかに記載の化合物。
(項目23)
Zが * −NR 4b CH 2 −である項目1〜17の何れかに記載の化合物。
(項目24)
R 4b がHである項目23記載の化合物。
(項目25)
R 4b が(1−6C)アルキル、フルオロ(1−6C)アルキル、ジフルオロ(1−6C)アルキル及びトリフルオロ(1−6C)アルキルから選択される項目23記載の化合物。
(項目26)
R 4b が(1−6C)アルキルである項目25記載の化合物。
(項目27)
R 4b が(1−6Cアルキル)C(O)−、(3−6Cシクロアルキル)C(O)−、Ar 1 C(O)−及びHOCH 2 C(O)−から選択される項目23記載の化合物。
(項目28)
R 4b が(1−6Cアルキル)C(O)−である項目27記載の化合物。
(項目29)
R 4b が(1−6Cアルキル)スルホニル、(3−6Cシクロアルキル)スルホニル及びAr 2 (SO 2 )−から選択される項目23記載の化合物。
(項目30)
R 4b が(1−6Cアルキル)スルホニルである項目29記載の化合物。
(項目31)
R 4b がHO 2 CCH 2 −である項目23記載の化合物。
(項目32)
R 4b が(1−6Cアルキル)NH(CO)−である項目23記載の化合物。
(項目33)
Dが炭素であり、R 2 及びR 2a は独立してH、F、(1−3C)アルキル又はOH(ただしR 2 及びR 2a は共にOHではない)であり、そしてR 3 及びR 3a は独立してH、(1−3C)アルキル又はヒドロキシ(1−3C)アルキルである項目1又は3〜32の何れかに記載の化合物。
(項目34)
R 2 及びR 2a が各々水素である項目1〜33の何れかに記載の化合物。
(項目35)
R 2 及びR 2a が各々フルオロである項目1〜33の何れかに記載の化合物。
(項目36)
R 2 が水素であり、そしてR 2a がフルオロである項目1〜33の何れかに記載の化合物。
(項目37)
R 2 が水素であり、そしてR 2a がOHである項目1〜33の何れかに記載の化合物。
(項目38)
R 2 がHであり、そしてR 2a がメチルであるか、又はR 2 及びR 2a が共にメチルである項目1又は3〜33記載の化合物。
(項目39)
R 3 及びR 3a がHであるか;又は、
R 3a がメチルであり、そしてR 3 がHであるか;又は、
R 3a 及びR 3a が共にメチルである;
項目1又は3〜33記載の化合物。
(項目40)
Dは炭素又は窒素であり、R 2 及びR 3 は存在せず、そしてR 2a 及びR 3a はそれらが結合している原子と一緒になって1〜2個の環ヘテロ原子を有する5〜6員のヘテロアリール環を形成する項目1又は3〜32記載の化合物。
(項目41)
環Bが下記環B−1:
であり;
R 5 及びR 6 は独立してH、F、OH、メチル、エチル、HOCH 2 −又はHOCH 2 CH 2 −である項目1〜40の何れかに記載の化合物。
(項目42)
R 5 が水素であり、そしてR 6 がH、F、OH、メチル、エチル、HOCH 2 −又はHOCH 2 CH 2 −である項目41記載の化合物。
(項目43)
R 6 がHである項目42記載の化合物。
(項目44)
環Bが下記環B−2:
である項目1又は3〜40記載の化合物。
(項目45)
mが0である項目1〜44の何れかに記載の化合物。
(項目46)
mが1である項目1〜44の何れかに記載の化合物。
(項目47)
mが2である項目1〜44の何れかに記載の化合物。
(項目48)
下記図1−a:
の絶対配置を有する項目1〜47の何れかに記載の化合物。
(項目49)
下記式図1−b:
の絶対配置を有する項目1〜47の何れかに記載の化合物。
(項目50)
項目1〜49の何れか1項に記載の式Iの化合物又は製薬上許容しうるその塩、及び、製薬上許容しうる希釈剤又は担体を含む医薬組成物。
(項目51)
項目1〜49の何れか1項に記載の式Iの化合物又は製薬上許容しうるその塩の治療有効量を哺乳類に投与することを含む、該哺乳類における疼痛、癌、炎症、神経変性疾患又はクルーズトリパノソーマ感染症から選択される疾患又は障害を治療するための方法。
(項目52)
疾患又は障害が疼痛である項目51記載の方法。
(項目53)
疼痛、癌、炎症、神経変性疾患又はクルーズトリパノソーマ感染症の治療において使用するための項目1〜49の何れか1項に記載の式Iの化合物又は製薬上許容しうるその塩。
(項目54)
下記工程:
(a)Zが * −NHC(=O)−であり、そして環A、環B、W、D、R 2 、R 2a 、R 3 、R 3a 及びmが式Iに関して定義したとおりである式Iの化合物に関しては、下記式II:
[式中P 1 はH又はカルボキシル保護基である]を有する相当する化合物をカップリング試薬及び塩基の存在下に環化すること;又は、
(b)WがOであり、環Aが下記式A−1:
[式中nは1、2、3又は4であり、そしてL 1 は脱離基又は原子である]を有する相当する化合物を塩基の存在下に環化すること;又は、
(c)WがCH 2 であり、環Aが下記式A−2:
であり、そして環B、Z、D、Y、R 1 、R 2 、R 2a 、R 3 、R 3a 及びmが式Iに関して定義したとおりである式Iの化合物に関しては、下記式IV:
[式中L 2 は脱離基又は原子である]を有する相当する化合物を塩基の存在下に環化すること;又は、
(d)Zが * −NHC(=O)−であり、そして環A、環B、W、D、R 2 、R 2a 、R 3 、R 3a 及びmが式Iに関して定義したとおりである式Iの化合物に関しては、下記式V:
(e)Zが * −NHCH 2 −であり、そして環A、環B、W、D、R 2 、R 2a 、R 3 、R 3a 及びmが式Iに関して定義したとおりである式Iの化合物に関しては、下記式VI:
を有する相当する化合物を還元剤の存在下に環化すること;又は、
(f)Zが * −NHCH 2 −であり、そして環A、環B、W、D、R 2 、R 2a 、R 3 、R 3a 及びmが式Iに関して定義したとおりである式Iの化合物に関しては、下記式VII:
を有する相当する化合物をトリフェニルホスフィンの存在下に環化すること;又は、
(g)環A、環B、W、D、m、R 2 、R 2a 、R 3 、及びR 3a が式Iに関して定義したとおりであり、Zが * −NR 4b CH 2 −であり、そしてR 4b が(1−6Cアルキル)C(O)−、(3−6Cシクロアルキル)C(O)−、Ar 1 C(O)−、HOCH 2 C(O)−、(1−6Cアルキル)スルホニル、(3−6Cシクロアルキル)スルホニル、(1−6Cアルキル)スルホニル、(3−6Cシクロアルキル)スルホニル、又はAr 2 (SO 2 )−である式Iの化合物に関しては、下記式VIII:
を有する相当する化合物を式(1−6Cアルキル)C(O)−L 3 、(3−6Cシクロアルキル)C(O)−L 3 、Ar 1 C(O)−L 3 、HOCH 2 C(O)−L 3 、(1−6Cアルキル)(SO 2 )−L 3 、(3−6Cシクロアルキル)(SO 2 )−L 3 又はAr 2 (SO 2 )−L 3 (それぞれ式中L 3 は脱離原子である)を有する試薬と塩基の存在下にカップリングさせること;又は、
(h)環A、環B、W、D、R 2 、R 2a 、R 3 、R 3a 及びmが式Iに関して定義したとおりであり、Zが * −NR 4b CH 2 −であり、そしてR 4b が(1−6Cアルキル)NH(CO)−である式Iの化合物に関しては、下記式VIII:
を有する化合物を式(1−6Cアルキル)N=C=Oを有する試薬と塩基の存在下に反応させること;又は、
(i)R 2 がFであり、R 2a がHであり、そして環A、環B、Z、W、D、R 3 、R 3a 、及びmが式Iに関して定義したとおりである式Iの化合物に関しては、下記式IX:
を有する相当する化合物をフッ素化試薬と反応させること;
(j)WがOであり、環Aが下記式A−1:
であり、XがCHであり、そしてY、R 1 、D、環B、Z,R 2 、R 2a 、R 3 及びmが式Iに関して定義したとおりである式Iの化合物に関しては、下記式X:
[式中nは1、2、3又は4であり、そしてL 1 は脱離基又は原子である]を有する相当する化合物を塩基の存在下に環化すること;及び、
場合により何れかの保護基を除去すること、及び、場合によりその塩を調製すること;
を含む項目1記載の化合物の調製のためのプロセス。
(項目55)
環Bが下記構造:
を有する環B−1であり;
Dが炭素であり;
R 2 及びR 2a は独立してH、F、(1−3C)アルキル又はOHであるが、ただしR 2 及びR 2a は共にOHではなく;そして、
R 3 及びR 3a は独立してH、(1−3C)アルキル又はヒドロキシ(1−3C)アルキルである;
項目54記載のプロセス。
を有する環A−1、A−2及びA−3から選択され;
を有する環B−1及びB−2から選択され;
を有する環B−2であり;
を有する環A−1であり;
を包含する。
を有する環A−2であり;
を有する環A−3であり;
を包含する。
であり;
を包含する。
を有する環B−2である。
であり;
を有する環A−1、A−2及びA−3から選択され;
を有する環A−1、A−2及びA−3から選択され;
により表わされる環A−1であり;
により表わされる環B−1であり;
により表わされる環A−2であり;
により表わされる環B−1であり;
で表わされる環A−3であり;
で表わされる環B−1であり;
で表わされる環A−1であり;
で表わされる環B−1であり;
下記式II:
であり、式中:
下記式III:
であり;
であり、
を有する環B−1であり;
(実施例A)
TrkAELISAアッセイ
(実施例B)
TrkA結合アッセイ
調製例A
(R)−5−フルオロ−2−メトキシ−3−(ピロリジン−2−イル)ピリジン
調製例B
(R)−5−(2−(5−フルオロ−2−メトキシピリジン−3−イル)ピロリジン−1−イル)ピラゾロ[1,5−a]ピリミジン−3−カルボン酸
MS(apci)m/z=357.9(M+H)。
調製例C
(R)−4−((t−ブチルジメチルシリル)オキシ)−2−(5−フルオロ−2−メトキシフェニル)ピロリジン2,2,2−トリフルオロアセテート
調製例D
(R)−5−(2−(5−フルオロ−2−ヒドロキシフェニル)−4−ヒドロキシピロリジン−1−yl)ピラゾロ[1,5−a]ピリミジン−3−カルボン酸
実施例1
(6R)−9−フルオロ−2,11,15,19,20,23−ヘキサアザペンタシクロ[15.5.2.1 7,11 .0 2,6 .0 20,24 ]ペンタコサ−1(23),7,9,17(24),18,21−ヘキサエン−16,25−ジオン
実施例2
(6R)−12−オキサ−2,16,20,21,24,26−ヘキサアザペンタシクロ[16.5.2.1 7,11 .0 2,6 .0 21,25 ]ヘキサコサ−1(24),7(26),8,10,18(25),19,22−ヘプタエン−17−オン
実施例3
(6R)−9−フルオロ−13−オキサ−2,11,17,21,22,25−ヘキサアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン−18−オン
実施例4
(6R)−9−フルオロ−15−ヒドロキシ−13−オキサ−2,11,17,21,22,25−ヘキサアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン−18−オン
実施例5
(6R,13S)−9−フルオロ−13−ヒドロキシ−2,11,15,19,20,23−ヘキサアザペンタシクロ−[15.5.2.1 7,11 .0 2,6 .0 20,24 ]ペンタコサ−1(23),7,9,17(24),18,21−ヘキサエン−16,25−ジオン
実施例6
(6R)−9−フルオロ−15−ヒドロキシ−13−オキサ−2,11,17,21,22,25−ヘキサアザペンタシクロ−[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン−18−オン
実施例7
(6R,15R)−9−フルオロ−15−ヒドロキシ−13−オキサ−2,11,17,21,22,25−ヘキサアザペンタシクロ−[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン−18−オン
実施例8
(6R,13R)−9−フルオロ−13−ヒドロキシ−2,11,15,19,20,23−ヘキサアザペンタシクロ−[15.5.2.1 7,11 .0 2,6 .0 20,24 ]ペンタコサ−1(23),7,9,17(24),18,21−ヘキサエン−16,25−ジオン
実施例9
(6R)−9−フルオロ−13−オキサ−2,11,16,20,21,24−ヘキサアザペンタシクロ[16.5.2.0 2,6 .0 7,12 .0 21,25 ]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−17−オン
実施例10
(6R)−9−フルオロ−13−オキサ−2,11,18,22,23,26−ヘキサアザペンタシクロ[18.5.2.0 2,6 .0 7,12 .0 23,27 ]ヘプタコサ−1(26),7,9,11,20(27),21,24−ヘプタエン−19−オン
実施例11
(6R)−9−フルオロ−2,11,16,20,21,24−ヘキサアザペンタシクロ[16.5.2.1 7,11 .0 2,6 .0 21,25 ]ヘキサコサ−1(24),7,9,18(25),19,22−ヘキサエン−17,26−ジオン
実施例12
(6R)−9−フルオロ−2,11,13,16,20,21,24−ヘプタアザペンタシクロ[16.5.2.0 2,6 .0 7,12 .0 21,25 ]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−17−オン
(0.5g、35%収率)。MS(apci)m/z=201.1(M+H−Boc)。
実施例13
(6R)−9−フルオロ−2,11,13,17,21,22,25−ヘプタアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン−18−オン
実施例14
(6R)−9−フルオロ−13,16−ジオキサ−2,11,20,21,24−ペンタアザペンタシクロ[16.5.2.0 2,6 .0 7,12 .0 21,25 ]−ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−17−オン
実施例15
(6R)−9−フルオロ−14−オキサ−2,11,18,19,22−ペンタアザペンタシクロ[14.5.2.1 7,11 .0 2,6 .0 19,23 ]テトラコサ−1(22),7,9,16(23),17,20−ヘキサエン−15,24−ジオン
実施例16
(6R)−9−フルオロ−13,16−ジオキサ−2,11,17,21,22,25−ヘキサアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン−18−オン
実施例17
(6R,13R)−9,13−ジフルオロ−2,11,15,19,20,23−ヘキサアザペンタシクロ[15.5.2.1 7,11 .0 2,6 .0 20,24 ]ペンタコサ−1(23),7,9,17(24),18,21−ヘキサエン−16,25−ジオン
実施例18
(6R)−9−フルオロ−17−メチル−13−オキサ−2,11,17,21,22,25−ヘキサアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン−18−オン
実施例19
(6R)−9,15,15−トリフルオロ−13−オキサ−2,11,17,21,22,25−ヘキサアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン−18−オン
実施例20
(6R)−9−フルオロ−13−オキサ−2,17,21,22,25−ペンタアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン−18−オン
実施例21
(6R)−9−フルオロ−13−オキサ−2,16,20,21,24−ペンタアザペンタシクロ[16.5.2.0 2,6 .0 7,12 .0 21,25 ]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン
実施例22
1−[(6R)−9−フルオロ−13−オキサ−2,16,20,21,24−ペンタアザペンタシクロ[16.5.2.0 2,6 .0 7,12 .0 21,25 ]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−16−イル]エタン−1−オン
実施例23
1−[(6R)−9−フルオロ−13−オキサ−2,16,20,21,24−ペンタアザペンタシクロ[16.5.2.0 2,6 .0 7,12 .0 21,25 ]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−16−イル]−2−ヒドロキシエタン−1−オン
実施例24
(6R)−9−フルオロ−13−オキサ−2,17,21,22,25−ペンタアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン
実施例25
(6R)−9−フルオロ−16−メタンスルホニル−13−オキサ−2,16,20,21,24−ペンタアザペンタシクロ[16.5.2.0 2,6 .0 7,12 .0 21,25 ]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン
実施例26
2−[(6R)−9−フルオロ−13−オキサ−2,16,20,21,24−ペンタアザペンタシクロ[16.5.2.0 2,6 .0 7,12 .0 21,25 ]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−16−イル]酢酸
実施例27
(6R)−9−フルオロ−17−メタンスルホニル−13−オキサ−2,17,21,22,25−ペンタアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン
実施例28
(6R)−N−エチル−9−フルオロ−13−オキサ−2,17,21,22,25−ペンタアザペンタシクロ 17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン−17−カルボキサミド
実施例29
(6R)−N−エチル−9−フルオロ−13−オキサ−2,16,20,21,24−ペンタアザペンタシクロ−[16.5.2.0 2,6 .0 7,12 .0 21,25 ]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−16−カルボキサミド
実施例30
(6S)−9−フルオロ−4,13−ジオキサ−2,11,17,21,22,25−ヘキサアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7(12),8,10,19(26),20,23−ヘプタエン−3,18−ジオン
MS(apci)m/z=186.9(M+H)。
実施例31
(6S)−9−フルオロ−4,13−ジオキサ−2,11,16,20,21,24−ヘキサアザペンタシクロ[16.5.2.0 2,6 .0 7,12 .0 21,25 ]ペンタコサ−1(24),7(12),8,10,18(25),19,22−ヘプタエン−3,17−ジオン
実施例32
(6R)−9−フルオロ−2,11,16,20,21,24−ヘキサアザペンタシクロ[16.5.2.0 2,6 .0 7,12 .0 21,25 ]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−17−オン
実施例33
(6R)−9−フルオロ−15−メチル−2,11,16,20,21,24−ヘキサアザペンタシクロ[16.5.2.0 2,6 .0 7,12 .0 21,25 ]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−17−オン
実施例34
(6R,13R)−9−フルオロ−13−メチル−2,11,15,19,20,23−ヘキサアザペンタシクロ[15.5.2.1 7,11 .0 2,6 .0 20,24 ]ペンタコサ−1(23),7,9,17(24),18,21−ヘキサエン−16,25−ジオン
実施例35
(6R,13S)−9−フルオロ−13−メチル−2,11,15,19,20,23−ヘキサアザペンタシクロ[15.5.2.1 7,11 .0 2,6 .0 20,24 ]ペンタコサ−1(23),7,9,17(24),18,21−ヘキサエン−16,25−ジオン
実施例36
(6R)−9−フルオロ−15,15−ジメチル−13−オキサ−2,11,17,21,22,25−ヘキサアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン−18−オン
実施例37
(6R)−9−フルオロ−15,15−ジメチル−2,11,16,20,21,24−ヘキサアザペンタシクロ[16.5.2.0 2,6 .0 7,12 .0 21,25 ]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−17−オン
実施例38
(6R)−9−フルオロ−13−オキサ−2,11,16,17,21,25,26,29−オクタアザヘキサシクロ[21.5.2.0 2,6 .0 7,12 .0 16,20 .0 26,30 ]トリアコンタ−1(29),7,9,11,17,19,23(30),24,27−ノナエン−22−オン
実施例39
(6R)−9−フルオロ−13−オキサ−2,11,19,21,25,26,29−ヘプタアザヘキサシクロ[21.5.2.0 2,6 .0 7,12 .0 15,20 .0 26,30 ]トリアコンタ−1(29),7,9,11,15(20),16,18,23(30),24,27−デカエン−22−オン
実施例40
(6R)−9−フルオロ−13,13−ジメチル−2,11,15,19,20,23−ヘキサアザペンタシクロ[15.5.2.1 7,11 .0 2,6 .0 20,24 ]ペンタコサ−1(23),7,9,17(24),18,21−ヘキサエン−16,25−ジオン
実施例41
(4R,6R,15S)−9−フルオロ−4,15−ジヒドロキシ−13−オキサ−2,17,21,22,25−ペンタアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7(12),8,10,19(26),20,23−ヘプタエン−18−オン
実施例41−B
(4R,6S,15S)−9−フルオロ−4,15−ジヒドロキシ−13−オキサ−2,17,21,22,25−ペンタアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7(12),8,10,19(26),20,23−ヘプタエン−18−オン
実施例42
(4R,6R)−9−フルオロ−4−ヒドロキシ−13−オキサ−2,17,21,22,25−ペンタアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7(12),8,10,19(26),20,23−ヘプタエン−18−オン
実施例42−B
(4R,6S)−9−フルオロ−4−ヒドロキシ−13−オキサ−2,17,21,22,25−ペンタアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7(12),8,10,19(26),20,23−ヘプタエン−18−オン
実施例43
(4R,6R)−9−フルオロ−4−ヒドロキシ−13−オキサ−2,16,20,21,24−ペンタアザペンタシクロ[16.5.2.0 2,6 .0 7,12 .0 21,25 ]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−17−オン
実施例43−B
(4R,6S)−9−フルオロ−4−ヒドロキシ−13−オキサ−2,16,20,21,24−ペンタアザペンタシクロ[16.5.2.0 2,6 .0 7,12 .0 21,25 ]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−17−オン
実施例44
(4R,6R,15R)−9−フルオロ−4,15−ジヒドロキシ−13−オキサ−2,17,21,22,25−ペンタアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7(12),8,10,19(26),20,23−ヘプタエン−18−オン
実施例44−B
(4R,6S,15R)−9−フルオロ−4,15−ジヒドロキシ−13−オキサ−2,17,21,22,25−ペンタアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7(12),8,10,19(26),20,23−ヘプタエン−18−オン
実施例45
(15S)−4,4,9−トリフルオロ−15−ヒドロキシ−13−オキサ−2,17,21,22,25−ペンタアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7(12),8,10,19(26),20,23−ヘプタエン−18−オンのジアステレオマー1及びジアステレオマー2
Claims (71)
- 下記一般式I:
環Aは下記構造:
[式中、1と標記された波線は環Aの環Bへの結合点を示し、そして2と標記された波線は環AのWへの結合点を示す]を有する環A−1、A−2及びA−3から選択され;
XはN又はCHであり;
YはH又はFであり;
R1はH、(1−3C)アルキル、(1−3C)アルコキシ又はハロゲンであり;
環Bは下記構造:
[式中、3と標記された波線は環Aへの結合点を示し、そして4と標記された波線は式Iのピラゾロ[1,5−a]ピリミジン環への結合点を示す]を有する環B−1及びB−2から選択され;
WはO、NH又はCH2であり、ここで環AがA−2である場合は、WはCH2であり;
mは0、1又は2であり;
Dは炭素であり、R2及びR2aは独立してH、F、(1−3C)アルキル又はOH(ただしR2及びR2aは共にOHではない)であり、そしてR3及びR3aは独立してH、(1−3C)アルキル又はヒドロキシ(1−3C)アルキルであるか、又は
Dは炭素又は窒素であり、R2及びR3は存在せず、そしてR2a及びR3aはそれらが結合している原子と一緒になって1〜2個の環ヘテロ原子を有する5〜6員のヘテロアリール環を形成し;
Zは*−NR4aC(=O)−、*−ONHC(=O)−、*−NR4bCH2−又は*−OC(=O)−であり、ここでアスタリスクはR3を担持している炭素へのZの結合点を示し;
R4aはH、(1−6C)アルキル、フルオロ(1−6C)アルキル、ジフルオロ(1−6C)アルキル、トリフルオロ(1−6C)アルキル、ヒドロキシ(1−6Cアルキル)又はジヒドロキシ(2−6Cアルキル)であり;
R4bはH、(1−6C)アルキル、フルオロ(1−6C)アルキル、ジフルオロ(1−6C)アルキル、トリフルオロ(1−6C)アルキル、ヒドロキシ(1−6Cアルキル)、ジヒドロキシ(2−6Cアルキル)、(1−6Cアルキル)C(O)−、(3−6Cシクロアルキル)C(O)−、Ar1C(O)−、HOCH2C(O)−、(1−6Cアルキル)スルホニル、(3−6Cシクロアルキル)スルホニル、Ar2(SO2)−、HO2CCH2−又は(1−6Cアルキル)NH(CO)−であり;
Ar1はハロゲン、(1−6C)アルキル及び(1−6C)アルコキシから独立して選択される置換基1つ以上で場合により置換されたフェニルであり;
Ar2はハロゲン、(1−6C)アルキル及び(1−6C)アルコキシから独立して選択される置換基1つ以上で場合により置換されたフェニルであり;そして、
R5及びR6は独立してH、ハロゲン、OH、(1−6C)アルキル又はヒドロキシ(1−6C)アルキルである]の化合物又は製薬上許容しうるその塩。 - 下記一般式:
[式中、環Aは下記構造:
[式中1と標記された波線は環Aの式Iのピロリジン環への結合点を示し、そして2と標記された波線は環AのWへの結合点を示す]を有する環A−1、A−2及びA−3から選択され;
XはN又はCHであり;
YはH又はFであり;
R1はH、(1−3C)アルコキシ又はハロゲンであり;
WはO、NH又はCH2であり、ここで環AがA−2である場合は、WはCH2であり;mは0、1又は2であり;
R2及びR2aは独立してH、F又はOHであるが、ただしR2及びR2aは共にOHではなく;
R3はH、(1−3C)アルキル又はヒドロキシ(1−3C)アルキルであり;
Zは*−NR4aC(=O)−、*−ONHC(=O)−、*−NR4bCH2−又は*−OC(=O)−であり、ここでアスタリスクはR3を担持している炭素へのZの結合点を示し;
R4aはH、(1−6C)アルキル、フルオロ(1−6C)アルキル、ジフルオロ(1−6C)アルキル、トリフルオロ(1−6C)アルキル、ヒドロキシ(1−6Cアルキル)又はジヒドロキシ(2−6Cアルキル)であり;
R4bはH、(1−6C)アルキル、フルオロ(1−6C)アルキル、ジフルオロ(1−6C)アルキル、トリフルオロ(1−6C)アルキル、ヒドロキシ(1−6Cアルキル)、ジヒドロキシ(2−6Cアルキル)、(1−6Cアルキル)C(O)−、(3−6Cシクロアルキル)C(O)−、Ar1C(O)−、HOCH2C(O)−、(1−6Cアルキル)スルホニル、(3−6Cシクロアルキル)スルホニル、Ar2(SO2)−、HO2CCH2−又は(1−6Cアルキル)NH(CO)−であり;
Ar1はハロゲン、(1−6C)アルキル及び(1−6C)アルコキシから独立して選択される置換基1つ以上で場合により置換されたフェニルであり;
Ar2はハロゲン、(1−6C)アルキル及び(1−6C)アルコキシから独立して選択される置換基1つ以上で場合により置換されたフェニルであり;そして、
R5及びR6は独立してH、ハロゲン、OH、(1−6C)アルキル又はヒドロキシ(1−6C)アルキルである]を有する請求項1記載の化合物又は製薬上許容しうるその塩。 - 環Aが下記構造:
- XがCHである請求項3記載の化合物。
- XがNである請求項3記載の化合物。
- 環Aが下記構造:
を有する環A−3である請求項1又は2記載の化合物。 - WがOである請求項1〜6の何れかに記載の化合物。
- WがNHである請求項1〜6の何れかに記載の化合物。
- WがCH 2 である請求項1〜6の何れかに記載の化合物。
- 環Aが下記構造:
を有する環A−2である請求項1又は2記載の化合物。 - YがFである請求項1〜10の何れかに記載の化合物。
- YがHである請求項1〜10の何れかに記載の化合物。
- R1がHである請求項1〜12の何れかに記載の化合物。
- R1が(1−3C)アルキル又は(1−3C)アルコキシである請求項1〜12の何れかに記載の化合物。
- R1がメチル又はメトキシである請求項14記載の化合物。
- R1がハロゲンである請求項1〜12の何れかに記載の化合物。
- R1がフルオロである請求項16記載の化合物。
- Zが*−NR4aC(=O)−である請求項1〜17の何れかに記載の化合物。
- R4aが水素である請求項18記載の化合物。
- R4aが(1−6C)アルキル、フルオロ(1−6C)アルキル、ジフルオロ(1−6C)アルキル、トリフルオロ(1−6C)アルキル、ヒドロキシ(1−6Cアルキル)又はジヒドロキシ(2−6Cアルキル)である請求項18記載の化合物。
- R4aが(1−6C)アルキルである請求項20記載の化合物。
- Zが*−ONHC(=O)−である請求項1〜17の何れかに記載の化合物。
- Zが*−NR4bCH2−である請求項1〜17の何れかに記載の化合物。
- R4bがHである請求項23記載の化合物。
- R4bが(1−6C)アルキル、フルオロ(1−6C)アルキル、ジフルオロ(1−6C)アルキル及びトリフルオロ(1−6C)アルキルから選択される請求項23記載の化合物。
- R4bが(1−6C)アルキルである請求項25記載の化合物。
- R4bが(1−6Cアルキル)C(O)−、(3−6Cシクロアルキル)C(O)−、Ar1C(O)−及びHOCH2C(O)−から選択される請求項23記載の化合物。
- R4bが(1−6Cアルキル)C(O)−である請求項27記載の化合物。
- R4bが(1−6Cアルキル)スルホニル、(3−6Cシクロアルキル)スルホニル及びAr2(SO2)−から選択される請求項23記載の化合物。
- R4bが(1−6Cアルキル)スルホニルである請求項29記載の化合物。
- R4bがHO2CCH2−である請求項23記載の化合物。
- R4bが(1−6Cアルキル)NH(CO)−である請求項23記載の化合物。
- Dが炭素であり、R2及びR2aは独立してH、F、(1−3C)アルキル又はOH(ただしR2及びR2aは共にOHではない)であり、そしてR3及びR3aは独立してH、(1−3C)アルキル又はヒドロキシ(1−3C)アルキルである請求項1又は3〜32の何れかに記載の化合物。
- R2及びR2aが各々水素である請求項1〜33の何れかに記載の化合物。
- R2及びR2aが各々フルオロである請求項1〜33の何れかに記載の化合物。
- R2が水素であり、そしてR2aがフルオロである請求項1〜33の何れかに記載の化合物。
- R2が水素であり、そしてR2aがOHである請求項1〜33の何れかに記載の化合物。
- R2がHであり、そしてR2aがメチルであるか、又はR2及びR2aが共にメチルである請求項1又は3〜33記載の化合物。
- R3及びR3aがHであるか;又は、
R3aがメチルであり、そしてR3がHであるか;又は、
R3a及びR 3 が共にメチルである;
請求項1又は3〜33記載の化合物。 - Dは炭素又は窒素であり、R2及びR3は存在せず、そしてR2a及びR3aはそれらが結合している原子と一緒になって1〜2個の環ヘテロ原子を有する5〜6員のヘテロアリール環を形成する請求項1又は3〜32記載の化合物。
- 環Bが下記環B−1:
であり;
R5及びR6は独立してH、F、OH、メチル、エチル、HOCH2−又はHOCH2CH2−である請求項1〜40の何れかに記載の化合物。 - R5が水素であり、そしてR6がH、F、OH、メチル、エチル、HOCH2−又はHOCH2CH2−である請求項41記載の化合物。
- R6がHである請求項42記載の化合物。
- 環Bが下記環B−2:
である請求項1又は3〜40記載の化合物。 - mが0である請求項1〜44の何れかに記載の化合物。
- mが1である請求項1〜44の何れかに記載の化合物。
- mが2である請求項1〜44の何れかに記載の化合物。
- 下記図1−a:
- 下記式図1−b:
- 以下:
(6R)−9−フルオロ−2,11,15,19,20,23−ヘキサアザペンタシクロ[15.5.2.17,11.02,6.020,24]ペンタコサ−1(23),7,9,17(24),18,21−ヘキサエン−16,25−ジオン;
(6R)−12−オキサ−2,16,20,21,24,26−ヘキサアザペンタシクロ[16.5.2.17,11.02,6.021,25]ヘキサコサ−1(24),7(26),8,10,18(25),19,22−ヘプタエン−17−オン;
(6R)−9−フルオロ−13−オキサ−2,11,17,21,22,25−ヘキサアザペンタシクロ[17.5.2.02,6.07,12.022,26]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン−18−オン;
(6R)−9−フルオロ−15−ヒドロキシ−13−オキサ−2,11,17,21,22,25−ヘキサアザペンタシクロ[17.5.2.02,6.07,12.022,26]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘ プタエン−18−オン
(6R,13S)−9−フルオロ−13−ヒドロキシ−2,11,15,19,20,23−ヘキサアザペンタシクロ−[15.5.2.17,11.02,6.020,24]ペンタコサ−1(23),7,9,17(24),18,21−ヘキサエン−16,25−ジオン;
(6R)−9−フルオロ−15−ヒドロキシ−13−オキサ−2,11,17,21,22,25−ヘキサアザペンタシクロ−[17.5.2.02,6.07,12.022,26]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン−18−オン;
(6R,15R)−9−フルオロ−15−ヒドロキシ−13−オキサ−2,11,17,21,22,25−ヘキサアザペンタシクロ−[17.5.2.02,6.07,12.022,26]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン−18−オン;
(6R,13R)−9−フルオロ−13−ヒドロキシ−2,11,15,19,20,23−ヘキサアザペンタシクロ−[15.5.2.17,11.02,6.020,24]ペンタコサ−1(23),7,9,17(24),18,21−ヘキサエン−16,25−ジオン;
(6R)−9−フルオロ−13−オキサ−2,11,16,20,21,24−ヘキサアザペンタシクロ[16.5.2.02,6.07,12.021,25]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−17−オン;
(6R)−9−フルオロ−13−オキサ−2,11,18,22,23,26−ヘキサアザペンタシクロ[18.5.2.02,6.07,12.023,27]ヘプタコサ−1(26),7,9,11,20(27),21,24−ヘプタエン−19−オン;
(6R)−9−フルオロ−2,11,16,20,21,24−ヘキサアザペンタシクロ[16.5.2.17,11.02,6.021,25]ヘキサコサ−1(24),7,9,18(25),19,22−ヘキサエン−17,26−ジオン;
(6R)−9−フルオロ−2,11,13,16,20,21,24−ヘプタアザペンタシクロ[16.5.2.02,6.07,12.021,25]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−17−オン;
(6R)−9−フルオロ−2,11,13,17,21,22,25−ヘプタアザペンタシクロ[17.5.2.02,6.07,12.022,26]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン−18−オン;
(6R)−9−フルオロ−13,16−ジオキサ−2,11,20,21,24−ペンタアザペンタシクロ[16.5.2.02,6.07,12.021,25]−ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−17−オン;
(6R)−9−フルオロ−14−オキサ−2,11,18,19,22−ペンタアザペンタシクロ[14.5.2.17,11.02,6.019,23]テトラコサ−1(22),7,9,16(23),17,20−ヘキサエン−15,24−ジオン;
(6R)−9−フルオロ−13,16−ジオキサ−2,11,17,21,22,25−ヘキサアザペンタシクロ[17.5.2.02,6.07,12.022,26]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン−18−オン;
(6R,13R)−9,13−ジフルオロ−2,11,15,19,20,23−ヘキサアザペンタシクロ[15.5.2.17,11.02,6.020,24]ペンタコサ−1(23),7,9,17(24),18,21−ヘキサエン−16,25−ジオン;
(6R)−9−フルオロ−17−メチル−13−オキサ−2,11,17,21,22,25−ヘキサアザペンタシクロ[17.5.2.02,6.07,12.022,26]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン−18−オン;
(6R)−9,15,15−トリフルオロ−13−オキサ−2,11,17,21,22,25−ヘキサアザペンタシクロ[17.5.2.02,6.07,12.022,26]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン−18−オン;
(6R)−9−フルオロ−13−オキサ−2,17,21,22,25−ペンタアザペンタシクロ[17.5.2.02,6.07,12.022,26]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン−18−オン;
(6R)−9−フルオロ−13−オキサ−2,16,20,21,24−ペンタアザペンタシクロ[16.5.2.02,6.07,12.021,25]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン;
1−[(6R)−9−フルオロ−13−オキサ−2,16,20,21,24−ペンタアザペンタシクロ[16.5.2.02,6.07,12.021,25]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−16−イル]エタン−1−オン;
1−[(6R)−9−フルオロ−13−オキサ−2,16,20,21,24−ペンタアザペンタシクロ[16.5.2.02,6.07,12.021,25]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−16−イル]−2−ヒドロキシエタン−1−オン;
(6R)−9−フルオロ−13−オキサ−2,17,21,22,25−ペンタアザペンタシクロ[17.5.2.02,6.07,12.022,26]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン;
(6R)−9−フルオロ−16−メタンスルホニル−13−オキサ−2,16,20,21,24−ペンタアザペンタシクロ[16.5.2.02,6.07,12.021,25]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン;
2−[(6R)−9−フルオロ−13−オキサ−2,16,20,21,24−ペンタアザペンタシクロ[16.5.2.02,6.07,12.021,25]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−16−イル]酢酸;
(6R)−9−フルオロ−17−メタンスルホニル−13−オキサ−2,17,21,22,25−ペンタアザペンタシクロ[17.5.2.02,6.07,12.022,26]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン;
(6R)−N−エチル−9−フルオロ−13−オキサ−2,17,21,22,25−ペンタアザペンタシクロ 17.5.2.02,6.07,12.022,26]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン−17−カルボキサミド;
(6R)−N−エチル−9−フルオロ−13−オキサ−2,16,20,21,24−ペンタアザペンタシクロ−[16.5.2.02,6.07,12.021,25]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−16−カルボキサミド;
(6S)−9−フルオロ−4,13−ジオキサ−2,11,17,21,22,25−ヘキサアザペンタシクロ[17.5.2.02,6.07,12.022,26]ヘキサコサ−1(25),7(12),8,10,19(26),20,23−ヘプタエン−3,18−ジオン
(6S)−9−フルオロ−4,13−ジオキサ−2,11,16,20,21,24−ヘキサアザペンタシクロ[16.5.2.02,6.07,12.021,25]ペンタコサ−1(24),7(12),8,10,18(25),19,22−ヘプタエン−3,17−ジオン;
(6R)−9−フルオロ−2,11,16,20,21,24−ヘキサアザペンタシクロ[16.5.2.02,6.07,12.021,25]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−17−オン;
(6R)−9−フルオロ−15−メチル−2,11,16,20,21,24−ヘキサアザペンタシクロ[16.5.2.02,6.07,12.021,25]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−17−オン;
(6R,13R)−9−フルオロ−13−メチル−2,11,15,19,20,23−ヘキサアザペンタシクロ[15.5.2.17,11.02,6.020,24]ペンタコサ−1(23),7,9,17(24),18,21−ヘキサエン−16,25−ジオン;
(6R,13S)−9−フルオロ−13−メチル−2,11,15,19,20,23−ヘキサアザペンタシクロ[15.5.2.17,11.02,6.020,24]ペンタコサ−1(23),7,9,17(24),18,21−ヘキサエン−16,25−ジオン;
(6R)−9−フルオロ−15,15−ジメチル−13−オキサ−2,11,17,21,22,25−ヘキサアザペンタシクロ[17.5.2.02,6.07,12.022,26]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン−18−オン;
(6R)−9−フルオロ−15,15−ジメチル−2,11,16,20,21,24−ヘキサアザペンタシクロ[16.5.2.02,6.07,12.021,25]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−17−オン;
(6R)−9−フルオロ−13−オキサ−2,11,16,17,21,25,26,29−オクタアザヘキサシクロ[21.5.2.02,6.07,12.016,20.026,30]トリアコンタ−1(29),7,9,11,17,19,23(30),24,27−ノナエン−22−オン;
(6R)−9−フルオロ−13−オキサ−2,11,19,21,25,26,29−ヘプタアザヘキサシクロ[21.5.2.02,6.07,12.015,20.026,30]トリアコンタ−1(29),7,9,11,15(20),16,18,23(30),24,27−デカエン−22−オン;
(6R)−9−フルオロ−13,13−ジメチル−2,11,15,19,20,23−ヘキサアザペンタシクロ[15.5.2.17,11.02,6.020,24]ペンタコサ−1(23),7,9,17(24),18,21−ヘキサエン−16,25−ジオン;
(4R,6R,15S)−9−フルオロ−4,15−ジヒドロキシ−13−オキサ−2,17,21,22,25−ペンタアザペンタシクロ[17.5.2.02,6.07,12.022,26]ヘキサコサ−1(25),7(12),8,10,19(26),20,23−ヘプタエン−18−オン;
(4R,6S,15S)−9−フルオロ−4,15−ジヒドロキシ−13−オキサ−2,17,21,22,25−ペンタアザペンタシクロ[17.5.2.02,6.07,12.022,26]ヘキサコサ−1(25),7(12),8,10,19(26),20,23−ヘプタエン−18−オン;
(4R,6R)−9−フルオロ−4−ヒドロキシ−13−オキサ−2,17,21,22,25−ペンタアザペンタシクロ[17.5.2.02,6.07,12.022,26]ヘキサコサ−1(25),7(12),8,10,19(26),20,23−ヘプタエン−18−オン;
(4R,6S)−9−フルオロ−4−ヒドロキシ−13−オキサ−2,17,21,22,25−ペンタアザペンタシクロ[17.5.2.02,6.07,12.022,26]ヘキサコサ−1(25),7(12),8,10,19(26),20,23−ヘプタエン−18−オン;
(4R,6R)−9−フルオロ−4−ヒドロキシ−13−オキサ−2,16,20,21,24−ペンタアザペンタシクロ[16.5.2.02,6.07,12.021,25]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−17−オン;
(4R,6S)−9−フルオロ−4−ヒドロキシ−13−オキサ−2,16,20,21,24−ペンタアザペンタシクロ[16.5.2.02,6.07,12.021,25]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−17−オン;
(4R,6R,15R)−9−フルオロ−4,15−ジヒドロキシ−13−オキサ−2,17,21,22,25−ペンタアザペンタシクロ[17.5.2.02,6.07,12.022,26]ヘキサコサ−1(25),7(12),8,10,19(26),20,23−ヘプタエン−18−オン;
(4R,6S,15R)−9−フルオロ−4,15−ジヒドロキシ−13−オキサ−2,17,21,22,25−ペンタアザペンタシクロ[17.5.2.02,6.07,12.022,26]ヘキサコサ−1(25),7(12),8,10,19(26),20,23−ヘプタエン−18−オン;
(15S)−4,4,9−トリフルオロ−15−ヒドロキシ−13−オキサ−2,17,21,22,25−ペンタアザペンタシクロ[17.5.2.02,6.07,12.022,26]ヘキサコサ−1(25),7(12),8,10,19(26),20,23−ヘプタエン−18−オンのジアステレオマー1;及び
(15S)−4,4,9−トリフルオロ−15−ヒドロキシ−13−オキサ−2,17,21,22,25−ペンタアザペンタシクロ[17.5.2.02,6.07,12.022,26]ヘキサコサ−1(25),7(12),8,10,19(26),20,23−ヘプタエン−18−オンのジアステレオマー2
から選択される、化合物。 - 請求項1〜49または50の何れか1項に記載の式Iの化合物又は製薬上許容しうるその塩、及び、製薬上許容しうる希釈剤又は担体を含む医薬組成物。
- 請求項1〜49または50の何れか1項に記載の式Iの化合物又は製薬上許容しうるその塩を含む、哺乳類における疼痛、癌、炎症、神経変性疾患又はクルーズトリパノソーマ感染症から選択される疾患又は障害を治療するための組成物。
- 疼痛、癌、炎症、神経変性疾患又はクルーズトリパノソーマ感染症から選択される疾患又は障害の治療において使用するための組成物であって、請求項1〜49または50の何れか1項に記載の式Iの化合物又は製薬上許容しうるその塩を含む、組成物。
- 下記工程:
(a)Zが*−NHC(=O)−であり、そして環A、環B、W、D、R2、R2a、R3、R3a及びmが式Iに関して定義したとおりである式Iの化合物に関しては、下記式II:
(b)WがOであり、環Aが下記式A−1:
(c)WがCH2であり、環Aが下記式A−2:
であり、そして環B、Z、D、Y、R1、R2、R2a、R3、R3a及びmが式Iに関して定義したとおりである式Iの化合物に関しては、下記式IV:
(d)Zが*−NHC(=O)−であり、そして環A、環B、W、D、R2、R2a、R3、R3a及びmが式Iに関して定義したとおりである式Iの化合物に関しては、下記式V:
(e)Zが*−NHCH2−であり、そして環A、環B、W、D、R2、R2a、R3、R3a及びmが式Iに関して定義したとおりである式Iの化合物に関しては、下記式VI:
(f)Zが*−NHCH2−であり、そして環A、環B、W、D、R2、R2a、R3、R3a及びmが式Iに関して定義したとおりである式Iの化合物に関しては、下記式VII:
(g)環A、環B、W、D、m、R2、R2a、R3、及びR3aが式Iに関して定義したとおりであり、Zが*−NR4bCH2−であり、そしてR4bが(1−6Cアルキル)C(O)−、(3−6Cシクロアルキル)C(O)−、Ar1C(O)−、HOCH2C(O)−、(1−6Cアルキル)スルホニル、(3−6Cシクロアルキル)スルホニル、(1−6Cアルキル)スルホニル、(3−6Cシクロアルキル)スルホニル、又はAr2(SO2)−である式Iの化合物に関しては、下記式VIII:
(h)環A、環B、W、D、R2、R2a、R3、R3a及びmが式Iに関して定義したとおりであり、Zが*−NR4bCH2−であり、そしてR4bが(1−6Cアルキル)NH(CO)−である式Iの化合物に関しては、下記式VIII:
(i)R2がFであり、R2aがHであり、そして環A、環B、Z、W、D、R3、R3a、及びmが式Iに関して定義したとおりである式Iの化合物に関しては、下記式IX:
(j)WがOであり、環Aが下記式A−1:
であり、XがCHであり、そしてY、R1、D、環B、Z,R2、R2a、R3及びmが式Iに関して定義したとおりである式Iの化合物に関しては、下記式X:
場合により何れかの保護基を除去すること、及び、場合によりその塩を調製すること;
を含む請求項1記載の化合物の調製のための方法。 - 環Bが下記構造:
を有する環B−1であり;
Dが炭素であり;
R2及びR2aは独立してH、F、(1−3C)アルキル又はOHであるが、ただしR2及びR2aは共にOHではなく;そして、
R3及びR3aは独立してH、(1−3C)アルキル又はヒドロキシ(1−3C)アルキルである;
請求項54記載の方法。 - 前記疾患又は障害が癌である、請求項52または53に記載の組成物。
- 前記疾患又は障害が疼痛である、請求項52または53に記載の組成物。
- 前記疾患又は障害がトロポミオシン関連キナーゼ(TrK)によって媒介される、請求項52または53に記載の組成物。
- 前記疾患又は障害がTrK媒介癌である、請求項56に記載の組成物。
- 以下の一般式:
[式中1と標記された波線は環Aの式Iのピロリジン環への結合点を示し、そして2と標記された波線は環AのWへの結合点を示す]を有する環A−1及びA−2から選択され;
XはNであり;
YはFであり;
R 1 はHであり;
WはCH 2 又はOであり;
mは0又は1であり;
R 2 及びR 2a は独立してH、F、(1−3C)アルキル、又はOHであるが、ただしR 2 及びR 2a は共にOHではなく;
R 3 はH、(1−3C)アルキル又はヒドロキシ(1−3C)アルキルであり;
Zは * −NR 4a C(=O)−であり、ここでアスタリスクはR 3 を担持している炭素へのZの結合点を示し;
R 4a はH、(1−6C)アルキル、フルオロ(1−6C)アルキル、ジフルオロ(1−6C)アルキル、トリフルオロ(1−6C)アルキル、ヒドロキシ(1−6Cアルキル)又はジヒドロキシ(2−6Cアルキル)であり;そして
R 5 及びR 6 は独立してH、ハロゲン、OH、(1−6C)アルキル又はヒドロキシ(1−6C)アルキルである]を有する請求項1記載の化合物又は製薬上許容しうるその塩。 - 以下の一般式を有する請求項1記載の化合物又は製薬上許容しうるその塩であって:
ここで:
環Aが以下の構造:
式中1と標記された波線は環Aの式Iのピロリジン環への結合点を示し、そして2と標記された波線は環AのWへの結合点を示し、
XはNであり;
YはFであり;
R 1 はHであり;
WはCH 2 又はOであり;
mは0又は1であり;
R 2 及びR 2a は独立してH、F、(1−3C)アルキル、又はOHであるが、ただしR 2 及びR 2a は共にOHではなく;
R 3 はH又は(1−3C)アルキルであり;
Zは * −NR 4a C(=O)−であり、ここでアスタリスクはR 3 を担持している炭素へのZの結合点を示し;
R 4a はHであり;そして
R 5 及びR 6 は独立してH、ハロゲン、OH、又は(1−6C)アルキルである、
化合物又は製薬上許容しうるその塩。 - 以下の一般式を有する、請求項1に記載の化合物
又は製薬上許容しうるその塩であって、ここで:
環Aは以下の構造を有し:
YはFであり;
R 1 はHであり;
WはCH 2 であり;
mは0又は1であり;
R 2 及びR 2a は独立してH、F、(1−3C)アルキル、又はOHであるが、ただしR 2 及びR 2a は共にOHではなく;
R 3 はH又はメチルであり;
Zは * −NR 4a C(=O)−であり、ここでアスタリスクはR 3 を担持している炭素へのZの結合点を示し;
R 4a はHであり;そして
R 5 及びR 6 は独立してH、ハロゲン、OH、又は(1−6C)アルキルである、
化合物又は製薬上許容しうるその塩。 - (6R)−9−フルオロ−2,11,15,19,20,23−ヘキサアザペンタシクロ[15.5.2.1 7,11 .0 2,6 .0 20,24 ]ペンタコサ−1(23),7,9,17(24),18,21−ヘキサエン−16,25−ジオン;
(6R,13R)−9,13−ジフルオロ−2,11,15,19,20,23−ヘキサアザペンタシクロ[15.5.2.1 7,11 .0 2,6 .0 20,24 ]ペンタコサ−1(23),7,9,17(24),18,21−ヘキサエン−16,25−ジオン;
(6R,13R)−9−フルオロ−13−メチル−2,11,15,19,20,23−ヘキサアザペンタシクロ[15.5.2.1 7,11 .0 2,6 .0 20,24 ]ペンタコサ−1(23),7,9,17(24),18,21−ヘキサエン−16,25−ジオン;
(6R,13S)−9−フルオロ−13−メチル−2,11,15,19,20,23−ヘキサアザペンタシクロ[15.5.2.1 7,11 .0 2,6 .0 20,24 ]ペンタコサ−1(23),7,9,17(24),18,21−ヘキサエン−16,25−ジオン;および
(6R)−9−フルオロ−13,13−ジメチル−2,11,15,19,20,23−ヘキサアザペンタシクロ[15.5.2.1 7,11 .0 2,6 .0 20,24 ]ペンタコサ−1(23),7,9,17(24),18,21−ヘキサエン−16,25−ジオン
から選択される、請求項60に記載の化合物。 - (6R)−9−フルオロ−2,11,16,20,21,24−ヘキサアザペンタシクロ[16.5.2.0 2,6 .0 7,12 .0 21,25 ]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−17−オン;
(6R)−9−フルオロ−15−メチル−2,11,16,20,21,24−ヘキサアザペンタシクロ[16.5.2.0 2,6 .0 7,12 .0 21,25 ]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−17−オン;および
(6R)−9−フルオロ−15,15−ジメチル−2,11,16,20,21,24−ヘキサアザペンタシクロ[16.5.2.0 2,6 .0 7,12 .0 21,25 ]ペンタコサ−1(24),7,9,11,18(25),19,22−ヘプタエン−17−オン;
(6R)−9−フルオロ−13−オキサ−2,11,17,21,22,25−ヘキサアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン−18−オン;および
(6R)−9,15,15−トリフルオロ−13−オキサ−2,11,17,21,22,25−ヘキサアザペンタシクロ[17.5.2.0 2,6 .0 7,12 .0 22,26 ]ヘキサコサ−1(25),7,9,11,19(26),20,23−ヘプタエン−18−オン
から選択される、請求項60に記載の化合物。 - 請求項60〜64の何れか1項に記載の化合物または製薬上許容されるその塩および製薬上許容しうる希釈剤又はキャリアを含む医薬組成物。
- 疼痛、癌、炎症、神経変性疾患又はクルーズトリパノソーマ感染症の治療において使用するための組成物であって、請求項60〜64の何れか1項に記載の化合物または製薬上許容しうるその塩を含む、組成物。
- 哺乳類における、疼痛、癌、炎症、神経変性疾患又はクルーズトリパノソーマ感染症から選択される疾患又は障害を治療するための組成物であって、該組成物は、請求項60〜64の何れか1項に記載の式Iの化合物または製薬上許容しうるその塩を含む、組成物。
- 前記疾患又は障害が癌である、請求項66または67に記載の組成物。
- 前記疾患又は障害が疼痛である、請求項66または67に記載の組成物。
- 前記疾患又は障害がトロポミオシン関連キナーゼ(TrK)によって媒介される、請求項66または67に記載の組成物。
- 前記疾患又は障害がTrK媒介癌である、請求項70に記載の組成物。
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LT3372605T (lt) | 2008-10-22 | 2022-02-10 | Array Biopharma, Inc. | Pakeistieji pirazolo[1,5-a]pirimidino junginiai, kaip trk kinazės inhibitoriai |
AR077468A1 (es) | 2009-07-09 | 2011-08-31 | Array Biopharma Inc | Compuestos de pirazolo (1,5 -a) pirimidina sustituidos como inhibidores de trk- quinasa |
BR112013029201B1 (pt) | 2011-05-13 | 2022-08-09 | Array Biopharma Inc | Compostos de pirrolidinil ureia e pirrolidinil tioureia, seu processo de preparação, seu uso e composições farmacêuticas |
DK2822953T5 (en) * | 2012-03-06 | 2017-09-11 | Pfizer | Macrocyclic derivatives for the treatment of proliferative diseases |
US9546156B2 (en) | 2012-11-13 | 2017-01-17 | Array Biopharma Inc. | N-bicyclic aryl,N'-pyrazolyl urea, thiourea, guanidine cyanoguanidine compounds as TrkA kinase inhibitors |
RU2664541C2 (ru) | 2012-11-13 | 2018-08-20 | Эррэй Биофарма Инк. | Бициклические соединения мочевины, тиомочевины, гуанидина и цианогуанидина, пригодные для лечения боли |
US9828360B2 (en) | 2012-11-13 | 2017-11-28 | Array Biopharma Inc. | Pyrrolidinyl 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 |
UA116455C2 (uk) | 2012-11-13 | 2018-03-26 | Еррей Біофарма Інк. | Сполуки n-піролідинілсечовини, n'-піразолілсечовини, тіосечовини, гуанідину та ціаногуанідину як інгібітори кінази trka |
US9969694B2 (en) | 2012-11-13 | 2018-05-15 | Array Biopharma Inc. | N-(arylalkyl)-N′-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors |
US9790178B2 (en) | 2012-11-13 | 2017-10-17 | Array Biopharma Inc. | Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors |
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 |
WO2014078322A1 (en) | 2012-11-13 | 2014-05-22 | Array Biopharma Inc. | Thiazolyl and oxazolyl urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors |
US9822118B2 (en) | 2012-11-13 | 2017-11-21 | Array Biopharma Inc. | Bicyclic heteroaryl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors |
MY193524A (en) * | 2014-01-24 | 2022-10-18 | Turning Point Therapeutics Inc | Diaryl macrocycles as modulators of protein kinases |
EP3125920B1 (en) | 2014-04-04 | 2020-12-23 | Del Mar Pharmaceuticals | Dianhydrogalactitol, diacetyldianhydrogalactitol or dibromodulcitol to treat non-small-cell carcinoma of the lung and ovarian cancer |
RS59286B1 (sr) | 2014-05-15 | 2019-10-31 | Array Biopharma Inc | 1-((3s,4r)-4-(3-fluorofenil)-1-(2-metoksietil)pirolidin-3-il)-3-(4-metil-3-(2-metilpirimidin-5-il)-1-fenil-1h-pirazol-5-il)urea kao inhibitor trka kinaze |
TWI736134B (zh) * | 2014-09-11 | 2021-08-11 | 美商特普醫葯公司 | 作為蛋白質激酶之調節劑的二芳基巨環 |
SG11201701936WA (en) * | 2014-09-17 | 2017-04-27 | Oncodesign Sa | Macrocyclic lrrk2 kinase inhibitors |
EA032872B1 (ru) * | 2014-09-17 | 2019-07-31 | Онкодизайн С.А. | Макроциклические ингибиторы rip2-киназы |
RS64122B1 (sr) | 2014-11-16 | 2023-05-31 | Array Biopharma Inc | Kristalni oblik (s)-n-(5-((r)-2-(2,5-difluorofenil)-pirolidin-1-il)-pirazolo[1,5-a]pirimidin-3-il)-3-hidroksipirolidin-1-karboksamid hidrogensulfata |
US9708350B2 (en) | 2014-12-04 | 2017-07-18 | Shin-Etsu Chemical Co., Ltd. | Method for producing polyalkylene glycol derivative having amino group at end, polymerization initiator for use in the same, and alcohol compound as raw material for the polymerization initiator |
US10377775B2 (en) | 2014-12-04 | 2019-08-13 | Shin-Etsu Chemical Co., Ltd. | Method for producing polyalkylene glycol derivative having amino group at end |
JP6460937B2 (ja) * | 2014-12-04 | 2019-01-30 | 信越化学工業株式会社 | 末端にアミノ基を有するポリアルキレングリコール誘導体の製造方法 |
KR102659741B1 (ko) * | 2014-12-15 | 2024-04-23 | 주식회사 씨엠지제약 | 융합된 고리 헤테로아릴 화합물 및 trk 억제제로서의 이들의 용도 |
WO2016116900A1 (en) | 2015-01-23 | 2016-07-28 | Gvk Biosciences Private Limited | Inhibitors of trka kinase |
TN2017000502A1 (en) * | 2015-06-01 | 2019-04-12 | Loxo Oncology Inc | Methods of diagnosing and treating cancer |
KR102599788B1 (ko) * | 2015-07-02 | 2023-11-07 | 터닝 포인트 테라퓨틱스, 인크. | 단백질 키나제의 조절물질로서 키랄 디아릴 매크로사이클 |
LT3319969T (lt) * | 2015-07-06 | 2024-06-10 | Turning Point Therapeutics, Inc. | Diarilo makrociklo polimorfas |
LT3322706T (lt) | 2015-07-16 | 2021-03-10 | Array Biopharma, Inc. | Pakeistieji pirazolo[1,5-a]piridino junginiai, kaip ret kinazės inhibitoriai |
JP6817287B2 (ja) * | 2015-07-21 | 2021-01-20 | ターニング・ポイント・セラピューティクス・インコーポレイテッドTurning Point Therapeutics,Inc. | キラルジアリール大環状分子及びその使用 |
WO2017049383A1 (en) | 2015-09-24 | 2017-03-30 | Cyclenium Pharma Inc. | Libraries of heteroaryl-containing macrocyclic compounds and methods of making and using the same |
BR112018008357A2 (pt) | 2015-10-26 | 2018-11-27 | Array Biopharma Inc | mutações de ponto em câncer resistente a inibidor de trk e métodos relacionados às mesmas |
US10045991B2 (en) | 2016-04-04 | 2018-08-14 | Loxo Oncology, Inc. | Methods of treating pediatric cancers |
AU2017246554B2 (en) | 2016-04-04 | 2022-08-18 | Loxo Oncology, Inc. | Liquid formulations of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo(1,5-a)pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide |
WO2017176744A1 (en) | 2016-04-04 | 2017-10-12 | Loxo Oncology, Inc. | Methods of treating pediatric cancers |
HRP20230704T1 (hr) | 2016-05-18 | 2023-10-27 | Loxo Oncology, Inc. | Priprava (s)-n-(5-((r)-2-(2,5-difluorfenil)pirolidin-1-il)pirazolo[1,5-a]pirimidin-3-il)-3-hidroksipirolidin-1-karboksamida |
US10689400B2 (en) * | 2016-07-28 | 2020-06-23 | Turning Point Therapeutics, Inc. | Macrocycle kinase inhibitors |
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 |
JOP20190077A1 (ar) | 2016-10-10 | 2019-04-09 | Array Biopharma Inc | مركبات بيرازولو [1، 5-a]بيريدين بها استبدال كمثبطات كيناز ret |
JOP20190092A1 (ar) | 2016-10-26 | 2019-04-25 | Array Biopharma Inc | عملية لتحضير مركبات بيرازولو[1، 5-a]بيريميدين وأملاح منها |
CA3049136C (en) | 2017-01-18 | 2022-06-14 | Array Biopharma Inc. | Substituted pyrazolo[1,5-a]pyrazine compounds as ret kinase inhibitors |
WO2018136663A1 (en) | 2017-01-18 | 2018-07-26 | Array Biopharma, Inc. | Ret 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 |
JP2020524701A (ja) * | 2017-06-22 | 2020-08-20 | サイクルニウム ファーマ インコーポレイテッド | ピリジン含有大環状化合物ライブラリーならびにその製造および使用方法 |
CN111182903A (zh) * | 2017-07-28 | 2020-05-19 | 特普医药公司 | 巨环化合物及其用途 |
CN113735881A (zh) * | 2017-08-23 | 2021-12-03 | 正大天晴药业集团股份有限公司 | 含有氨基吡唑并嘧啶的大环化合物及其药物组合物和用途 |
TW202410896A (zh) | 2017-10-10 | 2024-03-16 | 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 |
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 |
US20190247398A1 (en) * | 2017-10-26 | 2019-08-15 | Array Biopharma Inc. | Formulations of a macrocyclic trk kinase inhibitor |
CN109516999B (zh) * | 2017-11-01 | 2021-08-17 | 郑州泰基鸿诺医药股份有限公司 | 用作蛋白质激酶调节剂的化合物及其应用 |
AU2018364938B2 (en) * | 2017-11-10 | 2021-11-11 | Angex Pharmaceutical, Inc. | Macrocyclic compounds as TRK kinase inhibitors and uses thereof |
EP4151641A1 (en) * | 2017-12-19 | 2023-03-22 | Turning Point Therapeutics, Inc. | Macrocyclic compounds for treating cancer |
WO2019120194A1 (zh) | 2017-12-22 | 2019-06-27 | 深圳市塔吉瑞生物医药有限公司 | 一种取代的吡唑并[1,5-a]嘧啶化合物及其药物组合物及用途 |
CN109956957B (zh) * | 2017-12-22 | 2021-11-09 | 广州白云山医药集团股份有限公司白云山制药总厂 | 一种咪唑并[1,2-b]哒嗪大环类激酶抑制剂 |
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 |
JP6997876B2 (ja) | 2018-01-18 | 2022-02-04 | 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ラゾリル[4,3-c]ピリジン化合物 |
US11524963B2 (en) | 2018-01-18 | 2022-12-13 | Array Biopharma Inc. | Substituted pyrazolo[3,4-d]pyrimidines as RET kinase inhibitors |
CN109575025B (zh) * | 2018-01-23 | 2020-09-11 | 深圳市塔吉瑞生物医药有限公司 | 取代的吡唑并[1,5-a]嘧啶类的大环化合物 |
TW201932472A (zh) * | 2018-01-30 | 2019-08-16 | 大陸商上海吉倍生物技術有限公司 | 具有大環分子結構的化合物及其用途 |
CN110156813B (zh) * | 2018-02-13 | 2023-07-25 | 北京诺诚健华医药科技有限公司 | 作为trk抑制剂的杂环化合物 |
JP7323748B2 (ja) * | 2018-02-28 | 2023-08-09 | ナンジン ザイミン ファーマシューティカル カンパニー リミテッド | ピラゾロピリミジン誘導体及びその使用 |
JP7294677B2 (ja) * | 2018-03-14 | 2023-06-20 | フォチョン・ファーマシューティカルズ・リミテッド | TRKキナーゼ阻害剤としての置換(2-アザビシクロ[3.1.0]ヘキサン-2-イル)ピラゾロ[1,5-a]ピリミジン化合物及び置換(2-アザビシクロ[3.1.0]ヘキサン-2-イル)イミダゾ[1,2-b]ピリダジン化合物 |
WO2019184955A1 (en) * | 2018-03-28 | 2019-10-03 | Fochon Pharmaceuticals, Ltd. | Macrocyclic compounds as trk kinases inhibitors |
US20210023086A1 (en) | 2018-03-29 | 2021-01-28 | Loxo Oncology, Inc. | Treatment of trk-associated cancers |
JP7092405B2 (ja) * | 2018-04-16 | 2022-06-28 | 深▲チェン▼市塔吉瑞生物医薬有限公司 | キナーゼ活性を阻害するためのジ(ヘテロ)アリール大環状化合物 |
JP7128345B2 (ja) * | 2018-04-25 | 2022-08-30 | プライムジーン(ベイジン)カンパニー リミテッド | ジアリール大員環化合物、医薬組成物及びその用途 |
CN111918868B (zh) * | 2018-05-04 | 2022-12-30 | 正大天晴药业集团股份有限公司 | 作为蛋白激酶调节剂的二芳基大环化合物 |
CN110577532B (zh) * | 2018-06-08 | 2022-06-03 | 江苏威凯尔医药科技有限公司 | 原肌球蛋白受体激酶抑制剂及其制备方法和应用 |
WO2019233461A1 (zh) * | 2018-06-08 | 2019-12-12 | 江苏威凯尔医药科技有限公司 | 原肌球蛋白受体激酶抑制剂及其制备方法和应用 |
CN110627812B (zh) * | 2018-06-25 | 2022-10-11 | 北京诺诚健华医药科技有限公司 | 作为trk抑制剂的杂环化合物 |
AU2019314302A1 (en) | 2018-07-31 | 2021-01-28 | Loxo Oncology, Inc. | Spray-dried dispersions and formulations of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoro propan-2-yl)-1H-pyrazole-4-carboxamide |
US11964988B2 (en) | 2018-09-10 | 2024-04-23 | Array Biopharma Inc. | Fused heterocyclic compounds as RET kinase inhibitors |
EP3858834A4 (en) * | 2018-09-29 | 2022-06-22 | Shandong Luye Pharmaceutical Co., Ltd. | PYRAZOLOPYRIMIDE DERIVATIVES AS SELECTIVE TRK INHIBITORS |
WO2020086616A1 (en) | 2018-10-22 | 2020-04-30 | Fronthera U.S. Pharmaceuticals Llc | Tyk2 inhibitors and uses thereof |
CN111171049B (zh) * | 2018-11-09 | 2021-06-04 | 山东轩竹医药科技有限公司 | 酪氨酸激酶抑制剂及其用途 |
WO2020094112A1 (zh) | 2018-11-09 | 2020-05-14 | 山东轩竹医药科技有限公司 | 大环类酪氨酸激酶抑制剂及其用途 |
CN111253402B (zh) * | 2018-11-30 | 2021-08-03 | 广州白云山医药集团股份有限公司白云山制药总厂 | 一种trk激酶抑制剂化合物的中间体化合物及制备方法 |
US20220041579A1 (en) | 2018-12-19 | 2022-02-10 | Array Biopharma Inc. | Substituted quinoxaline compounds as inhibitors of fgfr tyrosine kinases |
CN113490666A (zh) | 2018-12-19 | 2021-10-08 | 奥瑞生物药品公司 | 作为fgfr酪氨酸激酶的抑制剂的取代的吡唑并[1,5-a]吡啶化合物 |
AU2020242735B2 (en) | 2019-03-19 | 2022-12-01 | Central China Normal University | Pyrazolopyrimidine compound, pharmaceutical composition, and application therefor |
KR20220004641A (ko) | 2019-03-26 | 2022-01-11 | 벤틱스 바이오사이언스, 인크. | Tyk2 슈도키나아제 리간드 |
CN113727984B (zh) * | 2019-05-21 | 2024-03-15 | 浙江海正药业股份有限公司 | 大环类衍生物、及其制备方法和用途 |
CN112110938B (zh) * | 2019-06-21 | 2021-11-09 | 成都海博为药业有限公司 | 一种作为蛋白质激酶抑制剂的化合物及其制备方法和用途 |
CN114258394B (zh) * | 2019-08-28 | 2024-04-23 | 南京再明医药有限公司 | 一种致癌性融合激酶抑制剂的晶型及其应用 |
CN110804059B (zh) * | 2019-09-30 | 2024-03-12 | 郑州泰基鸿诺医药股份有限公司 | 氨基甲酸酯类化合物、药物组合物及其应用 |
WO2021083345A1 (zh) * | 2019-10-30 | 2021-05-06 | 先声药业有限公司 | 吡唑并嘧啶类化合物的制备方法及其中间体 |
WO2021092246A1 (en) | 2019-11-08 | 2021-05-14 | Ventyx Biosciences, Inc. | Tyk2 pseudokinase ligands |
WO2021098703A1 (zh) * | 2019-11-18 | 2021-05-27 | 南京明德新药研发有限公司 | 作为高选择性ros1抑制剂的化合物及其应用 |
KR20220113771A (ko) | 2019-12-13 | 2022-08-16 | 시노허브 파마슈티컬 씨오., 엘티디 | 마크로사이클릭 구조를 갖는 불소-함유 헤테로사이클릭 유도체 및 이의 용도 |
CN113004305B (zh) * | 2019-12-19 | 2024-04-09 | 赛诺哈勃药业(成都)有限公司 | 大环化合物及其制备方法和用途 |
JP7495035B2 (ja) * | 2020-05-08 | 2024-06-04 | シュエンジュウ バイオファーマシューティカル カンパニー リミテッド | 大環類チロシンキナーゼ阻害剤の結晶形及びその製造方法 |
CN111777549A (zh) * | 2020-07-07 | 2020-10-16 | 中瀚(齐河县)生物医药科技有限公司 | 一种2-甲氧基-3-溴-5-氟吡啶的合成工艺 |
CN114073704B (zh) * | 2020-08-14 | 2023-08-11 | 赛诺哈勃药业(成都)有限公司 | 具有大环结构的含氟并杂环衍生物的应用 |
CN112174982A (zh) * | 2020-09-10 | 2021-01-05 | 上海希迈医药科技有限公司 | 一种洛普替尼晶型及其制备方法 |
CN111875620B (zh) * | 2020-09-28 | 2020-12-11 | 上海美迪西生物医药股份有限公司 | 吡唑并嘧啶类大环衍生物及其应用 |
US20240092759A1 (en) * | 2021-01-08 | 2024-03-21 | Yale University | Non-Covalent Inhibitors of the Main Protease of SARS-CoV-2 and Methods of Use |
TWI804266B (zh) * | 2021-04-07 | 2023-06-01 | 大陸商上海齊魯製藥研究中心有限公司 | Tyk2抑制劑及其用途 |
CN115368379A (zh) * | 2021-05-18 | 2022-11-22 | 广州嘉越医药科技有限公司 | 一种含氰基取代的大环类化合物的晶型及其制备方法 |
WO2022262671A1 (zh) * | 2021-06-15 | 2022-12-22 | 中国医药研究开发中心有限公司 | 杂环大环化合物及其医药用途 |
WO2023025141A1 (zh) * | 2021-08-23 | 2023-03-02 | 正大天晴药业集团股份有限公司 | 含有氨基的大环化合物在治疗trk激酶介导的肿瘤中的用途 |
CN113582994B (zh) * | 2021-09-28 | 2022-02-11 | 北京鑫开元医药科技有限公司 | 具有trk激酶抑制活性的化合物、制备方法、组合物及其用途 |
WO2023133375A1 (en) * | 2022-01-05 | 2023-07-13 | Blossomhill Therapeutics, Inc. | Macrocyclic compounds and use as kinase inhibitors |
WO2023208244A1 (zh) * | 2022-04-29 | 2023-11-02 | 南京明德新药研发有限公司 | 大环类化合物及其应用 |
Family Cites Families (324)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US755047A (en) * | 1902-03-17 | 1904-03-22 | Alexander Roth Robertson | Bottle-seal. |
EP0009517A1 (en) | 1978-10-04 | 1980-04-16 | THE PROCTER & GAMBLE COMPANY | Vaginal contraceptive |
ATE212985T1 (de) | 1993-11-30 | 2002-02-15 | Searle & Co | Tricyclische,substituierte pyrazolyl- benzolsulfonamide und ihre verwendung als cyclooxygenase ii inhibitoren |
US5844092A (en) | 1994-03-18 | 1998-12-01 | Genentech, Inc. | Human TRK receptors and neurotrophic factor inhibitors |
US5430021A (en) | 1994-03-18 | 1995-07-04 | Pharmavene, Inc. | Hydrophobic drug delivery systems |
US5877016A (en) | 1994-03-18 | 1999-03-02 | Genentech, Inc. | Human trk receptors and neurotrophic factor inhibitors |
US6677135B1 (en) | 1996-05-08 | 2004-01-13 | Biogen, Inc. | Ret ligand (RetL) for stimulating neutral and renal growth |
ES2270465T3 (es) | 1996-05-08 | 2007-04-01 | Biogen Idec Ma Inc. | Ligando 3 ret para estimular el crecimiento neural y renal. |
CA2206201A1 (en) | 1996-05-29 | 1997-11-29 | Yoshiaki Isobe | Pyrazole derivatives and their pharmaceutical use |
US6682921B1 (en) | 1996-08-21 | 2004-01-27 | New York University | Crystals of the tyrosine kinase domain of non-insulin receptor tyrosine kinases |
JP3898296B2 (ja) | 1996-08-28 | 2007-03-28 | ポーラ化成工業株式会社 | ピロロピラゾロピリミジン化合物及びこれを有効成分とする医薬 |
EP0979231B1 (en) | 1997-04-25 | 2004-11-24 | Takeda Chemical Industries, Ltd. | Condensed pyridazine derivatives, their production and use |
US6531152B1 (en) | 1998-09-30 | 2003-03-11 | Dexcel Pharma Technologies Ltd. | Immediate release gastrointestinal drug delivery system |
UA74546C2 (en) * | 1999-04-06 | 2006-01-16 | Boehringer Ingelheim Ca Ltd | Macrocyclic peptides having activity relative to hepatitis c virus, a pharmaceutical composition and use of the pharmaceutical composition |
WO2001016169A2 (en) | 1999-09-01 | 2001-03-08 | Biogen, Inc. | RET LIGAND 5 (Retl5) FROM HUMAN AND MOUSE |
US6534085B1 (en) | 1999-09-23 | 2003-03-18 | Bioresponse L.L.C. | Phytochemicals for promoting weight loss |
FI20000403A0 (fi) | 2000-02-22 | 2000-02-22 | Hannu Sariola | GDNF perhesukuisten yhdisteiden käyttö kivessyövän hoitoon tarkoitettujen tuotteiden valmistamiseksi |
KR100823764B1 (ko) | 2000-06-22 | 2008-04-21 | 제넨테크, 인크. | 아고니스트 안티-티알케이-씨 모노클로날 항체 |
TWI312347B (en) | 2001-02-08 | 2009-07-21 | Eisai R&D Man Co Ltd | Bicyclic nitrogen-containing condensed ring compounds |
CN101653604A (zh) | 2001-05-30 | 2010-02-24 | 基因技术股份有限公司 | 抗ngf抗体用于治疗各种疾病 |
WO2003020698A2 (en) | 2001-09-06 | 2003-03-13 | Prochon Biotech Ltd. | Protein tyrosine kinase inhibitors |
US20030199525A1 (en) | 2002-03-21 | 2003-10-23 | Hirst Gavin C. | Kinase inhibitors |
MXPA04010441A (es) | 2002-04-23 | 2005-02-14 | Shionogi & Co | Derivado de pirazolo[1,5-a]pirimidina e inhibidor de nad(p)h oxidasa que contiene el mismo. |
US7449488B2 (en) | 2002-06-04 | 2008-11-11 | Schering Corporation | Pyrazolopyrimidines as protein kinase inhibitors |
EP1526854A1 (en) | 2002-07-24 | 2005-05-04 | University Of Cincinnati | 4-4(methylpiperazin-1-ylmethyl)-n- 4-methyl-3-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl -benzamide for treating mutated-ret kinase associated diseases |
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 |
EP1537116B1 (en) | 2002-09-04 | 2010-06-02 | Schering Corporation | Pyrazolopyrimidines suitable for the treatment of cancer diseases |
US7196078B2 (en) | 2002-09-04 | 2007-03-27 | Schering Corpoartion | Trisubstituted and tetrasubstituted pyrazolopyrimidines as cyclin dependent kinase inhibitors |
US7119200B2 (en) | 2002-09-04 | 2006-10-10 | Schering Corporation | Pyrazolopyrimidines as cyclin dependent kinase inhibitors |
RU2357967C2 (ru) * | 2002-09-16 | 2009-06-10 | Глаксо Груп Лимитед | ПРОИЗВОДНЫЕ ПИРАЗОЛО[3, 4-b]ПИРИДИНА, ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ (ВАРИАНТЫ), ПРИМЕНЕНИЕ (ВАРИАНТЫ), КОМПОЗИЦИЯ (ВАРИАНТЫ) |
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 |
US20070037150A1 (en) | 2003-02-21 | 2007-02-15 | 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 |
WO2004087707A1 (en) | 2003-03-31 | 2004-10-14 | Vernalis (Cambridge) Limited | Pyrazolopyrimidine compounds and their use in medicine |
WO2004089415A2 (en) | 2003-04-11 | 2004-10-21 | Novo Nordisk A/S | COMBINATIONS OF AN 11β-HYDROXYSTEROID DEHYDROGENASE TYPE 1 INHIBITOR AND A GLUCOCORTICOID RECEPTOR AGONIST |
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 |
CN1795206A (zh) | 2003-04-28 | 2006-06-28 | 株式会社嘉尔药物 | 半乳糖凝集素-9诱导因子 |
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 |
EA013614B1 (ru) | 2003-07-15 | 2010-06-30 | Амджен Инк. | Изолированное антитело к фактору роста нервов (ngf) и способы его применения |
US7642235B2 (en) * | 2003-09-22 | 2010-01-05 | Boehringer Ingelheim International Gmbh | Macrocyclic peptides active against the hepatitis C virus |
US7491794B2 (en) * | 2003-10-14 | 2009-02-17 | Intermune, Inc. | Macrocyclic compounds as inhibitors of viral replication |
US20090143399A1 (en) | 2003-10-14 | 2009-06-04 | Arizona Board Of Regents On Behalf Of The University Of Arizona | Protein Kinase Inhibitors |
MY141220A (en) | 2003-11-17 | 2010-03-31 | Astrazeneca Ab | Pyrazole derivatives as inhibitors of receptor tyrosine kinases |
RU2006121646A (ru) | 2003-11-21 | 2008-01-10 | Новартис АГ (CH) | Производные 1h-имидазохинолина в качестве ингибиторов протеинкиназы |
TW200529849A (en) | 2003-11-28 | 2005-09-16 | Novartis Ag | Diaryl urea derivatives in the treatment of protein kinase dependent diseases |
UA83881C2 (en) * | 2003-12-18 | 2008-08-26 | Янссен Фармацевтика Н.В. | Pyrido- and pyrimidopyrimidine derivatives as anti-proliferative agents |
PL1696920T3 (pl) | 2003-12-19 | 2015-03-31 | Plexxikon Inc | Związki i sposoby opracowywania modulatorów Ret |
GB0330043D0 (en) | 2003-12-24 | 2004-01-28 | Pharmacia Italia Spa | Pyrrolo [2,3-b] pyridine derivatives active as kinase inhibitors process for their preparation and pharmaceutical compositions comprising them |
GB0330042D0 (en) | 2003-12-24 | 2004-01-28 | Pharmacia Italia Spa | Pyrrolo [2,3-b] pyridine derivatives active as kinase inhibitors process for their preparation and pharmaceutical compositions them |
AR049769A1 (es) | 2004-01-22 | 2006-09-06 | Novartis Ag | Derivados de pirazolo(1,5-a)pirimidin 7-il-amina para utilizarse en el tratamiento de enfermedades dependientes de la quinasa de proteina |
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 |
UA91677C2 (ru) * | 2004-03-30 | 2010-08-25 | Интермюн, Инк. | Макроциклические соединения как ингибиторы вирусной репликации |
WO2006001310A1 (ja) | 2004-06-25 | 2006-01-05 | Mitsubishi Materials Corporation | 金属コロイド粒子、金属コロイド、及び金属コロイドの用途 |
TW200615268A (en) | 2004-08-02 | 2006-05-16 | Osi Pharm Inc | Aryl-amino substituted pyrrolopyrimidine multi-kinase inhibiting compounds |
PE20060664A1 (es) | 2004-09-15 | 2006-08-04 | Novartis Ag | Amidas biciclicas como inhibidores de cinasa |
US7855205B2 (en) | 2004-10-29 | 2010-12-21 | Janssen Pharmaceutica Nv | Pyrimidinyl substituted fused-pyrrolyl compounds useful in treating kinase disorders |
US20060127982A1 (en) | 2004-10-29 | 2006-06-15 | Shih Jason C | Development of an asporogenic bacillus licheniformis and production of keratinase therefrom |
US7452847B2 (en) | 2004-11-02 | 2008-11-18 | Ricoh Company, Ltd. | Reversible thermosensitive recording medium, reversible thermosensitive recording label, reversible thermosensitive recording device, image processing apparatus, and image processing method |
ES2354824T3 (es) | 2004-11-04 | 2011-03-18 | Vertex Pharmaceuticals, Inc. | Pirazolo[1,5-a]pirimidinas útiles como inhibidores de proteínas cinasas. |
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 |
GB0501999D0 (en) | 2005-02-01 | 2005-03-09 | Sentinel Oncology Ltd | Pharmaceutical compounds |
CN101119996A (zh) | 2005-02-16 | 2008-02-06 | 阿斯利康(瑞典)有限公司 | 化学化合物 |
MX2007009842A (es) | 2005-02-16 | 2007-08-23 | Astrazeneca Ab | Compuestos quimicos. |
WO2006089298A2 (en) | 2005-02-18 | 2006-08-24 | Attenuon, Llc | Pyrimidine-fused diazepine derivatives and indole-fused pteridines |
SI1869049T1 (sl) * | 2005-03-21 | 2009-08-31 | Lilly Co Eli | Spojine imidazopiridazina |
GB0507575D0 (en) | 2005-04-14 | 2005-05-18 | Novartis Ag | Organic compounds |
EP1874731A4 (en) | 2005-04-15 | 2009-08-05 | Cylene Pharmaceuticals Inc | CHINOBENZOXAZINANALOGA AND METHOD FOR THE APPLICATION |
EP1877057A1 (en) | 2005-04-27 | 2008-01-16 | AstraZeneca AB | Use of pyrazolyl-pyrimidine derivatives in the treatment of pain |
KR20080015409A (ko) | 2005-05-16 | 2008-02-19 | 아스트라제네카 아베 | 티로신 키나제 억제제로서 유용한 피라졸릴아미노피리미딘 유도체 |
US20100047777A1 (en) | 2005-05-26 | 2010-02-25 | The Johns Hopkins University | Methods for identifying mutations in coding and non-coding dna |
JP2008542382A (ja) | 2005-05-31 | 2008-11-27 | ザ ファール ファミリー トラスト (デイティド 9 ジュライ 1996) | 癌および他の疾患の処置用プロテインキナーゼ阻害剤としての置換ビアリール複素環誘導体 |
US7541367B2 (en) | 2005-05-31 | 2009-06-02 | Janssen Pharmaceutica, N.V. | 3-benzoimidazolyl-pyrazolopyridines useful in treating kinase disorders |
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. |
BRPI0611863B1 (pt) | 2005-06-22 | 2021-11-23 | Plexxikon, Inc | Composto, bem como composição e kit compreendendo o mesmo, composto intermediário na preparação do mesmo, método para tratamento e uso do mesmo |
US20070025540A1 (en) | 2005-07-07 | 2007-02-01 | Roger Travis | Call center routing based on talkativeness |
GB0515026D0 (en) | 2005-07-21 | 2005-08-31 | Novartis Ag | Organic compounds |
BRPI0613962A2 (pt) * | 2005-07-25 | 2009-03-24 | Intermune Inc | inibidores macrocìclicos inovadores de replicação de vìrus da hepatite c |
WO2007013673A1 (en) | 2005-07-29 | 2007-02-01 | 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 |
WO2007024680A1 (en) | 2005-08-22 | 2007-03-01 | 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 |
PT1919979E (pt) | 2005-08-25 | 2014-03-07 | Creabilis Therapeutics Spa | Polímeros conjugados de k-252a e seus derivados |
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 |
CA2624500A1 (en) | 2005-10-06 | 2007-04-19 | Schering Corporation | Pyrazolopyrimidines as protein kinase inhibitors |
TWI421078B (zh) | 2005-10-06 | 2014-01-01 | Merck Sharp & Dohme | 關卡激酶抑制劑及其用途 |
JP5030961B2 (ja) | 2005-10-11 | 2012-09-19 | サーントゥル ナシオナル ドゥ ラ ルシェルシュ シャーンティフィク | 細胞のアポトーシスの検出および定量化用の化合物およびキット |
GEP20104956B (en) * | 2005-10-11 | 2010-04-12 | Array Biopharma Inc | Compounds for inhibiting hepatitis c viral replication and use thereof |
US8101625B2 (en) | 2005-10-21 | 2012-01-24 | Exelixis, Inc. | Pyrimidinones as Casein Kinase II (CK2) modulators |
CA2628474A1 (en) | 2005-11-03 | 2007-05-10 | Sgx Pharmaceuticals, Inc. | Pyrimidinyl-thiophene kinase modulators |
US20070149523A1 (en) | 2005-11-14 | 2007-06-28 | Jan Ehlert | Thiazole Analogues and Uses Thereof |
EP1785420A1 (en) | 2005-11-14 | 2007-05-16 | 4Sc Ag | Thiazole analogues and uses thereof |
WO2007057397A1 (en) | 2005-11-15 | 2007-05-24 | Boehringer Ingelheim International Gmbh | Treatment of cancer |
GB0524436D0 (en) | 2005-11-30 | 2006-01-11 | Novartis Ag | Organic compounds |
RU2008127263A (ru) | 2005-12-08 | 2010-01-20 | Новартис АГ (CH) | ПИРАЗОЛ [1,5-a] ПИРИДИН-3-КАРБОНОВЫЕ КИСЛОТЫ В КАЧЕСТВЕ ИНГИБИТОРОВ EphB-И VEGFR2-КИНАЗЫ |
US20080108611A1 (en) | 2006-01-19 | 2008-05-08 | Battista Kathleen A | Substituted thienopyrimidine kinase inhibitors |
BRPI0707312B1 (pt) | 2006-01-27 | 2022-06-07 | Shanghai Hengrui Pharmacetical Co., Ltd | Inibidores de pirrolo [3,2-c] piridina-4-ona 2-indolinona proteína cinase, seu uso e seu processo de fabricação, intermediário e seus processos de fabricação, composição farmacêutica e seu uso |
WO2007102679A1 (en) | 2006-03-06 | 2007-09-13 | Je Il Pharmaceutical Co., Ltd. | Novel thienopyrimidine derivatives or pharmaceutically acceptable salts thereof, process for the preparation thereof and pharmaceutical composition comprising the same |
EP2001880A2 (en) | 2006-03-07 | 2008-12-17 | Array Biopharma, Inc. | Heterobicyclic pyrazole compounds and methods of use |
AU2007227602A1 (en) | 2006-03-16 | 2007-09-27 | Novartis Ag | Heterocyclic organic compounds for the treatment of in particular melanoma |
CA2646437C (en) | 2006-03-17 | 2016-05-17 | Ambit Biosciences Corporation | Imidazolothiazole compounds for the treatment of disease |
GB0606805D0 (en) | 2006-04-04 | 2006-05-17 | Novartis Ag | Organic compounds |
US7781433B2 (en) | 2006-04-26 | 2010-08-24 | Piramed Limited | Pharmaceutical compounds |
JP2009537520A (ja) | 2006-05-15 | 2009-10-29 | アイアールエム・リミテッド・ライアビリティ・カンパニー | Fgf受容体キナーゼ阻害剤のための組成物および方法 |
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 |
US20100029619A1 (en) | 2006-08-04 | 2010-02-04 | Takeda Pharmaceutical Company Limted | Fused heterocyclic compound |
US7531539B2 (en) | 2006-08-09 | 2009-05-12 | Bristol-Myers Squibb Company | Pyrrolotriazine kinase inhibitors |
US8063225B2 (en) | 2006-08-14 | 2011-11-22 | Chembridge Corporation | Tricyclic compound derivatives useful in the treatment of neoplastic diseases, inflammatory disorders and immunomodulatory disorders |
WO2008030579A2 (en) | 2006-09-07 | 2008-03-13 | Biogen Idec Ma Inc. | Irak modulators for treating an inflammatory condition, cell proliferative disorder, immune disorder |
WO2008031551A2 (en) | 2006-09-12 | 2008-03-20 | Novartis Forschungsstiftung, Zweigniederlassung | Non-neuroendocrine cancer therapy |
CN101553482B (zh) | 2006-09-15 | 2013-11-20 | 艾科睿制药公司 | 激酶抑制剂化合物 |
US20090286779A1 (en) | 2006-09-29 | 2009-11-19 | Novartis Ag | Pyrazolopyrimidines as lipid kinase inhibitors |
US20120225057A1 (en) | 2006-10-11 | 2012-09-06 | Deciphera Pharmaceuticals, Llc | Methods and compositions for the treatment of myeloproliferative diseases and other proliferative diseases |
EP1918291A1 (en) | 2006-10-30 | 2008-05-07 | Novartis AG | 3-Aminocarbonyl-substituted fused pyrazolo-derivatives as protein kinase modulators |
CN101522682A (zh) | 2006-10-30 | 2009-09-02 | 诺瓦提斯公司 | 作为抗炎剂的杂环化合物 |
AU2007316417B2 (en) | 2006-11-06 | 2013-08-22 | Tolero Pharmaceuticals, Inc. | Imidazo[1,2-b]pyridazine and pyrazolo[1,5-a]pyrimidine derivatives and their use as protein kinase inhibitors |
AU2007321719B2 (en) | 2006-11-15 | 2013-11-21 | Ym Biosciences Australia Pty Ltd | Inhibitors of kinase activity |
US8741849B2 (en) | 2007-01-10 | 2014-06-03 | Purdue Research Foundation | Kinase inhibitors and uses thereof |
US20080199426A1 (en) | 2007-01-11 | 2008-08-21 | Sukhatme Vikas P | Methods and compositions for the treatment and diagnosis of vascular inflammatory disorders or endothelial cell disorders |
CA2675979A1 (en) | 2007-01-19 | 2008-07-24 | Bayer Healthcare Llc | Treatment of cancers having resistance to chemotherapeutic agents |
CN101641349A (zh) * | 2007-02-08 | 2010-02-03 | 泰博特克药品有限公司 | 嘧啶取代的大环抑制剂 |
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 |
CN101801972A (zh) | 2007-03-28 | 2010-08-11 | 英诺瓦西亚公司 | 作为硬脂酰-辅酶a去饱和酶抑制剂的吡唑并[1,5-a]嘧啶 |
WO2008124323A1 (en) | 2007-04-03 | 2008-10-16 | Array Biopharma Inc. | Imidazo[1,2-a]pyridine compounds as receptor tyrosine kinase inhibitors |
US20110189167A1 (en) | 2007-04-20 | 2011-08-04 | Flynn Daniel L | Methods and Compositions for the Treatment of Myeloproliferative Diseases and other Proliferative Diseases |
EP2152688A1 (en) | 2007-05-04 | 2010-02-17 | Irm Llc | Compounds and compositions as c-kit and pdgfr kinase inhibitors |
WO2008138184A1 (fr) | 2007-05-14 | 2008-11-20 | Shanghai Hengrui Pharmaceutical Co.Ltd. | Dérivés de pyrrolo-azacycles, leur procédé de fabrication et leur utilisation en tant qu'inhibiteurs de protéine kinases |
WO2008155421A2 (en) * | 2007-06-21 | 2008-12-24 | Janssen Pharmaceutica Nv | Indolin-2-ones and aza-indolin-2-ones |
US20090012045A1 (en) | 2007-06-26 | 2009-01-08 | Rigel Pharmaceuticals, Inc. | Methods of Treating Cell Proliferative Disorders |
WO2009012262A1 (en) | 2007-07-16 | 2009-01-22 | The Regents Of The University Of California | Protein kinase modulating compounds and methods for making and using them |
PL2176231T3 (pl) | 2007-07-20 | 2017-04-28 | Nerviano Medical Sciences S.R.L. | Podstawione pochodne indazolu aktywne jako inhibitory kinazy |
CA2695997C (en) | 2007-08-10 | 2016-11-22 | Regeneron Pharmaceuticals, Inc. | High affinity human antibodies to human nerve growth factor |
EP2025678A1 (en) | 2007-08-17 | 2009-02-18 | Oncalis AG | Pyrazolo[3,4-d]pyrimidine compounds and their use as modulators of protein kinase |
WO2009042646A1 (en) | 2007-09-24 | 2009-04-02 | Curis, Inc. | Anti-proliferative agents |
CA2702838A1 (en) | 2007-10-16 | 2009-04-23 | Wyeth Llc | Thienopyrimidine and pyrazolopyrimidine compounds and their use as mtor kinase and pi3 kinase inhibitors |
JP2011501760A (ja) | 2007-10-23 | 2011-01-13 | ノバルティス アーゲー | 呼吸器疾患の処置のためのtrkb抗体の使用 |
WO2009060197A1 (en) | 2007-11-08 | 2009-05-14 | Centro Nacional De Investigaciones Oncologicas (Cnio) | Imidazopyridazines for use as protein kinase inhibitors |
MX2010005950A (es) | 2007-11-28 | 2010-06-17 | Schering Corp | 2-fluoropirazolo[1,5-a]pirimidinas como inhibidores de proteina quinasa. |
CN102015769B (zh) | 2008-01-17 | 2014-12-10 | Irm责任有限公司 | 改进的抗-trkb抗体 |
TW200942537A (en) | 2008-02-01 | 2009-10-16 | Irm Llc | Compounds and compositions as kinase inhibitors |
US20090209496A1 (en) | 2008-02-15 | 2009-08-20 | David Chaplin | Methods and compositions for enhancing the efficacy of rtk inhibitors |
AU2009226153B2 (en) | 2008-03-19 | 2014-02-20 | Chembridge Corporation | Novel tyrosine kinase inhibitors |
US8822500B2 (en) | 2008-03-19 | 2014-09-02 | Chembridge Corporation | Tyrosine kinase inhibitors |
US8507488B2 (en) | 2008-05-13 | 2013-08-13 | Irm Llc | Fused nitrogen containing heterocycles and compositions thereof as kinase inhibitors |
WO2009155527A2 (en) | 2008-06-19 | 2009-12-23 | Progenics Pharmaceuticals, Inc. | Phosphatidylinositol 3 kinase inhibitors |
CA2730190A1 (en) | 2008-07-14 | 2010-01-21 | Queen's University At Kingston | Pharmaceutical compositions comprising ret inhibitors and methods for the treatment of cancer |
JP5677296B2 (ja) | 2008-07-29 | 2015-02-25 | ネルビアーノ・メデイカル・サイエンシーズ・エツセ・エルレ・エルレ | グリオーマの治療のためのcdk阻害剤の使用 |
WO2010028254A2 (en) | 2008-09-05 | 2010-03-11 | Auspek Pharmaceuticals, Inc. | Substituted quinazoline inhibitors of growth factor receptor tyrosine kinases |
EP2161271A1 (en) | 2008-09-08 | 2010-03-10 | Università Degli Studi Di Milano - Bicocca | Alpha-carboline inhibitors of NMP-ALK, RET, and Bcr-Abl |
CN103965200B (zh) | 2008-09-22 | 2016-06-08 | 阵列生物制药公司 | 作为trk激酶抑制剂的取代的咪唑并[1,2-b]哒嗪化合物 |
WO2010036629A2 (en) | 2008-09-26 | 2010-04-01 | National Health Research Institutes | Fused multicyclic compounds as protein kinase inhibitors |
LT3372605T (lt) | 2008-10-22 | 2022-02-10 | Array Biopharma, Inc. | Pakeistieji pirazolo[1,5-a]pirimidino junginiai, kaip trk kinazės inhibitoriai |
BRPI0914404A2 (pt) | 2008-10-31 | 2019-03-06 | Genentech Inc | "compostos, composição farmacêutica e método para tratar ou atenuar a gravidade de uma doença ou condição responsiva à inibição da atividade jak quinase em um paciente" |
EP2358725A1 (en) | 2008-11-06 | 2011-08-24 | Ambit Biosciences Corporation | Imidazolothiazole compounds as modulators of protein kinase |
WO2010058006A1 (en) | 2008-11-24 | 2010-05-27 | Nerviano Medical Sciences S.R.L. | Cdk inhibitor for the treatment of mesothelioma |
KR101061599B1 (ko) | 2008-12-05 | 2011-09-02 | 한국과학기술연구원 | 비정상 세포 성장 질환의 치료를 위한 단백질 키나아제 저해제인 신규 인다졸 유도체, 이의 약학적으로 허용가능한염 및 이를 유효성분으로 함유하는 약학적 조성물 |
ES2637174T3 (es) | 2009-02-12 | 2017-10-11 | Cell Signaling Technology, Inc. | Expresión de ROS mutante en el cáncer de hígado humano |
TWI410418B (zh) | 2009-04-29 | 2013-10-01 | Ind Tech Res Inst | 氮雜薁化合物、藥學組合物與抑制一細胞中蛋白質激酶之活性的方法 |
KR101614572B1 (ko) | 2009-05-08 | 2016-04-21 | 아스테라스 세이야쿠 가부시키가이샤 | 디아미노 헤테로환 카르복사미드 화합물 |
JP6073677B2 (ja) | 2009-06-12 | 2017-02-01 | デイナ ファーバー キャンサー インスティチュート,インコーポレイテッド | 縮合複素環式化合物およびそれらの使用 |
AR077468A1 (es) | 2009-07-09 | 2011-08-31 | Array Biopharma Inc | Compuestos de pirazolo (1,5 -a) pirimidina sustituidos como inhibidores de trk- quinasa |
KR101256018B1 (ko) | 2009-08-20 | 2013-04-18 | 한국과학기술연구원 | 단백질 키나아제 저해활성을 갖는 1,3,6-치환된 인돌 화합물 |
KR101147550B1 (ko) | 2009-10-22 | 2012-05-17 | 한국과학기술연구원 | 단백질 키나아제 저해활성을 가지는 2,7-치환된 티에노[3,2-d]피리미딘 화합물 |
KR101116756B1 (ko) | 2009-10-27 | 2012-03-13 | 한국과학기술연구원 | 단백질 키나아제 저해활성을 갖는 신규의 1,6-치환된 인돌 화합물 |
WO2011053861A1 (en) | 2009-10-29 | 2011-05-05 | Genosco | Kinase inhibitors |
EA024729B1 (ru) | 2009-11-13 | 2016-10-31 | Джиноско | Киназные ингибиторы |
KR101094446B1 (ko) | 2009-11-19 | 2011-12-15 | 한국과학기술연구원 | 단백질 키나아제 저해활성을 가지는 2,4,7-치환된 티에노[3,2-d]피리미딘 화합물 |
US9180127B2 (en) | 2009-12-29 | 2015-11-10 | Dana-Farber Cancer Institute, Inc. | Type II Raf kinase inhibitors |
ES2636262T3 (es) | 2010-01-29 | 2017-10-05 | Hanmi Science Co., Ltd. | Derivados de tieno[3,2-d]pirimidina que tienen actividad inhibidora en las proteínas cinasas |
KR101483215B1 (ko) | 2010-01-29 | 2015-01-16 | 한미약품 주식회사 | 단백질 키나아제 저해활성을 갖는 비시클릭 헤테로아릴 유도체 |
WO2011101408A1 (en) | 2010-02-18 | 2011-08-25 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Method for preventing cancer metastasis |
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 |
KR102132405B1 (ko) * | 2010-05-20 | 2020-07-09 | 어레이 바이오파마 인크. | Trk 키나제 저해제로서의 매크로시클릭 화합물 |
LT3333188T (lt) | 2010-08-19 | 2022-06-10 | Zoetis Belgium S.A. | Anti-ngf antikūnai ir jų panaudojimas |
WO2012034095A1 (en) | 2010-09-09 | 2012-03-15 | Irm Llc | Compounds and compositions as trk inhibitors |
UY33597A (es) | 2010-09-09 | 2012-04-30 | Irm Llc | Compuestos y composiciones como inhibidores de la trk |
WO2012047017A2 (ko) | 2010-10-05 | 2012-04-12 | 크리스탈지노믹스(주) | 2,3-디히드로-이소인돌-1-온 유도체 및 이를 포함하는 조성물 |
WO2012075340A2 (en) | 2010-12-01 | 2012-06-07 | Alderbio Holdings Llc | Anti-ngf compositions and use thereof |
US8618146B2 (en) | 2011-01-03 | 2013-12-31 | Dr. Reddy's Laboratories Limited | Epothilone compound formulations |
CN102093421B (zh) | 2011-01-28 | 2014-07-02 | 北京康辰药业有限公司 | 一种含磷取代基的喹啉类化合物及其制备方法、以及含有该化合物的药物组合物及其应用 |
JP5959541B2 (ja) | 2011-02-25 | 2016-08-02 | ノバルティス アーゲー | Trk阻害剤としてのピラゾロ[1,5−a]ピリジン |
WO2012135631A1 (en) | 2011-03-30 | 2012-10-04 | Arrien Pharmaeuticals Llc | Substituted 5-(pyrazin-2-yl)-1h-pyrazolo [3, 4-b] pyridine and pyrazolo [3, 4-b] pyridine derivatives as protein kinase inhibitors |
BR112013025387B1 (pt) | 2011-04-01 | 2021-07-27 | University Of Utah Research Foundation | Compostos análogos substituídos da n-fenilpirimidin-2-amina como inibidores da quinase axl, uso dos ditos compostos para o tratamento de um distúrbio de proliferação celular descontrolada, bem como kit compreendendo ditos compostos |
BR112013029201B1 (pt) | 2011-05-13 | 2022-08-09 | Array Biopharma Inc | Compostos de pirrolidinil ureia e pirrolidinil tioureia, seu processo de preparação, seu uso e composições farmacêuticas |
RU2477723C2 (ru) | 2011-06-16 | 2013-03-20 | Общество С Ограниченной Ответственностью "Фьюжн Фарма" | Ингибиторы протеинкиназ (варианты), их применение для лечения онкологических заболеваний и фармацевтическая композиция на их основе |
WO2013016720A2 (en) | 2011-07-28 | 2013-01-31 | Gerinda Therapeutics, Inc. | Novel substituted biarylheterocycle derivatives as protein kinase inhibitors for the treatment of cancer and other diseases |
JP6032616B2 (ja) | 2011-08-04 | 2016-11-30 | 国立研究開発法人国立がん研究センター | Kif5b遺伝子とret遺伝子との融合遺伝子、並びに該融合遺伝子を標的としたがん治療の有効性を判定する方法 |
AU2012298884B2 (en) | 2011-08-23 | 2017-11-16 | Foundation Medicine, Inc. | Novel KIF5B-RET fusion molecules and uses thereof |
AU2012341028C1 (en) | 2011-09-02 | 2017-10-19 | Mount Sinai School Of Medicine | Substituted pyrazolo[3,4-D]pyrimidines and uses thereof |
WO2013036232A2 (en) | 2011-09-08 | 2013-03-14 | Deciphera Pharmaceuticals, Llc | Methods and compositions for the treatment of myeloproliferative diseases and other proliferative diseases |
CN102408411B (zh) | 2011-09-19 | 2014-10-22 | 北京康辰药业股份有限公司 | 一种含喹啉基的羟肟酸类化合物及其制备方法、以及含有该化合物的药物组合物及其应用 |
WO2013042137A1 (en) | 2011-09-19 | 2013-03-28 | Aurigene Discovery Technologies Limited | Bicyclic heterocycles as irak4 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 |
CA2858958C (en) | 2011-12-12 | 2016-10-04 | Dr. Reddy's Laboratories Ltd. | Substituted pyrazolo[1,5-a]pyridine as tropomyosin receptor kinase (trk) inhibitors |
PE20141404A1 (es) | 2011-12-30 | 2014-10-28 | Hanmi Pharm Ind Co Ltd | Derivados de tieno[3,2-d]pirimidina que tienen actividad inhibidora por las quinasas de las proteinas |
JP2015109806A (ja) | 2012-03-22 | 2015-06-18 | アステラス製薬株式会社 | 新規ret融合体の検出法 |
JP6160613B2 (ja) | 2012-04-26 | 2017-07-12 | 小野薬品工業株式会社 | Trk阻害化合物 |
WO2013170159A1 (en) | 2012-05-10 | 2013-11-14 | Synta Pharmaceuticals Corp. | Treating cancer with hsp90 inhibitory compounds |
NZ703124A (en) | 2012-05-23 | 2016-07-29 | Nerviano Medical Sciences Srl | Process for the preparation of n-[5-(3,5-difluoro-benzyl)-1h-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide |
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 |
CN104619841A (zh) | 2012-07-26 | 2015-05-13 | 日本国立癌症研究中心 | Cep55基因与ret基因的融合基因 |
EP2689778A1 (en) | 2012-07-27 | 2014-01-29 | Pierre Fabre Medicament | Derivatives of azaindoles or diazaindoles for treating pain |
US20150218652A1 (en) | 2012-08-31 | 2015-08-06 | The Regents Of The Unversity Of Colorado, A Body Corporate | Methods for diagnosis and treatment of cancer |
ES2726605T3 (es) | 2012-09-07 | 2019-10-08 | Exelixis Inc | Inhibidores de MET, VEGFR y RET para usar en el tratamiento del adenocarcinoma de pulmón |
US20140084039A1 (en) | 2012-09-24 | 2014-03-27 | Electro Scientific Industries, Inc. | Method and apparatus for separating workpieces |
WO2014050781A1 (ja) | 2012-09-25 | 2014-04-03 | 中外製薬株式会社 | Ret阻害剤 |
JP2014082984A (ja) | 2012-10-23 | 2014-05-12 | Astellas Pharma Inc | 新規ntrk2活性化変異の検出法 |
WO2014072220A1 (en) | 2012-11-07 | 2014-05-15 | Nerviano Medical Sciences S.R.L. | Substituted pyrimidinyl and pyridinyl-pyrrolopyridinones, process for their preparation and their use as kinase inhibitors |
JP6262246B2 (ja) | 2012-11-12 | 2018-01-17 | イグニタ、インク. | ベンダムスチン誘導体およびこれを使用する方法 |
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 |
US9790178B2 (en) | 2012-11-13 | 2017-10-17 | Array Biopharma Inc. | Pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors |
US9546156B2 (en) | 2012-11-13 | 2017-01-17 | Array Biopharma Inc. | N-bicyclic aryl,N'-pyrazolyl urea, thiourea, guanidine cyanoguanidine compounds as TrkA kinase inhibitors |
US9822118B2 (en) | 2012-11-13 | 2017-11-21 | Array Biopharma Inc. | Bicyclic heteroaryl urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors |
US9969694B2 (en) | 2012-11-13 | 2018-05-15 | Array Biopharma Inc. | N-(arylalkyl)-N′-pyrazolyl-urea, thiourea, guanidine and cyanoguanidine compounds as TrkA kinase inhibitors |
WO2014078322A1 (en) | 2012-11-13 | 2014-05-22 | Array Biopharma Inc. | Thiazolyl and oxazolyl urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors |
RU2664541C2 (ru) | 2012-11-13 | 2018-08-20 | Эррэй Биофарма Инк. | Бициклические соединения мочевины, тиомочевины, гуанидина и цианогуанидина, пригодные для лечения боли |
UA116455C2 (uk) | 2012-11-13 | 2018-03-26 | Еррей Біофарма Інк. | Сполуки n-піролідинілсечовини, n'-піразолілсечовини, тіосечовини, гуанідину та ціаногуанідину як інгібітори кінази trka |
WO2014078417A1 (en) | 2012-11-13 | 2014-05-22 | Array Biopharma Inc. | Pyrazolyl urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors |
BR112015002626A2 (pt) | 2012-11-29 | 2017-09-26 | Yeda Res & Dev | métodos para prevenção de metástases tumorais, tratamento e prognostico do câncer e identificação dos agentes que são inibidores da metástase putativa |
WO2014086284A1 (zh) | 2012-12-04 | 2014-06-12 | 上海医药集团股份有限公司 | 一类氘代3-氰基喹啉类化合物、其药用组合物、制备方法及其用途 |
DK2940014T3 (en) | 2012-12-28 | 2018-12-10 | Crystalgenomics Inc | 2,3-DIHYDRO-ISOINDOL-1-ON DERIVATIVE AS BTK KINase INHIBITORS AND PHARMACEUTICAL COMPOSITION INCLUDING THE SAME |
FR3000493A1 (fr) | 2012-12-28 | 2014-07-04 | Oribase Pharma | Nouveaux inhibiteurs de proteines kinases |
FR3000494B1 (fr) | 2012-12-28 | 2015-08-21 | Oribase Pharma | Nouveaux derives d'azaindoles en tant qu'inhibiteurs de proteines kinases |
FR3000492B1 (fr) | 2012-12-28 | 2015-09-11 | Oribase Pharma | Nouveaux derives azaindole en tant qu'inhibiteurs multikinases |
US9127055B2 (en) | 2013-02-08 | 2015-09-08 | Astellas Pharma Inc. | Method of treating pain with anti-human NGF antibody |
SG11201506514QA (en) | 2013-02-19 | 2015-09-29 | Ono Pharmaceutical Co | Trk-INHIBITING COMPOUND |
US20160010068A1 (en) | 2013-02-22 | 2016-01-14 | Boris C. Bastian | 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 |
CN113337604A (zh) | 2013-03-15 | 2021-09-03 | 莱兰斯坦福初级大学评议会 | 循环核酸肿瘤标志物的鉴别和用途 |
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 |
TW201524958A (zh) | 2013-03-15 | 2015-07-01 | Glaxosmithkline Ip Dev Ltd | 用作轉染期間重排抑制劑之新穎化合物 |
MA38394B1 (fr) | 2013-03-15 | 2018-04-30 | Glaxosmithkline Ip Dev Ltd | Dérivés pyridine utilisés comme inhibiteurs de la kinase réarrangée au cours de la transfection (ret) |
JP2016515508A (ja) | 2013-03-15 | 2016-05-30 | ザ・トラスティーズ・オブ・コロンビア・ユニバーシティ・イン・ザ・シティ・オブ・ニューヨーク | 融合タンパク質及びその方法 |
WO2014172046A2 (en) | 2013-04-17 | 2014-10-23 | Life Technologies Corporation | Gene fusions and gene variants associated with cancer |
WO2015003658A1 (en) | 2013-07-11 | 2015-01-15 | Betta Pharmaceuticals Co., Ltd | Protein tyrosine kinase modulators and methods of use |
JP6534930B2 (ja) | 2013-07-26 | 2019-06-26 | 公益財団法人がん研究会 | Ntrk3融合体の検出法 |
US10407509B2 (en) | 2013-07-30 | 2019-09-10 | Blueprint Medicines Corporation | NTRK2 fusions |
US20150057335A1 (en) | 2013-08-20 | 2015-02-26 | National Cancer Center | Novel fusion genes identified in lung cancer |
WO2015031613A1 (en) | 2013-08-30 | 2015-03-05 | Ambit Biosciences Corporation | Biaryl acetamide compounds and methods of use thereof |
EP3060207A4 (en) | 2013-10-24 | 2017-04-12 | Georgetown University | Methods and compositions for treating cancer |
WO2015064621A1 (ja) | 2013-10-29 | 2015-05-07 | 公益財団法人がん研究会 | 新規融合体及びその検出法 |
CN105792637B (zh) | 2013-11-27 | 2019-12-27 | 恩普乐股份有限公司 | 发射器和滴灌用输送管 |
GB201321146D0 (en) | 2013-11-29 | 2014-01-15 | Cancer Rec Tech Ltd | Quinazoline compounds |
EP3076966A2 (en) | 2013-12-02 | 2016-10-12 | BerGenBio AS | Use of kinase inhibitors |
MY193524A (en) | 2014-01-24 | 2022-10-18 | Turning Point Therapeutics Inc | Diaryl macrocycles as modulators of protein kinases |
JP6197125B2 (ja) | 2014-02-05 | 2017-09-13 | ブイエム オンコロジー リミテッド ライアビリティ カンパニー | 化合物の組成物およびその使用 |
BR112016018450A2 (pt) | 2014-02-14 | 2018-09-18 | Exelixis Inc | formas sólidas cristalinas de n-{4-[(6,7-dimetoxiquinolin-4-il)oxi]fenil}-n'-(4-fluorofenil)ciclopropano-1,1-dicarboxamida, processos de preparo e métodos de uso |
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 |
RS59286B1 (sr) | 2014-05-15 | 2019-10-31 | Array Biopharma Inc | 1-((3s,4r)-4-(3-fluorofenil)-1-(2-metoksietil)pirolidin-3-il)-3-(4-metil-3-(2-metilpirimidin-5-il)-1-fenil-1h-pirazol-5-il)urea kao inhibitor trka kinaze |
WO2015183837A1 (en) | 2014-05-27 | 2015-12-03 | Brian Haynes | Compositions, methods, and uses related to ntrk2-tert fusions |
US20170114415A1 (en) | 2014-05-30 | 2017-04-27 | The Regents Of The University Of Colorado, A Body Corporate | Activating ntrk1 gene fusions predictive of kinase inhibitor therapy |
CN105222097A (zh) | 2014-06-26 | 2016-01-06 | 欧普照明股份有限公司 | 一种灯具及其光学模组 |
HUE046008T2 (hu) | 2014-07-17 | 2020-02-28 | Sunshine Lake Pharma Co Ltd | I-(5-terc-butil)-izoxazol-3-il)-3-(4-((feniI)-etinil)-fenil)-kabamid származékok, valamint az ezekkel rokon vegyületek FLT-3 inhibitorokként rák kezelésére |
WO2016019341A1 (en) | 2014-08-01 | 2016-02-04 | Pharmacyclics Llc | Biomarkers for predicting response of dlbcl to treatment with a btk inhibitor |
CN110655502A (zh) | 2014-08-18 | 2020-01-07 | 小野药品工业株式会社 | 抑制Trk的化合物的酸加成盐 |
CN107148418A (zh) | 2014-09-08 | 2017-09-08 | 葛兰素史密斯克莱知识产权发展有限公司 | 2‑(4‑(4‑乙氧基‑6‑氧代‑1,6‑二氢吡啶‑3‑基)‑2‑氟苯基)‑n‑(5‑(1,1,1‑三氟‑2‑甲基丙‑2‑基)异噁唑‑3‑基)乙酰胺的晶型 |
PE20170705A1 (es) | 2014-09-10 | 2017-05-21 | Glaxosmithkline Ip Dev Ltd | Nuevos compuestos como inhibidores de ret (reorganizado durante la transfeccion) |
AU2015316438B2 (en) | 2014-09-10 | 2018-05-24 | Glaxosmithkline Intellectual Property Development Limited | Novel compounds as Rearranged during Transfection (RET) inhibitors |
TWI538914B (zh) | 2014-10-03 | 2016-06-21 | 國立交通大學 | 蛋白質激酶之選擇性抑制劑、其醫藥組成物及其用途 |
EP4245376A3 (en) | 2014-10-14 | 2023-12-13 | Novartis AG | Antibody molecules to pd-l1 and uses thereof |
RS64122B1 (sr) | 2014-11-16 | 2023-05-31 | Array Biopharma Inc | Kristalni oblik (s)-n-(5-((r)-2-(2,5-difluorofenil)-pirolidin-1-il)-pirazolo[1,5-a]pirimidin-3-il)-3-hidroksipirolidin-1-karboksamid hidrogensulfata |
KR102659741B1 (ko) * | 2014-12-15 | 2024-04-23 | 주식회사 씨엠지제약 | 융합된 고리 헤테로아릴 화합물 및 trk 억제제로서의 이들의 용도 |
EP3233840B1 (en) | 2014-12-16 | 2018-11-21 | Eudendron S.r.l. | Heterocyclic derivatives modulating activity of certain protein kinases |
WO2016127074A1 (en) | 2015-02-06 | 2016-08-11 | Blueprint Medicines Corporation | 2-(pyridin-3-yl)-pyrimidine derivatives as ret inhibitors |
KR101675984B1 (ko) | 2015-02-23 | 2016-11-14 | 한양대학교 에리카산학협력단 | 티에노디아제핀 유도체 또는 이의 약학적으로 허용가능한 염, 및 이를 유효성분으로 포함하는 약학적 조성물 |
EP3265079A4 (en) | 2015-03-03 | 2019-01-02 | Caris MPI, Inc. | Molecular profiling for cancer |
US20160273049A1 (en) | 2015-03-16 | 2016-09-22 | Personal Genome Diagnostics, Inc. | Systems and methods for analyzing nucleic acid |
CN108137593B (zh) | 2015-04-21 | 2021-01-05 | 上海交通大学医学院附属瑞金医院 | 蛋白激酶抑制剂的制备和用途 |
MX2017014700A (es) | 2015-05-20 | 2018-08-15 | Broad Inst Inc | Neoantigenos compartidos. |
AU2016270321B2 (en) | 2015-05-29 | 2020-09-10 | Ignyta, Inc. | Compositions and methods for treating patients with RTK mutant cells |
TN2017000502A1 (en) | 2015-06-01 | 2019-04-12 | Loxo Oncology Inc | Methods of diagnosing and treating cancer |
US9782400B2 (en) | 2015-06-19 | 2017-10-10 | Macau University Of Science And Technology | Oncogenic ROS1 and ALK kinase inhibitor |
AU2015101722A4 (en) | 2015-06-19 | 2016-05-19 | 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 |
KR102599788B1 (ko) | 2015-07-02 | 2023-11-07 | 터닝 포인트 테라퓨틱스, 인크. | 단백질 키나제의 조절물질로서 키랄 디아릴 매크로사이클 |
GB201512365D0 (en) | 2015-07-15 | 2015-08-19 | King S College London | Novel therapy |
LT3322706T (lt) | 2015-07-16 | 2021-03-10 | Array Biopharma, Inc. | Pakeistieji pirazolo[1,5-a]piridino junginiai, kaip ret kinazės inhibitoriai |
EP3120851A1 (en) | 2015-07-21 | 2017-01-25 | Pangaea Biotech S.L. | 4-amino-6-(2,6-dichlorophenyl)-8-methyl-2-(phenylamino)-pyrido[2,3-d]pyrimidin-7(8h)-one for treatment of solid cancers |
KR101766194B1 (ko) | 2015-08-07 | 2017-08-10 | 한국과학기술연구원 | RET 키나아제 저해제인 신규 3-(이속사졸-3-일)-피라졸로[3,4-d]피리미딘-4-아민 화합물 |
US10550124B2 (en) | 2015-08-13 | 2020-02-04 | San Diego State University Foundation | Atropisomerism for increased kinase inhibitor selectivity |
MA41559A (fr) | 2015-09-08 | 2017-12-26 | Taiho Pharmaceutical Co Ltd | Composé de pyrimidine condensé ou un sel de celui-ci |
WO2017049462A1 (zh) | 2015-09-22 | 2017-03-30 | 合肥中科普瑞昇生物医药科技有限公司 | 一类新型的flt3激酶抑制剂及其用途 |
CN105255927B (zh) | 2015-09-30 | 2018-07-27 | 温州医科大学附属第一医院 | 一种kiaa1217-ret融合基因 |
BR112018008357A2 (pt) | 2015-10-26 | 2018-11-27 | Array Biopharma Inc | mutações de ponto em câncer resistente a inibidor de trk e métodos relacionados às mesmas |
CA3003721C (en) | 2015-11-02 | 2024-02-06 | Blueprint Medicines Corporation | Inhibitors of ret to treat cancer |
JP2018537980A (ja) | 2015-12-08 | 2018-12-27 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 癌治療のための非小細胞肺癌(nsclc)および甲状腺癌患者を選択するためのバイオマーカーとしてret融合遺伝子を使用する方法 |
WO2017122815A1 (ja) | 2016-01-15 | 2017-07-20 | 公益財団法人がん研究会 | 新規融合体及びその検出法 |
WO2017127835A2 (en) | 2016-01-22 | 2017-07-27 | The Medicines Company | Aqueous formulations and methods of preparation and use thereof |
TWI620748B (zh) | 2016-02-05 | 2018-04-11 | National Health Research Institutes | 氨基噻唑化合物及其用途 |
WO2017145050A1 (en) | 2016-02-23 | 2017-08-31 | Glaxosmithkline Intellectual Property Development Limited | Pyridylpyridone derivative useful as a ret kinase inhibitor in the treatment of ibs and cancer |
IL261107B2 (en) | 2016-02-23 | 2023-11-01 | Taiho Pharmaceutical Co Ltd | A novel compressed pyrimidine compound or a salt 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 |
AR107912A1 (es) | 2016-03-17 | 2018-06-28 | Blueprint Medicines Corp | Inhibidores de ret |
US10045991B2 (en) | 2016-04-04 | 2018-08-14 | Loxo Oncology, Inc. | Methods of treating pediatric cancers |
AU2017246554B2 (en) | 2016-04-04 | 2022-08-18 | Loxo Oncology, Inc. | Liquid formulations of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo(1,5-a)pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide |
RS62322B1 (sr) | 2016-04-15 | 2021-10-29 | Cancer Research Tech Ltd | Heterociklična jedinjenja kao inhibitori ret kinaze |
WO2017178845A1 (en) | 2016-04-15 | 2017-10-19 | Cancer Research Technology Limited | Heterocyclic compounds as ret kinase inhibitors |
MA44733A (fr) | 2016-04-19 | 2019-02-27 | Exelixis Inc | Procédé de traitement du cancer du sein négatif triple |
WO2017197051A1 (en) | 2016-05-10 | 2017-11-16 | C4 Therapeutics, Inc. | Amine-linked c3-glutarimide degronimers for target protein degradation |
HRP20230704T1 (hr) | 2016-05-18 | 2023-10-27 | Loxo Oncology, Inc. | Priprava (s)-n-(5-((r)-2-(2,5-difluorfenil)pirolidin-1-il)pirazolo[1,5-a]pirimidin-3-il)-3-hidroksipirolidin-1-karboksamida |
WO2017201156A1 (en) | 2016-05-18 | 2017-11-23 | Duke University | Method of treating kras wild-type metastatic colorectal cell carcinoma using cabozantinib plus panitumumab |
CN109312406A (zh) | 2016-06-01 | 2019-02-05 | 豪夫迈·罗氏有限公司 | 预测肺癌患者中对alk抑制剂疗法的响应的间变性淋巴瘤激酶中的新型突变 |
US10227329B2 (en) | 2016-07-22 | 2019-03-12 | Blueprint Medicines Corporation | Compounds useful for treating disorders related to RET |
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 |
CN117205312A (zh) | 2017-01-20 | 2023-12-12 | 埃克塞里艾克西斯公司 | 治疗癌症的卡博替尼与阿特珠单抗组合 |
CN108456163A (zh) | 2017-02-20 | 2018-08-28 | 中国科学院上海药物研究所 | 含邻氨基杂芳环炔基的化合物及其制备方法和用途 |
JOP20190213A1 (ar) | 2017-03-16 | 2019-09-16 | Array Biopharma Inc | مركبات حلقية ضخمة كمثبطات لكيناز ros1 |
US20190247398A1 (en) | 2017-10-26 | 2019-08-15 | Array Biopharma Inc. | Formulations of a macrocyclic trk kinase inhibitor |
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JP2017082018A (ja) * | 2010-05-20 | 2017-05-18 | 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マクロ環化合物 |
JP2019104756A (ja) * | 2010-05-20 | 2019-06-27 | 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マクロ環化合物 |
JP2021054840A (ja) * | 2010-05-20 | 2021-04-08 | 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マクロ環化合物 |
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